J Neurol (2011) 258 (Suppl 1):S1–S295
DOI 10.1007/s00415-011-6026-9
ABSTRACTS
Twenty-first Meeting of the European
Neurological Society 28–31 May, 2011
Lisbon, Portugal
Symposia and Free Communications
The abstracts have been reviewed by:
F. Antonaci, Z. Argov, I. Arnulf, A. Arzimanoglou, T. Back, O. Bajenaru,
E. Bartels, P.D. Berlit, K. Bhatia, P. Boon, T. Brandt, B. Brochet, M.J. Brodie,
A. Bronstein, H. Cock, G. Comi, J. de Keyser, M. de Visser, L. Deecke,
R. Dengler, S. Di Donato, H.C. Diener, M. Dieterich, V. Dietz, M. Donaghy,
M. Eraksoy, T. Ettlin, F. Fazekas, L. Ferini-Strambi, J. Ferro, M. Filippi,
D. Galimberti, A. Grau, W. Grisold, O. Hardiman, H.P. Hartung, W. Heide,
C. Helmchen, D.M. Hermann, G. Ickenstein, L. Kappos, R. Khatami,
B. Kieseier, T. Klopstock, C. Krarup, G. Lammers, G. Lauria, A. Luft, P. Lyrer,
Z. Martinovic, G. Mayer, S.I. Mellgren, G. Meola, R. Milo, I. Milonas,
C. Möller, X. Montalban, G. Moonen, M. Mumenthaler, N. Nardocci,
O. Nascimento, E. Nobile-Orazio, W.H. Oertel, M. Onofrj, D. Pareyson,
Y. Parman, H.W. Pfister, D. Pohl, P. Portegies, J. Rees, H. Reichmann,
P.F. Reyes, A. Rossetti, M. Rousseaux, E. Ruzicka, G. Said, J. Santamaria,
E. Scarpini, N. Schaeren-Wiemers, B. Schalke, P. Schestatsky, E. Schmutzhard,
J. Schoenen, M. Seeck, A. Sena, S. Sergay, V. Silani, M. Sinnreich, A. Siva,
R. Soffietti, C. Sommer, A. Steck, G. Stoll, D. Straumann, E. Tolosa,
A. Toscano, K.V. Toyka, H. Tumani, J. Valls-Solé, J. van Gijn,
P. Vermersch, M.J. Vidailhet, R.D. Voltz, J. Wokke
We would like to thank the reviewers for their precious help and asistance.
123
S2
Symposia
Joint ENS-PNS Symposium—Familial amyloid
polyneuropathy
POSTER SESSIONS
46–49
Presidential Symposium
Treatment of muscle diseases:
The future is already here
91–94
Symposium
Molecular and cellular mechanisms of ischaemic stroke
Psychiatric aspects of neurological disorders
Metals and movement disorders
Biomarkers for diagnosis, prognosis
and response to treatment in MS
96–99
101–103
134–136
140–141
Oral Sessions
Section 1: Cerebrovascular disorders I
Section 2: Multiple sclerosis: pathogenesis
Section 3: Muscle disorders
Section 4: Dementia: clinical and neuro-imaging
Section 5: Experimental stroke
Section 6: Multiple sclerosis: clinical aspects
Section 7: Peripheral neuropathy
Section 8: Dementia/Higher function disorders
Section 9: Parkinson: clinical and preclinical findings
Section 10: Neuropathic pain and primary headache
Section 11: Disorders of consciousness
Section 12: Cerebrovascular disorders II
Section 13: Movement disorders
Section 14: Neuro-otology
Section 15: Neuro-imaging
Section 16: Clinical neurophysiology
Section 17: Stroke
Section 18: Multiple sclerosis: monitoring
and treatment
Section 19: General neurology
Section 20: Extrapyramidal disorders: treatment
Section 21: Epilepsy
Section 22 Sleep disorders
Session 23 Motor neuron disorders: ALS
Session 24 Child neurology
123
O178–O183
O184–O189
O190–O195
O196–O201
O202–0207
O208–O213
O214–O219
O220–O225
O226–O231
O232–O237
O238–O242
O243–O248
O249–O254
O255–O260
O261–O266
O267–O272
O273–O278
O279–O284
O285–O290
O291–O295
O296–O301
O302–O307
O308–O312
O313–O318
Cerebrovascular disorders: clinical features of stroke I
Experimental neurology
Dementia/Higher function disorders: cognitive disorders
Motor neuron diseases
Extrapyramidal disorders
Multiple sclerosis: clinical aspects
Neuro-oncology
Peripheral neuropathy
Cerebrovascular disorders: clinical features of stroke II
Clinical neurophysiology
Neuro-rehabilitation
Epilepsy: management
Neuro-ophthalmology/neuro-otology
Multiple sclerosis: markers
General neurology
Neuro-imaging: healthy brain and psychiatric disorders
Cerebrovascular disorders: stroke/aetiology and
mechanisms
Clinical neurophysiology
Dementia/Higher function disorders: other
dementia/frontotemporal dementia
Epilepsy: monitoring/management
Neuro-genetics
Multiple sclerosis: pathology and pathogenesis
General neurology
Neuro-imaging: neurological disorders
Cerebrovascular disorders: management
and outcome of stroke
Child neurology
Dementia/Higher function disorders: vascular
dementia/Alzheimer’s disease
Infections
Muscles and neuromuscular junction disorders
Multiple sclerosis: treatment
Pain and headache
Sleep disorders/Restless leg syndrome
Author Index
P319–P332
P333–P347
P348–P371
P372–P380
P381–P404
P405–P440
P441–P461
P462–P486
P487–P504
P505–P521
P522–P547
P548–P565
P566–P577
P578–P604
P605–P629
P630–P642
P643–P659
P660–P677
P678–P699
P700–P712
P713–P726
P727–P754
P755–P783
P784–P800
P801–P819
P820–P833
P834–P851
P852–P863
P864–P889
P890–P926
P927–P947
P948–P957
S3
Symposia
Joint ENS-PNS Symposium—Familial
amyloid polyneuropathy
46
Clinical aspects and management
I. Conceicao
47
The genetics of FAP: a global problem
V. Plante´-Bordeneuve
Santa Maria University Hospital and Institute of Molecular Medicine
(Lisbon, PT)
University Hospital Henri Mondor (Paris, FR)
The hereditary forms of amyloidosis are autosomal dominant diseases
characterized by deposition of variant proteins. The most common
hereditary form is transthyretin amyloidosis (ATTR) caused by the
misfolding of protein monomers derived from the tetrameric protein
transthyretin (TTR).
ATTR is a rare disorder, with unequal distribution around the
world. Certain clusters have been described, mainly in Portugal, Japan
and Northern Sweden. Substitution of valine for methionine at position 30 (Val30Met) results in the classic Swedish-PortugueseJapanese amyloid polyneuropathy first described in Portugal by
Andrade, in 1952.
Familial amyloid polyneuropathy (FAP) is an autosomal dominant progressive disorder characterized by systemic extracellular
deposition of amyloid fibrils throughout the connective tissue
affecting particularly the peripheral nervous system. Val30Met is
the most common TTR mutation in patients presenting with neuropathy. The natural history of the disease is characterized by a
rapidly progressive sensory-motor and autonomic neuropathy. The
disease onset is usually in the third or fourth decade, but a variable
age of onset, clinical expression and penetrance are largely
reported.
The disease initially affects small myelinated and unmyelinated
nerve fibers which mediate pain and temperature sensations, and
autonomic nerve functions. Typically, sensory neuropathy with
paresthesias/neuropathic pain starts in the feet and progresses
proximally. With progression of the neuropathy, larger myelinated
fibers become involved. Motor involvement occurs later in the
course of the disease causing wasting and weakness with severe
trophic changes. Autonomic neuropathy often accompanies the
sensory and motor deficits and may represent the initial disease
presentation. The gastrointestinal involvement results in weight
loss and ultimately in cachexia. Cardiomyopathy may develop after
the onset of neuropathy or may be the predominant feature of
ATTR.
Renal involvement is common and usually presents with proteinuria at the beginning with progression to end-stage renal disease
requiring dialysis.
TTR mutations are associated with vitreous opacities derived from
amyloid, glaucoma, dry eyes, leading to visual impairment.
There is currently no specific pharmacologic therapy available for
ATTR. Symptomatic therapy is used.
As TTR is primarily formed in the liver, orthotopic liver transplantation is the only disease modifying treatment available to
patients with hereditary ATTR. This procedure results in an
improvement of the general condition and a stabilization of the
neuropathy, in a majority of patients.
New therapies aiming to stabilize TTR tetramers and avoid fibril
formation are being tested. A new drug, with TTR stabilization
properties (Tafamidis) as being proved to stabilize disease progression, in 60% of patients in a recent clinical trial.
Transtryretin familial amyloid polyneuropathy is the most severe
systemic amyloidosis of adulthood of autosomal dominant transmission with a sensory-motor polyneuropathy as main clinical expression
often associated with cardiac manifestations. Survival is averaging
10–12 years. Liver transplantation is the main therapeutic approach.
Less invasive pharmacological strategies are currently being developed. The disease, initially described in Portugal,, then in Sweden and
Japan is now reported worldwide. Among 100 point mutations
identified in the TTR gene, the TTR-Val30 Met substitution is by far
the most frequent and virtually the only one detected in Portugal and
in Sweden. In Japan, a heterogeneity of TTR variants is reported
including TTR-V30M. Phenotypic differences particularly in the age
of onset are observed depending of the geographic origin of the
families; Recent studies allow estimate penetrance in different populations, with newly developed unbiased methods Penetrance is a
variable of age, defined by the rate of symptomatic individuals among
carriers, These studies showed that at age 80 y-o, penetrance was
incomplete in all populations with striking differences at intermediate
ages. Such differences are important in order to guide genetic counselling and to improve management of carriers and early symptomatic
patients. In addition, differences were elicited according different
factors like the sex of the transmitting parent. Taken together, these
findings should help to better delineate the underlying molecular
genetic factors that might explain the variability in phenotypic
expression. Since now, different strategies are being used to unravel
possible modifying genes.
48
Treatment of familial amyloid polyneuropathy by liver
transplantation
O. Suhr
Umeå University (Umeå, SE)
Familial amyloid polyneuropathy (FAP) is a hereditary amyloidosis
caused by a mutated transthyretin (TTR). Since the liver produces
more than 90% of the circulating TTR, a liver transplantation should
stop the production of circulating variant TTR and thereby cease the
formation of amyloid. This should stop the progression of the disease
and even lead to an improvement of the patients’ symptoms. Based on
those assumptions, the first liver transplantation for the disease was
performed on a Swedish FAP-patient in 1990, and since the outcome
was encouraging, transplantation was soon accepted world wide as a
treatment of this incapacitating fatal disease.
However, with time it became obvious that not all patients with
FAP had any benefit of the procedure, and for several patients,
especially among those with a non-TTR V30M mutation the development or an increase of an existing cardiomyopathy was observed.
In addition, patients with long standing disease and a depleted
123
S4
nutritional status had an outcome that did not differ from that of nontransplanted historical controls, thus, selection of suitable patients is
of vital importance for an acceptable outcome of the procedure.
It should be noted, that wild type TTR is an amyloidogenic
protein that can assembles into amyloid as is the case in senile
system amyloidosis, where cardiomyopathy is dominating the clinical picture Similarly, it appears that wild type transthyretin in
certain individuals assembles into amyloid fibrils especially in the
heart after liver transplantation. Why this occur en certain individuals is unknown, though differences in amyloid fibril composition
may play a role.
The shortage of organs for transplantation lead to the suggestion,
that the well functioning liver from a FAP patient could be offered to
a patients with end stage liver disease or liver cancer, and this
‘‘domino’’ procedure is widely used today. Since FAP mostly has an
onset above the age of 30 it was expected, that patients that received a
FAP-liver would not develop the disease for several decades after the
transplantation. However, development of FAP disease has been
noted in recipients within 10 years after the procedure, which should
be taken into consideration when patients are selected for the
procedure.
49
New pharmacological treatment
T. Coelho
Hospital Santo António (Porto, PT)
Introduction: Familial Amyloid Polyneuropathy is a severe and
invariably fatal hereditary neuropathy due to deposition of a mutant
protein, most frequently transthyretin (TTR-FAP), as amyloid. Liver
transplant is the only available treatment but carries significant
mortality and morbidity. Tafamidis. a novel small molecule selectively binds to transthyretin preventing its dissociation into toxic
intermediates and was hypothesized to prevent progression of the
disease.
Methods: Tafamidis (20 mg, QD) was compared with placebo in
an 18-month, randomized, double-blind, multicentered trial; an
open-label 12-month extension followed, providing data on
30 months of tafamidis administration. The co-primary endpoints at
18 months were the percentage of patients with no disease progression [\2-point worsening in Neuropathy Impairment ScoreLower Limbs (NIS-LL)] and the change from baseline in quality of
life [Norfolk Quality of Life-Diabetic Neuropathy total scores
(TQOL)] in the intent-to-treat (ITT) and efficacy evaluable (EE)
populations. Changes in modified BMI (mBMI, BMI 9 serum
albumin), objectively-measured nerve fiber function, and TTR tetramer stabilization were also assessed.
Results: Demographics (N = 128 randomized, 70 women, mean
age *39 years) and baseline disease were similar between groups.
At 18 months, a greater proportion of tafamidis-treated patients
(ITT 45%, EE 60%) had no disease progression versus placebo (ITT
30%, p = 0.068, EE 38%, p = 0.041). Neurologic deterioration
(change in NIS-LL versus placebo at 18 months) decreased by 52%
(p = 0.027); quality of life and mBMI were maintained for tafamidis (TQOL mean change 2.4, mBMI ±37.9) and worsened for
placebo (6.9, p = 0.116; 32.7, p \ 0.001). The monthly rates of
change for all endpoints were maintained over 30 months. TTR
tetramer stabilization occurred in 98% of tafamidis-treated, and no
placebo-treated patients (p \ 0.001). The incidence of adverse
events was similar.
Conclusions: Tafamidis stabilized the TTR tetramer, and over
30 months slowed TTR-FAP disease progression, reduced burden of
disease, and was well tolerated.
123
Presidential symposium
Treatment of muscle diseases: the future is
already here
91
Can we bypass a muscle metabolic defect?
Z. Argov
Hadassah-Hebrew University Medical Centre (Jerusalem, IL)
The metabolic myopathies are thought to be more amenable to
treatment once the defect in the biochemical pathway is identified.
Some of the defects cause mainly exercise intolerance and its
improvement can be regarded as therapeutic success. In others muscle
weakness and degeneration is seen and functional and strength
improvement is the goal.
Therapy of such disorders can be achieved through enzyme
replacement (e.g. therapy of Pompe’s disease which will not be dealt
in this presentation) or its up regulation (bezafibrate in carnitine
palmityl transferase 2 deficiency), and also by: (1) supplementation of
the missing compound (e.g. CoQ10 which is effective only in primary
Q10 deficiency but is given at doses of 400–600 mg/day to most
patients with mitochondrial disorders); (2) pharmacologically
increasing the oxidative capacity of muscle (by giving various
‘cocktails’ of oxygen species scavengers like menadione ± K3,
vitamin C, riboflavin, carnitine or by providing extra creatine); (3)
changing the diet composition in order to increase the availability of
compensatory fuel sources (e.g. 75 g of sucrose given before exercise
or a carbohydrate-rich diet in McArdle’s disease). Because of the
rarity of metabolic myopathies no proper double blind studies
were performed to assess these therapeutic modalities, but the currently existing data will be presented along with management
recommendations.
With these considerations in mind, planned therapy of hereditary
inclusion body myopathy (HIBM) due to defects in GNE (an enzyme
in the synthetic pathway of sialic acid) is now reaching human trials.
Providing a metabolic intermediate that is downstream to the enzymatic defective site (e.g. ManNac or sialic acid) was shown to be
effective in a mouse model and toxicity studies are now in progress.
92
Exercise therapy in muscle disease: a current overview
T. Taivassalo
McGill University (Montreal, CA)
Exercise intolerance is a common clinical presentation in patients
with neuromuscular disorders, resulting from the primary disease
process and in most cases, secondary effects of cardiovascular
deconditioning and muscle disuse. Exercise training can counter the
effects of deconditioning in healthy and various chronic disease
conditions, however it has traditionally been discouraged for patients
with myopathies because of fear of exacerbating symptoms and
because of a general lack of evidence-based knowledge on the effects
of strength or aerobic exercise on the disease process. Over the past
decade, progress has been made regarding the safety and efficacy of
exercise training as therapy in various metabolic and inflammatory
myopathies and in muscular dystrophies. These few studies have
assessed the ability of the exercise stimulus [aerobic training (AT) at
60–80% peak heart rate, 20–40 min 3 times per week or strength
training (ST) at variable intensities 2 to 3 times per week) to reverse
S5
deconditioning and affect the disease process. In McArdle’s disease,
moderate intensity AT improved exercise capacity by increasing
circulatory delivery and mitochondrial metabolism of blood-borne
fuels, without causing pain, cramps or increases in serum CK. Despite
training adaptations, fuel availability continued to limit oxygen utilization and exercise capacity. Due to the concern for muscle injury in
this population, the effects of ST on muscle strength have not been
evaluated. In a handful of studies assessing exercise therapy in
mitochondrial myopathies, AT and ST reversed deconditioning and
increased peak exercise capacity as well as muscle strength. The
specific effects of AT on the disease process (levels of mutant mitochondrial DNA in heteroplasmic defects or enzymatic deficiency in
nuclear-encoded defects) are still unresolved. An alternate rationale for
ST in certain heteroplasmic mutations involves the activation of satellite
cells in response to muscle overload or injury, and is currently being
assessed as a strategy to increase levels of wild-type mitochondrial DNA.
Patients with sporadic inclusion body myositis improved aerobic capacity
and muscle strength as a result of combined AT and low-intensity ST of
the upper and lower limbs. These benefits were achieved without unfavorable muscle symptoms or increases in elevated baseline serum CK,
however significant increases in muscle size have not thus far been
detected. To achieve greater gains in muscle size and strength, a novel
strategy using moderate-intensity ST with vascular occlusion increased
muscle cross-sectional area and strength in a single patient with sporadic
IBM. Limited studies assessing exercise training in muscular dystrophies
showed that low-intensity AT improved peak exercise capacity with no
signs of muscle damage in FSH, myotonic or Becker’s dystrophy. In the
first two conditions, moderate-intensity ST is reported to have no negative
effects, however improvements in muscle strength or size are limited or
non-existent. The application of neuromuscular electrical stimulation, as
a surrogate for ST in patients with severe muscle weakness, has recently
been reported to be well-tolerated resulting in improved muscle strength
in FSHD. In conclusion, despite the initial progress made thus far, there is
an urgent need for larger, randomized controlled studies to confirm the
safety and develop specific exercise guidelines to optimize efficacy of
exercise therapy in various muscle diseases.
93
Antisense therapy of muscular dystrophies
F. Muntoni
University College of London (London, UK)
The improved understanding of the genetic basis and molecular events
leading to muscle degeneration in muscular dystrophies, coupled with
advances in antisense oligomers, has very rapidly moved in the last
decade from in vitro experiments and in-vivo studies in appropriate
animal models to phase I; IIa; IIb and now III clinical trials in Duchenne
muscular dystrophy, the most common of the severe and childhood onset
muscular dystrophies. The pace of the development of these novel
genetic approaches to treat muscular dystrophies is exciting and one of
the fastest in recent drug development program.
The research program that has paved the way to the other developments is the one in Duchenne muscular dystrophy: the first
description of the use of antisense oligonucleotides to modify the
splicing of the dystrophin gene in cultured mdx muscle cells was
published only in 2008; less than 10 years after, in 2007, the results of
the first intramuscular proof of concept study in DMD boys was
published, followed by a second one in 2009. During the course of
2009–2010 two separate repeated systemic dosing studies using two
different antisense oligomers have been completed, and in 2012 large
international randomised placebo controlled studies initiated. The
outcome of these studies is expected by early 2012; and additional
studies are being planned.
Preclinical studies in myotonic dystrophy are also rapidly advancing,
followed by also attempts to utilise antisense oligomers in other less
common muscular dystrophy variants, for example in LGMD2B.
In parallel to these human studies using these ‘‘first generation’’
chemistries, experimental work focused on optimizing the efficacy of
new generation antisense is very rapidly progressing, with unparalleled efficacy in preclinical models.
In my presentation I will summarise the status of the art of the
clinical and preclinical work being performed in this field.
94
Gene therapy: myth, milestones, and momentum
J.R. Mendell
Nationwide Children’s Hospital (Columbus, US)
Therapeutic options for muscular dystrophy are limited. Presently only
corticosteroids have been found to benefit boys with Duchenne muscular
dystrophy (DMD), although the results are modest and side effects significant. The translational research community has introduced molecular
strategies to potentially enhance mutant gene expression through exon
skipping, mutation suppression, and gene replacement. Each of these
approaches has merit and is being tested in clinical trials. For gene
replacement therapy, adeno-associated virus (AAV) has been established
as a safe vehicle for gene transfer with the recognition that pre-existing
exposure to this virus can present obstacles. As the most common severe
form of inherited muscle disease, DMD has been a particular target for
gene therapists. In the first AAV-mediated gene therapy trial for this
disease, a surprising finding was that hidden epitopes of expressed dystrophin, usually found on revertant fibers proved to be immunogenic for
some individuals. It had previously been considered that dystrophin
expressed on revertant fibers was tolerizing. The lesson learned is that
patients can be screened prior to participation, paving the way for safe
gene transfer. Clinical experience has also demonstrated that transfer of
mini-dystrophin genes must be carefully matched with endogenous DMD
gene deletions to avoid expression of novel immunogenic epitopes.
A major milestone for gene therapy was the first successful gene
transfer using AAV to deliver the a-sarcoglycan gene in LGMD2D
(rAAV1.MCK.hSGCA). Sustained gene expression for 6 months was
achieved following intramuscular gene transfer. Further advantages
accrued through the use of a muscle specific promoter. An exception
was a patient exhibiting pre-existing AAV neutralizing antibody that
will be necessary to avoid in future trials. Other strategies for gene
transfer are poised for clinical trials including building muscle size
and strength through AAV-mediated gene transfer of follistatin. In
addition, AAV5 is uniquely capable of transferring genes that exceed
the usual packaging limit of *5 kb.
__________________________________
Symposium
Molecular and cellular mechanisms
of ischaemic stroke
96
Novel molecular targets for acute stroke treatment
G. Stoll
Julius-Maximilians-University (Würzburg, DE)
In acute thrombo-embolic stroke the principal treatment goal is to
rapidly achieve recanalization of occluded vessels. Patients may,
123
S6
however, develop progressive stroke despite early reperfusion of
previously occluded major intracranial arteries (e.g. by thrombolysis),
a process referred to as ‘‘reperfusion injury’’. The cellular and
molecular mechanisms underlying reperfusion injury in the brain are
still elusive. This talk will summarize recent advances in our understanding of platelet function in mouse models of acute ischemic
stroke and provide new molecular targets for treatment.
The initial tethering of platelets at sites of vascular injury is
mediated by GPIb-V-IX, a structurally unique receptor complex
expressed on platelets. We could recently show that interference with
these early steps of platelet adhesion/activation by inhibition of the
von Willebrand factor (vWF) receptor glycoprotein (GP) Ib, its ligand
vWF, or the collagen receptor GPVI profoundly limited infarction in
the mouse stroke model of transient middle cerebral artery occlusion
(tMCAO) (Stoll et al., 2008 Blood 112:3555–62). Importantly, this
protective effect was not associated with bleeding complications.
Contrastingly, blockade of GPIIb/IIIa receptors instrumental in
platelet aggregation led to increased intracerebral hemorrhages and
mortality. GPIb contains a binding site for coagulation factor XII
(FXII) as a link between platelet activation and the coagulation system. In the tMCAO model, cerebral infarct volumes in FXII-deficient
mice were less than 50% of those observed in wildtype controls, and
pharmacological blockade of FXII by infestin was highly effective in
stroke prevention (Hagedorn et al., 2010 Circulation 121:1510–7).
Taken together these findings strongly suggest that microvascular
thrombus formation is the leading pathophysiological event in acute
stroke even during reperfusion, but GPIb and GPVI have the additional capacity to guide inflammatory processes. Since mice lacking T
cells are similarly stroke-protected (Kleinschnitz et al., 2010 Blood
115:3835–42), ischemic stroke can be redefined as a thromboinflammatory disorder, and multifunctional molecules such as GPIb,
GPVI, and FXII may provide new therapeutic targets linking
inflammation and thrombus formation.
Work in the author’s team and lab was supported by the DFG, SFB
688 (A1, A13 and B1).
97
Brain-immune interactions, infection, and inflammation
in acute stroke
X. Urra
University Hospital (Barcelona, ES)
The central nervous system (CNS) and the immune system are
tightly interconnected. Immunity contributes to the pathogenesis of
the ischemic brain injury, and CNS lesions can have systemic
consequences over immunity. A stroke-induced immunodepression
syndrome was described in a murine model of cerebral ischemia, in
which animals were at high risk of infectious complications.
Infections are also the most frequent complication in stroke
patients and could reflect an immunosuppressive state after stroke.
In turn, infections can be a source of systemic inflammation and
several inflammatory markers are associated to worse outcome in
stroke.
In stroke patients, the study of pro- and anti-inflammatory
pathways was mainly focused in the assessment of systemic levels
of different cytokines. Recently, the study of immune cells has
provided additional insights, showing that the immune response
during acute stroke can influence the clinical course of the patients,
and that the mechanisms linked to the risk of poor prognosis and
the risk of stroke associated infection are different. Thus, poor
prognosis has been found to be related to markers of greater
inflammation such as high TLR4 expression in monocytes, greater
activation of B cells, and predominance of classic inflammatory
123
monocytes over minor populations of CD16+ monocytes that are
involved in tissue repair. Contrarily, infections are associated to
features of the stroke-induced immunodepression syndrome, characterized mainly by lymphocytopenia, lower TNF-a production and
low HLA-DR expression in monocytes. The magnitude of the
immunodepression seems to be related to the size of the brain
lesion and the neurohormonal stress response associated to it
(raised levels of cortisol and metanephrin). Interestingly, the
immune changes induced by ischemic and hemorrhagic strokes are
similar, suggesting that they are mainly an unspecific consequence
of the acute lesion of the central nervous system and not dependent
on the specific nature of it.
Overall, a better understanding of the reciprocal effects between
the CNS and the immune system could pave the way to more effective
therapies for this devastating condition, including strategies aimed to
inhibit TLR-4 signaling, promoting minor subpopulations of monocytes that favour tissue repair and angiogenesis and selecting patients
at high risk of infection for antibiotic prophylaxis.
98
Hypothermia: from animal models and translation
to humans
S. Schwab
University Hospital (Erlangen, DE)
Hypothermia (HY) is the most powerful neuroprotective therapy in
pre-clinical models and the only proven clinical therapy for
patients with global cerebral ischemia. In experimental and early
phase human trials, HY was rated one of the most active modes
of neuroprotection. HY improves neurological outcome in survivors of cardiac arrest and in infants with hypoxic-ischemic
encephalopathy.
The neuroprotective potential of HY after ischemic stroke and
traumatic brain injury remains under investigation. Studies in acute
ischemic stroke that target the acute phase and aim to reduce neurological injury from ischemia are ongoing and early reports of its
feasibility and safety are promising. Major questions remain to be
answered for and within studies in stroke patients. Depth, duration,
methods for cooling, side effects including pneumonia and coagulation disturbance, patients’ dyscomfort, acid–base management, ICU
or stroke unit care are some of those. However, the use of HY showed
promise in the reduction of mortality after stroke that causes a space
occupying lesion.
99
Stem cells in experimental stroke: translation
to humans?
E. Diez-Tejedor
Foundation for Biomedical Research of the University Hospital
La Paz (Madrid, ES)
Brain repair is a natural endogenous process that is activated after
injury and includes processes of cell proliferation,neurogenesis,angiogenesis and synaptogenesis. They are interrelated repair
processes could provide new therapeutic targets to mitigate the
damage in cerebral ischemia. The promotion of brain plasticity can be
achieved through stimulation of endogenous capacities,both for
rehabilitation or for the use of trophic factors or by exogenous
stimulating with cell therapy.
Stem cells are immature cells with prolonged self-healing capacity. Diverse stem cell lines have been tested in neurological diseases.
S7
Preclinical data with mesenchymal stem cells (MSCs) suggests that
these cells can become truly effective and safe therapy in diseases
associated with inflammation and/or destruction of tissue. These cells
were transplanted into the brains of stroke patients with excellent
tolerance and no complications. Also intravenous infusion of autologous MSCs was feasible and safe, and has suggested an
improvement in neurological recovery in patients with severe stroke.
Besides, it has also been reported the safety of this treatment at
5 years of treatment.
Cell therapy may be autologous, allogeneic, or xenogeneic.
Autologous transplantation may avoid rejection. However, its main
limitation is that only possible to apply this therapy several weeks
after the stroke. Thus,the use of allogeneic stem cells could be an
alternative as it is demonstrated the lack of HLA-class II of mesenchymal cells. In this sense,the creation of biobanks of stem cells may
be an excellent alternative for treating patients with cerebral infarction much earlier.
Recent studies have suggested that stem cells favor the repair by
releasing factors. Besides,it has not yet been established which would
be the best route of administration in humans,the better would be the
intravenous versus intraarterial.
We have the experience developed in our Neuroscience and
Cerebrovascular Diseases Laboratory with allogeneic MSCs
administration in an animal model of cerebral ischemia using
intravenous and intracarotid routes. We have found that both routes
were equally effective in neurological recovery. Although stem cell
therapy did not reduce infarct volume analyzed by image analysis
and hematoxylin-eosin,we observed a reduction in cell death and
increased endogenous cell proliferation (increase BrdU), so as an
increase in VEGF, GFAP and NeuN (angiogenesis and neurogenesis). We did not observed migration of cells in the lesion area
when stem cells were administered intravenously. This would
indicate that it is not necessary to form cell niches in brain infarct
area for achieving good functional recovery and reinforce the
hypothesis that probably stem cells stimulate endogenous trophic
factors or release new trophic factors, which would be responsible
for brain repair and functional recovery.
Translational clinical trials showed safety and feasibility in
phase I and phase II with neuronal stem cells and bone marrow
mesenchymal stem cells. In this line, we designed to clinical trial
to assess the safety of treatment with allogeneic stem cells from
adipose tissue by intravenous via in acute stroke patients. Further
studies in phase III are needed to assess the effect of stem cells on
stroke outcome.
In short, this progress has opened the way for promising research
into new therapeutic strategies in stroke remedial enhancing brain
plasticity, which would complement the current standard treatment of
acute cerebral infarction.
Psychiatric aspects of neurological disorders
101
Psychiatric aspects of PSP, MSA and ALS
A.C. Ludolph
Universitätsklinikum Ulm (Ulm, DE)
It is now generally accepted that neurodegenerative diseases are
multisystem disorders which affect large parts of the central nervous
system and a number of tissues outside the brain and spinal cord.
Therefore, the occurrence of symptoms of disease beyond the
classically affected brain structures and their symptomatology is not a
surprise.
Psychiatric aspects of PSP, MSA and ALS can be divided into two
important groups of symptoms:
1. Impairment of the cognitive status of the patient.
Whereas frontal lobe deficits are known for a long time in the
tauopathy PSP, the occurrence of deficits in tests thought to mirror
frontal lobe function was only recently acknowledged in patients with
ALS. Although these deficits appear to impair critical judgement only
in a minority of ALS patients (\10 %) and do not seem to be progressive in most cases, their recognition supported the recent insight
clinically that the molecular signature (‘‘TDP43’’) of the SOD1
negative ALS patients is identical with the one found in Tau-negative
forms of FTD. Also, current evidence seems to show that the cognitive deficits in ALS patients are often non-progressive. The close
relation between FTD and ALS is also important for genetic studies of
both diseases. A recent large study (NNIPPS) clearly showed the
presence of cognitive deficits in MSA patients ([20 % in early
patients) although they are much less pronounced and frequent than in
PSP (about 50% in early stages).
2. Psychosocial consequences of MSA, PSP and ALS
Recent data show that the rate of depressions is comparatively
high in MSA and PSP patients alike; it reaches fourfold the number
than in normal populations. In contrast, in ALS patients the rate of
depression is comparatively low, only doubling the numbers of normal populations. Most studies demonstrate in ALS patients that the
depression rate is independent from the degree of functional motor
deficits and disease duration, but dependent from the level of education. The reason for this difference in prevalence of depressions
between atypical parkinsonian syndromes and ALS remains unexplored; its importance is underlined by the seemingly higher rates of
suicides in MSA and PSP if compared with ALS.
Taken together, the recent data show that psychiatric aspects of
these rare neurodegenerative diseases are important since they are a
major feature of the patients, the carers and the physicians experience
of the diseases.
102
Psychiatric symptoms in Parkinson’s disease
E. Ruzicka
Charles University (Prague, CZ)
The four D’s indicate the classical categories of psychiatric disorders
that can be found in Parkinson’s disease (PD): Depression, Druginduced psychosis or impulse control disorders, Delirium, and
Dementia. Their timely recognition and appropriate treatment comprise an important part of the daily routine in a PD clinic. Studies on
the neuropathological and pathophysiological mechanisms have
shown that psychiatric disturbances represent both non-motor manifestations of the primary pathology and associated cortical and
subcortical involvement.
While depression and anxiety may appear in the earliest stages,
hallucinations and delusions are usually associated with dopaminergic
medication or combined drug therapies in more advanced PD, often
against the background of preexisting cognitive impairment. Conversely, impulse control disorders (ICD) such as gambling,
hypersexuality and other inappropriate behaviors can arise at any
stage, frequently in younger patients treated with dopamine agonists.
The so-called hedonistic homeostatic dysregulation syndrome is close
to ICD and involves the abuse of levodopa or dopamine agonists.
Finally, the cognitive deficit typically found in PD mainly features
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executive dysfunction and it progresses to dementia of the subcortical
type in a substantial proportion of patients. In advanced PD, dementia
predisposes to delirium induced by drugs, concurrent infection or
metabolic disturbances.
103
Behavioural and psychological symptoms of dementia
(BPSD) in Alzheimer’s disease: update on management
R. Heun
Royal Derby Hospital (Derby, UK)
Behavioural and Psychological Symptoms in Dementia (BPSD)
consist of a variety of symptoms that are common in patients with
Alzheimer’s disease as well as other types of dementia. These
symptoms have a high prevalence in all stages of dementia. BPSD
represent a severe burden to the patients, but also to their relatives and
carers. They often lead to the transfer of patients to nursing homes.
There is an ongoing discussion on the best pharmacological and nonpharmacological treatment approaches. Current guidelines recommend the preferential use of non-pharmacological behavioural
approaches to the treatment. This presentation will provide an overview on the evidence and on current guidelines for the treatment of
BPSD from a psychiatric UK perspective.
Metals and movement disorders
134
Wilson’s disease
E.R. Barbosa
University Hospital (Sao Paulo, BR)
Wilson’s disease (WD) is a rare inborn autosomal recessive disorder
of copper metabolism secondary to ATP7B gene mutations. This gene
encodes an ATPase protein, which is responsible for the billiard
copper excretion. This results in copper accumulation in the liver and
later on in other organs, such as the brain. Since the first reports in the
1990s more than 400 mutations have been identified in diverse populations around the world. Neurological manifestations, appearing in
the second or third decade, are the initial presentation in about half the
patients and can be highly variable. The majority of cases have a
neurological clinical picture with a wide range of combinations of
dysarthria, tremor, gait disorders, dystonia, and parkinsonism. The
diagnosis of WD may be suspected in all patients with chronic progressive movement disorder of unknown etiology, mainly if onset is
in the second or third decade of life. The accurate, prompt diagnosis
of individuals with WD is important since early treatment, halts
disease progression and may reverse established liver and brain
damage to some degree. The diagnosis first step for the diagnosis of
WD is a sensible clinical suspicion. No single test is definitive and
here is no universally accepted biochemical ‘‘gold standard’’. The
diagnosis is based on the clinical picture and the combination of the
results of several tests. The main diagnostic procedures in WD are:
slit-lamp examination, serum ceruloplasmin level, urinary copper
excretion (UCE), penicillamine challenge UCE, hepatic copper concentration, MR Imaging and genetic test to detect ATP7B gene
123
mutations. In this presentation diagnostic criteria in Wilson’s disease
will be discussed. The aim of pharmacological treatment of Wilson0 s
disease is to restore the copper balance. The main drugs employed are
chelating agents as d-penicillamine and trientine or zinc salts to limit
gastrointestinal absorption of copper. Orthotopic liver transplantation
is indicated for patients with fulminant hepatic failure and for those
with chronic, severe hepatic insufficiency that do not respond to
pharmacological therapy.
135
Neurodegeneration with brain iron accumulation
disorders: an update
K. Bhatia
University College London (London, UK)
NBIA constitutes a group of neurodegenerative disorders presenting
with a progressive extrapyramidal syndrome and excessive iron
deposition in the brain, particularly affecting the basal ganglia, mainly
the globus pallidus. Several genes have recently been identified to
cause NBIA, most of them (except for neuroferritinopathy) inherited
in an autosomal recessive fashion.
The two core syndromes are pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz
disease) and PLA2G6-associated neurodegeneration (PLAN), both
neuroaxonal dystrophies.
Of these, PKAN (NBIA type 1, PARK14) due to mutations in the
PANK2 gene, usually presents as an early-onset pyramidal extrapyramidal disease, often with prominent oromandibular involvement.
Atypical cases with adult-onset have been reported. Retinopathy is
common, and the MRI ‘‘eye of the tiger sign’’ seen on T2*-weighted
images is a characteristic feature.
NBIA type 2, due to PLA2G6 mutations gene has been associated
with infantile neuroaxonal dystrophy (INAD). When onset is late the
phenoptype may be predominated by complicated dystonia parkinsonism. Cerebellar atrophy occurs in early stages. Iron accumulates in
the globus pallidus and sometimes, in the more atypical cases, in the
substantia nigra. Pathological studies revealed widespread presence of
a-synuclein-positive Lewy pathology, a link between PLA2G6 and
parkinsonian disorders.
Kufor Rakeb disease (PARK9) causes early-onset, often complicated parkinsonism. Recently, iron accumulation in the putamen and
caudate nuclei was observed in gene-proven cases, and classification
as NBIA type 3 was proposed.
FA2H mutations, previously known to cause leukodystrophy and
a form of hereditary spastic paraplegia (HSP), were recently identified as another cause of NBIA. Like PANK2 and PLA2G6 the
metabolic pathway of FA2H involves the lipid and ceramide
metabolism.
Aceruloplasminemia due to mutations of the ceruloplasmin gene is
characterized by adult-onset movement disorders and dementia.
Presence of diabetes mellitus may be a directive feature. Finally, there
is neuroferritinopathy due to FTL mutations, an autosomal dominant
form of NBIA. Mean age of onset is in midlife, around age 40 with
extrapyramidal features including chorea, dystonia with prominent
oromandibular dyskinesias with phenotypic similarity with Huntington disease. Due to a founder effect there is clustering in the
Cumbrian region of England. MRI may reveal cystic changes in the
basal ganglia and bilateral pallidal necrosis.
These conditions will be discussed and an approach to diagnosis
and management for these disorders will be outlined.
S9
136
Manganese-related movement disorders
P. Taba
University of Tartu (Tartu, EE)
Manganese (Mn) is an essential tracer metal present in tissues but
excessive exposure of Mn may cause development of a parkinsonian
syndrome known as manganism. It was first described as a gait and
speech disorder in men employed in grinding the ‘‘black oxide of
manganese’’, by John Couper in 1837, twenty years after James
Parkinson’s ‘‘An Essay on the Shaking Palsy’’.
Occupational inhalation exposure in welding, smelting and mining
has been the main cause of Mn intoxication. Mn is used in industries
for manufacturing of batteries and steel, gasoline, bactericidal agents,
and the water purification process. Manganism has also been described in non-occupational settings like chronic liver failure, long term
total parenteral nutrition, or exposure to contaminated well water.
Parkinsonism with symmetric bradykinesia and rigidity, gait disorder, falls, and speech disorder are characteristic manifestations of
manganism. Dystonias in limbs and face, and behavioral and cognitive changes may develop. Blood manganese concentration reflects
current exposure, and hyperintense signal in T1-weighted sequences
in magnetic resonance imaging show accumulation of Mn in the
globus pallidus and other basal ganglia structures. Parkinsonism
caused by Mn exposure does not respond to levodopa treatment but
chelating therapy with CaNa2EDTA may be of clinical benefit.
During recent years, the syndrome that closely resembles manganism,
has been described in addicts who have chronically administered a
‘designer’ psychostimulant methcathinone (ephedrone), synthesised
from ephedrine or pseudoephedrine by adding potassium permanganate
and acetic acid to induce oxidation. The neurologic symptoms are evidently caused by Mn accumulation but methcathinone may have
pathogenic effects on nigral neurons compounding the risk.
It has been debated could exposure of Mn cause an increased risk
for development of Parkinson’s disease but the overwhelming evidence shows that manganism and Parkinson’s disease are different
entities, based on neuropathology, neuroimaging, and clinical manifestations. Mechanisms of manganese toxicity are not completely
known. The most prominent pathological changes are in pallidum but
there is no conclusive evidence on nigrostriatal mechanism of manganism.
Biomarkers for diagnosis, prognosis
and response to treatment in MS
138
Transcriptomics
R. Martin (Zurich, CH)
Multiple sclerosis (MS) is considered an autoimmune disease that
leads to brain and spinal cord inflammation, demyelination and
axonal/neuronal loss in young adults. A complex genetic trait and
multiple environmental factors contribute to disease etiology, and, as
a consequence, MS varies in clinical presentation, disease course, and
response to treatment. Currently, we do not take disease heterogeneity
into account, and e.g. treat all patients with the same first-line drugs,
interferon-ß and glatirameracetate, despite the fact that many patients
do not respond to one or both. Similar to oncology, where treatment
strategies are based on particular mutations of the respective cancer or
other markers that are related to prognosis or treatment outcome, it
will be important to identify biomarkers that allow to diagnose MS as
early as possible, provide prognostic information as to who will
develop active disease and accumulate disability rapidly, and who
will respond to a certain single drug or combination treatment or not.
The current state of biomarker research in MS as well as the strategies
to identify biomarkers for the above applications will be presented.
140
CSF markers
G. Giovannoni
Barts and The London School of Medicine and Dentistry
(London, UK)
The field of CSF biomarkers in MS continues to expand. Despite the
widely held view that MS is an organ specific autoaggressive immune
mediated disease, there is a large body of epidemiological data supporting a role for an environmental cause. The invariable finding of
intrathecal oligoclonal immunoglobulin bands (OCBs) with clonal
expansion and affinity maturation of intrathecal B cell indicates that an
antigen-specific intrathecal immune response occurs in MS, similar to
that that has been described with neurotropic viruses. Unfortunately, the
antigen specificity of these oligoclonal bands in MS continues to elude
investigators, but the rapid developments in the fields of genomics and
proteomics are allowing investigators to exploit new technologies to
probe the antigen-specificity of these oligoclonal bands. New technologies have been applied to MS with the hope of identifying novel CSF
diagnostic markers; to date none of the identified markers have been
validated and translated into clinical practice. A large and overwhelming
body of work on various immunological markers in the CSF in MS
already exists. Making sense of these data is a daunting task. Many of the
studies have been poorly designed and results are difficult to reproduce.
The field is also hampered by publication bias, with most negative
studies failing to be published. Some studies have tried to define and
establish aberrant autoimmune reactivity that is believed to cause MS,
whilst others have investigated the immunological basis for disease
heterogeneity and the transition from the relapsing remitting to secondary progressive phase of the disease. Immunological studies have
also focused on trying to find surrogate markers of disease activity.
Despite the extensive literature there are currently no immunological
markers, apart from oligoclonal IgG bands that are being used in routine
clinical practice. With the emergence of several disease modifying
therapies biomarkers to assess treatment response or lack of response are
needed. This will become increasingly important as we try to optimise
therapies for individual patients. Regardless of the cause of MS, the
identification of specific in vivo markers of key pathological processes
known to occur in MS, particularly axonal loss, gliosis, demyelination,
remyelination, synaptic plasticity, oligodendrocyte apoptosis, complement activation and cell mediated cytotoxicity to name a few, we may be
able to use them to define pathological disease subtypes, select homogeneous groups of patients for clinical trial, assess therapeutic responses
to disease modifying therapies and to use them as predictive markers of
disease course. In conclusion CSF biomarkers will have a major impact
on several areas of MS-related research and specific biomarkers will
almost certainly be incorporated in clinical trials and following that
clinical practice in the near future.
141
Biomarkers for diagnosis, prognosis and response
to treatment in MS: magnetic resonance imaging
M. Filippi
University Hospital San Raffaele (Milan, IT)
Due to its exquisite sensitivity to multiple sclerosis (MS) abnormalities, magnetic resonance imaging (MRI) has become an established
123
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tool to diagnose the disease and to monitor its evolution. MRI has been
formally included in the diagnostic work up of patients at presentation
with clinically isolated syndromes suggestive of MS, and ad hoc criteria
have been proposed and are updated on a regular basis. On the contrary, in
patients with established MS, the ability of MR measures in explaining
patient clinical status and progression of disability is still suboptimal.
This has prompted the extensive application of modern MR-based
technologies to estimate overall MS burden in patients at different stages
of the disease. The use of these techniques has allowed to grade in vivo the
heterogeneity of MS pathology not only in focal lesions, but also in the
normal-appearing white matter and gray matter. More recently, additional aspects of MS pathology, including macrophage infiltration and
abnormal iron deposition have become quantifiable. All of this, combined
with the use of functional imaging techniques is ameliorating progressively our understanding of the factors associated to MS progression.
Only a few of the available MR techniques are at present applied in the
context of clinical trails aimed at monitoring the efficacy of experimental
treatment. As a consequence, the scientific MS/MRI community should
develop standardized multiparametric approaches to improve our ability
to screen new treatments rapidly and efficiently. Such protocols should be
tailored to the phase of the disease studied and the modes of action of the
tested therapies. In the new scenario of several treatment options for MS,
it is also of the outmost importance to identify reliable MR markers of
individual patient response to disease-modifying treatments.
––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Oral sessions
Oral session 1
Cerebrovascular disorders I
O178
Genetic associations of cerebral amyloid angiopathy:
a systematic review and meta-analysis
K. Rannikmae, N. Samarasekera, R. Al-Shahi Salman,
N. Martinez-Gonzalez, R. Annan, C.L. Moore Sudlow
University of Edinburgh (Edinburgh, UK)
Objectives: Cerebral amyloid angiopathy (CAA) is characterised by
amyloid deposition in cortical and leptomeningeal vessels. It is an
important cause of cerebrovascular disorders, in particular lobar cerebral
haemorrhage. Many studies have attempted to find associations between
polymorphisms in various candidate genes (mostly the apolipoprotein
gene [APOE]) and CAA. We aimed to evaluate the evidence for these
associations with a systematic review and meta-analysis.
Methods: We used a comprehensive search strategy to identify
studies of the association between any genetic polymorphism and
pathologically diagnosed CAA (on autopsy or biopsy). For studies of
the association between the APOE and CAA, we extracted data on the
study populations, methodology, and number of subjects with and
without CAA or the mean CAA score for different APOE genotypes.
We compared the effects of epsilon4 allele possession (e4+) versus
absence (e4–) by calculating study-specific and random effects pooled
odds ratios (OR) for dichotomous data and standardised mean differences (SMDs) in CAA scores for continuous data.
Results: We identified 46 relevant studies (6,541 subjects) of association between APOE and CAA. Of those, 23 studies (3,524
subjects, *50% of the total) provided enough data for meta-analysis.
Both the pooled OR for studies with dichotomous data and the pooled
SMD for studies with continuous data demonstrated a statistically significant association of e4+ genotypes with CAA [OR 4.1, 95% confidence
123
interval (CI) 2.8–6.1, SMD 0.44, 95% CI 0.25–0.62). There was heterogeneity between the studies‘ results (dichotomous data studies: p = 0.03,
I2 = 45%, continuous data studies: p = 0.005, I2 = 59%).
Conclusion: Although our results suggest a clear association
between APOE and CAA, it will be important to exclude reporting
bias by confirming these findings in the substantial proportion of
studies (and subjects) without published data for meta-analysis.
Reasons for heterogeneity between studies need further exploration.
Kristiina Rannikmae is funded by the European Federation of
Neurological Societies scientific fellowship. Cathie Sudlow is funded
by the Scottish Funding Council. Rustam Salman and Neshika Samarasekera are funded by the UK Medical Research Council. Nahara
Martinez-Gonzalez was funded by Conacyt-Mexico.
O179
Cerebral venous thrombosis in Behçet’s disease:
a systematic review
D. Aguiar de Sousa, J. Ferro
University of Lisbon (Lisbon, PT); Hospital de Santa Maria (Lisbon, PT)
Background: Behçet’s disease (BD) is a chronic inflammatory multisystem disorder which can involve the central nervous system
(CNS). Cerebral venous thrombosis (CVT) is one of its major neurological manifestations.
Objectives: To review the epidemiologic and clinical features of
CVT in patients with BD, as well as the available data on therapeutic
interventions and prognosis.
Methods: Systematic review of all observational studies of BD
patients. Search strategy: electronic searches of MEDLINE (1966–
August 2009). Extracted data: occurrence of CVT in BD and NeuroBehçet patients, occurrence of CVT as the inaugural manifestation of
BD, clinical and neuro-imaging characteristics of CVT, prothrombotic evaluation, treatment options and prognosis. A meta-analysis of
available results was performed when feasible.
Results: Twenty-three studies were included, with 290 cases of
CVT in patients with BD. The incidence of CVT per 1,000 person–
year was 3.1 (95% CI 1–8), being higher in retrospective studies (3.2:
95% CI 1–10) than in prospective studies (2.7: 95% CI 1–13). Among
patients with neurologic involvement, the incidence rate was 15.1/
1,000 person–year. The onset was progressive in 77% of the patients.
Intracranial hypertension syndrome was a frequent presentation of
CVT in BD. The most frequent sites of occlusion were the superior
sagittal and the transverse sinus. Most of the studies did not evaluate
the prevalence of prothrombotic disorders. Treated CVT was associated with a good prognosis.
Conclusions: CVT is a frequent neurological manifestation of BD.
When treated, BD-associated CVT bears a good prognosis. There is
insufficient information regarding the role of concomitant prothrombotic disorders and specific treatments.
O180
Functional inflammatory genotypes: are they useful
in the prediction of age of onset and long-term outcome
of an ischaemic stroke?
S. Marousi, A. Antonacopoulou, M. Karakantza,
P. Papathanasopoulos, J. Ellul
University Hospital of Patras (Patras, GR)
Objectives: Inflammatory processes participate both into the manifestation and evolution of brain ischemia. Functional singlenucleotide polymorphisms (SNPs) of inflammatory cytokines have
S11
been previously related to the occurrence of an ischemic stroke (IS).
We investigated whether five functional SNPs [i.e. Tumor Necrosis
Factor a (TNFa)-308G [ A, Interleukin (IL)6-174G [ C, IL12B
1188A [ C, IL4-589C [ T and IL10-1082G [ A] might be associated with the age of onset and 6-month outcome of an acute IS.
Methods: A probe-free real-time PCR methodology was used to
genotype 145 consecutively admitted cases with a first-ever IS. Disease-free survival analyses were applied to test for possible
associations with the age of IS onset. Outcome by month 6 was
assessed using mortality rates and scores of the Barthel Index. A
binary logistic regression was applied for the prediction models of
6-month functional outcome.
Results: Simple Kaplan–Mayer and adjusted Cox regression
analyses showed no association between inflammatory genotypes and
the age of IS onset. IL6-174G [ C, IL12B 1188A [ C, IL4589C [ T and IL10-1082G [ A were not found to significantly
contribute in the long-term outcome of the disease. However, carriage
of the TNFa-308 GG genotype presented a significant protective
effect, by reducing the odds for an adverse outcome [Odds Ratio
(95% Confidence Intervals) = 0.19 (0.04–0.86)].
Conclusion: Our results show that age of IS onset may not be
associated with functional genotypes of major pro- and anti-inflammatory cytokines, and possibly suggest that IS is a multifactorial
phenotype, in which the effect of conventional risk factors may not
become easily overwhelmed. We provide preliminary evidence for a
possible predictive role of TNFa-308G [ A polymorphism into
6-month post-stroke functional outcome. Further studies are needed to
confirm our results.
more collateral vessels than the contralateral unaffected hemisphere
compared to younger patients (p \ 0.0001, ref Maas et al., Stroke
2009;40:3001–3005).
Conclusion: While the acute pathophysiology may not be entirely
unique in older patients with stroke, at least in a similarly selected,
hospital based stroke population; determinants of long-term functional outcomes in older patients remain unclear. Increased collateral
recruitment may explain partial maintenance of penumbral tissue in
the acute phase; however, this is insufficient to maintain long term
recovery. There is a need to focus further investigation on biological
determinants of neuroplasticity, which may have an impact on long
term functional outcome.
S. Agarwal is supported by a Royal College of Physicians(UK)/
Dunhill Medical Trust Research fellowship. EA Warburton is supported by an National Institute of Health Research(UK), Biomedical
Research Centre Grant.
O182
No evidence for increased iron deposition in deep gray
matter regions in subjects with MRI findings suggestive
of cerebral small vessel disease
C. Enzinger, M Jehna, C. Langkammer, P. Linortner,
E. Aspeck, B. Pendl, T. Gattringer, K. Petrovic, S. Ropele,
F. Fazekas
Medical University Graz (Graz, AT)
O181
Ageing and the ischaemic penumbra in acute stroke
S. Agarwal, P.S. Jones, J. Alawneh, S.T. Marappu,
D.J. Scoffings, J.-C. Baron, E.A. Warburton
University of Cambridge (Cambridge, UK)
Objectives: Risks and benefits of thrombolysis for acute ischaemic
stroke in patients over the age of 80 are unclear. Observational data
indicates that although it may be a safe treatment, older patients have
poorer functional outcomes and higher mortality than younger
patients. It remains unknown if this represents the natural course of
disease in old age or whether pathophysiology of acute ischaemic
injury is different in older patients.
Methods: 39 acute stroke patients were prospectively, consecutively recruited within 6 h of symptom onset and underwent
multislice CT perfusion imaging. Quantitative maps of cerebral blood
volume (CBV), cerebral blood flow (CBF) and mean transit time
(MTT), and an intra cranial CT angiogram (CTA) were obtained.
Functional outcomes were assessed by the modified Rankin score
(MRS B3 good outcome, C4 poor outcome) at discharge and
3 months. Ischaemic penumbra and core were defined using relative
thresholds for MTT (145%) and CBV (0.65) respectively.
Results: Admission NIHSS scores (median 10), thrombolysis rates
and discharge outcomes were not significantly different between the
older ([80 years of age, n = 12) and younger (B80 years, n = 27)
groups. However, older patients were more likely to have a poorer
outcome at 3 months (p = 0.038). Core infarct volume was not significantly different; however, penumbral volume was smaller in the
older age group (p = 0.048). There was a non-significant trend for a
negative correlation of penumbral volume with age (Pearson correlation coefficient = -0.210, p = 0.218). CTA derived overall
collateral vessel scores were not significantly different between the
groups (p = 0.357, ref. Tan et al., Annals of Neurology,
2007;61:533–543); however older patients recruited significantly
Background: Recent investigations have shown increased iron deposition in the deep grey matter of patients with multiple sclerosis (MS)
which is an immune mediated inflammatory demyelinating disorder
of the white matter. Small vessel diseases (SVD) are a further cause of
white matter damage and are also frequently associated with microbleeds, i.e. hemosiderin deposition in the brain parenchyma. We
therefore speculated that iron concentrations might also be increased
in patients with severe white matter hyperintensities (WMH) as a
hallmark of SVD.
Methods: A cohort of 61 patients (mean age 71 ± 8 years) with
some degree of WMH was dichotomized according to WMH severity
according to the Fazekas scale into a group A with minor changes
(n = 25, age = 68 ± 9 years) and a group B with early confluent to
confluent lesions (n = 36, age = 74 ± 7 years). R2* imaging was
performed on a 3 T magnet and maps were calculated for several deep
gray matter structures (thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens) and the brainstem
(segmented using FIRST, as part of FSL). WMH volume was
assessed using DispImage and brain tissue volume was estimated
using SIENAX, as part of FSL.
Results: The two groups significantly differed in age, WMH and
cerebrospinal fluid volume. Regarding iron concentrations, group
comparisons (controlled for these three covariates) did not yield
significant differences between subjects with minor and more severe
WMH, except for the globus pallidum with a higher concentration in
group A (34.96 ± 4.88) rather than group B (32.68 ± 3.88;
F1 = 4.410; p \ 0.04).
Discussion: Using a sensitive MRI method to quantitatively map
iron deposition, we could not substantiate the speculation of increased
iron deposition in deep gray matter in SVD. This indicates that not
white matter damage per se but rather its aetiology is linked with such
observations in MS.
References: Khalil M et al., Mult Scler. 2009 Sep;15(9):1048-54;
Doraiswamy PM, Finefrock AE. Lancet Neurol 2004;3:431-434;
Fazekas F et al. AJR 1987;149:351-356 and Brain. 2005;128:2926-32.
Langkammer C et al. Radiology 2010; 257:455-462.
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O183
Lumbar puncture is not harmful in patients
with cerebral venous thrombosis
L. Faria Abreu, P. Canhão, J. Stam, M.-G. Bousser,
F. Barinagarrementeria, J. Ferro for the ISCVT Investigators
Background: Lumbar puncture (LP) may cause cerebral venous
thrombosis (CVT), probably by decreasing intracranial pressure,
traction on sinus walls, and lowering venous flow velocity. In some
CVT patients LP has to be performed as part of the etiologic work up.
It is unclear if LP is deleterious in patients with CVT. The aim of this
study was to assess if LP was associated with a worse outcome.
Methods: 624 patients included in a prospective multicentre international study, the International Study on Cerebral Veins and Dural
Sinus Thrombosis (ISCVT). We compared the prognosis of patients
submitted or not submitted to LP: ‘‘death or dependency’’ (mRS 3–6,
with adjustment for variables associated with poor prognosis), ‘‘worsening during admission’’, ‘‘acute death’’, and ‘‘complete recovery’’
(mRS 0–1), all at 6 months. We analyzed the same outcomes in subgroups of patients with intracranial hypertension syndrome (IHS) and in
those with lesions on the admission brain CT or MRI.
Results: LP was performed in 224 patients (35.9%). There was no
difference in frequency of ‘‘death or dependency’’ between patients with
or without LP [13.5 vs. 14.1%; OR = 1.0, 95% CI 0.7–1.6; p = 0.823].
LP was not associated with ‘‘worsening’’ during hospitalization [21.5 vs.
23.5%; OR = 1.1; 95% CI 0.8–1.5; p = 0.577], ‘‘acute death’’ [4.9 vs.
4.0%; OR = 0.8; 95% CI 0.4–1.7; p = 0.605] or ‘‘complete recovery’’
[79.4 vs. 77.2%; OR = 1.0; 95% CI 0.9–1.1; p = 0.529]. In the subgroups of patients with IHS and those with brain lesions, the prognosis
was not different between patients submitted or not to LP.
Conclusion: LP was not associated with a worse functional outcome of patients with CVT. These results should not be applied to
patients where a LP is contra-indicated due to risk of developing brain
herniation. Although we did not observe spinal hematomas, anticoagulation remains a contraindication for LP. If indicated, LP should
thus be performed before starting heparin.
___________________________________
Oral session 2
Multiple sclerosis: pathogenesis
immunomagnetic cell sorting. SlanDC and MO were stimulated by
TLR-4 or TLR-7/8 ligands in presence and absence of IFN, GA or
Methylprednisolone (MP) to investigate their cytokine release,
T-cell-programming and -priming and activation phenotype.
By ex vivo analysis slanDC showed no differences between
untreated MS-patients and CON, whereas MO demonstrated a higher
release of IL-6 and TNF-a, but decrease in IL-10 production. Baseline
secretion of IL-10 is increased resp. of TNF-a and IL-6 is decreased in
slanDC and MO of GA-treated patients compared to other treatment
groups. In IFN-treated patients we found decreased TNF-a baseline
secretion in slanDC, but not in MO. MO and DC of NA-treated
patients were comparable with them in CON.
By in vitro experiments with sorted slanDC and MO, a dosedepending increase of IL-10 secretion by GA could be demonstrated
in slanDC and MO, whereas IFN decreased IL-10 release in SlanDC.
Addition of IFN inhibited release of TNF-a, IL-1b and IL-6 in slanDC
and MO, but increased IL-12 secretion in slanDC. Incubation with
MP reduced secretion of IL-6, TNF-a and IL-12, whereas secretion of
IL-10 was not effected. Especially IFN and MP prevent maturation
and activation of SlanDC and MO characterized by lower expression
of surface activation markers like CD83 and CD150.
In this study we demonstrate differential effects of different
immunomodulatory drugs on two major groups of APC. While
treatment with GA induces an up-regulation of antiinflammatory
cytokines, IFN reduces the proinflammatory processes by suppression
of IL-6, TNF-a and T-cell-priming. Further investigations about
antigen-presentation are needed to understand pathophysiological
processes in innate immune system as potential treatment target.
K. Thomas received educational support by Teva. H. Reichmann
serves on scientific advisory boards, receives speaker honoraria, and/
or receives funding for travel from Cephalon, Novartis, TEVA,
Lundbeck, GlaxoSmithKline, Boehringer Ingelheim, Schering/Bayer
HealthCare, UCB/Schwarz Pharma, Desitin, Pfizer, and Solvay.
T. Ziemssen has received speaker honoraria from Biogen Idec, Sanofi-Aventis, MerckSerono, Novartis, Teva, and Bayer Healthcare.
He serves as a consultant for Teva, Novartis, and Bayer HealthCare,
and receives research support from the Roland Ernst Foundation.
O185
A phenotypic analysis of novel multiple
sclerosis-associated non-HLA risk alleles
K.E. Baker, Y. Ben Shlomo, G. Ingram, M.D. Cossburn,
C. Hirst, T.P. Pickersgill, N.P. Robertson
Cardiff University (Cardiff, UK); University of Bristol (Bristol, UK)
O184
SlanDC-Key-player in pathogenesis and treatment
of multiple sclerosis
K. Thomas, M. Schmitz, H. Reichmann, T. Ziemssen
University Hospital Dresden Carl Gustav Carus (Dresden, DE)
SlanDC are a major population of human blood dendritic cells (DC)
characterized by their special phenotype and selective expression of
6-sulfo-LacNAc. As hybrid between monocytes (MO) and DC they
act as potent antigen-presenting cells (APC) releasing large amount of
TNF-a and IL12p70. Recently, we demonstrated presence of SlanDC
in MS lesions and other inflammatory CNS diseases by histopathological and CSF analysis. Here we show that the novel
proinflammatory DC plays a crucial role in pathogenesis and immunomodulatory therapy in multiple sclerosis (MS).
SlanDC of healthy controls (CON), untreated and treated MS
patients on immunomodulatory therapy [Interferon-b (IFN), Glatiramer Acetate (GA) and Natalizumab (NA)] were isolated by
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Objectives: Recent advances in the genetic analysis of multiple
sclerosis (MS) have led to the identification of novel disease associated non-HLA genes. Whilst the contribution to disease susceptibility
of individual genes is relatively small (OR 1.0–1.2), their effect on
disease outcome may be more significant and relevant in understanding pathological mechanisms and informing therapeutic
decisions. As yet, the absence of longitudinal phenotypic data on
large populations of patients has limited more detailed interrogation.
In this study we have examined the phenotypic impact of a series of
recently identified non-HLA disease associated single nucleotide
polymorphisms (SNPs) in a large population-based sample of patients
with detailed cross-sectional and longitudinal clinical data.
Methods: Genotypic information from 14 SNPs in 13 disease
associated genes were analysed from 1008 patients with MS followed
for a mean interval of 10.4 years. Primary outcome measures included time to disability milestones (EDSS 4.0, 6.0, 8.0) and secondary
progression, tested by survival analysis in Stata. Association between
SNPs and cross-sectional aspects of phenotype including age at onset,
S13
degree of recovery from first event and disease course were analysed
with chi squared tests on PLINK software and results corrected for
multiple testing using permutation analysis.
Results: No SNPs were associated with a systematic deflection in
time to disability milestones, disease progression, or age at onset.
rs12122721 (KIF21B) was associated with incomplete recovery of
first demyelinating event (OR = 1.28, p = 0.04), progressive disease
from onset (OR = 1.57, p = 0.04), and time to EDSS 8 (HR = 1.83,
p = 0.01). rs17824933 (CD6) was association with incomplete
recovery of first demyelinating event (OR = 1.41, p = 0.008) and
progressive disease from onset (OR = 1.79, p = 0.014). rs34536443
(TYK2) was associated with progressive disease from onset
(OR = 2.29, p = 0.007) and with time to EDSS 6 (HR = 1.56,
p = 0.02). rs4680534 (IL-12) was associated with progressive disease
from onset (OR = 1.49, p = 0.05).
Conclusions: This study suggests that individual non HLA genes
are unlikely to have a major systematic impact on long term disability. However, effects on specific elements of disease outcome
were observed. Further interrogation of more subtle phenotypic
effects in selected genes is required to determine whether these
observations can be replicated in larger alternate patient cohorts and/
or are population specific.
O186
Application of a rapid semi-automatic segmentation
method of the cervical cord for measuring longitudinal
atrophy in multiple sclerosis
M.A. Rocca, M.A. Horsfield, M. Copetti, S. Sala,
P. Valsasina, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT); University of Leicester
(Leicester, UK); Hospital Casa Sollievo della Sofferenza
(San Giovanni Rotondo, IT)
Objectives: In this longitudinal study, we compared the sensitivity of
a new semi-automatic method for segmenting the cervical cord from
C2 to C5 (the active surface [AS] method) to an existing cord segmentation method (the Losseff method) and a manual outlining
method when detecting cervical cord atrophy rate in MS patients and
its correlation with clinical worsening.
Methods: Brain and cervical cord MRI scans were obtained from 35
MS patients (12 relapsing-remitting [RR], 14 primary progressive [PP]
and 9 secondary progressive [SP]) and 9 healthy controls at baseline and
after a mean follow up of 2.3 years. Normalized cervical cord crosssectional area (CSAn) was measured using the three methods at baseline
and at follow up. Baseline and longitudinal between-group comparisons
were performed using hierarchical linear models.
Results: During the follow up, the Losseff method detected a 1%
increase of CSAn in healthy controls and 4% decrease in MS patients
(p = 0.02), the AS method detected a 2% decrease in healthy controls
and 5% decrease in MS patients (p = 0.2), and the manual outlining
method detected a 12% decrease in healthy controls and 6% decrease
in MS patients (p = 0.5). The three methods performed significantly
differently when applied to the various clinical phenotypes. In particular, no atrophy was detected in SPMS patients with the Losseff
method, while significant atrophy was found with the AS
(p = 0.0006) and manual outlining (p = 0.007) methods. Conversely,
no atrophy was detected in PPMS patients with the AS and manual
outlining methods, while significant atrophy was found with the
Losseff method (p = 0.003). No association between CSAn and
worsening disability was found with either method.
Conclusions: The AS method, which was shown to provide
reproducible measures of cord CSA in about 1–3 min, has been
proposed as an alternative to the Losseff technique in cross-sectional
studies. We found that, when applied in a longitudinal setting, the
sensitivity of this method might be different from that of the Losseff
method according to MS clinical phenotypes. Since the AS method
provides a quantification of atrophy along a large portion of the cord,
differences in subject repositioning over time, as well as an increased
susceptibility to age-related degenerative phenomena might help to
explain these results.
O187
Primary retinal pathology in neuromyelitis optica
detected by optical coherence tomography
N. Kim, H.J. Kim, W. Kim
Dongguk University Hospital (Goyang-si, KR);
National Cancer Center (Goyang-si, KR)
Background: Retinal changes in neuromyelitis optica (NMO) are
thought to result from degeneration secondary to massive inflammation of optic nerve resulting in marked thinning of the retinal nerve
fiber layer (RNFL) and macula. To date, in vivo quantitative analysis
of the deeper nuclear layers of the retina has not been reported in
NMO. Fovea area has no or sparse RNFL which enables to give
primary retinal pathologic status.
Objectives: To determine if NMO patients may have primary
retinal neuronal layer pathology in the absence of degeneration of the
RNFL, and to assess if such patients have distinguishing clinical
characteristics.
Methods: Retinal imaging was performed using optical coherence
tomography (OCT; model OCT3). Average fovea thickness (AFT),
macular volume (MV), and RNFL thickness (RNFLT) were measured
in the eyes without a history of optic neuritis. Visual evoked potential
(VEP), visual acuity (VA), and 2.5% contrast sensitivity (CS) were
determined in NMO subjects and age-matched healthy controls.
Results: 44 eyes of NMO without optic neuritis and 70 healthy
eyes were evaluated. RNFL showed no significant difference (105
microm in NMO patients and 108 microm in healthy controls). AFT
was significantly lower in NMO eyes (185 microm) compared to
healthy controls (205 microm, p \ 0.001). MV, VEP latency and
amplitude, and VA presented no significant difference. However, CS
(logMAR) was significantly decreased in NMO eyes (0.8 in NMO and
0.5 in healthy controls, p = 0.002).
Conclusions: CS has been known to be predictive for changes in
MS disability and sensitive test to distinguish MS and healthy eyes.
We have identified that a subset of NMO eyes without history of optic
neuritis presented primary retinal pathology with reduced CS. These
data suggest the possibility that there is a direct pathologic process in
retinal neurons in NMO before RNFL changes.
O188
Natalizumab binding to peripheral blood mononuclear
cells analysed by flow cytometry can be used
for monitoring treatment response in patients
with multiple sclerosis
A. Harrer, G. Pilz, M. Einhaeupl, K. Oppermann,
P. Wipfler, W. Hitzl, S. Afazel, E. Haschke-Becher,
E. Trinka, J. Kraus
Paracelsus Medical University (Salzburg, AT)
Objective: The therapeutic antibody natalizumab (TysabriTM) interferes with leukocyte transmigration into the central nervous system by
blocking the a-4 subunit of the heterodimeric very late activation
123
S14
antigen (VLA)-4 integrin. In former studies we observed surfacebound natalizumab (anti-human(hu)IgG4) correlating with diminished a-4 expression levels on PBMC during the first 6 months of
therapy. In this study we examined whether natalizumab binding to
peripheral blood mononuclear cells (PBMC) from patients with
relapsing remitting multiple sclerosis (RRMS) is informative on the
individual treatment response.
Methods: Quantitative surface levels of a-4 (anti-CD49d-FITC)
and natalizumab (anti-huIgG4-FITC) on T cells, B cells, natural killer
(NK) cells, and NKT cells from 8 RRMS patients were determined by
5-color flow cytometry (Beckman Coulter FC500). Samples were
collected at baseline (before start of therapy), and after 12, 24, 36, and
48 weeks before the subsequent natalizumab infusions.
Results: Analysis of mean relative fluorescence intensities (rfi) of
natalizumab binding from 7 patients showed a significant and sustained increase of anti-huIgG4 signals in the 12, 24, 36, and 48 week
measurements (p \ 0.007) on all lymphocyte subsets compared to
baseline levels. Detailed examination of individual data sets revealed
only slight variations and a decline of anti-IgG4 rfi after 24 and
36 weeks in 5 patients. Two patients showed additional peaks after 24
and 36 weeks which corresponded with clinical disease activity. A-4
expression levels were diminished at all time-points. In one patient
anti-huIgG4 signals did not exceed background levels until the
36 week measurement due to non-persisting neutralizing antibodies
(NAB).
Conclusion: Increased binding of natalizumab to immune cells
might result from variances in surface expression of VLA-4 and
possibly represents an early indication of underlying disease activity.
Low anti-natalizumab signals provide immediate and direct evidence
of NAB. Natalizumab binding to immune cells is a potential biomarker for the individual patients’ treatment response.
Supported by Biogen Idec, Austria.
O189
Ocrelizumab in relapsing-remitting multiple sclerosis:
72-week efficacy and safety results of a phase II,
randomised, placebo-controlled, multi-centre trial
L. Kappos, D. Li, P. Calabresi, P. O’Connor, A. Bar-Or,
F. Barkhof, M. Yin, D. Leppert, R. Glanzman, J. Tinbergen,
S. Hauser
University Hospital Basel (Basel, CH); University of British
Columbia (Vancouver, CA); Johns Hopkins University (Baltimore,
US); University of Toronto (Toronto, CA); Mc Gill University
(Montreal, CA); VU Medical Center (Amsterdam, NL); Genentech
Inc. (South San Francisco, US); F. Hoffmann-La Roche Ltd. (Basel,
CH); University of California San Francisco (San Francisco, US)
Objectives: B lymphocytes play an important role in MS pathogenesis. Anti-CD20 therapy has a positive effect on MRI and clinical
outcomes in RRMS. This trial evaluated the efficacy and safety of the
humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) in
patients with RRMS treated for 72 weeks.
Methods: 220 RRMS patients were randomized 1:1:1:1 to receive,
at Days 1 and 15, placebo (A), intravenous OCR at total doses of
600 mg (B), or 2000 mg (C), or weekly interferon-b 1a, 30 lg (D) in
Cycle 1 for 24 weeks. For Cycle 2 and 3 until Week 72, groups A, B,
and D received OCR 600 mg; group C received OCR 1,000 mg. A, B,
and C were double-blinded, whereas D was open-label.
Results: At Week 72, 191/220 (86.8%) patients were still enrolled
in the trial (A: 50 [92.6%], B: 49 [87.5%], C: 45 [81.8%], D: 47
[85.5%]). OCR effectiveness was well-maintained through Week 72
(ARR Cycle 1 = 0.125, Cycles 1–3 = 0.188 in B; 0.169 and 0.228 in
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C). Patients in A and D continued to show the improved low disease
activity in Cycle 3 after being switched to OCR for Cycle 2 (in A:
ARR = 0.636 Cycle 1 vs. 0.161 Cycle 2 and 0.184 Cycle 3; in D:
ARR = 0.364 Cycle 1 vs. 0.136 Cycle 2 and 0.20 Cycle 3). The
proportion of relapse-free patients by Week 72 (all 3 cycles considered) was 84% (B), and 82% (C) There were no imbalances in AEs
across groups. Serious AEs related to study treatment occurred in 0 %
(A), 2.0% (B), 2.2% (C), and 2.0% (D) of patients between Weeks
48–72. Serious infection events were similar among groups. No
opportunistic infections were reported. The incidence of infusionrelated events reduced in all subsequent infusions after initial higher
events for the first infusion of Cycle 1 and remained low in Cycle 3:
12.0% (A), 8.2% (B), 15.2% (C) and 10.2% (D). No withdrawals due
to adverse events were reported during Cycle 3.
Conclusion: OCR treatment resulted in an early and persistent
reduction of relapse rates with a manageable adverse event profile
through Week 72.
Supported by F. Hoffmann-La Roche Ltd. and Biogen Idec.
___________________________________
Oral session 3
Muscle disorders
O190
A retrospective study of the treatment of slow channel
congenital myasthenic syndromes
A. Chaouch, J.S. Muller, U. Schara,
V. Rakocevic-Stojanovic, C. Lindberg, R.H. Scola,
J. Colomer, J.J. Vilchez, N. Muelas, Z. Argov,
H. Lochmuller
Institute of Human Genetics (Newcastle Upon Tyne, UK); University
of Essen (Essen, DE); University Clinical Centre (Belgrade, RS);
Sahlgrenska University Hospital (Göteborg, SE); Federal University
Parana (Curitiba, BR); Hospital Sant Joan de Déu (Barcelona, ES);
University Hospital La Fe (Valencia, ES); Hadassah-Hebrew
University Medical Centre (Jerusalem, IL)
Background and objectives: Congenital myasthenic syndromes
(CMS) are a heterogeneous group of inherited neuromuscular disorders in which the safety margin of neuromuscular transmission is
compromised. Slow channel CMS are a very rare form of CMS that
arise from mutations in the postsynaptic acetylcholine receptors
(AChR) causing distinct kinetic ‘‘gain of function’’ abnormalities in
the receptor. Slow channel CMS are typically dominant in inheritance
and can involve any of the AChR subunits. In spite of clear clinical
heterogeneity, the neck muscles and the long finger and wrist extensors seem to be preferentially weaker in these patients. In contrast
to other forms of CMS, conventional treatment with anticholinesterases can worsen symptoms and open channel blockers such as
fluoxetine and quinidine are recommended. This study was carried out
to provide further clinical insight into this very rare subgroup of CMS
patients with a particular focus on response to therapy.
Method and patients: We carried out a small retrospective clinical
follow up study of 11 slow channel CMS patients referred to the
Munich CMS Centre. Detailed clinical data were collected by clinicians involved in the care of each patient, with a particular focus on
response and tolerability to recommended therapy.
Results: Our preliminary results support previous reported findings
in terms of clinical features as well as the poor response to
S15
pyridostigmine. We were interested to note that although treatment
with fluoxetine was beneficial, a number of our patients suffered
significant adverse effects that hindered optimum dose titration or led
to treatment cessation. Patients receiving quinidine seem to tolerate
this treatment better.
Conclusion: Slow channel CMS are a rare category of CMS with
distinct clinical and neurophysiological features. Establishing the
underlying genetic diagnosis is essential in selecting the correct
treatment. In contrast to other published series, our study suggests that
fluoxetine can be associated with significant side effects thus reducing
treatment effectiveness.
O191
Histopathological and transcriptional characterisation
of inflammatory features in facioscapulohumeral
muscular dystrophy muscles
G. Tasca, M. Pescatori, M. Mirabella, M. Monforte,
T. Cubeddu, E. Iannaccone, R. Frusciante, E. Ricci
Catholic University (Rome, IT); Porto Conte Ricerche Srl (Alghero, IT)
Objectives: Facioscapulohumeral muscular dystrophy (FSHD) is a
hereditary myopathy in which the occurrence of inflammatory changes
can be observed in diagnostic muscle biopsies. Indeed, in FSHD patients,
lower limb muscle magnetic resonance imaging (MRI) detects focal
areas of signal hyperintensity on T2-short tau inversion recovery (T2STIR) sequences, commonly supposed to account for muscle inflammation/edema. T2-STIR hyperintensities can be observed in muscles that
do not show signs of fatty-fibrous replacement, as judged by their normal
T1-weighted (T1-W) sequences appearance. To characterize the changes
associated with muscle T2-STIR hyperintensity in FSHD patients, we
studied the histopathology and performed genome-wide transcriptome
analysis on bioptic samples from muscles showing hyperintense T2STIR but normal T1-W sequences.
Methods: Biopsies were obtained from muscles with different MRI
pattern (T1-W normal/T2-STIR normal and T1-W normal/T2-STIR
hyperintense). Immunohistochemical study, expression profiling and real
time PCR were performed. Results: inflammatory alterations are a
common finding in T2-STIR hyperintense muscles. Immunocharacterization of the inflammatory infiltrates confirms earlier findings described
in the literature (predominance of CD8+ cells in endomysial infiltrates
and of CD4+ cells in perivascular infiltrates). T2-STIR positive FSHD
muscle shows a transcriptional pattern clearly distinct from T2-STIR
negative muscle. Additionally, comparison of T2-STIR positive FSHD
muscles with muscles from inflammatory myopathies or other muscular
dystrophies showed the presence of peculiar changes, although many
alterations were common across conditions.
Conclusion: Our data support the evidence of a selective, multifocal inflammatory process that may play an active role in FSHD
disease progression at the single muscle level.
O192
Muscle histopathology in a large cohort of 65 Italian
DM2 patients: diagnostic role and pitfalls
of ribonuclear inclusions
G. Meola, E. Bugiardini, L.V. Renna, R. Cardani
University of Milan (San Donato Milanese, IT);
University of Milan (Milan, IT)
Objectives: Myotonic dystrophy type 2 (DM2) is an autosomal
dominant multisystemic disorder caused by a CCTG expansion in
intron 1 of the ZNF9 gene. The mutant transcripts aggregate in
multiple ribonuclear inclusions (RNIs), which interact with RNA
binding proteins, as muscleblind-like protein 1 (MBNL1). The
nuclear sequestration of MBNL1 appears to be involved in splicing
defects of genes directly related to the DM phenotypes. Muscle histopathology from DM2 patients shows type 2 nuclear clumps and
preferential type 2 fibre atrophy suggesting that DM2 is a disease of
type 2 myofibre. Recently, detection of RNIs in DM2 muscle biopsy
by fluorescence in situ hybridization (FISH) has been proved to be a
useful method for routine DM2 diagnosis. However FISH sensitivity
has not yet been evaluated and the small-sized CCUG expansions
detectable by this technique are still unknown. Moreover we cannot
exclude the existence of a DM2-linked myopathy in which RNIs are
not present. The objective of this work is to revaluate the diagnostic
role and pitfalls of RNIs in DM2 pathology and to emphasize the
diagnostic role of muscle biopsy.
Methods: Routine histological/histochemical stainings, immunohistochemistry against fast or slow myosin heavy chain and FISH
with (CAGG) 5-probe in combination with MBNL1-immunofluorescence have been performed on muscle biopsy from 65 Italian DM2
patients.
Results: Increased fibre size variation, central nucleation and
nuclear clumps are present in almost all DM2 patients. Immunostaining for fast and slow myosin confirms preferential type 2 fiber
atrophy. Moreover central nucleation affects selectively fast positive
fibres (type 2) and the majority of the nuclear clumps are of type 2
fibres. FISH in combination with MBNL1-immunofluorescence
demonstrates the presence of nuclear foci of CCUG-containing RNA
co-localizing with foci of MBNL1 in all samples examined.
Conclusions: Our findings demonstrate that muscle biopsy may
show specific histopathological findings consistent with DM2 even
when symptoms and signs are minimal. Therefore, since FISH technique could not detect the small-sized CCUG expansions a DM2
diagnosis may not be excluded when RNIs are not present in
myonuclei but muscle histopathological features are evocative for
DM2. Thus we suggest that routine histological/histochemical
investigations and FISH analysis should be supported by immunohistochemistry against fast and slow myosin in DM2 diagnosis.
O193
Auditory system involvement study in 20 patients
with late-onset Pompe disease
O. Musumeci, N. Catalano, E. Barca, S. Ravaglia,
G. Gangemi, A. Fiumara, G. Sorge, B. Galletti, F. Galletti,
A. Toscano
University of Messina (Messina, IT); University of Pavia (Pavia, IT);
University of Catania (Catania, IT)
Objectives: Glycogen storage disease type II (GSD II), also known as
Pompe disease, is an autosomal recessive inherited disorder, caused
by a reduced activity of the acid maltase. Two different clinical forms
have been described: a rapidly fatal infantile form with and a late
onset form. Hearing loss has been described in classic infantile Pompe
patients (Van Capelle C. et al. 2010) but, so far, no extensive studies
have been performed in the late onset form. The main purpose of this
study was to investigate the possible involvement of the auditory
system in a cohort of patients with the late onset GSD II.
Methods: We have enrolled 20 patients with late onset GSD II, 12
males and 8 females. The age range was from 8 to 74 years (mean
value 45). Acid maltase residual activity ranged from 0.5 to 35%. The
auditory system assessment included vocal and pure tone audiometry,
transient evoked oto-acoustic emissions (TEOAE), impedenziometry
and auditory brainstem responses (ABR). A combined interpretation
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of those tests let us to define the origin of the hearing deficit (conductive, cochlear or retro-cochlear). Traumatic, inflammatory,
iatrogenic and otosurgical causes have been excluded.
Results: From the clinical point of view, all but one, patients
denied subjective hearing disturbances. On the other hand, audiological evaluation revealed that 11/20 patients (55%) had an hearing
impairment. Among them, 3 pts showed a conductive hearing loss,
while 7 pts had a sensorineural hearing deficit (5 pts with a cochlear
dysfunction and 2 pts with a retro-cochlear pathology) and just one
had a mixed pattern.
Conclusions: Our observations revealed that, in this group of late
onset Pompe patients, the auditory impairment is often present with a
more prominent involvement of the cochlear compartment. These data
seems to be in agreement with the studies, performed in GAA knockout
mice, where a glycogen storage has been demonstrated in the inner and
outer hairy cells of cochlea and spiral ganglion cells (Kamphoven J et al.
2004). These data emphasize the importance of monitoring the auditory
function in all patients with Pompe disease.
O194
Clinical findings in patients with exercise intolerance
with and without signs of mitochondrial dysfunction
E.H. Carvalho, W. Marques, A.A. Barreira, L.N. Serafini,
C.F. Sobreira
University of Ribeirão Preto (Ribeirão Preto, BR)
Exercise intolerance is a nonspecific term used to describe precocious
fatigue, myalgia and/or cramping as a consequence of muscular
exertion. Although it’s a common complaint, a specific etiologic
diagnosis is rarely achieved, even after comprehensive investigation.
Objective: To describe clinical and laboratorial findings in patients
with exercise intolerance as the main symptom of a myopathy,
comparing patients with and without signs of mitochondrial
dysfunction.
Patients and methods: 107 patients with exercise intolerance as the
main symptom of a myopathy were evaluated prospectively. They
were divided into two groups (with and without laboratorial signs of
mitochondrial dysfunction—elevated serum lactate after effort above
2.5 times the upper normal limit and muscle biopsy with ragged red
fibers and/or cytochrome c oxidase negative fibers). Clinical picture,
laboratorial and histoenzymological findings were recorded. Patients
with exercise intolerance were considered to have a myopathy when
presenting elevated serum CK, myopathic motor unit potentials at
ENMG, and/or myopathic changes at muscle biopsy.
Results: 67 patients presented signs of mitochondrial dysfunction
(26 men/41 women: group I); 40 did not present mitochondrial dysfunction (29 men/11 women: group II). Mean age at onset was
30.6 years (group I) and 25.9 years (group II). Twenty nine patients
showed Mendellian inheritance: AD- 10 patients (group I) and 4
patients (group II); AR- 14 patients (group I) and 1 patient (group II).
Five patients showed maternal inheritance (group I). There was a
higher occurrence of epilepsy, deafness and heart conduction disturbances in group I and of cramps, myoedema and hyperuricemia in
group II. Post exercise serum lactate levels were elevated in 57 of
group I and the highest levels were seen in 7 patients (above 5 times
the upper limit). Electroneuromyography showed myopathic changes
in 22 patients of group I and in 19 patients of group II. In group I,
muscle biopsy showed ragged red fibers in 23 patients and cytochrome c oxidase negative fibers in 37 patients.
Conclusion: Laboratorial signs of mitochondrial dysfunction are
common in patients with exercise intolerance and laboratorial evidence of a myopathy. Although exercise intolerance is a non-specific
symptom, clinical findings indicating multisystem disease are more
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common in the group showing mitochondrial dysfunction, whereas
cramps and myoedema were less frequent in this group of patients.
O195
A salbutamol responsive myopathy
A. Fitzpatrick, R. Walsh, O. Hardiman, J. McConville
Royal Victoria Hospital (Belfast, UK); Beaumont Hospital
(Dublin, IE); Trinity College (Dublin, IE);
Ulster Hospital Dundonlad (Belfast, UK)
Background: Reversibility of weakness is rare in inherited muscle
disease and suggests a channelopathy as the underlying pathology.
Improvement in muscle strength after treatment with b-adrenergic
agonists has been documented in hyperkalaemic periodic paralysis
and only very recently in the congenital myasthenic syndromes. The
exact mechanism of action is not understood.
Case description: Case A, the second youngest of 10 siblings from a
non-consanguineous Irish kindred, presented at the age of 46 years with
mild limb-girdle muscle weakness with no other symptoms and no
demonstrable fatiguability. Three siblings were similarly affected (2/3
were examined, 1/3 died before examination from unrelated causes).
Case B and C reported first symptoms aged 62 and 45 respectively. All 3
remained independently mobile with a waddling gait after follow up of
between 11 and 25 years from first symptoms. Case A reported marked
improvement in function after a short course of inhaled Salbutamol
prescribed by his GP. On oral Salbutamol treatment limb-girdle strength
returned to MRC grade 5, but deteriorated to MRC grade 4 when treatment was stopped. The other siblings showed similar response.
Results: Initial investigation of cases A and B revealed slightly elevated creatinine kinase (CK 307, CK 283) and some fibre atrophy and
type II predominance on muscle biopsy. Case B showed 16% decrement
on repetitive nerve stimulation but the others had no abnormality on
neurophysiological examination. Homozygous c.1143dupC mutations in
exon of the DOK7 gene were found in all three affected cases confirming
a Dok-7 congenital myasthenic syndrome.
Discussion: The Dok-7 CMS phenotype is that of a predominantly limbgirdle muscle weakness and a characteristic waddling gait; fatiguability may
be very subtle and so these cases may be mistaken for congenital myopathy.
The serendipitous prescription of Salbutamol was the clue to a myasthenic
pathology in this kindred. Dok-7 CMS has been reported with adult onset but
62 years is the latest reported age at onset to date.
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Oral session 4
Dementia: clinical and neuro-imaging
O196
White matter damage in frontotemporal lobar
degeneration spectrum
M. Filippi, F. Agosta, E. Scola, E. Canu, A. Marcone,
G. Magnani, L. Sarro, M. Copetti, F. Caso, C. Cerami,
G. Comi, S. Cappa, A. Falini
University Hospital San Raffaele (Milan, IT); San Raffaele Turro
Hospital (Milan, IT); Hospital Casa Sollievo della Sofferenza (San
Giovanni Rotondo, IT)
Objectives: To assess white matter (WM) damage in patients with a
clinical diagnosis of the behavioural variant frontotemporal dementia
S17
(bvFTD) and the three primary progressive aphasia (PPA) variants,
and to compare these results with the corresponding brain atrophy
patterns.
Methods: Diffusion tensor (DT) and T1-weighted MR images
were obtained from 13 bvFTD and 20 PPA (9 nonfluent/agrammatic,
7 semantic, and 4 logopenic) patients. Tract-based spatial statistics
was applied to investigate brain WM damage in a voxel-by-voxel
analysis. DT MRI metrics were also measured in ‘‘critical’’ WM
tracts. Grey matter (GM) and WM atrophy was assessed using voxelbased morphometry.
Results: Patients with bvFTD showed a widespread pattern of DT
MRI abnormalities affecting most of the WM, bilaterally. In PPA
patients, WM damage was more focal and varied across the three syndromes: a predominant left fronto-temporo-parietal damage was seen in
nonfluent, a predominant left frontotemporal injury in semantic, and a
selective left frontoparietal involvement in logopenic patients. In each
syndrome, DT MRI changes extended beyond the topography of GM
loss. Left uncinate damage was the best predictor of patient diagnosis in
each group, followed by the involvement of anterior corpus callosum in
bvFTD, left superior longitudinal fasciculus in nonfluent, and left inferior
longitudinal fasciculus in semantic patients.
Conclusions: This study provides insight into the similarities and
differences of WM damage in bvFTD and PPA variants. DT MRI metrics
hold promise to serve as early markers of WM integrity loss that only at a
later stage may be detectable by volumetric measures, and contribute to
the diagnostic work-up of frontotemporal lobar degeneration syndromes.
O197
Recollection and familiarity processes in probable
Alzheimer’s disease: an fMRI study
S. Genon, E. Salmon, F. Collette, C. Bastin
University of Liège (Liège, BE)
Alzheimer’s disease (AD) is characterised by deficits of recollection,
with relatively preserved familiarity. Neural correlates of recollection
and familiarity differ, with recollection recruiting additional brain
regions in prefrontal, medial temporal, posterior cingulate and inferior
parietal cortices by comparison to familiarity. However, little is
known about the brain regions underlying recollection and familiarity
in AD. Therefore, the present study sought to measure directly
cerebral activity associated to recollection and familiarity in AD
patients and in healthy elderly controls by isolating the processes via
the process-dissociation procedure (PDP).
Cerebral activity associated with recollection and familiarity of
words pairs in 28 patients with Alzheimer’s disease (AD) and 17
healthy controls (HC) was directly measured in an event-related fMRI
experiment during performance of a recognition memory task with
the PDP. This procedure included a condition in which recollection
and familiarity may be engaged (inclusion condition: intact pairs) and
a condition in which recollection opposed familiarity (exclusion
condition: rearranged pairs), allowing to isolate the contribution of the
two processes to performance. Brain regions associated to recollection were evidenced by contrasting activations for inclusion and
exclusion conditions whereas brain regions related to familiarity were
explored with the mean effect of the two conditions. Preprocessing
and statistical analyses were performed with SPM8 (p \ 0.05 corrected for multiple comparisons).
Twelve patients had null recollection estimates (AD-), whereas
16 patients did experience some recollection although significantly
less than controls (AD+). In AD+ and controls, recollection activated
the posterior cingulate cortex (PCC). In contrast, familiarity estimates
were equivalent in the 3 groups and were associated with brain
activations around the intraparietal sulcus (IPS).
In AD patients, recollection was severely impaired but not
familiarity. Familiarity processes engaged a brain region around IPS
both in AD and HC as shown in previous fMRI studies in healthy
adults. Recollection process was supported by PCC in AD with
residual recollection process and in HC. This result suggests that AD
patients’ controlled memory deficit is related to PCC alterations. The
PCC might mediate successful and controlled comparison of current
information with episodic memories.
O198
Episodic autobiographical memory in amnestic mild
cognitive impairment: a FDG-PET study
C. Bastin, D. Feyers, H. Jedidi, M. Bahri, C. Degueldre,
C. Lemaire, F. Collette, E. Salmon
University of Liège (Liège, BE)
Objectives: Autobiographical memory in amnestic Mild Cognitive
Impairment (aMCI) is characterized by impaired retrieval of episodic
memories, but relatively preserved personal semantic knowledge. The
current study aimed at identifying the neural substrates of impaired
episodic specificity of autobiographical memories in aMCI.
Methods: Forty aMCI patients and 24 healthy elderly controls
reported memories for personally experienced events from early
adulthood and the last year. The total number of episodic and
semantic details was measured for each period. Each participant also
underwent an FDG-PET scan.
Results: Significant correlations between regional cerebral activity
and the proportion of episodic details in autobiographical memories
from two life periods were found in specific regions of an autobiographical brain network. The clusters of correlations were always
wider in aMCI than in control participants. In aMCI patients more
than in controls, specifically-episodic memories from early adulthood
were associated with relative metabolic activity in the cuneus and in
parietal regions. For recent memories (last year), a correlation
emerged between the proportion of episodic details and activity in
lateral temporal regions and the temporo-parietal junction.
Conclusion: We hypothesize that variable retrieval of remote episodic autobiographical memory in our aMCI patients is related to their
variable capacity to reactivate specific sensory-perceptual and contextual details of early adulthood events linked to reduced (occipitoparietal) visual imagery and less efficient (parietal) attentional processes. Accordingly, variable episodic memory for recent events may
be related to inefficient controlled search through general events
susceptible to provide cues for the retrieval of episodic details and to
difficulties in establishing a self perspective favouring recollection.
O199
Ventral and dorsal visual streams in posterior cortical
atrophy
R. Migliaccio, F. Agosta, E. Scola, G. Magnani, S. Cappa,
E. Pagani, G. Comi, A. Falini, P. Bartolomeo, M. Filippi
University Hospital San Raffaele (Milan, IT); San Raffaele Turro
Hospital (Milan, IT); Hospital de la Salpêtrière (Paris, FR)
Objectives: Posterior cortical atrophy (PCA) is characterized by a
progressive cognitive impairment involving visual and visuo-motor
functions. Recently, a classification of PCA into dorsal and ventral
subtypes has been suggested. The ventral subtype is mostly characterized by visual agnosia, prosopagnosia, achromatopsia, and alexia,
while the dorsal subtype is associated with optic ataxia and apraxia,
123
S18
neglect, and agraphia. Our aim was to explore the brain pathways
underlying cognitive deficits in PCA, using diffusion tensor (DT)
MRI tractography.
Methods: Seven PCA patients and 13 age- and sex-matched healthy
controls were studied. Bilateral inferior longitudinal (ILF), inferior
fronto-occipital (IFOF), arcuate, and fronto-parietal superior longitudinal (SLF) fasciculi were tracked. The corpus callosum (CC) and
cortico-spinal tracts (CST) were also studied. From each tract, mean
diffusivity (MD), fractional anisotropy (FA), as well as parallel and
transverse diffusivities were obtained. Grey (GM) and white (WM)
matter atrophy patterns were assessed using voxel-based morphometry.
Results: PCA patients showed a clinical syndrome primarily characterized by visual object agnosia and prosopagnosia. Compared with
controls, they had significantly higher MD, parallel diffusivity, and
transverse diffusivity; and lower FA in the left ILF and IFOF. In addition,
the right ILF had significantly higher MD and transverse diffusivity; and
lower FA, the right IFOF had higher MD and transverse diffusivity, and
the CC higher MD. The fronto-parietal SLF, arcuate fasciculus, and CST
were spared bilaterally. PCA patients also had GM atrophy in posterior
temporal, inferior parietal and occipital regions bilaterally, and WM
atrophy in the ventral occipito-temporal region, bilaterally.
Conclusions: PCA patients in the present series harbor a prevalent
damage to the ventral WM pathways of both hemispheres, with relative sparing of dorsal fronto-parietal connections. These results
contribute to the definition of a more complete picture of the anatomical changes that occur in PCA in term of involved pathologic
networks, and shed light onto the cognitive deficits and the different
phenotypes of the syndrome.
Dr. Migliaccio received an ENS Fellowship grant.
O200
The fornix in ageing and memory decline:
a diffusion MRI tractography study
C. Metzler-Baddeley, D. Jones, J. Aggleton, M. O’Sullivan
Cardiff University (Cardiff, UK)
Objective: Memory decline is a major affliction of ageing. The fornix
is the main white matter output tract of the hippocampus, and a
critical structure for memory. Alterations in the fornix could be
secondary to hippocampal damage or could result directly from factors know to affect white matter microstructure including
cerebrovascular risk factors and healthy ageing.
Methods: 46 asymptomatic individuals, aged 53–93, were recruited from a panel of volunteers and local medical practices. Diffusion
tensor MRI (DTI) was performed on a 3T GE HDx system with an
optimised 30 direction gradient vector scheme. 3D reconstructions of
the fornix were made using spherical harmonic deconvolution and a
novel method to correct for partial volume error through atrophy.
Tractography of the uncinate fasciculus and parahippocampal cingulum, was also performed. Deterministic tractography (implemented
in ExploreDTI) was performed using landmarking techniques shown
to be highly reproducible for these tracts. Tract-specific measures of
fractional anisotropy (FA) and mean diffusivity were generated.
Episodic memory was assessed using the Free and Cued Selective
Reminding Test (FCSRT) (Buschke and Grober) and Doors and
People Test. A battery of tests of attention, working memory and
general intelligence were also employed.
Results: Age correlated with FA of the fornix, uncinate and
parahippocampal cingulum. FA of the fornix correlated with measures of free and delayed recall (free recall, r = 0.566, p B 0.001 and
the FCSRT total recall, r = 0.487, p B 0.002). Fornix FA also correlated with memory independent of age. A multivariate model
including both age and fornix FA accounted for twice as much of the
variance in visual recall as age alone.
123
Conclusions: Age-related decline in memory performance is mediated by changes in fornix microstructure. The relationship between
fornix FA and memory independent of age suggests that other factors
such as genetic factors, vascular risk and subclinical onset of disease
may have an effect on fornix microstructure and memory.
O201
Cognitive rehabilitation and functional brain activity
in multiple sclerosis
M.A. Rocca, G. Riccitelli, F. Mattioli, R. Capra,
C. Stampatori, E. Pagani, P. Valsasina, M. Copetti,
A. Falini, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT); Civil Hospital
of Brescia (Brescia, IT); Multiple Sclerosis Centre (Brescia, IT);
Hospital Casa Sollievo della Sofferenza (San Giovanni Rotondo, IT)
Objectives: Cognitive impairment affects a large proportion of multiple
sclerosis (MS) patients and has a profound impact on their daily-life
activities. We used structural and functional (f) magnetic resonance
imaging (MRI) techniques to assess brain changes following cognitive
rehabilitation in clinically stable, relapsing remitting (RR) MS patients.
Methods: RRMS patients with an Expanded Disability Status Scale
(EDSS) score \4 and selective deficits at the Paced Auditory Serial
Addition Test and Wisconsin Card Sorting Test were assigned randomly to
treatment (TG) or to serve as a control (CG) group. All patients underwent
a standardized neuropsychological assessment and MRI acquisition (dualecho, 3D T1-weighted, diffusion tensor MRI, and fMRI during the performance of the Stroop task and at rest) at baseline and after 12 weeks.
During this period, TG patients underwent intensive computer-assisted
cognitive rehabilitation of attention/information processing and executive
functions. Structural changes of gray matter (GM) volumes and normalappearing white matter (NAWM) architecture at follow up were assessed.
Longitudinal changes of functional activity were also investigated.
Results: Ten patients were randomized to each group. At baseline,
age, disease duration, EDSS, neuropsychological performance, T2
lesion volume and normalized brain volume did not differ between
the study groups. After rehabilitation, the TG showed a significant
improvement at tests of attention/information processing and executive functions. No structural changes to the GM and NAWM were
detected at follow up. FMRI analysis disclosed treatment-related
modifications of the activity of the anterior cingulum, posterior cingulum/precuneus, left dorsolateral prefrontal cortex, and right inferior
parietal lobule. In TG, fMRI changes were correlated with cognitive
improvement (r ranging from -0.88 to 0.88, p \ 0.05).
Conclusions: Rehabilitation of attention/information processing
and executive functions in RRMS is effective possibly through a
selective enhanced recruitment of brain networks specifically
involved in the trained functions.
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Oral session 5
Experimental stroke
O202
The functional role of sialoadhesin, a macrophagerestricted adhesion molecule, in experimental stroke
N. Heydenreich, C. Kleinschnitz, G. Stoll
University of Würzburg (Würzburg, DE)
S19
Background: Ischemic stroke induces a profound local inflammatory
response, involving various types of immune cells. While T cell
deficiency protects from ischemic stroke in the transient middle
cerebral artery occlusion (tMCAO) model (Kleinschnitz et al., 2010,
Blood 115:3835–42), the role of macrophages that infiltrate the
lesions is less clear.
Sialoadhesin (Sn), a cell adhesion molecule, belongs to the group
of sialic acid-binding immunoglobulin-like lectins and is only
expressed in macrophage-like cells (Crocker et al., 1994, EMBO J.
13:4490–4503). Sn-deficient mice are protected from inflammatory
tissue damage in experimental autoimmune uveoretinitis and inherited demyelination in the central nervous system (Ip et al., 2007,
Neurobiol Dis. 25:105–11).
Objectives: To analyze the effect of Sn deficiency in macrophages
on infarct size and neurological outcome in mice after tMCAO.
Methods: Focal cerebral ischemia was induced in mouse mutants
homozygously deficient for Sn and corresponding wildtype littermates by 1 hour of tMCAO. In a first set of experiments infarct size
was compared by 2,3,5-triphenyltetrazolium chloride staining at day 1
after tMCAO. Global neurological function was assessed by the Bederson score and motor deficits by the grip test. In a second
experiment cranial magnetic resonance imaging (MRI) using T2-w
images on a 1.5T MR scanner was performed to follow delayed
infarct development between day 1 and 3 after tMCAO.
Results: Sn null mice developed brain infarctions of roughly the
same size (84.48 ± 15.58 mm3 vs. 102.44 ± 28.06 mm3, respectively; p = 0.09) as wildtype littermates at day 1 after tMCAO.
Surprisingly, Bederson scores (1.9 ± 1.2 vs. 3.5 ± 0.8, respectively;
p \ 0.01) and motor-function (4.2 ± 0.8 vs. 2.5 ± 1.8, respectively;
p \ 0.05) had improved in Sn null mice at day 1. Moreover, no
further increase in infarct volumes was seen between day 1 and 3 in
the Sn knockout group.
Conclusion: Our data provide evidence that sialoadhesin-deficiency in macrophages/microglia ameliorates functional outcome in
the tMCAO model of stroke. Surprisingly, this was not due to reduced
primary stroke volumes, but points to a pathophysiological role of
macrophages/microglia in secondary tissue remodelling. The underlying molecular mechanisms await further clarification.
Supported by the DFG/SFB 688 B1.
O203
Thrombin-activatable fibrinolysis inhibitor deficient
mice are susceptible to intracerebral thrombosis
and ischaemic stroke
P. Kraft, T. Schwarz, J.C. Meijers, G. Stoll, C. Kleinschnitz
University of Würzburg (Würzburg, DE); University of Amsterdam
(Amsterdam, NL)
Objectives: Thrombus formation is a key step in the pathophysiology
of acute ischemic stroke and results from the activation of the
coagulation cascade. Thrombin plays a central role in this coagulation
system and contributes to thrombus stability via activation of
thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI
levels are a risk factor for thrombotic events including ischemic
stroke. Although substantial in vitro data on the influence of TAFI on
the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia
are still lacking. In the present study we analyzed stroke development
and post stroke functional outcome in TAFI-/- mice.
Methods: TAFI-/- mice and wild-type controls were subjected to
60 min transient middle cerebral artery occlusion (tMCAO) using the
intraluminal filament method. After 24 h, functional outcome scores
were assessed and infarct volumes were measured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin
and eosin (H&E) staining was used to estimate the extent of neuronal
cell damage. Thrombus formation within the infarcted brain areas was
analyzed by immunoblot.
Results: Infarct volumes and functional outcomes did not significantly differ between TAFI-/- mice and controls (p [ 0.05).
Histology revealed extensive ischemic neuronal damage regularly
including the cortex and the basal ganglia in both groups. TAFI
deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO.
Conclusion: Our study shows that TAFI does not play a major role
for thrombus formation and neuronal degeneration after ischemic
brain challenge.
Supported by Deutsche Forschungsgemeinschaft SFB 688 (TP B1
to GS and A13 to CK).
O204
Deficiency of vasodilator-stimulated phosphoprotein
increases blood-brain-barrier damage and oedema
formation after ischaemic stroke in mice
P. Kraft, P.M. Benz, M. Austinat, M.E. Brede,
K. Schuh, U. Walter, G. Stoll, C. Kleinschnitz
University of Würzburg (Würzburg, DE)
Objectives: Stroke-induced brain edema formation is a frequent cause
of secondary infarct growth and deterioration of neurological function. The molecular mechanisms underlying edema formation after
stroke are largely unknown. Vasodilator-stimulated phosphoprotein
(VASP) is an important regulator of actin dynamics and stabilizes
endothelial barriers through interaction with cell-cell contacts and
focal adhesion sites. Hypoxia has been shown to foster vascular
leakage by downregulation of VASP in vitro but the significance of
VASP for regulating vascular permeability in the hypoxic brain in
vivo awaits clarification.
Methods: Focal cerebral ischemia was induced in Vasp(-/-)
mice and wild-type (WT) littermates by transient middle cerebral
artery occlusion (tMCAO). Evan’s Blue tracer was applied to
visualize the extent of blood-brain-barrier (BBB) damage. Brain
edema formation and infarct volumes were calculated from 2,3,5triphenyltetrazolium chloride (TTC)-stained brain slices. Both
mouse groups were carefully controlled for anatomical and physiological parameters relevant for edema formation and stroke
outcome.
Results: BBB damage (p \ 0.05) and edema volumes
(1.7 ± 0.5 mm2 vs. 0.8 ± 0.4 mm2; p \ 0.0001) were significantly
enhanced in Vasp(-/-) mice compared to controls on day 1 after
tMCAO. This was accompanied by a significant increase in infarct
size (56.1 ± 17.3 mm2 vs. 39.3 ± 10.7 mm2, respectively; p \ 0.01)
and a non significant trend (p [ 0.05) towards worse neurological
outcomes.
Conclusion: Our study identifies VASP as critical regulator of
BBB maintenance during acute ischemic stroke. Therapeutic modulation of VASP or VASP-dependent signalling pathways could
become a novel strategy to combat excessive edema formation in
ischemic brain damage.
Supported by Deutsche Forschungsgemeinschaft (DFG), Bonn,
Germany, SFB 688, TP A2 (to UW), A13 (to CK), and B1 (to GS)
and Wilhelm Sander-Stiftung, Munich, Germany (2009.017.1 to
CK).
123
S20
O205
Sleep disturbance impairs stroke recovery in the rat
C. Zunzunegui, B. Gao, E. Cam, A. Hodor, C. Bassetti
Neurocenter of Southern Switzerland (Lugano, CH);
University Hospital of Zurich (Zurich, CH)
Introduction: There is lack of experimental evidence supporting the
hypothesis that sleep may modulate stroke outcome as suggested by
clinical observations. We have previously shown that sleep disturbance (SDis) over 3 days aggravates brain damage in a rat model of
focal cerebral ischemia. The aim of this study is to further investigate
effects of SDis on long term stroke recovery and neuroplasticity as
assessed by neural repairing axonal sprouting, neurogenesis and
angiogenesis. Design: 12 h after initiation of focal cerebral ischemia
(ischm) by permanent occlusion of the distal branches of Middle
Cerebral Artery (MCA), SDis was performed over 3 consecutive days
by deprivation of 80% sleep during the 12-h light phase. Control
groups included ischemia without SDis (ischm/nSDis), sham/SDis
and sham/nSDis. The single pellet reaching test (SPR) was used for
assessing sensorimotor function. Axonal sprouting was assessed by
anterograde tracing with biotinylated dextran amine (BDA), neurogenesis/angiogenesis was by bromodeoxyuridine (BrdU) labelling
along with cell-type markers. Results: After MCAo the SPR performance dropped to 4 % of baseline (100%). At day 35 the recovery in
the ischm/SDis group was less than 50% whereas in the ischm/nSDis
group was almost complete. Repeated measures ANOVA indicated a
significant difference (p = 0.001) in group 9 time interaction (F (12,
101) = 11). Independent t tests showed significant difference at day
14 (ischm/nSDis 45% ± 17 vs./SDis 19% ± 25, p = 0.031), 21 (ischm/nSDis 55% ± 26 vs./SDis 21% ± 21, p = 0.008), 28 (ischm/
nSDis 50% ± 24 vs. /SDis 25% ± 24, p = 0.045) and 35 (ischm/
nSDis 71% ± 30 vs./SDis 38% ± 34, p = 0.052). There was significant increase (p = 0.035) in the damage area in the ischm/SDis
group (18% ± 4.3) compared with the ischm/nSDis group
(11% ± 4.5). The BDA stained area in the injured motor cortex and
striatum was significantly smaller in the ischm/SDis than in the ischm/nSDis group. Furthermore there was significant decrease in the
number of BrdU positive cells in the peri-infarct area in the ischm/
SDis group compared with the ischm/nSDis group. Double staining
showed that in both groups about 70% of BrdU stained cells were
associated with a neuronal marker (NeuN) and about 30% with the
endothelial marker Von Willebrand factor.Conclusion: SDis has
detrimental effects on functional and morphological/structural outcomes after stroke, suggesting a role of sleep in the modulation of
brain injury-associated neuroplasticity.
O206
Anti-Aquaporin-4 antibodies increase vasogenic
and cytotoxic oedema formation and infarct size
in a rat stroke model
T. Braun, S. Doenges, M. Nedelmann, C. Mueller,
G. Bachmann, F. Blaes, T. Walther, T. Gerriets,
M. Tschernatsch
Justus-Liebig University (Giessen, DE)
Objectives: Anti-aquaporin-4-immunoglobulins (anti-AQ4-Ig) are
markers for Neuromyelitis optica (NMO; Devic0 s Syndrome).
Knowledge of the biological function of anti-AQ4-Ig, however, is
sparse. We tested whether anti-AQ4-Ig has effects on oedema formation in ischemic stroke.
Methods: Anti-AQ4-IgG were obtained from a NMO-patient using
plasmapheresis.
123
14 Male Wistar-rats were randomised in two groups and were
given either anti-AQ4-IgG (2 ml, 9.5 g/l) or placebo. I.v.-injection
was performed 24 h and 30 min before transient middle cerebral
artery obstruction (tMCAO).
Cerebral MRT was performed 90 min and 24 h after tMCAO,
including a T2- and a diffusion weighted imaging sequence (Bruker
Pharma Scan, 7.0T). T2 relaxation time (T2RT) and apparent diffusion coefficient (ADC) were measured in regions of interest in the
centre of the ischemic lesions and on corresponding positions of the
contralateral hemisphere. Side-to-side differences were calculated.
Lesion volumes and midline shift were measured using computer
aided planimetry by an observer blinded for group assignment.
Results: 24 h after MCAO all rats showed clinical signs of stroke.
Lesion volume was significantly increased in anti-AQ4-IgG treated rats (27.1 ± 11.1%) compared to 14.3 ± 7.2% in control group
(p \ 0.05). Furthermore anti-AQ4-Ig increased midline shift
(0.53 ± 0.37 mm vs. 0.31 ± 0.16 mm; p [ 0.05).
After 90 min T2-RT measurements indicated a non-significant
increase of vasogenic oedema formation within the cortex (anti-AQ4Ig: 5.0 ± 2.9 ms; Control-Ig 3.8 ± 2.2 ms; p = 0.5) and within the
basal ganglia (anti-AQ4-Ig: 8.1 ± 4.7 ms; Control-Ig: 8.5 ± 3.2 ms;
p = 0,85). After 24 h there was a significant increase of vasogenic
edema in the cortex (anti-AQ4-Ig: 19.5 ± 9.7 ms; Control-Ig:
9.2 ± 5.3 ms; p = 0.045) but not within basal ganglia (anti-AQ4-Ig:
26.4 ms ± 6.1 ms; Control-Ig: 22.1 ms ± 9.5 ms; p = 0.33).
ADC-measurement showed no differences between anti-AQ4-Igtreated animals and controls 90 min after MCAO. After 24 h, however, anti-AQ4-Ig caused a significant ADC-decline within the cortex
(anti-AQ4-Ig: 2.7 ± 0.99 m/s2; Control-Ig: 1.28 ± 0.82 m/s2;
p = 0.02), but not within basal ganglia(anti-AQ4-Ig: 2.12 ± 0.47 m/
s2; Control-Ig: 1.68 ± 0.75 m/s2; p = 0.21).
Conclusion: Anti-AQ4-antibodies derived from a NMO-patient
significantly increased infarct size as well as vasogenic and cytotoxic
brain oedema in a rat stroke model. Our findings indicate that these
antibodies affect cerebral water homeostasis under pathological
conditions.
O207
A rat model for cerebral air microembolisation
T. Gerriets, S. Doenges, N. Schleicher, K. Mayer,
P. Urbanek, G. Erhart, J. Blumenstein, M. Tschernatsch,
M. Schoenburg, T. Walther
Justus-Liebig University (Giessen, DE); Kerckhoff Klinik
(Bad Nauheim, DE)
Objectives: Cerebral air microembolisation (CAM) is a typical
complication of various medical interventions (such as open heart
surgery or angiography) or after scuba diving. Minor CAM is the
suspected cause of white matter lesions (i.e. in divers) or of long-term
memory deficits (i.e. after open heart surgery).
Animal models are required for the evaluation of the underlying
pathophysiology. Herein, we introduce an animal model, that allows
cerebral air microembolisation under strictly defined experimental
conditions.
Methods: Air was infused through a custom-made glass capillary
into a laminar flow of saline. Size of the air bubbles was adjusted by
the diameter of the glass capillary, the air flow and by increasing the
shear-off forces at the tip of the capillary by means of horizontal
vibration. The bubbles were then infused into the right internal carotid
artery of Wistar rats. Number and diameter of the air bubbles were
assessed by a computer aided high-speed camera.
Animals were randomised into 5 groups (n = 5 each) and received
0, 50, 100, 400 or 800 air microemboli of 160 lm in diameter.
S21
Clinical evaluation and histology (TTC-staining) was performed after
24 h.
Results: 1. The actual bubble size was 159.95 lm ± 9.25 (range
144–188 lm). The effective bubble count amounted to 0.2 ± 0.5,
50.4 ± 0.6, 100.0 ± 0.0, 401.4 ± 0.6 and 804.4 ± 5.4 in the individual groups. 2. On TTC-staining, 1 to 4 rats per group developed
territorial infarcts. The number of animals affected and the mean
infarct size rose with increasing numbers of air bubbles infused 3.
Neurological score and Rotarod performance worsened with
increasing air bubble burden. Interestingly, not only animals with
infarcts worsened clinically, but also those without abnormalities seen
on TTC-staining. 4. In the sham group, TTC-staining and clinical
findings were normal.
Conclusion: The method introduced here allows reliable embolisation of gas bubbles of defined number and diameter into the carotid
artery. Higher numbers of air microemboli (160 lm) cause brain
infarcts in some animals. Even animals without infarcts on TTCstaining reveal neurological deficits in a dose-dependent fashion.
The present study suggests that cerebral gas microembolisation
might cause cerebral dysfunction even beyond the threshold of
macroscopic brain lesions.
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Oral session 6
Multiple sclerosis: clinical aspects
O208
Efficacy of cladribine tablets for relapsing–remitting
multiple sclerosis in patients with high disease activity:
results from the phase III, 96-week CLARITY study
K. Rammohan, G. Comi, S. Cook, G. Giovannoni,
P. Rieckmann, P. Soelberg Sørensen, P. Vermersch,
N. Kurukulasuriya, P. Chang, S. Greenberg
University of Miami (Miami, US); University Vita-Salute San
Raffaele (Milan, IT); University of Medicine and Dentistry (Newark,
US); Barts and The London School of Medicine and Dentistry
(London, UK); University of Erlangen (Bamberg, DE); Copenhagen
University Hospital (Copenhagen, DK); University of Lille Nord de
France (Lille, FR); Merck Serono S.A. (Geneva, CH)
Objectives: The CLARITY study of short-course cladribine tablets
therapy (cumulative doses 3.5 or 5.25 mg/kg over 96 weeks) demonstrated significant benefits on key efficacy endpoints in patients
with relapsing–remitting multiple sclerosis (RRMS). Patients with
disease characteristics indicative of high disease activity (HDA),
assessed by relapses, disability progression and active brain magnetic
resonance imaging (MRI) lesions, also may be more resistant to
treatment, warranting further investigation in these patients. This
analysis explores the efficacy of cladribine tablets in RRMS patients
with characteristics suggestive of HDA.
Methods: Efficacy endpoints, including relapse rate, disability
progression, and key MRI parameters, were assessed in subgroups of
patients with HDA defined as C2 relapses in the previous year (Group
1; n = 392), C2 relapses in the previous year and C1 T1 Gd ± lesion
(Group 2; n = 138); C2 relapses and C9 T2 lesions (Group 3;
n = 352); C2 relapses and C1 T1 Gd ± lesion or C9 T2 lesions
(Group 4; n = 354); C2 relapses and T2 lesion volume [5 mL
(Group 5; n = 272); and Expanded Disability Status Scale (EDSS)
score C3.5 (Group 6; n = 540).
Results: Cladribine tablets 3.5 mg/kg treatment (the cumulative
dose anticipated for marketing) reduced annualized relapse rates
versus placebo by 66.7, 67.2, 61.7, 61.7, 73.3 and 57.1% in Groups
1–6, respectively (all p \ 0.001). The mean number (standard deviation) of combined unique lesions/patient/scan on MRI over 96 weeks
was also reduced with cladribine tablets 3.5 mg/kg versus placebo, at
0.46 (0.83) versus 2.14 (2.82), 0.69 (0.93) versus 3.73 (3.41), 0.45
(0.80) versus 2.26 (2.89), 0.45 (0.80) versus 2.26 (2.88), 0.41 (0.74)
versus 2.52 (3.12) and 0.31 (0.12) versus 1.73 (0.12) in Groups 1–6,
respectively (all p \ 0.001). Additional clinical and MRI endpoints
also showed significant differences between placebo and cladribine
tablets for all HDA subgroups. Data will also be reported for the
5.25 mg/kg group.
Conclusion: Consistent with results reported previously for the
overall CLARITY study population, treatment with cladribine tablets
was highly effective in patient subgroups with clinical and MRI
characteristics suggestive of HDA, who may have a more active or
rapidly progressing clinical course. These findings support the
potential of cladribine tablets as a promising new therapeutic option
in RRMS.
Funded by Merck Serono S.A., Geneva.
O209
Fingolimod reduces annualised relapse rates
and the risk of 3-month confirmed disability
progression versus placebo: subgroup analysis
from the 2-year FREEDOMS study in relapsing
multiple sclerosis
E. Havrdova, V. Devonshire, P. O’Connor,
L. Zhang Auberson, B. Li, L. Kappos
Charles University in Prague (Katerinska, CZ); University of British
Columbia Hospital MS Clinic (Vancouver, CA); St Michael’s
Hospital (Toronto, CA); Novartis Pharma AG (Basel, CH);
Novartis Pharmaceutical Corporation (East Hanover, US);
University Hospital (Basel, CH)
Objectives: To assess the clinical benefits of the first-in-class sphingosine 1-phosphate receptor modulator, fingolimod, in reducing
annualised relapse rates (ARR) and 3-month (M) confirmed disability
progression across patient subgroups in the FREEDOMS study.
Methods: FREEDOMS was a double-blind, parallel-group, phase
III study in which patients with relapsing–remitting multiple sclerosis
were randomised to once-daily fingolimod 0.5 mg or 1.25 mg capsules or matching placebo for up to 2 years. These analyses assessed
the effect of fingolimod on ARR (primary endpoint) and 3M confirmed disability progression (secondary endpoint). ARR subgroup
analyses were conducted using negative binomial regression models.
Disability progression was defined as a 1-point increase from baseline
(with 3M confirmation) in Expanded Disability Status Scale (EDSS)
score in patients with baseline EDSS = 0–5.0 or 0.5-point increase
with baseline EDSS C5.5. Survival analysis of time to disability
progression was performed within each subgroup. Patients were
stratified by age, gender, number of relapses in the 1 year and 2 years
prior to enrolment, prior treatment (yes/no), baseline EDSS score, T2
lesion volume (above or below median), and presence or absence of
Gadolinium-enhancing T1 lesions.
Results: At 2 years, 1,033/1,272 (81%) patients completed the
study. Across all patient subgroups, fingolimod consistently reduced
ARR vs. placebo: Patients with (1) mild disability (n = 1,060) (EDSS
B3.5; 0.5 mg, 52% relative reduction; 1.25 mg, 63% [p \ 0.001])
and (2) moderate to severe disability (n = 212) (EDSS [3.5; 0.5 mg,
66%; 1.25 mg, 54% [ p \ 0.001]), (3) treatment-naı̈ve (n = 752)
123
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(0.5 mg, 64%; 1.25 mg, 62% [p \ 0.001]) and (4) previously treated
patients (n = 520) (0.5 mg, 46%; 1.25 mg, 59% [p \ 0.001]). Fingolimod also reduced 3M confirmed disability progression across all
subgroups versus placebo. The risk of disability progression was
similar between previously treated (0.5 mg, HR 0.70; 1.25 mg, HR
0.68) and treatment-naı̈ve (0.63, 0.65) patients. Patients with
EDSS [3.5 at baseline were at lower risk (0.5 mg, HR 0.32; 1.25 mg,
HR 0.31) of disability progression than patients with EDSS B3.5 (HR
0.77 and 0.76). Additional details from the subgroup analyses will be
presented.
Conclusions: In the FREEDOMS study, fingolimod had beneficial
effects in reducing ARR and risk for disability progression overall
and irrespective of key baseline patient demographics, MRI and
clinical characteristics.
Supported by Novartis Pharma AG.
O210
Summary of specific safety evaluations in clinical
studies of fingolimod in multiple sclerosis:
cardiovascular, ophthalmic, hepatic events
and relationship between lymphocyte reduction
and infections
W. Collins, J.P. DiMarco, M. Zarbin, L. Zhang Auberson,
G. Francis, D.J. Tang, L. Kappos, J. Cohen
Novartis Pharma AG (Basel, CH); University of Virginia Health
System (Charlottesville, US); NewJersey Medical School (New
Jersey, US); Novartis Pharmaceutical Corporation (East Hanover,
US); University Hospital (Basel, CH); Cleveland Clinic Foundation
(Cleveland, US)
Objectives: We present an overview of key aspects of fingolimod
safety—cardiovascular (CV), ophthalmic, hepatic, and lymphocyte
reduction—infection correlation.
Methods: Various pooling strategies were employed to best
evaluate safety aspects of fingolimod therapy. CV effects were analysed based on clinical (pulse, blood pressure, symptoms) and
electrocardiogram measures, focusing on dose initiation. Macular
oedema (ME) was infrequent and exclusive to fingolimod, so pooled
data on all fingolimod-treated patients were used. Comparisons to
placebo, e.g., infection rates, hepatic enzyme elevations, used
FREEDOMS (2-year, placebo-controlled study) data.
Results: Fingolimod treatment initiation was associated with a
dose-dependent decrease in heart rate (HR) that reached nadir at 5
hour post-dose (0.5 mg: -8 bpm; 1.25 mg, -11 bpm). Bradycardia
was generally well tolerated being symptomatic in \0.5% of 0.5 mg
patients. Heart block was more common with fingolimod 0.5 mg than
placebo, both first degree (4.8 vs. 1.5%) and second degree (0.2 vs.
0%) blocks. AV conduction and HR changes were attenuated with
continued therapy and returned to baseline levels by the end of month
(M) 1.
Sixteen confirmed cases of ME were reported in 2615 fingolimodtreated patients (0.5 mg: 2, 0.2%; 1.25 mg: 14, 1.1%). Most (75%)
cases onset within 3–4M of commencing treatment. ME usually
improved or resolved after drug discontinuation. Lymphocyte counts
dropped rapidly, approaching steady-state levels (nearly 70–75%
reduction) within 2–4 weeks and remained stable on therapy. Counts
returned to within normal range within 45 days of study drug discontinuation. The incidence (95% CI) of infections per patient-year
for placebo was 1.44 (1.29, 1.60). In the fingolimod cohorts with
lymphocyte counts of 0.2 to 0.5 9 109/L, infection rate was comparable to placebo though higher [1.41 (1.20, 1.65) to 1.56 (1.35, 1.79)]
123
than for those with counts above this level [0.96 (0.80, 1.15) to 1.04
(0.84, 1.30)] except for the group with lowest lymphocyte count
of \0.2 9 109/L [1.03 (0.64, 1.66)]. Three-fold or greater elevation of
alanine transaminase was seen in 8.5% of 0.5 mg patients versus
1.7% placebo. No cases of liver failure occurred related to fingolimod.
Conclusions: The safety profile of fingolimod has been well
characterised with comprehensive safety assessments of patients in a
large clinical trial programme that allows clinicians to better understand safety aspects of this new therapy for MS patients.
Supported by Novartis Pharma AG.
O211
Efficacy and safety of onabotulinumtoxinA in multiple
sclerosis patients with urinary incontinence due
to neurogenic detrusor overactivity
F. Cruz, S. Herschorn, J. Heesakkers, P. Aliotta,
C. Thompson, W. Lam, G. Daniell, C. Haag-Molkenteller
Hospital S. João (Porto, PT); University of Toronto (Toronto, CA);
Radboud University (Nijmegen, NL); State University of New York
at Buffalo (Buffalo, US); Allergan (Irvine, US)
Objective: To assess efficacy and safety of onabotulinumtoxinA
(onabotA) 200U and 300U for treatment of urinary incontinence (UI)
in the subset of multiple sclerosis (MS) patients (pts) with neurogenic
detrusor overactivity (NDO) enrolled in a multicenter, double-blind,
randomized, placebo (PBO)-controlled, Phase 3 clinical trial.
Methods: MS pts with UI (C14 UI episodes/week) due to NDO not
adequately managed by anticholinergics received 30 intradetrusor
injections of PBO, onabotA 200U, or 300U, avoiding the trigone. Pts
could continue to take anticholinergics and request a 2nd treatment
from 12 weeks onward after initial treatment. Primary endpoint was
change in weekly UI episodes at week 6 after 1st treatment. Secondary endpoints included changes from baseline (BL) in the
urodynamic parameters maximum cystometric capacity (MCC),
maximum detrusor pressure (MDP) during 1st involuntary detrusor
contraction, as well as Incontinence Quality of Life (I-QOL) total
score. Adverse events (AEs) were recorded throughout.
Results: A total of 154 MS pts (80% female) (PBO n = 50;
onabotA 200U n = 53; onabotA 300U n = 51) with mean age of
50 years were enrolled. Overall at BL, mean expanded disability
status scale (EDSS) score was 5.03; 51% of pts were taking anticholinergics, UI frequency was 34.4 episodes/week; 21% were using
clean intermittent catheterization (CIC). At Week 6, the change from
BL in weekly UI was significantly reduced in the onabotA 200U (23.8, p \ 0.020) and 300U (-19.2, p \ 0.003) groups versus PBO (13.8). In addition, significant increases in both onabotA groups versus
PBO in MCC (p \ 0.001) and I-QOL total score (p \ 0.001), and
significant decreases in MDP (p \ 0.017) were noted. Responses
were similar after a re-treatment. Most common AEs were urinary
tract-related with 32, 59, and 70% of patients reporting UTIs and 4,
30, and 54% reporting urinary retention in the PBO, 200U and 300U
groups, respectively. In patients not using CIC at baseline, 3, 24, and
38% had initiated CIC by 6 weeks in the PBO, 200U and 300U
groups, respectively. Annualized MS exacerbation event rates were
0.19, 0.36, and 0.20 in the PBO, 200U and 300U groups, respectively,
consistent with background rates in this population.
Conclusion: In MS patients with NDO, significant improvements
were observed in UI frequency, MCC, MDP, and QOL with onabotA
200U and 300U. No clinically relevant differences in efficacy were
noted between onabotA doses. OnabotA was well tolerated, particularly at 200U.
This study was funded by Allergan, Inc.
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O212
Risk stratification for progressive multifocal
leukoencephalopathy in multiple sclerosis patients using
natalizumab
A. Sandrock, C. Hotermans, S. Richman, A. Natarajan,
S. Lee, T. Plavina, G. Bloomgren, M. Subramanyam,
C. Bozic
Biogen Idec Inc. (Weston, US)
Objectives: Progressive multifocal leukoencephalopathy (PML) is a
rare, demyelinating central nervous system disease caused by the JC
virus (JCV) and a complex interaction between host immune and
genetic factors. Data collected from 75,500 natalizumab-treated
patients (29,400 treated for C2 years as of September 2010) worldwide indicated that prior immunosuppressant (IS) use and
natalizumab treatment duration are independently associated with
increased risk of PML. Detectable anti-JCV antibody may be another
potential risk factor. The objective of this analysis is to assess risk
stratification for natalizumab-associated PML by prior IS use, natalizumab treatment duration, and anti-JCV antibody status.
Methods: On the basis of 70 confirmed cases as of November 2010,
the incidence of PML by prior IS use and natalizumab duration was
calculated. Frequency of prior IS use was estimated based on reported use
in the TYGRIS observational study. The potential utility for risk stratification by anti-JCV antibody status was evaluated by determination of
antibody status in sera archived prior to PML diagnosis from 21 natalizumab-treated multiple sclerosis (MS) PML patients.
Results: At the time of analysis, the estimated PML risk for MS
patients without prior IS was 0.19 per 1,000 patients (95% CI 0.10,
0.33) with B2 years’ natalizumab, and 1.13 per 1,000 patients (95%
CI 0.75, 1.65) with [2 years’ natalizumab exposure. PML risk for
patients with prior IS exposure was 0.42 per 1,000 patients (95% CI
0.16, 0.92) with B2 years’ natalizumab, and 4.35 per 1,000 patients
(95% CI 2.82, 6.42) with [2 years’ natalizumab. Pre-PML sera from
21 MS patients with PML [prior IS use (9/21, 43%), median natalizumab doses (31, range 17–49)] consistently tested positive for antiJCV antibodies. In these 21 MS patients with PML, the observed
100% anti-JCV antibody positivity is significantly different from the
54% anti-JCV antibody seroprevalence observed in natalizumabtreated MS patients from the STRATA study (P \ 0.0001).
Conclusion: Risk of PML may be stratified by prior IS use and
natalizumab treatment duration. The 100% anti-JCV antibody positivity in pre-PML sera from 21 PML patients supports the hypothesis
that anti-JCV antibodies using a two-step ELISA can stratify subpopulations of patients for lower or higher risk of developing PML.
This hypothesis is being further evaluated in large clinical studies.
This study was supported by Biogen Idec Inc. and Elan Pharmaceuticals, Inc.
O213
Epidemiological, clinical, laboratory, and radiological
findings in 151 patients with neuromyelitis optica
and related disorders: a multi-centre observational
study
S. Jarius, K. Ruprecht, F. Paul, O. Aktas on behalf
of the Neuromyelitis Optica Study Group (NEMOS)
Objective: To systematically evaluate the epidemiological, clinical,
laboratory, and MRI features of NMO and its formes frustes in
Germany.
Background: NMO is a severely disabling autoimmune disorder of
the central nervous system (CNS),which predominantly affects the
optic nerves and spinal cord. Recent systematic immunological and
pathological studies suggest that NMO represents a disease in its own
right rather than a subtype of multiple sclerosis.
Methods: Multicenter, observational, cross-sectional survey
including 25 NMO centers participating in the NEMOS group.
Results: So far, we have identified 151 patients with NMO or its
formes frustes. Median age at onset was 39 years (range 11–81).
Gender ratio (f:m) was 5:1 (6:1 in patients positive for NMO-IgG/
AQP4-Ab; 2:1 in patients negative for NMO-IgG/AQP4-Ab). NMOIgG/AQP4-Ab was positive in 79%. In 43.7% of patients, disease
started with optic neuritis (ON), and the second relapse followed after
17 months (median; range 0.5–201). In 45.6% of patients, disease
onset was myelitis, and the second relapse followed after 6.5 months
(0–216). The correct NMO diagnosis was made after 65 months
(0–390) if the first relapse was ON, and after 14 months (0–255) if the
first relapse was myelitis. Detailed data on epidemiological, clinical,
laboratory, MRI, and outcome characteristics as well as statistical
information including multivariate analysis will be shown at the time
of presentation.
Conclusions: Our study provides further insight into the epidemiological, clinical, laboratory, and MRI characteristics of patients
with NMO and related disorders. Our data, which is generated from
the largest cohort investigated so far, may help to improve the
diagnostic and therapeutic management of patients with this devastating condition.
The work of S.J. was supported by a Fellowship from the European Committee for Treatment and Research in Multiple Sclerosis
(ECTRIMS). S.J. received research grants from Bayer HealthCare
and Merck Serono. F.P. received research grant from the German
Research Council (Exc 257) and speaker honoraria from Merck
Serono and Bayer Schering. O.A. received research funding from the
German Research Council (DFG SFB-TRR43) and honoraria and
travel grants from Bayer HealthCare, BiogenIdec, Merck Serono,
Novartis and Teva/Sanofi-Aventis.
__________________________________
Oral session 7
Peripheral neuropathy
O214
Charcot-Marie-Tooth disease with myopathy,
hoarseness and hearing loss with a mutation
in nonmuscle myosin heavy chain 14 (MYH14) gene
B.-O. Choi, G. Lee, E. Park, H.-K. Jung, J. Hyun, J. Park,
S.-H. Kim
Ewha Womans University (Seoul, KR)
Objectives: Charcot-Marie-Tooth disease (CMT) is a genetically and
clinically heterogeneous disorder characterized by progressive
weakness and atrophy of the distal limb muscles. An autosomal
dominant sensorimotor neuropathy with myopathy, hoarseness, and
hearing loss was diagnosed in a large Korean CMT2 family. In the
present study, we investigated the causative gene by genomewide
linkage analysis mapped on the underlying gene to chromosome
19q13.3 and sequencing of candidate genes.
Methods: This study included a total of 33 members (15 affected
and 18 unaffected) of a large Korean autosomal dominant CMT
123
S24
family, and 283 healthy controls. A genomewide SNP linkage scan
was performed on 28 members of this family applying the Infinium II
Human Linkage-12 Panel. Fine mapping of the chromosome 19q13
region was performed by genotyping 29 fluorescent-labeled microsatellites. Sequencing analysis of all coding exons and flanking
intronic sequences was performed on 34 candidate genes in the
linkage region at 19q13.3 including previously reported genes with
autosomal dominant CMT or distal myopathy.
Results: A high density SNP-based linkage study mapped the
underlying gene to a region on chromosome 19q13.3. The maximum
multipoint LOD score was 3.794. Sequencing of 34 positional candidate genes in the segregating haplotype revealed a novel
c.2822G [ T (Arg941Leu) mutation in the gene MYH14, which
encodes the nonmuscle myosin heavy chain 14. Clinically we
observed a sequential pattern of the onset of muscle weakness starting
from the anterior to the posterior leg muscle compartments followed
by involvement of intrinsic hand and proximal muscles. Leg MRI
revealed a sequential pattern of onset of muscle weakness associated
with disease duration: from the anterolateral to the posterior compartment of leg muscles. The hearing loss and hoarseness followed
the onset of distal muscle weakness. Histopathologic and electrodiagnostic studies revealed both chronic neuropathic and myopathic
features in the affected patients.
Conclusion: While mutations in MYH14 have been shown to
cause nonsyndromic autosomal dominant hearing loss (DFNA4), the
sensorimotor neuropathy, myopathy, and hoarseness have not been
associated with MYH14. Therefore, we suggest that the identified
mutation in MYH14 significantly expands the phenotypic spectrum of
this gene. Future molecular studies of similar patients should consider
MYH14 as the underlying cause.
O215
Mutation distribution and genotype-phenotype
correlation in Charcot-Marie-Tooth disease
in a Spanish region
R. Sivera, C. Espinos, M.D. Martinez-Rubio,
M.J. Chumillas, L. Bataller, N. Muelas, P. Marti,
F. Palau, J.J. Vilchez, T. Sevilla
University Hospital La Fe (Valencia, ES); Institute for Biomedicine
(Valencia, ES)
Objectives: Charcot-Marie-Tooth disease (CMT) is a genetically
heterogeneous group of inherited motor and sensory neuropathies.
Molecular studies have shown extensive genetic heterogeneity in
CMT neuropathies with an ever-growing list of causative mutations
and loci (http://molgen-www.uia.ac.be/CMT mutations). Our objective is to describe the genotype distribution in a clinically well defined
series of patients from the Valencian region, so as to establish an
accurate genotype-phenotype correlation.
Methods: A cohort of 172 probands with CMT were identified and
classified according to motor median nerve conduction velocities as
CMT-1 (104 families: 18 of gypsy origin) and CMT-2 (68 families).
The PMP22 duplication was studied in all patients. If not found, a
sequential extensive screening was performed including most causative genes described in demyelinating or axonal forms of the disease.
In patients with gypsy ethnicity the genetic study was appropriately
centered in the founder mutations associated with this population (
http://www.molgen.ua.ac.be).
Results: Mutations were identified in 94.2 % of the CMT1 families
and 53.7% of CMT-2. In CMT1 probands of non-gypsy origin, the
PMP22 duplication was present in 67 cases, and in 19 families other
causative mutations were identified (2 point mutations in the PMP22
123
gene, 3 in MPZ, 3 in GJB1, 2 in PRX, 1 in FGD4 and 2 in SH3TC2). 7
of those mutations were novel. The most severe cases corresponded to
point mutations in the PMP22 gene and one with a MPZ mutation
which developed a congenital hypomyelinating neuropathy. Mutations were identified in all the families of gypsy origin, 13 suffered
the p.R1109X mutation in the SH3TC2 gene, 2 in NDRG1 and 3 in
HK1. No mutation was found in 6 CMT1 families.
36 mutations were identified in CMT-2 patients: 9 in GJB1, 15 in
GDAP1, 3 in MPZ, 3 in MFN2, 3 in NEFL, 2 in HSP27/HSPB1 and 1
in HSP22/HSPB22. 13 of them are novel mutations. 32 CMT2 families have yet to be genetically diagnosed.
Conclusion: The establishment of an accurate genetic diagnosis in
a CMT cohort is important not only for genetic counseling but also to
develop algorithms that can provide a local rationalization of future
genetic studies and possible therapeutic agents.
Supported by the Fondo de Investigación Sanitaria (Grants number
PI08/90857, PI08/0889, CP08/00053 and PS09/00095), co-funded
with FEDER funds.
O216
Responsiveness of clinical outcome measures
in Charcot-Marie-Tooth disease 1A
D. Pareyson, M. Reilly, A. Schenone, G. Fabrizi,
T. Cavallaro, L. Santoro, G. Vita, A. Quattrone, L. Padua,
F. Visioli, M. Laurà, D. Calabrese, R. Hughes, D. Radice,
A. Solari on behalf of the CMT-TRIAAL & CMT-TRAUK Group
Objectives: To analyse responsiveness of clinical outcome measures
(OMs) in the placebo arm of an ascorbic acid trial in Charcot-MarieTooth disease (CMT) type 1A (CMT1A). CMT is a very slowly
progressive disorder and responsive OMs are needed to assess disease
course and response to novel treatments.
Methods: The CMT-TRIAAL/CMT-TRAUK is a two-year long,
randomised, double blind, placebo-controlled study with ascorbic acid
or placebo in CMT1A adults. The placebo arm included 133 adults
(85 females; mean age 41.8 years, SD 12.4). The following OMs were
assessed at 6 or 12 month-intervals for two years: (1) CMT Neuropathy Score (CMTNS, primary endpoint), a composite of sensory
and motor symptoms/signs and electrophysiology (score range 0–36);
(2) distal maximum voluntary isometric contraction (MVIC, with a
myometer) of 4 movements; (3) 10-m timed walking; (4) 9-hole peg
test (9HPT); (5) Overall Neuropathy Limitations Scale (ONLS); (6)
pain and fatigue visual analogue scales (VAS); (7) health-related
quality of life (SF36). Mean change (SD; 95% Confidence Interval)
from baseline to study end was determined for each OM. Distributionbased responsiveness was evaluated by the standardized response
mean (SRM), which is the ratio of the mean score change to the
standard deviation of the score change. Although there are no absolute
standards for SRM, it has been suggested (as for other measures of
effect size) that small, moderate and large responsiveness should
correspond to SRMs of 0.20–0.49, 0.50–0.79, and 0.80 or more,
respectively.
Results: Worsening of CMTNS was 0.23 point/year; deterioration
of its clinical component (the CMT examination score, CMTES) was
larger, 0.27 point/year. OMs responsiveness was overall small to
negligible: SRMs were small for myometry (foot dorsiflexion -0.42,
handgrip -0.34), 9HPT (0.31), the clinical components of the
CMTNS (CMT examination score 0.25, CMTNS signs 0.30) and
VAS for pain (0.21); SRMs were \0.20 for the other measures.
Conclusion: We found limited OM worsening over two years.
Figures for CMTNS were low compared to previous studies. CMTNS
is not a sensitive OM and needs improvement as its clinical
S25
components showed higher responsiveness. Myometry of handgrip
and foot dorsiflexion (using a stabilising frame for the foot) proved to
be the most responsive OM, it is likely to be clinically meaningful and
should be considered in clinical trials. Complete loss of foot dorsiflexion and ankle surgery are limiting factors.
Supported by Telethon-UILDM (GUP04005, GUP05007) and
AIFA (Italian Medicines Agency, FARM53APAH) in Italy and by the
Muscular Dystrophy Campaign in the UK.
O217
An evaluation of the quality of life in symptomatic
patients in the Transthyretin Amyloidosis Outcomes
Survey (THAOS)
I. Conceição, T. Coelho, V. Plante´-Bordeneuve,
M. Waddington Cruz, B. Ericzon, R. Falk, S. Ikeda,
M. Mauer, O. Suhr, Y. Ando, A. Mazzeo, D. Grogan
Hospital Santa Maria (Lisbon, PT); Hospital Santo Antonio (Porto,
PT); University Hospital Henri Mondor (Créteil, FR); University
Hospital Clementino Fraga Filho (Rio de Janeiro, BR); Karolinska
Institute (Stockholm, SE); Harvard Vanguard Medical Associates
(Boston, US); Shinshû University School of Medicine (Matsumoto,
JP); Columbia University Medical Center (New York, US); Umeå
University Hospital (Umeå, SE); Kumamoto University (Kumamoto,
JP); University of Messina (Messina, IT); FoldRx Pharmaceuticals,
Inc. (Cambridge, US)
Objectives: Transthyretin familial amyloid polyneuropathy (TTRFAP) is a fatal neurodegenerative disease characterized by progressive loss of sensory, motor, and autonomic function. The impact of
TTR-FAP on health related quality of life (HRQL) has not been
studied extensively. Data from the Transthyretin Amyloidosis Outcomes Survey (THAOS), a web-based international registry that
enrolls individuals with TTR amyloidosis, and asymptomatic carriers
of TTR mutations, were used to evaluate HRQL status in symptomatic patients with TTR mutations associated with peripheral
neuropathy.
Methods: Upon enrollment, patients were asked to complete the
EQ-5DTM, a standardized, patient-reported health-related quality of
life instrument that measures 5 health status dimensions (mobility,
self-care, usual activities, pain/discomfort, and anxiety/depression)
yielding a single EQ-5D index score (lower scores indicate poorer
HRQL). Mean EQ-5D index scores of symptomatic THAOS patients
with polyneuropathy were compared with the general population (by
age category) and those with other chronic ailments (data from Sullivan et al, Med Care 2005;43:736-49). P values are from t tests
comparing EQ-5D index score group means.
Results: Of 668 patients enrolled in THAOS at 31 sites, 225 were
symptomatic, had mutations associated with polyneuropathy, and
completed the EQ-5D. Patients with cardiomyopathy-related
(Val122Ile, Leu111Met), polymorphisms (Gly6Ser), or protective
(Thr119Met) variants were not included. Mean (±SE) EQ-5D index
scores were significantly lower in THAOS patients (18–34 years:
0.81 ± 0.02; 35–49 years: 0.68 ± 0.03; 50–64 years: 0.57 ± 0.04;
65 ± years: 0.58 ± 0.05) versus the general population (0.92 ± 0.00,
0.88 ± 0.00, 0.84 ± 0.00, and 0.79 ± 0.00, respectively; all P values \0.0001). THAOS patients also had significantly poorer HRQL
when compared with individuals with other chronic diseases [THAOS
patients (50–64 years): 0.58; diabetes: 0.76; stroke: 0.69; emphysema: 0.68; congestive heart failure: 0.64; rheumatoid arthritis: 0.66;
all P values \0.0001).
Conclusions: Poorer HRQL status as assessed by the EQ-5D was
observed in symptomatic patients with mutations associated with
peripheral neuropathy relative to the general population and those
with other chronic diseases. Participation in THAOS is open to any
physician who cares for patients with transthyretin amyloidosis.
This study was sponsored by FoldRx, which was acquired by
Pfizer Inc in October 2010.
O218
Chemotherapy-induced peripheral nerve toxicity:
evidence for damage at neuronal level
J. Casanova-Molla, N. Solà-Valls, O. Grau, C. Uriburu,
C. Font, J. Valls-Sole´
Hospital Clinic of Barcelona (Barcelona, ES)
Introduction: Dying-back degeneration of sensory and motor nerves is
the common pattern of axonal damage in many polyneuropathies.
Although the initial damage in most toxic and metabolic disorders
may lie in the cell body, conventional neurophysiological tests reveal
only the damage.at distal axons.
Objective: We aimed at investigating the neurophysiological
evidence for dorsal root ganglia dysfunction and the histopathological
findigs at cutaneous sensory axons in chemotherapy-induced neuropathy (CH-NP) and diabetic polyneuropathy (DM-NP).
Methods: We studied 12 patients (mean age of 59.6 ± 13 years
old) who were treated with bortezomid or oxiplatin and developed
predominantly sensory CH-NP and a group of 12 diabetic patients
with DM-NP who were matched with CH-NP patients for the clinical
and neurophysiological characteristics of their involvement of small
fibres. We performed a systematic sensory and motor nerve conduction study, determined the shortest F wave latency in peroneal and
tibial nerves and assessed the presence or absence of the soleus H
reflex. Contact heat evoked potentials (CHEPs) were also recorded by
applying stimuli at the dorsum of the foot. A distal leg skin biopsy
was performed and stained with the panaxonal marker PGP 9.5 to
measure the intraepidermic nerve fibres density (IENFD).
Results: We found no differences between both CH-NP and DMNP patients in regard to sensory and motor action potential amplitude,
nerve conduction velocity, F wave shortest latency, CHEPs amplitude
and latency, and IENFD (U Mann-Whitney p [ 0.05 for all of them).
However, the H reflex was absent in 6 (50%) CH-NP patients, while it
was present in all DM-NP patients (Chi-square p = 0.014). A negative correlation between sensory nerve action potential amplitude and
latency of the H-reflex was only found in DM-NP patients (Rho
Spearman -0.61; p = 0.04). Data on skin biopsy revealed more
prominent morphological changes in CH-NP than in DM-NP samples.
Conclusions: The finding of abnormalities in the H reflex but not
in the sural nerve action potentials or the F wave points to a dysfunction in large sensory neurons in CH-NP. Our findings may
indicate more prominent neuronal damage in chemotherapy neurotoxicity than in diabetes mellitus at similar distal axonal small fibre
involvement.
O219
Micro-neurographic evaluation of sympathetic activity
in small-fibre neuropathy
R. Liguori, M. Giannoccaro, V. Di Stasi, F. Pizza,
P. Cortelli, A. Baruzzi, P. Montagna, V. Donadio
University of Bologna (Bologna, IT)
Objectives: Small fiber neuropathy (SFN) may involve somatic and
autonomic fibers. Assessment of somatic epidermal nerve fiber
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density (ENFs) is considered the gold standard test in the diagnosis of
SFN. By contrast, autonomic involvement is more difficult to ascertain. Here we investigate peripheral sympathetic outflow by
microneurography in patients with selective SFN of different origin
with and without autonomic symptoms to ascertain the ability of
microneurography and the corresponding skin organ effector
responses (sympathetic skin activity-SSR and skin vasomotor reflexSVR) to disclose autonomic involvement.
Methods: We studied 59 patients with SFN because of reduced leg
ENFs and normal conduction studies. Thirty patients reported only burning
paresthesia (somatic SFN) whereas twenty-nine patients complained of
additional autonomic dysfunctions (autonomic SFN). They underwent to
microneurography from peroneal nerve with the recording of muscle
sympathetic nerve activity (MSNA), skin sympathetic nerve activity
(SSNA) and the corresponding SSR and SVR in the same innervation field.
Thirty age and sex-matched healthy subjects served as controls.
Results: Autonomic SFN patients mainly complained of loss of
sweating. They showed a significant absence of indirect (SSR and
SVR) and direct (MSNA and SSNA) sympathetic tests compared to
somatic SFN patients and controls. SSNA, SSR and SVR were more
often absent than MSNA. In addition, SSR and SVR were absent in all
patients with no recordable SSNA but no significant relationship was
found with MSNA recording.
Conclusion: SSR and SVR, simple indirect tests of sympathetic
activity, could help to disclose autonomic involvement in SFN with a
good sensitivity as microneurography which additionally contribute to
express the extension of autonomic involvement. Our data pointed out
that the skin sympathetic branch is more often involved than the
muscle sympathetic branch in SFN.
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Oral session 8
Dementia/Higher function disorders
O220
The strong relationship between neuropsychiatric
symptoms and quality of life in Alzheimer’s disease
patients
M. Gomez-Gallego, J. Gomez-Garcia
Catholic University of Murcia (Murcia, ES);
University of Murcia (Murcia, ES)
Objective: The aim of this study is to establish the predictive and
discriminatory power of neuropsychiatric symptoms for patients’
quality of life (QOL).
Methods: 110 community-dwelling patients with mild-to-moderate Alzheimer’s disease and their carers were administered
DEMQOL. Patients rated their mood state with Geriatric depression
scale (GDS) and carers completed Neuropsychiatric inventory (NPI).
Correlational and discriminant function analyses were performed with
groups of different DEMQOL score (cut-off point = 80).
Results: DEMQOL patients’ ratings correlated significantly and
negatively with GDS scores, severity and frequency scores of NPIdepression and severity scores of NPI-anxiety, (p \ 0.05). DEMQOL
carers’ ratings were significantly and negatively correlated with the
severity, frequency and distress scores of NPI subscales anxiety,
depression, agitation, delusions, liability and sleep disorders, and with
severity scores of NPI subscales apathy and appetite disorders,
(p \ 0.05). The results of the discriminant function analysis indicated
that GDS and NPI-anxiety frequency retained statistically significant
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association with patient-reported DEMQOL ratings (standardized
coefficients = 0.776 and 0.634, respectively). This model correctly
classified 72.5% of the patients (p \ 0.000; canonical correlation = 0.57; Wilks’s lambda = 0.673). A discriminant function
analysis performed on carer-reported DEMQOL ratings revealed that
any patient with high frequency scores of anxiety, delusions, liability
and high severity scores of depression would be placed correctly in
the group of low QOL 90.2% of the time in this sample (p = 0.000;
canonical correlation = 0.78; Wilks’s lambda = 0.390). The variable
with the highest discriminatory power was the severity of depression
(standardized coefficient = 0.773).
Conclusions: Our study suggests that behavioural disturbances can
discriminate well between patients with high and low QOL. The
frequency of anxiety, delusions and liability, and the depression
severity of the patients allow for predicting the level of patients QOL
according carers’ ratings with high level of certainty. However, only
self-perceived mood and anxiety frequency could be useful to differentiate patients with low QOL. A comprehensive assessment of
neurobehavioral abnormalities could substitute the administration to
carers of a very subjective QOL scale.
O221
Role of OLR1 and its regulating hsa-miR369-3p
in Alzheimer’s disease: genetic and expression analysis
D. Galimberti, M. Serpente, C. Fenoglio, C. Villa,
F. Cortini, C. Cantoni, E. Ridolfi, F. Clerici, A. Marcone,
L. Benussi, R. Ghidoni, S. Gallone, S. Cappa, G. Binetti,
M. Franceschi, I. Rainero, M. Giordana, C. Mariani,
N. Bresolin, E. Scarpini
University of Milan (Milan, IT); Ospedale Sacco (Milan, IT);
San Raffaele Turro Hospital (Milan, IT);
Research Centre S.Giovanni di Dio (Brescia, IT);
University of Turin (Turin, IT);
Casa di Cura Santa Maria di Castellanza (Varese, IT)
Aims: (1) To carry out an association analysis of Oxidised LDL Receptor
1 (OLR1) in a population of 443 patients with Alzheimer’s disease (AD)
compared with 391 age-matched controls. (2) To perform out an
expression analysis of OLR1 and its regulatory hsa-miR-369-3p in
Peripheral Mononuclear Blood Cells (PBMC) from patients and controls.
Methods: The genetic analysis was performed by allelic discrimination. The expression analysis was done by Real-time PCR.
Results: A statistically significant increased frequency of OLR1
rs1050283C allele was observed in AD patients compared with controls (46 vs. 43%, P = 0.011, OR 1.48, 95% CI 1.10–2.00).
Stratifying according to gender, a statistically increased frequency of
OLR1 rs1050283C allele was observed in female AD patients as
compared to female controls (51 vs. 37%, P \ 0.001, OR 2.90, 95%
CI 1.97–4.24), but not in males.
A significantly decreased relative expression level of OLR1 in
PBMC was observed in AD patients carrying the rs1050283C allele
(0.23 ± 0.13 vs. 0.92 ± 0.8, P = 0.04) as compared with AD
patients not carrying the C allele. Increased relative expression levels
of the hsa-miR369-3p was observed in AD patient carrying the
rs1050283C allele, although the significant threshold was not reached
(2.23 ± 1.35 vs. 1.16 ± 0.31, P [ 0.05). A negative correlation
between OLR1 and hsa-miRNA-369-3p gene expression was found in
AD patients carrying rs1050283C allele (r = -0.313, P = 0.05).
Conclusions: The OLR1 rs1050283C allele likely acts as a risk
factor for sporadic AD; OLR1 and its transcriptional regulatory factor
hsa-miR-369-3p are deregulated in AD patients carrying the
rs1050283C allele.
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O222
Prevalence and timing of cognitive and behavioural
symptoms in right temporal variant frontotemporal
lobar degeneration
C. Koros, T. Kontaxis, C. Routsis, A. Bonakis, N. Kalfakis,
S.G. Papageorgiou
University of Athens (Athens, GR)
Objectives: The right temporal variant of frontotemporal lobar
degeneration (rtvFTLD) represents an emerging subgroup of the
frontotemporal dementias and is characterized by a selective or predominant atrophy of the right temporal lobe. Our aim was to assess
the timing of cognitive and behavioral symptoms in this variant of
FTLD.
Methods: From 105 patients with FTLD referred to our unit during
a 6 years period, 5 patients (4 men/1 woman) were meeting clinical
and magnetic resonance imaging (MRI) criteria for rtvFTLD.
Described symptoms were classified according to their nature (cognitive or behavioral) and timing as early onset (\1 year since disease
appearance) or late onset.
Results: Mean onset age was 70.8 ± 7.3 years (range
57–81 years). Mean Mini Mental Status Examination score at presentation was 20.6 ± 7.4. Initial cognitive symptoms included
prosopagnosia (3/5), mild episodic memory impairment (3/5), naming
and word finding problems (2/5) and notably difficulties in voice
recognition (1/5).
As the disease progressed, practically all patients experienced
memory deficits and prosopagnosia. Executive dysfunction was then
present in 4/5 patients and speech related problems also increased (3/
5). Disorientation in space and time was demonstrated for 3/5
patients.
Behavioral symptoms were largely heterogenous during the first
year of the disorder, including emotional blunting (2/5), depression
(1/5), irritability (1/5) and unprovoked laughter (1/5). Apathy
appeared to be the prevailing early behavioral symptom (3/5).
The most striking late onset behavioral symptoms were disinhibition and loss of insight, present in most patients (4/5).
Aggressiveness or sexually deviating behaviors were also described.
Some patients exhibited irritability (4/5), visual hallucinations (2/5),
altered food preference /sweet craving (2/5), deterioration of personal
hygiene (2/5) and changes in sleep schedule (1/5). We have to point
out the uprising compulsive behaviors in 3/5 patients, including
obsession with number-based games (sudoku).
Conclusion: The main presenting symtoms of rtvFTLD appeared
to be prosopagnosia, episodic memory impairment and apathy. In
contrast, social awkwardness and compulsive behaviors were dominant in later stages of the disease as a result of disinhibition and loss
of insight of patients along with a marked personality change.
O223
The overlap between the corticobasal degeneration
syndrome and nonfluent aphasia
G. Longoni, F. Agosta, F. Mattioli, G. Comi, R. Gasparotti,
M. Filippi
University Hospital San Raffaele (Milan, IT); Civil Hospital
of Brescia (Brescia, IT); University of Brescia (Brescia, IT)
Objectives: Recent clinicopathological studies demonstrated an
association between the presenting syndrome of nonfluent aphasia and
the pathological diagnosis of corticobasal degeneration. In this study,
we present clinical, neuropsychological, and structural MRI data of
patients with nonfluent aphasia, apraxia of speech, ideomotor limb
apraxia and extrapyramidal signs at presentation compared to those of
patients with the classic primary progressive aphasia (PPA).
Methods: Four patients with a CBS-nonfluent aphasia syndrome at
presentation and three patients with the nonfluent PPA variant were
studied. Structural MRI scans were obtained also from 10 age- and
sex-matched healthy controls were studied. Grey matter (GM) atrophy patterns were assessed using voxel-based morphometry.
Results: Compared with controls, both CBS-nonfluent and nonfluent PPA patients showed atrophy of the left insula. In addition,
CBS-nonfluent patients had GM atrophy involving the left rolandic
operculum, precentral and postcentral gyri, superior temporal gyrus,
middle cingulum, and inferior parietal lobule, while patients with
nonfluent PPA experienced atrophy of the left superior frontal gyrus,
inferior temporal gyrus, anterior/middle cingulum, and bilateral
amygdala. The direct comparison between the two patient groups
showed that CBS-nonfluent patients had a greater atrophy of the left
rolandic operculum, postcentral gyrus, and inferior parietal lobule
compared with nonfluent PPA. On the contrary, patients with nonfluent PPA had a greater tissue loss of the left superior frontal gyrus,
inferior temporal gyrus, and bilateral amygdala compared with those
with the CBS-nonfluent variant.
Conclusions: Our findings corroborate the overlap between nonfluent PPA and CBS. This study also suggests that specific anatomical
substrates are associated with different clinical symptoms in these
patients. The damage to the left insula in all patients highlights its role
in motor speech deficits, while the parietal damage is likely to be
related to limb apraxia.
O224
Cognitive impairment is related to damage of specific
white matter pathways in multiple sclerosis
S. Mesaros, M.A. Rocca, P. Preziosa, K. Kacar, M. Copetti,
S. Sala, T. Stosic-Opincal, D. Caputo, M. Absinta,
J. Drulovic, V. Kostic, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT); Hospital Casa Sollievo
della Sofferenza (San Giovanni Rotondo, IT); University of Belgrade
(Belgrade, RS); Foundation Don Gnocchi (Milan, IT)
Objective: We applied a random forest (RF) approach in a large
cohort of patients with multiple sclerosis (MS) to investigate the
correlation between cognitive impairment and overall vs. regional
central nervous system (CNS) damage, quantified using conventional
and modern magnetic resonance (MR) based techniques.
Methods: Brain dual-echo, T1-weighted and diffusion tensor (DT)
MRI were acquired from 102 MS patients with the major MS clinical
phenotypes, and 46 matched healthy controls. DT tractography was
used to produce probability maps of the corpus callosum (CC), corticospinal tract (CST), thalamocortical connection, inferior frontooccipital fasciculus, uncinate fasciculus (UF), cingulum (CIN),
arcuate fasciculus, inferior longitudinal fasciculus (ILF), optic radiation, superior cerebellar peduncle (SCP), and middle cerebellar
peduncle (MCP). Patients with deficits in more than three tests of the
Rao Battery were defined as cognitively impaired (CI). RF analysis
was performed to classify CI versus unimpaired patients using a set of
MRI covariates (including measures of global brain damage and
damage to selected WM fiber bundles).
Results: Significant correlations were found between the majority
of the MRI variables analyzed and the scores at the different neuropsychological tests (r values ranging from -0.57 to 0.53). The RF
analysis showed a high performance in classifying patients as CI or
preserved, with al low global error (GE) (18.6%), as well as in
classifying patients’ impairment in individual neuropsychological
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S28
tests (GE between 11.8 and 22.5%). DT MRI measures of damage in
the CIN, UF, MCP, SCP, ILF, CST and CC, rather than measures of
global CNS damage, had the highest classification power in identifying neuropsychological abnormalities.
Conclusions: RF analysis, applied to DT MRI tractography data,
might contribute to a better understanding of the pathophysiology of
cognitive impairment in MS.
O225
Supraspinal locomotor control during the lifespan
K. Jahn, S. Schröder, A. Deutschländer, G. Xiong,
T. Brandt, F. Heinen, A. Zwergal
University of Munich (Munich, DE)
Standing, walking, and running are sensorimotor tasks that develop
during childhood and are preserved throughout life. The supraspinal brain
network controls spinal pattern generators for automated locomotion.
The present study used mental imagery of stance and locomotion in
functional magnetic resonance imaging (fMRI) to investigate changes in
the supraspinal network of healthy subjects during aging. Eighty healthy
subjects (age 6–78 years) were trained for the conditions lying, standing,
walking, and running in order to imagine these conditions on command in
20-sec sequences with the eyes closed while lying supine in an MRI
scanner. The following BOLD signal changes during locomotion and
stance were found to be independent of age: (1) prominent activations in
the supplementary motor areas, the caudate nuclei, visual cortical areas,
vermal and paravermal cerebellum; (2) significant deactivations in the
multisensory vestibular cortical areas (posterior insula, parieto-insular
vestibular gyrus, superior temporal gyrus) and the anterior cingulate
during locomotion. The following differences in brain activation during
locomotion and stance were age-dependent: relative increases in the
cortical BOLD signals in the multisensory vestibular cortices, motionsensitive visual cortices (MT/V5), and somatosensory cortices (right
post-central gyrus). In children and in advanced age the multisensory
activation was increased.
In conclusion, the functional activation of the basic locomotor and
postural network, which includes the prefrontal cortex, basal ganglia,
brainstem, and cerebellar locomotor centers, is preserved throughout
lifetime. The mechanism of cortical inhibitory reciprocal interaction
between sensory systems during locomotion and stance develops in
childhood and declines in advanced age. Consequently, multisensory
cortical control of locomotion and stance is increased in children and
in the elderly. These findings may indicate a more conscious locomotor and postural strategy in children and aged people.
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Oral session 9
Parkinson: clinical and preclinical findings
O226
Patterns of white matter damage in patients at different
stages of Parkinson’s disease
M. Filippi, F. Agosta, E. Canu, L. Sarro,
M. Jecmenica-Lukic, G. Comi, V. Kostic
University Hospital San Raffaele (Milan, IT);
University of Belgrade (Belgrade, RS)
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Objective: To assess the white matter damage in Parkinson’s disease
(PD) patients at different stages of the disease classified on the basis
of Hoehn and Yahr (H&Y) scale.
Methods: Ninety-four consecutive patients who fulfilled the criteria for a diagnosis of PD without dementia were studied. Sixty-eight
PD patients were classified as early PD (H&Y scores 1–2) and 26 PD
patients as late PD (H&Y scores: 3–4). Forty-two matched healthy
controls (HC) were also involved. Participants underwent structural
and diffusion tensor (DT) MRI scans. Patients were also administered
the Unified Parkinson’s Disease Rating Scale III. Voxel-based morphometry (VBM) in Statistical Parametric Mapping (SPM8) was used
to assess GM volume loss differences between groups. Tract-based
spatial statistics (TBSS) in FSL was used to compare mean diffusivity
(MD) and fractional anisotropy (FA) maps between groups.
Results: PD patients and HC were similar for age and gender. Late
PD patients had significantly longer disease duration and more severe
motor impairment compared with early PD patients. Compared with
HC, all PD patients showed GM volume loss in the left dorsal prefrontal and superior parietal cortices. The same GM pattern was
observed when comparing each PD group vs. HC, with late PD
patients showing larger clusters of atrophy. No GM volume differences between patient groups were found. When all PD patients or
early PD patients were compared with controls, no WM MD and FA
differences were found. Conversely, late PD patients showed a distributed pattern of WM abnormalities compared with both HC and
early PD patients, including the corpus callosum, cingulum, anterior
thalamic radiations, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus, and corticospinal tract,
bilaterally.
Conclusions: In PD patients, microstructural damage to cerebral
WM tracts occur with increasing disease severity. The involvement of
WM networks may be related to the accumulation of motor and
cognitive deficits in these patients along the disease course.
O227
Mild cognitive impairment in Parkinson’s disease is
associated with white matter damage
E. Canu, F. Agosta, L. Sarro, E. Stefanova, A. Tomic,
V. Spica, G. Comi, V. Kostic, M. Filippi
University Hospital San Raffaele (Milan, IT);
University of Belgrade (Belgrade, RS)
Objectives: To assess the white matter (WM) damage in patients with
Parkinson’s disease (PD) and mild cognitive impairment (MCI)
compared to healthy controls (HC) and cognitively unimpaired PD
patients.
Methods: Diffusion tensor (DT) MRI were obtained from 45 PD
patients and 42 age- and gender-matched HC. Cognition was assessed
using the Revised Addenbrooke’s Cognitive Examination (ACE-R)
battery. According to standardized criteria, those patients who scored
1.5 standard deviations below the normative mean value in at least
one cognitive domain were diagnosed as having MCI. Tract-based
spatial statistics was applied to compare voxel-by-voxel mean diffusivity and fractional anisotropy between groups.
Results: Nineteen PD patients had a MCI (amnestic in 11 patients,
non-amnestic in 8 patients). The cognitive domains most frequently
affected were orientation and attention (13 patients), memory (11
patients), verbal fluency (8 patients), visuospatial abilities (6 patients),
and language (2 patients). PD patients with and without MCI were
similar for age, gender, and disease duration, Hoehn and Yahr stage,
and motor impairment. No region of altered WM was found when
comparing PD patients without MCI with HC. Compared with HC,
PD-MCI showed a diffuse pattern of WM abnormalities in the corpus
S29
callosum, cingulum, anterior thalamic radiation, superior longitudinal
fasciculus (SLF), corticospinal tract (CST), inferior fronto-occipital
fasciculus (IFOF), uncinate fasciculus (UF), parahippocampal WM,
bilaterally. The direct comparison between patient groups showed
that, compared with PD without MCI, those with MCI had DT MRI
alterations in the corpus callosum, cingulum, CST and SLF, bilaterally, and right anterior thalamic radiation, IFOF and UF. No region of
WM damage was found in PD patients without MCI when contrasted
to those with MCI.
Conclusions: This study shows that MCI in PD patients is associated with an intrinsic structural damage to the major WM
interhemispheric and cortico-cortical pathways. DT MRI may contribute to our understanding of the development of cognitive
dysfunction in patients with PD.
O228
Grey matter loss is associated with freezing of gait
in Parkinson’s disease
F. Agosta, V. Kostic, M. Pievani, M. Jecmenica-Lukic,
E. Stefanova, A. Scarale, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT);
University of Belgrade (Belgrade, RS)
Objectives: Despite an increasing evidence for a role of a functional
brain impairment in the genesis freezing of gait (FOG) in Parkinson’s
disease (PD), the relationship between selective regional brain volume loss and this phenomenon has not been fully investigated yet.
This study investigated whether a specific pattern of gray matter
(GM) loss is associated with FOG in PD patients.
Methods: Thirty-eight PD patients and 34 healthy controls were
studied. Patients were classified as PD-FOG patients (n = 18), if they had
both a score [1 on item 3 of the FOG Questionnaire and observation of
FOG by the examiners. Patient groups were matched for age, disease
duration and Hoehn and Yahr stage. Patients were also administered the
Unified Parkinson’s Disease Rating Scale III (UPDRS III), Hamilton
Depression and Anxiety Rating Scales, and a neuropsychological battery.
GM atrophy was assessed using voxel-based morphometry.
Results: PD patients versus healthy controls showed GM atrophy in
the bilateral dorsolateral prefrontal cortex, medial and lateral temporal
lobe, inferior parietal lobule, middle occipital gyrus, and left middle
cingulate cortex. The pattern of GM atrophy was similarly widespread
when considering PD-FOG patients only versus healthy controls. On the
contrary, patients without FOG (PD-noFOG, n = 20) versus healthy
controls showed only small regions of GM atrophy in the frontal and
temporal cortex, bilaterally. Significant GM atrophy of the left frontal
cortex was found in PD-FOG vs. PD-noFOG patients. In all PD patients,
FOG score was significantly associated with GM atrophy in the left
frontal cortex. This association was independent of UPDRS III, and
MMSE, executive functioning, depression, and anxiety scores.
Conclusions: FOG in PD patients is associated with GM frontal
atrophy. Such a relationship is independent of executive deficits. This
finding suggests that the frontostriatal system may be involved in the
pathophysiology of FOG in PD.
O229
Neurophysiological study of pull test in patients
with Parkinson’s disease and controls
P. Schestatsky, T. Gomes-Araújo, A. Gamarra, C. Mello-Rieder
Hospital of Porto Alegre (Porto Alegre, BR)
Objectives: The pull test (PT) is used as a measure of postural
instability in Parkinson’s disease (PD) and other movement disorders.
Surface electromyography (EMG) is a widely used technique for
muscle contraction evaluation. Our aim was to assess EMG activity of
the principal muscles recruited during PT in patients with PD.
Methods: The study was carried out in 8 newly diagnosed PD
patients and 8 controls. Fallers were excluded. By means of surface
electrodes we registered electrical activity from the following muscles
during the PT maneuver: tibialis anterior, gastrocnemius and biceps
femoralis. We also placed an electrode at the anterior part of deltoid
muscle to serve as a screen trigger and performed the PT 10 times at
both ‘‘on’’ and ‘‘off’’ states. At each maneuver we noted the number
of abnormal tests and steps necessary to regain postural stability after
pulling.
Results: The mean duration and amplitude of muscle burst activity
were similar between patients and controls. Surprisingly, the mean
latency of all tested muscles were shorter in patients than in controls.
In the latter we observed a progressive prolongation of the latencies
from trial 1st to 8th., whereas in patients, the latency of muscle burst
remained constant in all trials for all muscles. As expected, the
prevalence of abnormal PTs and the total number of steps after 10
maneuvers were higher in patients when compared to controls. After
l-dopa intake, neurophysiological data remain unchanged.
Conclusions: Patients with PD have a characteristic pattern of
muscle activation during PT that is not reversed after levodopa
administration. This methodology underscores the possibilities of
physiological and clinical studies using PT monitored by EMG in the
assessment of parkinsonian syndromes.
O230
Evaluation of motor and non-motor symptoms
in atypical tremor—a DaTSCAN study
T. Lampreia, P. Bugalho, A. Dias, T. Martins, J. Vale
Hospital Egas Moniz (Lisbon, PT)
Objectives: To study the relation between pre-synaptic dopaminergic
deficit and motor and non-motor features in patients with Atypical
Tremor (AT).
Methods: From December 2010 to January 2011, patients with AT
[defined by unilateral postural tremor and/or a rest tremor for more
than 2 years without other criteria for Parkinson Disease (PD)], were
recruited from our Neurology Department. None had iatrogenic tremor. DaTSCAN was performed and classified by a Nuclear Medicine
Physician in normal, pathologic or uncertain. The Non-Motor
Symptons Scale for Parkinson Disease (NMSS) and the REM Sleep
Behavioral Disorder Screening Questionnaire (RBDSQ) were applied
to all patients. v2 test was used to correlate categorical variables.
Results: 22 patients were included (54.5% women), mean age of
76.52 ± 6.6 years. DaTSCAN was positive in 27.3% (6) and nonpathologic (10 normal and 6 uncertain) in 72.7% of the cases. Mean
disease duration was 15.2 ± 8.8 years (2–30), 14.8 ± years in the
non-pathologic DaTSCAN and 16.33 ± years in the pathologic
DatSCAN group. The non pathologic group showed a trend
(p = 0.054) for a family history of tremor. The type of rest tremor
(unilateral vs. bilateral) did not correlate with the presence of dopaminergic deficit, nor did the presence of dubious parkinsonian
symptoms. Instead, a higher intensity of rest tremor (scoring 2 or
more in the UPDRS III.20) did correlate with a pathological finding in
DaTSCAN (p = 0.025). Concerning the non-motor symptoms, the
pathologic group had a slight superior NMSS score (78.8 vs. 71) but,
neither any of the NMSS domains nor the RBDSQ results correlated
significantly with the DaTSCAN.
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Conclusion: Higher rest tremor intensity seems to be associated
with a dopaminergic deficit in AT patients. Indeed, other authors have
found rest and postural tremor intensity to correlate with dopaminergic and non-dopaminergic deficit in atypical tremor, respectively.
Against what we had expected, we did not find a correlation between
the presence of non-motor symptoms and dopaminergic deficit, which
could be explained by a possible low test specificity and the study
small sample size. Increasing sample size could allow us to draw
more conclusions on this.
O231
Psychiatric symptoms screening in the early stages
of Parkinson’s disease
P. Bugalho, J. Alves da Silva, I. Cargaleiro, M. Serra,
B. Neto
Hospital Egas Moniz (Lisbon, PT); Hospital de S. Francisco Xavier
(Lisbon, PT)
Objectives: Psychiatric complains are common in Parkinson’s disease
(PD), and have a significant influence in disease outcome and quality
of life. Little attention has been paid to psychiatric symptoms at early
stage disease. We aimed to screen a population of early stage PD
patients for psychiatric symptoms and to study the relation with motor
and cognitive function.
Methods: Thirty-six early stage PD patients underwent motor (HY,
Unified Parkinson’s Disease Rating Scale) and cognitive [Frontal
Assessment Battery, Mini-Mental State Examination (MMSE)] assessment as well as general psychiatric (Symptom Check-list 90 SCL90) and
psychosis (Brief Psychiatric Rating Scale BPRS) screening. Relation
between psychiatric domains scores was studied with principal component analysis. Relation between psychiatric, disease related, cognitive
and motor function was assessed with correlation coefficient.
Results: SCL90 scores were higher for somatization (significant scores
in 66.7% of patients), depression (36.1%), anxiety (27%) and obsessive
compulsive symptoms (OCS) (52.8%). Scores were highly correlated,
except for psychosis and phobia. Depression and anxiety were negatively
correlated to MMSE score and dopaminergic doses, respectively. BPRS
scores were higher for somatic concern, depression, anxiety and hallucinations (present in 13 patients). There was segregation between
depression, anxiety, hallucinations, other positive psychotic symptoms
and negative psychotic symptoms. Depression was related to MMSE.
Conclusions: We found a high prevalence of psychiatric complaints in
PD patients, mostly related to depression, anxiety, somatization and OCS.
Depression was correlated to global cognitive function. Hallucinations
were also frequent, but not associated to cognitive function or dopaminergic doses, suggesting a different physiopathological background.
___________________________________
Oral session 10
Neuropathic pain and primary headache
O232
Langerhans cells contribution to neuropathic pain
in small-fibre neuropathies
J. Casanova-Molla, M. Morales, J. Valls-Sole´
Hospital Clinic of Barcelona (Barcelona, ES)
Introduction: The immune hystiocitic Langerhans cells (LCs) might
be related to sensitization of nociceptive nerve endings at skin in
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patients with neuropathic pain. We aimed to evaluate differences in
LCs between healthy subjects (HS) and patients with small and mixed
fiber neuropathy with or without burning neuropathic pain. Furthermore, we examined if these differences in LCs would be related to the
etiology of the neuropathy (diabetic or not diabetic).
Methods: The study was carried out in 27 patients with polyneuropathy (PN): 20 with pain (PN-P), mean VAS of 6/10 and 7 without
pain (PN-noP), mean VAS of 1/10 in comparison to 10 HS. A total of
14 patients were diabetics (DM-PN) and 13 patients had other etiology (immunologic or toxic) for their neuropathy (noDM-PN). In all of
them we performed a skin biopsy at distal leg. Using double immunofluorohistochemistry with panaxonal marker PGP 9.5 and the
antibody to langerin/CD207 we quantified the intraepidermal nerve
fibers density (IENFD) and LCs per mm2 in the whole epidermis of
one skin section. Confocal analysis was done to evaluate LCs PGP
9.5-immuno reactive (LCs PGP-ir).
Results: We found a mean value of 334.3 LC/mm2 in HS, 288.1
LC/mm2 in PN-noP and 430.2 LC/ mm2 in PN-P. ANOVA showed a
significant group effect on IENFD [F(2, 24) = 3.7; p \ 0.03] and on
LC/mm2 [F(2, 24) = 3.5; p \ 0.04]. The post-hoc analysis showed a
significantly reduced IENFD for patients (PN-P and PN-noP) in
comparison to HS (p \ 0.05). We found significant differences in LC/
mm2 among groups: PN-P respect to PN-noP (t test p = 0.02; DMNP respect to noDM-NP (t test p = 0.008). In patients, the ANCOVA
adjusted by IENFD showed that the presence of DM-NP (F = 7.4,
p = 0.01) and PN-P (F = 5.9, p = 0.02) were both associated with
an increase number of LC/mm2. There was a positive correlation
between the IENFD and the LCs PGP-ir (r2 = 0.46, p = 0.005).
Conclusion: Patients with neuropathic pain in the context of a
small fibre neuropathy have an increased number of epidermal LCs,
especially in diabetics. The role of LCs might be related with the
generation or maintenance of pain in sensory polyneuropathies and
the process of axonal degeneration.
O233
Hemicrania continua in a headache clinic: referral
source and diagnostic delay in a series of 22 patients
E. Cortijo, A.L. Guerrero, S. Herrero, P. Mulero,
M. Pedraza, M.L. Peñas, E. Rojo, D. Campos,
N. Te´llez, R. Fernández
Universitary Clinic Hospital of Valladolid (Valladolid, ES)
Objectives: Hemicrania continua (HC) is a primary headache, characterized by continuous unilateral pain, and superimposed
exacerbations frequently associated with autonomic features. Diagnostic criteria of HC, accordingly to the II Edition of International
Classification of Headache Disorders (ICHD-II) require response to
therapeutic doses of oral or parenteral indomethacin. As it has been
shown with other primary headaches, HC is probably misdiagnosed.
We aim to analyze demographic and nosological characteristics of a
series of 22 new cases of HC, including referral source and latency of
diagnosis.
Methods: We prospectively evaluated consecutive new patients
with HC attended in a headache outpatient clinic in a tertiary hospital
over a 3-year period (January 2008 to January 2011). In every patient
we gathered age at onset, sex, background pain (side, site, type,
intensity) and exacerbations characteristics (frequency, intensity,
periodicity, autonomic symptoms). We considered referral source and
delay between onset of the headache and diagnosis of HC.
Results: Twenty two patients (15 females, 7 males) out of 1,150
attended in the mentioned clinic during inclusion period (1.9%)
were diagnosed of HC. Mean age at onset was 43.1 ± 18.9 years
(range 6–75). In all patients pain was strictly unilateral, in 13 (59%)
S31
right-sided and in 9 (41%) left-sided. Patients in our series rated the
continuous pain 5.6 ± 1.4 and exacerbations as 8.4 ± 1.1 on a verbal
analogical scale (VAS). Only 3 patients (13.6%) suffered episodic
instead of continuous pain. All of them presented exacerbations, and 9
(40.9%) did not associated autonomic symptoms. All cases responded
to indomethacin, though side effects were documented in 59.1% of
the patients, mainly dyspepsia and dizziness. No patient received a
diagnosis of HC before being attended in our headache office. Mean
latency of diagnosis was 86.1 ± 106.5 months (range 3–360). 11
patients (50%) were referred from primary care, with 9 (40.9%)
coming from other neurology clinics and 2 (9.1%) from other specialties offices.
Conclusion: According to our series, HC is not an infrequent
diagnosis in a headache outpatient clinic. Diagnostic delay is comparable to data collected in previous study. HC is frequently
misdiagnosed. There is a need for increasing the understanding of this
entity, potentially responsive to indomethacin.
O234
Migraine outcome in postmenopausal women:
are there predictive factors?
C. Condello, L. Savi, M. Anoaica, E. Novelli, L. Pinessi
University Hospital of Turin (Torino, IT); Hospital of Novara
(Novara, IT)
Introduction: Common experience shows that in the course of
reproductive life changes in hormonal levels can be associated with
significant headache modifications.
In the general migraineurs population prevalence decreases with
age, but at menopause migraine can either regress or worsen or even
stay unchanged.
Aim of the study: To the best of our knowledge the possible
factors associated with the different courses of headache after
menopause onset have not been identified yet. To define some of
them we studied the course of postmenopausal migraine focusing
the attention on the existence of a possible link between the evolution of migraine after menopause and particular features during
reproductive life.
Materials and methods: We evaluated 367 post-menopausal
women (291 natural and 76 surgical menopause) suffering from
migraine according to ICHD-II criteria. We studied if and how the
characteristics of migraine changed after menopause, and possible
predictive factors of the outcome of the illness after menopause, as
association between menses and migraine, number of pregnancies,
use of oral estroprogestinic pills, outcome in their mothers if there
was a positive family history.
Results: Migraine improved after menopause in 48 (16.5%) natural menopause patients and in 8 (14.3%) surgical menopause
women, showing no significant differences between two groups.
44 (91.7%) of the 48 patients whose migraine improved after
menopause had migraine attacks correlated to the menstruation, while
only 174 (71.6%) of the patients whose migraine worsened or
remained unchanged had this correlation (p \ 0.05).
The outcome of migraine after menopause significatively followed
the one of the patients’ mothers (p = 0.04).
Discussion: According to our data, the association of migraine
attacks with periods during reproductive life and the improvement
of migraine after menopause in the patient’s mother seem to significatively predict a headache improvement after menopause. The
surgical origin of menopause does not seem to affect the clinical
outcome.
More studies are needed to assess this tendency. If these data will
be confirmed this will be a very useful indication for many women
approaching the menopausal period.
O235
Effects on habituation of preventive migraine therapy
with topiramate: a laser evoked potential study
F. Puledda, L. Di Clemente, A. Biasiotta, A. Truini,
G. Cruccu, V. Di Piero
Sapienza University of Rome (Rome, IT)
Objectives: Lack of habituation during repetitive stimulation is the
most consistent interictal abnormality observed in migraine patients,
showing that they are vulnerable to any kind of sensory overload. This
neurophysiological finding may indicate an abnormal cortical excitability in migraine patients.
It has been hypothesized that some preventive treatments might
protect migraineurs brain from attacks by stabilizing cortical excitability level and thus the response to external nociceptive stimuli.
Aim of the present study was to investigate the effects of preventive treatment with topiramate on cortical responses to nociceptive
stimuli induced by Laser (LEPs) in migraine patients.
Methods: Scalp potentials were evoked by Nd-YAP Laser stimulation of the hand dorsum and first trigeminal division in 13 patients
with migraine without aura (MO) and 14 control subjects (CS). The
exam was repeated twice in MO patients, before (T0) and after (T1)
two month treatment.
Results: Topiramate was effective in all MO patients in reducing
intensity and frequency of attacks. We found that the initial amplitudes of both temporo-parietal N1 and vertex N2/P2 potentials were
lower in MO patients compared to CS (p = 0.02) and we confirmed
the lack of habituation typical of MO patients (p = 0.05). Moreover
we found that treatment was significant in normalizing the habituation
pattern in MO patients for the N1 component, generated in the
secondary somatosensory cortex (SII) (p = 0.05), but not for the
N2/P2 complex, generated in the anterior cingulated cortex (ACC).
We also observed a significant correlation between clinical effects
and normalization of neurophysiological responses (p = 0.001,
r = 0.838).
Conclusions: Our results indicate a modulating action of topiramate on cortical processing of sensorial stimuli, regarding the
sensory-discriminative component of pain, elaborated by the SII,
without a significant effect on the affective dimension of pain, in
which the ACC has an important role. We therefore demonstrate that
the significant improvement of symptoms in MO patients can be
related to the effects of topiramate on modulating cortical responses
in the SII.
O236
Lateralized central facilitation of trigeminal
nociception in cluster headache
D. Holle, C. Gaul, S. Zillessen, S. Krebs, H.C. Diener,
H. Kaube, Z. Katsarava, M. Obermann
University Duisburg-Essen (Essen, DE); University of Freiburg
(Freiburg, DE)
Background: Central facilitation of trigeminal pain processing was
demonstrated in different primary headache and facial pain
123
S32
disorders. Whether it is also part of the pathophysiology of cluster
headache (CH) has been intensively discussed due to inconsistent
study results.
Objective: To investigate the function of the trigeminal nociceptive system in patients with episodic and chronic CH.
Methods: Sixty-six patients with CH (18 episodic CH inside bout,
28 episodic CH outside bout, 20 chronic CH) according to the ICHDII-classification, as well as 30 healthy controls were investigated
using simultaneous recordings of the nociceptive blink reflex (nBR)
and pain related evoked potentials (PREP) following nociceptive
electrical stimulation on both sides of the forehead (V1).
Results: NBR latency ratio (headache side/non-headache side) was
decreased in all CH patients independently of CH subtype compared
with healthy controls indicating central facilitation at brainstem level.
Area-under-the-curve (AUC) ratio was increased in patients with
episodic CH inside bout only. PREP showed decreased N2 latency
ratio in patients with chronic CH indicating central facilitation at
supraspinal (thalamic or cortical) level.
Conclusion: In CH asymmetric facilitation of trigeminal nociceptive processing predominantly on brainstem level was detected.
This alteration is most pronounced in the acute pain phase of the
disease, but appears to persist in remission periods. Only chronic CH
patients show additional changes of the PREP prompting to supraspinal changes of pain processing related to the chronic state of
disease in regard to neuronal plasticity, which exceeds changes
observed in episodic CH.
O237
Selective grey matter atrophy in the pain-matrix
network in cluster headache
M. Absinta, M.A. Rocca, B. Colombo, A. Falini, G. Comi,
M. Filippi
University Hospital San Raffaele (Milan, IT)
Objective: Morphologic and functional imaging studies have indicated
that a primary hypothalamic dysfunction might have a role in the
pathogenesis of cluster headache (CH), whereas a few neurophysiologic and metabolic studies have suggested a more global dysfunction
of central modulation of peripheral stimuli in these patients. Aim of this
study is to assess the pattern of regional abnormalities in the white
matter (WM) and gray matter (GM) in patients with CH, using tractbased spatial statistics (TBSS) and voxel-based morphometry (VBM).
Methods: Using a 3.0 Tesla scanner, dual-echo, diffusion tensor
(DT) and 3D T1-weighted scan were acquired from 15 patients with
chronic CH (10 with a right and 5 with a left lateralization of the
cluster attacks), and 19 sex- and age-matched controls. TBSS analysis
was performed using FMRIB’s Diffusion Toolbox. From 3D T1weighted images, VBM was performed using SPM8 and DARTEL.
This latter analysis was performed with and without mirroring the
hemispheres of 5 patients with a left lateralization of the attacks.
Results: No abnormalities of the brain WM were detected in
patients with CH. Compared to controls, CH patients showed GM
atrophy in the right (R) thalamus, head of the R caudate nucleus,
bilateral (B) posterior cingulate cortex, B middle frontal gyrus, left
(L) precuneus, R middle temporal gyrus and R precentral gyrus
(p \ 0.001, cluster extent more than 10 voxels). Similar results were
obtained after mirroring of the hemispheres in 5 patients. This latter
analysis showed no volume abnormalities in the hypothalamus.
MFG atrophy was significantly correlated with disease duration
(r = -0.79, p \ 0.001).
Conclusions: Similar to other chronic pain condition, CH patients
have structural abnormalities in GM regions that are part of the
antinociceptive system.
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Oral session 11
Disorders of consciousness
O238
Sleep in disorders of consciousness: electrophysiological
correlates of behavioural changes in vigilance
M.A. Bruno, E. Landness, Q. Noirhomme, B. Riedner,
O. Gosseries, C. Schnakers, M. Massimini, S. Laureys,
G. Tononi, M. Boly
University Hospital of Liège (Liège, BE); University of Wisconsin
(Madison, US); University of Milan (Milan, IT)
Objectives: The existence of normal sleep in vegetative state (VS) and
in minimally conscious state (MCS) patients is still a matter of debate.
Previous electrophysiological sleep studies in patients with disorders
of consciousness did not differentiate patients in VS from patients in
MCS.
Methods: Using high-density electroencephalographic sleep
recordings, eleven patients with disorders of consciousness (five VS,
six MCS) were studied to correlate the electrophysiological changes
associated with sleep to behavioural changes in vigilance. Polysomnographic recordings were pre-processed and analyzed using EEGLab
and in-house Matlab software. For each patient, sleep staging was
based on EEG electrodes C3 and C4 referenced to mastoid electrodes
A1 and A2. Sleep was scored in 20 s epochs according to standard criteria. To compute differences in slow wave activity
(SWA) between behavioural states, artefact free EEG power was
averaged across all electrodes and compared using a paired, one-way
t test.
Results: All MCS patients showed clear EEG changes associated
with decreases in behavioural vigilance. In the five MCS patients
showing sustained behavioural sleep periods, we identified several
electrophysiological characteristics typical of normal sleep. Compared to periods of wakefulness, non rapid eye movements (REM)
sleep showed a global increase in SWA. In addition, all MCS patients
showed an alternating non REM/REM sleep pattern and a homeostatic decline of electroencephalographic SWA across the night. In
contrast for most patients in a VS, while preserved behavioural sleep
was observed, the electroencephalographic patterns remained virtually unchanged in periods with eye closed compared to periods of
behavioural wakefulness. No slow wave sleep or REM sleep stages
could be identified. There was no significant change in SWA when the
VS patients closed their eyes and no homeostatic regulation of sleeprelated SWA was observed across the night.
Conclusions. We observed behavioural but no electrophysiological
sleep wake patterns in patients in a VS, while there were near-to-normal
patterns of sleep in patients in a MCS. These results shed light on the
relationship between sleep electrophysiology and the level of consciousness in severely brain-damaged patients. We suggest that the study of sleep
and homeostatic regulation of SWA may provide a complementary tool for
the assessment of brain integrity in MCS and VS patients.
O239
A recurrent increase of synchronisation in the EEG
is distinguished by pointwise transinformation in all
physiological states of vigilance
R. Landwehr, J. Treib, A. Jowaed
Westpfalz-Klinikum GmbH (Kaiserslautern, DE)
S33
Objectives: The analysis of EEG synchronization patterns provides
essential information how interrelations between brain sites change
with the wake-sleep-cycle. The spatio-temporal dynamics of such
patterns independent of spectral and phase parameters remains largely
unclear. EEG pointwise transinformation (PTI) might be suitable for
the registration of the spatio-temporal dynamics of cortical coupling
patterns.
Methods: The waking and sleep EEGs of 21 healthy sleepers were
analyzed by PTI of FP1-FP2, F3-F4, C3-C4, P3-P4, O1-O2, F7-F8,
T3-T4, T5-T6, A1-A2, F3-O1, F4-O2. A spectral analysis of F3 was
performed by a fast Fourier transformation. Stage dependent differences of PTI and spectral parameters were assessed by an ANOVA.
Results: A pattern of recurrent EEG synchronization was distinguished throughout all waking and sleep phases, with low levels of
mean PTI and clearly separated phases of elevated coupling. Synchronization phases appeared burst-like in the frontal, central and
anterior / midtemporal derivations, and more fluctuating in the posterior derivations. The mean synchronization levels also differed
regionally, with high frontal and occipital coupling levels and lower
central and midtemporal coupling levels. However, the temporal
dynamics of EEG synchronization remained almost constant
throughout waking and sleeping. The spectral content of synchronized
phases, though, differed significantly for waking and all sleep stages.
Conclusion: A fundamental recurrent synchronization pattern seems
to exist in the EEG, which is only subtly modulated by vigilance.
Therefore, a new descriptive entity, the recurrent synchronization in the
EEG—‘‘RISE’’—is proposed. RISE seems to reflect the persistent
aspects of spatiotemporal EEG synchronization patterns on small time
scales, since it detects the recurrence of microstates independent of
specific EEG graphoelements and the spectral content of the EEG. While
distinct regional differences of EEG synchronization exist, the temporal
synchronization pattern remains remarkably constant throughout all
physiological states of vigilance.
O240
PROgnosis of PostAnoxic Coma after treatment
with hypothermia: results of PROPACII, a multi-centre
prospective cohort study
A. Bouwes, J.M. Binnekade, M.A. Kuiper, F.H. Bosch,
D.F. Zandstra, A.C. Toornvliet, H.S. Moeniralam,
B.M. Kors, J.H. Koelman, M.M. Verbeek, H.C. Weinstein,
A. Hijdra, J. Horn
Academic Medical Center (Amsterdam, NL); Medical Center
Leeuwarden (Leeuwarden, NL); Rijnstate Hospital (Arnhem, NL);
Onze Lieve Vrouwe Gasthuis (Amsterdam, NL); Medical Center
Alkmaar (Alkmaar, NL); St. Antonius Hospital (Nieuwegein, NL);
Kennemer Gasthuis (Haarlem, NL); Radboud University Nijmegen
Medical Center (Nijmegen, NL); Sint Lucas Andreas Hospital
(Amsterdam, NL)
Objectives: Current guidelines for outcome prediction in patients with
postanoxic coma after cardiopulmonary resuscitation (CPR) are based
on data from patients not treated with hypothermia. New information
is required. Aim of this study was to establish the reliability of neurological examination, neuron-specific enolase (NSE) and median
nerve somatosensory evoked potentials (SEP) to predict poor outcome
in patients treated with mild hypothermia after CPR.
Methods: Multicenter prospective cohort study, including adult
comatose patients, admitted to the ICU after CPR and treated with
hypothermia (32–34C). Neurological examination (Glasgow Coma
Score and brain stem reflexes) was performed 72 h after CPR.
Samples for NSE levels were drawn on admission, 12 h after reaching
target temperature, 36 and 48 h after CPR. Median nerve SEP was
recorded during hypothermia and after rewarming. Neurological
outcome was assessed with the Glasgow Outcome Scale (GOS), after
1 week, 1 month and 6 months. Primary outcome was poor outcome,
defined as death, vegetative state or severe disability after 6 months.
Results: 391 patients were included, 53% had a poor outcome.
Absent pupillary light responses (FPR 1, 95% CI 0–7), corneal
reflexes (FPR 1, 95% CI 0–7) and N20 responses in SEP after
rewarming (FPR 0, 95% CI 0–18) were reliable predictors. Motor
scores 72 h after CPR and NSE levels were not.
Conclusion: Poor outcome after CPR and therapeutic hypothermia
can reliably be predicted by testing brain stem reflexes and SEP.
Other methods recommended in current guidelines could possibly
lead to inappropriate withdrawal of treatment.
Supported by a research grant from The Netherlands Heart
Foundation, 2007B039.
O241
Comparison of the Full Outline of UnResponsiveness
(FOUR), the Glasgow Coma Scale (GCS)
and the Glasgow Liege Scale (GLS) in an intensive care
unit population
M.A. Bruno, D. Ledoux, B. Lambermont, F. Damas,
C. Schnakers, A. Vanhaudenhuyse, O. Gosseries,
S. Laureys
University Hospital of Liège (Liège, BE)
Objectives: The Full Outline of UnResponsiveness (FOUR) has been
proposed as an alternative for the Glasgow Coma Scale (GCS) in the
evaluation of consciousness in severely brain-damaged patients. We
compared the FOUR, GCS and Glasgow Liege Scale (GLS) in
intensive care unit patients who were admitted in a comatose state.
Methods: FOUR, GCS and GLS evaluations were performed in
randomized order in 176 acutely (\1 month) brain injured patients.
Inter-rater agreement was assessed in 20% of the studied population.
A logistic regression analysis adjusted for age and etiology was
performed to assess the link between the studied scores and the
outcome 3 months after injury (n = 136).
Results: GCS verbal component was scored 1 in 146 patients,
among these 131 were intubated. We found that the inter-rater reliability was good for the FOUR score, the GCS and the GLS. FOUR,
GCS, as well as the GLS total scores predicted functional outcome
with and without adjustment for age and etiology. 71 patients were
considered as being in a vegetative/unresponsive state based on the
GCS. The FOUR scale identified 8 of these 71 patients as being
minimally conscious given that these patients showed visual pursuit.
Conclusions: The FOUR score is a valid tool with good inter-rater
reliability that is comparable to the GCS and GLS in predicting
outcome. It offers the advantage to be performable in intubated
patients and to identify non-verbal signs of consciousness by
assessing visual pursuit, and hence minimal signs of consciousness
(11% in the present study), not assessed by GCS and GLS scales.
O242
Informing family members of traumatic coma patients
S.T. Verhaeghe, T. Defloor, M.H. Grypdonck,
F. Van Zuuren
Ghent University (Gent, BE); University of Amsterdam
(Amsterdam, NL)
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Aims: To assess the interplay between hope and the information
provided by health care professionals.
Background: Earlier research learned that hope is crucial for relatives of traumatic coma patients. Also it has been reported that the
need for information is extremely important for relatives of critically
ill patients.
Design: A qualitative approach according to the ‘grounded theory’
method with constant comparison was used.
Method: We held 24 in-depth interviews with 22 family members
of 16 patients with traumatic coma. Data processing and data analysis
took place in a cyclic process wherein the induction of themes was
alternated by confrontation with new material.
Results: Family members of traumatic coma patients want information that is as accurate as possible, provided by doctors and nurses
in an understandable manner and leaving room for hope. At first,
family members can do no more than passively absorb the information they receive. After some time, they actively start working with
information and learn what to build their hope on. In this way, concrete hope evolves and seems to be strongly determined by
information. Information that is more positive than warranted is not
appreciated at all. It leads to false hope and once its real nature
becomes apparent, to increased distress and loss of trust in the
professionals.
Conclusion: The process of hope is crucial in coping with traumatic coma and information can facilitate this process. Relevance to
clinical practice. If professionals keep the process in mind that family
members go through in handling information, they can not only
facilitate this process but also help them to establish realistic hope.
__________________________________
Oral session 12
Cerebrovascular disorders II
O243
Early vascular risk after TIA: comparison
between a weekly and daily TIA clinic
M. Fonseca, P. Canhão
University of Lisbon (Lisbon, PT); Hospital de Santa Maria
(Lisbon, PT)
Objectives: Several studies have shown high risk of stroke after
transient ischemic attack (TIA). We aimed to evaluate the stroke and
vascular events recurrence assessed in a TIA Clinic with two types of
functioning: weekly and daily.
Methods: Prospective cohort of consecutive patients referred to a
TIA Clinic from March 2004 to October 2010, at the Neurology
Department of Hospital de Santa Maria. Until September 2009 the TIA
Clinic functioned once a week; after that it worked daily. Standard
clinical assessment and follow-up data were registered. The primary
outcome was the frequency of stroke at 30 days after the TIA. The
secondary outcome was the frequency of combined vascular events
(TIA, stroke, myocardial infarction, vascular death) at 30 days. The
outcomes were compared between the weekly and daily TIA Clinic.
Results: 612 patients with transient neurological signals lasting
less than 24 h were referred: 457 patients to the weekly Clinic, 258
with the final diagnosis of TIA; 155 patients to the daily Clinic, 75
patients with the final diagnosis of TIA. Mean delay from the TIA and
TIA Clinic was significantly lower in the daily TIA Clinic (2.2 vs.
8.6 days, p \ 0.001). The mean age of patients, vascular risk factors,
and clinical characteristics and severity (ABCD2 score) were similar.
123
15 patients (4.6%) had a stroke in the first 30 days after TIA, mostly
in the first days (8 in the first 24 hours). The recurrence of stroke was
higher in the daily TIA Clinic [7 (9.3%) vs. 8 (3.1%), p = 0.05].
There were no differences in the recurrence of combined vascular
events [7 (9.3%) vs. 25 (9.8%), p = 0.976].
Conclusions: The risk of stroke after TIA is higher in the first days.
Selection bias could be an explanation for underestimation of the risk
by the weekly TIA clinic due to the non inclusion of patients with
early recurrences. These results have implications for TIA Clinic’s
organization and public education about TIA.
Supported by GAPIC.
O244
Long-term follow-up helps to clarify the diagnosis
of transient neurological attacks difficult to classify
in a TIA clinic
M.J. Correia, A.C. Fonseca, P. Canhão
University of Lisbon (Lisbon, PT); Hospital Santa Maria (Lisbon, PT)
Objectives: Transient neurological attacks (TNA) are a miscellaneous
group of patients, some with vascular origin (TIA), some accomplishing criteria for a specific Mimic, and others difficult to classify
(Possible TIA). We aimed to identify if the long-term follow-up could
clarify the diagnosis of Possible TIA patients.
Methods: Consecutive TNA patients referred to a TIA Clinic
during five years were classified as TIA, Possible TIA or Mimic. TNA
difficult to classify (Possible TIA) was considered when clinical
features were less convincing of being from vascular origin and an
alternative explanation may have been present, although without a
definitive proof of a specific mimic diagnosis. We analyzed baseline
data and long-term follow-up of Possible TIA patients. Recurrence of
TNA events was analyzed to clarify the inclusion TNA episode.
Results: From 458 TNA patients referred to the TIA Clinic, 109
were classified as Possible TIA. The median age of patients was
62 years, and 65 (59.6%) were men. The follow-up time was 230.3
person-years, median time of 679 days. Vascular events occurred in
10 patients (9.9%, 95% CI 5.5–17.3). Non-vascular events occurred in
25 patients (24.8%, 95% CI 17.4–34), mainly during the first year (21
patients). Repeated stereotyped TNA were reported in 12 cases. The
characteristics of the recurrent TNA allowed the clarification of the
inclusion TNA in 15 patients (15%): 14 Mimic (conversion disorder
in 7, vestibular dysfunction in 2, migraine in 2, metabolic disorder in
2, and angioedema in one); a recurrent TNA allowed the diagnosis of
TIA in one patient. In 11 patients we were not able to determine the
diagnosis of the inclusion event.
Conclusion: TNA difficult to classify is a heterogeneous group of
patients. The reasons limiting the diagnosis at the initial presentation
were related to atypical clinical features, insufficient symptoms
description, or restraints from established diagnosis criteria of specific
mimic. The long-term follow-up was important to clarify the diagnosis of some of them, avoiding unnecessary secondary prevention
and allowing for specific treatments.
O245
Amelioration of risk estimation after a transient
ischaemic attack—the ABCDE– score
A. Burow, M. Amort, F. Jax, F. Weisskopf, M. Katan,
L. Bonati, F. Hatz, F. Fluri, P. Lyrer, S. Engelter
University Hospital Basel (Basel, CH); Vista Clinic Basel (Basel, CH)
S35
Background and purpose: The risk of stroke after a transient ischemic
attack (TIA) can be predicted by scores incorporating age, blood
pressure, clinical features, duration (ABCD-score) and diabetes
(ABCD2-score). However, some patients have strokes despite a low
predicted risk according to these scores. We designed the ABCDE+ score by adding the variables ‘‘etiology’’ and ischemic lesion
visible on diffusion-weighted-imaging (DWI) —‘‘DWI-positivity’’—
to the ABCD-score. We hypothesized that this refinement increases
the predictability of recurrent ischemic events.
Methods: We performed a prospective cohort study among all
consecutive TIA patients in a university hospital emergency department. Area under the computed-receiver-operating curves (AUCs)
were used to compare the predictive values of the scores with regard
to the outcome stroke or recurrent TIA within 90 days.
Results: Among 248 patients, 33 (13.3%, 95% CI 9.3–18.2%) had
a stroke (n = 13) or a recurrent TIA (n = 20). Patients with recurrent
ischemic events more often had large-artery-atherosclerosis as the
cause for TIA (46 vs. 14%, p \ 0.001) and positive DWI (61 vs. 35%;
p = 0.01) compared with patients without recurrent events. Patients
with and those without events did not differ with regard to age,
clinical symptoms, duration, blood pressure, risk factors, and stroke
preventive treatment. The comparison of AUCs (95%CI) showed superiority of the ABCDE+ score [0.67 (0.55–0.75)] compared to the
ABCD2-score [0.48 (0.37–0.58); p = 0.04), and a trend towards superiority compared to the ABCD-score [0.50 (0.40–0.61); p = 0.07).
Conclusion: In TIA patients, the addition of the variables ‘‘etiology’’ and ‘‘DWI-positivity’’ to the ABCD-score seems to enhance the
predictability of subsequent cerebral ischemic events.
The study was supported by research grants from the Swiss Heart
Foundation and the Foundation of Health and Cardio-Neurovascular
Research, Basel, Switzerland.
O246
Ambulatory blood pressure levels are associated
with the total extent of silent cerebral small-vessel
disease in first-ever lacunar stroke patients
P. Klarenbeek, R.J. van Oostenbrugge, R.P.W. Rouhl,
I.L.H. Knottnerus, J. Staals
Maastricht University Medical Centre (Maastricht, NL)
Objectives: Asymptomatic lacunar infarcts, white matter lesions,
brain microbleeds (BMB) and enlarged Virchow-Robin spaces
(eVRs) have all been identified as ‘‘silent’’ markers of cerebral small
vessel disease (cSVD). Blood pressure is considered an important and
treatable risk factor for cSVD. Previous studies showed that higher
blood pressure levels are associated with the presence of each of the
markers of cSVD separately. However, the association between
higher blood pressure levels and the presence of all these markers
combined is unknown. We hypothesize that the combined presence of
the individual markers of cSVD increases with higher 24 h ambulatory blood pressure levels. In order to study this relation, we introduce
a new scale for the total extent of cSVD.
Methods: We performed 24-h ambulatory blood pressure monitoring in 122 first-ever lacunar stroke patients after the acute stroke
phase. On brain MRI we scored the presence of any asymptomatic
lacunar infarcts, any BMB, extensive eVRs in the basal ganglia and
extensive white matter lesions. One point was awarded for the presence of each of these markers producing a minimum score of 0 and a
maximum of 4.
Results: Twenty-five (20%) patients had no signs of cSVD on
MRI, the categories 1 to 4 contained 41 (34%), 24 (20%), 19 (16%)
and 13 (11%) patients respectively. In ordinal regression analyses
higher day (OR 1.26; 95%CI 1.04–1.54 per 10 mmHg) and night (OR
1.21; 95%CI 1.01–1.45 per 10 mmHg) systolic blood pressures were
associated with the extent of cSVD after correction for age and sex.
Higher day (OR 1.36; 95%CI 1.16–1.58 per 5 mmHg) and night (OR
1.34; 95%CI 1.14–1.68 per 5 mmHg) diastolic blood pressures were
also associated with the extent of cSVD after correction for age and
sex.
Conclusion: We found that higher ambulatory blood pressure
levels were associated with increasing total extent of cSVD after
correction for age and sex. This implies that with increasing blood
pressure levels there is a ‘‘piling up of damage’’ in the brain. Although
this relation is now described for the first time and needs to be confirmed, it points to the high impact of blood pressure on the total
extent of silent cerebral SVD.
O247
Acute stroke patients benefit from emergency transfer
within a telemedicine stroke network
J. Kepplinger, I. Dzialowski, V. Puetz, H. Hentschel,
H. Schneider, M. Wolz, T. Schultheiss, G. Gahn,
G. Schackert, R. von Kummer, H. Reichmann, U. Bodechtel
University of Technology (Dresden, DE); Community Hospital
(Karlsruhe, DE)
Objectives: Telemedicine aids selection of stroke patients who may
require an emergency transfer to a comprehensive stroke center to
receive additional therapies other than intravenous (IV) thrombolysis.
We report our experience on emergency transfers in the telemedical
Stroke East Saxony Network (SOS-NET) of 14 cooperating hospitals
covering a population of 1.7 million people in eastern Saxony,
Germany.
Methods: We reviewed all consecutive acute stroke patients who
were transferred emergently from remote stroke sites to our comprehensive stroke center. Certified stroke neurologists performed
teleconsultations 24 h/day with access to high-speed videoconferencing and transfer of neuroimages. They recommended emergent
transfer when necessary. Clinical data including National Institutes of
Health Stroke Scale (NIHSS) score at baseline and the modified
Rankin Scale (mRS) score at discharge were prospectively documented in the databank of the telestroke service. Favourable outcome
at discharge was defined as mRS scores 0–2.
Results: In 2009, we conducted 550 teleconsultations and
recommended transfer in 139 (25%) patients [mean age
63.8 ± 14.4 years, 55% male, median NIHSS score 6.5 (range
0–32)]. The mean time from teleconsultation to arrival at our stroke
center was 1.8 ± 0.9 h. Twenty-nine (21%) emergent transfers had a
non-stroke diagnosis [brain tumours, 9 (6%); seizures, 5 (4%); other
etiologies, 15 (11%)]. The remaining 110 transferred patients had
stroke diagnoses [ischemic strokes, 47 (34%); transient ischemic
attacks, 5 (4%); intracranial hemorrhages (ICH), 58 (42%)]. Of the 47
ischemic stroke patients 12 (26%) received IV tPA at spokes
(‘‘drip&ship’’). Intra-arterial reperfusion procedures were performed
in 6 (13%) and decompressive hemicraniectomy was done in 6 (13%)
ischemic stroke patients. In ICH patients, acute interventions were:
endovascular procedures, 3 (5%); neurosurgical hematoma evacuation, 19 (33%); aneurysm clipping, 3 (5%); and additional or isolated
external ventricular drainage, 13 (22%). At discharge, 37 (34%)
stroke patients had a favourable outcome while mortality rate was
9%.
Conclusions: Telemedicine based triage of acute stroke patients
can be a beneficial concept for delivering additional stroke therapies
that require advanced multi-specialty experts.
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O248
Influence of lipid profiles on the risk of haemorrhagic
transformation in ischaemic stroke patients:
a systematic review
K. Nardi, D. Leys, P. Eusebi, C. Cordonnier, S. Gautier,
H. He´non, R. Bordet
University of Perugia (Perugia, IT); University Lille nord de France
(Lille, FR); Regional Health Authority of Umbria (Perugia, IT)
Background and purpose: It has been suggested that low cholesterol
levels are associated with a slightly increased risk of haemorrhagic
transformation (HT) in patients with cerebral ischaemia. We systematically reviewed published studies to determine the influence of
lipid profiles on the HT risk.
Methods: We searched PubMed from 1966 and Embase from 1980
for studies that investigated the association between lipid profiles and
HT. We performed a meta-analysis separately for the comparison
between HT vs. no-HT, for total-, LDL-, HDL-cholesterol and triglycerides (weighted mean difference method). This analysis was
performed for any-HT and symptomatic-HT.
Results: Eight studies gathering 1,763 patients were eligible. No
study recruited consecutive acute ischaemic stroke patients irrespective of the cause and treatment received. No study was designed
specifically for this question. The meta-analysis showed that (1) LDLcholesterol levels were significantly lower in patients with any-HT
(p = 0.008), but not total cholesterol (p = 0.129) and triglycerides
(p = 0.900), while HDL-cholesterol tended to be higher (p = 0.066);
and (2) total cholesterol levels were significantly lower in patients
with symptomatic-HT (p = 0.035), while LDL-cholesterol levels
(p = 0.056) and HDL-cholesterol levels (0.138) tended to be lower,
but not triglycerides (p = 0.851).
Conclusion: LDL-cholesterol levels are lower in HT patients, but
results are not conclusive for HDL-cholesterol. There is no association with triglycerides levels. The next step will be to focus on the
mechanisms of this association, especially in patients treated by rtPA
who are those with the highest risk of HT in practice.
Dr. K. Nardi received a grant from the European Neurological
Society.
__________________________________
Oral session 13
Movement disorders
O249
N-acetyl-aspartate serum levels in Huntington’s disease
patients
M. Ruggieri, E. Ceci, C. Serpino, C. Pica, M. Trojano,
P. Livrea, M. de Tommaso
University of Bari (Bari, IT)
Objectives: Huntington’s disease (HD), a genetic neurodegenerative
disease caused by a polyglutamine expansion in the Huntingtin (Htt)
protein, is accompanied by multiple mitochondrial alterations, apoptotic signals and energy depletion. N-acetyl-Aspartate (NAA) is a
significant indicator in the assessment of neuronal activities and
abnormalities in the cerebral metabolism; it is synthesized in neuronal
mitochondria, then it is transported by a sodium/dicarboxylate molecule (NaC3) to aspartoacyclase-containing oligodendrocytes, which
represent the NAA main catabolic route, and to astrocytes, which take
up extracellular NAA and excrete it to the circulation.
123
Methods: The aim of the present study was the evaluation of NAA
serum levels in a cohort of HD patients, compared to age and sexmatched controls. This study enrolled 22 consecutive out-patients (13
females, age 31–75, mean 53 ± 2.08), affected by genetically confirmed HD, attending the Ambulatory for Huntington’s chorea of the
Neurological Science Department of Bari University. They were
recruited during their first visit. Fourteen were taking neuroleptics. All
patients underwent the motor section of Unified Huntington’s Disease
Rating Scales (UHDRS) and the Total Functional Capacity Scale.
Twenty-one age and sex matched control subjects (10 females, age
36–62, mean 47.57 ± 7.68: t test 0.23; n.s.) were also enrolled. A
methodological approach of recent interest, the liquid chromatographymass spectrometry (LC–MS) with stable isotope dilution, was used.
Results: The NAA serum levels were on average 0.084 ±
0.013 mM/L in normal controls and 0.65 ± 0.15 mM/L in HD
patients. (t test: 5 p 0.00001). Patients taking neuroleptics did not
display different NAA serum levels compared with drug-free patients
(t test: 0.93; n.s.). Moreover, the NAA levels displayed a positive
correlation with the global motor impairment and the degree of ocular
movement disturbances.
Conclusion: NAA levels were significantly higher in HD patients
compared to controls, independently from drugs intake. They were
correlated with motor impairment, tapping and oculomotor deficits,
and functional decline. The NAA serum levels seemed to correlate
with motor and functional deterioration, as a potential biomarker of
illness progression. The relative feasibility of this method would
support the replication of this study in a large premanifest and early
HD cohort, necessary to fully validate these findings.
O250
Transcranial sonography could discriminate
between hepatic and neurologic form of Wilson’s
disease
M. Mijajlovic, M. Svetel, A. Tomic, N. Kresojevic,
T. Pekmezovic, V. Kostic
Neurology Clinic (Belgrade, RS)
Aim: To determine usefulness of the transcranial brain parenchyma
sonography (TCS) in detection of potentially patterned finding in
Wilson disease (WD) with and without neurological involvement and
its correlation with disease duration and severity.
Patients and methods: 54 patients with WD (33 with neurologic,
16 with hepatic, 5 with mixed form) and 60 age-and sex matched
subjects without any psychiatric or neurodegenerative disease were
investigated. TCS was carried out by 2.5-MHz transducer (Aloka, A
10) by one investigator who was not aware of the group of the subject.
Echogenicity of substantia nigra (SN), thalami, the lenticular nuclei
(LN), and the heads of the caudate nuclei was investigated and
classified as hyperechogenic when it was more intense than the surrounding white matter. The hyperechogenic areas were calculated
planimetrically and given in cm2. Echogenicity of the brainstem raphe
was rated semiquantitatively on a two point scale, and the diameter of
the ventricular system was measured on diencephalic plane.
Results: In comparison with controls, WD patients had significantly increased SN- (p = 0.007) and LN-echogenicity (p = 0.001).
Patients with neurologic form had significantly increased SN echogenicity (p = 0.025) and the third ventricle diameter (p = 0.002)
compared with hepatic form. Disease severity correlated with SN and
LN echogenicity (r = 0.303; p = 0.029, respectively) and with the
third ventricle diameter (r = 0.351; p = 0.011), while there were no
correlation between disease duration and any of the brain structures
studied.
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Conclusion: TCS differentiate WD from healthy individuals, but
also neurologic- from hepatic-form of WD. It allows correlation
between disease severity and hiperechogenicity of certain basal
ganglia structures.
O251
Abnormal processing and noise within the neckproprioceptive control loop in cervical dystonia
D. Anastasopoulos, C. Maured, T. Mergner
University of Athens (Athens, GR); University of Freiburg (Freiburg, DE)
Objectives: The excessive muscle activation in spasmodic torticollis
is associated with abnormal sensory processing. Not only tactile, but
also vestibular and particularly proprioceptive signals may be
implicated. This study aimed at investigating which sensorimotor
function is responsible for the development of the abnormal head
postures.
Methods: Resistive neck muscle torque to imposed head/trunk
and/or head-in-space displacements was measured in 13 cervical
dystonia patients and 23 control subjects. Patients (Ps) were seated
on a Barany rotation chair, their heads being stabilized by means of
a dental bite-board. The board was attached to a head holder, which
was mounted on the chair, but could be rotated independently from
the latter in the horizontal plane. The shaft of the head holder
contained the device for measuring the torque. Ramp rotations of
14 amplitude were applied in darkness. Three different stimulus
durations were used (10, 5 and 1.25 s).18 stimuli were dispensed in
a randomized order. Torque response parameters were analysed and
described in a formalized way by means a previously established
head control model, based on data derived from normal subjects and
parkinsonian patients (Anastasopoulos et al. Exp Neurol
2009,217:336-346).
Results: Baseline torque in Ps was offset to 0.36 ± 0.31 Nm in the
direction of the torticollis (controls 0.02 ± 0.02 Nm, p \ 0.0001. Ps
showed large spontaneous torque fluctuations (intrasubject variability
was larger than in normals; p \ 0.0001). Upon both trunk-only and
head-only rotations, peak torque and after-stimulus torque with
respect to baseline were larger in Ps (p \ 0.02 and p \ 0.0005
respectively, Fig. 1). In Ps, there was no difference between responses
contra- and ipsilateral to torticollis direction. Their baseline torque
correlated with both peak torque and after-stimulus torque level.
Power spectral density plots of spontaneous torque variation showed
essentially 1/f characteristics. In Ps, the level was abnormally
enhanced across all frequencies.
Conclusions: Signal noise level is enhanced in the Ps’ neck control
loops. We assume that the enhancement leads (e.g. in combination
with peripheral trauma, strain injury) to a directional offset bias in the
long latency loop through basal ganglia and cortex. In model simulations we show that this bias may affect the set-point signal of the
neck joint stabilization and lead to the abnormal spontaneous torque
and related response characteristics.
O252
Dystonia in adult patients with classical galactosemia
I. Rubio-Agusti, M. Carecchio, R. Lachman, M. Edwards,
K. Bhatia, E. Murphy
University College (London, UK); National Hospital for Neurology
and Neurosurgery (London, UK)
Objective: To define the prevalence and phenotype of dystonia in a
cohort of adult patients with galactosemia
Background: Classical galactosemia is an autosomal recessive disorder due to mutations of the enzyme galactose-1-phosphate
uridyltransferase, resulting in the accumulation of galactose and its
metabolites. Prior to the introduction of neonatal screening, the disease
presented in the newborn with grave systemic complications (liver
damage, sepsis, failure to thrive), but early identification and treatment
with galactose restricted diet has had a tremendous impact on prognosis.
Nevertheless long term complications affecting the CNS, with cognitive
and motor involvement, including dystonia, have been described,
although their exact prevalence and phenotype are not known.
Methods: All patients with classical galactosemia attending the
adult metabolic clinic at the National Hospital for Neurology (London, UK) from September to December 2010 were examined and
their notes reviewed by the authors.
Results: A total of 18 patients were seen. All had been diagnosed
within the first 2 months of life, except 1 (6 years of age), starting a
galactose restricted diet since diagnosis. 5 patients had dystonic
features: 3 patients had segmental craniocervical dystonia and 2 had
generalized dystonia. All patients had associated tremor (1 head tremor, 1 rest tremor, 4 postural tremor, 2 action tremor). Patients with
generalized dystonia had widespread neurological involvement
(pyramidal, cerebellar, cognitive) and were disabled. One of the
patients with segmental dystonia, the oldest in the series, had also
evidence of parkinsonism. There was no correlation with systemic
complications (cataracts, osteopenia, premature ovarian failure) or
with levels of galactose-1-phosphate.
Conclusions: Dystonia is a relatively frequent complication of
classical galactosemia, usually mild and predominantly involving the
craniocervical region. It is frequently associated with tremor, especially postural. Motor complications can be a cause of disability in
these patients, despite early and adequate treatment.
O253
Biperiden may improve segmental and generalised
dystonia
N. Kovacs, J. Janszky, G. Dibo, F. Nagy, S. Komoly
University of Pecs (Pecs, HU)
Objectives: Anticholinergics are one of the first-line pharmacological
treatments of dystonia. Trihexyphenidyl is the most frequently recommended and investigated anticholinergic drug for dystonia;
however, it is not available worldwide. Our primary aim was to
investigate the efficacy of biperiden, another anticholinergic drug, on
the severity and disability related to dystonia of non-tardive origin.
Methods: Twenty-three patients with segmental or dystonia (primary n = 15, juvenile cerebral palsy n = 3; neurodegeneration with
brain iron accumulation n = 2, post-stroke n = 2; deafness-dystoniaoptic neuropathy syndrome n = 1) aged 22–76 years were enrolled.
Biperiden was slowly titrated to the highest tolerated dose. Burke–
Fahn–Marsden Dystonia Rating and Dystonia Disability Scales were
obtained before and 12 weeks after biperiden treatment was initiated.
Due to biperiden side-effects, four patients did not complete the trial.
Results: Severity of dystonia improved from 44 points (median
31.5–47 points, 25th and 75th percentiles respectively) to 30 points
(median 23.5–47 points), which was considered as a significant
change (p = 0.01). The size of improvement correlated with the
applied biperiden dosage (r = 0.451, p \ 0.01). Of 19 participants
completed the study, only 7 (36.9%) had an improvement larger or
equal to 25% (treatment responders). Simultaneously, the disability
scale also showed a significant improvement (10%).
Conclusions: Comparing our results to that of other studies, we
may conclude that biperiden may be tried for treating segmental or
generalized dystonia in those countries where trihexyphenidyl is
123
S38
unavailable. However, further studies are required involving larger
population of patients and utilizing double-blinded, placebo-controlled design to precisely evaluate its therapeutic efficacy.
NK and JJ were supported by the government-based Bolyai
Scholarship of the Hungarian Academy of Sciences.
O254
Moving towards ‘‘laboratory supported’’ criteria
for psychogenic tremor
P. Schwingenschuh, P. Katschnig, S. Seiler, T. Saifee,
M. Aguirregomozcorta, R. Schmidt, J. Rothwell, K. Bhatia,
M. Edwards
Medical University of Graz, Austria (Graz, AT); University College
(London, UK)
Objective: Psychogenic tremor (PT) can be remarkably variable in its
presentation and therefore remains a diagnostic challenge. The importance of a positive diagnosis rather than one of exclusion has been
repeatedly emphasized, and there is a need for a ‘‘laboratory supported’’
level of diagnostic certainty. With this study we aimed to test the sensitivity and specificity of parameters of tremor analysis in differentiating a
broad spectrum of organic tremors (OT) from PT.
Methods: We investigated 13 patients with PT and a group of 25
patients with OT (nine patients with Parkinson’s disease, eight with
dystonic tremor, six with essential tremor, and two with neuropathic
tremor). Bilateral tremor analysis using accelerometry and surface
EMG was performed using a wide range of previously reported
techniques to differentiate between OT and PT.
Results: Patients with PT had a significantly higher tremor amplitude
during rest, posture, and action compared to OT. There was no distinguishing effect regarding tremor frequency during the following tasks:
counting backwards, subtracting seven, Stroop test, and mass loading.
Tremor amplitude however significantly decreased in the PT group
during subtracting sevens at rest and posture, and during counting
backwards at posture, whereas tremor amplitude significantly increased
in PT during mass loading. Transient arrest of tremor induced by contralateral ballistic movements was significantly more common in PT
compared to OT. Neither group showed significant entrainment during
finger tapping tasks at 1, 3, and 5 Hz, but the quality of performance of the
tapping task was significantly poorer in the PT group at 1 Hz, without any
significant difference between PT and OT at 3 and 5 Hz. Sensitivity and
specificity of these tests ranged from 54–80% and 53–84%, respectively.
Conclusion: The documentation and quantification of the effects of
distraction tasks and ballistic movements on contralateral arm tremor are
of clinical relevance for the identification of patients with PT, and the
combination of certain subtests may help to move towards a ‘‘laboratory
supported’’ level of diagnostic certainty.
__________________________________
Oral session 14
Neuro-otology
O255
Quantification of the vestibulo-ocular reflex
in cerebellar patients
O. Kremmyda, H. Kirchner, S. Glasauer, K. Jahn, M. Strupp
Ludwig-Maximilians-University (Munich, DE)
123
Objective: To correlate the findings of the clinical examination of the
vestibuloocular reflex (VOR) by the head impulse test, the caloric
excitability and the measured VOR gain (-eye velocity/ head velocity)
in patients with cerebellar disease.
Methods: Sixteen patients with cryptogenic cerebellar ataxia and bilateral pathological head impulse test during clinical examination were
included in this study and examined by means of caloric irrigation and, in
order to measure the gain of the angular VOR, using the scleral search coil
technique. We divided these patients into two groups according to their
caloric response: a group with patients with pathological calorics and a group
with patients with normal calorics. In addition to the head impulse test, slow
(0.33 Hz) VOR gains were calculated in dark and during target fixation.
Results: Eight cerebellar patients (mean age 69.8 years) with normal
calorics (mean max Slow Phase Velocity (SPV): 15 /s) showed slightly
reduced VOR gains (on average 0.72) during the head impulse test. These
patients made a small refixational saccade at 195 ms after initiation of the
head impulse. In comparison, the remaining eight patients (mean age
73.1 years) with pathological calorics (mean SPV 1.1 /s) showed lower
VOR gains (up to 0.37) at 80 and 100 ms. Moreover, in these patients, the
first refixational saccade was initiated much earlier (on average at 126 ms
after head impulse initiation). VOR gains in light and dark were also
higher in the normal calorics group.
Conclusions: Scleral search coil recordings revealed reduced VOR
gains and clinical examination a bilateral pathological head impulse
test in patients with cerebellar ataxia, also when caloric irrigation was
normal. In these patients the bilateral pathological head impulse test
could be attributed to a central, not a peripheral vestibular deficit.
O256
Absence of Alexander’s law effects during high
acceleration head rotations in normal subjects
and patients with unilateral vestibulopathy
E. Anagnostou, J. Heimberger, S. Sklavos,
D. Anastasopoulos
University of Athens (Athen, GR); University of Tübingen
(Tübingen, DE)
Objectives: Alexander’s law (AL) states that the amplitude of the spontaneous nystagmus of a patient with a unilateral vestibular lesion grows
with increasing gaze in the direction of the fast phase. Little is known
about the underlying neural mechanisms and the few available studies
emphasize the role of gaze dependent vestibulo-ocular reflex (VOR)
modulation and the need for non-reciprocal vestibular stimulation,.
Methods: We tested (1) whether the normal human VOR in the
behaviorally relevant high frequency range has intrinsic properties
that could account for AL and (2) whether patients with unilateral
vestibular neuritis (VN) in the postacute phase exhibit AL-compatible
effects upon high acceleration head rotations.
Head and eye movements were recorded with the search-coil
method during passive head-impulses in yaw while subjects were
asked to hold gaze at various azimuth angles (±16).
Results: The gain of the VOR remained unaffected by eye-in-orbit
position in normals as well as in VN patients, both during ipsilesional
as well as contralesional head impulses.
Conclusion: These findings suggest that eye-in-orbit position does
not directly modulate the activity in VOR pathways in the behaviorally relevant frequency range. This was true both for unbalanced
but reciprocal vestibular stimulation (healthy controls) as well as for
unbalanced, non-reciprocal natural vestibular stimulation of short
duration (VN patients). These findings should be taken into account
when trying to explain AL with models based on the interaction of
vestibular and eye position signals within the three-neuron arc.
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O257
Single motor unit recordings of ocular vestibular
evoked myogenic potentials in human extraocular
muscles
S.M. Rosengren, K.P. Weber, R. Michels, V. Sturm,
K. Landau, D. Straumann
Zurich University Hospital (Zurich, CH)
Objectives: To investigate the neural pathway of the vestibuloocular reflex (VOR) to individual extraocular muscles and determine the source of the ocular vestibular evoked myogenic potential
(oVEMP) in response to vestibular activation with vibration and
sound.
Methods: Three healthy subjects were stimulated with 500 Hz,
4 ms bursts of bone-conducted vibration (using a hand-held ‘minishaker’ at the hairline near Fz) and air-conducted sound (using
headphones). Motor units from the inferior oblique (IO) eye muscles
were recorded with concentric needle electrodes. Standard oVEMPs
were recorded simultaneously with surface electrodes below the eyes.
Single motor units were extracted from multi-unit recordings and
quantified in peri-stimulus histograms.
Results: Following vibration, an increase in IO single motor unit
discharge was seen at a mean peak latency of 11.0 ms (range
10–13 ms, n = 6 units). At this latency, discharge was 4.1 times the
level seen during the 40 ms pre-stimulus period. Similar modulation
was seen in multiple unit recordings (mean latency 11.0 ms, range
10–14 ms, mean amplitude 2.8 times baseline level, n = 14
recordings). Following sound stimulation, an increase in IO activity
was seen in the muscle contralateral to the stimulus at a mean
latency of 13.8 ms (range 13–14 ms, amplitude 1.9 times baseline
level, n = 4 multiple unit recordings). Latency and polarity of the
simultaneous surface oVEMPs corresponded to the needle
recordings.
Conclusion: The study identifies the IO, specifically its excitation,
as the source of oVEMP signals in response to both sound and
vibration. The result confirms a direct VOR pathway from the vestibular organs to individual eye muscles in humans.
The authors received funding from the National Health and
Medical Research Council Australia, the Betty and David Koetser
Foundation, and the Swiss National Science Foundation.
O258
When the brain misses the vestibular compass—
complete vestibular loss alters navigational behaviour
and brain activation during real navigation
A. Zwergal, C. La Fouge`re, G. Xiong, G. Kugler,
J. Schlichtiger, T. Brandt, M. Dieterich, M. Strupp,
P. Bartenstein, E. Schneider, K. Jahn
University of Munich (Munich, DE)
Objectives: Characterisation of the navigational strategy and
supraspinal navigational network activation during real navigation
in patients with complete vestibular loss compared to healthy
controls
Methods: 8 normal persons and eight patients with bilateral vestibulopathy had to perform a navigation paradigm in a complex
unknown spatial environment of an outpatient clinic. The area, in
which five items had been placed, was shown to the subjects first.
Afterwards FDG was injected and subjects had to find the items in a
pseudo-randomized order over the next 10 min. Subjects carried a
gaze-controlled head-camera throughout the experiment to document
their visual exploration behaviour. As a control condition all subjects
had to perform a steady-state locomotion paradigm without navigation following FDG injection at a second time point. Brain activation
patterns were compared for the navigation vs. locomotion paradigm
and were correlated with the recorded visual exploration behaviour
during navigation.
Results: During navigation in normal persons brain activation
was found in the pontine brainstem tegmentum and the anterior
hippocampus (right [ left). The comparison of navigation-induced
brain activation in normal persons and patients with bilateral vestibulopathy showed a significantly higher activation of the right
anterior hippocampus as well as the posterior insula bilaterally in
controls, whereas an increased activation of the posterior parahippocampus was found in patients with bilateral vestibulopathy.
Analysis of visual exploration behaviour indicated a navigation
strategy following a cognitive spatial map for normal persons,
whereas patients with bilateral vestibulopathy navigated more by a
landmark-based strategy.
Conclusions: The navigational behaviour in normal persons and
patients with complete vestibular loss is significantly different. A
navigational strategy using a cognitive spatial map in normal persons
correlates with an activation of the anterior hippocampus, while a
landmark-based strategy in patients with bilateral vestibulopathy goes
with an increased activation of the posterior parahippocampus. It can
be assumed, that the lack of vestibular information impairs the construction of a spatial cognitive map via head direction and place cells
in the hippocampus.
O259
Visual dependency after vestibular neuritis
S. Cousins, N. Cutfield, D. Kaski, B. Seemungal,
J. Golding, M. Gresty, A. Bronstein
Imperial College London (London, UK); University of Westminster
(London, UK)
Objectives: Vestibular patients often report visually induced dizziness
‘visual vertigo’, where dizziness and disorientation are brought on by
complex or moving visual surroundings. These symptoms are
believed to stem from increased visual dependency in response to
vestibular injury. We now examine the interplay between symptoms,
visual dependency and psychological factors in the acute and recovery stages after vestibular neuritis (VN).
Methods: Twenty-five VN patients (mean age = 48.5,
range = 20–75) were tested acutely (mean 2 days after onset).
Eighteen were followed up in the early recovery stage
(mean = 9.9 weeks). A separate ‘chronic’ group of 20 VN patients
(mean age 52.9) were tested [6 months from onset. Visual dependency was measured with a laptop version of the Rod and Disc test:
patients have to set a straight line to their subjective visual vertical
against a roll-plane disk rotating at 30 /s. Validated questionnaires
were completed—Dizziness Handicap Inventory (DHI); Hospital
Anxiety and Depression scale (HADS); Body Sensations Questionnaire (BSQ). Speilberger Trait Anxiety Inventory and Situational
Vertigo Questionnaire (visual vertigo) were given at follow up only.
All patients had caloric testing acutely and at follow up.
Results: Factor analysis revealed 3 factors. The first factor
accounting for 42% of the variance loaded recovery measure (DHI),
visual dependency (acute and follow up), situational vertigo and
follow up HADS and BSQ scores. Symptom score at follow up
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S40
correlated significantly with acute and follow up visual dependency (R = 0.66, p = 0.001 and R = 0.54, p = 0.01,
respectively). The ‘chronic’ group showed a similar pattern, with
those suffering from higher levels of handicap showing increased
visual dependency. The second factor loaded acute HADS score
and trait anxiety, whilst the third factor loaded acute and follow
up caloric function only—these two latter factors thus are not
associated with recovery.
Conclusion: Patients suffering from higher levels of handicap
show increased visual dependency. Visual dependency both acutely
and at follow up predicts symptom recovery, highlighting the
importance of compensatory strategies adopted early after a vestibular
insult. Dizzy psychological syndromes, such as chronic subjective
dizziness, may at least partly be due to inadequate central processes
after vestibular injury, resulting in increased visual dependency and
chronic symptoms.
O260
A dual-centre, double-blind, cross-over trial of 4aminopyridine in the downbeat nystagmus syndrome—
effects of the drug on slow-phase eye velocity
R. Kalla, J. Claassen, R. Spiegel, M. Foldon, C. Kennard,
C. Danchaivijitr, S. Bardins, T. Dera, N. Rettinger,
E. Schneider, S. Glasauer, T. Brandt, A. Bronstein,
M. Strupp
Ludwig-Maximilians University (Munich, DE); Imperial College
(London, UK); Oxford University (Oxford, UK)
Objective: Animal experiments demonstrated that aminoypyridines
increase Purkinje-cell excitability (Etzion et al. 2001) and 4-aminopyridine (4-AP) improved downbeat nystagmus in clinical studies
(Strupp et al. 2003, Kalla et al. 2004). In this two centre, double-blind
prospective crossover study, the effects of 4-AP were analysed in
terms of slow-phase velocity of the downbeat nystagmus (DBN,
patient-satisfaction and side-effects.
Methods: 27 patients with DBN were included. They were randomly assigned to receiving four single capsules (in the morning, at
noon, in the afternoon, in the evening) of 5 mg 4-AP (or placebo) for
the first 3 days and four single capsules of 10 mg 4-AP (or placebo),
administered at equal times of day, for the following 4 days. This was
followed by 6 days with no medication (=wash-out period). One week
later the treatment was switched over. Recordings were done with
three-dimensional videooculography (gaze straight ahead with fixation turned on) before the first drug administration (=baseline),
60 min after the first drug administration (=5 mg 4-AP or placebo)
and 60 min after the last drug administration (=10 mg 4-AP or
placebo).
Results: There was an overall decrease of slow phase velocity
from baseline in the 4-AP group (p \ 0.05) with a significant posthoc difference between baseline and 5 mg 4-AP (p = 0.04, twotailed). In the placebo-condition, there was no significant decrease in
terms of slow phase velocity (p = 0.31). There was no statistical
difference in terms of patient satisfaction (p [ 0.2) or in terms of
reported side-effects between placebo or 4AP (p [ 0.08). Focusing on
the 4-AP-condition, it turned out that there was a significant correlation between increasing age and the amount of decrease in SPV
(Spearman’s rho = 0.48, p \ 0.05).
Conclusions: 4-AP reduced slow phase velocity of DBN whereas
placebo did not. Additional analyses revealed that older patients in
particular benefited from 4-AP (at 5 mg dose) by reducing their slow
phase velocity of DBN. Clinically, 4-AP is a useful medication for
patients with DBN, but not all patients respond to the drug. Based on
123
patients’ characteristics and their own satisfaction with the drug,
clinicians should decide individually whether or not a particular
patient should enter long term treatment.
__________________________________
Oral session 15
Neuro-imaging
O261
Neuroanatomical substrates of emotion recognition
and Theory of Mind: a multi-modal MRI study
in multiple sclerosis
A. Mike, R. Herold, E. Stammer, M. Aradi, G. Orsi,
G. Perlaki, A. Hajnal, J. Sandor, C.R.G. Guttmann, Z. Illes
University of Pecs (Pecs, HU); Diagnostic Center of Pecs (Pecs, HU);
University of Debrecen (Debrecen, HU); Harvard Medical School
(Boston, US)
Objectives: Cognitive processing of socially relevant information is
fundamental to the adaptation to the social environment. The capacity
to interpret thoughts, intentions, desires and beliefs of other people is
known as mentalization (Theory of Mind). Here, we investigated
cortical and white matter (WM) pathologies associated with emotion
recognition dysfunction in multiple sclerosis (MS) using a multimodal MRI study. With this approach we also explored neuroanatomic substrates and connectivity of mentalization.
Methods: Forty-nine patients with MS according to McDonald
Criteria underwent emotion recognition testing including Eyes test,
psychometric assessment, and brain MRI; 24 gender- and age-matched healthy subjects served as controls. Total, and regional lesion
load, and cortical thickness were assessed on three-dimensional
MPRAGE sequence; fiber tractography was performed on diffusionweighted echo-planar imaging on 3 Tesla.
Results: After correction for gender, depression, and anxiety, MS
patients performed significantly poorer in Eyes test compared to
controls (p \ 0.001, 2R = 0.263). After controlling, Eyes test performance significantly correlated with cortical thickness of focal
areas in the right precentral gyrus, right caudal middle frontal gyrus,
left anterior pole, and left fusiform face area (p \ 0.001). As for
WM, Eyes test performance also correlated with T1 regional lesion
volume of the splenium of corpus callosum (SCC) (p = 0.002,
2R = 0.288). To examine relationship between regional WM lesion
volume and cortical atrophy, tractography was performed: tracts in
T1 lesions in SCC projected into the occipital, temporal, and parietal lobes. Finally, using a stepwise linear regression model, cortical
thicknesses of the left temporal pole (St b = 0.291), right caudal
middle frontal gyrus area (St b = 0.251), right precentral gyrus area
(St b = 0.234), and T1 lesion volume of SCC (St b = -0.278)
independently contributed to the Eyes test performance
(R2 = 0.525, p \ 0.001).
Conclusion: Both multifocal thinning of fronto-temporal cortical
areas involved in the social-cognitive neural network and interhemispheric integration disturbances of high-level visual processing
impact emotion recognition in MS patients. Thus, early deficit of
social cognition in MS can be regarded as a disconnection syndrome
of mirror neuron areas important in ToM due to regional lesions; in
addition, primary and secondary cortical atrophy related to WM
lesions also contribute.
Dr. Mike is a recipient of the 2008 McDonald Fellowship from the
Multiple Sclerosis International Federation.
S41
O262
Gender differences in brain structure and resting state
activity: a study in a large cohort of healthy young
subjects
M. Filippi, M.A. Rocca, P. Valsasina, G. Riccitelli,
A. Falini, G. Comi
University Hospital San Raffaele (Milan, IT)
Objectives: Previous functional MRI (fMRI) studies have shown that
cortical activations differ between males (M) and females (F) when
performing the same tasks. Using voxel-based morphometry (VBM),
gender-related differences of gray matter (GM) volume have also
been demonstrated. In this study, we assessed, in a large group of
young healthy subjects, gender-related differences in the resting state
(RS) activity in all RS networks (RSNs) with a possible functional
relevance, and investigated their correspondence with GM volume
differences assessed with VBM.
Methods: Using a 3.0 Tesla scanner, RS fMRI scans and 3D highresolution T1-weighted images were acquired from 104 right-handed
healthy controls (48 M/56 F, mean age = 23.5/22.8 years). Independent component analysis was used to decompose resting fMRI
data into spatially independent components (ICs) using the GIFT
software. This analysis produced 41 ICs. A frequency analysis of IC
time courses and correlation with custom-made templates based on
previous studies was used to identify RSNs with potential functional
relevance. VBM analysis was performed using SPM8. Betweengender differences of RSNs and GM volumes were analyzed using
SPM8 and two-sample t-tests.
Results: The analysis of RS data detected 11 networks with
potential functional relevance. Differences in the entity of RS activity
were found in the majority of the detected RSNs. In summary, M had
higher RS fluctuations than F in several regions of the temporal and
parietal lobes, including the bilateral middle temporal gyrus (MTG),
the right (R) insula, the R postcentral gyrus and the bilateral paracentral lobule. Conversely, F had higher RS activity than M in several
regions of the frontal lobes (the middle frontal gyrus [MFG], the
inferior frontal gyrus [IFG] and the anterior cingulate cortex [ACC]),
the bilateral cerebellum, and some visual and auditory regions.
Compared to F, M had an increased GM volume in the R occipital
cortex. Conversely, F showed an increased GM volume than M in the
L superior orbitofrontal cortex, the bilateral precuneus, the R ACC
and the L caudate.
Conclusions: Gender-related differences were found in the
majority of the brain RSNs. Functional differences had only a minimal overlap with volumetric GM differences.
O263
A voxel-based diffusion tensor MRI study of intrinsic
damage of the major white matter fibre bundles
in multiple sclerosis patients
P. Preziosa, M.A. Rocca, S. Mesaros, E. Pagani, K. Kacar,
D. Caputo, M. Absinta, J. Drulovic, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT); University of Belgrade
(Belgrade, RS); Foundation don Gnocchi (Milan, IT)
Objective: Multiple sclerosis (MS) is characterized by heterogeneous
patterns of clinical manifestations and disease evolution. In this study,
we applied a voxel-wise analysis to diffusion tensor (DT) tractography magnetic resonance imaging (MRI) data from a large sample of
MS patients to characterize intrinsic damage to the major brain white
matter (WM) fiber bundles in the main disease clinical phenotypes.
Methods: Brain dual-echo (DE) and DT MRI (with diffusionencoding gradients applied in 12 non collinear directions) sequences
were collected from 172 MS patients and 46 age- and sex-matched
healthy controls (HC). Twenty-two patients had clinically isolated
syndrome (CIS) suggestive of MS, 51 relapsing-remitting (RR) MS,
44 secondary progressive (SP) MS, 20 benign (B) MS [Expanded
Disability Status Scale (EDSS) score \3.0 and disease duration [15 years], and 35 patients had primary progressive (PP) MS.
DT tractography was used to produce probability maps of the corpus
callosum (CC), corticospinal tract (CST), thalamocortical connection,
inferior fronto-occipital fasciculus, uncinate fasciculus, fornix, cingulum, arcuate fasciculus, inferior longitudinal fasciculus, optic
radiation, superior cerebellar peduncle, and middle cerebellar
peduncle. Using SPM5, an analysis of covariance (ANCOVA) was
used to compare DT MRI-derived quantities between the studied
groups at a voxel level.
Results: Compared to HC, CIS patients had a significant
increased mean diffusivity (MD), axial (axD) and radial diffusivity
(radD) in the majority of WM fiber bundles, while no fractional
anisotropy (FA) abnormalities were found. PPMS patients showed
widespread increased MD, axD and radD, whereas FA damage
involved only a group of the tracts analyzed. No differences were
found between CIS and RRMS patients. Compared to BMS patients,
RRMS patients had reduced FA values in all WM fiber bundles and
decreased axD in the majority of them. SPMS patients had pronounced damage in the majority of tracts compared to other
phenotypes, while compared to BMS, pronounced FA changes in
tracts relevant for motor impairment was the most striking. The
correspondence between diffusivity changes and T2 lesion probability maps between SPMS and other phenotypes showed different
pattern of MD and FA behaviour.
Conclusion: Voxel-wise assessment of regional distribution of
tissue damage may represent a rewarding strategy for understanding
the heterogeneity of clinical course in patients with MS.
O264
Regional grey matter atrophy is largely unrelated
to white matter tissue loss in relapsing-remitting
multiple sclerosis
G. Riccitelli, M.A. Rocca, E. Pagani, V. Martinelli,
M. Radaelli, A. Falini, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT)
Objectives: Atrophy is a well-known feature of multiple sclerosis
(MS). The patterns of regional distribution of atrophy in the white
matter (WM) and gray matter (GM) in these patients deserve further
investigations. In this study, we applied voxel-based morphometry
(VBM) to investigate the regional distribution of GM and WM
atrophy in a large sample of relapsing remitting (RR) MS patients and
their relationship with focal lesions and clinical disability.
Methods: Using a 3.0 Tesla scanner, dual-echo and three-dimensional (3D) T1-weighted images were acquired from 78 RRMS
patients and 88 sex- and age-matched healthy controls (HC).
Expanded disability status scale (EDSS) score was assessed in all the
patients, and 67 patients were evaluated with the Paced Auditory
Serial Addition task (PASAT). T2 hyperintense and T1 hypointense
lesions were measured. Then, T1-hypointense lesions were refilled
with values randomly extracted from a gaussian distribution with
mean and standard deviation estimated from the normal appearing
WM. Using SPM8 and DARTEL, VBM was performed for the GM
and the WM. A two sample t-test was used to assess between-group
differences at a voxel level. A regression analysis was used to
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S42
investigate the correlations between atrophy and lesion load, EDSS
and the PASAT test. We report results at a threshold of 0.05, familywise error corrected.
Results: Compared to HC, RRMS patients had GM atrophy in the
deep GM nuclei, and in several regions mainly located in the frontoparietal lobes, including the cingulum. WM atrophy mainly involved
posterior regions in the brain (i.e, cerebellar peduncles, temporooccipital lobes), the corpus callosum and the corona radiate. T2 and
T1 lesion volumes were correlated with GM loss in the basal ganglia
and the cingulum, as well as with WM loss in the temporal regions
and the corpus callosum. PASAT score correlated with GM loss in the
parietal lobes, posterior cingulum, caudate, insula, and in the cerebellum, as well as with WM loss in the fronto-parietal-temporal lobes
and the middle cerebellar peduncles.
Conclusions: In patients with RRMS, GM and WM atrophy tends
to have distinct patterns of regional distribution, with a prominent
involvement of anterior areas of the brain for the GM and posterior
regions for the WM. The correlation between atrophy and PASAT
performance supports the theory of an anterior-posterior rather than
an interhemispheric disconnection syndrome.
The study was partially supported by a grant from FISM/2008/R/
13.
O265
A multi-centre assessment of cervical cord atrophy
among MS clinical phenotypes
M.A. Rocca, M.A. Horsfield, S. Sala, M. Copetti,
P. Valsasina, S. Mesaros, V. Martinelli, D. Caputo,
T. Stosic-Opincal, J. Drulovic, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT); University of Leicester
(Leicester, UK); Hospital Casa Sollievo della Sofferenza (San
Giovanni Rotondo, IT); University of Belgrade (Belgrade, RS);
Foundation Don Gnocchi (Milan, IT)
Objective: In this multicenter study, a new semi-automatic method for
segmenting the cervical cord from C2 to C5 was used to investigate
the correlation between cord atrophy and clinical disability in a large
sample of MS patients.
Methods: T2- and 3-D T1-weighted cervical cord scans, and
dual-echo brain scans were acquired from 143 healthy controls, 22
clinically isolated syndromes (CIS) patients, 101 relapsing-remitting (RR) MS, 79 secondary progressive (SP) MS, 58 benign
(B) MS and 75 primary progressive (PP) MS) in three European
centers. Normalized cervical cord cross-sectional area (CSAn) was
measured by an active surface cord model. Between-group comparisons were performed using linear mixed-effect models. A nonparametric kernel estimator was used to obtain smoothed plots of
CSA along the cervical cord.
Results: Cord CSAn was significantly lower in PPMS versus
healthy controls, BMS versus RRMS, SPMS versus BMS and RRMS.
From C2 to C5, a net separation and definition of the plots of patients
with BMS, PPMS and SPMS was seen with respect of those of the
other study groups. CSAn was correlated with EDSS (r = -0.49;
p \ 0.0001), with a differential effect among disease clinical phenotypes: no association in either CIS patients or in BMS; association
in RRMS (r = -0.30, p = 0.001), SPMS (r = -0.34, p = 0.001)
and PPMS (r = -0.27, p = 0.01).
Conclusions: Cervical cord atrophy provides a relevant and useful
marker for the characterization of clinical heterogeneity of MS
patients. The stability of this measure among different centers supports its use as surrogate marker to monitor disease progression in
multicenter trials.
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O266
Increased cortical excitability in patients
with vestibular migraine: An fMRI-Study
C. Best, P. zu Eulenburg, H. Krämer, T. Bauermann,
P. Stoeter, M. Dieterich
Johannes Gutenberg-University (Mainz, DE); Justus-LiebigUniversity (Gießen, DE); Ludwig-Maximilians-University (Munich, DE)
Objectives: Vestibular migraine (VM) is the second most frequent form
of central vertigo syndromes (1). In VM episodic vertigo is accompanied
by migraine typical symptoms such as hypersensitivity of light and noise.
Possible causal mechanisms are trigemino-vascular dysfunctions (2),
increased neuronal excitability or decreased intracortical inhibitory
activity (3). Aim of the present study was to investigate if there is evidence for an intracortical reciprocal inter-sensory inhibition that can be
shown by fMRI during visual optokinetic stimulation (OKN). In healthy
volunteers OKN induces an activation of visual cortex areas bilaterally
and a simultaneous deactivation of multisensory vestibular cortex areas
[e.g., in the posterior insula and superior temporal gyrus (GTS)].
Methods: 10 VM patients and 14 age-matched healthy volunteers
were examined by fMRI, while two different OKN stimulations
(OKN-R und OKN-L; horizontally right- or leftward moving vertical
black and white stripes pattern) and a rest condition (stationary
stripes) were performed in randomized order. Statistical analyses
were calculated by SPM5.
Results: Cortical activations: comparing OKN-R versus OKN-L a
significant asymmetry of cortical activations could be found in VM
patients. OKN-L: significantly increased responses of a cortical network were present, particularly bilaterally within visual and somatosensory areas and the cerebellar crus 1. OKN-R: no significantly
increased activations could be revealed. Cortical deactivations: significant deactivations were found within the claustrum and the
inferior parietal lobule (IPL). Typical deactivations—known from
healthy volunteers—within the posterior insular and anterior cingulate
cortex or the GTS were lacking.
Conclusion: In comparison to healthy subjects VM patients
revealed (1) a distinctive asymmetry of cortical activation patterns for
right- and left-sided OKN stimulation, (2) an increased cortical
activation pattern particularly within visual and somato-sensory areas,
(3) an increased subcortical deactivation within the claustrum and the
IPL, and especially (4) a lack of deactivation within vestibular cortex
areas. These results support the hypothesis of a dysfunctional intracortical inhibition in patients with vestibular migraine.
Supported by the German ministry of education and research
(BMBF; 01 GW 0642).
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Oral session 16
Clinical neurophysiology
O267
Assessing cortical effective connectivity in patients
with disorders of consciousness
M. Rosanova, O. Gosseries, S. Casarotto, M. Boly,
A.G. Casali, M.A. Bruno, P. Boveroux, G. Tononi,
S. Laureys, M. Massimini
University of Milan (Milan, IT); University of Liege (Liège, BE);
University of Wisconsin (Madison, US)
S43
Aim: Brain-injured patients are considered conscious if they can
interact with the environment and unconscious otherwise. As suggested by other works, a key requirement for consciousness is that
multiple, specialized cortical areas can interact rapidly and effectively. Here we employ Transcranial Magnetic Stimulation combined
with Electroencephalography (TMS/EEG) in order to assess cortical
effective connectivity at the bedside of brain-injured patients with
disorders of consciousness.
Methods: We used a TMS-compatible 60-channels EEG amplifier
to record TMS-evoked potentials in 17 brain-injured patients. A first
group of 12 patients (Group I) underwent a single TMS/EEG session
after one week of behavioral evaluations (Coma Recovery ScaleRevised). Five of these patients were diagnosed as vegetative state
(VS), five were minimally conscious (MCS) and two were in a
locked-in syndrome (LIS). A second group of five patients (Group II)
were recruited as soon as they awakened from coma and underwent
longitudinal TMS/EEG measurements. Three of them recovered
consciousness evolving from VS through MCS to emergence from
MCS. We stimulated bilaterally the parietal and the frontal lobes in
each patient.
Results: In Group I, VS patients, who were open-eyed, behaviorally awake but unresponsive, TMS triggered a stereotypic and local
response indicating a breakdown of effective connectivity, similar to
the one observed in sleep or anesthesia. On the contrary, in MCS
patients, who showed fluctuating signs of non-reflexive behavior,
TMS triggered rapidly changing, widespread responses similar to the
ones recorded in LIS and healthy awake subjects. In Group II, a
simple and local response to TMS was also recorded in all patients as
soon as they transitioned from coma to VS. In the three patients who
recovered consciousness and functional communication, intracortical
effective connectivity resurged soon after they switched from VS to
MCS as well as they emerged from MCS.
Conclusion: TMS/EEG measurements performed in Group I
suggest that clear-cut differences in intracortical effective connectivity underlie the subtle clinical discrimination between VS and
MCS patients. TMS/EEG measurements performed in Group II
showed that cortical effective connectivity resurged in VS patients
who recovered consciousness as soon as they recover to MCS. Thus,
perturbing directly the brain to assess effective connectivity may
represent a sensitive way to uncover a brain’s capacity for
consciousness.
O268
Selective modulation of motor cortex excitability
during listening to known melodic sequences in pianists
A. Nuara, J. Gonzalez-Rosa, R. Chieffo, F. Spagnolo,
E. Coppi, M. Bianco, L. Straffi, L. Ferrari, G. Comi,
L. Leocani
University Hospital San Raffaele (Milan, IT)
Introduction: The ability to transform auditory information into a
motor representation, defined as audio-motor integration, is a
complex process requiring interaction between brain systems
mediating sound perception and movement. Because of their consolidated association between motor and auditory systems,
musicians constitute an interesting population for investigating
audio-motor integration.
Objectives: To assess the modulation of motor cortex excitability
in professional pianists while listening to known, predictable
melodic sequences, by means of Transcranial Magnetic Stimulation
(TMS).
Methods: Two groups of subjects were studied: pianists (n = 8, 5
men, 3 women; mean age 26 ± 5.8 years) and controls (n = 9, 6
men, 3 women, mean age 25 ± 4.5 years). Participants listened to a
melodic tone sequence containing the alternating repetition of a
pentatonic scale in two different octaves. In order keep adequate
attention subjects had to detect a random deviant tone in the sequence.
Using a circular coil placed at the vertex, Motor Evoked Potentials
(MEPs) were simultaneously recorded bilaterally over the abductor
pollicis brevis (APB) and abductor digiti minimi (ADM) at distinct
points of the melodic sequence. MEPs amplitude was expressed as
percentage of that obtained in a resting condition.
Results: Pianists (not controls) showed a MEPs amplitude modulation of right hand muscles according to the timing of their activation
during actual performance of the melodic sequence. Moreover, in a
subgroup of pianists that preferred to use the right hand to perform the
low-octave scale, there was a tendency to inhibit the hand opposite to
the preferred one.
Conclusions: Results in pianists indicate a phenomenon of audioinduced motor resonance with dynamic modulation of motor excitability, involving not only facilitation of the hand muscles that the
musicians would use during actual musical performance, but also the
inhibition of homologous muscles in the opposite limb.
O269
Evoked potential abnormalities predict disability
progression at 5 years in patients with CIS
G. Di Maggio, M. Bianco, S. Medaglini, L. Moiola,
M. Radaelli, L. Straffi, U. Del Carro, S. Amadio,
M. Romeo, V. Martinelli, G. Comi, L. Leocani
University Hospital San Raffaele (Milan, IT)
Introduction and objective: The usefulness of evoked potentials (EPs)
in patients with clinically isolated syndrome (CIS) suggestive of
multiple sclerosis (MS) has not been fully clarified. The aim of this
study was to assess the role of EPs in predicting future disability and
the risk of conversion to clinically definite multiple sclerosis (CDMS)
after CIS.
Methods: We retrospectively analyzed 91 patients with CIS.
Medical files were reviewed for clinical presentation. All patients
underwent multimodal EPs after a mean time of 2 ± 1.9 months from
onset: visual (VEP), somatosensory (SEP) and motor (MEP) evoked
potentials were obtained in all patients, brainstem auditory evoked
potentials (BAEP) in 86. Each EP received an abnormality score from
0 to 3 (normal to absent; maximum possible multimodal total sum
score = 36).
Results: Average global score of abnormal EPs was 5 ± 4. Basal
global EPs score significantly correlated with EDSS5 (rho = 0.27,
p = 0.008) and disability progression (EDSS5–EDSS2; rho = 0.30,
p = 0.004). EP global score [5 predicted a higher risk of disability at
5 years, defined as an EDSS C3 (PPV = 24%, p = 0.001). Lower
limb SEP and MEP sum score was better able to predict the development of disability at 5 years (46%, p = 0.0001). Subclinical EP
abnormalities predicted the development of involvement of the corresponding FS at 5 years. This predictive value was found for VEP
(PPV = 15.8% p = 0.04) BAEP (PPV = 55.6%, p = 0.04), SEP
(PPV = 30.6%, p = 0.03), MEP (PPV = 90%, p = 0.03). When
excluding, in monofocal patients, EPs related to the symptomatic
pathway, patients with 2 or 3 abnormal EPs at onset had a higher risk
of conversion to CDMS (PPV = 40.4%, p = 0.05).
Conclusions: The present findings suggest that multimodal EPs at
onset in patients with CIS have a predictive value regarding the
evolution of disability. Moreover, a subclinical wide involvement of
multiple sensorimotor pathways, detected as abnormalities in at least
2 EPs, increases the risk of conversion to CDMS.
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O270
Abnormalities in subcortical motor preparation
in patients with idiopathic cervical dystonia
T. Serranova, J. Valls-Sole, R. Jech, M.J. Marti,
F. Valldeoriola, R. Modreanu, T. Sieger, E. Ruzicka
Charles University (Prague, CZ); University of Barcelona (Barcelona,
ES); Czech Technical University (Prague, CZ)
Objectives: In patients with cervical dystonia (CD), bradykinesia
(slowness of movement) may co-exist with hyperkinesia. The pathophysiological mechanisms of bradykinesia in dystonia are
incompletely understood. Our hypothesis is that, because of abnormalities in the integration of sensory inputs, patients with focal
dystonia may not reach the adequate level of subcortical motor
excitability that would lead to execution of the intended movement at
the desired speed.
Our aim therefore was to study preparation of subcortical motor
circuits for task execution and neurophysiological measures of bradykinesia in patients with cervical dystonia (CD) by means of the socalled StartReact (SR) method. In this method, a startling auditory
stimulus (SAS) is applied together with the imperative signal in a
reaction time task paradigm. This causes faster movement execution
of the prepared motor program.
Methods: We examined 7 patients with idiopathic CD (4 females
and 3 males, mean age 46.9 (SD = 10) and 7 controls. Subjects were
instructed to prepare for reacting as quickly as possible by performing
head rotation at perception of the imperative signal (a low intensity
electric stimulus in a finger). In seven random trials out of 39 a SAS
(130 dB) was delivered together with the imperative signal (SR trials). Bilateral surface EMG of the sternocleidomastoid muscles
(SCM) and unilateral orbicularis oculi and masseter muscles and head
mounted accelerometers (ACC) were used to measure the muscle
response and movement kinematics.
Results: The onset of the ACC activity and the EMG activity in the
SCM muscles was shortened in the SR trials in comparison to the
baseline trials in both groups (p \ 0.01 in the controls, p \ 0.05 in
CD group, corrected). However, in SR trials, onset of ACC and EMG
activity was delayed in CD patients in comparison to the control
group (p \ 0.05, corrected) and the percentage shortening in patients
was significantly reduced with respect to that in control subjects
(p \ 0.05, corrected). No differences were found in the baseline trials
between the two groups.
Conclusions: Although we did not find slowness of movement
initiation in the affected body segment in CD patients, our results
suggest insufficient motor preparation for ballistic head rotation at the
subcortical level in CD patients.
Supported by the European Neurological Society.
O271
Autonomic dysreflexia is not just an episodic
but a permanent disorder in patients with spinal
cord injury
J. Gutierrez, I. Panyavin, M. Este´vez, V. Soto-Leon,
A. Olivares, A. Oliviero
Cuban Institute of Neurology (La Habana, CU); National Hospital
of Paraplegics (Toledo, ES)
Objectives: Episodic autonomic dysreflexia (AD) is frequently
reported in patients with spinal cord injury (PSCI), however permanent autonomic disorders, between AD episodes, runs usually
unrecognized. The purpose of this paper was to evaluate
123
cardiovascular autonomic reflexes in patients with SCI while resting
in supine position.
Methods: We recorded electrocardiogram, to derive R-R intervals
variability (RRV), and finger photoplethysmography, to evaluate
beat-to-beat blood pressure variability (BPV), in 21 PSCI (lesions
between C6 and T4 (N = 8); T5 and T11 (N = 10); T12 and L5
(N = 3) and 20 normal age-matched controls. The following
parameters were derived in all subjects: Resting RR intervals duration
(RR); time domain RRV (RSMM); relative power of the low frequency components of RRV (LF-RRV) and BPV (LF-BPV); relative
power of the high frequency component of RRV (HF-RR); the
sympatho-vagal balance index (LF/HF) and the transfer function
between BPV and RRV (BPV-RRV) in the low frequencies.
Results: PSCI, compared to controls, showed increments in the
following parameters: LF-RRV (46.2 vs. 29%; p \ 0.001), LF/HF
index (3.5 vs. 2.2; p \ 0.1) and decrements in: RR (848 vs.
950 ms; p \ 0.03), RSMM (22.1 vs. 57.4 ms; p \ 0.000), HF-RRV
(27.8 vs. 39.2%; p \ 0.05), LF-BPV (43 vs. 48.1%; p \ 0.4) and
BPV-RRV (12.5 vs. 17; p \ 0.02). The intensity of these disorders
was more severe in PSCI with cervical and high dorsal lesions than in
those with low dorsal and lumbar lesions.
Conclusions: These findings demonstrate that PSCI, even while
resting in the supine position, have an autonomic imbalance characterized by reduced cardiovagal and increased sympathetic cardiac
influence with relative preservation of blood pressure regulation.
These abnormalities are probably dependent on compensatory
adjustments of the baroreflex system. The occurrence of this pattern in
PSCI at rest, suggests that this is a permanent, rather than an episodic
dysfunction as previously reported in AD. Persistently increased
sympathetic activity increases the risk of fatal cardiovascular events
in PSCI, and therefore should be early identified and managed.
This paper was supported by the Cuban Ministry of Public Health
and the National Hospital of Paraplegics of Toledo, Spain.
O272
Ross syndrome: sympathetic activity evaluated
by microneurography
V. Donadio, M. Giannoccaro, M. Nolano, V. Di Stasi,
P. Cortelli, A. Baruzzi, R. Liguori
University of Bologna (Bologna, IT); University of Naples
(Telese Terme, IT)
Objectives: Ross syndrome (RS) is characterized by tonic pupil,
areflexia and anhidrosis and the underlying lesion affects postganglionic skin sympathetic nerve fibers whereas postganglionic muscle
sympathetic branch is usually spared. Microneurography allows to
explore both skin and muscle peripheral sympathetic branches. In
chronic dysautonomic syndromes such as pure autonomic syndrome
(PAF) microneurography usually did not disclose peripheral sympathetic outflow in both branches. The aim of this study is to confirm the
selective involvement of postganglionic skin sympathetic nerve fibers
in RS.
Methods: We studied 8 RS patients (50 ± 16 years, 4 males) with
typical clinical picture and skin biopsy findings. They underwent to
microneurography from peroneal nerve with the recording of muscle
sympathetic nerve activity (MSNA), skin sympathetic nerve activity
(SSNA) and the corresponding organ effector responses (skin sympathetic response-SSR and skin vasomotor response-SVR) in the
same innervation field. The absence of sympathetic bursts was
established after exploring at least 3 different corresponding nerve
fascicles (i.e. skin for SSNA and muscle for MSNA). Thirty age and
sex-matched healthy subjects served as controls.
S45
Results: RS patients complained of anhidrosis, abnormalities of
accommodation due to tonic pupils and they showed areflexia. All
patients displayed absent SSNA, SSR and SVR whereas MSNA was
always recorded showing normal characteristics.
Conclusion: Microneurographic study of sympathetic activity
confirmed the selective involvement of skin sympathetic activity in
RS. Microneurography is an useful functional tool contributing to the
RS diagnosis.
__________________________________
Oral session 17
Stroke
O273
Bringing the hospital to the patient: stroke treatment
directly at the emergency site
S. Walter, P. Kostpopoulos, A. Haass, P. Papanagiotou,
C. Roth, I. Grunwald, D. Kubulus, Y. Liu, T. Volk, W. Reith,
K. Fassbender
University Hospital of the Saarland (Homburg, DE); John Radcliffe
Hospital (Oxford, UK)
Background: Early treatment is critical for favorable outcome of acute
stroke. Since the therapeutic time window is narrow, implementation
of rt-PA therapy is difficult and rt-PA thrombolysis is strongly underused. Acute stroke management needs to be reconfigured to allow
rapid screening of eligible stroke patients for time-limited therapy.
Methods: We newly developed an ambulance equipped with
computed tomography, point-of-care laboratory system for complete
stroke laboratory work-up, and telemedicine contact with hospital
experts (‘‘Mobile Stroke Unit’’) to achieve delivery of causal stroke
treatment directly at the site of the emergency.
Results: The Mobile Stroke Unit approach could successfully be
integrated into the routine emergency medical service chain. Different
from current practice, stroke patients could now be treated according
to their ischemic or hemorrhagic etiology in the prehospital phase of
stroke management. We report the first patients that obtained causal
prehospital stroke treatment, i.e., thrombolysis in ischemic stroke and
etiology-specific blood pressure adjustment and telemedicine consultation regarding surgical intervention in cerebral hemorrhage.
Interpretation: This report proofs the feasibility of an etiologyspecific and causal treatment of acute stroke directly at the site of
emergency rather than awaiting hospital arrival.
O274
Urgent carotid endarterectomy in patients with acute
neurological symptoms
M. Gorlitzer, A. Froeschl, E. Locker, G. Weiss,
J. Meinhart, M. Grabenwoeger
Hospital Hietzing (Vienna, AT); Karl Landsteiner Institute
(Vienna, AT)
Objective: The aim of the present case-control study was to assess
patients with acute neurological symptoms requiring urgent carotid
endarterectomy (CEA) and compare the outcome of the procedure in
this group with that achieved in stable patients.
Methods: Fourty-eight CEAs (7.5%) were performed in patients
with an acute neurological deficit and 639 in stable patients from 2007
to 2010. Those selected for urgent surgery fulfilled the following
criteria: acute onset of hemispheric neurological symptoms or crescendo TIAs, significant carotid pathology, the absence of cerebral
hemorrhage, uncompromised vigilance, and stable cardiopulmonary
conditions.
Results: Perioperative mortality in the stable patients cohort was
0.47%. Two patients died during the hospital stay because of myocardial infarction. Perioperative neurological events were observed in
1.7%: two ipsilateral stroke in stage II A, two contralateral stroke in
stage I A, and a prolonged neurological deficit with complete restitution at the time of discharge in seven patients. No mortality or
neurological morbidity was encountered in those who underwent
urgent CEA.
Conclusion: Compared to stable patients with stage I, II or IV
disease, neither mortality nor morbidity was increased in those
who underwent urgent CEA. Urgent CEA after non-disabling
stroke or crescendo TIAs is a safe procedure with a favorable
outcome.
O275
Evolution or revolution? 1-year results for mechanical
thrombectomy with the Solitaire stent in acute stroke
A. Mpotsaris, M. Bussmeyer, J. Fuehrer, H. Buchner,
W. Weber
Klinikum Vest (Recklinghausen, DE)
Background: To report the effectiveness of mechanical thrombectomy
with the Solitaire stent in severe acute ischemic stroke in conjunction
with intravenous systemic thrombolysis.
Methods: Prospective, ongoing single center study of patients with
acute ischemic stroke based on proven large artery occlusion via CTangiography in anterior or posterior circulation. Following strict
inclusion criteria patients were triaged for eligibility for mechanical
thrombectomy, independently of intravenous thrombolysis with tissue
plasminogen activator (rTPA). Clot retrieval was performed with the
Solitaire stent (AB and FR, ev3 Inc, Plymouth, MN, USA) with up to
4 maneuvers. NIHSS and mRS scores were assessed on admission,
discharge, after 90 days and after one year. For evaluation of outcome
patients were stratified in early, intermediate and late treatment
subgroups.
Results: Till January 2011 54 patients were eligible for
mechanical thrombectomy with the Solitaire stent since October
2009. 92% had a NIHSS score of C10 and 96% mRS 4 or 5 on
admission. 40 of 54 patients received intravenous rTPA prior to
mechanical thrombectomy (bridging technique), 14 were treated
with thrombectomy alone. 27 of 54 had tandem stenosis and were
a priori stented. Recanalization rate was 88%; in 50% of cases the
first attempt led to recanalization. There were no procedural complications. Overall 37% (20 of 54) patients had a good clinical
outcome (mRS B2) in the 90 days follow up interval. In the early
treatment subgroup (n = 21) with recanalization in B4.5 h from
symptom onset good outcome was reached in 50%. Of 13 patients
with carotid-T-occlusions 6 had a good outcome after 90 days.
Patients who were treated in bridging-technique with intravenous
rTPA had a higher NIHSS score reduction (p = 0.06) than nonbridging patients. By May 2011 the 1-year results of 25 patients will
be available for analysis.
Conclusions: The combination of rTPA and mechanical thrombectomy is safe. The Solitaire stent can be deployed safely and
quickly. The 90 day results are encouraging, especially in combination with i.v. rTPA; the Solitaire may play a key role in further
improvement of outcome in severe acute stroke, especially in carotidT-occlusions.
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S46
O276
Charles Bonnet syndrome-like pseudo-hallucinations
following heart surgery in patients with normal vision
S. Kastaun, T. Gerriets, N. Schwarz, M. Tschernatsch,
M. Kaps, J. Kraus, M. Schoenburg, T. Walther
Justus Liebig University (Giessen, DE); Christian Doppler Clinic
(Salzburg, AT); Kerckhoff Clinic (Bad Nauheim, DE)
Background: Following major cardiac surgery, visual hallucinations
occur frequently as a result of postoperative delirium. However, we
sporadically noted visual pseudo-hallucinations also in non-delirious
patients. This phenomenon reminds to Charles Bonnet Syndrome,
although these patients lack of visual impairment.
We examined patients following open heart surgery with extracorporeal circulation to determine the incidence of this phenomenon.
Methods: We examined 100 patients with a short screening
questionnaire. Patients that reported pseudo-hallucinations received
neurological and psychiatric testing, ophthalmologic screening, neuropsychological assessment (Mini Mental Status Test, Confusion
Assessment Method) and if possible cranial MRI between day 4 and 9
after surgery.
Results: We identified 11 non-delirious patients (3 female, 8 male;
64.8 ± 12.3 years) with pseudo-hallucinations after coronary artery
bypass grafting or aortic valve replacement.
Patients described seeing vivid, typically coloured images of
animate or inanimate objects (i.e. meshes, posies, individuals, paint
splatters). At any time the patients were aware of the unreal nature of
the illusions. Pseudo-hallucinations were first noticed several days
after surgery. They typically appeared several times per day and
lasted from several seconds up to a few hours and were not found to
be related to patients’ activity, time of day or room lighting. Frequency, duration and brightness decreased over time and disappeared
within 3 days to 3 weeks. None of the patients had a history of severe
visual impairment or suffered from migraine. Neurological and neuropsychological examination showed no evidence of any psychiatric
or neurologic disorder. MRI was done in 5/11 patients. Only 1 patient
showed multiple small infarcts within the middle and posterior
cerebral artery territory.
Conclusion: Visual pseudo-hallucinations occur frequently after
cardiac surgery and seem not to be related to postoperative delirium
or structural brain damage. Although MRI showed multiple small
infarction in only one patient, it can be speculated that cerebral
microembolisation, caused by extracorporeal circulation, leads to
subclinical deficits i.e. of the visual cortex, which become manifest in
visual pseudohallucinations. Further studies are required to determine
the underlying pathophysiology.
O277
Post-stroke depression and anxiety: a longitudinal
cohort study
J.H. White, P. Magin, J. Attia, J. Sturm, G. Carter,
M. Fitzgerald, P. McElduff, M. Pollack
Hunter New England Area Health Service (Newcastle, AU);
University of Newcastle (Newcastle, AU)
Background: Few longitudinal studies explore the patterns of psychological morbidity and factors contributing to their change over
time post-stroke. The study aims is to explore the predictors of PostStroke Depression (PSD) and anxiety and factors contributing to
change in symptoms in stroke survivors over a 12 month period.
123
Method: A prospective cohort study of 130 stroke survivors participating in face-to-face interviews at baseline (stroke onset), 3, 6, 9,
and 12 months. Outcome measures were depression and anxiety
(HADS). Independent variables included MRS, BI, AQOL social
support and community participation.
Results: Natural history of anxiety is positively associated with
PSD (\0.0001), anxiety at baseline (\0.0001), greater community
participation (0.028) and a past history of depression (0.049). Natural
history of PSD is associated with anxiety (\0.0001), depression at
baseline (0.006), high MRS (0.0289), low social support (0.004) and
low community participation (0.002). No baseline factors predicted
the resolution of PSD (if depressed at baseline). Baseline factors that
predicted the onset of depression (if not depressed at baseline) where
low community participation (0.026) and past history of depression
(0.047).
Discussion: Anxiety tends to resolves over time. Depression
remains problematic and is associated with higher disability and low
social support. Predicting recovery from or development of depression post-stroke is difficult. Clinical implications are a need for longterm psychological monitoring of post-stroke with early intervention
strategies (counseling and low threshold introduction of anti-depressants). Ongoing rehabilitation should address disability and social
support.
O278
The modified Rankin scale with structured interview
is more sensitive and reliable
A. Just, A. Ghitu, C. Leclercq, P.Y. Garcia,
J.M. Bugnicourt, C. Lamy, S. Canaple, O. Godefroy
General Hospital (Beauvais, FR); University Hospital (Amiens, FR)
Objectives: The modified Rankin scale (mRS) is the most widely used
poststroke disability scale. However, there are no precise criteria
defining each stage. This contributes to the substantial interobserver
variability. The objective of this study was to test whether a new mRS
with formal structured interview was more sensitive and reliable than
conventional mRS.
Methods: The study was performed in 70 patients (infarct n = 60;
hemorrhage n = 10) at the follow-up visit (delay 185 ± 100 days).
It used the mRS applied conventional (examiner A) and the new mRS
with structured interview (examiner B) in a double blind study. Retest
was performed in a subgroup of 36 randomized patients by telephone
interview (delay 42.8 ± 39 days) by a blinded examiner. Finally we
examined the relation with impairment of Instrumental Activities of
Daily Living (IADL) using PAQUID cutoff score suggestive of
dementia.
Results: The new mRS was more sensitive (p = 0.0001) than the
conventional mRS (13/70 increased mRS score of 1 grade and 5/70
patients increased mRS score of 2 grades). The new mRS (j = 0.886)
was more reliable than the conventional mRS (j = 0.743). The new
mRS detected all patients with impaired IADL corresponding to
dementia stage (sensitivity = 1, specificity = 0.9, PPV = 0.88,
NPV = 1) contrary to conventional mRS (sensitivity = 0.75, specificity = 0.93, PPV = 0.88, NPV = 0.85). Finally the duration of the
new mRS (3 m 42 s) did not differ (p = 0.9) from that of conventional mRS (3 m 36 s).
Conclusions: The new mRS is more sensitive to poststroke disability, more reliable and does not take more time. In addition it
detects accurately patients with impaired IADL corresponding to
dementia stage. This should improve the assessment of poststroke
disability and dementia.
S47
Oral session 18
Multiple sclerosis: monitoring and treatment
O279
Clinical outcomes of natalizumab-associated
progressive multifocal leukoencephalopathy
J. Foley, P. Vermersch, R. Gold, L. Kappos, T. Olsson,
D. Cadavid, C. Bozic, S. Richman
Rocky Mountain Multiple Sclerosis Clinic (Salt Lake City, US);
University of Lille Nord de France (Lille, FR); Ruhr University
(Bochum, DE); University Hospital (Basel, CH); Karolinska Hospital
(Stockholm, SE); Biogen Idec Inc. (Weston, US)
Objectives: Through September 2010, natalizumab has been used to
treat 75,500 patients with multiple sclerosis (MS), corresponding to
122,900 patient-years. Natalizumab’s efficacy is well established, but
a small minority of patients develop the rare opportunistic CNS
infection progressive multifocal leukoencephalopathy (PML), which
is associated with JC virus. The present analysis sought to identify
predictors of survival and describe functional status in postmarketing
cases of natalizumab-associated PML.
Methods: PML cases were categorized by survival outcome (fatal/
nonfatal) and functional status (mild/moderate/severe disability). Treating
physicians provided patient information on motor and cognitive function,
performance of daily activities, and Karnofsky Performance Scale score.
Additional data were from the natalizumab global safety database.
Results: Sixty of 75 (80%) PML patients identified as of November
2010 were alive. Most deaths were within approximately 2 months after
PML diagnosis. Survival rates were 93% (39/42) and 64% (21/33) in
Europe and the United States, respectively. In the first 35 cases (25/35 or
71% survived), nonfatal cases were younger (median 43 vs. 51.5 years),
had less pre-PML disability (median Expanded Disability Status Scale
score 3.8 vs. 5.5), and had shorter time from PML symptom onset to
diagnosis (mean 37 vs. 62 days) than fatal cases. Widespread PML on
MRI characterized most (69%) fatal cases. The variables of gender, MS
duration, natalizumab exposure, prior immunosuppressant use, and CSF
JC virus DNA load at PML diagnosis were similar between fatal and
nonfatal cases. In all 35 cases, natalizumab was withheld, and for most
patients natalizumab was rapidly removed by plasma exchange or
immunoadsorption. Immune reconstitution inflammatory syndrome
(IRIS) developed in 32 of 35 (91%) of cases and was commonly treated
with high-dose corticosteroids. Disability was mild (33%), moderate
(33%), or severe (33%) in the 12 PML survivors with C6 months of
follow-up. Available updated outcomes data will be presented.
Conclusion: Survival in patients with natalizumab-associated PML
was associated with younger age, less disability prior to PML, more
localized PML on MRI, and more rapid PML diagnosis. These data
suggest that earlier diagnosis through enhanced clinical vigilance as well
as aggressive management of PML and IRIS may improve outcomes.
Supported by Biogen Idec Inc. and Elan Pharmaceuticals, Inc.
O280
Fingolimod reduces the brain volume loss in relapsingremitting multiple sclerosis irrespective of baseline
inflammatory activity: results from FREEDOMS phase
III study
L. Kappos, E. Radue, A. De Vera, P. Burtin, F. Holdbrook,
G. Francis
University Hospital (Basel, CH); Novartis Pharma AG (Basel, CH);
Novartis Pharmaceutical Corporation (East Hanover, US)
Objective: Brain atrophy, as measured by magnetic resonance
imaging, is an important measure of the underlying destructive
pathological processes involved in multiple sclerosis (MS). We
evaluated the effect of fingolimod on the rate of loss of brain volume
in patients with relapsing-remitting MS (RRMS), stratified according
to baseline inflammatory lesion activity status in the phase III,
FREEDOMS trial.
Methods: Patients with RRMS were randomised to receive oncedaily fingolimod 0.5 mg (n = 425), 1.25 mg (n = 429) or placebo
(PBO, n = 418) for 2 years. Within each cohort patients were further
stratified by the presence of gadolinium (Gd)-enhancing lesions (Gd+,
n = 482) or absence (Gd-, n = 782) at baseline. The percentage
brain volume change (PBVC) was obtained using the Structural
Image Evaluation of Normalised Atrophy (SIENA) programme from
baseline to months (M) 6, 12 and 24, from M 6–12 and M 12–24.
Results: Overall brain volume decreased more rapidly in
Gd+ compared to Gd- patients. For Gd+ patients on fingolimod
0.5 mg, PBVC was comparable to PBO after 6 M (-0.51% fingolimod vs. -0.54% PBO, p = 0.09), and after 12 M (-0.89%
fingolimod vs. -0.97% for PBO, p = 0.16), but significantly lower
after 24 M (-1.33% fingolimod vs. -1.90% for PBO, p = 0.01). For
Gd- patients, fingolimod 0.5 mg was associated with a slower rate of
decline of brain volume already at 6 M (-0.05% fingolimod vs. 0.23% for PBO, p = 0.01), at 12 M (-0.26% fingolimod vs. -0.47%
for PBO, p = 0.06) and at 24 M (-0.55% fingolimod vs. -0.98% for
PBO, p = 0.002). The PBVC between M6-12 was not significant in
both Gd+ and Gd- patients (-0.35% fingolimod vs. -0.43% for
PBO, p = 0.08 and -0.20% fingolimod vs. -0.23% for PBO,
p = 0.72, respectively). However M 12–24 results showed a significant reduction in PBVC irrespective of Gd status at baseline (Gd+: 0.51% fingolimod vs. -0.92% PBO, p \ 0.001; Gd-: -0.28% fingolimod vs. -0.53% PBO, p = 0.002). A similar pattern was
observed in the fingolimod 1.25 mg group.
Conclusions: Overall treatment with fingolimod was associated
with a slower rate of PBV reduction, but in Gd+ patients at baseline
this effect was probably antagonised by its anti-inflammatory effect
leading to some degree of volume reduction (pseudoatrophy). The
significantly slower decline in brain volume as early as the first 6 M
in Gd- patients at baseline together with the clear cut effect shown
over M 0–24 and during M 12–24 for both Gd+ and Gd- patients
further supports an early and continuous direct effect of fingolimod on
PBVC.
Supported by Novartis Pharma AG.
O281
Magnetic resonance imaging subgroup analysis
from the TEMSO placebo-controlled phase III trial
of oral teriflunomide in multiple sclerosis with relapses
F. Nelson, A. Miller, P. O’Connor, C. Confavreux,
G. Comi, L. Kappos, T. Olsson, M. Freedman,
H. Benzerdjeb, P. Truffinet, L. Wang, J. Wolinsky
for the Teriflunomide Multiple Sclerosis Trial Group
and the MRI Analysis Center in Houston, US
Objective: To report findings from a subgroup analysis of TEMSO
(the Teriflunomide Multiple Sclerosis Oral trial) brain magnetic resonance imaging (MRI) data.
Methods: TEMSO was a randomised, double-blind, placebo
(PBO)-controlled, parallel-group study (N = 1,088). Patients with
relapsing forms of multiple sclerosis (RMS) were randomised (1:1:1)
to PBO or teriflunomide, 7 or 14 mg, once daily for 108 weeks. The
key prespecified MRI endpoint was burden of disease (total lesion
123
S48
volume). Other MRI endpoints included the number of gadolinium
(Gd)-enhancing T1 lesions and the number of unique active lesions.
Subgroup analyses were performed for these endpoints according to
baseline demographics (sex, race, age), disease characteristics (EDSS
strata, number of relapses within 2 years prior to randomisation, MS
subtype), MRI parameters (baseline T1 gadolinium-enhancing
lesions, burden of disease) and previous use of MS drugs. Descriptive
statistics are presented for this post hoc analysis.
Results: In the overall study population, teriflunomide significantly reduced brain MRI activity. The mean change from baseline in
burden of disease at week 108 was significantly lower with teriflunomide 7 mg and 14 mg compared with PBO, with relative risk
reductions (RRRs) of 39.4% (p = 0.03) and 67.4% (p \ 0.001).
Patients in the teriflunomide 7 and 14 mg groups also had significantly fewer Gd-enhancing T1 lesions (RRR vs. PBO of 57.2% and
80.4%; p \ 0.001 for both doses) and unique active lesions per scan
(RRR vs. PBO of 47.7% and 69.4%; p \ 0.001 for both doses) at
week 108 than those in the PBO group. In general, effects were
homogeneous and in favour of teriflunomide on all MRI parameters
across all patient subgroups analysed.
Conclusion: Teriflunomide is a novel oral disease-modifier in
development for RMS. Both teriflunomide doses provided sustained
benefits on brain MRI activity during the 108-week period. There was
a trend toward a dose-effect, with greater improvements observed
with the 14 mg dose. The beneficial effect of teriflunomide on a range
of MRI endpoints was, in general, consistent across selected subgroups in the TEMSO study population.
Study supported by Sanofi-Aventis.
O282
Exploring correlations between changes in lymphocyte
counts and clinical/magnetic resonance imaging
outcomes in cladribine-treated patients with relapsing–
remitting multiple sclerosis: analyses from the doubleblind, 96-week CLARITY study
P. Rieckmann, P. Soelberg Sørensen, G. Comi, S. Cook,
G. Giovannoni, K. Rammohan, P. Vermersch, N.
Kurukulasuriya, D. Bock, S. Greenberg
Bamberg Academic Hospital (Bamberg, DE); Copenhagen University
Hospital (Copenhagen, DK); University Vita-Salute San Raffaele
(Milan, IT); University of Medicine (Newark, US); Barts and The
London School of Medicine and Dentistry (London, UK); University
of Miami (Miami, US); University of Lille (Lille, FR); University
(Erlangen, DE); Merck Serono S.A. (Geneva, CH)
Objectives: Cladribine tablets therapy demonstrated significant clinical and magnetic resonance imaging (MRI) efficacy, and
preferentially reduced peripheral lymphocyte counts in patients with
multiple sclerosis (MS) in the 96-week Phase III CLARITY study.
Here we investigate correlations between changes in peripheral
lymphocyte/lymphocyte subset counts and therapeutic effect using
data from the CLARITY study.
Methods: Correlations between lymphocyte counts and clinical/
MRI outcomes over 96 weeks, including the composite outcome
disease activity-free (DAF) status (absence of relapse, disability
progression and MRI activity), were investigated in patients who
received at least 1 dose of trial medication with follow-up safety data
(n = 435, 430, and 454 in placebo, cladribine 3.5 and 5.25 mg/kg
groups, respectively). Haematological parameters analyzed included:
absolute lymphocyte count (ALC) and, in a subset of patients
(n = 98, 101, and 101, respectively), CD4+ and CD8+ lymphocyte
subpopulations. Spearman’s correlations were calculated.
123
Results: The ALC (including mean, median, mean/median change
from baseline, and nadir count per patient during 96 weeks) correlated with T1 gadolinium-enhancing (Gd+) lesion number
[r = 0.291–0.391 (all p \ 0.001)] in the pooled population (all three
treatment groups). CD4+ and CD8+ counts also correlated with T1
Gd+ lesions [r = 0.286–0.352 and 0.216–0.266, respectively (all
p \ 0.001); pooled population]. In addition, mean and nadir ALC,
CD4+ and CD8+ counts correlated with active T2 lesions
[r = 0.256–0.308 (all p \ 0.001); pooled population]. For mean and
nadir ALC counts, weaker correlations were apparent with DAF
status [r = -0.200 to -0.217 (p \ 0.001); pooled population] and
with relapse-free status [r = -0.148 to -0.179 (p \ 0.001); pooled
population]. CD4+ and CD8+ counts also weakly correlated with
DAF status [r = -0.120 to -0.134 (all p B 0.039); pooled population] and CD4+ counts correlated with relapse-free status [r = 0.130 to -0.170 (p B 0.024); pooled population]. Using the above
described methods, a correlation with progression-free status was not
found. Additional correlation analyses are currently underway.
Conclusion: These exploratory analyses indicate that cladribineinduced reductions in lymphocyte counts moderately correlate with
select MRI and clinical outcomes, and suggest an association between
biological markers of cladribine activity and the observed treatment
effect in MS.
Funded by Merck Serono S.A., Geneva, Switzerland.
O283
MRI results from a phase III, randomised, doubleblind, placebo-controlled, multi-centre trial (REFLEX)
of two dosing frequencies of subcutaneous interferon
b-1a in patients with a first demyelinating event
suggestive of multiple sclerosis
N. De Stefano, G. Comi, M. Freedman, L. Kappos,
C. Polman, B. Uitdehaag, F. Casset-Semanaz,
B. Hennessy, S. Rocak, B. Stubinski, F. Barkhof
University of Siena (Siena, IT); University Hospital San Raffaele
(Milan, IT); The Ottawa Hospital (Ottawa, CA); University Hospital
Basel (Basel, CH); VU University Medical Center (Amsterdam, NL);
Merck Serono S.A. (Geneva, CH)
Objective: Brain magnetic resonance imaging (MRI) outcomes are
valuable in predicting disease activity and burden in patients with a
single demyelinating event. Moreover, they may complement clinical
markers in assessing the optimal benefit–risk balance of different
dosing regimens in multiple sclerosis (MS) clinical trials. The REbif
FLEXible dosing in early multiple sclerosis (REFLEX) study was
designed to assess the effect of subcutaneous (sc) interferon (IFN) b1a once-weekly (qw) or three-times weekly (tiw) in patients with a
first demyelinating event suggestive of MS, including MRI outcomes.
Methods: Patients with a single demyelinating event and C2
clinically silent lesions on T2 brain MRI were randomized (1:1:1) to
the serum-free formulation of IFN b-1a, 44 mcg sc, either tiw, or qw
plus placebo twice-weekly for blinding, or placebo tiw for B24 months. Upon conversion to clinically definite MS, patients
started open-label IFN b-1a, 44 mcg sc tiw. The primary endpoint was
time to conversion to McDonald MS. MRI endpoints included number of combined unique active (CUA) lesions [defined as either new
T1 gadolinium-enhancing (Gd+) lesions or new/enlarging T2 lesions
that were not Gd+] per patient per scan and numbers of new T1
hypointense and new T1 Gd+ lesions.
Results: 517 patients were randomized (171 tiw, 175 qw, 171
placebo). Baseline patient characteristics were similar across treatment groups; baseline number (%) of patients with C1 Gd ± lesion:
S49
213 (41.2); mean (standard deviation; SD) number of T2 lesions: 22.3
(20.0). Over the double-blind period, mean (SD) numbers of CUA
lesions per patient per scan were: IFN b-1a tiw, 0.50 (0.06); IFN b-1a
qw, 0.95 (0.11); placebo, 2.58 (0.30). There was an 81% (tiw) and
63% (qw) reduction vs placebo for IFN b-1a; both p \ 0.000001. IFN
b-1a also decreased the mean number of new T1 hypointense lesions
(tiw 57% and qw 37% reduction vs. placebo; both p \ 0.001) and the
mean number of new T1 Gd+ lesions (tiw 92% and qw 76% reduction
vs placebo; both p \ 0.001). For MRI parameters of disease activity
and burden, the tiw regimen was significantly superior to qw
(p = 0.002 for CUA lesions; p = 0.008 for new T1 hypointense
lesions; p \ 0.001 for new Gd+ lesions).
Conclusion: Both dosing frequencies of sc IFN b-1a significantly
improved MRI outcomes reflecting reduced disease activity in
patients with a first demyelinating event compared with placebo, with
more pronounced effects in the tiw treatment arm.
Supported by Merck Serono S.A., Geneva, Switzerland.
O284
Voxel-wise assessment of WM architecture integrity
in MS patients with different clinical phenotypes
G. Riccitelli, M.A. Rocca, E. Pagani, V. Martinelli,
F. Martinelli-Boneschi, A. Falini, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT)
Objectives: Diffusion tensor (DT) magnetic resonance imaging (MRI)
is sensitive to microstructural damage in multiple sclerosis (MS). In
this study, we used tract-based spatial statistics (TBSS) to compare
white matter (WM) integrity abnormalities among MS patients with
the major disease clinical phenotypes.
Methods: Using a 3.0 Tesla scanner, brain T2, T1 and DT MRI scans
were acquired from 199 MS patients [34 benign (B) MS, 81 relapsingremitting (RR) MS, 50 secondary progressive (SP) MS, and 34 primary
progressive (PP) MS] and 89 sex- and age-matched healthy controls
(HC). TBSS (http://www.fmrib.ox.ac.uk/fsl/tbss/index.html) was
applied for voxel-wise analysis of fractional anisotropy (FA) and mean
diffusivity (MD) maps. Significant differences were reported at a
threshold of 0.05, family-wise error corrected.
Results: Compared to HC, RRMS patients had a significant FA
decrease in the majority of the skeleton voxels. Similar results were
found in PPMS, who, however, had a sparing of the cerebellum,
cingulum and splenium and genu of the corpus callosum (CC).
Compared to RRMS, SPMS patients showed a generalised decrease of
FA. FA was decreased in the majority of WM tract in BMS vs.
RRMS, except for the cerebellum. Compared to HC, RRMS patients
had significant MD increase in the majority of skeleton voxels, with a
sparing of the cerebellum; PPMS had an overlap between areas of
increased MD and those of decreased FA. Compared to RRMS,
SPMS patients had an increases MD in the CC, fornix and the anterior
portion of the cingulum. No difference was found between RRMS and
BMS, whereas compared to BMS, SPMS had a diffuse increase of
MD in the infratentorial regions and in the anterior portion of the CC.
Conclusions: Diffuse WM microstructural abnormalities occur in all
MS patients, but with a different topographical pattern in the different
clinical phenotypes. Interestingly, while the supratentorial regions of the
brain showed changes of both FA and MD in all the disease phenotypes,
the involvement of the infratentorial regions differed markedly among
the various clinical phenotypes (spared in PPMS, heterogeneously
damaged in RRMS and SPMS, less damaged in BMS vs. SPMS). This
suggests that the assessment of damage in these regions might contribute
to a better characterization of the MS phenotypes.
The study was partially supported by a grant from FISM/2008/R/13.
Oral session 19
General neurology
O285
Efficacy of radiation therapy on epileptic seizures
of grade II and III gliomas: a retrospective study
E. Trevisan, U. Magliola, C. Mantovani, R. Rudà,
R. Soffietti
Hospital S.Giovanni Battista (Turin, IT)
Objectives: Epilepsy is very common in patients with slowly
growing tumors, and can be pharmacoresistant. Total surgical
resection and, recently, chemotherapy may have an impact in the
control of seizures, while the role of radiation therapy is unclear.
The aim of this study was to investigate the efficacy of radiotherapy in controlling the epileptic seizures in slowly growing
gliomas.
Methods: We retrospectively analyzed from the neuro-oncological
database of the University Hospital of Torino 40 patients with
hemispheric grade II and III gliomas (according to WHO classification), either newly diagnosed or recurrent, who had an active epilepsy
before receiving radiation therapy between 1989 and 2009. Seizure
decrease following radiotherapy was considered as significant
when C50% reduction in seizure frequency from baseline was
observed, being steroids stable and concomitant AEDs unchanged or
reduced. Response on MRI was evaluated based on changes of the
tumor area.
Results: Overall, seizure frequency was significantly decreased
in 24/40 (60%) and 29/40 (72.5%) patients at 1 and 3 months
following radiotherapy respectively. In most patients seizure
reduction began during radiation therapy. We did not find any
correlation between seizure response and response of tumor on
MRI: at 3 months following radiotherapy, among patients with a
significant seizure reduction, half had a partial response (C50%) on
MRI and half no change. Factors, such as histology, grade of
malignancy, type of original surgery, tumor location and contrast
enhancement on MRI did not influence the seizure response to
radiotherapy.
Conclusions: Epileptic seizures of patients with grade II and III
gliomas can benefit from radiation therapy. Future studies must better
clarify factors associated with this efficacy and the underlying
mechanisms.
O286
Preliminary results of whole brain radiotherapy
with concurrent trastuzumab as a potential
radiosensitiser for treatment of brain metastases
in breast cancer patients
C. Chargari, H. Riahi Idrissi, J. Pierga, M. Bollet,
V. Die´ras, F. Campana, P. Cottu, A. Fourquet, Y. Kirova
Institut Curie (Paris, FR)
Purpose: Brain metastases are a significant source of morbidity and
mortality in breast cancer patients with a positive status for human
epidermal growth factor receptor 2 (HER2). While clinical benefit
was reported for treatment of brain metastases with trastuzumab,
preclinical results recently suggested that trastuzumab may radiosensitize breast cancer cell lines to ionizing radiation. We
123
S50
retrospectively assessed the use of trastuzumab concurrently with
whole-brain radiotherapy (WBRT).
Materials: From April 2001 to April 2007, 31 patients with brain
metastases from HER2-positive breast cancer were referred for
WBRT with concurrent trastuzumab. At the time of brain progression,
median age was 55 years (range 38–73 years) and all patients had a
performance status of 0–2. Patients received trastuzumab 2 mg/kg
weekly (n = 17) or 6 mg/kg repeated every 21 days (n = 14). In 26
patients, concurrent WBRT delivered 30 Gy in 10 daily fractions. In
six patients, other fractionations were chosen because of either poor
performance status or patients’ convenience.
Results: Following WBRT, radiological responses were observed
in 23 patients (74.2 %), including six patients (19.4%) with complete
radiological responses and 17 patients (54.8%) with partial radiological response. Clinical responses were observed in 27 patients
(87.1%). Median survival from the start of WBRT was 18 months
(range 2–65 months). Median time to brain progression was
10.5 months (range 2–27 months). No grade 2 or more acute toxicity
was observed.
Conclusions: Our results suggest that trastuzumab may have a
potential clinical impact with low toxicity concurrently with
WBRT. Although promising, these preliminary data warrant further validation of trastuzumab as a radiosensitizer for WBRT in
brain metastases from breast cancer in the setting of a clinical
trial.
O287
A randomised, placebo-controlled trial of idebenone
in Leber’s hereditary optic neuropathy
T. Klopstock, P. Yu-Wai-Man, K. Dimitriadis, J. Rouleau,
S. Heck, M. Bailie, A. Atawan, S. Chattopadhyay,
M. Schubert, A. Garip, M. Kernt, D. Petraki, C. Rummey,
M. Leinonen, G. Metz, P. Griffiths, T. Meier, P. Chinnery
Ludwig-Maximilians-University Munich (Munich, DE); Newcastle
University (Newcastle, UK); University of Montreal (Montreal, CA);
Newcastle University (Newcastle, UK); Santhera Pharmaceuticals
(Liestal, CH); 4Pharma (Stockholm, SE)
Objectives: Major advances in understanding the pathogenesis of
inherited metabolic disease caused by mitochondrial DNA (mtDNA)
mutations have not yet translated into treatments of proven efficacy.
Leber’s hereditary optic neuropathy (LHON) is the most common
mtDNA disorder causing irreversible blindness in young adult life and
affecting [1 in 14,000 males. Anecdotal reports support the use of
idebenone in LHON, but this has not been evaluated in a randomized
controlled trial (RCT).
Methods: We conducted a 24-week multi-centre RCT of idebenone 900 mg/day in 85 patients with LHON due to the
m.11778G [ A, m.14484T [ C or m.3460G [ A mtDNA mutations.
The primary end point was the best recovery in visual acuity (VA).
The main secondary end point was the change in best VA. Other
secondary end points were change in VA of the best eye at baseline
and change in VA for both eyes in each patient. Colour-contrast
sensitivity and retinal nerve fibre layer thickness were measured in
subgroups.
Results: Idebenone was safe and well tolerated. The primary end
point did not reach statistical significance in the intention to treat
population. However, interaction analysis showed a different response
to idebenone in patients with discordant VAs at baseline, where primary and secondary end points were significantly different between
the idebenone and placebo groups.
123
Conclusions: This first RCT in the mitochondrial disorder LHON
provides evidence that patients with discordant VA benefit most from
idebenone treatment, which is safe and well tolerated.
Sponsored by Santhera Pharmaceuticals.
O288
Pyogenic ventriculitis in adult patients
with pneumococcal meningitis
B. Woehrl, J. Linn, M. Klein, T. Pfefferkorn, U. Koedel,
H.W. Pfister
Ludwig-Maximilians-University (Munich, DE)
Objectives: S. pneumoniae is the leading cause of communityacquired bacterial meningitis among adults. With 15 to 30% pneumococcal meningitis (PM) still has a very high case fatality rate, more
than half of survivors develop long term sequelae. This unfavourable
clinical outcome is often due to intracranial complications. Among
those, pyogenic ventriculitis is believed to to be rather rare. Systematic prospective studies are missing. Diffusion weighted magnetic
resonance imaging (DWI) is an accepted tool for diagnosing pyogenic
ventriculitis. In this study, we scanned consecutive patients with PM
for pyogenic ventriculitis using DWI.
Methods: Between January 2009 and now nine patients (age range
32–69 years) with a definite diagnosis of PM based on positive
cerebral spinal fluid (CSF) culture, Gram stain, or antigen detection
(latex particle agglutination) were included. Magnetic resonance
imaging (MRI) was performed between day 1 and day 25 after
admission depending on the patients clinical condition. The sequence
protocol comprised axial fluid attenuated inversion recovery
(FLAIR)-weighted, DWI-weighted, and T1-weighted spin echo
sequences, prior to and after the administration of intravenous contrast-agent.
Results: DWI revealed intraventricular material with diffusion
restriction, corresponding to intraventricular pus, within the occipital
horns of one (n = 2) or both (n = 7) lateral ventricles in all patients.
Ventricular diffusion-restriction was observed as early as one day
after diagnosing the disease. It was accompanied by periventricular
contrast enhancement in three patients. In one patient with a complicated clinical course serial MRI scans were performed that showed
increase of ventricular empyema with clinical deterioration and only
slow resolution with persisting restricted diffusion up to 43 days after
admission. Follow-up MRI that was performed in five patients
between three and twelve months after discharge, showed complete
resolution of ventricular diffusion-restricted areas.
Conclusions: By systematic scanning of patients with PM using
DWI we showed that all examined patients displayed ventricular
diffusion-restriction reflecting pyogenic ventriculitis. We therefore
conclude that pyogenic ventriculitis is an underestimated complication in patients with PM. Besides, our findings support the hypothesis
that the choroid-plexus is a possible route for bacteria to cross the
blood-CSF barrier for subsequent meningeal invasion and infection.
O289
Cerebrospinal fluid findings in adults with acute
neuroborreliosis
M. Djukic, C. Schmidt-Samoa, P. Lange, A. Spreer,
K. Neubieser, H. Eiffert, R. Nau, H. Schmidt
Evangelisches Krankenhaus (Göttingen, DE);
University of Göttingen (Göttingen, DE)
S51
Objectives: The cerebrospinal fluid (CSF) and serum alterations were
retrospectively studied in relation to the clinical presentation in 118
patients diagnosed with acute Lyme neuroborreliosis (LNB). Few
data are available on the CSF lactate concentration in European adults
with the definite diagnosis of acute LNB. The aim of this study was to
evaluate the CSF lactate levels in patients with definite acute LNB.
Methods: CSF was examined for leukocyte count (pleocytosis [4
cells/mm3), levels of total protein, albumin and lactate (pathological C2.1 mmol/l). Albumin, IgG, IgA and IgM were measured by
nephelometry, and intrathecal synthesis of IgG, IgA and IgM was
studied by the nomograms. Furthermore, isoelectric focusing was
used to detect intrathecal IgG synthesis. To prove the intrathecal
production of BB-specific antibodies, BB IgG and IgM were measured in serum and CSF by quantitative ELISA, and the BB-specific
antibody index (AI) was calculated for IgG and IgM. The AI was
defined as pathologic (i.e., indicative of a synthesis of antibodies
against BB antigen within the CNS), if the ratio was C 1.5 either for
IgG or IgM.
Results: 81.4% of patients included in this study had a pathologic
AI for BB. 22 were diagnosed as presumably LNB. 15.3% of patients
presented with neck stiffness and fever. Most of these patients were
younger than 50 years. Radiculoneuritis was frequently found in
patients older than 50 years (p = 0.02). Patients presenting with
facial palsy were found in both groups (p = 0.09). Lymphomonocytic
pleocytosis was found in all patients. 94.2% had elevated protein
concentrations. Only 5 patients had a CSF lactate C3.5 mmol/l, and
the mean CSF lactate level was not elevated (2.1 ± 0.6 mmol/l).
Elevated lactate levels were accompanied by fever and headache
(Fishers Exact Test, p = 0.02). No correlation was found between
other symptoms and CSF parameters. In the Reiber nomograms,
intrathecal immunoglobulin synthesis was found for IgM (70.2%) and
IgG (19.5%). Intrathecal synthesis of three classes of immunoglobulins (IgM, IgG and IgA) was found in 11 patients. Isoelectric
focussing detected an intrathecal igG synthesis in 71 patients (60.2%).
Conclusion: In acute LNB, patients had elevated cerebrospinal
fluid leukocyte counts and protein concentrations. In contrast to
infections by other bacteria, CSF lactate was below 3.5 mmol/l in all
but 5 patients. The CSF findings did not differ substantially between
radiculoneuritis, facial palsy and meningitis.
lymphocytic pleocytosis with raised protein but normal glucose
concentrations. CSF stains, cultures and an extensive battery of PCRs
were negative, apart from a positive HIV PCR with a viral load of
4,850 copies/ml. In spite of empirical treatment the patient’s condition steadily deteriorated. He became increasingly encephalopathic
and ataxic, developed rigidity of all limbs and frequent multifocal
myoclonus. A brain biopsy was performed. The histology was consistent with nonspecific viral encephalitis. Again, the only positive
PCR result from the biopsy tissue was for HIV. Resistance testing
performed on HIV isolated from CSF showed a different profile to
that previously documented from serum-derived virus. HAART was
changed to include CSF penetrating agents to which the CSF isolated
virus was sensitive. The patient then made a slow but remarkable
recovery. Within several weeks of drug change he was transferred to a
rehabilitation unit and discharged approximately three months later.
Six months after his initial admission he was living independently and
back in employment as a chef.
Discussion: There are increasing examples of HIV positive individuals developing a viral ‘quasi-species’ in the CSF that is distinct
from serum HIV. This can lead to discordance between serum and
CSF HIV viral load, and in some cases to distinctly different resistance patterns. This case provides a striking example of the clinical
relevance of this phenomenon and the potential benefit of HAART
modification in this situation.
O290
HIV encephalitis with discordance in drug resistance
profile between serum and CSF isolated virus
A. Jamieson, K. Childs, K. Perez, D. Plessis, D. Mckee
University of Pecs (Pecs, HU)
University of Manchester (Manchester, UK); Manchester Royal
Infirmary (Manchester, UK); Salford Royal Hospitals NHS Trust
(Manchester, UK)
Case History: A 53-year-old man, known to be seropositive for
human immunodeficiency virus (HIV) for 20 years, had been on
highly active antiretroviral therapy (HAART) for 4 years. He had
good CD4 counts and suppressed viral load. He had never acquired
any HIV related complications and was otherwise medically well.
Two weeks prior to admission he had been working successfully as a
chef. He was admitted to hospital in a confusional state. On examination he was encephalopathic with a fluctuating level of alertness.
There was a postural tremor of the arms, gait ataxia and extensor
plantar responses. General/metabolic blood tests were normal. EEG
showed generalised slowing. HIV was detected in the serum by
polymerase chain reaction (PCR) with a low viral load of 128 copies/
ml. His CD4 count was 320. Brain magnetic resonance imaging
showed diffuse high signal in the deep white matter, consistent with
HIV encephalitis. The cerebrospinal fluid (CSF) showed mild
__________________________________
Oral session 20
Extrapyramidal disorders: treatment
O291
High-frequency repetitive transcranial magnetic
stimulation of the motor cortex does not improve motor
symptoms in Parkinson’s disease: a randomised,
double-blind, placebo-controlled study
N. Kovacs, J. Janszky, F. Nagy, Z. Aschermann, E. Pal
Introduction: Based on several open-label and case studies, repetitive
transcranial magnetic stimulation (rTMS) of the motor cortex seems
to have an effect on clinical symptoms of patients with Parkinson0 s
disease (PD). However, this hypothesis requires further confirmation.
Aims: We conducted a randomized, double-blind placebo-controlled study to evaluate the effect of rTMS over bilateral motor
cortex on various motor and non-motor features of PD.
Methods: Twenty-two PD patients were assigned into two groups,
one receiving real-rTMS (90% of resting motor threshold, 5 Hz,
600 pulses-a-day for 10 days) over the motor cortex, and another
group receiving sham-rTMS. An investigator blinded to the treatment
performed three video-taped examinations on each patient: before
stimulation (baseline), 1 (short-term) and 30 days after treatmentsession ended (long-term effect). MMSE, UPDRS, Hoehn-Yahr,
Epworth Sleepiness, Visual Analogue and Montgomery-Asberg
Depression Rating Scales (MADRS), Beck Depression Inventory
(BDI), and Trail making and Stroop tests were applied.
Results: No side-effects occurred and the effectiveness of blinding
was acceptable.Thirty day after treatment ended, the UPDRS-III
improved by 11 points in the stimulated group compared to baseline.
However, the size of improvement was also similar (10 points) in the
sham-treated group. Between the stimulated and the sham-stimulated
123
S52
groups, none of the examined variables showed any statistically significant differences.
Discussion: Both real and sham stimulation produced a considerable improvement in the UPDRS-III. Because we could not find any
significant changes between the two groups, we might conclude that
this improvement is probably due to the placebo effect of rTMS NK
and JJ are supported by the government-based Bolyai Scholarship of
Hungarian Academy of Sciences.
O292
Low-frequency repetitive deep transcranial magnetic
stimulation improves motor performance in patients
with Parkinson’s Disease
O. Cohen, A. Zangen, R. Amiaz, G. Yahalom, Z. Nitzan,
L. Ephraty, Y. Orlev, H. Strauss, E. Kozlova, S. Hassin-Baer
Sheba Medical Center (Ramat Gan, IL); Weizmann Institute
of Science (Rehovot, IL)
Background: Repetitive transcranial magnetic stimulation (rTMS) using
the new H-coil, designed to affect deeper neuronal pathways, can induce
neuroplasticity and be an effective method for nonsurgical brain stimulation in patients with Parkinson’s disease (PD). Our previous studies
using high frequency rTMS showed a modest effect but failed to achieve
clinically significant improvement of motor functions.
Objectives: Given reports on increased excitability in the motor
cortex in PD patients, we tested the safety and efficacy of low frequency deep rTMS over the motor cortex with and without high
frequency rTMS over the prefrontal cortex.
Methods: 14 PD patients with asymmetric disease were randomized
to one of two treatment protocols: (1) Low frequency (1 Hz) stimulation
over the motor cortex along with high frequency stimulation (10 Hz) over
the prefrontal cortex. (2) Low frequency stimulation over the motor
cortex alone. All patients had 12 treatment sessions in a 30 days period.
Outcome measures, collected on days 1, 10, 30 and 60 included: Unified
PD rating scale (UPDRS), Clinical Global Impression of severity and of
change scales (CGIS and CGIC), pegboard test, foot and finger tapping
tests, timed Up & Go test (TUG), as well as measures of depression and
neuropsychological functioning.
Results: In the dual stimulation group (n = 8) there was a significant
improvement in motor UPDRS (5.6 points in average, p = 0.004), motor
UPDRS (2.33 points, p = 0.015) and foot tapping (7.84 taps, p = 0.034)
of the more affected side, and pegboard test (7.68 s, p = 0.007). The
beneficial effect of stimulation was still significant for the motor UPDRS,
UPDRS of the afflicted side, and pegboard at day 60. In the second group
(n = 6) a smaller but significant improvement was evident on day 30
alone. In neither group did rTMS have a beneficial effect on depression or
cognitive measures and the treatment was well tolerated.
Conclusions: In this open study, rTMS proved to be a promising,
safe and effective treatment, causing significant improvement of
motor functions in PD patients.
Low frequency deep rTMS over the motor cortex along with high
frequency deep rTMS over the prefrontal cortex should be tested in a
larger, double blind study against sham stimulation.
O293
Does subthalamic nucleus deep brain stimulation affect
cardiovascular dysautonomia in Parkinson’s disease?
E. Trachani, M. Frima, V. Sirrou, C. Constantoyannis,
E. Chroni
University of Patras (Patras, GR)
123
Objectives: To assess the potential impact of the Subthalamic Deep
Brain Stimulation (STN DBS) on the cardiovagal regulation in
patients with advanced idiopathic Parkinson’s disease (PD). Methods:
15 patients (10 males; mean age 62.00 ± 7.32 and mean disease
duration 12.87 ± 6.39 years) with PD, who underwent STN DBS
implantation to improve motor function, were included in the study
and matched for age and sex with 15 healthy subjects. The patients’
motor performance and subsequently the DBS improvement were
evaluated through Unified Parkinson’s Disease Rating Scale (UPDRS). The neurophysiological examination was performed under two
treatment conditions: 3 days before the surgery while the patients
were receiving their medication (pre-op group) and 6 months after the
implantation on DBS plus medication state (post-op group). The
assessment included: (1) RR interval variation during 1 min of normal breathing and 1 min of deep breathing (DB RR). (2) Valsalva
maneuver: ratio of the longest RR interval to the shortest R-R interval
(3) Tilt test: (a) ratio of the RR interval at 30 s to RR interval at 15 s
after sudden change from supine to standing position (b) Systolic and
Diastolic Blood pressure (SBP and DBP) was recorded only in the
patient group, at supine position and at the third minute of standing
position.
Results: The mean DBS motor improvement was 66.71 ± 23.06%.
DB RR, Valsalva ratio and Tilt ratio were in pre and post DBS
patients significantly lower than in controls (ANOVA test,
p \ 0.001). There was no statistical significant difference in the
values of the above parameters or in the SBP and DBP between preop and post-op groups. Five pre DBS patients suffered of orthostatic
hypotension, which sustained in 1 patient after surgery. Three pre
DBS patients had orthostatic dizziness, which remained in 2 of them
post-op. No correlation between orthostatic hypotension and feeling
of orthostatic dizziness either before or after implantation was found.
Conclusion: Although STN DB resulted in a considerable motor
improvement, it did not offer a clear benefit on the reduced autonomic
nervous system regulation of cardiovascular function.
O294
Effects of high-dose ropinirol on sexual functions
in Parkinson’s disease
N. Kovacs, J. Janszky, F. Nagy
University of Pecs (Pecs, HU); Kaposi Mor County Hospital
(Kaposvar, HU)
Among the non-motor symptoms of Parkinson’s disease (PD), sexual
dysfunction (SD) is of great importance. In the present study, we
analyzed the effects of high-dose ropinirole on SD associated with
PD.
Fifteen patients diagnosed with PD and reporting sexual dysfunction were enrolled in the study. SD was assessed by both clinical
interview and Arizona Sexual Experience Scale (ASEX). After a
3-month high-dose ropinirole treatment, Clinical Global Impression
of Improvement Scale (CGI-I) and changes in ASEX scores were
analyzed and correlated to age, disease-duration and ropinirole
dosage.
The average dose of ropinirole was 16.0 ± 3.2 mg at the followup; however, no serious side-effects occurred. None of the patient
developed impulsive control disorder based on the clinical interviews,
either. Based on the CGI-I scale, eight subjects reported either ‘‘very
much improvement’’ or ‘‘much improvement’’; they were treated as
treatment responders (53.3% of enrolled patients). Out of the five
domains measured by ASEX, only sexual drive, arousal and satisfaction from orgasm demonstrated significant improvement. The dose
of ropinirole was significantly correlated with the follow-up values of
sexual drive and arousal subscales of ASEX (r = -0.694 and r = -
S53
0.818, p \ 0.01, respectively). Interestingly, neither the age nor the
disease duration of patients correlated with the size of sexual
improvement.
Based on our results, we may conclude that high-dose ropinirole
may improve several domain of sexual life, e.g. sexual drive, arousal
and satisfaction from orgasm. These domains mainly represent the
psychological factors associated with sexuality. Further controlled
studies are required to reliably examine this phenomenon.
NK and JJ were supported by the government-based Bolyai
Scholarship of Hungarian Academy of Sciences.
O295
Subtypes of mild cognitive impairment in Parkinson’s
disease—a longitudinal study
Y. Zhelev, M. Raycheva, M. Petrova, L. Traykov
Medical University (Sofia, BG)
Objectives: Parkinson’s disease (PD) is often associated with mild
cognitive impairment (MCI). Although PD subjects with MCI have a
high risk of developing dementia some of them exhibit cognitive
deterioration at follow-up whereas others remain cognitively stable.
The subtypes of MCI probably could predetermine cognitive prognosis in PD. The aim of the study was to investigate the
transformation of PD-MCI subtypes in a longitudinal study.
Methods: We investigated 26 PD-MCI patients. All subjects were
assessed, at the baseline and average 24 months later, with a neuropsychological battery covering multiple cognitive domains. PD and
subtypes of MCI were diagnosed according to established criteria.
Results: At follow-up five (19%) patients were demented, two
(7.7%) were considered normal. At baseline one of demented patients
had amnestic MCI, three had non-amnestic MCI and one had multiple
domains MCI.
Conclusion: In this study 80% of PD patients who developed
dementia at follow-up were initially classified as MCI subtype (single
or multiple domain) with characteristic of executive impairment. The
executive impairment in PD-MCI might be the ‘‘malignant’’ state
related to further cognitive deterioration. Although a significant
amount (73%) of patients remained in MCI state a dynamic transformation of single domain MCI to multiple domain MCI has been
observed.
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Oral session 21
Epilepsy
O296
Treatment of status epilepticus: a comparison
of phenytoin, valproate, or levetiracetam
V. Alvarez, J.-M. Januel, B. Burnand, A. Rossetti
University Hospital of Lausanne (Lausanne, CH)
Objectives: Phenytoin (PHT), valproic acid (VPA), or levetiracetam
(LEV) are commonly used as second-line treatment of status epilepticus (SE), but comparative studies are not available to date.
Methods: In our tertiary care hospital, among 279 SE episodes
prospectively collected over four years, and occurring in adults, we
identified 187 episodes in which PHT, VPA or LEV were prescribed
after benzodiazepines. Patients with post-anoxic SE were not included. Demographics, clinical SE features, failure of second-line
treatment to control SE, new handicap and mortality at hospital discharge were assessed. Uni- and multivariable statistical analyses were
applied to compare the three agents.
Results: Each compound was used in about one third of episodes.
VPA failed to control SE in 25.4%, PHT in 41.4% and LEV in 48.3%
of episodes in which these were prescribed as second-line agents.
After adjustment for known SE outcome predictors, LEV failed more
often than VPA (OR 2.69; 95% CI 1.19–6.08); in others words, 16.8%
(95% CI 6.0–31.4%) of second-line treatment failures could be
attributed to prescription for LEV instead of VPA. PHT was statistically not different from the other two compounds. At discharge,
second-line treatment did not influence new handicap and mortality,
while etiology and severity of the SE episode were robust independent predictors.
Conclusions: Even without significant differences on outcome at
discharge, LEV seems less efficcacious than VPA to control SE after
benzodiazepines. A prospective comparative trial is needed to address
this potentially concerning finding. The second interesting finding is
that the outcome seems more influenced by the SE characteristics than
the treatment.
O297
Automated quantification of spiking and spike
potentiation in electrical status epilepticus in sleep
I. Sánchez Fernández, V. Chavakula, J. Peters,
A. Rotenberg, S. Kothare, T. Loddenkemper
University of Barcelona (Barcelona, ES); Children0 s Hospital Boston
(Boston, US)
Objectives: To validate a novel automated method for quantification
of the electroencephalographic (EEG) epileptiform abnormality accross phases of the sleep-wake cycle in patients with electrical status
epilepticus in sleep (ESES).
Methods: By visual review, we calculated the EEG epileptiform
activity in patients (n = 25) with ESES to obtain the spike wave index
(SWI: percentage of one-second bins with spikes), and spike count (SC:
number of spikes per 100 s). The same EEG data were analyzed by our
automated discrete wavelet transform based computer algorithm to
obtain an automated spike count (ASC: number of spikes per 100 s). Per
patient, we analyzed three segments of 1 min each during: (1) the first
clearly recognizable segment of wakefulness (W), (2) the first clearly
recognizable segment of stage II sleep (N2), and (3) the first clearly
recognizable segment of stage III sleep (N3). We used the Pearson correlation coefficient (R) to compare the values of SWI, SC and ASC.
Results: All EEG data were from patients with ESES
(SWI [50%). SWI and SC correlated in W (R = 0.967; p \ 0.0001),
in N2 (R = 0.871; p \ 0.0001), and in N3 (R = 0.898; p \ 0.0001).
SWI and ASC correlated in W (R = 0.588; p = 0,002), in N2
(R = 0.434; p = 0.03) and in N3 (R = 0.494; p = 0.012). SC and
ASC correlated in W (R = 0.652; p \ 0.0001), in N2 (R = 0.575;
p = 0.003), and in N3 (R = 0.484; p = 0.014). The percentage of
spikes detected by ASC (sensitivity) was 94.2% of the one-second
bins with spikes detected by SWI, and 54.5% of spikes detected with
SC. The sleep potentiation factors (SPF: times the median of spikes
was higher from wakefulness to sleep) were: with SWI, 4.58 for N2
and 4 for N3; with SC, 6.31 for N2 and 4.75 for N3; and with ASC,
5.88 for N2 and 6.5 for N3. The SPF for N2 and N3 were not significantly different (Wilcoxon Z = -0.535; p = 0.593).
Conclusions: ASC can mirror manual SWI and SC in patients with
ESES. We anticipate that this method will facilitate objective quantification of sleep potentiation of EEG epileptiform activity in ESES.
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S54
The ASC may also be a useful real-time tool for spike and seizure
detection as a component of a responsive closed loop treatment
strategy in ESES and, possibly, in status epilepticus.
O298
Emotional perception in focal epilepsies: frontal lobe
and mesial temporal sclerosis
C. Cunha, C. Bento, F. Sales, I. Santana
University Hospital Coimbra (Coimbra, PT)
Objective: This study examined the performance of patients with
epilepsy- Frontal Lobe Epilepsy (FLE), Temporal Lobe Epilepsy
(Mesial Temporal Sclerosis, MTS) and normal controls (NC) in
the Comprehensive Affect Testing System (CATS), a battery
designed to measure perception of emotion via facial affect,
prosody, and semantic content. The 13 CATS subtests are comprised of the same set of male and female faces that are posed in
six emotional expressions (happy, sad, angry, surprised, fearful,
and disgusted).
Methods: We study 14 patients with FLE, 32 with MTS (20 leftMTS and 12 right-MTS) and 30 NC. Measures were obtained by
scores in the Subtests (ST), Primary Scales (PS) which assess emotions via facial expressions, prosody and cross-modal task face/
prosody- and Discrete Emotional Scales (DES)—happy, sad, angry,
surprised, fearful and disgusted. Non-parametric tests (Mann–Whitney) were conducted to compare the performances of patients and
controls.
Results: MTS patients scored significantly lower than NC in all
emotion tasks (p \ 0.005) with exception for the simple visuoperceptive scales and were impaired in perception of happiness, surprised
and anger (p \ 0.05). FLE patients scored lower than NC in the
Global Emotional Perception index and in the Cross-Modal tasks
(p \ 0.05). Also, FLE patients had impairment on perception of
surprised (p = 0.014). MTS patients had greater impairment than
FLE patients in prosody tasks (p = 0.032). Right-MTS patients had
higher impairment than Left-MTS in the Global Emotional Perception
index (p \ 0.05) and in perception of fear (p = 0.023).
Conclusions: Our results suggest that the CATS is a reliable
instrument of EP with the capacity to discriminate between patients
with MTS, FLE and NC. NC shows higher scores in all facial and
prosody tasks while MTL patients had greater impairment. Prosody
tasks can discriminate MTL from FLE patients. Performances on
Global Emotion Perception and Fear Perception were more impaired
in Right-MTS.
O299
Developing optic radiation tractography to reduce
visual field deficits following anterior temporal lobe
resection
G.P. Winston, P. Daga, J. Stretton, M. Modat,
M.R. Symms, A.W. McEvoy, S. Ourselin, J.S. Duncan
University College (London, UK); National Hospital for Neurology
and Neurosurgery (London, UK)
Objectives: Anterior temporal lobe resection (ATLR) is an effective
treatment for refractory temporal lobe epilepsy. Damage to Meyer’s
loop of the optic radiation (OR) leads to postop visual field deficits
(VFD) in 52–100% of patients and may prevent driving. The OR
cannot be seen on clinical MRI sequences, but can be visualised using
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diffusion tensor imaging (DTI) tractography. Incorporating these data
into the neuronavigational system during surgery should reduce the
risk of VFD. However, preop tractography is no longer valid due to
brain shift/distortion. A new image registration technique to compensate for brain shift/distortion is described and validated it in a
cohort of patients undergoing ATLR with the aim of using this to
guide future neurosurgery.
Methods: Pre-/postop structural MRI and DTI scans were acquired
on 16 patients undergoing ATLR. The OR was delinetaed using
probabilistic tractography on preop data and propagated onto postop
structural images using a novel image registration technique. Degree
of resection was quantified by the maximum A–P distance between
the anterior of the OR on the propagated tractography and the
resection margin. Postop VFD was quantified as percentage of upper
quadrant lost using Goldmann perimetry.
Results: Postop VFD were seen in 8 patients (10–92% of the upper
quadrant, mean 51%). In 8 patients without VFD, the propagated OR
was 0.0–15.0 (mean 3.4 mm) posterior to the resection margin. In 8
patients with VFD, the propagated OR lay 3.8–15.9 (mean 7.7 mm)
anterior to the resection margin. The Pearson correlation coefficient between A–P distance and VFD was 0.809 (one-tailed
p = 0.008). Linear regression showed for each additional 1 mm of
resection, 5.8% more upper quadrant vision was lost. Mean image
registration time by implementation on a GPU (graphical processing
unit) was 3.2 min.
Conclusions: A novel non-linear registration algorithm was used
to propagate preop OR tractography onto postop images. Results
obtained were highly predictive of the VFD. MRI and DTI scans can
be acquired during surgery in an interventional MRI suite. As transfer
of the patient from the MRI scanner back to the operating table takes
7–10 min, the algorithm is fast enough to be applied to propagate
preop tractography onto intraop images before surgery recommences.
Future work will display the propagated tractography to the surgeon
in the neuronavigation system to determine whether this additional
information can reduce the risk of a VFD.
O300
Impact of early-onset complex partial epilepsy
on cognition, brain structure and function
N. Kitchener, A. AbdelKader, S. Aziz, N. Nagy
General Organization for Teaching Hospitals (Cairo, EG);
Cairo University (Cairo, EG); Ain Shams University (Cairo, EG)
Purpose: To characterize neurodevelopmental correlate of early onset
complex partial epilepsy (cps) on cognition, brain structure and
function compared with late onset complex partial epilepsy and
control group.
Methods: Control group includes 50 orthopedic patients with
traumatic bone fracture and 49 patients with early, versus 36 patients
with late onset cps; were compared with high resolution quantitative
Magnetic Resonance (MRI) volumetrics, and comprehensive neuropsychological assessment.
Results: Patients with early onset complex partial epilepsy (mean
age 6.4 years) exhibited poorer neuropsychological performance and
comparative reduction in brain tissue volume in temporal and extratemporal regions compared to control group, and late onset group
(mean age 26.9 years). Reduced total white matter volume and significantly poor cognitive functions were more evident in early onset
group compared with other two groups.
Conclusions: Early onset complex partial epilepsy has a detrimental impact not only on cognitive functions, but also on brain
structure, which seems to be generalized.
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O301
mToR positive neurons and diffuse cortical gliosis are
common in children with focal cortical dysplasia type Ib
M.V. Miles, F. Mangano, K. Lee, J. Leach, P.S. Horn,
A. DeGrauw
Cincinnati Children’s Hospital Medical Center (Cincinnati, US)
Objective: Focal cortical dysplasia (FCD) is commonly associated
with intractable epilepsy in children and adults. Since the description
by Taylor et al. in 1971 and revision by Palmini et al. in 2004, the
classification of FCD has been widely used but understudied. Recent
reports indicated that activation of mammalian target of rapamycin
(mTOR) is associated with FCD type II in patients with tuberous
sclerosis and with treatment-resistant epilepsy (Lancet Neurol
2009;8:830–43; Acta Neuropathol 2010;120:85–96). The current
study provides the first evidence that mTOR is also commonly
overexpressed in brain of children with FCD type Ib. The objective of
this study is to evaluate relationships between immunohistochemistry
(IHC) neuropathology and FCD classification in the epileptogenic
brain resected from patients with intractable epilepsy.
Methods: This retrospective study evaluated the pathological
findings in brain specimens resected from patients with intractable
epilepsy between Jan. 2007 and Nov. 2010. Prior to surgery all
patients were evaluated by members of the Epilepsy Surgery Program. Hematoxylin and eosin (H&E), glial fibrillary acidic protein
(GFAP), mammalian target of rapamycin (mTOR) stains were performed. Based upon GFAP stains cortical gliosis was classified as
superficial (sGFAP), involving only subpial and first layer of cortex,
or diffuse (dGFAP), involving all 6 layers of cortex. This study was
approved by the Institutional Review Board.
Results: Forty-one patients were included (age 1.3–20 years; 18
females). There were 61 specimens due to some patients having
multiple surgeries or multiple resections during the same surgery.
The most common areas of resection were the frontal (56%) and
temporal (31%) lobes. Based on H&E slides, the FCD classifications
were: IA (n = 6); IB (n = 25); IIA (n = 25); and IIB (n = 5) specimens. dGFAP was noted in 19% (6/31) type I FCD and 83% (25/30) type
II FCD (P \ 0.001). mTOR(+) neurons were found in 26% (8/31) type I
FCD and 77% (23/30) type II FCD specimens. All brain tissue classified
as type IA FCD showed sGFAP and no mTOR(+) neurons. In contrast,
100% of specimens classified as type IIB FCD showed dGFAP and
contained clusters of mTOR(+) neurons.
Conclusions: mTOR(+) neurons and diffuse cortical gliosis were
common in type Ib and type II FCD specimens resected from children
with intractable epilepsy. Evaluation of mTOR and GFAP may provide improved understanding of epileptogenesis, and help in the
classification of FCD.
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Oral session 22
Sleep disorders
O302
Iron infusion in restless legs syndrome in pregnancy
J. Schneider, A. Krafft, A. Bloch, A. Huebner,
M. Raimondi, C. Baumann, E. Werth, C. Bassetti
University Hospital Zurich (Zurich, CH); Neurocenter of Southern
Switzerland (Lugano, CH)
Background/aim: Restless legs syndrome (RLS) affects 10–20% of
women during pregnancy. Treatment options are very limited. Ferric
carboxymaltose (Ferinject) is approved in Switzerland for treatment
of iron-deficiency anaemia in pregnancy. The objective of this openlabel non-controlled exploratory double centre study is to assess the
effect of an infusion of Ferinject in pregnant women with RLS and
iron deficiency.
Patients/Methods: Pregnant women in the third trimester of
pregnancy with moderate-severe RLS (IRLS [20) with iron deficiency (Ferritin \35 lg/l) or anaemia (Hb \11 g/dl) can be included
in this study. Depending on Hb, iron substitution is performed with an
infusion of 500–900 mg of ferric carboxymaltose. Assessment of
treatment effects is done by questionnaires (international RLS Study
Group questionnaire (IRLS), fatigue severity scale, Epworth sleepiness scale, Pittsburgh sleep quality index), blood tests (iron, ferritin,
CRP) at the screening visit, 28 days after therapy, as well as 2 weeks
and 6 weeks after ferric carboxymaltose delivery. Foot actigraphy is
additionally performed 1 week before and 1 week after the treatment.
Results: So far 10 patients were included. All but one patient
reported from the first night following a marked decrease in RLS.
Four weeks after treatment the RLS score was reduced from 25 ± 7
to 8 ± 5 (p \ 0.01). A reduction in PLMS was also documented in 7
out of 10 patients (from 34 ± 22 to 25 ± 19) (p \ 0.02). Ferritin
levels increased from 17 ± 10 lg/l to 73 ± 25 lg/l. Ferric carboxymaltose was well tolerated without severe adverse.
Conclusions: Preliminary results of this ongoing study suggest that
infusion of ferric carboxymaltose is (rapidly) effective in improving
moderate-severe RLS in pregnant women with iron deficiency or
anaemia.
O303
A prospective, controlled, ambulatory study
on idiopathic restless legs syndrome, measuring skin
temperature, periodic limb movements in sleep
and wrist activity
V. Uhl, K. Kräuchi, B. Gompper, C. Bassetti, U. Kallweit
Kamillus-Klinik (Asbach, DE); Psychiatric University Clinics
(Basel, CH); Neurocenter of Southern Switzerland (Lugano, CH);
University Hospital Zurich (Zurich, CH)
Objectives: Restless Legs Syndrome (RLS) is the syndrome of
‘‘fidgety’’ legs. One theory for the occurrence of RLS symptoms is a
malfunction of the sympathetic nervous system (SNS), with an elevation of sympathetic activity, caused by a reduced inhibition of A11
neurons at the diencephalospinal pathway. As the SNS controls the
constriction and vasodilatation of blood vessels, a higher sympathetic
tone leads to more constricted blood vessels and therewith a reduced
perfusion of remote body parts like the legs, thus abating local skin
temperature. Previous studies on body temperature in RLS mainly
concentrated on changes in core temperature and moreover these were
inpatient studies. Regarding this we wanted to examine idiopathic
RLS patients and matched controls under ‘‘real-life’’ ambulant conditions, measuring skin temperatures to find out if there are any
differences between RLS patients and healthy controls.
Methods: Patients suffering from idiopathic RLS were included.
Controls had to be healthy in all aspects. All participants were nonsmokers. No RLS or CNS medication was allowed. Assessment
included iButtons at 13 parts of the body, periodic limb movements in
sleep (PLMS), wrist actigraphy and questionnaires (e.g. sleep-wakediary).
Results: In each group 8 subjects (3 m, 5w RLS; 2 m, 6w controls)
could be included. Mean IRLS-Score was 19.5 (±1.9 SE) with a
PLMS-index of 31.3 (±10.3 SE) in RLS versus 2.4 (±1.1 SE) in
controls (p = 0.002). Mean BMI was 26.9 (±1.5 SE) for RLS and
23.7 (±1.4 SE) for controls with a mean age of 55 (±2.8 SE) (RLS)
123
S56
versus 48 (±3 SE) years (controls) (each with p [ 0.05). RLS patients
had a lower skin temperature than controls at night at the ankle, upper
and lower leg (p \ 0.05). Accordingly, RLS patients quoted a cooler
temperature sensation at the foot in the morning and the evening
(p = 0.028 and p = 0.046). Patients and controls showed no significant temperature differences at the wrist and torso. In RLS, activity
was significantly higher for about the first half of the night (p \ 0.05).
Conclusion: In idiopathic RLS, a lower leg skin temperature at
night indicates an elevated sympathetic tone which could lead to a
sensitisation of afferent muscles and thus to a higher sensory output.
As cool limbs aggravate falling asleep, the lower leg temperature in
combination with the higher responsiveness might be involved in the
development of the RLS symptoms.
O304
Rivastigmine treatment for REM behaviour disorder
in Parkinson’s disease
R. Di Giacopo, G. Della Marca, S. Colicchio, E. Testani,
A. Bentivoglio
Background: Cluster headache is a rare primary headache disorder
often related to sleep. Many patients experience cluster headache attacks
at night lasting between 15 min and several hours. The suspected relationship of hypothalamic dysfunction in the pathophysiology of cluster
headache has often raised the suspicion that typical headache attacks
might be related to REM sleep. This would underline hypothalamic
involvement in this disease.
Design/Methods: We performed polysomnography in 4 patients with
cluster headache according to the diagnostic criteria of the International
Headache Society (ICHD-II) in four consecutive nights. An independent,
experienced sleep medicine specialist blinded to the diagnosis evaluated
a total of 14 nights where typical headache occurred.
Results: We found no association of the occurrence of headache in
patients with cluster headache with a particular sleep phase. Headache
onset was arbitrarily distributed to REM and non-REM sleep.
Headache occurred most often in sleep phase 2, which also is the most
likely finding as this is the most common sleep phase.
Conclusion/Relevance: The occurrence of cluster headache attacks is
not associated with a particular sleep phase, neither REM nor non-REM
sleep. These findings dispute the common understanding that hypothalamic dysfunction is the hallmark of cluster headache pathophysiology.
Catholic University (Rome, IT)
Background: Rapid-eye movement (REM) sleep behaviour disorder
(RBD) is characterized by loss of muscular atonia and prominent motor
behaviours during REM sleep. RBD can cause severe injuries for the
patient or the bed partner. The disorder is strongly associated with synucleinopathies, mainly with Parkinson’s disease (PD), and can precede
that by several years. Pathophysiology of RBD includes pontomedullary
pathways, mainly cholinergic and GABA-ergic, underlying muscular
atonia during REM sleep. Clonazepam and Melatonin are the treatment
of choice for RBD, but the 10% of patients have not therapeutic response.
The use of cholinesterase inhibitors Donepezil and Rivastigmine is still
controversial. Our Objective is to evaluate the efficacy of Rivastigmine
treatment in PD patients with RBD in whom traditional treatment failed.
Methods: We enrolled 12 PD (11 males) patients (middle
64.5 years) with RBD confirmed by polysomonography; 4 had severe
RBD ([5 episodes/week) 8 mild RBD. A double blind, cross-over
design was applied. Each patient received Exelon 4.5 mg/day or
placebo for three weeks, then shifted to the alternative treatment.
Patients and their bed partners filled in a diary of RBD episodes as
long as the study. Polisomnography was performed after each treatment in three patients. Patients underwent neuropsychological
assessment before starting the treatment.
Results: Two patients dropped-out of the study for hypotension.
RBD episodes frequency was reduced over the 50% in all patients
with severe RBD and in three patient with mild RBD who referred
refreshing sleep. In the last three the RBD frequency remained
unchanged. The efficacy of rivastigmine was not related to the cognitive impairment of patients.
Conclusions: Rivastigmine seems an effective secondary option for
RBD treatment in a cohort of patients refractory to conventional therapies.
O305
Serial polysomnography in cluster headache shows
no association with REM sleep
M. Obermann, D. Holle, S. Naegel, T. Wessendorf,
S. Zaremba, H.C. Diener, Z. Katsarava
University of Duisburg-Essen (Essen, DE)
Objective: To identify associations of REM sleep with the occurrence
of headache in patients with cluster headache.
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O306
Pain-autonomic interaction in sleep-deprived healthy
subjects
P. Schestatsky, L. Dall-Agnol, L. Gheller, L. Stefani,
P. Sanches, I. Ferreira, I. Torres, W. Caumo
Hospital of Porto Alegre (Porto Alegre, BR)
Objectives: Sleep restriction is commonly associated with alterations
in pain perception. However there is lack of studies addressing
alterations in non-nociceptive perception and autonomic responses
after sleep deprivation.
Methods: The study was carried out in 15 medical students. We
firstly assessed clinical characteristics of subjects using scales for
depressive and anxious symptoms. We also performed quantitative
sensory testing for electrical and temperature sensations and recorded
double-electric-induced sudomotor skin responses (SSR) at different
interstimulus intervals (ISI) of 1, 2 and 3 s. Evaluations were done
before and after 12 h sleep deprivation (SD).
Results: Symptoms of anxiety and depression were not induced by
SD. However, sleep restriction produced a significant decrease in heat
pain, but not in electrical and warm thresholds. Regarding autonomic
responses, subjects showed abnormal recovery of SSR excitability at
ISIs 1 and 2 s after SD. There was no correlation between anxiety
scores and SSR parameters. After SD, subjects with abnormal autonomic responses had presented lower heat pain thresholds in
comparison with those with normal autonomic responses.
Conclusions: The effects of sleep restriction on pain are specific
and not due to more general changes in sensory perception. Abnormal
autonomic responses were associated with hyperalgesia, but not with
anxiety scores, suggesting a positive correlation between autonomic
and nociceptive systems, independent of emotional state.
O307
Which objective measure of pathological sleepiness can
better predict driving performance in patients
with sleep disorders?
P. Philip, M. Raimondi, A. Capelli, P. Sagaspe, J. Taillard
University Hospital (Bordeaux, FR); Neurocenter of Southern
Switzerland (Lugano, CH)
S57
Objectives: Different sleepiness measures, both subjective and
objectives are currently used in clinical practice. The Multiple Sleep
Latency Test (MSLT) and the Maintenance of Wakefulness Test
(MWT) are the gold standards for the detection of Excessive Daytime
Sleepiness (EDS) in sleep medicine. Although the MWT seems to
predict better than MSLT the performance on simulated driving in
patients with obstructive sleep apnoea syndrome (OSAS), the validity
of those tests to estimate the driving ability in patients with different
sleep disorders is not well known.
The aim of our study is to determine the ability of objective
sleepiness measures (MWT or MSLT) to predict driving performance
measured on driving simulator in patients suffering from different
sleep disorders associated with daytime sleepiness, especially narcolepsy/ hypersomnia and obstructive sleep apnea compared to healthy
controls.
Methods: 148 subjects (38 healthy controls, 42 narcolepsyhypersomnia and 70 OSAS patients) performed a total of 96 MWT
(4 9 40-min trials) and 77 MSLT (5 9 20-min trials). For each test, a
40 min driving session on real car driving simulator with monotonous
driving scenario was performed. Participants were classified into 3
groups defined by their scores at MWT or MSLT (pathological
(0–19 min for MWT and 0–8 min for MSLT), intermediate
(20–33 min for MWT and 9–11 min for MSLT), and alert
(34–40 min for MWT and 12–20 min for MSLT).
Results: The results showed that only sleep latencies at MWT
were correlated with number of inappropriate line crossings (r = 0.31, p \ 0.002) for both patients and controls. In addition, the MWT
pathological group had significantly more inappropriate line crossings
than intermediate and alert groups [F (2.93) = 3.25, p \ 0.05).
MSLT scores did not predict driving performances.
Conclusion: The issue of fitness to drive in sleepy patients raised
the need to identify objective, reliable clinical tool for this purpose.
Our results show that sleep latencies on MWT can predict a driving
performance according to the degree of sleepiness, independently of
underlying sleep pathology. In contrast, no relationship between
sleep latencies on MSLT and driving performance was observed.
MWT test is a tool currently used to evaluate the treatment efficacy
in patients with pathological sleepiness. We suggest that MWT could be
also useful to estimate driving performance in those patients.
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Oral session 23
Motor neuron disorders: ALS
O308
Benefit of the Awaji diagnostic algorithm for ALS,
a prospective study
M. Schrooten, C. Smetcoren, W. Robberecht,
P. Van Damme
University Hospitals Leuven (Leuven, BE)
Objective: Early and accurate diagnosis of amyotrophic lateral sclerosis (ALS) is important for patient care and for entry in clinical trials.
Retrospective studies suggest that the use of the Awaji algorithm for
the diagnosis of ALS is more sensitive to make an early diagnosis
than the currently used revised El Escorial criteria.
Methods: We prospectively compared the revised El Escorial
criteria with the Awaji algorithm in patients seen with suspected ALS
at the University Hospital Leuven between January 2008 and April
2010.
Results: Out of 200 patients referred for the diagnosis of ALS, 66 and
85% could be categorized to definite or probable ALS at first presentation
according to the revised El Escorial and the Awaji algorithm, respectively
(p \ 5.6 9 10–17). This corresponds to a [50% reduction of patients
not eligible for clinical trial entry. Application of the Awaji algorithm
made the diagnosis of ALS more likely by at least one diagnostic category
in 25.7% of patients and identified at least one additional region with
electrodiagnostic signs of ongoing lower motor neuron loss in 46.4% of
electrodiagnostic investigations. Application of the Awaji algorithm did
not result in a single false positive diagnosis of ALS in this study.
Conclusion: Our data demonstrate that the Awaji algorithm is
significantly more sensitive compared to the revised El Escorial criteria, without resulting in false positive diagnoses of ALS. It should
therefore be used in clinical trials.
O309
Congruent handedness and side of onset in ALS—
evidence in favour of the exercise hypothesis?
E. Bunting*, C. Wood-Allum*, S. Barber, P. Shaw
Nottingham University Hospitals NHS Trust (Nottingham, UK);
Sheffield Institute for Translational Neuroscience (Sheffield, UK);
University of Leeds (Leeds, UK)
Objective: The only proven risk factors for amyotrophic lateral
sclerosis (ALS) are male sex, increasing age and the inheritance of a
genetic predisposition. Many ALS specialists, however, notice an
excess of particularly physically active people in their clinics, suggesting exercise as a possible further risk factor. We hypothesized that
over a lifetime dominant arm motor neurons will fire more often than
their non-dominant colleagues and if the exercise hypothesis is true,
might succumb first in those otherwise predisposed to ALS. It follows
that disease, if it begins in the upper limbs, should do so more often in
the dominant arm. No similar effect would be predicted in the lower
limbs. Our study set out to test this hypothesis.
Methods: Case notes from 687 deceased ALS patients seen in
Newcastle 1983-2000 and in Sheffield 2000–2010 by PJS were
examined. Only patients meeting Airlie House criteria for clinically
definite, clinically probable or clinically probable-laboratory supported ALS by the time of death were included in the handedness
analysis. Those with dementia at presentation, active malignancy or a
complicating second neurological diagnosis were excluded. The null
hypothesis was tested using the exact binomial test.
Results: The mean age, sex ratio and distribution of disease onset
of the study population were as expected. Of 204 eligible upper-limb
onset cases, 153 had clear unilateral onset and known handedness.
Onset was congruent in 64.1% (n = 98) and non-congruent in 35.9%
(n = 55), (p = 0.0006). Mean age at onset was higher in congruent
than non-congruent cases (59 years vs. 55 years, p = 0.0447). Lower
limb onset, in contrast, was divided equally between right and left.
Conclusions: When ALS begins in the upper limbs, onset occurs
more often in the dominant arm as hypothesized. Congruence of
handedness and side of onset may increase with increasing age at
onset but a larger study is needed to confirm this. Along with the work
of Turner et al., this study provides good evidence of an until recently
unrecognized feature of ALS. Our study does not prove an association
between physical activity and the development of ALS but we contend that it provides evidence in its favour. It also suggests that further
probing of the relationship between exercise and ALS may be
worthwhile. There are other plausible interpretations of our data and
these will be discussed in our presentation.
Reference: Turner M. et al. JNNP. First published online June 18th,
2010.
* joint first authors
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O310
Relationship between white matter tract damage
and executive functions in amyotrophic lateral
sclerosis: a DT-MRI tractography study
L. Sarro, F. Agosta, E. Canu, N. Riva, A. Prelle,
M. Copetti, M. Comola, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT); Scientific Institute
and University Hospital San Raffaele (Milan, IT); Hospital
Fatebenefratelli e Oftalmico (Milan, IT); Hospital Casa Sollievo della
Sofferenza (San Giovanni Rotondo, IT)
Objective: Amyotrophic lateral sclerosis (ALS) has been associated
with characteristic patterns of focal gray matter atrophy and degeneration of the corticospinal tracts (CST). A frontal dysexecutive
syndrome may occur in ALS patients. The anatomical correlates of
such a syndrome have not been fully investigated yet. The aim of this
study was to investigate the relationship between executive functioning and white matter (WM) tract damage in patients with ALS and
mild disability.
Methods: DT MRI scans were obtained from 16 ALS patients with
mild disability (ALS Functional Rating Scale score-revised [ALSFRS-r] C20). Patients with frontotemporal dementia were excluded.
Attention and executive functions were investigated using the Trail
Making (TMT) test, Stroop test, Wisconsin Card Sorting Test, and
Fluency test. DT MRI tractography was used to asses the integrity of
the major WM tracts. Fractional anisotropy (FA) and mean diffusivity
were obtained from each tract. The relationship between WM damage
and executive functions was tested using regression analyses, corrected for subject’s age and ALSFRS-r.
Results: Seven ALS patients scored at or below the 5th percentile
on at least one executive test, compared to age- and education-matched norms. In ALS patients, TMT scores significantly correlated
with the microstructural alterations of the corpus callosum, the major
cortico-cortical association tracts (including inferior fronto-occipital,
inferior longitudinal, and uncinate fasciculi), and the CST, bilaterally.
Conclusions: The relationship between WM DT MRI metrics and
executive performance in ALS patients with subtle cognitive
impairments suggests that damage to WM tracts may precede the
appearance of a frontal dysexecutive syndrome. DT MRI may have
the potential to identify ALS patients at risk for cognitive impairment.
O311
Presence of CD34+ cells in the CSF after G-CSF
induced mobilisation and mannitol treatment
in patients with amyotrophic lateral sclerosis
P. Bossolasco, C. Morelli, F. Servida, C. Lunetta,
F. Onida, S. Argenton, M. Corbo, G. Lambertenghi
Deliliers, V. Silani
University of Milan (Milan, IT); Hospital Niguarda Ca’ Granda
(Milan, IT); Lanzo Hospital (Lanzo d’Intelvi, IT)
Objectives: Stem cells (SCs) transplantation is an exciting alternative
for the treatment of neurodegenerative diseases, still at an early stage
of development. Growth factors, holding the capacity to activate
endogenous SCs, received major attention during the last years. In
particular, granulocyte-colony stimulating factor (G-CSF) mobilizes
SCs from bone marrow and has a significant neuroprotective action
on cerebral ischemia, also inducing neurogenesis. We investigated the
permeability of the blood-brain barrier (BBB) to endogenous SCs
mobilized from bone marrow by G-CSF in patients affected by
amyotrophic lateral sclerosis (ALS).
123
Methods: After informed consent, four ALS patients recruited
from the ALS Centre at IRCCS Istituto Auxologico Italiano in Milan,
received subcutaneously human recombinant G-CSF (5 lg/kg/day for
4 days) associated to 18% mannitol administration, for one to three
courses of mobilization at three-month intervals. A spinal catheter
was positioned to allow CD34+ count in cerebrospinal fluid (CSF)
daily. One patient was treated both with and without mannitol
administration. The number of CD34+ cells in the peripheral blood
(PB) and CSF was monitored by cytofluorimetric analysis (FACSCanto II Becton Dickinson) for the entire treatment to establish the
kinetics of the mobilization. Quantitative determination of G-CSF
concentration was performed using the human G-CSF immunoassay
Quantikine (R&D System).
Results: Successful mobilization in the PB was achieved in all the
patients, with CD34+ cell count significantly increased after G-CSF
administration. Conversely, the number of cells in the CSF augmented only when mannitol administration was associated to the
G-CSF mobilization. An increase in the concentration of G-CSF was
observed both in the PB and CSF of all patients, independently of
mannitol administration. One tracheotomised patient presented an
acute respiratory distress syndrome with favourable evolution. All
patients referred a mild but transient improvement of motor
performance.
Conclusions: We observed that G-CSF administration was relatively safe and tolerable in ALS patients. We demonstrated that SCs
need mannitol to pass BBB after mobilization with G-CSF. Instead,
G-CSF crossed BBB without restrictions. The transient positive
clinical effect may be due to different cell types, including mobilized
CD34+ cells co-expressing the neural progenitor antigen CD133.
O312
Resting-state network abnormalities in amyotrophic
lateral sclerosis mirror those of frontotemporal
dementia
E. Canu, F. Agosta, P. Valsasina, N. Riva, A. Prelle,
G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT); Hospital
Fatebenefratelli e Oftalmico (Milan, IT)
Objective: Amyotrophic lateral sclerosis (ALS) is increasingly recognized to be a multisystem disorder which includes both clinical and
neuropathological features of frontotemporal dementia (FTD). Previous studies have demonstrated that patients with FTD undermined
the RS connectivity in frontal cortex, but intensified the connectivity
of the posterior regions of the default mode network (DMN). How
resting state brain networks (RSNs) other than the sensorimotor are
affected by ALS have not been fully investigated yet. The aim of this
study was to investigate whether RSNs subserving cognition are
affected in patients with ALS.
Methods: Using RS functional MRI (fMRI) and independent
component analysis, the connectivity patterns of the DMN, as well as
the fronto-parietal, executive, and salience networks were explored in
16 non-demented patients with sporadic ALS and no cognitive
impairment, and 15 healthy controls.
Results: Compared with healthy controls, ALS patients showed a
decreased connectivity of the DMN in the right middle and inferior
orbitofrontal cortex, but enhanced DMN connectivity in the left
precuneus. ALS patients relative to healthy controls also had
increased fronto-parietal network connectivity in the left inferior
parietal lobule and right angular gyrus, and a decreased connectivity
in the left inferior frontal gyrus. No change was found in the executive and salience network connectivity in ALS patients relative to
healthy controls.
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Conclusions: In non-demented ALS patients, there is an alteration
of large-scale functional brain networks associated with cognition.
The increased parietal coactivation seen in these patients may have a
role in an attempt to maintain cognitive efficiency in the presence of
structural frontotemporal injury. The pattern of RSN abnormalities in
ALS (i.e., decreased connectivity in frontal regions, enhanced connectivity in posterior parietal regions) mirrors that observed in FTD
patients. RS fMRI may contribute to shed light on to the overlap
between ALS and FTD.
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Oral session 24
Child neurolgy
O313
Classification and therapy of habitual toe walkers
D. Pomarino, M. Klawonn, S. Stock, C. Walther,
J. Dittmer, L. Zoernig
Centrum for Physiotherapy Pomarino (Hamburg, DE)
Objective: Habitual toe-walking can be a common variant in children’s gait development. Furthermore, persistent toe-walking presents
a symptom that can occur in children with neurological disorders and
may affect children0 s physiological posture and development. By
classifying habitual toe walkers in three different types and exclusion
of neurologic toe walkers, the treatment with a Step-by-Step Concept
for habitual toe walkers increase the efficiency and benefit for the
patient.
Methods: Over a period of 8 years 800 Toe Walker were treated.
They were systematically examined (Parents’ anamnesis, initial
physical examination and re-checks in frequent intervals) with electromyography and a pressure measuring plate for gait analysis. On
this measuring plate equilibrium reaction was tested as well as the
severity of the toe-walking.
Results: The following types could be distinguished by the statistical evaluations of the parents’ anamnesis and the results of the
physical examinations.
Type 1 by Pomarino, congenital shorter Achilles tendon, Symptoms: wrinkle formations on the Achilles tendon, Pes equinus, a sharp
heel, a wider forefoot.
Type 2 by Pomarino: genetic predisposition, Symptoms: a V-sign
in the heel area, an increased horny skin between the metatarsal bones
II and III, a wider forefoot.
Type 3 a/b by Pomarino: toe-walking in loaded situations, usually
without any visual symptoms, Type 3b shows additional behavioural
problems, such as sensory disturbances. After the classification a
Step-By-Step Concept was applied and evaluated, which starts with
pyramid insoles and optional physiotherapy. Further treatment can be
completed by night splints and the injection of Botolinumtoxin.
During the examination process, it was paid attention to a possible
differential diagnosis like spastic toe-walking, hemiparesis, the
Duchenne muscular dystrophy or autistic behaviour, which have been
excluded from the Step-by-Step concept for habitual toe-walkers.
By applying the Step-by-Step concept for Type I the chances of
recovery are on the first year by 90%. The chances of recovery for
Type II are on the first year by 95%.
Type 3b. Children with Type 3 are usually cured without any
treatment. Occupational therapy could be promising with Type 3a.
Long term impairments are not expected.
Conclusion: After distinguishing toe walkers in different types and
by using the Step-By-Step Concept the efficiency of the therapy could
increase by decreasing costs for treatment at the same time.
O314
Hearing assessment in children with cerebral palsy
by brainstem auditory evoked potentials and wave V
audiometry
E.H. Carvalho, J. Valicek, E.S. Tavares, A.C. Araújo
Sarah Network of Rehabilitation Hospitals (Belo Horizonte, BR)
Objectives: To describe the prevalence of auditory pathway dysfunction in children with cerebral palsy who were evaluated in our
service and to investigate positive correlation between this prevalence
and clinical radiology findings in this series of cases.
Methods: This is a retrospective study. Brainstem auditory evoked
potentials (BAEP) and wave V audiometry (BERA) findings of 201
children with cerebral palsy were analysed and subsequently correlated with etiology and type of cerebral palsy and neuroradiological
findings. Cerebral palsy was classified, as the predominant type and
distribution of the motor abnormality using the Rosenbaum et al.
classification (2006). All the patients have their BAEP, BERA and
neuroradiological images accomplished in our service, based in
standard techniques, between 1997 and 2007. The results were
compared with scientific literature by MEDLINE research.
Results: We analysed electrophysiological findings of 201 patients
with cerebral palsy (106 men e 95 women), whose mean age at the
hearing investigation was 6.4 years. The cerebral palsy etiology was
determined in 182 patients (90.5%), based in clinical data and neuroradiological images. BAEP and BERA findings were analysed and
classified as peripheral or central dysfunction of the auditory tract.
We found hearing impairment in 58 patients (28.9%). Statistical
analysis showed significant correlation between hearing impairment
and dyskinetic type (Chi2 yates = 11,24; p \ 0.001; OR 3.84),
quadriplegia (Chi2 yates = 4.71; p 0.03; OR 2.33) and hyperbilirubinemia (Fischer p \ 0.001). Central dysfunction had higher
prevalence in patients with hyperbilirubinemia (Fischer p \ 0.001)
and dyskinetic type (Fischer p \ 0.001).
Conclusions: The prevalence of hearing impairment in our serie
was 28,9% and it showed positive correlation with dyskinetic type,
quadriplegia and hyperbilirubinemia. The hearing impairment is frequent in children with cerebral palsy and, despite limitations, BAEP
and BERA are important exams to determinate the integrity of the
auditory tract and the electrophysiological hearing thresholds in the
evaluation of patients with cerebral palsy.
O315
Psychiatric aspects of deafness and language disorder:
related to motor disorder?
B.C. Flapper, M. Schoemaker
University Medical Centre Groningen (Haren, NL); University
Medical Centre Groningen (Groningen, NL)
Children with ‘‘pure’’ receptive hearing impairment (RHI) and with
specific language impairment (SLI) are not supposed to have additional developmental disabilities. However, mental health problems
(MHP) may be associated with communicative disorders, and should
be detected. Also motor coordination disorder (DCD) has an overlap
of 50% with language developmental disorders. Screening and early
detection of mental health and motor problems might have considerable health benefits for children with SLI. Aim of this study was to
assess MHP and DCD in pure RHI and SLI.
Methods: In a sample of 104 children (mean age 6.6 (SD 0.9)
years; boys 71%) with well established SLI and of 51 RHI children
(5–8 years old), we applied the parental strengths and difficulties
questionnaire (SDQ) to detect mental health problems and DCD-
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S60
criteria. DCD was defined as not only severe difficulties on the
Movement-ABC-test (total score \P5), but also substantial impact of
poor co-ordination on daily motor performance in the parental
(DCDQ \P10) or teacher (MOQ \P15) motor-questionnaire, and
after paediatric exam to exclude other diagnoses (7 pervasive (MABC [P5) and 5 neurological disorders (M-ABC \P5) (Leeds
consensus).
Results: 25 of 104 children with SLI and 18 of 51 with RHI met
strict criteria for DCD (24 and 37%) consisting of severe problems
(domain-scores \P5) in manual-dexterity (75%), ball-skill (74%) and
balance (43%). Only 16% of all DCD had recently received motor
treatment. 30% of HI and 32% of SLI had MHP. Correlation between
parental total behavioural (MHP) and DCDQ-scores (dichotomised
clinical/normal) was significant and large (rho .50). Correlation
between SLI/RHI and DCDQ-scores (dichotomised clinical/normal)
was not significant.
Conclusion: This study shows that a diagnosis of pure language or
hearing impairment, even when strict criteria are applied, does not
guarantee the absence of additional mental and motor problems. As
motor and mental problems are correlated in SLI/RHI, it is important
to early detect the third that should be referred for a psychiatric
diagnosis; and the 25% DCD in SLI and 37% in deaf children. Clear
DCD in these children, had remained unnoticed in 84% due to more
apparent social and emotional problems. Recognition is necessary to
prevent further developmental delay by offering a correct multidisciplinary treatment plan, and input of paediatric neuro-developmental
specialists is essential.
O316
Clinical and genetical heterogeneity in a cohort
of paediatric patients affected with mitochondrial
disorders
M. Ranieri, D. Ronchi, S. Orcesi, V. Spartà, A. Cosi,
A. Bordoni, V. Lucchini, F. Fortunato, E. Fassone,
G. Rulfi, M. Rizzuti, M. Ripolone, M. Sciacco, M. Moggio,
S. Corti, S. Savasta, A Berardinelli, P Veggiotti, G.P. Comi
Policlinic (Milan, IT); Institute C. Mondino (Pavia, IT); Policlinic San
Matteo (Pavia, IT)
Objective: To describe clinical, biochemical and molecular features
of 22 early-onset patients affected by mitochondrial disease collected
in our Center in the last years.
Methods: We reviewed our cohort of pediatric patients (n = 22,
age of onset between 2 months and 7 years old) affected by mitochondrial disorders. An in-depth clinical assessment was performed.
Biochemical and histological studies on muscle biopsy were performed on almost patients. Molecular studies included: mitochondrial
DNA investigations (Southern blot, qPCR, direct sequencing) and
sequence analysis of several nuclear genes related to mitochondrial
disorders.
Results: Main clinical symptoms shared by our patients included:
mental retardation, developmental delay, epileptic seizures, hypotonia
and hypotrophy, ptosis. Isolated respiratory chain complex I and IV
defects were observed in five and four patients, respectively. Multiple
complex deficit was observed in 12 patients, mainly affected (n = 7)
by mitochondrial DNA depletion syndrome. Molecular diagnosis was
achieved in 16 patients (72.7% of the sample). In particular pathogenic mutations in mitochondrial DNA were disclosed in a third of
subjects and a novel mutation in MT-COII gene (m.8255A [G) was
identified.
Conclusions: Mitochondrial disorders are clinical syndromes
associated with abnormalities of the common final pathway of the
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mitochondrial energy metabolism. Due to the frequent involvement of
skeletal muscle and central nervous system, which are largely energydependent tissues, they are often collectively defined as mitochondrial
encephalomyopathies. In general, their molecular etiology remains
undefined in a relatively large proportion of patients, particularly in
the neonatal, infantile, and juvenile periods of life. In this relatively
small. highly selected, sample of pediatric cases, extensive investigation led to a high mutation rate finding.
This study provides information needed for clinical diagnosis,
prognosis and genetic counseling. Patients’ data collected will be
useful to improve diagnosis, management and eventually treatment of
mitochondrial pathology.
O317
Reading abilities and cognitive functions of children
with epilepsy syndromes
N. Kitchener, A. AbdelKader, H. El-Khayat, S. Aziz,
N. Nagy
General Organization for Teaching Hospitals (Cairo, EG);
Cairo University (Cairo, EG); Ain Shams University (Cairo, EG)
Purpose: To explore the influence of some epileptic syndromes on
reading abilities and cognitive functions.
Methods: we have compared the neuropsychological profile of 26
children with benign idiopathic epilepsy with rolandic spikes, 36 with
temporal lobe epilepsy and 26 with idiopathic generalized epilepsy.
Children underwent a selection of standardized tests designed to
assess: reading, oral language, short-term memory, attention and
adjustment. Analysis of variance was adjusted according to age of
onset of the epileptic syndrome, duration of the syndrome, and IQ for
each group.
Results: Children with temporal lobe epilepsy (TLE) had significantly lower scores for reading speed and comprehension, but
epileptic variables (the age of onset of epilepsy, duration and activity
of epilepsy) had detrimental effect on academic performances. In the
TLE group there was a clear effect of the laterality of the epileptic
foci (left-side TLE vs. right-side TLE) on reading profile. Furthermore, the effect of epileptic syndromes was found in phonological,
semantic and verbal working memory deficits in the TLE group.
Children, with idiopathic generalized epilepsy (IGE), exhibit some
cognitive deficits.
Conclusions: Epilepsy syndromes do affect reading, comprehension, academic performances and memory. Children with specific
epileptic syndromes must receive more attention to improve their
academic achievement.
O318
Clinical features and aetiology of stroke in term
neonates l
M. Salam, A. Hashim, U. Bhalala
Newark Beth Israel Medical Center (Newark, US)
Background and purpose: Term neonatal stroke results from asphyxia,
thromboembolism, coagulopathy or vascular anomaly, but can occur
without any identifiable cause. This study describes clinical presentation, etiology and neurological deficits.
Methods: Record of 18 neonates less than 28 days at time of
diagnosis of stroke were reviewed from 1998 to july 2007. All had CT
head or MRI Brain. EEG were done in 15, all had blood workup
S61
including coagulation studies and if indicated echocardiogram. Follow up record was reviewed.
Results: Clinical features included low apgars requiring mechanical ventilation 8, seizures 12, poor feeding and lethargy 7 and focal
neurological deficit in 2 neonates. Neuroimaging was abnormal in all
18 patients and 14 left hemisphere and 4 right hemisphere stroke. 16
patients had ischemic stroke and 2 had hemorrhagic stroke. Etiology
determined 8 with abnormal clotting parameters and one with HSV
infection. V-EEG was abnormal in 12 infants with background
abnormalities and ictal discharges. Incidence of neurologic deficits
was higher in group with low apgars. At 1 year followup 10 patients
had hemiparesis, 3 monoparesis and 2 quadreparesis and 3 were
normal.
Conclusion: Stroke in neonates may present with varing symptoms. Etiopathogenesis is not clear in the majority but hypercoagulability, and intracranial infection should be considered. The incident
of neurological sequelae is higher by two times in those requiring
respiratory support and it is also significantly higher in those presenting in the early neonatal period as compared to late neonateal
period. Neonates with no seizure at presentation had higher nerological morbidity than those with focal or focal seizures. Further
studies needed to determine etiology.
References: Predictive value of clinical and EEG features in
diagnosis of stroke and hypoxic ischemic encephalopathy in neonates with seizures . Stroke 2009 40(7):2402–2407; Early
continuous video-eeg in neonatal stroke. Dev Med Child Neurol
2011 53(1): 89–92; An international survey of EEG use in the
neonatal intensive care unit .acta paediatrics 2010 aug 99(8):1150-5
Epub 2010 mar 26
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POSTER SESSIONS
Cerebrovascular disorders: clinical features
of stroke I
P319
TOAST classification in patients with ischaemic
cerebellar stroke
J. Chojdak-Lukasiewicz, E. Kowalczyk, A. KrupinskaDulemba, M. Sluzewska-Niedzwiedz, B. Paradowski,
J. Kamienowski
Wroclaw Medical University (Wroclaw, PL); Hospital T. Marciniak’s
(Wroclaw, PL)
Introduction: Cerebellar ischemic strokes account for about 3% of all
strokes. Accurate classification of stroke subtypes in the acute phase
seems important for establishing treatment, evaluating prognosis and
setting secondary prevention.
The aim of the study was to classify ischemic cerebellar strokes
according to the TOAST classification in patients treated in two
neurological wards of a 6,00,000 population city.
Methods: We retrospectively analysed 132 adult patients with a
diagnosis of cerebellar infarction hospitalized at Department of
Neurology Medical University and at Department of Neurology
Hospital T. Marciniak’s from 2008 to 2010. Hemorrhagic stroke was
diagnosed in 17 patient and ischemic stroke in 115, the mean age of
patients is 65.6 (27–91). 65% of patients with ischemic stroke were
male (75/115), 35% were female (40/115). Hypertension was the most
frequent risk factor in stroke patients (58%), atrial fibrillation occur in
30%, dyslipidemia in 35%. During hospitalization 19 patients died.
Results: According to the TOAST classification 50% (58/115) of
ischemic cerebellar events were of undetermined cause, in 24% (28/
115) the stroke was caused by large-artery atherosclerosis, in 25%
(29/115) by cardioembolism. The most common cause of ischemic
cerebellar stroke in the group of patients who died was cardioembolism 58% (11/19).
Conclusion: Based on the results of the study we recommend more
common application of the TOAST classification for patients with
ischemic cerebellar stroke—similar to brain strokes. The TOAST
classification is easy to use and helps evaluating stroke etiology.
P320
Medical complications among stroke patients
at the University of Maiduguri teaching hospital,
northeastern Nigeria
M.M. Watila, Y.W. Nyandaiti, A. Ibrahim, I.D. Gezawa,
S.A. Bwala
University of Maiduguri Teaching Hospital (Maiduguri, NG); Federal
Medical Centre (Azare, NG); Murtala Muhammed Specialist Hospital
(Kano, NG)
Objectives: Complications occurring during strokes adversely affects
outcome. This study sought to assess the types and frequency of
complication occurring in African stroke patients.
Methods: The study population consisted of 480 patients admitted
for stroke during the period, January 2005 and November 2010. We
recorded clinical state and all complications during hospital stay and
follow-up. Deaths within this period were also recorded.
Results: A total of 136 (28.3%) of stroke patients had complication
during their admissions and follow-ups. The most common complications were hyperglycemia (admission random blood sugar C11.0
mmol/l) 37 (7.7%), aspiration pneumonia 37 (7.7%), depression 25
(5.2%), and seizure 22 (4.6%), Less common complications include,
Contractures 13 (2.7%), cerebral oedema 11 (2.3%), urinary tract
infection 8 (1.7%), decubitus ulcer 4 (0.8%), hypoglycaemia
3 (0.6%), hyperthermia [38C in 16 (3.3%), deep venous thrombosis
2 (0.4%) and pulmonary thromboembolism 1 (0.2%) Twenty-nine
(21%) patients had more than complication, commonest combination
being seizure and aspiration pneumonia 4 (3%), and hyperglycaemia
and seizure 4 (3%). Of the mortalities recorded during this period 52
(62%) had one or more complications, with pneumonia occurring in
33% of patients who died.
Conclusions: Complication after strokes is common, and influences mortality. Therefore stroke rehabilitation will require
proactive medical input in prevention and treatment of these
complications.
P321
Posterior reversible leukoencephalopathy syndrome:
clinical study
D.C. Jianu, S.T. Kory-Calomfirescu, D.S. Ioncu
Victor Babes University of Medicine and Pharmacy (Timisoara, RO);
Iuliu Hatieganu University of Medicine and Pharmacy (Cluj, RO)
Background: PRES is used to describe a unique syndrome, clinically
expressed during hypertensive and uremic encephalopathy, eclampsia
and during immunosuppressive therapy. It is characterized by headaches, altered mental status, seizures, and visual loss and is associated
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with white matter vasogenic edema predominantly affecting the
posterior occipital and parietal lobes of the brain.
Objective: To analyze neurologic signs and imaging pattern in
PRES in early diagnosis and to evaluate cognitive impact after
3 months.
Materials and methods: The study comprises 10 female subjects,
admitted in the Arad Neurology Clinic, during 2007–2010. They were
evaluated at admission, 7 and 3 months, using a standard neurological
exam, CTscan/MRI, Rankin Modified Scale(mRS), Glasgow coma
scale (GCS), and Mini Mental State Evaluation test (MMSE). The
patients were evaluated 3 months after episode of PRES with MRI,
mRS and MMSE testing.
Results: The average age was 32.2 ± 2.34 years. As etiology of
PRES, 4 presented severe hypertension and primary seizures with
eclampsia, 4 collagen vascular disorders and 2 acute renal failure. All
had generalized seizures and a GCSscore\8. The IRM showed hypert
T2 lesions primarily in the frontal, parieto-occipital and cerebellar
regions, in all cases. At 3 months, 80% of the subjects had normal
MRI exam with complete resolution of abnormalities. The mRS score
varied from 4.8 at admission to 1.9 at 3 months. The 7 days average
MMSE score was 18.6, with marked aphasia and amnesia, and 25.6 at
3 months with defaults majorly in attention, short term memory and
slight aphasia. The most severe MMSE scores at 7 days and 3 months
correlated to an extended vasogenic edema in the posterior circulation
at admission (70% of the subjects).
Discussion: The cause of the reversible posterior leukoencephalopathy syndrome is multifactorial. Endothelial dysfunction cause
profound vasospasm and reduced organ perfusion, activation of the
coagulation cascade, and loss of fluid from the intravascular compartment. Nonetheless, the long term cognitive disabilities are
unknown in case of PRES.
Conclusion: Leukoencephalopathy and severe hypertension are the
major characteristic of the PRES. Vasogenic edema in the posterior
circulation is associated with poor prognosis and the persistent of
imaging abnormalities after 3 months show a severe mental deterioration. The neuropsychological testing using MMSE correlated with
MRI may be a predictor to identify subjects with cognitive decline for
at least short-term prognosis.
P322
Cognitive function in stroke patients and contralateral
arterial stenosis
S. Pires-Barata, L. Rebocho, I. Mendes, S. Mateus,
S. Claro, C. Sousa, L. Gil, J. Gavela, V. Pós-de-Mina,
C. Santos, S. Galo, S. Lourenço, C. Corzo,
M.H. Teixeira da Silva, R. Garcia
Hospital do Espirito Santo (Évora, PT); University of Salamanca
(Salamanca, ES)
The association between vascular risk factors and cognitive impairment is well documented.However, new risk factors have been
questioned. The purpose of the present study is to understand if
patients with stroke and contralateral arterial stenosis (intra or
extracranial) have worst cognitive performance then stroke patients
without contralateral stenosis.
During a 12 months period, 35 subjects were selected fulfilling our
inclusion and exclusion criteria: 15 with stroke and contralateral
arterial stenosis (intra and extra-cranial), 10 with stroke and without
stenosis and 10 healthy controls, with a mean age of 57.7 years
(±6.6). All subjects were submitted to complementary exams and to
neuropsychological evaluation.
123
A significant statistical relation was verified between stroke subjects and healthy controls, in cognitive domains such as attention,
executive function and memory. When considering stroke subjects
with and without contralateral arterial stenosis, a significant statistical
relation was verified for executive function domain. For stroke subjects with contralateral intracranial stenosis and contralateral
extracranial, a significant statistical relation was verified considering
attention.
Associations between having a stroke and cognitive impairment
were verified. Intracranial stenosis or extracranial stenosis, contralateral to stroke location, were associated to cognitive impairment not
justified by the vascular lesion, nevertheless the sample size might
contribute to the lack of association between variables.
Cognitive impairment is associated to stroke, however this
impairment was not verified in all of the cognitive domains studied.
Contralateral arterial stenosis contributed for the difference on the
cognitive performance. The short dimension and characteristics of
our sample might contribute to the study bias. Nevertheless, arterial
stenosis are a risk factor for vascular cognitive impairment and may
create the need to include in clinical check-ups, a standard neuropsychological evaluation and an eco-doppler. More research is
needed to understand the mechanisms that might lead to this
process.
P323
Vertebral artery dissection presented as sudden
sensorineural hearing loss: a case report of delayed
neurological deficits and a normal brain magnetic
resonance imaging making it difficult to diagnose
R.S. Scalco, C.N. Manenti, M.R. Fighera, L.B. Mallmann,
L.C. Marrone, I. Canali, A.G. Almeida
Pontifical Catholic University of Rio Grande do Sul
(Porto Alegre, BR)
Objectives: Vertebral artery dissection is the most common cause of
stroke in young people. Symptoms may vary making it difficult to
diagnose. We report a case of sudden sensorineural hearing loss
(SSHL) and occurrence of delayed neurological deficits.
Methods: Case report
Results: A 31-year-old man presented with bilateral SSHL, nausea, vertigo and tinnitus. He reported previous episode of occipital
headache 2 weeks before hospital admission. First brain magnetic
resonance imaging (MRI) was normal. Physical examination revealed
a spontaneous horizontal left beating nystagmus in rest position of the
eye. Audiometric evaluation documented a severe and profound
sensorineural hearing loss. He previously had a moderate sensorineural and conductive hearling loss documented by audiometric exam
as he worked as a bus driver. Laboratory findings revealed leukocytosis without infection focus, antinuclear antibody test 1:80,
C-reactive protein 4.3 mg/dL. With probable diagnosis of Cogan
syndrome, prednisone was started. During next days he complained of
bilateral intermittent paresthesias and nuchal pain. His neurological
exam changed acutely, revealing vertical nystagmus, puntiform
pupils, bilateral Babinski sign and enhanced deep tendon reflexes.
MRI showed bilateral cerebellar and brain stem stroke. The diagnosis
of bilateral vertebral artery dissection (VAD) was made by arteriography. Treatment involved stenting and anticoagulation.
Conclusion: SSHL is should always be considered a medical
emergency even when brain MRI is normal. SSHL may be the
principal symptom of VAD.
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P324
Cerebral venous sinus thrombosis: an experience of 16
cases in a Turkish stroke unit
O. Oz, H. Akgun, M. Yucel, S. Demirkaya, Z. Gokcil,
Z. Odabasi
Gulhane Military Medical Academy (Ankara, TR)
Objectives: The present study was designed to describe the characteristics, risk factors and prognosis of patients diagnosed with CVT in
our center.
Methods: The demographic characteristics, initial symptoms and
signs, clinical features, etiologies, imaging findings and treatments
were retrospectively reviewed in 16 patients accepted to our hospital
between May 2003 and July 2010 with Cerebral Venous Thrombosis
diagnosed by cranial magnetic resonance imaging (MRI) and MR
venography. Results: There were 9 female (56.25%) and 7 male
(43.75%). The mean age was 25.81 (17–54). Headache was the most
common symptom and reported by all of our patients. eight of the
patients (50%) had epileptic seizures, six of the patients (37.5%) had
motor deficits and/or sensory deficit. The most detectable etiologic
factors were pregnancy in three patients (18.75%) and oral contraceptives in three patients (18.75%). Interestingly in one patient
developed CVT following epidural anesthesia. We could not be able
to detect any etiological factor in three patients. Eight of the patients
(50%) had thrombosis in a single dural sinus, and the remaining eight
patients had thrombosis in two or more than two sinuses (50%).
Superior sagittal sinus in 10 patients (62.5%), transverse sinus in 13
patients (81.25%), sigmoid sinus in 8 patients (50%), inferior sagittal
sinus in 1 patient (6.25%) were involved in isolation or with other
sinus involvements. All the patients were diagnosed with cerebral
venous thrombosis were managed by anticoagulation therapy. One
(6.25%) of our patients died because of intracranial haemorrhage.
Conclusion: CVT should be considered in patients with headache,
papilledema and epileptic seizure, especially in conditions those with
a tendency to thrombosis. Early diagnosis is important for CVT and
anticoagulant, thrombolytic, antiepileptic and etiologic treatments
should be done. Anticoagulant therapy is the first-line treatment for
cerebral venous sinus thrombosis because of its efficacy and safety.
P325
Capsula interna-related restless legs syndrome
in a patient having stroke due to coagulability problems
M. Yucel, C. Erdogan, O. Oz, H. Akgun, Y. Kutukcu,
Z. Gokcil, Z. Odabasi
Gulhane Military Medical Academy (Ankara, TR);
Pamukkale Medical Faculty (Ankara, TR)
Introduction: Restless Leg Syndrome (RLS) is a relatively frequent
disorder which effects the patients quality of daily life. It may be
caused by secondary reasons or may be primary. RLS after stroke has
rarely been reported in the literature. Here we present a 48 years old
patient whose paresis totally recovered after having stroke but
experiencing RLS symptoms.
Case report: 48 years old female admitted to our hospital with
right hemiparesis and right central facial paralysis. Her cranial MRI
revealed a lacunar infarct affecting the posterior leg of the left internal
capsule. We determined heterozygote F5R506-Q506 Leiden mutation
and homozygote MTHFR C677T. On her examination on the first
month she described the feeling of uncomfortably on her both legs,
worsening at nights, improving with movement on exercise. When her
complaints were determined with the criteria’s the patient was diagnosed as RLS. The medication of pramipexole 0.5 mg at nights was
started and with the therapy the patient’s complaints were totally
cured.
Discussion: There already are some cases whose RLS symptoms
have started with stroke. In most of these cases the lesions were
localized to basal ganglias whereas in some cases to lenticulostriate
region and in some cases to internal capsule. In the duration of first
month the symptoms of the existing stroke should be detailly examined for the differential diagnosis.
Conclusion: Our case was accepted as a typical example of post
stroke RLS. Because her RLS symptoms started in the first month and
her neuroimaging methods showed a probable anatomic correlation
with the symptoms.
P326
Executive functions in patients with subcortical
ischaemic vascular disease
J. Dackovic, G. Ocic, N. Covickovic Sternic, D. Pavlovic,
T. Stosic-Opincal, M. Vukovic, P. Smiljkovic, S. Zˇugic,
V. Ilic, A. Parojcic, B. Salak Djokic
Clinical Center of Serbia (Belgrade, RS); University of Belgrade
(Belgrade, RS)
Introduction: Subcortical ischemic vascular disease (SIVD) arises
from small vessel disease. Primary type of brain lesions are lacunar
infarctions and ischemic white matter changes (WMC). The cognitive
profile of SIVD is characterized by executive functions (EF)
impairment.
Methods: 35 patients with SIVD and 30 normal control subjects
participated in the study. All the participants were administered a
neuropsychological test battery incorporating: Mini Mental Status
Examination, Wechsler Adult Intelligence Scale (Serbian version),
Trail making test A and B, Wisconsin Card Sorting Test, Tower of
Toronto test, Verbal fluency tests and Hamilton Depression Rating
Scale.
Results: Patients with SIVD performed less well on cognitive
measures, had significantly lower scores on executive functioning and
were more depressed in contrast to control subjects. Ischemic WMC
were more abundant in the frontal and parieto-occipital regions.
There were no relationship between WMC and performance on the
tests of abstraction and problem solving ability. Severity of WMC
correlated with worse performance on tests assessing speed of mental
processing. The degree of WMC also highly correlated with the age of
patients.
Conclusion: Incipient impairment of EF functions with patients
with SIVD is characterized by limited divergent thinking capabilities,
difficulties with conceptual reasoning, planning and developing
strategies, while attention deficit and slowing of information processing occurs later. Tests assessing speed of mental processing
highly correlated with severity of WMC, but didn’t provide good
sensitivity for identifying initial impairments of EF.
P327
Intracerebral haemorrhage iron content measured
by X-ray absorption correlates with amount
of perihaemorrhagic oedema
I. Wagner, B. Volbers, S. Schwab, D. Staykov
University Hospital Erlangen (Erlangen, DE)
Objectives: Preclinical evidence indicates that iron plays a key role in
mediating neuronal injury and edema formation after intracerebral
123
S64
hemorrhage (ICH). There are also indications that blood clot iron
content correlates with the amount of perihemorrhagic edema (PHE)
after ICH. Iron content accounts for a major part of the X-ray
absorption properties of the hemorrhage. Therefore we investigated
the relationship between X-ray absorption of the intracerebral blood
clot [mean count of Hounsfield Units (HU)] and relative PHE formation after spontaneous supratentorial ICH.
Methods: We retrospectively investigated 121 patients with
spontaneous lobar and deep ICH with at least 3 CT-scans during the
first 7 days after ICH onset. Measurements of the blood and edema
volumes were performed with a semiautomatic threshold based volumetry algorithm. The software reconstructed a three dimensional
data set for blood and perihematomal edema volume and added up all
voxel within a HU-threshold range. Mean HU of the blood clot was
computed automatically.
Results: We found a significant correlation between mean HU of
the blood clot at admission and relative perihematomal edema volume
(REV) at day 6 (p = 0.028) during a 7 days observation period.
Conclusion: Our findings suggest that in vivo hematoma iron
content, as measured by CT, is linked to perihematomal edema after
spontaneous ICH, and provide further support to existing preclinical
evidence linking iron-mediated toxicity to delayed neuronal injury
after ICH.
P328
Detection of subarachnoid haemorrhage using
susceptibility weighted magnetic resonance image
in acute stage
S.H. Hayashi
Tosei General Hospital (Seto, JP)
Background: In the assessment of patients with suspected Subarachnoid Hemorrhage (SAH), Fluid-Attenuated Inversion Recovery
(FLAIR) Magnetic Resonance Imaging (MRI) will be more sensitive
than Computed tomography (CT). Susceptibility Weighted magnetic
resonance Image (SWI) is new technique that is exquisitely sensitive
to paramagnetic substances. And it can contribute to an accurate
diagnosis of SAH.
Purpose: We investigated clinical utility of SWI for the assessment
of SAH comparing to CT and FLAIR MRI.
Methods: From January 2008 to December 2009, patients who
took a FLAIR and SWI MRI at the same time within 30 days after
aneurysmal SAH or traumatic SAH were retrospectively analyzed.
The case who had taken MRI after the craniotomy, lumber drainage
and the case with a brain contusion were excluded. Subarachnoid
hemorrhage were assessed by CT taken on admission, FLAIR and
SWI MRI for five anatomical area of the subarachnoid space (basal
cistern, sylvian fissure, convexity, interhemisphere and ambient
cistern).
Results: Fourteen patients who included this study comprised six
male and eight female with an age range of 41–90 years. MRI was
taken from day1 to day 28 after onset (mean days 7.6). Twenty-seven
areas with SAH were identified by both CT and SWI (basal cistern:
7 cases, sylvian fissure: 8 cases, convexity: 1 case, interhemisphere:
4 cases, and ambient cistern: 7 cases). Six areas with Subarachnoid
hemorrhage that SWI identified could not detect on CT (basal cistern:
2 cases, sylvian fissure: 1 case, convexity: 2 cases, interhemisphere:
1 case, and ambient cistern: 1 case). In one aneurysmal SAH case,
FLAIR MRI taken 13 days after onset could not clarify SAH at basal
cistern that SWI could detect.
Conclusion: In our preliminary study, SWI can be superior to
FLAIR MRI in the detection of SAH in acute stage.
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P329
Stroke and embolism from left ventricular
hypertrabeculation/noncompaction
J. Finsterer, C. Stöllberger, G. Blazek, C. Dobias,
C. Wegner
Wiener Krankenanstaltenverbund (Vienna, AT); Hanusch Hospital
(Vienna, AT); Vienna Institute of Demography of the Austrian
Academy of Sciences (Vienna, AT)
Background and purpose: Left ventricular hypertrabeculation/noncompaction (LVHT) is assumed to be associated with stroke or
embolism (SE). It is uncertain if LVHT per se or if concomitant
cardiac abnormalities like systolic dysfunction or atrial fibrillation
(AF) contribute to SE. Aim of the study was to assess the rate, risk
factors and etiology of SE in LVHT patients.
Methods: Records of patients with LVHT, diagnosed between
1995 and 2009, were screened for SE. For classification of strokeetiology, the TOAST-criteria were applied, for peripheral embolism
angiographic and surgical findings. Clinical, echocardiographic and
electrocardiographic data were compared between patients with and
without SE.
Results: In 22/144 patients (15%), stroke (n = 21) or peripheral
embolism (n = 1) had occurred. The etiology of SE was cardioembolic (n = 14), atherosclerotic (n = 5) and undetermined (n = 3). SE
occurred either prior (n = 14) or after (n = 8) the diagnosis of
LVHT. At baseline, only the mean age (60 vs. 53 years, p \ 0.05)
and the prevalence of hypertension was higher in patients with SE
than without SE (32 vs. 59%, p \ 0.05). Among the patients with
cardioembolic SE, 13/14 had either atrial fibrillation (n = 6) or systolic dysfunction (n = 11), and atrial fibrillation as well as systolic
dysfunction were found in 4 patients.
Conclusion: SE in LVHT is not always cardioembolic but may be
also atherosclerotic. In the absence of AF or systolic dysfunction
cardioembolic SE is rare in LVHT. Patients with LVHT with systolic
dysfunction or AF should receive oral anticoagulation as primary
prophylaxis against SE.
P330
Neurological manifestations of atrio-oesophageal
fistulas from left atrial ablation
J. Finsterer, C. Stöllberger, T. Pulgram
Wiener Krankenanstaltenverbund (Vienna, AT)
Background: Atrio-esophageal fistulas (AEFs) are increasingly recognized as a complication of left atrial ablation (LAAB), which is
carried out for atrial fibrillation refractory to conservative measures.
Neurological manifestations usually dominate the presentation and
result from cardiac embolism of thrombi, transgressed esophageal
contents, or air.
Results: AEFs have been reported after LAAB in 55 patients (24
males, age 35–76 years), described in 25 publications, so far. AEFs
manifest clinically on the average 20 d (3–38 days) after ablation.
Neurological manifestations include embolic strokes (n = 30), seizures (n = 9), transitory-ischemic attacks (n = 6), coma (n = 6), or
psychiatric abnormalities (n = 5). Imaging studies of the cerebrum
most frequently show multiple embolic strokes or air embolism. The
diagnosis is made upon thoracic computed tomography with contrast
media. An act of swallowing, transesophageal echocardiography,
gastroscopy, or esophageal stenting must be avoided not to enlarge
the shunt. The only expedient therapy is surgical closure of the fistula
but even then the prognosis is poor with a mortality of 70%.
S65
Conclusions: AEFs should be suspected if there is a history of
LAAB followed by fever, thoracic pain, postprandial cerebral strokes,
seizures, coma, or confusion with a latency of days to five weeks after
ablation. Diagnostic work-up must avoid measures, which enlarge the
fistula. Treatment is surgical exclusively.
P331
Stroke as a cause of parkinsonism
A. Chitsaz
Alzahra Hospital (Isfahan, IR)
Objective: Vascular parkinsonism (VP) is a highly controversial
concept, there is no doubt that cerebovascular disease can cause
parkinsonism. confusion has also arisen because incidental vascular
lesions occurring in true idiopathic parkinson’s disease. VP refers to
isolated gait disorders called ‘‘lower body parkinsonism’’ and characterized by sudden onset and rapid progression of clinical symptoms.
resting tremor is absent and poorly or non responsive to L-dop.
Patients may have other signs of cerebrovascular disease and suffer
from hypertension, diabetes, heart disease, and several stroke in the
past.
Material and methods: To determine the lesions responsible for
VP in patients clinically suspected of having vascular parkinsonism
suggested by: sudden onset and rapid progression of gait and balance
problems, predominant involvement of the legs, lack of tremor, absent
or poor response to levodopa, having vascular risk factors (hypertension, diabetus, heart disease), and past history of stroke we
compared 15 such patients with 15 patients who had idiopathic parkinson’s disease and 10 hypertensive control.
Results: Of the patients with suspected VP 100% had one or
more vascular lesions in brain MRI. The percent of different types
MRI finding in patient with suspected VP was as follows: Subcortical white matter changes and small-vessel cerebral disease
commonly periventricular ischemia 54%, lacunes in striatum 40%,
territorial infarct and striatal infarct 5%, one patient had a single
lesions in the contralateral peduncle between the substantia nigra
and nucleus rubber, thus the lesions responsible for VP are mostly
basal ganglionic lcunes and subcortical white matter vasculopathy.
patients who had idiopathic Parkinson disease and had not any
change MRI. In Hypertensive control 85% had periventricular
ischemia.
Conclusion: Cerebrovascular disease can cause elements of parkinsonism. When strokes affect the basal ganglia parkinsonism can
result. In our study like previous studies there were two types of VP:
one had an acute onset and lesions located in the subcortical gray
nuclei (striaum, globus pallidus, thalamus), the other had an insidious
onset and lesions diffusely distributed in the watershed areas.
P332
Movement disorders during and after acute stroke
A. Chitsaz
Alzahra Hospital (Isfahan, IR)
Objective: Many different types of hyperkinetic and hypokinetic
movement Disorders (MD) have been reported after ischemic and
hemorrhagic stroke. Post stroke movement disorders can present or as
a delayed sequel. They can be hyperkinetic (most commonly hemichorea hemiballism) or hypokinetic (most commonly vascular
parkinsonism). Most of movement disorders are caused by lesions in
the basal ganglia or thalamus but can occur with strokes at many
different locations in the motor circuit. Many of (MD) are limiting but
treatment may be required for symptom control.
Methods: To study consecutive patients with acute or delayed
movement disorders in the Isfahan, we have identified 25 patients
with acute or delayed movement disorders In the two years.
Results: From 25 patients, 10 patients presents with hemichoreahemibalism, 5 patients with hemidystonia, 2 patients with stereotypies, 2 patients with asterixis, 2 patients had initial limb-shaking, 1
patient with bilateral tremor and 1 patient with hemiakathesia, on
neuroimaging a lesion was found in 21 of the 25 cases in the territory
of the middle cerebral artery, the posterior cerebral artery (15 patient)
both middle cerebral arteries (3 patients), or the anterior cerebral
artery (1 patient). Small-vessel disease was the commonest cause of
stroke (15 patients). Only 3 patients had persistent movements
([6 months).
Conclusion: Hyperkinetic movement disorders are uncommon in
acute stroke (1%), the commonest type being hemichorea-hemipallism and hemidystonic. These movement disorders associated with
stroke involving the basal ganglia and adjacent with matter in the
territory of the middle or posterior cerebral ortery. MD after stroke
usually regress spontaneously.
Experimental neurology
P333
Repeated intracisternal infusion of sigma-1 receptor
agonist evokes headache-like symptoms in rats
Y.C. Jeong, Y.B. Kwon
Chonbuk National University (Jeonju, KR)
Intracranial headaches including migraine are generally accepted to
be mediated by prolonged nociceptive activation of trigeminal
nucleus caudalis (TNC) but the precise mechanisms are poorly
understood. Our accumulative studies demonstrate that sigma-1
receptors (Sig-1R) facilitate nociceptive transmission in the spinal
cord. From these findings, present study was further investigated
whether activation of Sig-1R affects TNC neuronal activation as a key
mechanism underlying the generation of headache. We studied the
effect of single or repeat intracisternal administration of selective Sig1R agonist PRE084 for 3, 7 and 14 days on TNC neuronal sensitization in rats. A single infusion of PRE084 dose-dependently
increased Fos immunoreactive neurons (Fos-IR) in TNC with
BD1047 (Sig-1R antagonist) reversed manner, but the number of FosIR was lower than that of single capsaicin infusion as one of headache
models. Chronic infusion of PRE084 over 7 day led to comparable
number of Fos-IR in TNC with that of capsaicin single infusion.
Consistently, the increase of face grooming/scratching behavior was
evident from 7 day and peaked at 14 day after PRE084 infusion,
which was co-related with the elevation of deltaFosB in TNC as a
marker of sustained pain. Following 2 week-PRE084 infusion, the
number of Fos-IR did not reduce until 3 day after final infusion, while
this prolonged evaluation of Fos-IR was significantly reversed by the
pre-single infusion of MK801 or sumatriptan rather than BD1047.
Furthermore, PRE084 infusion for 14 days significantly increased
protein kinase A and the phosphorylation of its downstream factors
including NMDA receptor subunit 1, extracellular-signal regulated
kinase and cAMP response element-binding protein in TNC. Thus,
our findings indicated that the chronic activation of Sig-1R may evoke
prolonged neuronal activation in trigeminovascular system relating to
migraine.
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P334
Gene silence of NMDA receptor NR1 subunit
by subcutaneous injection of vector containing DNA
templates encoding microRNA precursors reduces
formalin-induced nociception in rat
P. Tan, K. Hung
I-Shou University (Kaohsiung, TW)
Objectives: There is accumulating evidence to implicate the importance of N-methyl-D-aspartate (NMDA) receptors to the induction
and maintenance of central sensitization during pain states. However,
the use of NMDA receptor antagonists can often be limited by serious
side effects of central nervous system. The development of peripheral
NMDA receptor antagonists that do not interfere with central glutamate processing can avoid adverse effects of central nervous system.
Recent discoveries have revealed that the transfection of small
interfering RNAs into animal cells results in the potent, long-lasting
post-transcriptional silencing of specific genes. Stable knockdown can
be achieved by continuous expression of synthetic short hairpin
RNAs, typically from RNA polymerase III promoters. RNA polymerase II promoters expressing rationally designed primary
microRNA (miRNA)-based short hairpin RNAs could produce 12
times more potently and stable gene knockdown than RNA polymerase III does in animals. Thus, in this study, we examined the
effect of gene silence and antinociception on formalin-induced pain
by subcutaneous injection of vector encoding miRNA targeting NR1
subunit of NMDA receptor.
Methods: The rats were randomly assigned to different groups: (1)
NR1 miRNA (1, 5, 10 lg). All treatment were administered 3 day
prior to formalin test. (2) Recovery periods: 1, 3, 7, 14, 21 days
recovery group (injection of 5 lg NR1 miRNA 1, 3, 7, 14, 21 days
before formalin test). Skin tissues of rats in each group were dissected
immediately after the formalin test for use in real-time polymerase
chain reaction, western blotting, and immunostaining of NR1.
Results: Subcutaneous injection of 1, 5, and 10 lg vector
expressing NR1 miRNA could effectively diminish formalin-induced
nociception and inhibit gene expression of NR1 in skin and dorsal
root ganglion evidenced by decrease level of mRNA and protein. The
effect of antinociception and inhibition of NR1 expression by NR1
miRNA started at 1 day after injection, persisted for 3 days and
recovered at 7 day after injection of 5 lg plasmid.
Conclusions: This study provide novel evidence supporting miRNA even with its expression vector can be used in the investigation of
functional gene expression in the skin tissue. The data suggest NR1
miRNA has potential therapeutic of providing potent and long term
treatment of pathological pain which are induced or maintained by
peripheral nociceptor activity.
P335
Expression of chemokines and neurodegeneration
in experimental model of stroke
P. Wolinski, A. Glabinski
Medical University of Lodz (Lodz, PL)
Background: Ischemic stroke is the third most common cause of death
and the main cause of permanent disability in adults. Recently it is
known that inflammation may play an important role in pathogenesis
of stroke.
Objectives: The aim of this study was to analyze the expression of
chemokines, their receptors and inflammatory markers and correlate
123
them with neurodegeneration in endothelin-1 (ET-1) induced model
of ischemic stroke.
Methods: Stroke model was induced by stereotaxic injection of
ET-1 into brain parenchyma. Potential role of chemokine system was
detected using ELISA and real time PCR methods. Development of
neurodegeneration was measured using ELISA for neurofilaments.
Results: We observed that neurodegeneration increases with the
time and correlate with infiltration of the brain by lymphocytes and
monocytes during stroke model. Despite upregulated in the brain level
of chemokines CCL2, CCL3, CCL5, CXCL2 and chemokine receptor
CCR5 during first three days of the model we did not observed any
correlation between their expression and intensity of neurodegeneration.
Conclusions: Our results suggest that inflammation may be
involved in development of neuronal cell death during our stroke
model.
P336
Features of cells that coexist within injured region of rat
cerebral cortex following surgical brain injury
M. Frontczak-Baniewicz, D. Sulejczak
Polish Academy of Sciences (Warsaw, PL)
Objectives: Surgical injury of the rat cerebral cortex is a model of the
insult occurring during life-saving neurosurgical procedures, e.g.
removal of a brain tumor. Our earlier studies have shown that physical
insults to the brain induce a cascade of changes that result in massive
gliosis as well as degeneration and death of neurons. In the vicinity to
the damaged area new vessel formation was reported. It is known, that
several types of brain trauma initiate an increase in the number of
mitotically active cells in the brain. In our model we detected within
the perilesional area a lot of cells with morphological features different from mature brain cells. In the present study we aim to identify
these atypical cells occurring in rat brains 4 days following the lesion.
Methods: We investigated the morphological features and immunophenotypes of cells within cerebral cortex in the proximity to
the injury by light immunohistochemical and electron microscopic
techniques.
Results: Four days following the lesion we detected reactive
astrocytes positive for GFAP (glial fibrillary acidic protein, astroglial
marker) in the injured cerebral cortex. Many astroglial cells were
immunoreactive for vimentin. In the proximity to the damage many
dying neurons were observed. Some neurons in that area survived.
Around the lesioned area nestin-positive cells were detected. A lot of
them showed an astrocytic morphology but only a small number of
them were labeled for GFAP. In that same time point we detected a
small number of cells double stained for nestin and NeuN (neuronal
marker). We found only a small number of cells positive for doublecortin (marker of migrating neuronal precursors). In the vicinity to
the lesioned region a massive angiogenesis was seen. Close to the
blood vessels we detected many endothelial progenitor cells positive
for AC133/Flk1. They showed the presence of atypical fibrils in the
cytoplasm and created a new blood vessels. However, a lot of newly
formed capillaries were dysfunctional.
Conclusion: Our results indicate that in the proximity to the
injured area of brain parenchyma coexist mature and immature cells
of different origin (astroglial, neuronal and endothelial cells). This coexistence and their cooperation may promote the brain rebuilding/
remodeling following the injury.
This study was supported by grant No. 404 52 2838 from the
Ministry of Scientific Research and Information Technology, Poland.
S67
P337
Increased expression of tumour necrosis factor-a in rat
hippocampus after homocysteine-induced seizures
S.H. Kim
Changwon Fatima Hospital (Changwon, KR)
Background and objective: Homocysteine, a thiol-containing amino
acid derived from the metabolism of methionine, is epileptogenic and
can induce seizures in immature and adult animals. Homocysteine is
structurally similar to glutamate and express a direct excitatory effect
on N-methyl-D-aspartate (NMDA) receptors. Increased homocysteine
plays a role in the pathophysiology of several neurodegenerative and
neuroinflammatory diseases. Tumor necrosis factor-a (TNF-a) is an
important proinflammatory cytokine modulating inflammatory
responses which is known to be increased in inflammatory diseases.
Vitamin C is an antioxidant and has protective effects against the
oxidative stress due to homocysteine. In order to evaluate whether
elevated homocysteine levels associated with proinflammatory
process mediated by cytokines, and apoptosis, the present study
was designed to evaluate the effect of acute homocysteine administration on inflammatory cytokine TNF-a expression and neuronal
apoptosis in rat hippocampus, and to determine the effects of vitamin
C treatment against homocysteine-induced inflammation and neuronal
death.
Methods: Three-week-old Sprague-Dawley male rats were used.
They were separated for three groups. As a control group, rats of the
first group were administered with saline solution into abdominal
cavity for a week, and rats of the second group were once injected
with homocysteine (11 mmol/kg) into abdominal cavity after
administered saline solution for a week. Rats of the third group were
once injected homocysteine after administered with vitamin C
(100 mg/kg) for a week. The degrees of TNF-a expression and of
apoptosis in the hippocampus were compared, and the neuroprotective effect of vitamin C against homocysteine-induced inflammation
and apoptosis were evaluated.
Results: All rats of control group showed no expression of TNF-a
in the hippocampus. Homocysteine-injected experimental groups
showed strong expression of TNF-a in every region of the hippocampus. The expression of TNF-a in CA1 region of hippocampus was
reduced by administration of vitamin C. Apoptosis in the hippocampus after acute homocysteine administration didn’t occur.
Conclusion: These results suggests that high homocysteine levels
are related with inflammatory reaction mediated by proinflammatory
cytokine TNF-a, and vitamin C has some effect of alleviation about
inflammatory reaction in CA1 region of hippocampus.
P338
Spontaneous and odour-evoked seizures in Synapsin
I/II/III knockout mice: electrophysiological
characterisation
M. Cambiaghi, M. Cursi, L. Teneud, E. Monzani,
F. Minicucci, G. Comi, F. Valtorta, L. Leocani
University San Raffaele Hospital (Milan, IT)
Tuberous Sclerosis Complex (TSC) is a disorder caused by inactivation of Tsc1 or Tsc2 genes and characterized by central nervous
system alterations, such as cortical tubers and subependymal nodules
leading to severe epilepsy. Essential in using these animal models is
the ability to monitor ongoing pathological electrophysiological
activity, mainly by electroencephalograms (EEG) and synchronous
video.
Objectives: The aim of this project is to study the electrophysiological behavior of a TSC mouse model by video-EEG analysis, even
in very early stages of the disease.
Methods: We analyzed video-EEG in a conditional mouse model
of TSC in which Tsc1 expression was deleted in cortical neural stem
cells (NSCs) through Cre-mediated recombination. Since mutant mice
prematurely died by postnatal day (P)19, we implanted epidural
electrodes in pups at P10-11. Remarkably, the procedure was successfully accomplished, without side effects and complications.
Time–frequency analysis was performed offline and results were
represented by power spectrum and density spectral arrays. A subset
of animals was treated with rapamycin, a drug normally used in TSC
affected patients, to observe a reversion of phenotype.
Results: Background activity in both control and mutant mice was
composed by phases of 1–4 Hz or 6–9 Hz. Spontaneous epileptic
seizures were observed in 100% of mutant mice, that died within day
19 if not treated with rapamycin. In mutants, concomitantly with a
rising number of seizures, normal background activity progressively
got worse by decrease in amplitude, slowing of activity and manifestation of epileptiform abnormalities. Treatment of mutant mice
with rapamycin fully reverted the mutant phenotype.
Conclusions: Video-EEG proved to be essential to study this
model of epilepsy and effects of rapamycin treatment. Moreover, we
showed that is possible to perform it also in very young mice.
P339
Death-resistant neural progenitors yield mostly
neurons: an erythropoietin-dependent process
G. Marfia, R. Campanella, S. Carelli, F. Messaggio,
A. Gorio
University of Milan (Milan, IT); San Carlo Hospital (Milan, IT)
Traumatic lesions of the cord are characterized by a secondary process of degeneration, that is a complex condition of ischemia-like
syndrome and neuroinflammation. We reported that mouse adult
neural stem cells, isolated from the subventricular zone (SVZ),
accumulate at the site of injury and improve the early rate of hind
limb functional recovery, however, few weeks later the transplanted
are totally phagocytated by macrophages. In view of such results we
aimed at isolating adult neural stem cells after a prolonged ischemic
insult, this could provide a population of cells capable of resisting at
the unfavourable site of injury. The cellular responses to hypoxia are
manifested by activation of the hypoxia-inducible factor-1 (HIF-1), a
transcription factor of the basic helix loop-helix family (Huang et al.
1998). HIF-1 consists of two subunits, one is O2 - regulated HIF-1 a
subunit, and the other is O2 -independent HIF-1 b subunit. Under
hypoxic conditions, HIF-1 a is no longer hydroxylated and the two
subunits dimerize and migrate to the nuclei; this results in increased
expression of several key target genes such as erythropoietin, vascular
endothelial growth factor, tyrosine hydroxylase (TH) and OCT4,
which function as regulators of cellular proliferation and differentiation. Here we report the isolation from SVZ of neural precursors at
several hours after death of the donor mouse. These cells differentiate
mostly in neurons ([50% of total cells) showing high activation of
HIF1a and MAPK with the specific expression of erythropoietin and
its receptor. The addition of antibodies to erythropoietin to the specific medium inhibits the differentiation towards the neuronal
phenotype and obliterate the voltage sensitive calcium currents. These
results suggest that the expression of ischemia-induced EPO signaling
is an indispensable precondition to gain and maintain the neuronal
morphological and functional phenotype by the death resistant neural
precursors. The induction of EPO is of great importance in brain
preconditioning and suggest that these cells may represent a possible
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successful candidate for transplantation into the central nervous system after injury.
P340
Linear and non-linear analysis of rat cerebellar signals
under zoletil and ether anaesthesia
J. Podgorac, L. Martac, G. Stojadinovic, G. Kekovic,
S. Slobodan, M. Culic
University of Belgrade (Belgrade, RS); University of Novi Sad
(Novi Sad, RS)
It is still unclear how the cerebellum is involved in various pathophysiological conditions, what are the mechanisms by which longdistance coordination across different brain networks are maintained
and how synchronous burstplay role in coordinating activity in different frequency bands as animal progress from anesthesia towards
consciousness. Spectral analysis by Fast Fourier transform (FFT)
remains the most widespread signal processing method in this field.
Development of non-linear signal analysis (fractal dimension, Hurst
exponent and others) brought methods for better insight in works
concerning application of chaotic formalism to brain signals. We
aimed to define changes of cerebellar activity under Zoletil and ether
anaesthesia using linear and nonlinear measures . The experiments
were performed on adult male Wistar rats in accordance with the
European Council Directive (86/609/EEC). The misro-electrode array
was implanted at the vermal cerebellar cortex and the -18-pin Male
Omnetics connector was fixed by the dental cement under Zoletil
anaesthesia. The same day and few days after recovery, cerebellar
local field potentials were recorded by the wireless acquisition system
(Telespike, Alpha Omega Engineering Ltd, Nazareth), during next
10 min after Zoletil and ether anesthesia application. Cerebellar signals were sequentially digitized at the sampling rate of 788 Hz and
filtered to avoid artifacts due to movements and other non-brain
sources of electric activity. The fractal dimension and relative power
spectra of cerebellar signals calculated were calculated. Changes of
linear and nonlinear measures of explored cerebellar signals could
indicate the different effect of Zoletil and ether anesthesia in cerebellum which could point out the cerebellar role in coordinating
nonmotor functions in animal progress from anaesthesia.
This study was supported by the Serbian Ministry of Science and
Technological Development (project No. 175006).
P341
Stem cell transplantation in experimental autoimmune
encephalomyelitis
Y. Motuzova, A. Fedulau, D. Nizheharodova, S. Guzov,
S. Bagatka, M. Kolobova, M. Zafranskaya
Belorussian State Medical University (Minsk, BY); Belorussian
Medical Academy of Post-Graduated Education (Minsk, BY)
Objective: To investigate the efficacy and safety of mesenchymal
stem cell transplantation (MSCT), haematopoietic stem cell transplantation (HSCT) and co-transplantation of mesenchymal (MSC)
and haematopoietic (HSC) stem cells after immunosuppression in the
experimental autoimmune encephalomyelitis (EAE).
Methods: EAE in Wistar rats was induced with complete Freund’s
adjuvant. A single dose of cyclophosphamide (CY) (300 mg/kg) was
administered at the peak of the disease. On the next day MSC of the
second passage (1 9 106) and HSC (2 9 107) were injected intravenously (CY + HSC + MSC group). Second group of EAE rats
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received HSC after CY administration (CY + HSC group). Third
group of EAE rats were treated with MSC at the dose of 1 9 106
(MSC group). Control rats with EAE received the injection of the
same volume of medium. In some experiments prior to transplantation
MSC were stained by PKH26 (Sigma-Aldrich). Rats were observed
for 42 days after immunization. Section slides were stained by
hematoxylin and eosine, Kluwer-Barrera, and MSB methods. Brain
and spinal cord frozen sections were analyzed by fluorescence
microscopy for localization of PKH26-labeled cells.
Results: Both CY + HSC + MSC, CY + HSC and MSC-transplanted rats revealed significant inhibition of the disease severity
compared to control EAE rats. This clinical effect was associated with
a reduction of demyelination and mononuclear infiltration both in the
brain and spinal cord of treated rats. No significant difference in
reduction of disease activity (clinically and histologically) was
observed between groups of treated rats. Rats from
CY + HSC + MSC group showed more rapid improvement as compared with other treated rats. Stem cell transplantation was associated
with different mortality rates: 75% in CY + HSC group, 28,6% in
MSC group and 20% in CY + HSC + MSC group. Flow cytometry
showed PKH26-labeled MSC to be present in many organs (spleen,
liver, bone marrow) with rare incidence in brain and spinal cord. MSC
were also detected in the lymph nodes and exhibited systemic
immunomodulatory effects, down-regulating proliferation of lymphocytes in response to myelin antigens.
Conclusion: Both HSCT, MSCT and co-transplantation of MSC
and HSC after immunosuppression promotes recovery from EAE and
prevents relapses, but co-transplantation of MSC and HSC after
immunosuppression and MSCT seems to be safer in comparison with
HSCT after CY.
P342
Death-resistant neural stem cells regenerate neuronal
tissue and promote functional recovery
after transplantation in a spinal cord injury model
G. Marfia, R. Campanella, R. Andrea, S. Carelli, A. Gorio
University of Milan (Milan, IT); San Carlo Hospital (Milan, IT)
Introduction/Objectives: Traumatic injuries in central nervous system
lead to severe and permanent neurological deficit. In particularly
acute traumatic spinal cord injury often results in a devastating loss of
neurological function below the injury. Regeneration or replacement
of dead or damaged cells is the primary goal of regenerative medicine
and one of the prime motivations for the study of stem cells. NSCs
can participate in repair of damage.
Methods: Adult stem cells have been isolated from numerous adult
tissues and other non-embryonic sources, and have demonstrated a
surprising in vitro ability for transformation into other tissue or cell
types and for repair of damaged tissues. Unfortunately when administrated on a spinal cord injury they modulate the inflammatory
response but do not differentiate into mature cells and are quickly
engulfed by macrophages present at lesion site. Recently we isolated
a new class of neural stem cell from the subventricular zone of mice
forebrain named Death resistant neural stem cells (DR-NSCs), that
are capable of surviving after a powerful ischemic insult. DR-NSCs
for their potentiality, are a good tool for tissue replacement therapies.
In this study we focused on transplantation of DR-NSCs in a murine
model of spinal cord injury by endovenous injection within 2 h after
injury.
Results: After administration, cells migrate specifically to the site
of injury and improve the rate of hind limb function evaluated by
Basso Mouse Scale compared with animals treated with placebo.
interestingly DR-NSCs survive at the injury site and differentiate
S69
predominantly into cholinergic neurons, reconstitute a rich axonal
and dendritic network and promote a marked axonal regeneration
across the injury site of monoaminergic fibers within 30 days from
their administration. Moreover the molecular analysis of the lesion
site show that DR-NSCs induce a remodulation of inflammatory
response through the expression of proinflammatory cytokines and
release of neurotrophic factors. Proinflammatory cytokines significantly decrease after 48 h from spinal cord injury and DR-NSCs
transplantation, while after 7 days we observe an increase of IL-6
and TNF a probably because at longer time those cytokines are
necessary to support the regenerative process according to the
literature.
Conclusion: These data suggest that DR-NSCs may represent a
good source for cellular therapy in neurodegenerative disorders,
specially on spinal cord injury.
P343
The role of a synuclein in neurodegeneration
in a rat animal model
G. Stoica, F. Lungu, V. Murray
Texas A&M University (College Station, US)
Objectives: The primary objective was to better understand the
pathogenesis of an inherited motor neuronal degeneration in a rat
animal model.
Methods: A spontaneous inherited autosomal recessive rat model
for Parkinson’s disease was developed in a colony of Sprague
Dawley (SD) rats maintained at the Texas A&M University Lab
Animal Facility. This phenotype has been maintained in a line of
rats through sib-mating, and pedigree information demonstrates
clear autosomal-recessive transmission of this trait. This neurological disorder affects young rats during the first month of life.
Progressive development of tremor, spasticity and rigidity, and
bradykinesia, all of which are noticed at 15–20 days postnatal, and
significant low dopamine serum levels characterize the clinical
manifestation. Due to the fact that SD rats are outbred, we transferred the phenotype into a syngeneic black hooded rat, Berlin–
Druckrey (BD-IV), by inbreeding. The affected BD-IV offspring
can be identified during the first few days postnatal by the gray
color of their coat.
Results: In our rat model, western blot (wb) analysis showed that
a synuclein (a-syn) expression in affected rat brain was elevated
when compared with non-affected littermates. In addition, wb
analysis demonstrated that levels of both the S129 phosphorylated
and nitrated forms of a-syn were elevated. Histopathological
examination of the central nervous system demonstrated progressive
loss of dopaminergic neurons from the mesencephalon: in the
substantia nigra pars compacta and in the ventral tegmental area.
Histopathology, immunohistochemistry and transmission electron
microscopy (TEM) findings demonstrated that there is a retrograde
pathological process of degeneration (dying back) involved in
neuronal loss. Alteration of mitochondrial membrane potential was
demonstrated in vitro from isolated neurons of affected rats. The
presence of Lewy bodies that were labeled for a-syn was evident in
the brain striatum, substantia nigra and brain stem of affected rats.
Astrogliosis and microgliosis accompanied the neuronal loss in
affected rats. HPLC analysis of neurotransmitters performed on
brain tissue of affected and control rats demonstrated significant
increases in glutamate and decreases in GABA in affected rats
compared with controls.
Conclusion: Our preliminary data suggest that a-syn is a primary
factor incriminated in the pathogenesis of neurodegeneration in an
inherited rat animal model for Parkinson’s disease.
P344
Neurophysiological characterisation of the g93a ALS
rat model
D. Ungaro, N. Riva, M. Peviani, G. Spano, C. Bendotti,
S. Amadio, A. Quattrini, G. Comi, U. Del Carro
University Hospital San Raffaele (Milan, IT); ‘‘Mario Negri’’ Institute
for Pharmacological Research (Milan, IT)
Objectives: Recently a rat model of ALS harbouring a mutant
SOD1G93A gene has been generated, showing clinical features that
resemble the human phenotype. Clinical characteristics and larger
size of the rat model might give the opportunity for more extensive
studies for a better comprehension of ALS pathogenesis and testing
new therapeutic strategies. A detailed neurophysiological characterization of this model is still lacking so we performed longitudinal
neurophysiological study of this ALS rat model.
Methods: We analyzed 5 wild type rats and 5 ALS rats at 60, 90, 100,
120, 140 post natal days (pnd), for monitoring the development of the
disease. Sciatic nerve motor conduction velocity (MCV) and Motor
evoked potentials (MEP) by transcranial electric stimulation were
performed to obtain peripheral and central nervous system functional
parameters. An unpaired Student’s t test was performed for statistical
evaluation of the data. Needle analysis of brachial biceps and triceps,
vastus and gemini muscles was performed in all ALS animals.
Results: In ALS rats amplitude of tibial nerve (MAP) decrease at
120 pnd and dramatically falls down with statistical significance
(p \ 0.001) at 140 pnd. F wave latency, MCV and spinal MEP
latency didn’t modify at comparison with controls. Cortical MEP
(cMEP) amplitude decreases, in comparison with controls,since 90
pnd (p = 0.02)and worsen at 120 pnd(p \ 0.001). cMEP at 140 pnd
is not evocable in all affected animals.With reduction of cMEP
amplitude we observed a consensual reduction of MEP/MAP ratio in
all ALS rats and an increased cortical motor threshold (p = 0.04 at 90
pnd and p = 0.004 at 120 pnd). Needle analysis of ALS rats muscles
showed active denervation (jasper and fibrillation ++)at 120 pnd, that
worsen at 140 pnd (jasper and fibrillation +++).
Conclusion: In peripheral nervous system of ALS rats we found an
important reduction of cMAP amplitude, meaning an important axonal
loss only at the end stage of the disease. In central nervous system we
found an earlier reduction (until 90 pnd) of cMEP amplitude and a
reduction of MEP/MAP ratio, that even worse at 140 pnd when cMEP is
inevocable. Data suggests a more evident involvement of central nervous system,but the consensual increase of cortical motor threshold
could mean a reduced excitability of the system that can be due to a more
early functional dysfunction of upper or spinal motoneurons. This data
represent a starting point for monitoring the in vivo progression of the
pathology and test the efficacy of therapeutic strategies.
P345
The effects of angiotensin II and its receptor blockers
on anxiety status and central oxidative stress in rat
A. Ciobica, L. Hritcu, V. Bild, M. Padurariu, W. Bild
Alexandru Ioan Cuza University (Iasi, RO); Gr. T. Popa University
(Iasi, RO)
Objectives: In addition to its known classical roles, the renin angiotensin system (RAS) has also more subtle functions, which include
the regulation of emotional responses. Previous studies regarding the
anxiety related behavior of RAS have showed controversial results.
Also, there are evidences that oxidative stress accompanies Ang II
infusion, but the role of AT 1 versus AT 2 receptors is not very clear.
The aim of the present work was to evaluate the effects of central
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angiotensin II receptor blockers (losartan and PD-123177) on anxiety
state and oxidative stress status of rat brain.
Methods: Behavioral testing included elevated plus maze, used
to assess anxiety status, while oxidative stress status was measured
though the extent of a lipid peroxidation product (malondialdehydeMDA) and the specific activity of some defense antioxidant
enzymes (superoxide dismutase-SOD and glutathione peroxidaseGPX).
Results: The rats treated with angiotensin II spent significantly less
time in the open arms of elevated plus maze, while the administration
of losartan resulted in a significant increase of this time. We also
observed a significant increase of MDA concentration in angiotensin
II group and decrease of MDA levels in both losartan and PD-123177
groups. Also, significant correlations between the time spent in the
open arms and oxidative stress markers were found.
Conclusions: These findings could raise important therapeutic
aspects regarding the use of some Ang II receptor blockers in anxietyrelated disorders. Additionally, oxidative stress could exert an
important role in these effects.
P346
Filopodia branching of human neural cells cultured
over vertically grown multi-walled carbon nanotubes
J.W. Lee, N.S. Lee, H.K. Park
Kyung Hee University (Seoul, KR); Sejong University (Seoul, KR)
The biological behaviors of living cells over micro or nanoscale
patterns are closely related with their in-vivo responses to the specific
tissues or organs. However, not much things are known about those
phenomena. In this study, we introduced vertically grown carbon
nanotubes as a material for nanoscale structure formation and cultured
human neural cells to observe biological cellular activities over
nanoscale patterns. Multi-walled carbon nanotubes were grown vertically following the method conventionally suggested including
deposition area selection by photolithography, catalytic metal deposition, and nanotube growth. Human neuroblastoma cells (SK-NBE(2)) were cultured over the substrate with carbon nanotube column
pattern and differentiated to neural cells using differentiation medium
for 4 more days following the manufacturer’s instruction. After the
culture, cells were fixed and applied for IFA (Immuno Fluorescent
Assay) and SEM observation. The cell body was located initially at
the bottom of the figure, however, during the sample preparation,
most part of it was lost for bad contact with nanotube tips. Nevertheless, the feature of cytoskeletal rearrangement is quite interesting.
At first, filopodia extruded from a cell navigated its surrounding using
the side walls of carbon nanotubes in zigzag motion. It was also
observed that the tip of the filopodium became branched into several
sub-filopodia like as observed from the arrangement of actin filaments
in lamellipodia. From a biochemical point of view, the filopodia
branching is related with a new nucleation of actin polymerization
somewhere in the actin filament activated by Arp2/3 complex and is
common phenomenon easily found during cell migration. However,
the multiple branching into sub-filopodia is not found in the literature
related with nanopatterns. Two explanations can be suggested. The
first one is mechanical adaptation to the nanostructure developed by
carbon nanotubes and the other one is surface weak charge of carbon
nanotubes. We think the structure itself may induce the branching,
though the tip is not the branching point, because the thickness of
each filopodium tip is quite similar with the diameter of a nanotube,
that is, 30–40 nm. Surface galvanotaxis phenomenon is also reasonable for filopodia steering to the nanotubes. Though, the charge on a
single carbon nanotube is not enough for the phenomenon, the mass
of nanotubes possibly induces the phenomenon.
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P347
Estradiol reverses a neuronal biomarker of brain
ageing in female rats
P. Kumar, R. Kale, N. Baquer
Jawaharlal Nehru University (New Delhi, IN)
Objective: The objective of this study was to observe the changes in
activities of monoamine oxidase, glucose transporter-4 levels, membrane fluidity, lipid peroxidation levels and lipofuscin accumulation
occurring in brains of female rats of 3 months (young), 12 months
(adult) and 24 months (old) age groups, and to see whether these changes
are restored to normal levels after exogenous administration of estradiol.
Background: Aging in females and males is considered as the end
of natural protection against age related diseases like osteoporosis,
coronary heart disease, diabetes, Alzheimer’s disease and Parkinson’s
disease. These changes increase during menopausal condition in
females when the level of estradiol is decreased.
Methods: The aged rats (12 and 24 months old) (n = 8 for each
group) were given subcutaneous injection of 17-estradiol (E2)
(0.1 lg/g body weight) daily for one month. Controls animals
received an equal volume of vehicle. After 30 days of hormone
treatment experimental animals of all the groups were sacrificed and
brains were isolated for further study.
Results: The results obtained in the present work revealed that
normal aging was associated with significant increases in the activity
of monoamine oxidase, lipid peroxidation levels and lipofuscin
accumulation in the brains of aging female rats, and a decrease in
glucose transporter-4 level and membrane fluidity. Our data showed
that estradiol treatment significantly decreased monoamine oxidase
activity, lipid peroxidation and lipofuscin accumulation in brain
regions of aging rats, and a reversal of glucose transporter-4 levels
and membrane fluidity was achieved. Administration of E2 brought
these changes to near normalcy.
Conclusions: It can therefore be concluded that E2’s beneficial
effects seemed to arise from its antilipofuscin, antioxidant and antilipidperoxidative effects, implying an overall anti-aging action. The
results of this study will be useful for pharmacological modification
of the aging process and applying new strategies for control of age
related disorders.
Dementia/Higher function disorders: cognitive
disorders
P348
Cognitive function in depression: gender differences
A. Messina, A.M. Fogliani
University Hospital of Catania (Catania, IT)
Objectives: The cognitive function is frequently impaired in depression [1]. Fluid intelligence (abstract-logical-deductive reasoning) is
considered a good marker for the evaluation of the cognitive function
in patients with depression [2]. Few studies focused on the gender
differences in cognitive function of depressed patients. The aim of
this study was to investigate the cognitive function in female and male
patients with depression.
Methods: the sample consisted of 84 non psychiatric patients,
including 65 females and 19 males. The mean age of the sample was
46.1 years (SD = 6.9). Mean age difference between male
(M = 46.7, SD = 5.0) and female (M = 45.6, SD = 7.4) was not
significant (p [ 0.05). Each patient completed the Beck Depression
Inventory (BDI) for the assessment of depression and the Raven’s
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Standard Progressive Matrices (SPM) for the evaluation of the fluid
intelligence. All subjects with BDI score C10 (cut off for depression)
were included in this study.
Results: The mean score on SPM was significantly lower (t = 2.04, df = 82, p = 0.04) in male patients with depression(M = 49.7,
SD = 3.2) than in female patients with depression (M = 51.4,
SD = 3.2). Age and fluid intelligence were inversely correlated only
in male patients with depression (r = - 0.54, p = 0.04). No significant difference was observed in mean values of depression between
males and females. Conclusion: cognitive function was more affected
in depressed males than in females. Moreover only male patients with
depression showed an age-related decline of the cognitive function.
P349
Preliminary validation of the Portuguese version
of the INECO frontal screening
M.J. Caldeira, E. Baeta, B. Peixoto
Advanced Institute of Health Sciences - North (Gandra, PT); Hospital
Center of Alto Minho (Viana do Castelo, PT)
Introduction: The executive functions, commonly related to the
frontal lobe, are the result of complex cognitive processes directed
towards an objective. The INECO Frontal Screening (IFS), developed
by the Buenos Aires Institute of Cognitive Neurology, is a brief,
sensitive and specific test for the detection of executive dysfunction in
neurodegenerative pathology. The present work aims to adapt and to
establish the psychometric properties of the IFS Portuguese version.
Methods: Our sample is arranged in three groups as follows:
Control Group (CG) formed by 12 healthy individuals; Fronto-Temporal Dementia behavioral variant group (FTD) (n = 13) and
Alzheimer’s Disease group (AD) (n = 6). The IFS was administrated
to the three groups as well as the Mini Mental State Examination
(MMSE). In addition, the Lisbon Battery for the Assessment of
Dementia (BLAD) and the Trail Making Test (TMT) were applied to
the two clinical groups.
Results: The IFS revealed a good internal consistency. The IFS
total score was 24.5 for the CG, 13.17 for the AD group and 7.23 for
the FTD group. Considering a cut-off of 19 points, the IFS sensitivity
was 100% and specificity 99.4% in differentiating controls from
patients with dementia. With a cut-off of 8 points, the IFS sensitivity
was 83.3% and specificity 46.2% in differentiating AD from FTD
patients. The IFS total score correlated positively with the MMSE, the
BLAD total score and the TMT part B.
Conclusions: This study revealed that the Portuguese version of
the IFS has psychometric properties similar to the original version.
P350
Cerebral activations related to free and invariant
visuomotor practice, with dissociation of external
targets and body scheme
M. Beudel, B.M. de Jong
University Medical Center Groningen (Groningen, NL)
Objectives: Motor learning involves stimulus-response binding. In
this process, different movements rely on different contributions of
sensori-motor networks. This might implicate a task-specific recruitment of sensori-motor networks during motor learning. To investigate
this aspect of motor practice, time effects of cerebral activation patterns evoked by stimulus-response conditions that were either free or
invariantly defined (fixed) and either based on external targets (button) or body scheme (finger) were analyzed.
Methods: fMRI and behavioral data were obtained from 15 healthy volunteers while stimulus-response conditions that were either
free or invariantly defined (fixed) and either based on external targets
or body scheme were performed. Auditory commands instructed for
either selecting a button from a response box with the same finger or
selecting a finger to press the same button. Fingers represented the
body scheme, while the buttons represented external targets. Subjects
were able to view targets and performance via mirrors. Each experimental condition was repeated 16 times. Motor learning effects
within condition specific activation maps were obtained using a linear
model of consecutive repetitions (SPM5).
Results: Common subcortical (basal ganglia and thalamus) and
differential cortical activations were seen when comparing the time
effects between conditions. Specific cortical increases were only seen
in the fixed selection conditions, and not in the free selection conditions. In body-scheme (finger) based selection, enhancements over
time were seen in left parietal (angular gyrus) -premotor circuitry. In
external target (button) based selection, enhancement over time was
seen in the right dorsolateral prefrontal cortex.
Conclusion: The role of the basal ganglia in the selection of
movements is independent of an experimental task. Only when an
actual stimulus-response association is present, enhancement of
related cortical circuitry occurs. The differential enhancements in left
parieto-premotor circuitry, including the angular gyrus, and the right
dorsolateral prefrontal cortex in respectively body scheme and
external target based selection condition further supports the neural
correlates of Gerstmann’s and dysexecutive syndrome, respectively.
P351
Normal pressure hydrocephalus: a qualitative study
on outcome
P. Bugalho, L. Alves, J. Martins, O. Ribeiro
Hospital Egas Moniz (Lisbon, PT)
Objectives: To describe the evolution of cognitive and motor symptoms of NPH patients and its relation with clinical variables and
surgery.
Methods: Possible NPH was diagnosed according to clinical criteria (Relkin et al. 2005). Patients were evaluated at two different
time points (T0 and T1). The following variables were registered: age
of onset; first symptom of the triad; age at T0; symptoms of the triad
at T0; time from T0 to T1; cognitive and gait status at T0 and T1;
presence of cerebrovascular risk factors (CVRF) and of white matter
lesions (WML); submission to surgery. The relationship between
cognitive and gait status at follow up and each variable at T0 was
studied by chi-square statistics, both globally and separately according to treatment (shunt vs. non-shunt).
Results: We included 35 patients. Age of onset: 71.7 ± 6.86. Age
at T0: 74.5 ± 6.29. Time from T0 to T1: 3.1 ± 1.96 years. Fourteen
patients were submitted to surgery. Improvement in cognitive and gait
function occurred in 9 and 5 patients respectively. Younger age at
onset (\70) was more frequent in gait dysfunction improved patients
than in worsened ones (5 in 5 vs. 7 in 30, p = 0.002). The following
variables were also associated with gait improvement: younger age at
T0 (5 in 5 vs. 2 in 30, p \ 0.00001), absence of CVRF (4 in 5 vs. 5 in
30, p = 0.010), absence of WML (5 out of 5 vs. 10 out of 30,
p = 0.009) and shunt surgery (5 out of 5 vs. 5 out of 30, p = 0.006).
Only shunt surgery was associated with improvement in cognition (7
out of 9 vs. 7 out of 26, p = 0.015). On patients submitted to surgery,
improvement in motor function was related to younger age at T0 (5 in
5 vs. 1 in 9, p = 0.026), absence of CVRF (4 out of 5 vs. 1 out of 9,
p = 0.023) and absence of WML (5 out of 5 vs. 3 out of 9,
p = 0.028).
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Conclusion: Our data suggests that NPH outcome is highly variable. Although shunt surgery had a significant effect on both
cognition and gait, not all patients improved. Non treated patients
were seen to improve spontaneously in relation to cognitive dysfunction, which could be in relation with external and transient factors
present at T0. While cognitive outcome related only to shunt surgery,
gait improvement seems to be associated also with younger age at
onset and at T0 and with absence of CVRF and WML. These last
three variables seem also to have influenced the motor outcome of
patients treated with shunt surgery.
P352
c Association between CSF biomarkers
and neuropsychological impairment in normal
pressure hydrocephalus
M. Croce, P. Caroppo, F. D’Agata, M. Caglio, M. Ajello,
D. Imperiale, M. Fontanella, P. Mortara
University of Turin (Turin, IT)
Normal Pressure Hydrocephalus (NPH) is a condition in which disturbed cerebrospinal fluid (CSF) dynamics cause the typical
symptoms of gait disturbance, cognitive impairment and urinary
incontinence. NPH is one of the causes of dementia of the elderly and
it was proposed that some of the patients may develop Alzheimer’s
disease (AD) like pathology. The aim of this study was to compare
levels of different CSF biomarkers, including 14.3.3. protein, total-tau
protein, phospho-tau protein, amyloid-b peptide (Abeta) of NPH
patients and non NPH controls (NC). CSF was collected from 27
possible NPH patients and 15 NC during the Tap test.
We collected the number of steps and the velocity during a 10-m
walking test, before and after the Tap test, together with the Tinetti gait
scale, considering as positive outcome an improvement after Tap test
in one of the two parameters or a gain of at least 3 points at the Tinetti
gait scale.
We administered a complete neuropsychological battery of test
that covered many domains (general intelligence IQ, attention, verbal
and visual memory, frontal and visuo-spatial functions). We also used
psychological scales to assess depression, apathy, anxiety, quality of
life and the caregiver overload.
The 14.3.3 protein was always negative in the NPH group. We did
not observe any change in levels of total-tau, Abeta, and ratio of
phospho-tau/Abeta in NPH versus NC subjects. Phospho-tau levels
were significantly increased in the NPH patients vs. NC. Abeta peptide levels were low in a subgroup of 6 NPH patients.
We did not find any significant association between the neuropsychological results and the Tap test outcome; conversely, we noticed
that patients with low Abeta levels had the worse cognitive performance with multiple domains affected and patients with a high level of
phospo-tau had a significant association with frontal functions.
Our preliminary results confirmed that CSF biomarkers could be
useful in the NPH diagnosis and also in the identification of patients
that may develop AD like pathology over time.
P353
Benson’s syndrome or posterior cortical atrophy: two
case reports
R. Figueiredo, S. França, C. Reis, R. Fonseca, M. Pinto
Hospital S. João (Porto, PT)
Objectives: Benson’s syndrome or Posterior Cortical Atrophy (PCA)
is a rare, early-onset progressive dementing syndrome, clinically
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distinct from Alzheimer disease (AD), usually presenting as higher
order visuospatial and visuoperceptual deficits. Unlike AD, memory
and frontal lobe functions are relatively spared until late in the disease
course. Structural neuroimaging demonstrates prominent posterior
cortical atrophy. The most commonly associated neuropathology is
that of AD.
Methods: The authors describe two cases of PCA. The literature
on PCA was reviewed and analysed.
Results: Case 1: 73-year-old woman, graduated in Arts, evaluated
for cognitive deficits. Her past medical history was notable for
glaucoma. There was no relevant family history. Two years before
neurological observation she complained of memory loss, insomnia,
anorexia and progressive difficulties in drawing. Diagnosed with
depression, she started on mirtazapine. Since then, she noticed
worsening of symptoms, with difficulties in recognizing some objects.
Neurologic examination revealed left inferior homonymous quadrantanopsia. Neuropsychological testing demonstrated visual object
agnosia, right–left confusion, constructional apraxia and acalculia.
Laboratory findings were normal. Brain imaging showed atrophy of
the parieto-occipital cortex. The patient was started on donepezil with
mild improvement of memory complaints. Case 2: 60-year-old
woman, with history of myopia, glaucoma and diabetes. Family history was unremarkable. She presented a 5-year history of difficulties
in writing, which were attributed to decreased visual acuity. Later, she
developed progressive difficulties in performing simple tasks like
household appliances, environmental disorientation and memory
impairment. Neurological examination showed no focal deficits.
MMSE scored 14/30. Psychometric evaluation revealed disproportionate visuospatial impairments and imaging studies disclosed
bilateral parietal atrophy. Biochemical investigations were normal.
She was started on donepezil and antidepressant. At 1-year follow-up,
she presented dressing apraxia and alexia and her memory deficits had
worsened.
Conclusion: The presenting complaints of PCA are diverse and
may be nonspecific. This diagnostic hypothesis should be considered
on our daily practice, as this may resemble other psychiatric and
ophthalmologic disturbances and lead to a diagnostic delay of this
neurodegenerative disease.
P354
Dorsal-ventral integration in the recognition of 3D
structure-from-motion stimuli in mild cognitive
impairment
R. Lemos, I. Bernardino, M. Stokreef, B. Graewe,
R. Farivar, I. Santana, M. Castelo-Branco
Coimbra University Hospital (Coimbra, PT); University of Coimbra
(Coimbra, PT); McGill University (Montreal, CA)
Objectives: In structure-from-motion stimuli (SFM), 3D shape can
only be extracted from dot moving patterns by integrating motion
cues over time. Recent studies showed that integration of visual
information across dorsal and ventral visual streams is needed for the
perception of 3D SFM objects.
In a previous study, our group has found that 3D motion integration is specifically impaired in Mild Cognitive Impairment (MCI),
indicating that parietal function may become affected early in the
course of the disease.
In the present study, we investigated whether the ability to recognize 3D SFM objects is impaired in this condition.
Methods: We developed an experimental paradigm in which
participants had to discriminate 3D SFM objects (faces and chairs)
from 3D SFM meaningless objects (scrambled faces and scrambled
chairs). The chairs stimuli were used as a control task, at ceiling level
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of performance, to make sure that subjects understood the task
requirements. Stimuli duration was randomly manipulated (100, 160,
980 ms) as well as depth information (flat, intermediate and full
depth), resulting in a 4 9 3 9 3 design with ten trials per condition.
Groups of amnestic MCI patients (n = 25) and matched controls
(n = 22) were included. Patients were recruited from the Neurology
Department of Coimbra University Hospital, where diagnosis was
achieved through gold standard neurological and neuropsychological
assessment, following Petersen’s (2001) classification criteria for
MCI. All healthy control participants had normal or corrected-tonormal vision and no neurological history.
Results: We found significant main effects for depth and duration
(p \ 0.001) as well as for group (p \ 0.05), in MCI patients. Additionally, planned analyses using independent-samples t test revealed
significant differences between MCI patients and controls for the
160 ms duration, on both full and intermediate depth levels. No differences were found on the chairs stimuli confirming this as a control
condition for the task comprehension.
Conclusions: The intermediate duration (160 ms) was the only one
that enabled a distinction between MCI and old adults. This was
found for full and intermediate depth levels suggesting that more
difficult (null depth conditions) are not optimal for discrimination.
We conclude that pathological ageing is related to deterioration in
extracting object information from short lived motion and depth cues
processed in the visual dorsal stream.
Supported by a Fundação para a Ciência e Tecnologia (FCT)
Research Grant: PIC/IC/83206/2007.
P355
Profile and predictive value of the cognitive complaints
in non demented elderly people: a 5-year longitudinal
study
J. Al Aloucy, R. Cotteret, D. Semani, A. Boudebza,
M. Roudier
University Hospital Pitié-Salpêtrière (Paris, FR); University Hospital
Paul Doumer (Liancourt, FR); University Hospital Charles Richet
(Villiers Le Bel, FR); Assistance Publique Hôpitaux de Paris (Paris,
FR)
Objectives: To study, in non demented elderly people, the profile of
cognitive complaints and it’s predictive value for dementia.
Methods: Subjective complaints about cognitive abilities were
assessed with the Questionnaire of Perception of Cognitive Decline
(QPCD), designed for this study. This questionnaire was administrated to 153 non-demented people, issued from our memory clinic:
103 women and 50 men, 60–80 years old (72 5,5 years). Each participant was submitted to a clinical investigation, a cerebral imagery
(CT scan and/or MRI) and a neuropsychological battery evaluating
episodic memory, executive functions, language, visuo-spatial abilities, and mood.
Results: At baseline the total score of the QPCD was significantly
correlated with scores of anxiety (Goldberg) and depression (Montgomery and Asberg) (p \ 0.0001), but not with scores of the MiniMental Sate Examination. The follow up during five years showed a
specific profile of cognitive complaints of patients converted to
dementia (n 77 patients) compared to non converted people: complaint about space orientation and mood at baseline were significantly
higher in the converted group.
Conclusion: The results of the study confirm that global cognitive
complaints in healthy elderly people are associated with subjective
state rather than with objective performance in neuropsychological
tests. However, at 5 years of follow-up, the complaint about space
orientation and mood had a significant predictive value for dementia.
P356
Usability test on a rehabilitation tool designed
for intensive home-based cognitive training
—COGWEB
V. Tedim Cruz, J. Pais, C. Mateus, V. Ferro Bento, I. Alves,
P. Coutinho
Hospital São Sebastião (Santa Maria da Feira, PT);
University of Aveiro (Aveiro, PT)
Objectives: To develop and test a new rehabilitation tool to perform
home based intensive cognitive training, through the internet, under
clinical prescription and monitoring and at affordable costs.
Methods: Rehabilitation tool: from 60 original exercises, designed
for cognitive training, we developed 20 on a computer game format,
allowing automatic increase or decrease of difficulty levels. These
exercises were assembled in a clean, user friendly design and covered
attention (5), language (4), memory (5), praxias (1) and executive
functions (5). Together with, a web 2.0 platform was designed providing for: medical prescription of cognitive training sessions, to be
performed at patient’s home; continuous monitoring of compliance,
performance and evolution; algorithms for automatic adjustment and
long term learning through use; data base recording of all activities.
Usability test: from our memory clinic were selected patients from
several groups, including: subjective memory complaints (15); traumatic brain injury, stroke and other static brain lesions (15); mild
Alzheimer disease (15). During a one hour session, patients and relatives were taught to use the system and allowed to practice. At the
end a questionnaire was answered.
Results: From the 45 patients selected, 27 were able to attend the
training session (subjective memory complaints 13, traumatic brain
injury 9, mild Alzheimer disease 5). Mean age was 60 years old
(41–78), with a mean of 6 years (4–16) of formal education; 67% had
a previous use of the computer. All patients and relatives made a
positive evaluation of the cognitive training tool. Only 5% were not
interested in performing the exercises at home; 40% mentioned the
need for temporary coaching from a relative or health care professional. Patients that mentioned difficulties had no previous personal
use of the computer.
Conclusion: This new system was very well received by patients
and relatives, which showed high levels of motivation to use it on a
daily basis at home. The simplicity of use and comfort were outlined.
This way we are now able to test and implement intensive cognitive
training, at home, in a variety of diseases and settings. The system is
able to improve human resources management and eliminates
important physical and economical barriers to health care access.
COGWEB is a trade mark and the system here presented is under
patent protection.
Supported by Bolsa de Investigação Cientı́fica 2009, Sociedade
Portuguesa de Neurologia.
P357
A case of abortive Hashimoto encephalopathy
exhibiting a selective memory deficit
C. Koros, A. Economou, G. Mastorakos, A. Bonakis,
N. Kalfakis, S.G. Papageorgiou
University of Athens (Athens, GR)
Objectives: Hashimoto thyroiditis (HT) has been implicated in the
development of severe neurological and psychiatric symptoms, with a
clinical picture of encephalopathy even in euthyroid patients. Herein
we report a case of a long-standing selective memory deficit in a
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euthyroid (treated by L-thyroxin) 45-year-old female patient with HT.
The patient complained of memory problems and deterioration of
concentration skills, which started approximately 2 years before her
present examination. She also reported language problems in the form
of word-finding difficulties. It is of note that the patient didn’t express
any signs of depression, which had been proposed as a diagnosis by
her endocrinologist.
Methods: Upon initial assessment, the patient underwent complete
clinical examination, neuropsychological evaluation and routine
blood investigations, including serum vitamin B12, antinuclear antibody and angiotensin-converting enzyme, serum thyrotropin and
thyroxine levels, serum anti- thyroid peroxidase antibody (anti-TPO),
and anti-thyroglobulin antibody (anti-TG). Cerebrospinal fluid (CSF)
examination, brain MRI and electroencephalogram (EEG) were also
conducted. A complete follow-up evaluation took place after a four
month interval.
Results: The physical examination was normal. The patient scored
30 points in the MiniMental State Examination. However, detailed
neuropsychological testing showed a severe deficit in verbal memory
(WMS-story recall). Blood and CSF investigations were normal
except for serum anti-TPO which were elevated (452.4 reference
range \70 IotaU/ml). Brain MRI was normal. EEG showed scarce
intermittent bilateral multifocal theta waves (occasionally with a
spike morphology) with a left hemisphere prevalence. Assuming an
autoimmune-mediated brain dysfunction associated with HT, the
patient was started on small doses of corticosteroid therapy. She
gradually improved and both her cognitive function and EEG features
had returned to normal 4 months later.
Conclusion: Hashimoto thyroiditis has already been associated
with thyroid-antibodies-related pathologic entities such as optic
neuritis and encephalopathy. Our case suggests that beyond the
already known clinical picture of encephalopathy, HT can cause a
chronic and selective memory deficit that can spare executive functions and attention. This clinical picture, which can be misdiagnosed
as depression, can only be diagnosed with a detailed neuropsychological examination.
P358
Orbitofrontal cortex damage and hypermoral
syndrome
M. Mimura, A. Yamamoto, K. Takahata, J. Motoki,
M. Kobayakawa, M. Kawamura
Showa University (Tokyo, JP); Keio University (Tokyo, JP)
Background: The neural substrates of moral judgements have recently
been advocated to consist of widely distributed brain networks
including the orbitofrontal cortex (OFC), anterior temporal lobe and
superior temporal gyrus. Moral judgements could be regarded as a
conflict between the top-down rational/logical processes and the
bottom-up irrational/emotional processes. Individuals with OFC
damage are usually difficult to inhibit emotionally-driven outrages,
thereby frequently presenting with severe impairment of moral
judgements and anti-social behaviours. However, clinical observation
suggests that some patients with OFC damage may show ‘‘hypermoral’’ tendency in the sense that they are too strict to overlook other
person’s offenses. The aim of the present study was to further elucidate the ‘‘hypermorality’’ of individuals wth OFC damage.
Methods: The participants were eight patients with focal OFC
damage (mean age 39.1 years old) and age- and sex- matched eight
healthy control participants. The participants read fictitious scenarios
which described other person’s offenses. The scenarios, originally
based on those by Buckholtz et al. (2008), consisted of the 40 offenses
that varied in crime severity and perpetrator responsibility. The
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questions were divided into the following four conditions; (A) serious
crimes with responsibility and intention, (B) serious, but unintentional
crimes with exemption, (C) intentional but negligible violations, and
(D) serious but mitigating circumstances. The participants were asked
to determine punishment for each fictitious crime.
Results: The patients with OFC damage punished more strictly
than healthy controls throughout the four conditions. Specifically,
there observed significant differences between the two groups in the
condition (D).
Conclusion: The results are consistent with clinical observation in
that individuals with OFC damage are strictly rigid and inflexible
against third person’s offenses.
P359
Brief assessment of patients with cognitive dysfunction:
comparison between Addenbrooke’s Cognitive
Examination—Revised and Mini Mental State
Examination
L. Alves, O. Ribeiro, P. Bugalho, I. Carmo
Hospital Centre of East Lisbon (Lisbon, PT)
Objectives: Addenbrooke’s Cognitive Examination-Revised (ACE-R)
is a test battery that incorporates the Mini Mental State Examination
(MMSE), which has proved to be a valid cognitive screening
instrument. Our aim was to compare the performance of ACE-R and
MMSE in the detection of different degrees of cognitive dysfunction
as defined by the Clinical Dementia Rating scale (CDR).
Methods: We examined consecutive patients referred to our clinic
for cognitive complaints. We compared the scores of MMSE, ACE-R
and ACE-R incorporated MMSE between groups with different
degrees of cognitive function as assessed by CDR (normal = 0,
cognitive dysfunction without dementia = 0.5, dementia [0.5), by
using ANOVA followed by Bonferroni post-hoc analysis. We also
tested the ability of MMSE and ACE-R cut-off scores to distinguish
between normal and cognitively impaired patients, as assessed by
CDR classification (normal = 0, cognitively impaired [0), by using
Chi-square statistics.
Results: We included 36 patients (16 males). Mean age at
assessment and mean age at symptoms onset was 73.0 ± 8.40 and
70.1 ± 8.80, respectively. Patient distribution according to CDR
classification was: normal = 11, cognitive dysfunction = 19,
dementia = 9. According to ACE-R, ACE-R incorporated MMSE
and MMSE scores, 21, 15 and 11 patients presented cognitive
impairment, respectively. ACE-R incorporated MMSE scores were
significantly lower than MMSE scores. Significant differences were
found in ACE-R and ACE-R incorporated MMSE scores between all
three CDR classification groups. MMSE score was significantly different between normal/dementia and cognitive dysfunction without
dementia/dementia groups, but not between normal/cognitive dysfunction without dementia groups. ACE-R defined cognitive
impairment was significantly related to CDR classification, with a
sensitivity and specificity of 80 and 91 %. Cognitive impairment
defined by ACE-R incorporated MMSE and MMSE was not significantly related to CDR (sensitivity/specificity was 46/75% and
42/100%).
Conclusion: Our findings confirm the superiority of ACE-R in
relation to MMSE, demonstrating its better capacity in distinguishing
between different levels of cognitive dysfunction, as well as higher
sensitivity to cognitive impairment, with only slightly lower specificity. These results also show that MMSE and ACE-R incorporated
MMSE do not yield similar scores and are thus not comparable in this
setting.
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P360
Can Charles Bonnet syndrome herald a dementia
with Lewy bodies? Report of a case
S. Gil Navarro, L. Lillo, J. Orcajo, J. Olazarán,
D. Mateo Gonzalez, D. Ezpeleta
‘‘Gregorio Marañón’’ University General Hospital (Madrid, ES)
Objectives: Visual hallucinations (VH) have a prevalence of 10% in
the geriatric population. They appear in neurodegenerative diseases,
particularly in dementia with Lewy bodies (DLB). When patients with
significant visual loss and without other medical conditions (pharmacological, metabolic or psychiatric diseases) perceive VH as
complex and unrealistic, a diagnosis of Charles Bonnet syndrome
(CBS) can be made. We present a case of CBS that later developed a
DCL.
Methods: A 78 years old male with a chronic acquired blindness
(retinal and optic nerve ischemia) developed acute VH (animals and
people around him) properly criticized. He had no alteration of the
level of consciousness and no major pathological signs were found in
the neurological examination. VH were partially controlled with oxcarbazepine. Two years later he developed a memory disorder
followed by prosopagnosia, confabulation and conspiracy delusions,
falls, unexplained loss of consciousness, and, finally, motor activity
during sleep.
Results: Blood and urine analysis, brain magnetic resonance, and
cerebrospinal fluid study were normal. An electroencephalogram was
unremarkable. Visual evoked potentials and electroretinogram
showed severe damage of the visual pathway and slight damage of the
peripheral retina on both eyes. In a single photon emission computed
tomography (SPECT) there was a severe impairment of perfusion in
both hemispheres, mostly in the posterior structures, that was compatible with an evolved DCL. A diagnosis of DCL was made and he
starts treatment with rivastigmine 6 mg/day, with dramatic
improvement of all his symptoms.
Conclusion: The role of acquired peripheral visual deficits in the
pathogenesis of VH in DCL patients is not known. It is suggested that,
sometimes, a SCB could herald a DCL, as has been insinuated by
some authors. This case emphasizes the importance of clinical monitoring in CBS patients about the likelihood of developing a
DCL.
P361
Mild cognitive impairment: effect of education
on verbal and non-verbal tasks performance
A. Tsiakiri, K. Vadikolias, G. Tripsianis, P. Ioannidis,
G. Tsivgoulis, A. Serdari, J. Heliopoulos, M. Livaditis,
C. Piperidou
Democritus University of Thrace (Alexandroupoli, GR);
Aristotle University of Thessaloniki (Thessaloniki, GR)
Objectives: Education is considered to provide a cognitive and neurological ‘‘reserve’’ through neuronal changes and as a consequence
can delay the clinical onset of the symptoms. This functional reserve
appears to be at play also in the pre-dementia phase. The present
study aimed to evaluate the effect of education on change over time of
verbal and non-verbal tasks in subjects with Mild Cognitive Impairment (MCI).
Methods: We included patients with a diagnosis of MCI,
age [50 years, without concomitant medical or psychiatric disorders.
We sought to compare strictly homogenous groups excluding all
subjects with vascular risk factors or vascular lesions in brain MRI.
The use of centrally acting acetylcholinesterase inhibitors (donepezil,
rivastigmine and galantamine) and memantine or other drugs with
with known direct CNS effects, was considered as exclusion criterion.
Each patient underwent a clinical assessment packet and a series of
neuropsychological tests of the Language and Constructional praxis
subtests of Cambridge Cognitive Examination (CAMGOG) and the
Boston Naming Test (BNT), at baseline, 6 and 12 months. We
defined three educational levels (high–medium–low) taking into
account the total years of education, the school level and diplomas.
Results: Within the 36 MCI patients with one year follow up,
analysis of covariance, controlling for baseline scores, showed a
statistically significant effect of education on the naming objects (NO)
score - adjusted mean values in the three levels of education
(p = 0.004), definition (DF) score (p = 0.005), drawing (CD) score
(p = 0.005), naming without help (BXB) score (p = 0.003), language
(LT) (p = 0.020) and Boston Naming Test (BNT) (p = 0.005), with
lower scores being documented in the group of patients with low
education level. Conclusion. Education was found to influence tests
performance during follow up examinations in subjects with MCI.
Less educated MCI patients performed worse and this was evident in
verbal and non-verbal tasks. The high-educated group showed slower
or no deterioration compared with the low-educated group. How long
this ‘‘protective’’ effect persists could be an interesting area for further research.
P362
Out of sight, out of mind: the role of the hidden object
in a novel memory screening test
S.G. Papageorgiou, A. Economou
University of Athens (Athens, GR)
Objectives: To present preliminary data on the performance of healthy and memory-impaired individuals on a novel memory screening
test. To relate test performance to neuropsychological test
performance.
Methods: Participants: A community-dwelling sample of 81
middle-aged and older controls and a group of 62 memory-impaired
patients (29 mild AD, 3 AD, 7 other dementia and 23 MCI) spanning
a wide range of years of education (0–21), matched for education.
Task: The 5 objects test requires the recall of the locations of 5
everyday objects, 4 of which are placed on the 4 corners of two
adjacent sheets of paper (A4), and the 5th is placed in the pocket of
the examiner. The examiner first guides the examinee in placing the 5
objects and then hands each object to the examinee in a specific order,
to be placed in the correct location. The task is repeated until perfect
performance is achieved, up to 4 trials, with a delayed recall after 5
minutes. Procedure: Controls received a brief neuropsychological
battery that included a Greek research version of the California
Verbal Learning Test (CVLT). Patients received a battery of tests that
included the modified Mini Mental State Examination (mMMSE), the
5-words memory test (Dubois, 2000) and the Clock Drawing Test.
Results: Immediate and delayed recall performance was at ceiling
for the controls (trial 1 mean 4.57 ± .96, trials 1–4 mean
19.41 ± 1.48, delayed recall mean 4.98 ± 0.16) and was nearly
identical for a subset of age- and education-matched controls
(N = 34). Patients scored significantly lower on all 3 measures (trial 1
mean 2.95 ± 1.25, trials 1-4 mean 14.48 ± 4.95, delayed recall mean
3.81 ± 1.41) (all ps \ 0.001). Trial 1 scores showed the largest effect
size and the hidden object led to the highest percentage of incorrect
placement (88%) for the patients, differentiating the responses of the
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2 groups the most (v2 = 78.94, p \ 0.001). No relationship was
found between the 5 objects test scores and the CVLT for the control
group, due to near ceiling performance on the former test. Correlations of the 3 scores of the 5 objects test with the MMSE and
mMMSE were significant for the patients (all rs [ 0.41, ps \ 0.001).
Correlations of the 3 scores with age and years of education were
nonsignificant for both groups.
Conclusion: The 5 objects test is a quick, easy to administer and
sensitive to memory impairment screening test that can be used with
persons of minimal education.
P363
Contribution of a Test of Famous Faces to the diagnosis
of cognitive impairment and dementia
R. Rosa, C. Maruta, I.P. Martins
University of Lisbon (Lisbon, PT)
Objectives: Difficulties in the retrieval of proper names are a frequent
cognitive complaint among elderly people. Our objective was to study
the effect of normal aging in proper names retrieval.
Methods: We applied to 376 healthy subjects aged over 50 years
(mean 65.8 ± 8.8 and 7.2 years of literacy) and to a clinical group of
48 patients (with an age average of 69.02 ± 8.2 years and 6.5 years
of literacy) with the diagnosis of cognitive impairment or dementia of
different etiologies, a Test of Famous Faces (TFF) adapted to the
Portuguese population, consisting of 39 pictures of famous faces
divided into three different epochs (before 1974; between 1974 and
1990; after 1990).
Results: There was a marked positive effect of literacy and a
negative effect of age on TFF and subtests of TFF (old, recent and
current faces) performance. We established normative values
according to the contribution of demographic variables. The aged
groups considered in this study had significant differences on their
performance on recent and current faces subtests (episodic memory),
but not in old faces subtest (semantic memory), illustrating the
importance of organizing the items of TFF according to a temporal
gradient in the evaluation of patients with cognitive complaints. In a
clinical group, subtests have proved to be very specific (100%) but not
sensitive (36%) for the diagnosis of cognitive impairment or
dementia.
Conclusion: Future studies in larger clinical groups are needed to
conclude about the contribution of TFF in cognitive assessment.
P364
Clinical application of a short version of California
Verbal Learning Test for the diagnosis of memory
impairment
C. Maruta, V. Freitas, C. Chester, I.P. Martins
University of Lisbon (Lisbon, PT)
Objectives: The 16-item California Verbal Learning Test (CVLT) is a
widely used instrument but it is time consuming and demanding for
elderly and memory impairment patients. We report the results concerning the utility of a nine-item short version of CVLT (CVLT-9) in
the clinical diagnosis of memory impairment.
Method: Patients with memory impairment diagnosed by an
extensive neuropsychological battery which includes immediate and
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delayed recall of the two stories from the Logical Memory and Verbal
Paired-Associates subtests of the Wechsler Memory Scales and the
16-item CVLT were evaluated in Laboratory of Language Research
by CVLT-9. Raw scores were compared to age/education norms.
Results: Forty one patients (70.7% female) undertook the test.
Diagnosis was mild cognitive impairment (50%), temporal lobe epilepsy (13.2%), dementia (5.3%) and other conditions (31.5%). A cutoff score of 1.5 SD below age/education adjusted score for learning
(total recall trial 1-5) and long-delay cued recall were the best discriminators, with a sensitivity of, respectively, 64% (95% CI
0.41–0.82) and 72% (95% CI 0.49–0.88), and a specificity of,
respectively, 93% (95% CI 0.66–0.99) and 80% (95% CI 0.51–0.95).
Conclusion: It is demonstrated the clinical utility of this instrument in neuropsychological assessment of patients with diagnosed or
suspected memory impairment.
P365
Crossed Gerstmann syndrome
B. Miguel, A. Hernández, J. Domı´nguez, M.J. A´lvarez,
C. Valencia, JP. Cabello
General Hospital (Ciudad Real, ES)
Objectives: Gerstmann syndrome (GS) consists on acalculia, agraphia, finger agnosia and left-right disorientation. It has been described
in relation with damage to the left temporoparietal area, specifically
the angular gyrus. In fact, only lesions in this location can origin the
complete syndrome. We describe a case with a lesion in the right
hemisphere presenting the tetrad of symptoms of the syndrome,
associated to nominal aphasia.
Methods: We present an 83 years old, right-handed woman with
arterial hypertension, chronic atrial fibrillation without anticoagulation, and sleep apnea. She suffered sudden mutism, left hemianopsia,
spatial neglect, and left central facial paresis and hemiplegia. Computed tomography was normal and intravenous thrombolysis was
performed. At admission she was alert, disoriented, dysartric, with left
hemiparesis, and left visual and sensory extinction. The examination
revealed nominal aphasia, and some component of agraphia, alexia,
acalculia, left-right disorientation and digital anomia.
Results: Cranial magnetic resonance imaging seven days after the
onset, showed small focal injuries in territory of right middle cerebral
artery affecting caudate, insula, putamen, external capsule and parietal periventricular white matter, compatible with acute ischemia,
with microbleeding in basal nuclei. Fifteen days later, symptoms
persisted with improvement in the hemiparesis.
Conclusion: Crossed aphasia has been scarcely described in the
literature, usually in relation with cortical damage. However, only
four cases of crossed GS has been previously referred. In our patient,
the syndrome arises from very restricted lesions in right subcortical
structures and parietal white matter. This latter has been recently
recognized as the possible location of the intraparietal disconnection
that originates GS. Moreover, our case developed the full clinical
tetrad although the syndrome usually appears incomplete. Interestingly, the patient also associated nominal aphasia and symptoms
characteristics of right hemisphere damage. It has been postulated that
there would be people with reversed functional cerebral dominance,
or they could be left-handed subjects corrected in childhood. It is
possible, as our case suggests, that in some people functions related
with both hemispheres overlap on the same cerebral networks
(ambidextrous). Neuroimaging contributes to gain a better understanding of cerebral organization.
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P366
Genetic predictor factors on dementia development
in mild cognitive impairment patients: longitudinal,
observational and multi-centre study in Madrid, Spain
R. Garcia Cobos, A. Martı´nez-Garcı´a, I. Sastre,
C. Vincent-Lazaro, B. Frades Payo, J. Lopez-Arrieta,
G. Resler-Plat, M.J. Bullido, A. Frank-Garcia on behalf
of the DEMCAM group
Objectives: To identify genetic biomarkers as a risk predictor of
conversion from Mild Cognitive Impairment (MCI) to Alzheimer
Disease (AD) in Spanish patients in Madrid.
Methods: This is a multicenter, longitudinal, case-control study in
people older than 65. After the evaluation on selection criteria, the
sample of 74 subjects was distributed in 18 healthy controls, 31
amnestic MCI (15 single-domain and 16 multi-domain) and 25 with
mild AD. We asked for informed consent to each subject to obtain
genomic DNA from peripheral blood. Polymorphisms of APOE,
EIF2AK2, HMGCR, IGFBP7, MAP1LC3B, MTHFR, PLA2G,
PVRL2 and TAP2 were analyzed with TaqMan-MBG assays. The
statistical analyses were made with SPSS-17 (SPSS, inc).
Results: The APOE4 allele carriers increased, as expected, from
controls (28%) to amnestic multi-domain MCI (44%), single-domain
MCI (53%) and AD (72%), strengthen its diagnostic reliability. As
well, in all studied genes we found differences between groups, being
remarkable the association of HMGCR and MTHFR with MCI (risk
ratio of 2.4 y 1.9 respectively).
Conclusions: Genetic markers are a good approach to build a conversion pattern to dementia in patients with MCI. To increase the reliability
and statistic significance we are committed to increase the number of
subjects in each group and to follow them along the study as programmed.
P367
Clinical heterogeneity of argyrophilic grain disease:
autopsy report of two cases
K. Inoue, H. Fujimura, T. Saito, S. Sakoda, S. Sugae,
T. Naka
Toneyama National Hospital (Osaka, JP); East Osaka Medical Center
Hospital (Osaka, JP)
Objective: Argyrophilic grain disease (AGD) is a degenerative neurological disorder which is pathologically characterized by deposition
of argyrophilic grains (AGs) in certain structures of the central nervous system. Most reported AGD cases showed dementia or mild
cognitive impairment, while expressions of motor or non-cognitive
symptoms were rare except coexistence of other neurodegenerative
disorders. We report two autopsy cases who presented quite unique
clinicopathological features, representing the considerable heterogeneity of AGD.
Method: We describe the clinical and pathological features of two
cases of AGD.
Case 1: A 52-year-old man developed antecollis, upper limb
weakness, dysphagia and gait disturbance. On hospital admission, the
neurological examination disclosed masked face, bulbar palsy, spastic
quadriparesis and bradykinesia. The results of a neuropsychological
examination displayed mild cognitive impairment with disorientation
and dysmnesia (Mini Mental State Examination: 24/30). A brain MRI
showed atrophy of bilateral temporal tip and brainstem. He died at the
age of 55 years from aspiration pneumonia. His clinical diagnosis was
ALS with dementia.
Case 2: A 78-years-old woman developed left hand tremor,
bradykinesia and small step gait. At the age of 88, she had mild
cognitive impairment while she had never shown characteristic psychomotor problems such as abnormal behavior, aphasia or emotional
disturbance. She showed bradykinesia and frozen gait at initiation, but
had been able to walk ‘‘on’’-time without a cane. She died by
decrepitude at the age of 90. Her clinical diagnosis was Parkinson’s
disease.
Results: Pathologically, AGs and degeneration of ambient gyri
were seen in temporal cortices of these patients. In the former case,
pre-tangles and grobose type neurofibrillary tangles (NFTs) spread
out in basal ganglia, brainstem and gray matter of spinal cord. In the
latter case, there was tau pathology in the locus caeruleus, subthalamic nucleus, pallidum and brainstem tegmentum. In cases, minimal
neuronal degeneration and a few tau depositions were seen in the
substantia nigra.
Conclusion: The clinical and pathological spectrum of AGD could
be more comprehensive than conventional concept as a substrate for
the non-Alzheimer type dementias.
P368
An immunohistochemical study of glutamate N-methylD-aspartate receptors in human cerebellum
and hippocampus
E. Koutsouraki, J. Anastasiades, V. Costa, S. Baloyannis
Aristotelian University (Thessaloniki, GR)
The aim of our investigation was to demonstrate the wide distribution
of glutamate N-methyl-D-aspartate (NMDA) receptors, in the human
adult cerebellum as well as in hippocampus. Human hippocampus and
cerebellum were obtained at autopsy from two male individuals, aged
24 and 48 years, with no obvious brain injury and without great
differences in the immunohistochemical examination. The brains
were immunostained using human anti-rabbit polyclonal NR antibodies (NMDA R2A&B) and counterstained with Mayer’s
hematoxylin. These polyclonal antibodies were subsequently used to
map the cellular distribution of the NMDA receptor subunits.
The present immunohistochemical research of human adult cerebellum and hippocampus, using human anti-rabbit NMDA R 2A & B
at the light microscope, demonstrates that the majority of neurons in
the dentate gyrus, the large pyramidal neurons of the hippocampus,
the granular cells of the cerebellum as well as the main cerebellar
neuron, namely Purkinje cell, stained deeply by the monoclonal
antibody, suggesting that the majority of the neuronal network in
cerebellum and hippocampus uses as neurotransmitter the excitatory
aminoacids, widely on NMDA receptors, on the postsynaptic membrane on the system of NMDA R2A & B. It’s well known that many
other systems of neurotransmitters are used by both of those structures
of the CNS such as the GABA, the acetylcholine (Ach), the monoamines and the neuropeptides.
Our findings, demonstrating that the majority of cells are stained
by the monoclonal antibody related to NMDA receptors, emphasize
the importance of the excitatory system of the glutamate in the cerebellum and the hippocampus, underlying the important role that this
system may play in memory function and cognition and at the same
time the participation of the NMDA receptors in many phenomena of
excitation of the hippocampus and the cerebellum which might be
related to epileptic seizures, motor and behavioral disorders.
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P369
Vitamin D deficiency and cognition
H. Mrabet Khiari, D. Mrabet, H. Batti, N. Ben Ali,
S. Sellami, N. Meddeb, A. Mrabet
Charles Nicolle Hospital (Tunis, TN); La Rabta Hospital (Tunis, TN)
Introduction: Vitamin D deficiency, a widespread problem among the
elderly, has recently been linked to dementia, particularly to Alzheimer disease (AD).
Objective: To assess the prevalence of vitamin D deficiency in a
cohort of patients with AD and to compare it to age-matched healthy
controls.
Patients and Methods: Female patients with the diagnosis of AD
attending the neurological department of Charles Nicolle Hospital,
Tunis, Tunisia and age-matched cognitively normal controls were
enrolled in the study. All were free of other intercurrent disease and
none was taking any medication that might interfere with bone
metabolism. Demographic data, detailed laboratory studies were
obtained. BMD at the femoral neck and spine was measured.
Results: 20 female patients and 20 controls were included. The mean
age of the study population was respectively of 74.85 years in patients and
of 74.75 years in controls. Patients with AD had lower BMD and T-score
in comparison to controls with statistical significance (p = 0.002). The
overall prevalence of osteodystrophy in AD patients was 90% (40%
osteoporosis). Vitamin D deficiency was observed in almost all the cases
(95% of patients) and was severe in 75% of cases (\10 ng/ml).
Conclusion: Vitamin D deficiency is high among Tunisian patients
with AD in comparison to controls suggesting a possible role for
vitamin D on cognition. Simple supplementation can be benefit and
should be considered for elderly patients with memory loss.
P370
Hippocampal and posterior cinguli volumetric study
in mild cognitive impairment patients (Demcam pilot
study)
R. Garcia Cobos, J.A Hernandez-Tamames, G. Resler-Plat,
C. Vincent-Lazaro, J. Alvarez-Linera, A. Frank-Garcia
on behalf of the DEMCAM group
Objectives: During the latest years has been developed many
researches to determine which factors could predict dementia development in Mild Cognitive Impairment (MCI) patients. Our aim is to
find structural and functional neuroimaging alterations to the precociously detection of patients with MCI.
Methods: We carried on transversal study with 130 subjects: 31
healthy controls, 22 amnestic MCI single-domain, 24 amnestic MCI
multi-domain, 43 mild Alzheimer Disease (AD) and 10 moderate AD.
All participants followed a neuropsychological evaluation and 3 Tesla
MRI, being emphasizing volumetric and spectroscopy in hippocampus and posterior cinguli. Other covariates on the linear correlation
model were sex, age, and intracranial volumetric measures. Statistical
analysis was made with the software SPM8 and LCDMODEL.
Results: Mean volume of grey matter and hippocampus were
higher in the control group in 3 mm3, resulting in statistical significance of p \ 0.05. Likewise, spectrometry shows statistical
significance in N-acetylaspartate/mio-Inositol ratio (NAA/mI) on the
multi-domain MCI and AD against control group, being more pronounced in posterior cinguli.
Conclusions: The posterior cinguli volumetric and spectrometry
study is a useful method to detect early stages of MCI. The posterior
cinguli is the best preserved structure, both volumetric and morphologically, showing more accurate biochemistry (increased sign on
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MRI) helping to reduce statistical variance, increasing the significance and its predictive value.
P371
Distortions of lateral body representations in neglect
patients
M. Rousseaux, A. Sauer, T. Bernati, M. Leclercq, J. Honore´
Hopital Swynghedauw (Lille, FR); University of Lille (Lille, FR)
Objectives: Hemispheric lesions impair body representations,
including the projection of the anterior midline in the anterior space
(subjective straight ahead). In case of spatial neglect, this line is
deviated to the side of the lesion. But we do not know whether this
also concerns the representation of more lateral body parts and of the
posterior body surface. Our objective was to explore the possible
deviations of the representation of different body points located on the
one hand to the left and right of the midline, and on the other hand on
its anterior and posterior surfaces.
Methods: We included patients who suffered a right hemisphere
stroke. Nine neglect patients (paper and pencil tests) were compared
with six non-neglect patients and 13 healthy controls. They had to
designate on a mannequin placed in front of them the body site which
has been stimulated by a blunt spike. Participants were blind of
stimulation sites, located on horizontal lines placed at shoulder and
navel levels, on the anterior and posterior body surfaces. There were
five equidistant points of stimulation on each line, from left to center
and right positions (L4, L2, C0, R2, R4), and eleven points which
could be designated on the mannequin (L5, L4, L3, L2, L1, C0, R1,
R2, R3, R4, R5), with five trials at each stimulation point.
Results: The lateral deviation of the stimulation point depended
(p \ 0.05) on the group, location, and group 9 location interaction,
due to rightward deviation of the representation of left points (L4, L2)
and of the midpoint (C0), and leftward deviation of the rightmost
point (R4), in neglect patients. The estimate was fair in non-neglect
patients and control subjects. The surface (anterior, posterior) and line
(shoulder, navel) had no main effect and did not interact with the
group. Variability also depended on the group, location and group x
location interaction, and was increased on the neglected side. In
neglect patients, the subjective interval between adjacent points was
significantly shortened at leftmost (L4–L2) position and at a lesser
degree at rightmost (R2–R4) position.
Conclusion: Deformations of body representations extend to various body points and not only to the midline. There is a non-regular
gradient in the shift of representations of body points, with an ipsilesional shift for those located in the neglected space and a
narrowing of corresponding spaces. Deviations to the midline also
occur in the lateral non-neglected space.
Motor neuron diseases
P372
Brain FDG-PET changes in PLS, ALS, and ALS
with associated FTD
D. Renard, L. Collombier, G. Castelnovo, P. Kotzki,
P. Labauge
Hospital Carémeau (Nimes, FR)
Background: There are few reports on brain FDG-PET in motor
neuron disorders. In primary lateral sclerosis (PLS), FDG-PET
S79
demonstrates most typically a primary (and sometimes also supplementary) motor cortex hypometabolism. Amyotrophic lateral
sclerosis (ALS) patients seem to have more diffuse cortical hypometabolism, involving mostly the dorsolateral prefrontal cortex, the
medial and lateral premotor cortices, and the bilateral insular cortex
involvement. When ALS is associated with frontotemporal dementia
(FTD), extensive temporal hypometabolism is often seen in addition
to severe diffuse frontal hypometabolism.
Methods: This study analyses FDG-PET findings in 13 patients
with motor neuron disorders: 4 PLS patients, 5 ALS patients, and 4
patients with ALS-FTD.
Results: In addition to earlier described areas of hypometabolism
in PLS and ALS, we found also reduced FDG-PET metabolism in the
medial frontal cortex, the orbitofrontal cortex, and the anterior temporal lobe in both disorders. The anterolateral area was the best
preserved part of the frontal lobe in both PLS and ALS patients. The
distribution of hypometabolic areas in our PLS and ALS (and to a
lesser degree ALS-FTD) patients were comparable. However, there
was a quantitative gradient of reduced metabolism in the involved
areas from PLS over ALS to ALS-FTD, going from slight to severe
hypometabolism. In ALS-FTD, frontal and temporal hypometabolism
was often much more severe (and parietal hypometabolism was often
also present). Surprisingly, the perirolandic metabolism was relatively
preserved in ALS-FTD.
Conclusion: The severity of FDG-PET hypometabolism, rather
than the distribution of the hypometabolic areas, seems to be
related to the different motor neuron disorders, especially ALS and
PLS. In ALS-FTD, frontal and temporal hypometabolism was much
more severe, and the perirolandic metabolism was relatively
preserved.
P373
A potential tool for the diagnosis of amyotrophic lateral
sclerosis based on diffusion tensor imaging
D. Ben Bashat, M. Artzi, R. Tarrasch, O. Aizenstein,
B. Nefussy, I. Artmann, V.E. Drory
Tel-Aviv Sourasky Medical Center (Tel-Aviv, IL)
Objective: To quantify and better understand white matter (WM)
impairment in patients with amyotrophic lateral sclerosis (ALS) and
to propose a predictive model based on diffusion tensor imaging
(DTI) for diagnosing patients with suspected ALS with upper motor
neuron (UMN) signs.
Methods: Twenty-six ALS patients (24 with prominent UMN
signs and two with an isolated lower-motor neuron (LMN) syndrome)
and 22 healthy volunteers were examined using DTI. Data analysis
included: voxel-based WM tract-based-spatial statistics (TBSS),
volume-of-interest analysis of the TBSS results and stream-line
tractography analysis.
Results: Converging evidence revealed WM impairment along the
corticospinal tracts and in the midbody of the corpus callosum. This
was demonstrated by reduced fractional anisotropy values caused by
increased radial diffusivity, without significant changes in axial diffusivity. There were no significant correlations between diffusivity
indices and patients’ disability or disease duration. A discriminant
analysis model based on the tractography results was designed to
distinguish between patients with UMN signs and controls, yielding
87.5% sensitivity and 85% specificity.
Conclusion: DTI can detect WM impairment in patients with ALS
in several brain regions, and might be a sensitive tool for the diagnosis of ALS in the early stages of the disease with UMN
involvement.
P374
Extra-motor involvement in ALS patients: a cortical
thickness 3T MRI study
A. d’Ambrosio, A. Gallo, F. Trojsi, F. Esposito, D. Corbo,
M. Cirillo, A. Paccone, S. Cirillo, M. R. Monsurrò,
G. Tedeschi
Second University of Naples (Naples, IT); University of Naples
‘‘Federico II’’ (Naples, IT); Magnetic Resonnance Imaging Research
Centre (Naples, IT)
Background: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and simultaneous
degeneration of upper and lower motor neurons. The pathological
process associated to ALS, albeit more pronounced in the motor/
premotor cortices and along the corticospinal tracts, does not spare
extra-motor brain gray and white matter structures.
Neuropsychological and neuroimaging studies have showed
enough sensibility to characterize in vivo the extra-motor involvement in ALS patients. Advanced neuroimaging applications to
patients suffering from ALS and other motor neuron disorders have a
high potential in terms of understanding the pathophysiology and
visualizing the in vivo pathoanatomy of the diseases.
Objective: The aim of the present study was to assess in vivo the
extra-motor involvement in ALS patients using a cortical thickness
(CTh) analysis approach.
Methods: We measured the cortical thickness of the whole cerebral cortex in 16 patients with sporadic ALS and 14 age- and
sex-matched healthy volunteers. High resolution 3D-T1 anatomical
images were acquired on a 3T scanner. The Freesurfer software, a
validated automated method to accurately measure the CTh was used
for the analysis. For each subject the results of the segmentation and
surface reconstruction were double-checked and fixed, if required,
following the user’s manual. After completing the single subject
analysis a surface-based group analysis was run.
Results: We found a reduction of CTh in ALS patients with
respect to control subjects in several cortical areas. More specifically,
a significant thinning of the cerebral cortex was observed at the level
of the prefrontal cortex, supplementary motor area as well as mesial
and lateral aspects of temporal lobes. Contrariwise, just few spots of
significant CTh reduction were detected at the level of the primary
motor cortex.
Conclusions: Our data suggest that cortical thinning in ALS is a
common phenomena involving many extra-motor areas, especially at
the level of frontal and temporal regions. A cortical damage at such
level may subtend the ‘‘frontal’’ pattern of neuropsychological deficits
frequently observed in ALS subjects. Further studies are warranted in
order to confirm and expand these preliminary results.
P375
Detection of frontal cortical thinning in patients
with amyotrophic lateral sclerosis
M.J. Messina, F. Agosta, P. Valsasina, N. Riva, A. Prelle,
M. Comola, G. Comi, M. Filippi
University Hospital San Raffaele (Milan, IT); Hospital
Fatebenefratelli e Oftalmico (Milan, IT)
Objectives: The pathological process associated with amyotrophic
lateral sclerosis (ALS), although more pronounced in the motor cortices and in the corticospinal tracts, does not spare other brain gray
(GM) and white (WM) matter structures, especially those located in
the frontal lobes. However, measurements of whole brain atrophy in
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ALS by MRI achieved non-univocal results. Aim of this study was to
compare whole brain volumes and cortical thickness measurements
between ALS patients and control subjects.
Methods: High-resolution 3D T1-weighted MP-RAGE scans were
acquired from 25 patients with ALS and 12 age- and sex-matched
healthy controls. For each subject, whole brain, total GM, cortical
GM and WM volumes were assessed using the SIENAX software.
Cortical thickness analysis was conducted with FreeSurfer, a set of
automated tools for reconstruction of the brain cortical surface from
MRI data, which allows to detect submillimeter differences between
groups. The cortical surface was then parcellated into 35 gyral-based
regions from each hemisphere and the mean cortical thickness
calculated for each of these regions. Between-group differences in
global and regional measurements of cortical atrophy were analyzed using an univariate analysis of variance, adjusted for subject’s
age.
Results: Global atrophy measurements (including whole brain,
total GM, cortical GM and WM volumes) were not significantly
different between controls and ALS patients. Conversely, a significant
decrease of cortical thickness was detected in ALS patients vs. controls in several bilateral regions of the frontal lobe, mainly located in
the inferior and middle frontal gyri (p ranging from 0.05 to 0.004).
Conclusions: Regional atrophy analysis was able to reveal a subtle
GM tissue loss in regions located in the frontal lobes in ALS patients.
Cortical thickness measurements are very promising to gain additional insights on disease-related pathological changes of ALS,
especially those associated with cognitive deficits known to occur in
this condition.
P376
Pain in ALS: a case-control study
S. Cammarosano, A. Calvo, A. Canosa, S. Gallo,
E. Bersano, A. Ilardi, C. Moglia, D. Papurello, A. Chiò
University of Turin (Turin, IT)
Background: Traditionally, pain has been neglected in the management of ALS, but is more frequently reported by patients, especially
in the more advanced stages of disease; moreover it is likely to have a
marked influence on patients’ quality of life and suffering.
There are no studies devoted to the assessment of frequency and
characteristics pain in ALS, compared to a control population.
Aim: Our aim was to evaluate the frequence and the characteristics
of pain in a consecutive series of ALS patients, comparing to a control
population.
Methods: A total of 160 ALS patients consecutively seen in our
ALS Clinic were interviewed. Pain was evaluated with the Brief Pain
Inventory (BPI) questionnaire. Patients’ physical status was evaluated
with ALSFRS-R. Control population included persons matched by
age (±3 years) and gender, randomly selected from the patients’
general practitioners lists.
Results: Of the 160 ALS patients 91 were men, 69 women. Their
mean age at the time of the interview was 62.4 years, their mean
disease duration was 42.7 months (median, 31 months), and their
mean ALSFRS-R score was 28.7 (range 0–45). Controls were similar
to patients for the main demographic characteristics. Pain was
reported by 90 patients (56.3%) and 53 controls (33.1%) (p = 0.001).
Maximum and mean pain intensity were similar in patients and
controls. Forty-seven patients (68.8%) and 24 controls (45.3%) were
treated for pain at the time of the interview (p = 0.0001). The efficacy of therapy for pain received similar rates in patients (58.3%) and
controls (60.9%) (p = 0.88). The probability of being treated among
patients was not related to the rating of severity pain, but was sig-
123
nificantly higher in patients reporting negative effects of pain on
social relationship and enjoyment of life. Among patients, the presence of pain was not related to age, gender, but significantly increased
with the worsening of disability (ALSFRS-R score) (p = 0.04) and
disease duration (p = 0.03). Patients reported that pain caused an
interference with their social relationships and enjoyment of life and
to a lesser extent with their mood and sleep.
Comments: In our series, pain was more frequent in ALS patients
than in age and gender matched controls, although its intensity was
similar. The presence was related to patients’ disability. More patients
than controls received a treatment for their pain, but the control of
pain was reported to be not totally satisfactory both in patients and in
controls.
P377
Lithium carbonate does not prevent ALS: a case-report
of four patients on long-term therapy for the treatment
of bipolar disorder
A. Ilardi, A. Chiò, A. Calvo, C. Moglia, S. Cammarosano,
S. Giacone, A. Canosa, S. Gallo, E. Bersano, M. Nobili,
R. Mutani
University of Turin (Turin, IT)
Background: Lithium is a compound used as a mood stabilizer, which
is neuroprotective in a variety of disease models, like G93A transgenic mice. Lithium has been recently proposed as a treatment of
ALS, based on the possible effects on the SOD1 genetic mouse and a
small not controlled series of ALS patients.
Aim: To report four patients treated with lithium carbonate for
more than years due to bipolar disorder who successively developed
ALS.
Case report: The first patient is a 70 years old man who developed
muscle weakness and hypotrophy at the right upper limb, spreading rapidly to the lower left limb. Deep tendon reflexes were
hyperactive. A diagnosis of definite ALS was made. He reported a
story of bipolar disorder since six years treated with lithium carbonate
and quetiapine.
The second patient is a 66 years old man who developed muscle
weakness and hypotrophy at the right upper limb, followed by dysarthria, muscle weakness and hypotrophy at the left upper limb. Deep
tendon reflexes were hyperactive; Babinski and Hoffman signs were
present. A diagnosis of definite ALS was made. The patient reported a
story of bipolar disorder since 5 years, treated with lithium carbonate.
The third patient is a 67 years old man who developed muscle
weakness and hypotrophy at the right upper limb, spreading to all
limbs and followed by dysarthia, dysphagia, tongue fasciculations
with hypotrophy. Deep tendon reflexes were hyperactive; Babinski
sign was present bilaterally. A diagnosis of definite ALS was made.
He reported a history of bipolar disorder treated with lithium carbonate for over 10 years.
The fourth patient is a 51 years old woman who developed muscle
weakness at the upper left limb, spreading to involve the right lower
limb and followed by dysarthria. Deep tendon reflexes were hyperactive at lower limbs. A diagnosis of definite ALS was made. The
patient reported a story of bipolar disorder since twenty-seven years,
treated with lithium carbonate for 5 years (then stopped, eight years
before ALS onset, because of hypothyroidism).
Comment: We have reported four patients who have developed
ALS after long-term treatment with lithium carbonate at the standard
dose due to bipolar disorder. Our observation indicate few or no effect
on the onset and course of ALS due to lithium treatment.
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P378
In vitro and in vivo analysis of motoneurons obtained
from human-spinal muscular atrophy-induced
pluripotent stem cells free of vector and transgenic
sequences
G. Riboldi, M. Nizzardo, M. Nardini, C. Simone,
M. Falcone, D. Ronchi, C. Donadoni, S. Salani, F. Magri,
N. Bresolin, G.P. Comi, S. Corti
Hospital Maggiore (Milan, IT)
Objective: Spinal Muscular Atrophy (SMA) is a frequent autosomal
recessive disorder affecting the spinal cord motor neurons; until now
no definitive therapies are available. Stem cell transplantation is a
potential therapeutic strategy for SMA. In the present work we
obtained motoneurons by generation of human SMA-induced pluripotent stem cells (iPSCs) with non-integrating episomal vectors that
can be used as disease model and cell source for transplantation.
Methods: We used fibroblasts of a SMA 1 patient and his unaffected father, that were reprogrammed in iPSCs by nucleofection with
oriP/EBNA1 vectors encoding six reprogramming factors, with nonviral plasmids. Then, we generated motoneurons from iPSCs using
SHH, RA and other morphogens that promote motoneuron commitment. We first tested differentiated cells phenotype in vitro, by gene
expression, protein and morphological analysis. Then motoneurons
were tested in vivo after transplantation in SMA spinal cord analyzing
histochemical and neuropathological characters of engrafted cells.
SMA mice neuromuscular function and survival were also collected.
Results: We performed in vitro and vivo analysis of obtained SMA
and wild-type (WT) iPSC subclones free from exogenous sequences.
These cells could differentiate into all three germ layers and microarray analysis showed similar morphologic and transcriptional
characters with embryonic stem cells. We also obtained motoneurons
from iPSCs expressing motoneuron-specific proteins like HB9, Isl1
and ChAT. SMA motoneurons had significant reductions of cell
number, cell size, and axon length. The in vivo analysis showed
integration of human-derived motoneurons, expressing HB9 and
ChAT and holding motoneuronal phenotype, in the ventral horns of
transplanted mice. Transplanted SMA mice with WT and SMA
motoneurons improved phenotype and had longer lifespan ([50%),
even though quantification data reported smaller number of engrafted
SMA motoneurons, compared with WT cells.
Conclusions: Our results demonstrated the possibility of generating motoneurons free of exogenous elements form patient-specific
iPSCs, opening new possibility in studying SMA pathogenesis and
possible new therapeutic application.
P379
Expression of hepatocyte growth factor in the skin
of the patients with amyotrophic lateral sclerosis.
An immunohistochemical study
S. Ono, Y. Oketa, H. Ishikawa, K. Yasui, M. Nomura,
T. Watanabe, H. Mikami, M. Suzuki
Teikyo University Chiba Medical Center (Ichihara, JP)
Objectives: Studies of amyotrophic lateral sclerosis (ALS) skin have
shown unique pathological and biochemical abnormalities in collagen, elastic fibers, and the ground substance. The lack of bedsore
formation even in the terminal stages in ALS patients is considered
characteristic. Hepatocyte growth factor (HGF) is one of the most
potent survival-promoting factors for motor neurons, comparable to
glial cell line-derived neurotrophic factor in vitro. Neurotrophic
effects have been demonstrated in vivo on embryonic spinal motor
neurons during development and on adult motor neurons after axotomy of the hypoglossal nerve. In addition, overexpression of neuronal
HGF has been shown to result in the attenuation of neuronal cell death
and progression of disease in a familial ALS transgenic mouse model.
Therefore, HGF might be beneficial for motor neuron survival. It is
unknown, however, whether HGF-positive structures are present in
the skin from patients with sporadic ALS (SALS).
Methods: Skin biopsy samples were taken from the left biceps
from 16 SALS patients (59.7 ± 9.2 years) and 16 control subjects
with other neurologic disorders (59.3 ± 9.2 years). Routine formalinfixed paraffin-embedded 6 lm sections were immunostained according to standard techniques. A densitometric analysis was performed
using an image analysis system.
Results: HGF immunoreactivity was positive in the epidermis and
dermal blood vessels and glands in ALS patients. The HGF-immunopositive (HGF+) structureas of the epidermis were the nucleus and
the cytoplasm. These findings became more conspicuous as ALS
progressed. The optical density for HGF immunoreactivity of the
nucleus in the epidermal cells in patients with ALS was significantly
higher (p \ 0.001) than in controls. The optical density of the cytoplasm in the epidermal cells in patients with ALS was also
significantly higher (p \ 0.001) than in controls. The density of HGF
immunoreactivity in ALS patients showed a progressive increase in
relation to duration of illness. This positive correlation was highly
significant (r = 0.63, p \ 0.01 and r = 0.76, p \ 0.001, respectively)
in the nucleus and the cytoplasm in the epidermal cells, but there was
no such relationship in control subjects. Conclusion: These findings
suggest that changes of HGF in ALS skin are related to the disease
process and that metabolic alterations of HGF may take place in the
skin of patients with ALS.
P380
Heterogeneity in familial motor neuron disease
A. Antunes, S. Pinto, V. Almeida, B. Ohana,
M. de Carvalho
Hospital Santa Maria (Lisbon, PT)
Objectives: To report clinical cases of familial motor neuron disease
(MND), highlighting the large phenotypic variability in some families
Methods: Prospective follow-up of 6 patients from 3 families
regularly followed in our centre. Clinical, electrophysiological,
imagiological and genetic studies are shown.
Results: Three families are described. Family one: one man died
with typical Charcot-ALS after 5.5 years of clinical progression at the
age of 70; his brother has primary lateral sclerosis (PLS) as defined by
the Pringle criteria, presenting the first symptoms at the age of 67 and
with 5 years of clinical follow-up. Family two: one woman patient has
presented with left foot drop at the age of 59, with no progression for
5 years of follow-up; her sister had typical bulbar-onset ALS at the age
of 53 years, with rapid progression and dying one year later, she had
an associated ovarian and endometrial cancer, in the context of Lynch
syndrome. Family three: one woman is followed for 17 years in our
unit with the diagnosed of PLS, which started at the age of 49 years;
her cousin has a 2-year history of fail-leg syndrome, which began at
the age of 59. Neuroimaging studies excluded other conditions; electrophysiological investigations ruled-out neuropathies and confirmed
signs of ongoing motor units loss in patients without PLS. All individuals were negative to SOD1, FUS and VAPB mutations. The
woman with PLS was also negative for spastin and alsin mutations.
Conclusion: These cases illustrate the extreme phenotypic variability potentially observed in families with MND-ALS. The
neurologists should be aware of this variability and to carefully
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scrutinize the family history of patients with MND-ALS. This careful
ascertainment is important to increase our understanding of this group
of disorders.
Extrapyramidal disorders
P381
Giant hemispheric Virchow-Robin spaces causing
parkinsonism
F. van der Toorn, H. van Santbrink, G. Tissingh
Atrium Medical Centre Parkstad (Heerlen, NL)
An 59-year-old woman suffered from progressive problems with
walking since 1 year. She also had a resting tremor of her left arm and
leg, which became worse after initiating a selective serotonin reuptake
inhibitor. Her writing had become smaller and according to her husband she moved slower. She had no headache or memory difficulties.
Physical examination revealed a slight resting tremor of her left
hand, bradykinesia and rigidity, mainly on the left side. She had no
pathological reflexes, but her tendon reflexes seemed more pronounced on the left side.
High doses of levodopa, 250 mg t.i.d., did not give any
improvement.
Magnetic Resonance Imaging (MRI) of the brain revealed space
occupying multilobulated cysts in the right frontal lobe extending to
the basal nuclei and dilation of the lateral ventricle, without any
contrast enhancement. Most probably caused by enlarged VirchowRobin spaces (VRS).
Her condition deteriorated gradually and we decided to operate her.
After neuronavigation guided endoscopic fenestration of the right
sided cysts to the frontal horn of the left lateral ventricle our patient
recovered completely.
Unusual causes of secondary (hemi) parkinsonism have been
described in several case reports, such as an arachnoid cyst and VRS.
VRS are perivascular spaces surrounding small arteries and arterioles
which can occur in the midbrain and brainstem. Dilation of the VRS
can be observed in normal persons as a rare phenomenon. Sometimes
it is associated with many disorders. Dilation of the VRS in the lower
mesencephalon near the junction of the substantia nigra and cerebral
peduncle can cause obstructive hydrocephalus with sometimes
headache, seizures or dementia.
To our knowledge, this is the first case report of severe secondary
parkinsonism due to enlarged hemispheric VRS. Our case illustrates
that structural neuroimaging of patients with parkinsonism may be
very important, especially when there are atypical clinical signs such
as asymmetrical reflexes, as in our patient. Furthermore, neurosurgical intervention can be highly effective in case of secondary
parkinsonism due to space-occupying lesions.
P382
Variability of gait parameters in patients
with progressive supranuclear palsy and Parkinsons’s
disease
R. Schwarzkopf, R. Schniepp, M. Wühr, A. Zwergal,
S. Lorenzl, K. Jahn
University Hospital of Munich (Munich, DE)
Objective: Progressive supranuclear palsy (PSP) is a degenerative
disorder that is sometimes difficult to distinguish from Parkinson’s
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disease as in early stage both syndromes may present similarly. Along
the PSP-specific gaze palsy, both conditions show falls and postural
imbalance. Gait variability, especially stride time variability (STV) is
a measure of walking instability and has been reported as an useful
parameter of assessing the fall risk. In this study, we focused on STV
analysis of patients with PSP, PD and healthy controls.
Methods: So far we included 23 PSP patients, 18 with PD and 41
age-matched healthy controls. We assessed the unified parkinson’s
disease rating scale (UPDRS), the Golbe-score, the mini-mental status
examination (MMSE) and the frontal assessment battery (FAB). Gait
parameters were recorded with the GAITRite walkway and spatiotemporal parameters were calculated and analyzed with the application software.
Patients were asked to walk at three different speeds (preferred,
slow, as fast as possible). Additionally we tested different dual task
conditions at preferred speed (motor, serial seven word fluency). No
priorisation of any task was instructed. Each condition was tested
twice. The analysis focused on differences in STV between groups.
Results: A multifactoral ANOVA revealed a significant difference
between groups (p \ 0.01). PSP and PD patients showed a higher
STV than normal controls at preferred and slow speed, but not for
maximal speed. PSP and PD patients differed with respect to preferred speed (p \ 0,01). Dual tasks: ANOVA showed a significant
difference between patients and controls, but no difference between
patient groups, except for head inclination (p \ 0.05). Detailed
analysis of the PSP group revealed the lowest STV for maximum
speed (p \ 0.01). Cognitive dual tasks had a higher impact on STV
(p \ 0.05) than motor dual tasks.
Conclusions: High STV was present in both patient groups, indicating an enhanced risk to fall. PSP and PD patients differed during
head inclination only, which may reflect the deficiency of brainstem
functions in PSP patients. The SVT in PSP patients was lowest at
maximum speed when multisensory integration is of minor importance. Cognitive dual tasks increased the STV in patients and are
expected to increase the fall risk in PSP. This reflects the general
neurodegeneration and shows that SVT is sensitive to cognitive
distraction.
P383
Cerebellar ataxia and epilepsy caused by hereditary
folate malabsorption
T. Stojkovic, M. Svetel, V. Dobricic, I. Novakovic, V. Kostic
Institute of Neurology (Belgrade, RS)
Objective: to report a case of a 35 years old male with a hereditary
folate malabsorption (HFM) presenting with cerebellar ataxia, mental
retardation and epilepsy.
Background: HFM is a rare autosomal recessive disorder caused
by impaired intestinal folate absorption and transport into the central
nervous system (CNS). In infants, findings include poor feeding,
failure to thrive, anemia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, seizures and developmental delays. In older
untreated individuals cerebellar ataxia and cognitive impairment may
occur.
Methods: 35-year-old male was referred to our Clinic due to
cerebellar ataxia and epileptic seizures. Neurological examination
revealed cerebellar ataxia and mental retardation. When 15 months
old, he was treated for severe megaloblastic anemia (received folic
acid, irregularly, until 2 years old), diarrhea, failure to thrive and
frequent respiratory tract infections. Patients younger brother (31),
when 6 months old, was also treated for megaloblastic anemia
(received folic acid until 3 years old), prolonged diarrhea, failure to
thrive, sepsis, and epilepsy. He had seizures until he was 24. Now,
S83
except for mental retardation, neurological finding was normal. Both
brothers were born at term after an uncomplicated pregnancy and
were exclusively breast-fed. Parents denied consaquinity. Considering
clinical presentation and family history HFM was suspected. We
performed necessary blood work, neuroradiological and neuropsychological assessment in our patient. Our genetic analysis was
focused on testing the proton-coupled folate transporter (PCFT) gene
in order to confirm the HFM diagnosis.
Results: In our genetic laboratory we identified the mutation in
PCFT gene. Both brothers were homozygotes (D156H, mutation in
the second exon), parents were heterozygote carriers. Blood work
showed low serum folate levels and megaloblastic anemia. MR
showed demyelization changes and neuropsychological assessment
confirmed mental retardation (IQ 85). The appropriate supplemental
treatment was initiated in both brothers.
Conclusions: HFM is thought to be serious, and if untreated, lethal
disease. Still, here we report a case of a 35-year-old male patient, with
untreated disease, presenting with cerebellar ataxia, mental retardation and epilepsy.
P384
Sporadic adult onset primary torsion dystonia
(AOPTD) is a genetic disorder: the Temporal
Discrimination Threshold in patients with sporadic
AOPTD and their first-degree relatives
O. Kimmich, D. Bradley, R. Whelan, R. Walsh, P. Brady,
N. Mulrooney, R. Reilly, S. Hutchinson, F. Mulloy,
M. Hutchinson
St.Vincent’s University Hospital (Dublin, IE); Trinity College Dublin
(Dublin, IE); Beaumont Hospital Dublin (Dublin, IE)
Introduction: Adult-onset primary torsion dystonia (AOPTD) is an
autosomal dominant condition with markedly reduced penetrance of
12–15%. Reduced penetrance is considered to be the reason for the
high prevalence of apparently sporadic cases. The temporal discrimination threshold (TDT) is the shortest time interval at which two
stimuli are detected to be asynchronous and has been shown to be
abnormal in AOPTD.
Objective: The aim was to examine TDTs in sporadic AOPTD
cases and their first degree relatives to assess the frequency of
abnormal results and potential utility as an endophenotype. We
hypothesized that the frequency of abnormal TDTs in first relatives
would be compatible with an autosomal dominant endophenotype.
Methods: TDTs were examined in 61 control subjects (39 under
50 years, 22 over 50 years), 24 sporadic AOPTD patients (22 cervical
dystonia, 1 Meige’s Syndrome, 1 spasmodic dysphonia) and 52
unaffected first degree relatives (29 siblings, 22 offspring and 1
parent) using visual (2 LED lights) and tactile (non-painful electrical)
stimuli. Z-scores were calculated for all subjects; a Z-score greater
than 2.5 was considered abnormal.
Results: The mean TDT in controls under 50 was 24.54 ms (SD
8.97; 95% CI 21.53–27.44) and over 50 years was 31.11 ms (SD
8.69; 95% CI 27.36–35.96). Abnormal TDTs were detected in 1 of 61
(1%) control subjects, 19 of 24 (79%) AOPTD patients and 25 of 52
(48%) unaffected relatives. Rates were similar in siblings (15 of 29;
52%) and offspring (9 of 22; 41%).
Conclusion: The frequency of abnormal TDTs in first degree
relatives of patients with sporadic AOPTD is compatible with an
autosomal dominant disorder and supports the hypothesis that all
apparently AOPTD cases are genetic in origin. The TDT is a useful
technique in planning AOPTD genetic studies using sporadic patients
and relatives.
Supported by Dystonia Ireland and the Health Research Board
Ireland.
P385
Pallidal deep brain stimulation for dystonia:
progressive neuroplasticity or permanent correction
of an abnormal motor circuit?
M.J. Rosas, M.F. Gago, P. Linhares, M. Ayres-Basto,
E. Brandão, J. Volkmann, R. Vaz
Hospital s. Joao (Porto, PT); Hospita S. Sebastiao (Santa Maria
Da Feira, PT)
Objectives: Pallidal deep brain stimulation (DBS) is an established
treatment option for medically refractive dystonia but predictors of
outcome are still lacking. The aims of this study is to see the followup of patients undergoing DBS for different types of dystonia.
Methods: Since 2005 twelve patients with medically refractive
dystonia have been submitted to pallidal DBS in our center: idiopathic
dystonia [3 males/1 female, mean age of 23.5 years-old (10–33);
secondary dystonia [4 males, mean age of 25 years-old (14–34)];
tardive cervical dystonia (1 male, 33 years-old); focal cervical dystonia [2 females, mean age of 52.5 years-old (46–59)]; and
pantothenate kinase-associated neurodegeneration (PKAN) (1 male,
18 years-old).
Results: At 12 months of follow-up we observed a clinical
improvement in Burke Fahn Marsden Dystonia Rating Scale
(BFMDRS) motor/disability score of 59%/55% in idiopathic dystonia
and in secondary dystonia of 32%/20%. At 6 months of follow-up
tardive dystonia had a clinical improvement of 77%/71% and PKAN
an improvement of 55%/58%. In focal dystonia we observed in
Toronto Western Spasmodic Torticollis Rating Scale severity/disability scale a clinical benefit of 67.5%/74%.
Conclusion: Although our short follow-up, we observed a slow
motor improvement in generalized idiopathic and secondary dystonia.
In contrast, focal cervical dystonia and cervical tardive dystonia had a
quick and better sustained improvement. These results reflect different pathophysiology in dystonia with a possible progressive
neuroplasticity mechanism in generalized dystonia and probably a
permanent correction of an abnormal motor circuit in cervical
dystonia.
P386
Clinical evaluation of DYT6 dystonia in Serbia
N. Kresojevic, M. Svetel, V. Dobricic, I. Novakovic,
T. Stojkovic, V. Kostic
University of Belgrade (Belgrade, RS)
Objectives: To present phenotype of our DYT6 patients.
Methods: 230 Serbian patients with genetically undetermined
primary dystonia were screened for mutations in THAP1 gene.
Mutations were found in three patients. Here we describe phenotype
of these genetically confirmed carriers of mutation in THAP1 gene.
Results: In all three patients craniocervical regions were initially
affected, with spasmodic dysphonia in two of them. No one had
positive family history for dystonia. Two patients (24 years old male
and 36 years old female) developed torticollis at the age of 12 as a
first symptom. During disease course they developed mild generalised
dystonia with descendent spreading pattern. One patient (40 years old
male) reported spasmotic dysphonia as initial symptom at the age of
36. Torticollis was also noted at the examination.
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Conclusion: Although it is well known that mutations in DYT6
locus should be considered in patients with craniocervical dystonia,
especially spasmodic dysphonia, our work implicates that in patients
with early onset generalized dystonia DYT6 mutations should also be
considered.
P387
Atypical symptomatology of myoclonus dystonia
(DYT-11) with positive response to bilateral pallidal
deep brain stimulation
E. Papuc, K. Obszanska, T. Trojanowski, Z. Stelmasiak,
K. Rejdak
Medical University of Lublin (Lublin, PL)
Objective: Myoclonus–dystonia (M–D) is a childhood onset movement disorder characterized by a combination of brief myoclonic
jerks and dystonia. In patients with onset in childhood, the initial
presentation is gait disturbance, but in later stages of the disease, the
clinical manifestation dominates in neck and upper limbs. Our
32 year old patient is unusual as he had a persistent predominance of
lower limbs dystonia in adulthood. In patients who have correct
diagnosis, disabling symptoms, and insufficient improvement after
medical preventive treatment, the surgical treatment using deep brain
stimulation (DBS) may be proposed. For patients with generalized
primary dystonia excellent results are obtained after pallidal stimulation, but results of DBS in secondary dystonia are very
heterogenous, and presently it is difficult to predict which individual
will improve after surgical treatment. Bilateral pallidal deep brain
stimulation was performed in order to improve disabling symptoms of
myoclonus dystonia with atypical clinical manifestation in 32 year
male patient.
Methods: The diagnosis of M-D was confirmed by the presence of
epsilon sarcoglycan gene mutation in the patient. The procedure for
DBS was a one-stage bilateral stereotactic approach using the Leksel
G stereotactic frame, 1 mm axial MRI scans and 1.25 mm CT scans.
An initial target (sensorimotor GPi) point was chosen 21 mm lateral,
2 mm anterior and 4 mm posterior to the midpoint of the AC-PC line.
Five micro/macro-electrodes were used in an array with a central,
lateral, medial, anterior, and posterior position. Final target location
was guided by extracellular microelectrode recording and by monitoring motor, sensory and visual response to electrode stimulation.
Results: Continuous chronic pallidal stimulation positively influenced both gait and speech of the patient. His speech, which was
profoundly abnormal before DBS, with both dystonic and myoclonic
components, became easier to understand. Intermittent spasms of
lower limbs caused by myoclonic jerks almost disappeared after the
surgery, which considerably improved gait and balance of the patient.
Conclusions: Outcomes of deep globus pallidus stimulation for the
whole group of secondary dystonias are generally poor contrary to
primary dystonias. Nevertheless, for some secondary dystonias, like
myoclonus dystonia, the outcomes seem to be very promising, which
was confirmed in the presented case.
P388
Neuroacanthocytosis Syndroms in China
J. Liu, A. Danek, B. Bader
University Munich (Munich, DE)
Objectives: Neuroacanthocytosis (NA) is an umbrella term for a
group of rare genetic movement disorders. The most common ones
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are autosomal recessive chorea-acanthocytosis (ChAc), X-chromosomal McLeod syndrome (MLS) and Neurodegeneration with Brain
Iron Accumulation (NBIA). Clinical symptoms comprise seizures,
chorea, dystonia, orofacial tics and chronic elevation of CK/CPK
values in serum. From China with its population of more than 1.3
billion people, hardly any cases are known to Westerners. According
to estimates based on the situation in Europe and North America there
should be more than 100 NA patients in China.
Methods: We did a literature search on PubMed and several
Chinese medical databases (CNKI, WanFang and Weipu) to identify
Chinese NA cases using search terms ‘‘neuroacanthocytosis’’, ‘‘chorea-acanthocytosis’’, ‘‘McLeod syndrome’’ and ‘‘neurodegeneration
with brain iron accumulation’’ in both, English and Chinese language.
The geographical distribution, gender, age of onset and age of diagnosis as well as clinical features of all patients were summarized and
re-evaluated.
Results: In total, there were 28 case reports reporting 37 NA case
reports distributed in 15 provinces of China. The prominent symptoms include movement disorder (97.4%), dystonia (81.6%), orofacial
dyskinesias (76.3%), dysarthria (68.4%), dysphagia (42.1%), epilepsy
(21.1%), and psychiatric symptoms (18.4%). Diagnosis of NA was
made mainly according to the clinical manifestation, percentage of
acanthocytes in peripheral blood, as well as neuroimaging results and
EEG. No case was confirmed by Western blot or VPS13A sequencing, which is the golden standard for diagnosis. Because of limitations
in diagnostic methodology (i.e. Kx antigen testing on red blood cells
for MLS and chorein Western blot or VPS13A sequencing for ChAc)
is presently not available in China, the diagnosis of NA can not be
further classified into NA diseases ChAc, MLS or NBIA. After reevaluation of the cases by the Munich study team based on the
information given in the case reports, it is likely that 21 patients suffer
of ChAc, 2 of MLS and 2 of NBIA while 12 remain cryptic and would
need further evaluation.
Conclusion: There were fewer NA cases reported in China as
expected considering its estimated prevalence. This might be due to
limitations in the physicians’ awareness and diagnostic methodology
for NA. Thus, advanced diagnostic methods for screening and classification of NA syndromes are required in China.
P389
Screening for glucocerebrosidase mutations in patients
with parkinsonism, eye movement abnormalities
and cognitive decline
F. Moreira, M. Rosário Almeida, J. Lemos, C. Januário
Coimbra University Hospital (Coimbra, PT); University of Coimbra
(Coimbra, PT)
Introduction: Recent findings led to the hypothesis that heterozygous
mutations in glucocerebrosidase (GBA) gene might constitute a
genetic risk factor for the development of parkinsonism as well as for
Parkinson Disease (DP) susceptibility. In a previous study performed
in a cohort of Portuguese DP (n = 230) patients it was found a significantly higher frequency (6,1%) of known pathogenic GBA gene
mutations when compared with a control group (0.7%).
Objective: To report the frequency of GBA gene mutations performed in parkinsonian patients with some particular features like
early onset, cognitive decline and eye movement abnormalities.
Methods: We consecutively selected 10 patients from the Movement Disorders Department with a cluster of particular signs such as
parkinsonism of early onset, cognitive decline evaluated on Mini
Mental Status (MMSE) and eye movement abnormalities. Subsequent
GBA genotyping studies (screening total exon 9 and 10) were
S85
performed in all patients for the two most common pathogenic
mutations—N370S and L444P.
Results: Only one patient had a GBA gene mutation. Two different
known pathogenic mutations were found both in exon 10 - Leu444Pro
and Ala456Pro.
Conclusion: In this consecutive selected Portuguese sample in
despite of combining three different characteristics commonly
encountered in GBA mutation carriers, we only found one patient
with a GBA mutation that surprisingly could represent a Gaucher0 s
disease type 1. The nature of the association between GBA gene
mutations and the phenotype associated remains to be elucidated
particularly in PD patients.
P390
Earliest disfunction in Huntington’s disease
F. Moreira, F. Júlio, C. Nunes, C. Januário
Coimbra University Hospital (Coimbra, PT); Institute of Biomedical
Research in Light and Image (Coimbra, PT)
Introduction: Huntington disease (HD) is an autosomal dominant
neurodegenerative disorder characterized by progressively chorea,
cognitive and psychiatric disturbances. Different studies suggest that
prevalent psychiatric disturbances may appear before the onset of
motor impairment.
Objective: To evaluate behavioral/psychiatric profiles in subjects
at risk for HD. To compare behavioral profiles between two study
groups: nonmutation carriers and asymptomatic mutation carriers.
Methods: A total of 54 participants knowing they were at risk for
HD, because they have a first degree relative with manifested and
genetically confirmed HD and who decided to voluntarily undergo
genetic testing, were included in our study. All participants,
unknowing their genetic status, were assessed by the Unifed Huntington’s Disease Rating Scale (motor, cognitive and behavioral
scores), Hamilton and Beck depression inventory scale and Mini
Mental Status Examination. All subjects in the current study provided
informed consent prior to genetic analysis and to data collection.
Results: Participants were separated into two groups: nonmutation
carriers (n = 33) and asymptomatic mutation carriers (n = 21) and
behavioral profiles were compared using a composite score (frequency 9 severity) for each symptom category. The asymptomatic
mutation carriers group (mean CAG repeats of 43) have higher
behavior scores. We concluded that the probability of having a
positive predictive test is higher in patients with apathy (odds
ratio = 4.1), irritable behavior (odds ratio = 10.2), depression (odds
ratio = 7.5) and with low self-esteem (odds ratio = 4.1).
Conclusion: Our results show that neuropsychiatric disturbances
are frequently seen in asymptomatic HD patients. These treatable
symptoms constitute the most distressing aspect of HD interfering
with quality of life and early detection can prevent hospitalization.
P391
Disturbance in real space navigation in moderate
but not in mild Huntington’s disease
V. Majerova, T. Kalincik, J. Laczo, M. Vyhnàlek, J. Hort,
M. Bojar, E. Ruzicka, J. Roth
Charles University (Prague, CZ)
Background: Visuospatial skills including spatial navigation are
known to be impaired in Huntington’s disease. Spatial navigation
comprises two navigational frameworks, allocentric and egocentric.
Several studies have associated the allocentric navigation with the
hippocampus and the egocentric navigation with the striatum. The
striatum is predominantly impaired from the early stages of Huntington’s disease.
Objective: To find whether spatial navigation impairment is
present in the early stages of Huntington’s disease and to test the
hypothesis that the egocentric navigation is predominantly affected
compared to the allocentric navigation.
Methods: Twenty patients with Huntington’s disease were stratified based on their Total Functional Capacity score into the ‘‘mild’’
and ‘‘moderate’’ subgroups. We evaluated their cognitive functions,
with emphasis on the executive functions, and their egocentric and
allocentric navigation abilities using the Blue Velvet Arena, a human
analogue of Morris Water Maze. The outcomes were compared to
twenty age and gender-matched healthy controls.
Results: While in the patients with mild functional deficit no
changes in the spatial navigation skills were observed, in the patients
with moderate functional deficit both egocentric and allocentric
navigation frameworks were significantly impaired. These changes
occurred in both egocentric and allocentric frameworks simultaneously. The impairment of egocentric navigation paralleled, whereas
the impairment of allocentric navigation exceeded the executive
dysfunction.
Conclusion: Spatial navigation deficit is not an early marker of the
cognitive dysfunction in Huntington’s disease. We speculate that the
striatal circuitry that is known to degenerate early in the course of
Huntington’s disease is not directly associated with the spatial
navigation.
Supported by the Czech Ministry of Education, research program
MSM 0021620849, grants 1M0517, LC554 and research project
AV0Z50110509, and the Grant Agency of the Czech Republic, grants
309/09/1053 and 309/09/0286.
P392
Hemichorea after frontal cortical stroke
G. Matias, P. Bugalho, A. Boquinhas, J. Vale
Hospital of Egas Moniz (Lisbon, PT)
Background: Hyperkinetic movement disorders after stroke are
uncommon. Some studies found hemichorea to be the most frequent
post-stroke involuntary movement, with a prevalence ranging
between 0.4 and 1.3%.
Although contralateral caudate and subthalamic nucleus have been
considered the classical areas related to chorea, lesion of other
cerebral structures can lead to this presentation. The incidence, clinical outcome and lesion precise location responsible for post-stroke
hemichorea still remains unclear.
Methods: We report a patient with hemichorea after frontal cortical stroke and review the literature.
Results: A 89-year-old white female, with hypertension and
dyslipidemia was admitted with confused speech, right-sided hemiparesis, dysarthria and expression aphasia. Computed tomography
(CT) scan showed an acute left-sided cortico-subcortical frontal
ischemic lesion, later confirmed by magnetic resonance (MR). By the
3rd day, right-sided hemichorea emerged, with spontaneous resolution 10 days later, subsisting all the other neurological deficits.
After reviewing the literature, we found 6 patients with post-cortical stroke hemichorea. In all of them, but one, there was complete
disappearance of hemichorea a few days later after its start.
Conclusion: Although post-stroke hemichorea is usually associated with basal ganglia lesions, hemichorea after cortical lesion were
reported, whose patophysiology can’t easily be explained by the
frontostriatal circuitry. We admit that, in our patient, chorea might be
due to dysfunction of cortical areas directly responsible for the
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programming of motor acts (motor and pre-motor areas). The spontaneous remission of hemichorea in most of post-cortical stroke
patients makes its functional outcome better than in those with lesion
of the basal ganglia.
P393
HIV infection and Parkinson’s disease: is there a causal
relationship?
C. Cruto, J. Freitas, G. Carvalheiras, A. Mendes,
A. Bastos Lima
Hospital Santo António (Porto, PT)
Introduction: Parkinsonism was the most frequent movement disorder
in HIV patients before highly active antiretroviral therapy (HAART).
Nowadays it is less frequent, and in HIV patients with parkinsonism
suggestive of Parkinson’s disease (PD) there are discussion whether
HIV or the therapy may contribute to the symptoms appearance.
Case report: A 52-year-old man, diagnosed with HIV thirteen
years ago, on HAART since 2000, and presently at B1 disease stage
([500 CD4/mm3 and without AIDS related diseases). Two and an
half years ago he started with right hand rest tremor and bradykinesia
in the right limbs. Subsequently, he developed gait slowness, hypophonia and global bradykinesia, which conditioned partial daily
activities dependence. There were no symptoms of orthostatic hypotension/dysautonomia. Other than antiretroviral drugs he was not
exposed to any medication and there is not history of drug consumption. There was no relevant personal or familial history.
Clinically, he presented a mixed asymmetric parkinsonism with right
limbs predominance and scored 51 in motor UPDRS; he had normal
superior functions, normal eye movements and there were not any
pyramidal, cerebellar and sensitive abnormalities. Brain MRI was
normal. He started levodopa 6 months ago, up titrated to 600 mg per
day, and dopamine agonist ropinirole (6 mg per day). There was a
significant motor improvement and he regained autonomy to daily life
activities; presently he scores 33 in motor UPDRS, with no motor
fluctuations.
Discussion: The clinical features, the response to dopaminergic
treatment and a normal brain MRI suggests PD, but probably with
rapid evolution.
We discuss other possibilities, such as a PD worsened by HIV
infection, an unrelated association of two diseases or a parkinsonism
secondary to the HIV infection.
We believe it will be useful to characterize the evolution of parkinsonian features in HIV patients on HAART, and compare to the
patients on previous therapy.
P394
Liver meets brain: case report and review of acquired
hepatocerebral degeneration
S. França, S. Rodrigues, M. Metello, G. Macedo,
J. Massano
Hospital São João (Porto, PT)
Objectives: Acquired hepatocerebral degeneration (AHD) is a chronic
brain disorder associated with liver dysfunction and prolonged portalsystemic shunting. Symptoms usually begin in adulthood with parkinsonism, ataxia and other movement disorders. The pathogenesis is
uncertain but toxic brain insults, such as manganese, may be involved.
This work reports on a patient with AHD and reviews the literature
concerning this topic.
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Methods: A 50-year-old man with AHD is described. The literature on AHD was reviewed and synthesized.
Results: The patient had been diagnosed with liver cirrhosis due to
alcohol abuse and hepatitis C virus infection 10 years before neurological observation (now Child-Pugh score 7, class B). There were no
other relevant personal or family history data. Lactulose was his only
medication; there was no exposure to neuroleptics or known environmental toxics. He presented with a one year history of mental
slowness, disinhibition and cranial involuntary movements. Neurological examination: awake, normal attention, oriented, bradyphrenia,
disinhibition; hypometric saccades, dysarthria, orofacial dyskinesias,
slight bilateral limb akinesia and rigidity, asterixis and mild gait
ataxia; no pyramidal or sensory disturbances. Laboratory findings
were consistent with chronic impairment of liver function and portal
hypertension. Serum and 24 h urinary copper were normal, as well as
serum ceruloplasmin, ferritin, transferrin and iron. Transjugular liver
biopsy confirmed cirrhosis without excess copper content. Ammoniemia was increased (217 mmol/L). EEG showed global slowing, but
no triphasic waves. Brain MRI disclosed bilateral high T1 signal in the
pallidum, cerebellar white matter, cerebral crura and posterior arm of
the internal capsules, as well as high T2 signal in the cerebral cura,
pallidum, and cerebellar white matter. Kayser-Fleischer rings were not
seen on slit-lamp examination. The diagnosis of AHD was established.
Clonazepam brought slight benefit for dyskinesias. He awaits liver
transplantation. Clinical features, neuroimaging findings and management issues in AHD have been delineated after literature review.
Conclusion: AHD is probably under recognized, despite the fact
that the population at risk is common worldwide. The clinical manifestations are diverse, and may cause diagnostic confusion.
Therapeutic approaches are often unsatisfactory, but liver transplantation may result in neurological improvement.
P395
Pregabalin may worsen Parkinson’s disease.
First worldwide description
M. Golberg, P. Vadala, C. Jomñuk, M. Figueredo,
D. Cristalli
La Plata Neurological Centre (La Plata, AR)
Objectives: Pregabalin (PGB) is analogous with c-amino butiric acid
which is a calcium-dependent channels blocker. It is used in pain
neuropathy and some forms of epilepsy. Our objective is to show that
PGB can worse signs and symptoms of Parkinson disease (PD).
Methods: a 63-year-old woman with a year evolution PD; consulting because of rigidity and slowness. Neurological exam revealed
bilateral symmetrical bradykinesia without tremor. Rated 2 Hoenh
and Yahr Scale, Unified Parkinson’s Disease Rating Scale (UPDRS)
motor score was 44 and 90% at Sschawab and England Activities of
Daily Living Scale (S-E ADL). Taking Pramipexole 2.25 mg/day
with excellent results, UPDRS 0 points and 100% S-E ADL values
were obtained. A year later PGB 150 mg was added because of
suffering from fibromyalgia. Three months later there was visible
Parkinson’s symptoms worsening. In addition, the UPDRS motor
score was 52 points and 80% S-E ADL.
Results: PGB was withdrawn. Three months later the patient had
recovered almost entirely. Her UPDRS dropped to 4 and S-E ADL
rate was 100%.
Conclusion: there are hundreds of reports published where PGB is
prescribed to treat tremor, epilepsy, pain, even PD pain. To the best of
our knowledge, no prior reports have been published implicating PGB
in the worsening of PD. Therefore, we recommend strict and periodical PD patients control in which it is extremely necessary to
administrate PGB.
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P396
Significance of asymmetrical onset of symptoms
in Parkinson’s disease
D.K. Pokharel
Annapurna Neurological Institute and Allied Sciences (Kathmandu, NP)
Background: Hemispheric asymmetry and asymmetry in neuroplasticity of human brain is one of the most challenging mysteries in
neurology. This problem leads to asymmetrical clinical onset of PD
and which in turn leads to the particular model of disease setting in
PD.
Purpose of the study: To explore the significance on the disease
pattern of PD based on the left or right side predominance of
symptoms at onset of the disease.
Material and methods: 95 patients with idiopathic PD were followed
for 1 year (age of 55–75 years). Disease course - 3.1 ± 2.5 years,
dopaminergic therapy -2.8 ± 2.4 years. Analysis of anamnesis, neurologic exam, UPDRS tool, modified Hoehn Yahr Staging of PD, Schwab
and England Activities of Daily Living was performed to each patient.
Results: Out of 95 patients, Right Side Predominance (RSP) was
found in 63 (66.3%) and Left Side Predominance (LSP) in 32
(33.7%). Age of onset in RSP patients was variable while in LSP
patients it was below 65.In RSP group, tremor form of PD was found
in 21 (33.3%), tremor-rigid in 38 (60%) and rigid-tremor in 4 (6%).In
contrast, in LSP group, akinetic-rigid form was revealed in 12
(37.5%), rigid-tremor in 15 (46.8%) and tremor-rigid in 5 (15.6%).
Analysis of disease progression in the similar longitudinal course in
RSP and LSP patients with the help of UPDRS—in RSP \50 points
in 34 (54%) patients, [50 points -29(46%); in LSP \50—13
(40.6%) patients and [50–19 (59.3%). According to modified Hoehn
Yahr Staging, RSP group had 1–3 stages and LSP 2–4 stages, the time
period of disease course was similar in both groups. Estimation of
activities by Schwab and England Activities of Daily Living in RSP
patients was estimated as 60–90% and LSP as 50–80% in the similar
period of disease course.
Conclusion: In Parkinson’s disease, Right Side Predominance
(RSP) of symptoms at onset of the disease appears to be more frequent than Left Side Predominance (LSP) at onset. Symptoms as RSP
at onset are commonly found comparatively in older patients; tremor
is the very much presenting feature in them; the disease is less progressive and less severe. On the other hand, LSP of symptoms at onset
of the disease is found in early age group of patients suffering from
idiopathic PD; rigidity is the very much presenting feature in them;
the disease is progressive and severely disabilitating.
P397
Serum markers of neurodegeneration in Parkinson
disease
M. Ruggieri, C. Pica, E. Ceci, L. Polimeno, R. Pellicciari,
M. Pennelli, C. Spinelli, P. Livrea, G. Defazio
University of Bari (Bari, IT)
Objectives: Parkinson’s disease (PD) is a chronic, progressive disease
characterized by neurodegeneration in several brain areas. Biological
markers of neurodegeneration (NDMs) in the serum of PD patients
are poorly known. The aim of this study was to to compare the serum
levels of clusterin, neurofilament light chain (NFL), osteopontin
(OPN) and N-acetyl-aspartate (NAA) in patients suffering from PD
and in a sex and age-matched control subjects (HCS). We also correlated serum levels of these biomarkers to relevant PD clinical
features, including age of PD onset, disease duration, Hoehn-Yahr
staging and MMSE.
Methods: NDMs in the serum were assessed in 71 patients (mean
age 67.3 ± 9.5; 25 M) suffering from PD and in a control group of 78
subjects (mean age 64.7 ± 7; 37 M). Multivariable linear regression
analysis was used to assess the relationship of serum biomarkers with
PD clinical features. Enzyme linked Immunosorbent Assay (ELISA)
was used to quantify clusterin, OPN and NFL; NAA quantification
was obtained by a Liquid Chromatography/Mass Spectrometry (LC/
MS) method with stable isotope dilution.
Results: As compared to control subjects, we found significantly
higher serum levels clusterin (238.2 ± 143.4 vs. 190.8 ± 131.2;
p = 0.06), NAA (0.63 ± 0.09 mM/L vs. 0.16 ± 0.05 mM/L; p \
0.0001), OPN (70 ± 18 ng/mL vs. 59.5 ± 10.1 ng/mL; p = 0.0007)
and NFL (238.7 ± 901.2 ng/ml vs. 23.45 ± 59.5 ng/mL; p \
0.0001) in PD patients. NAA, OPN and NFL serum levels did not
correlate with any of the investigated PD clinical features, whereas
cluster in serum levels correlated significantly with MMSE (coeff.
-25.4, p = 0.007) but not with age of PD onset, disease duration, and
Hoehn-Yahr staging.
Conclusion: Our findings raise the possibility that, among the
investigated serum biomarkers, cluster in may be related to cognitive
impairment in PD.
P398
Altered functional organisation of the motor system
related to ankle movements in Parkinson’s disease –
insights from functional MRI
P. Katschnig, P. Schwingenschuh, M. Jehna, M. Sˇvehlı´k,
K. Petrovic, S. Ropele, E. Zwick, E. Ott, F. Fazekas,
R. Schmidt, C. Enzinger
Medical University of Graz (Graz, AT)
Objective: To search for differences in a functional network relevant
for gait in Parkinson’s disease patients compared to controls and to
determine whether inter-individual differences in the fMRI response
are correlated with the functional degree of gait impairment in the
patient group.
Gait dysfunction represents one of the cardinal and most incapacitating features of Parkinson’s disease (PD). Investigating the
cerebral control mechanisms for human gait and defining the associated functional neuroanatomy is important for understanding gait
disorders. In this context, ankle movement functional MRI (fMRI)
paradigms have been used to non-invasively investigate supraspinal
control mechanisms relevant for gait in healthy subjects, and patients
with Multiple sclerosis and stroke.
Methods: Using such a paradigm in 20 PD patients off medication
(mean age 66.8 ± 7.2 years) and 20 healthy controls (HC; mean age
62.3 ± 6.9 years), we here wished to probe for possible activation
differences between PD and HC and define functional correlates of
gait dysfunction in PD.
Results: Active ankle movements versus rest was associated with a
robust activation pattern in expected somatotopy involving key motor areas
both in PD and HC. However, contrasting activation patterns in patients
versus controls revealed excess activation in the patients in frontal regions
comprising pre-supplementary motor areas (pre-SMA). The extent of preSMA activation did not correlate with behavioural parameters related to gait
or motor function, and no differences were seen with the passive paradigms.
Conclusion: As pre-SMA activation, noted here with simple
repetitive ankle movements in PD patients, is usually associated with
more complex movements, this finding might be indicative of higher
demand and increased effort in the patients. The missing correlation
with behavioural variables and lack of differences with the passive
paradigm suggests that this excess activation is not exclusively
compensatory and also not hard-wired.
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P399
Parkinson’s disease in Dutch nursing homes
N.J. Weerkamp, G. Tissingh, P. Poels, S. Zuidema,
R. Koopmans, B. van Lange, B. Bloem
AtriumMedical Center (Heerlen, NL); Radboud University
(Nijmegen, NL); Brabant Zorggroep (Oss, NL)
Objective: There are reports from older date which suggests that care
and treatment of Parkinson’s disease (PD) in nursing homes is less
than optimal. Guidelines are mostly lacking.
The main objective of study is to describe nowadays practice
concerning many aspects of care and drug-treatment in PD. It will not
only offer insight in the motor and non-motor functions, but also the
quality of life. These data are of great importance when defining
guidelines for PD in the late stages of disease. In this presentation the
focus will be on diagnosis and motor function.
Methods: Approximately 100 Dutch nursing homes participated
successfully in this project. Patients with known or suspected PD or
atypical parkinsonism were included. Subjects using dopaminergic
medication, selected through a list provided by the local pharmacists
were also included.
When PD was confirmed by expert opinion and the MMSE score
was 18 or higher, patients were included in the second part of the
study. An extensive review of the medical file was performed and
clinimetric data were recorded. SPES-Scopa (Short Parkinson’s
Evaluation Scale- Scales for Outcomes of Parkinson’s Disease) was
used to examine motor function.
Results: 258 Patients were selected. In 49 subjects (19%) diagnosis was either changed or rejected.
Idiopathic parkinsonism, i.e. PD, was ultimately diagnosed in 147
patients, of which 73 patients had MMSE scores of 18 or higher.
Within this group of 73 subjects, 92% was treated with levodopa
(mean dose of 673 mg) and 21% with dopamine agonists. According
to the SPES motor scale, 44% of the patient is ‘off’ most of the time.
Discussion: In 1 out of 5 patients the clinical diagnosis was
changed compared to the diagnosis at nursing home admission.
Nearly half of the PD patients was having disabling motor signs
without significant responsfluctuations. Mean levodopa dose was
relatively low whereas some subjects did not receive any dopaminergic therapy at all.
In conclusion, recognising the correct underlying disorder in
subjects with (atypical) parkinsonism is very important in terms of
treatment and prognosis. We believe that a significant part of nursinghome patients with PD is undertreated. In the near future,
guidelines are needed to improve the quality of care in the nursing
homes.
P400
Factors affecting the quality of life in patients
with Parkinson’s disease
L. Kadastik-Eerme, T. Paju, M. Rosenthal, Ü. Krikmann,
P. Taba
University of Tartu (Tartu, EE)
Objectives: The aim of the study was to assess the impact of different
factors on the quality of life (QoL) in patients with Parkinson’s disease (PD).
Methods: The study included 56 patients (25 male and 31 female)
with the diagnosis of PD, with mean age of 69.7 ± 8.4 (range
47–85 years). The validated Estonian version of Parkinson0 s Disease
Quality of Life Questionnaire (PDQ-39) was used to assess the QoL.
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Demographic data (age, gender, duration of illness) was obtained, and
the clinical rating scales were used: Hoehn and Yahr scale (H-Y), and
Schwab and England scale (S-E) for disease severity and disability;
Beck Depression Inventory (BDI) for depression; Mini Mental State
Examination (MMSE) for cognitive status. Mean values were compared by student t test and one way ANOVA. The results were
considered significant at p \ 0.05.
Results: The mean total score of PDQ-39 was 30.9 ± 15.9.
Patients with depression (BDI [13), more severe disability (SE B70%), advanced disease (H-Y C3), longer duration of the disease
([5 years), and lower MMSE score (\25) had significantly worse
PDQ-39 total score. Women perceived their QoL significantly worse
than men in the domains of emotional well being, mobility and
communication. Women had significantly more depression than men
evaluated by BDI, and depression had the most significant negative
impact on emotional well being and mobility. Other QoL domains
including stigma, activities of daily living (ADL), bodily discomfort
and communication were also significantly affected by depression.
The domain of stigma was significantly worse in patients less than
65 years old compared to the older patients, and with the duration
from 6 to 10 years compared to the patients with shorter and longer
duration of PD. Disability and severity of PD had the most significant
effect on mobility and ADL.
Conclusion: The presence of depression, higher grade of severity
and disability of PD, and longer duration of the disease had the most
significant negative effect on the QoL in patients with PD. Depression
was the most important factor impairing the QoL, and had negative
impact on most domains of QoL.
P401
Cigarette-smoking in male patients with Parkinson’s
disease and its relation to rapid eye movement (REM)
sleep behaviour disorder: a Japanese multi-centre study
of Keio Parkinson’s disease database
K. Ohta, Y. Shinohara, N. Suzuki, A. Koto, B. Mihara,
Y. Morita, K. Isozumi, K. Muramatsu, K. Takahashi,
J. Gotoh, K. Yamaguchi, Y. Tomita, H. Satoh, M. Seki,
Y. Nihei, S. Iwasawa
Tachikawa Hospital (Tokyo, JP); Keio University (Tokyo, JP);
Yomiuri Land Keiyu Hospital (Tokyo, JP); Mihara Memorial
Hospital (Gunma, JP); National Hospital Organization Tokyo Medical
Center (Tokyo, JP); Ashikaga Red Cross Hospital (Tochigi, JP);
Saiseikai Yokohama-city Eastern Hospital (Kanagawa, JP); Saiseikai
Central Hospital (Tokyo, JP); Mito Red Cross Hospital (Ibaraki, JP);
Tomita Hospital (Aichi, JP); Saitama City Hospital (Saitama, JP)
Objectives: Although the relationships between cigarette smoking
and a variety of sleep disorders as well as Parkinson’s disease (PD)
have been pointed out, the relationship between smoking and rapid
eye movement (REM) sleep behavior disorder (RBD), which is a
sleep disorder that is characteristic of PD, has not been adequately
researched. In this study, we traced back the actual smoking habits
of PD patients and, furthermore, investigated their relationship with
RBD.
Methods: The subjects were 248 Japanese male PD patients (age
72 ± 9 years, disease duration 8 ± 10 years, mean ± SD) attending
11 hospitals participating in the Keio PD database. We surveyed their
smoking history and reasons for quitting smoking with a questionnaire, and also determined RBD to be present if five or more points
(possible/probable RBD) were scored on the Japanese version
(Miyamoto T, et al. 2009) of the RBD screening questionnaire
(Stiasny-Kolster K, et al. 2007).
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Results: (1) While few of the subjects were current smokers (4%),
61% had smoked in the past but had quit (past smokers) and 35% had
no history of smoking. The most common reason past smokers had for
quitting smoking was ‘‘because it is not good for your health’’ (68%).
Reasons such as smoking’s suspected links to motor and non-motor
PD symptoms were no more than 13%. (2) It was determined that
33% of subjects had RBD. Although it was estimated that the relative
risk of the existence of RBD in past smokers was not high compared
to PD patients with no history of smoking (odds ratio 1.10), the
relative risk of the existence of RBD in current smokers was estimated to be high (odds ratio 2.22).
Conclusion: From the results of this study, in which Japanese male
PD patients were subjects, the link between smoking history and
prevalence of PD was suspected. We were not able to indicate that the
reasons for quitting smoking of PD patients with a history of smoking
in the past were linked to non-motor symptoms such as hyposmia,
which is considered to be a precursor to the onset of PD. There is also
a possibility that current smoking habits are related to the onset of
RBD in PD patients.
P402
Understanding dyspepsia in patients with Parkinson’s
disease
D. Georgescu, C. Georgescu, M. Simu, L.-A. Georgescu
University of Timisoara (Timisoara, RO); County Hospital
(Timisoara, RO)
Objectives: Better understanding dyspepsia in Parkinson disease(PD)by assessment of gastric motility in order to improve
treatment and patients quality of life.
Methods: 27 patients (17 men,10 women, mean age =
68.11 ± 12.62 years) diagnosed with PD according to Hoehn-Yars
scale (1 = 1 patient, 1.5 = 1 patient, 2 = 7 patients, 2.5 = 1 patient,
3 = 14 patients, 4 = 2 patients, and 5 = 1 patient) treated with
levodopa or dopamine agonists, with associated nausea and
vomiting undertook a trial consisting of ultrasound assessment of
gastric motility (Bolondi method). Patients received a treatment
with Trimebutine 300 mg/day for 3 months with no drop out
cases. After finishing the treatment we repeated the ultrasound
exam of gastric motility. We ruled out gastric and gallbladder
conditions, infection with Helicobacter Pylori, treatment with
nonsteroidian antiinflammatory or aspirin, diabetes, thyroid and
collagen disorders, hepatic and renal failure. We have assessed
digestive severity symptoms scores before and after therapy
(0 = no symptoms, mild = 1, medium = 2, severe = 3) comparing also to gastric motility curves.
Results: Before therapy 15 patients showed delayed of the gastric
emptying (55.56%), 7 normal motility (25.92%) and 5 patients rapid
emptying (18.51%). Symptoms severity scores before therapy were:
8 patients (29,52%), mild,14 patients (51.85%), medium, 5 (18.51%).
severe. No correlation regarding severity of PD and dyspepsia was
set. Mean dyspepsia severity index in patients with gastric motility
disorders before therapy was 2.20 ± 0.52. After therapy the same
index decreased to 1.50 ± 0.69 (p = 0.0009; highly statistical significant). Mean severity index in patients with normal motility was 1
(before treatment) versus 0.43 ± 0.53 after therapy (p = 0.0152;
statistic significant). Gastric motility curves showed an improving
after therapy more important in those with delaying emptying:
23.45% ± 14.03 versus 15% ± 5.87 in patients with rapid emptying
(p \ 0.0001, statistic significant)
Conclusions: An important range of Parkinson patients treated
with levodopa or dopamine agonists, with nausea and vomiting,
presented gastric motility disorders (74.07%), most of them having
delay of the emptying. We recorded a satisfactory response to the
treatment with Trimebutine with improving of symptoms severity
index and gastric motility more expressed in patients with delaying of
the gastric emptying.
P403
The Lisbon-Barcelona cohorts and the San Francisco
VA Medical Center series: late-stage Parkinson’s
disease and today’s clinical needs
S.G. Echebarria Mendieta
Hospital San Eloy (Barakaldo-Bizkaia, ES)
Introduction: The concept of late-stage PD has emerged recently,
mainly by Coelho et al. (2010), describing the collaborative study in
Lisbon and barcelona academic medical centers cohorts.
The characteristics of Coelho study, with UPDRS ADL (28–29)
and S&E ADL and a mean duration of 17.94 years may be compared
with recent series (Ku S and Glass G, 2010) describing age of PD
onset and dyskinesia predictors.
Methods: Comparatives of Kaplan-Meier curves between Lisbonbarcelona cohorts and San Francisco VA series. Control series:
levodopa -dyskinesia incidence by age of PD onset (Kumar N, van
Gerpen JA, Bower J, Ahlskog E)
Results: The hazard model defined by Ku (age of onset PD - per
10 years and Lisbon-Barcelona cohorts application to DATATOP_PRECEPT studies are related with r = 0.296 (p \ 0.020)
Conclusions: The non-linearity of disease progression, is remarked
by Ku and glass, with dopa-treatment starting before or later than
2 years and long-disease duration leading to similarly advanced
neurodegenerative changes for all patients, independently from age
onset.This remark is related to PRECEPT-DATATOP series K-M
curves considering 0.35-0.4 probability per year of reaching the
endpoint (treatment onset).
P404
Undisclosability structure of Parkinson’s disease
V. Yudina, G. Yudina, O. Voskresenskaya
Saratov State Medical University (Saratov, RU); First Moscow State
Medical University (Moscow, RU)
Background: Parkinson’s disease (PD) is a totally disabling and
expensive illness, whose economical burden permanently increases
with the growing number of elderly people in the world. There is no
exact statistics of Parkinsonism patients in the RF; however, some
estimations allow suggestion of up to 0.5 million people involved. But
only 210 thousands of such patients are recorded in the country by
unofficial data. This difference is apparently due to operative
maldiagnostics of this chronic neurodegenerative disorder.
Problem: At outpatient reception in the RF, PD is diagnosed in
60–80 persons per 100,000 only, so 15–25 cases remain undisclosed.
Every 20–40 persons of 100,000 do not call for medical aid. Besides,
there is a problem of late taking medical advice by elderly people who
constitute the main contingent of Parkinsonism patients. This is
caused by some features of the early clinic (tremor, hypokinesia, onesided symptomatic), which are misapprehended as the inevitable
consequences of aging or the display of other age-related chronic
diseases. Gradual loss of the faith in effective out-patient medical aid
is another cause of poor taking medical advice by potential patients,
because this aid could often be burdened with diagnostically
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S90
erroneous notions of widespread diseases. Patients’ non-appearance
and poor diagnostics by general practitioners together entail the low
disclosability of the disease.
Methods: Patients’ non-appearance is noticeably reduced by
educational programs for elderly people and remote self-questioning.
We have designed a special questionnaire to allow for the obligate
symptoms of PD and typical concerns of these patients. It contains
nine statements, and selection of more than one of them would
include the person into the risk group. The validity of the questionnaire was estimated by screening of the clients of Social Service
Center (Saratov). 864 persons have responded to our questionnaire
call. As a result of our screening, a risk group of 190 people was
formed. After specifying phone interview, neurodegeneration of the
Parkinson type was suspected in 34 persons.
PD was diagnosed in 11 persons (7 for the first time). Such typical
symptoms of PD as resting tremor, hampered rising from the chair,
and shuffling gait have turned out to be diagnostically low-sensitive
than micrography and hypoosmia. The Parkinsonism patients make
up 1.3% of the population of aged pensioners.
marked in patients \39 (Chi2 = 26.4, p = 0.009). There was no
variation in patients aged 40–49 (Chi2 = 11.6, p = 0.47). The September trough was most apparent in patients [50 years (Chi2 = 28.0,
p = 0.005).
Conclusions: This study confirms significant seasonal variation of
relapse which is age and sex-specific. The reasons for this variation are unclear but infer modifiable environmental factors most
apparent in females \39 years and may be related to changing sex
ratios. Further studies are required to investigate environmental
triggers for relapse and may be most efficiently centred on young
women.
Multiple sclerosis: clinical aspects
Aristotelian University (Thessaloniki, GR)
P405
Multiple sclerosis relapses vary in a seasonal pattern
and by gender and age
K.E. Baker, C. MacIver, K. Tilling, G. Ingram,
M.D. Cossburn, C. Hirst, T.P. Pickersgill, Y. Ben Shlomo,
N.P. Robertson
Cardiff University (Cardiff, UK); University of Bristol (Bristol, UK)
Objectives: Events that precipitate the inflammatory cascade in
multiple sclerosis (MS) and result in clinical relapse remain unclear
but frequency is known to be affected by age, disease duration and
pregnancy. Some groups have also demonstrated tentative evidence of
seasonal variation in both hemispheres which has been corroborated
in radiological cohorts. The cause of this variation is unknown and
more detailed interrogation of clinical sub-groups limited by sample
size. However, if confirmed, this may be important in planning
clinical resources, interpretation of trial data and pathological
mechanisms. In this study we have analysed temporal relapse data
from a cohort of well-characterised patients.
Methods: Data was collected prospectively from a cohort of
patients in Wales over 6 years (2005–2010). Standardised clinical and
demographic data was collected at initial review. Patients were asked
to record details of new symptoms/events, and reviewed on an annual
or biannual basis. Standardised data at review including nature and
date of onset of relapses was established together with current status
including EDSS, disease type and change to medications. Patients
were also provided with open access to an urgent review clinic for
assessment of new symptoms and determination of relapse status.
Temporal variation of relapse was analysed by chi-squared analysis
using Stata.
Results: 1897 relapses in 1534 patients were modelled. There was
no significant yearly variation in relapse rates in the population. There
was a significant seasonal variation in relapse, with peaks in June and
December, and a trough in September (Chi2 = 40.4, p \ 0.0001).
Variation was sex-specific and present in females (Chi2 = 51.3,
p \ 0.0001) but not males (Chi2 = 5.8, p = 0.09). Relapse frequency
declined with age and seasonal peaks were age-related and most
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P406
Epidemiologic data of multiple sclerosis in the city
of Thessaloniki (northern Greece) during the last thirty
years (1979–2008)
E. Koutsouraki, A. Fotakidou, T. Kalatha, T. Gatsios,
M. Arnaoutoglou, V. Costa, S. Baloyannis
Background: Multiple Sclerosis (MS) is one of the most common
diseases of the central nervous system. It represents an inflammatory
demyelinating disease of young adults; the mean age of onset is
29–33 years. Women are more likely to develop multiple sclerosis
than men.
Aim of the study: There have been none recent epidemiologic
study in northern Greece and especially in Thessaloniki, on the
prevalence and characteristics of MS in this area. The purpose of the
present investigation is to analyze some of the epidemiologic data on
MS patients who originated mainly from the northern part of Greece
and especially from the city of Thessaloniki, like the incidence of the
disease, the female predominance, the seasonal and geographic distribution, the initial symptoms, the risk factors and the familial cases,
and how these epidemiologic data have been changed during the last
thirty years.
Methods: We analyzed retrospectively the records of the MS
patients admitted in the 1st Department of Neurology of Aristotelian
University, Thessaloniki, Greece, between the years of 1979 and
2008. We selected those patients with a definite MS diagnosis
according to the criteria of Poser; retrospective application of the
McDonald’s criteria was included. The analysis included 1,180 MS
patients.
Results: We studied a total of 1,180 MS patients, with an average
annual rate of 39 MS patients, 725 of them female (61.4%) and 455
male (38.6%), demonstrating a female to male ratio of 1.6:1. The
estimated prevalence of MS in the city of Thessaloniki, the largest in
northern Greece, on December 31 2008, was 23: 100,000 placing the
area in the medium-risk zone while it was 10: 100,000 on December
31, 1981. The highest incidence occurred in the year 1998 and the
lowest in 1980. The mean age during the exacerbation of the disease
was 31.4 years for the males and 32 years for the females. The
average annual rate of attacks was 0.15/patient/year. The maximum
incidence of attacks was noted during spring (29%) and summer
(29.24%), especially in May (130 patients, 11%). The minimum
incidence was in December (68 patients, 5.76%).
Conclusions: Our study indicates an increase of the incidence of
MS, probably due to improved diagnostic approaches or to changes
in the way of living. Further research is required to analyze the
underlying mechanisms of MS and be able to effectively treat MS
patients.
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P407
Dementia in multiple sclerosis: demographic, clinical
and genetic features
A. Martins Silva, A. Bettencourt, A. Ribeiro, A. Gonçalves,
C. Pinto, I. Moreira, E. Santos, E. Coutinho, A. Tavares,
P. Costa, B. M Silva, S. Cavaco
Hospital de Santo Antonio (Porto, PT); University of Porto (Porto,
PT); Hospital Magalhaes Lemos (Porto, PT); National Institute
Ricardo Jorge (Porto, PT)
Background: Cognitive dysfunction is relatively frequent in MS
patients (*40 to 60%). However, debilitating cognitive dysfunction
(i.e., dementia) without significant motor, sensory or cerebellar
impairments is rare in MS. Risk factors for predominantly cognitive
MS are largely unknown.
Objectives: (1) To describe the demographic and clinical characteristics of MS patients with dementia, but without significant
physical disability; and (2) to explore some possible genetic risk
factors for the occurrence of dementia in MS.
Methods: From a consecutive series of 455 MS patients (attending
CHP-Porto Neuroimmunology Clinic), 337 patients with EDSS B6
performed the Mini-Mental State Examination and were genotyped
for HLA-DRB1 alleles and ApoE polymorphisms. Non-parametric
tests (i.e., Mann–Whitney and Chi-square) were used for data
analyses.
Results: Evidence of dementia was found in 5.9% of MS patients
with EDSS B6 (n = 20; 13 women; mean age = 46.1 years, 21–66;
mean education = 11.75 years, 2-17, mean age at onset = 32.2 years, 12–55; and mean disease duration = 13.9 years, 1–47). Their
predominant initial presentations were: isolated dysfunction of long
tracts (n = 10), optic neuritis (n = 5), cortical and psychiatric
syndrome (n = 3), ‘‘encephalitis-like’’ syndrome (n = 2), and
severe psychiatric syndrome (n = 1). Sixteen patients had relapsing-remitting course, 2 had a primary progressive course, and 2 had
a secondary progressive course. This subgroup of patients, in
comparison with those without evidence of dementia, was significantly older (46.1 vs. 39.1 years; p = 0.014), had longer disease
duration (13.9 vs. 9 years, p = 0.015), had higher EDSS (3.9 vs.
2.5, p = 0.001), had poorer MSSS (4.43 vs. 3.33; p = 0.043), and
was more frequently treated with psychoactive drugs (60 vs. 32,1%,
p = 0.01). With reference to the normal Portuguese population, the
HLA-DRB1*15 allele was significantly increased in the nondemented MS sub-group (33 vs. 19.9%, OR = 2.9 9 10-4,
OR = 2.03, 95% CI = 1.38–2.97), but not in dementia MS (26.3 vs.
19.9%, p = 0.4). No significant group differences were found for APOE
genotype allele frequencies.
Conclusions: Dementia is a relatively uncommon presentation of
MS. Even though HLA-DR15 allele is a known risk factor for the
occurrence of MS, the results suggest that HLA-DR15 allele may
have a protective effect for the occurrence of dementia in MS. Previously reported data from the same cohort (Martins Silva et al. 2007)
showed that MS patients with HLA-DRB1*15 allele had better
physical outcome.
P408
Pregnancy and child-bearing in multiple sclerosis
K. Bencsik, M. Karacsony, T. Csepany, G. Gyorok,
E. Meszaros, J. Fuvesi, L. Vecsei
University of Szeged (Szeged, HU); University of Debrecen
(Debrecen, HU); Bajcsy-Zsilinszki Endre Hospital (Budapest, HU);
Markusovszky Hospital (Szombathely, HU)
Objectives: It is well established from epidemiological studies that
multiple sclerosis (MS) may be manifested after delivery among
women in reproductive ages.
The aims of our study are to assess the effects of the disease and
the possible immunomodulatory treatments on the developmental
parameters of newborn babies of women suffering from MS.
Methods: Seventy-two patients attended four Hungarian MS
Centres. Twenty-four women were treated with immunomodulatory
therapy and 48 were not treated. All patients completed our questionnaire concerning data of the pregnancy, the conditions of
delivery, and the development of newborn babies: Apgar scoring for
newborns, birth weight and length, age at rolling, sitting, walking
and speech development. The study was approved by the University
Ethics Committee. We compare our results to the data of the
Department of Obstetrics and Gynaecology, University of Szeged,
Hungary, published in 2008, and unpaired t-test was used as a
statistical analysis.
Results: The 72 women had 102 babies, 30 of them were delivered
by treated, and 72 by not treated mother. The mean duration of MS at
delivery was 7 years, 8.5 years in the treated and 5.7 years in the not
treated group. The mean EDSS score was 1.5, 1 in the treated, and 2
in the not treated group. Among children of the not treated group, the
mean birth weight was 3430 g and the mean length at birth was
51.4 cm. The treated women’s babies had mean birth weight of
3,190 g and mean birth length of 49.7 cm. Neither results are significantly lower than the results in the not treated group (birth length:
p = 0.0534 and birth weight: p = 0.0535). The mean Apgar score
was 9 in the treated and 10 in the not treated group. There are no
differences in the developmental parameters between the children of
women with or without MS.
Conclusion: Our study suggests for women with MS, that disease
does not affect the developmental parameters of newborn babies.
P409
The relationship between the clinical findings
and oral-dental health in multiple sclerosis patients
K. Demirkaya, G. Genc, S. Demirkaya
Gulhane Military Medical Academy (Ankara, TR)
Objective: Multiple sclerosis (MS) arises as a result of the interaction
of genetic and environmental factors. Chronic infections are the most
queried factors in the etiology. Mouth and teeth are important focal
infection sources of the organism. We aimed to investigate the relationship between oral-dental abnormalities and the course of the
disease by oral examination in MS patients.
Methods: 218 patients ranging from 21–54 years of age (56.4%
female, 43.6% male) with a diagnosis of definite MS according to
McDonald criteria were included in the study. 164 of the patients had
relapsing-remitting, 54 of the patients had secondary progressive MS.
The number of decayed teeth in the mouth, localization of decay, the
number of dental filling and apical surfaces were recorded during the
examination. In addition, neurological examination findings and
EDSS scores ot these patients were determined.
Results: Periapical periodontal disease was detected in 54% of the
cases. Motor involvement in 76%, cerebellar involvement in 28% of
the cases with periapical periodontal disease were found. Dental
caries and periodontal disease were observed much higher rate in
patients with higher EDSS scores than 5.5.
Conclusion: Periodontal diseases are more frequently seen in MS
patients with motor and cerebellar signs. Dental infections and dental
caries occur more frequently as disability increases. It’s an important
problem to be investigated whether this condition is a result of the
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severity of neurological examination findings, or these oral-dental
infections contribute to disease progression.
P410
The relationship between dental fillings and relapse rate
in multiple sclerosis patients
K. Demirkaya, G. Genc, S. Demirkaya
Gulhane Military Medical Academy (Ankara, TR)
Objective: 50% amalgam fillings consist of mercury. The role of
heavy metals has been discussed for a long time in the etiology
of multiple sclerosis (MS). Some authors propose that the risk of
developing MS increases with amalgam fillings, whereas some
authors report that there’s not any correlation between them. Since
there is no study evaluating the effects of amalgam fillings on relapse
rate and comparing different dental fillings in literature, we aimed to
investigate the relationship between dental fillings and clinical findings, especially the effects of amalgam fillings on relapse rate of MS
patients and compare composite and amalgam fillings.
Methods: 107 patients (70 female, 37 male) were included in the
study. Dental and neurological examination findings were recorded.
Results: 45.7% of patients with relapsing-remitting MS (RRMS)
had the amalgam fillings only, 7.4% had composite filling only,
14.8% had both composite and amalgam filling, whereas 32.1% had
no dental filling. No statistically significant difference was observed
between different fillings types in terms of age, age at onset, duration
of disease, and annual relapse rate. Also there was no significant
difference between the increasing number of the amalgam fillings and
relapse rate.
Conclusion: Our results suggest that although most of the RRMS
patients (60.5%)have amalgam fillings, there is no significant effect of
amalgam fillings on the frequency of relapses in RRMS patients. Our
study is the first study investigating the effects of amalgam fillings on
the frequency of exacerbations in MS patients and comparing amalgam and composite fillings in literature. Our results are similar to
most of the studies in literature investigating the relationship between
amalgam fillings and MS,and demonstrating the absence of this
relationship. Large prospective studies that will demonstrate the role
of amalgam fillings and exposure to mercury in the etiology of MS are
needed.
P411
Correlations of balance instability with disability
in multiple sclerosis patients
H. Gensicke, S. Corporaal, L. Kappos, J. Allum, Ö. Yaldizli
University Hospital (Basel, CH)
Background: Multiple sclerosis (MS) patients often complain about
balance problems even if neurological examination is normal. The
aims of this study are to test whether measures of trunk sway during
balance tasks are correlated with disease severity and are more sensitive than standard clinical examinations, which contain subjective
and rater-dependent elements, in identifying balance deficits.
Methods: We included 37 MS patients (mean age 43 ± 10 years;
76% female; 81% relapsing forms; mean disease duration
10 ± 7 years) who can walk at least 5 m without assistance. The
study protocol included the Dizziness Handicap Index (DHI) and 14
stance and gait balance tasks during which trunk sway angles and
velocities were measured with a Sway-StarTM system (Balance
123
International Innovations GmbH, Switzerland). Normal neurological
examination was defined as normal Romberg’s test and normal
tandem gait. Disease severity was assessed by Expanded Disability
Status Scale (EDSS) and T2 lesion load on brain magnetic resonance images (MRI) by \9 and C9 lesions). Seventy-six age- and
gender-matched healthy subjects served as controls (HCs). Nonparametric rank Spearman-Rho correlations and Mann–Whitney U
tests were performed and p-value were corrected for multiple
comparisons.
Results: The mean EDSS was 2.8 ± 1.1; 68% of patients had C9
T2-lesions.; mean DHI of patients was 30 ± 23.5%. Neurological
examination was normal in 16 patients (43%). EDSS correlated with
increased sway measures in 13 of 14 balance tests (rho [0.4). The
highest correlation to EDSS and DHI was found for the ‘‘2-legged
eyes closed on foam’’-task. In one-legged stance and tandem gait
higher T2-lesion load was associated by trend with higher roll angle
(p B 0.05) and velocity ranges (p = 0.05). In patients with a normal
neurological examination, the test standing on ’’one leg with eyes
open on foam’’ yielded the highest roll and pitch, angle and velocity
sway ranges compared to HCs (all p = 0.001).
Conclusions: Measures of trunk sway during balance tests reflect a
MS-related functional deficit and have the potential to provide
objective data of sub-clinical deficits. Further studies are needed to
validate this technique on individual basis and for follow-up
examinations.
P412
Lymphocyte calcium influx characteristics and its
modulation by Kv1.3 and IKCa1 potassium channel
inhibitors in multiple sclerosis
A. Folyovich, G. Toldi, Z. Simon, K. Zsiga, I. Vastagh,
A. Kaposi, G. Ambrus, T. Tulassay, B. Vásárhelyi
Szent János Hospital (Budapest, HU); Semmelweis University
(Budapest, HU)
Objective: Kv1.3 and IKCa1 potassium channels are known to be
involved in the regulation of calcium influx during activation of
lymphocytes. Our aim was to compare the calcium influx characteristics of T lymphocytes in multiple sclerosis (MS) patients and
healthy individuals and its modulation by Kv1.3 and IKCa1 channel
inhibitors.
Subjects and methods: We used flow cytometry to evaluate calcium influx in Th1, Th2, CD4 and CD8 subsets of lymphocytes
isolated from 10 healthy individuals, 11 MS patients without and 6
MS patients with interferon beta therapy. Lymphocytes were treated
with specific channel inhibitors and phytohemagglutinin was applied
to activate cells.
Results: Calcium influx kinetics and potassium channel function in
lymphocytes were in some aspects different in MS patients without
interferon b compared to healthy individuals. The reactivity of lymphocytes is increased in MS patients, however the amount of calcium
entering the cells during activation is not different from that of
healthy individuals. Potassium channels function more actively in
lymphocytes of MS patients. Inhibition of Kv1.3 potassium channels
in MS patients may be used to the CD8 subset, but as this effect is of
limited specificity and also involves the anti-inflammatory Th2 cells,
the therapeutic application of Kv1.3 channel inhibitors should be
further investigated and characterized in MS. In MS patients treated
with interferon b, calcium influx kinetics and potassium channel
function are more similar to those in healthy individuals, but these
observations are limited to the Th1 subset.
S93
Conclusion: Our results suggest that interferon b treatment may
have a selective effect on calcium influx in Th1 cells, and Th2 cells
are less affected.
P413
Systemic autoimmunity in multiple sclerosis:
a retrospective study of 229 Greek patients
E. Andreadou, V. Constantinides, A. Dimitriou,
M. Synetou, G. Makrydakis, M. Evangelopoulos, C. Sfagos,
P. Davaki, D. Vassilopoulos
Athens National University (Athens, GR)
Objectives: To determine the frequency and clinical significance of
non-organ specific and organ specific autoantibodies (AAbs) in
multiple sclerosis (MS) patients. To evaluate the prevalence and
clinical significance of other autoimmune disorders in the past medical or family history of MS patients.
Methods: We retrospectively reviewed the records of all the patients
examined at the Unit of Demyelinating Diseases of the Neurology
Department, University of Athens, during the period 2006–2010. All
patients who fulfilled the 2005 revised McDonald criteria for definite MS
or for clinically isolated syndrome (CIS) and had been tested for at least
one autoantibody were included in the study.
The AAbs examined were antinuclear antibodies (ANA), anti-ENA,
anticardiolipin antibodies (ACL), rheumatoid factor (RF), thyroperoxidase antibodies (anti-TPO) and thyroglobulin antibodies (anti-TG).
Clinical data collected were age at disease onset, disease duration,
initial symptomatology, disease subtype, past medical or family history of systemic autoimmune disease, medication and EDSS score at
the time of examination. CSF, visual evoked potentials and MRI data
were recorded where available.
Results: A total of 229 patients were identified. Mean age of the
patients was 38.7 years and percentage of females was 68%. Mean
age at disease onset was 31.3 years, mean disease duration was
89 months and mean EDSS score was 2.7. Relapsing-remitting MS
had 55.5%, CIS 22.7%, secondary progressive 13.5% and primary
progressive MS 8.3% of the patients. The prevalence of other autoimmune diseases in the past medical or family history of the patients
was 4.4% and 12.0% respectively. The percentage of patients with
positive titers of ANA, anti-TPO, anti-TG, RF, anti-ENA and ACLIgG were 22.6, 20.4, 9.9, 4.8, 2.6 and 2.3%, respectively.
Neither the presence of autoantibodies nor positive past medical or
family history of other autoimmune diseases did correlate with any of
the clinical or laboratory disease characteristics. The use of interferon
for at least 6 months prior to the evaluation was not associated with
clinical or laboratory evidence of autoimmunity.
Conclusions: Patients with positive titers of autoantibodies or
family/past medical history of an autoimmune disease did not differ
significantly from MS patients free of autoimmune features. Interferon use did not correlate with the prevalence of autoantibodies or
autoimmune diseases.
P414
Malignant paediatric multiple sclerosis
M. di Ioia, G. De Luca, D. Farina, D. Travaglini,
V. Di Tommaso, E. Pietrolongo, A. Lugaresi
Multiple Sclerosis Center (Chieti, IT)
Background: There are few studies on aggressive pediatric Multiple
Sclerosis (MS) and about treatment in this MS population.
Case report: A 15-year-old girl presented with diplopia, gait
ataxia, vomiting and impaired mentation, preceded by asthenia, fever
and left sensory loss lasting for 3 days, 1 month earlier. A first MRI
showed a diffuse leukoencephalopathy with large, confluent lesions in
brainstem, semioval centers (left [ right) and spinal cord with diffuse
gadolinium (Gd) enhancement. The IgG Index was increased. ADEM
was diagnosed. Two weeks later brain MRI showed new lesions in the
left frontal lobe. After i.v. Methylprednisolone (MP) and oral tapering
she recovered. Three months after onset, 1 month after steroid
withdrawal, she presented behavioural changes, ataxia, strabismus
and urinary incontinence. Brain MRI showed new large lesions with
ring enhancement. She was treated with MP and high dose i.v.
immunoglobulins for 5 days. One week later there was a worsening of
ataxia, apraxia, nausea and vomiting. Brain MRI, 4 months after
onset, showed new active lesions suggestive of MS; previous areas
were decreased in size with ring enhancement. She underwent 3
Mitoxantrone (8 mg/sqm) monthly infusions with partial clinical
recovery but persistent Gd enhancement and no lesion load reduction.
After 8 plasma exchanges, only mental function improved. MRI
showed new demyelinating areas with ring enhancement. A 10 d MP
course was followed by improvement in motor and mental functions;
apraxia and urinary incontinence persisted. She was started on
Natalizumab but after initial stabilization, after 8 monthly infusions
the girl had worsening in cognitive and motor function. Brain MRI
showed new subcortical demyelinating areas in temporal lobes
without enhancement. NABs were negative. At follow up the patient
underwent neuropsychological tests which revealed depression and
severe cognitive impairment in all cognitive domains, especially in
working memory and executive function.
Conclusions : A final diagnosis of malignant MS can be posed in
our patient on the basis of MRI, clinical and CSF analysis. This case
is extremely aggressive and up to now no treatment was effective.
Pediatric MS can lead to mental impairment and is more invalidating,
on the long term, than adult MS. It is necessary to establish new
therapeutic protocols for aggressive juvenile MS and to identify
clinical and radiological parameters for the management of unresponsive cases.
P415
Aggressive atypical multiple sclerosis
J. Domingues, G. Santos, A. Matos, L. Sousa
University Hospitals of Coimbra (Coimbra, PT)
Introduction: Patients with a particularly aggressive initial course of
multiple sclerosis (MS) may present with atypical manifestations that
difficult initial diagnosis and may delay immunomodulatory treatment. We describe a case of an unusual form of MS presenting first as
temporal lobe epilepsy and latter as an acute disseminated encephalomyelitis-like disease.
Case report: A 34-year-old woman presented with afebrile subacute encephalopathy without associated focal neurological signs. She
didn‘t have history of recent infection or vaccination. She had been
diagnosed temporal lobe epilepsy six months before. The initial workup was negative but cranial MRI showed few white matter lesions that
did not fulfil McDonald0 s MRI criteria for MS and there were CSF
oligoclonal bands not present in the blood. Admission brain MRI
revealed multiple bilateral T2 hyperintense lesions on periventricular
and subcortical white matter with nodular or ring-like contrast
enhancement. Systemic work-up was negative. The patient’s symptoms were unresponsive to High-dose steroids, Plasmapheresis and
two cycles of 1,200 mg of Cyclophosphamide. As the patient’s condition deteriorated and the MRI continued to show disease activity,
Natalizumab therapy was started. After few months on this treatment
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S94
there was clinical and MRI improvement but the patient still remained
with a severe cognitive fronto-temporal dysfunction.
Discussion: It is important to recognize atypical presentations of
MS in order to initiate disease-modifying drugs at early stages of
disease. To our knowledge this is the first reported case of MS presenting first as epilepsy and latter with an encephalopathy.
P416
Unusual presentations of multiple sclerosis
J. Domingues, M.I. Marques, M. Macário, F. Matias,
L. Sousa
University Hospitals of Coimbra (Coimbra, PT)
Objective: The aim of this study is to describe patients with unusual
symptoms that were the presenting manifestations of Multiple Sclerosis (MS).
Patients and methods: A retrospective study was conducted in 443
patients attending the MS appointment in the Neurology Department
of a University Hospital between January 2000 and January 2011 and
registered in iMED database. Patients with unusual symptoms as
primary manifestations of MS, in the absence of other obvious neurological symptoms or signs, were selected.
Results: We report 34 patients with rare presenting symptoms of MS
(hemifacial spasm n = 4, isolated headache n = 3, epilepsia n = 1,
progressive bilateral visual loss n = 3, parkinsonism n = 2, paroxysmal dyskinesia n = 1, dystonia n = 1, isolated facial myorhythmia
n = 1, foot drop n = 2, sleep apnea n = 1, trigeminal neuralgia n = 2,
fibromyalgia n = 1, stuttering n = 1, downbeat nystagmus n = 1,
psychosis n = 2, isolated depressive syndrome n = 1, oscilopsy n = 1,
hearing loss n = 4, saddle hypoesthesia n = 1 and writer’s cramp
n = 1). These patients represent about 8% of the cases followed in our
MS consultation. All patients were classified as clinically definite MS
and were relapsing-remitting forms of disease.
Discussion: The symptoms and signs of MS are notoriously variable but in general reflect the extent of involvement of those parts of
the central nervous system in which there is a dense concentration of
myelinated fibres. The initial manifestations of MS have been analysed in many series. McAlpine et al, in a review of all previous
published reports, found that the incidence of initial symptoms was
about 35% for weakness in one or more limbs, 20% for optic neuritis,
20% for paraesthesiae, 10% for diplopia, 5% for vertigo, 5% for
disturbance of micturition and 5% for other forms of presentation.
Our series reveals a higher incidence of unusual presentations and
describes patients with symptoms that have been considered extremely rare in MS, like hemifacial spasm. It is our conviction that
recent advances in MRI are expanding the spectrum of symptoms
recognized as MS manifestations. Physicians should consider these
other no classical presentations in the approach of young patients with
neurological complaints.
P417
Movement disorders in multiple sclerosis patients
—a twist of fate
A.C. Ribeiro, P. Coelho, C.C. Nunes, A. Morgadinho,
J.G. Gonçalves
Coimbra0 s General Hospital (Coimbra, PT)
Introduction: A variety of movement disorders (MD) other then
cerebellar or brainstem related secondary tremor have been described
in patients with multiple sclerosis (MS). However, despite the relatively frequent involvement of the basal ganglia and subthalamic
123
nucleus by MS plaques, MD are strikingly uncommon amongst MS
patients and a relationship between these two conditions has rarely
been demonstrated. The most frequent MD after tremor are dystonia,
chorea, ballismus and parkinsonism.
Case report 1: Fifty-year-old female patient complains of isolated
head tremor with a 6 month evolution. Her neurological examination
disclosed mild negative head tremor, increased leg spasticity with
bilateral Babinsky’s sign as well as altered coordination. All routine
and autoimmune blood analysis were normal and the CSF showed 6
oligoclonal bands. Her cranial MRI revealed several right cerebellar
hemisphere, superior cerebellar peduncle and periventricular lesions
strongly suggestive of MS. Treatment was started with b-1b interferon, topiramate and later propanolol was added with good tremor
improvement.
Case report 2: Fifty-eight year old female patient complains of
slowness of movement with increased gait disability and altered posture.
Her neurological examination showed left Mingazzini sign, globally
brisk reflexes and left Babinsky0 s sign. She also presented axial and
bilateral limb rigidity, severe body bradykinesia, forward-flexed posture
with postural instability and shuffling gait. Her blood analysis were all
normal and the CSF revealed 8 oligoclonal bands. Her cranial MRI was
compatible with central nervous system demyelinating lesions which did
not affect the basal ganglia. The DaTSCAN detected an asymmetric
isotope binding in the right striatum which confirmed a parkinsonian
syndrome and excludes secondary causes such as demyelinating lesions.
She was started on levodopa treatment.
Conclusion: MD in patients with MS are often secondary to
demyelinating lesions. The first patient was diagnosed with Relapsing-Remitting MS and presented a secondary head tremor with good
response to the usual anti-tremor medication. The second patient was
diagnosed with Primary Progressive MS and Parkinson’s Disease
(PD) but did not respond favorable to L-Dopa treatment. Even though
there might be a causal relationship between parkinsonism and MS it
is now clearer that PD and MS can coexist as two separate diseases in
the same patient.
P418
Cognitive impairment sclerosis: a Tunisian study
I. Ben Abdelaziz, H. Khiari, N. Aouadi, N. Anen, A. Cherif,
H. Batti, A. Mrabet
Charles Nicole Hospital (Tunis, TN)
Introduction: Cognitive impairment is frequent in multiple sclerosis
(MS) occurring at all stages of the disease.
Patients and methods: The study was performed at the Neurological Department of Charles Nicole Hospital, Tunis, Tunisia. Thirty
patients with clinically definite MS were included. 17 patients had
relapsing-remitting (RR) MS and 13 other had chronic progressive
MS [4 primary progressive (PP), 9 secondary progressive (SP)].
Demographic, clinical characteristics and EDSS scores were reported
for all patients. A battery of ten neuropsychological tests, validated to
the Tunisian population, exploring different cognitive spheres were
passed for these patients. The statistical analysis was performed with
SPSS Version 1.5. Significant threshold was fixed at 0.05.
Results: Almost all patients had at least one test disturbed.
Cognitive dysfunction was more severe in patients with progressive forms in comparison with RR forms. It consisted mostly of
impairment in processing information speed and attention (70%),
episodic memory (53 %) and executive functioning (40%).
Depression was found in more than half of the patients. Language
impairment and apraxia was found in patients with PP MS. Disease evolution was significantly linked with the cognitive deficit
mainly attention (p = 0.03). EDSS scores were significantly related with
S95
processing information speed and attention (p = 0.001). For the other
cognitive functions, no significant association was observed.
Conclusion: Cognitive impairment is almost constant in MS and
severe in progressive forms of MS. The disease evolution is closely
linked with the cognitive impairment. This connection is less evident
with EDSS scores.
P419
Frequent early relapses and long-term disease evolution
in multiple sclerosis
A. Scalfari, P. Giannetti, A. Neuhaus, M. Daumer,
P.A. Muraro, G. Ebers
Imperial College (London, UK); Sylvia Lawry Centre (Munich, DE);
Oxford University (Oxford, UK)
Objectives: The predictive effect of relapses in multiple sclerosis
(MS) is limited to the first two years of the disease (early relapses)
and it is primarily exerted by increasing the probability of entering the
secondary progressive (SP) phase and by shortening the latency to
progression. Our goal was to investigate the long term disease evolution in a subgroup of patients having high (C3) early relapse
frequency and therefore unfavourable overall outcome.
Methods: Among 730 relapsing onset patients from the London
Ontario database the risk of attaining hard disability outcomes (DSS
6-8-10) according to the duration of the relapsing remitting (RR)
phase was assessed using Cox regression analysis. Kaplan Meier
analysis investigated long term disease evolution of patient with high
(C3) relapse frequency during the first two years.
Results: The risk of attaining hard disability levels was inversely
correlated with the latency to progression. Being free from progression
for 5 or 15 years reduced the probability of requiring aid for walking
(DSS 6) from disease onset by twofold (HR = 0.50) and 8-fold
(HR = 0.12), respectively. Accordingly, those with a shorter duration of
the RR phase attained disability endpoints in significantly shorter times.
This effect largely disappeared when tested from onset of progression,
although it remained significant (DSS 6 HR per additional year = 0.98;
p = 0.03). Time to onset of SP exerted similar predictive effect even in
groups with the same number of early relapses, accounting for the variability of the outcome among patients sharing the same clinical features.
Patients with frequent early relapses (C3 attacks; N = 158) streamed into
two 2 subpopulations: 103 entered the SP phase and reached DSS 6-8-10
on average in 8.9, 15.2 and 20.5 years respectively. However, the
remaining 55 patients, despite having the same early relapse frequency
(1.92 attack/year), never converted to SP MS. The group that entered the
SP phase had a significant higher percentage of males (38 vs. 19%;
p = 0.01), older age at onset (28.4 vs. 25.4 years; p = 0.03) and shorter
time to DSS 3 (4.5 vs. 16.2 years; p \ 0.001).
Conclusions: The latency of progression strongly predicts late disability accumulation. Two extreme disability outcomes among patients
with high early relapse frequency suggest that selective vulnerability of
axons might be controlled by other factors than inflammatory mechanisms.
P420
Factors influencing adherence, quality of life
and depression symptoms in multiple sclerosis patients
C. Pozzilli, B. Schweikert, U. Ecari, J. Czekalla,
W. Oentrich
University Rome (Rome, IT); i3 innovus (Munich, DE); Domedica
s.r.l. (Bologna, IT); Bayer Schering Pharma AG (Berlin, DE)
Objective: Adherence to multiple sclerosis (MS) therapy is crucial to
treatment benefit and cost-effectiveness. Patient support programs are
designed to help patients to become familiar with treatment management and to improve adherence under the supervision of the
treating physician, thereby also affecting patient relevant outcomes as
quality of life (QOL) and depression. This study evaluated the effect
of different support elements on patients with multiple sclerosis.
Methods: The analysis used two year data from the prospective,
observational, BPlus study which included MS patients with relapsing
remitting MS (RRMS) or secondary progressive MS (SPMS) which
were switched by their physician from another disease modifying
drug to interferon b-1b (IFNB-1b; Betaferon) 1–3 months before
inclusion. At inclusion, and at each of the 6-monthly visits, patients’
choice of the supportive elements was documented.
Primary supportive elements were autoinjectors Bject and Bject
Light, and specialized MS nurses. Regression analyses were used to
analyse the effect of choosing a given support element on adherence,
the change in QOL and depressive symptoms as measured by FAMS
and CES-D respectively.
Results: A total of 1077 patients from 15 countries were included,
with a mean age of 35.9 years [standard deviation (SD) = 10.2]; 71%
were women and 74% had RRMS. After 24 months, 61.8% were
adherent to IFNB-1b. Depression, QOL and autoinjector use were
baseline predictors of adherence at 24 months. Bivariate analysis
showed that patients were significantly more adherent to therapy
when using a nurse or one of the autoinjectors ever during the study.
In regression analyses over time and controlling for potential
confounding variables the use of autoinjector Bject showed a positive significant association with QOL over time (p = 0.049) and the
support of a nurse was positively associated with lower depressive
symptoms (p = 0.039) and an increase in QOL.
Conclusions: The final two year results of the BPlus study suggest
that patient support by MS nurses and use of autoinjectors are
effective support elements in the treatment of patients with MS and
can positively influence adherence, QOL and depressive symptoms.
However, the principle limitations of an observational design have to
be taken into account when interpreting these results.
Funded by Bayer Schering Pharma AG.
P421
Influence of 6-week yoga on depression and fatigue
in patients with multiple sclerosis, North Khorasan,
northeastern Iran
R. Jajvandian, S. Nabavi, S. Oryan, S. Samadi, H. Khani,
A. Nikravesh
Islamic Azad University (Bojnourd, IR); Shahed University
of Medical Science (Tehran, IR); Islamic Azad University
(Tehran, IR); Iranian Applied Research Center for Public Health
and Sustainable Development (Bojnourd, IR); Zabol University
(Zabol, IR)
Objectives: depression and fatigue are common and frequent symptoms in multiple sclerosis (MS) patients that significantly reduce the
quality of life. Yoga is physical activities comprised a series of
stretching techniques, implementation of which demands body control and planning of complex movements. In this research, we tried to
find out the efficacy of Yoga as a nonpharmocological and safe
treatment to reduce depression mood and physical, cognitive and
psychosocial aspects of fatigue in MS patients.
Materials and methods: We enrolled 30 subjects with relapsing–
remitting or progressive MS, 16–45 years of age, with EDSS B5.5
and EDSS pyramidal functions score (EDSSpyr) [2 in two groups in
a randomized prospective study. We evaluated depression mood
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(based on BDI score) and fatigue (based on FSS and MFIS scores)
before and after 6 week (3 times a week for 2 h) yoga program.
Results: Results show that after 8 week yoga program, EDSSpyr
reduces 10% (p = 0.048) . There were no differences in depression
mood after the completion of yoga programs. There was a 18%
decrease in physical (p = 0.010), 85% decrease in psychosocial
fatigue (p = 0.001) and 12% in cognitive fatigue (p = 0.043) after
yoga (based on MFIS scores). There was not a significant difference
between total fatigue score based on FSS.
Conclusions: Our results show no change in depression mood and
total fatigue scores after 8 week yoga program in MS patients. But the
reduction in psychosocial and other aspects of fatigue, show that
Yoga could improve some of the MS symptoms and should be considered in the future as possible complementary treatments.
P422
Slower walking speed limits the activities of daily living
of multiple sclerosis patients
M. Yildiz
Cantonal Hospital St. Gallen (St. Gallen, CH)
Objective: To identify the relevance of walking speed to patients with
multiple sclerosis (MS). The prevalence of any degree of walking
impairment is estimated to be between 60-80% and increases with
disease duration. Clinicians normally assess walking impairment
using maximum walking distance [as in the expanded disability status
scale (EDSS)], the range of which is usually estimated by the patient.
Walking speed is less commonly assessed, and patients cannot intuitively report accurately their walking speed. In addition, our
knowledge about the impact of reduced walking speed due to MS on
activities of daily living (ADL) is rather limited.
Methods: Patients in the United Kingdom, France, Germany and
Sweden with a diagnosis of MS and minimum disease duration of
5 years were recruited to participate in a survey. Patients responded to
questions about how walking affected their daily activities either
using a 10-point visual analog scale (1 = no impact to 10 = extreme
impact) or with a yes/no response.
Results: 112 patients were recruited and participated in the survey;
60% were female. Type of MS was 54% relapsing remitting, 33%
secondary progressive, and 13% primary progressive. Impact of MS
was rated as very high (C8) by: 46% on general walking ability; 54%
on the ability to speed up over a short distance (e.g. crossing a road);
and 60% on the ability to walk a longer distance (e.g. 500 m). The
ability to walk fast over a short distance inside the home (e.g. to the
toilet or to answer the door) was rated as very important (C8) by 43%
of patients; 40% rated the ability to walk fast outside the home as very
important. Patients with concerns about their walking speed avoided
walking to nearby shops (53%), cleaning their home (46%), crossing
the street (31%) and visiting their neighbors (24%).
Conclusions: Patients perceive limitations in walking speed as
affecting their ability to participate in important ADL, including
crossing the street and cleaning their homes. Clinicians typically use
walking distance to assess patient disability. These data suggest that
walking speed may be as important to patients as walking distance,
and limitations in walking speed may reduce societal participation.
The study was funded by Biogen Idec, which also provided editorial support.
P423
Anosognosia in multiple sclerosis
E.G. Reich, E:D. Arias, M. Kerzberg
Hospital Julio Mendez (Buenos Aires, AR)
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Background: Anosognosia can be defined as an impaired ability to
recognize the presence or severity of deficit or disease. Is frequently
observed in neurological degenerative processes but is sparse studied
in MS patients.
Objective: To asses and determine the prevalence of anosognosia
in a Multiple Sclerosis (MS) group of patients.
Methods: 39 patients (27 females and 12 males) with diagnosis of
definite MS, (according Poser and Mc Donalds criteria) were studied.
The mean age was 34.6 years (SD 5.9) and the clinical picture was
Relapsing Remitting in 24 cases, and Secondary Progressive in the
remaining 14 patients. The mean time of evolution was 4.7 years (SD
3.8) and the mean EDSS was 3.0 (SD 2.0). The formal education
period was 8.4 years (SD 4.9). All the patients were evaluated utilizing clinical and neuropsychological standard assessment. The
specific scales in order to evaluate the presence of anosognosia were
the Visual-Analogue Test assessing anosognosia for motor impairment (VATA-m) and the Mayo-Portland Adaptability Inventory
(MPAI). The severity and stages of this disorder were measured
utilizing the Bisiach Scale. Particular emphasis was directed in the
observation of coincidences and discrepancies between caregivers and
patients related to the activities of daily living (IADL). Correlation
between MRI number,size, severity and localization of cerebral
lesions was established.
Results: In our population we observed a highly prevalence of
anosognosia (59%), measured with the different tools employed, with
remarkable dissociation between the perception of this symptom
when scales were administered to patients and caregivers. The grade
of anosognosia was mainly 1 or 2 (using the Bisiach Scale) and the
awareness of impairment was mainly linked to deficits in neurocognitive tasks and fine motility skills. Difficulties in activities of daily
living were frequently underestimated.Our findings correlated possitively with EDSS, evolution time and the presence of a large number
of lesions located in the right temporo-parietal subcortical areas. No
relationship with other variables (age, sex, education, treatments)
were observed.
Conclusions: Anosognosia is a highly prevalent disorder in MS
patients, suggesting a dysfunction in the mechanisms of self awareness, with implications in the ADL and with predictive value on poor
functional outcome. Neuroimaging studies revealed more often
localization of lesions in right parieto temporal hemispheric
localization.
P424
Headache in multiple sclerosis patients
G. Toncev, S. Miletic Drakulic, Z. Knezevic, T. Boskovic
Matic, A. Gavrilovic, S. Toncev
Clinical Center Kragujevac (Kragujevac, RS)
Introduction: Headache is one of the most prevalent symptoms in the
adult population but is not generally considered as a symptom of
multiple sclerosis (MS). The relationship between MS and headache
is poorly understood.
Objective: This is a population-based case-control study with aim
to estimate the prevalence of headache in MS patients.
Methods: The prevalence of headache was determined as point
prevalence defined as the proportion of patients with headache in the
MS population at a specified time (prevalence day). We had previously determined the prevalence of MS (prevalence day, December
31, 2006). These patients (total 194, 72 males and 122 females) and
123 controls, matched by age and sex, underwent an interview and
undergo a complete neurological examination. Diagnosis and classification of headaches were made according to International Headache
Society criteria. Data were analyzed using SPSS 10.0 software.
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Results: One hundred fifteen (59.28%) MS patients and 44
(35.77%) controls were found to have headache according to diagnostic criteria. MS patients had increased risk for headache (OR 2.53,
95% confidence interval 1.29, 4.12). Ninety five MS patients
(82.61%) were found to have primary headache (52 or 45.21% tension-type, and 43 or 37.39% migraine). Six MS patients (5.22%) were
affected by secondary headache, whereas 4 MS patients (3.48%) were
unclassifiable.
Conclusion: Our data support the increased risk of headache
within MS patients.
P425
Prevalence of anxiety in multiple sclerosis patients
in Lithuania
R. Leonavicius, V. Adomaitiene
Lithuanian University of Health Sciences (Kaunas, LT)
Background and aims: Compared to depression the prevalence of
anxiety is much less investigated in multiple sclerosis (MS) patients.
Regarding different sources it affects more than 40% of MS patients,
acting in morbidity, mortality and quality of life of these patients. The
aim of this study was to estimate the prevalence of anxiety in relation
to the clinical course and duration of MS, disability status of participants and prevalence of depression.
Material and methods: The study included 270 participants (187
females and 83 males) with definite MS according to McDonald
criteria. Mean age of patients at time of examination was 42.42 ±
11.71 years, mean MS duration—6.91 ± 5.12 years. Relapsingremitting course of MS represented 68.1% of cases, other progressive
MS courses—31.9%. Anxiety was evaluated using the Hospital
Anxiety and Depression Scale (HAD). Occurrence of depression was
assessed on the basis of ICD-10 classification. The disability of participants was rated including the Expanded Disability Status Scale
(EDSS). Statistical analysis included descriptive statistics, correlation
and regression analysis.
Results: Our survey showed that 17% of participants had anxiety
disorder. Depression was found in 20.7% of patients: 2.6% mild,
7.0% moderate and 11.1% severe. Patients with shorter MS duration
(\10 years), compared with MS patients with longer MS duration,
had 2.52 times higher odds ratio to be diagnosed with anxiety; and
patients with depression, compared with patients without depression,
had 3.03 times higher odds ratio to be diagnosed with anxiety.
Conclusion: Patients with shorter duration of MS and depression
are endangering anxiety in highest degree. The prevalence of anxiety
in our survey does not correlate with sex, age, course of MS and
disability status of participants.
P426
Extracranial venous vessel pathology in multiple
sclerosis
M. Denislic, Z. Milosevic, M. Zorc, O. Mendiz,
M. Leskosek, D. Ravnik
Multpile Sclerosis Centre Medicor (Ljubljana, SI); University
Clinical Centre (Ljubljana, SI); University of Ljubljana (Ljubljana,
SI); Favaloro Foundation (Buenos Aires, AR); Public Health Centre
(Vrhnika, SI)
Objectives: Venous vessel pathology in patients with multiple sclerosis (MS) has increased a great interest in the scientific community.
The new vascular entity named chronic cerebrospinal venous
insufficiency (CCSVI) is characterised by multiple stenoses of the
extracranial veins—jugular and azygous veins. A four patterns of
venous stenosis was described. Pathohistological studies described
perivenous distribution of demyelinating lesions, and by high resolution MR venography a central vein in the long axis of MS lesions
was highlighted. The role of an iron accumulation in the brain tissue
is discussed. The aim of our study was to elucidate the occurence of
the venous vessel pathology in patients with an advanced progressive
course of MS.
Methods: The MS patients who fulfilled 2 or more of the 5 proposed criteria obtained by Doppler sonography required for the
CCSVI, underwent selective venography. Disability status was
assessed by the Expanded Disability Status Scale (EDSS). Fatigue
was evaluated using Fatigue Severity Scale (FSS). Selective venography by placing a coronary catheter in the right femoral vein was
performed. Informed consent by participating subjects and agreement
of the National ethical committee was obtained.
Results: In this study we enrolled 30 consecutive MS patients
(aged 27–73 years) with progressive course of disease—17 patients
with secondary progressive and 13 with primary progressive MS with
mean EDSS 5.53 (range 2.0–7.5). The mean narrowing of the jugular
and azygous veins was 75% (range 50–95%). After 95 transluminal
dilations the improvement of the venous outflow was achieved. Endovascular treatment did not produced any serious side effects. The
significant improvement of EDSS score (less than 1.0 point) was not
noticed, but significant amelioration of the fatigue assessed by FSS
(p \ 0.001).
Conclusion: In all MS patients with the progressive course of
disease venous vessel pathology was discovered. Selective venography is a very important and sensitive method in detecting stenosis of
the extracranial venous pathway. By advanced pyramidal involvement an improvement of disability score is not expected. The
amelioration of fatigue plays an important role in defeating daily
obstacles in MS patients. Even in advanced disability, quality of life
could be well preserved. It seems that the endovascular treatment in
more disabled MS patients is promising.
P427
Proportion of in-hospital deaths in multiple sclerosis
patients related to septicaemia and the pulmonary
system exceeds that in non-multiple sclerosis patients
F. Ernst, R. Preblick, G. Cutter, D.W. Kaufman, H. Golub,
J. Pocoski, V. Knappertz
Premier Healthcare Alliance (Charlotte, US); Bayer HealthCare
Pharmaceuticals, Inc (Montville, US); University of Alabama
(Birmingham, US); Slone Epidemiology Center at Boston University
(Boston, US); Care-Safe LLC (Newton, US)
Objective: To examine related diagnoses, covariates and co-morbidities among multiple sclerosis (MS) patients who died in-hospital
compared with patients with another chronic condition, diabetes
mellitus (DM) and the general hospitalized population (GHP).
Methods: The US hospital-based Premier PerspectiveTM database
was analyzed for patients C18 years who died between January
2007–September 2010 with principal or secondary International
Classification of Diseases (ICD-9) codes for MS (340). Mutually
exclusive comparator groups included patients with a DM ICD-9 code
[250 (all subcodes)] and patients with any other ICD-9 (GHP).
Principal diagnoses associated with in-hospital death were identified
and classified into eight categories: cardiovascular (CV)/stroke, pulmonary/upper respiratory infection (URI), other infection,
septicaemia, cancer, accident/suicide, MS and other. Demographic
data, including age, gender, race, all patient-refined diagnosis-related
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groups and co-morbid conditions, were collected. All variables were
analyzed descriptively.
Results: Total deceased patients in each cohort were: 818 MS;
78,184 DM; and 185,227 GHP. Mean age at death was lower for the
MS cohort (63.2 ± 12.8 years) than for the DM (73.0 ± 12.8 years)
or GHP groups (73.0 ± 16.1 years). Septicaemia was the principal
diagnosis among deceased patients in the three groups (MS 34.0%,
DM 20.0%, GHP 16.9%). For deceased MS, DM and GHP patients,
respectively, other major diagnostic ICD-9 categories included pulmonary/URI (23.7, 19.1, 18.8%), CV/stroke (12.5, 26.6, 23.1%), other
(12.2, 19.1, 19.6%), cancer (6.5, 7.5, 12.0%), accident/suicide (5.7,
6.3, 7.9%), MS (4.3, 0, 0%) and other infection (1.1, 1.4, 1.8%).
Conclusions: This contemporary, large, US, in-patient sample
provides cause of death data for hospitalized MS patients. Septicaemia was the principal diagnosis associated with death in all cohorts.
Relative to the DM and GHP groups, the MS cohort experienced the
highest proportion of deaths with a principal diagnosis of septicaemia
or pulmonary/URI, and the lowest proportion of deaths with a principal diagnosis of CV/stroke, which may be age-related. The
relationship between in-hospital deaths and all MS deaths remains to
be determined for contemporary US MS patients.
Sponsored by Bayer HealthCare Pharmaceuticals, NJ, USA.
P428
Cancer in a population of multiple sclerosis patients
J. Sargento-Freitas, S. Batista, I. Marques, C. Macário,
F. Matias, L. Sousa
Coimbra University Hospital (Coimbra, PT)
Objectives: Our aim is to characterize a population of patients with
the diagnosis of Multiple Sclerosis (MS) and Cancer and consequently further clarify the complex and unsolved relationship between
these two pathologies.
Methods: Retrospective analysis of the clinical files of all patients
attending a tertiary Multiple Sclerosis centre with the diagnosis of
Multiple Sclerosis and Cancer. Demographic and clinical characteristics of both MS and Cancer were registered as well as all treatments
administered.
Results: From a total of 550 MS patients followed at our centre we
found 14 patients (2.54%) with the diagnosis of Cancer. Mean age
was 54.14 years (SD 11.35), 64.3% were female and mean MS disease duration was 13.79 years (SD 7.8). Mean age at MS diagnosis
was 40.21 years (SD 9.84) and at Cancer diagnosis 46.86 (SD 13.1).
Current median EDSS was 4.0 (interquartile range 2.88–6.0). The
diagnosis of Cancer preceded the diagnosis of MS In 21.43% and in
42.86% a clear clinical association with previous use of immunosuppression was determined. Patients with a diagnosis of malignancy
following the onset of MS had a mean disease duration of 10.55 years
(SD 6.02). All fatal cases (14.29%) were directly related to previous
immunosuppression.
Three cases of haematological malignancies (21.43%) and eleven
solid organ neoplasies were observed (78.57%), including the Central
Nervous System, with no organ or system-specific tendency . Comparing previous immunomodulators used we observed a
nonsignificant trend suggesting an higher previous use of Interferons
than Glatiramer Acetate (42.86 vs. 14.29%, p = 0.69).
Conclusion: Our work adds further evidence on the reported lower
frequency of malignancies among MS patients, confirming the
absence of a demographic or tissue-specific association. The promotion of cancerogenesis by immunosuppression was not unexpected
and should always be kept in mind by the treating physician. Among
immunomodulators the question of a possible association between
Interferons and cancer remains open and clearly needs to be
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addressed. Our study represents a relatively small, single-centred and
nonrandomized series. Notwithstandingly, we believe it contributes to
a better understanding of the possible physiopathological link
between these diseases.
P429
Cause of death in patients with multiple sclerosis
examined in the 21-Year Long-Term Follow-Up Study
G. Ebers, D. Goodin, A. Reder, G. Cutter,
M. Kremenchutzky, J. Oger, D. Langdon, M. Rametta,
K. Beckmann, V. Knappertz
John Radcliffe Hospital (Oxford, UK); University of California (San
Francisco, US); University of Chicago (Chicago, US); University
of Alabama (Birmingham, US); London Health Sciences Centre
(Ontario, CA); Neuroimmunology Laboratories and Multiple
Sclerosis Clinic UBC (Vancouver, CA); Royal Holloway, University
of London (Surrey, UK); Bayer HealthCare Pharmaceuticals (Wayne,
US); Bayer Schering Pharma AG (Berlin, DE); Bayer HealthCare
Pharmaceuticals (Montville, US)
Objective: To examine the underlying causes of death in the 81
deceased patients in the 21-Year Long-Term Follow-Up (21Y-LTF)
study. This study assessed the effects of interferon b-1b (IFNB-1b) on
mortality by assessing the fate of the 372 patients who participated in
the pivotal, randomized controlled trial (RCT), where patients were
randomized to receive IFNB-1b 50 mcg (n = 125), IFNB-1b 250 mcg
(n = 124) or placebo (n = 123). At a median of 21.1 years after RCT
enrolment, 98.4% (366/372) were identified and 81 deaths recorded
(21.8%). Those originally randomized to IFNB-1b 250 mcg had a
significant reduction in all-cause mortality over LTF compared with
placebo (hazard ratio = 0.560, P = 0.0272), with a 39.3% reduced
risk of death by Kaplan–Meier estimates.
Methods: Investigators at the study sites attempted to identify the
causes of death of all participants in the original pivotal trial. The
National Death Index was the predominant source for such information. The data were then reviewed by a cause-of-death adjudication
committee, which made its determinations based on the available
information.
Results: To date, cause of death information has been adjudicated for
77.8% of deceased patients (63/81). The mean age at death was
51.8 years (SD = 8.9 years). Of these, 53/63 (84.1%) were judged to be
MS-related. The remaining causes of death were not over-represented
by any one category, and no unusual causes were noted. These relatively
early deaths included only six cancers and eight vascular deaths.
Conclusions: The great majority of the 63/81 deaths with cause of
death information were attributable either directly or indirectly to MS
(84.1%). This reflects the relative youth of this RCT-derived cohort,
which had a mean age at death that was 6 years younger than the
overall cohort. This is consistent with MS mortality data from natural
history sources.
Supported by Bayer HealthCare Pharmaceuticals, Montville, NJ,
USA.
P430
Mortality and survival trends in US multiple sclerosis
patients
S. Reshef, G. Cutter, D.W. Kaufman, H. Golub, R. Preblick,
A. Bruckner, V. Knappertz
Bayer HealthCare Pharmaceuticals, Inc (Montville, US); University
of Alabama (Birmingham, US); Boston University (Boston, US);
S99
Care-Safe LLC (Newton, US); Bayer Schering Pharma AG (Berlin,
DE)
Objective: To assess current survival patterns and cause-specific
mortality in cohorts of patients with multiple sclerosis (MS) in the
US. Despite the importance of this disease, mortality studies of MS
patients have been limited, often examining small populations within
a restricted geography, with a short duration of follow up and without
a comparison group. Consequently, mortality trends in MS have been
difficult to assess.
Methods: A longitudinal, population-based study of data from a
large, i3-affiliated health plan and a US-based MS registry [North
American Committee on MS (NARCOMS)] was undertaken. The
health plan database captures 39 million individuals, spanning
1993–2008. Patients were selected through an algorithm combining
International Classification of Diseases (ICD)-9 codes and diseasemodifying treatment information. A non-MS comparison cohort from
the same population pool was identified and matched 3:1 on gender,
age, geographic residence and year of first identification of MS in the
database. NARCOMS has followed up over 34,000 individuals since
its inception in 1993. To assess mortality and survival trends, individuals were followed through 2008 by linking their data to the
National Death Index (NDI) and Social Security Administration Data
Master File databases to obtain vital status, and date and cause of
death information by calendar year. All-cause and cause-specific
mortality rates will be described. Kaplan-Meier curves since birth
(lifespan) will compare survival in MS and non-MS patients.
Results: In the healthcare database, 25,032 individuals satisfied the
MS selection criteria and 75,096 without MS were selected for
comparison. The majority of individuals with MS were women
(76.9%), resulting in a female to male ratio of 3.3:1. Most MS patients
were 35–54 years (65.2%). A total of 4515 (18.0%) of the MS
patients had a follow-up time in the database of at least 5 years.
Information on 20,861 participants in the NARCOMS registry was
sent to the NDI to obtain vital status. Interim analysis of a sub-sample
of these patients indicated that 78.4% of participants were women,
with a female to male ratio of 3.6:1. A total of 42.4% of all MS
patients were 35–54 years. Additional demographic, socioeconomic
and survival information will be presented.
Conclusion: The results from this study will enhance our understanding of survival patterns and mortality risk in US patients with
MS.
Sponsored by Bayer HealthCare Pharmaceuticals, NJ, USA.
P431
Leukaemia related to mitoxantrone therapy in MS
patients: mortality rate and relationship
with the cumulative dose
L. Straffi, V. Martinelli, E. Perego, F. Esposito, G. Comi
University Hospital San Raffaele (Milan, IT)
Objectives: Acute leukaemia (AL), is a severe adverse event in
Multiple Sclerosis (MS) patients treated with mtoxantrone (MTX).
With regard to timing of this adverse event 87.5% of reported cases
occurred within three years of MTX exposure, in keeping with
oncology experience. Reported mortality from therapy-related-AL
(TRAL) in MS is about 24%, this is also in line with that of spontaneously arising acute myeloblastic leukaemia (AML). Nevertheless,
the real mortality rate of TRAL remain uncertain.
Materials and methods: We searched all reported cases of leukaemia secondary to MTX therapy for MS in European and American
literature and combined this with our Italian database for a total of
106 patients (89 AML; 3 chronic myeloid leukaemia; 4 acute
lymphoblastic leukaemia; 1 myelodysplasia; 9 not otherwise specified). In this study we collected age at onset AML, cumulative dose of
MTX, latency of TRAL onset, outcome of 58 patients (23 relapsingremitting, 5 progressive relapsing, 12 secondary progressive MS and
18 not otherwise specified) affected by AML. Not all patients characteristics were available in each case.
Results: Mean age at onset of AL was 46 ± 11 sd and 68 (64%)
were women. 38 deaths occurred in the 106 (36 %) TRAL patients
whose outcome was reported; however it is not known how other
many patients in remission subsequently died.
Mean cumulative dose of MTX was 77 mg/m2 ± 30.3 sd and the
mean latency of leukaemia onset after the end of MTX was
18 months ± 15. The most common type of AML was acute promyelocytic leukaemia 60% (n = 35). We did not find any significant
difference in sex, MS course, latency of TRMAL onset between
remitted and died patients. Age of onset TRMAL was older in patients
with bad outcome (47y compared to 41y). In our study the majority
patients developed TRAL less than 30 months after the end of MTX
therapy (range: 1-60 months; median 15 months), we did not find a
correlation between MTX cumulative dose and onset TRAL.
Conclusion: We find a higher risk of death in TRAL patients, the
risk of develop TRAL could not be related to a MTX dose, maybe
related to age. Further study are needed. The potential risks of MTX
treatment should be carefully considered and it is very important to
follow these patients for years after stopping MTX.
P432
Cost of multiple sclerosis in Czech Republic: COMS
study
J. Blahova Dusankova, T. Kalincik, M. Vachova,
V. Sladkova, A. Novotna, L. Lhotakova, J. Fiedler,
E. Havrdova
Charles University (Prague, CZ); Teplice Hospital (Teplice, CZ);
Faculty Hospital Olomouc (Olomouc, CZ); Regional Hospital
Pardubice (Pardubice, CZ); Hospital Ceske Budejovice (Ceske
Budejovice, CZ); University Hospital (Pilsen, CZ)
Objectives: Despite the fact that disease-modifying drugs have been
used in Czech Republic in patients with multiple sclerosis (MS) since
1996, the cost-of-illness analysis has not been calculated so far. Our
objective was to analyze the expenses related to MS with respect to
the level of disease severity.
Methods: Patients with MS from 8 centers in Czech Republic
participated in the prospective survey. A total of 909 subjects [659
females/250 males; mean age 40.9 ± 12 years (mean ± standard
deviation); disease duration 8.4 ± 7.6; Expanded Disability Status
Scale (EDSS) 3.4 ± 2.2 (median 3, range 0–9.5)] were included.
The questionnaire evaluated patient’s disease status (type of MS,
number of relapses, level of disability), consumption of medical and
non-medical resources, informal care and work capacity. Based on
3-month data, we have extrapolated annual total cost per patient. The
annual costs are presented in € and Czech koruna (CZK) for 2007.
Results: Total annual cost of MS in Czech Republic was estimated
at € 229,475,400 (6,378,237,079 CZK), with approximately 17,000
individuals affected by MS. Intangible cost per patient was estimated
at € 13,516 (375,192 CZK).
The patients in our cohort were stratified in 3 groups: those with
mild [65% (n = 589; EDSS 0–3.5), moderate [26% (n = 235; EDSS
4–6.5)] and severe disease [9% (n = 85; EDSS C7)]. Total annual
mean cost per patient increased with the disease severity from €
10,572 (293,480 CZK) for those with mild disease, € 15,927 (442,128
CZK) for those with moderate disease to € 26,185 (726,892 CZK) for
those with severe disease.
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Overall, the proportions of costs were as follows: direct medical
45%, direct non-medical 3%, indirect 17% and loss of income 34% of
total cost. The proportion of direct medical cost decreased, while that
of direct non-medical, indirect and loss of income increased with the
disease progression.
Conclusions: This is the first study in Czech Republic to show the
total cost of MS and its dependence on the disease severity. The
detailed cost-of-illness analysis will enable us to calculate the costs of
MS from the healthcare and social perspectives and to create basis for
the future cost-benefit calculations of different medical approaches.
Acknowledgment: The study was supported from the Czech
Ministry of Education (research program MŠM 0021620849).
P433
Quality of life of multiple sclerosis patients in Poland
assessed by MusiQoL questionnaire
A. Jamroz-Wisniewska, Z. Stelmasiak, H. Bartosik-Psujek
Medical University of Lublin (Lublin, PL)
Aim: The aim of this study was to assess the quality of life of multiple
sclerosis (MS) patients with the Multiple Sclerosis International
Quality of Life Questionnaire (MusiQoL), a disease-specific quality
of life scale.
Materials and methods: Eighty nine randomly chosen patients
with definite MS (according to McDonald criteria) were examined (64
F:25 M), mean age was 39.4 ± 9.2 years, mean disease duration—
10.9 ± 7.3 years. The disability of patients was assessed according to
the Expanded Disability Status Scale (EDSS). Each patient completed
at baseline and day 28 ± 7 the MusiQoL.
Results: There were no differences between sexes and depending
on marital status. Patients with RR-MS type (comparing to PP-MS
type and SP-MS type), people living in an urban area, employed ones
and high-educated presented better health-related quality of life.
Conclusions: Health-related quality of life in MS patients depends on
MS type, place of living (urban area can be associated with better
possibilities of treatment), status of employment (that also depends on
disability of a patient), and the level of education.
Supported by Merck Serono.
P434
The coexistence of multiple sclerosis and hereditary
spastic paraparesis in a patient: a case report
I. Yazici, N. Yildirim, Y. Zorlu
Izmir Tepecik Educational and Research Hospital (Izmir, TR)
Objective: Multiple sclerosis (MS) is a chronic disease characterized
by multiple areas of central nervous system (CNS) inflammation,
demyelination and axonal loss. Hereditary spastic paraparesis (HSP)
is characterized clinically by progressive spasticity and weakness of
the lower limbs and pathologically by retrograde axonal degeneration
of the corticospinal tracts and posterior columns.
Method: We identified a patient with clinical history and investigation findings consistent with the concurrence of both MS and HSP.
The mother and sister of patient gave a history of MS. Three members
of the family had a history likely to HSP. Laboratory and radiological
investigations, cognitive tests were performed. Genetic confirmation
for spastin gene mutation has been completed.
Case/results: The patient admitted to our outpatient clinic because
of the tight, heavy sensation affecting his leg arm and foot at the age
123
of 34. Tremor was noted at his left leg while standing two years ago
and a visual disturbance for a week at his right eye aged 33. On
examination at the age of 34 he had bilateral gaze evoked nistagmus,
mild spastic gait abnormality, left ankle clonus and hypertonicity of
both legs with flexor plantars responses. A diagnosis of MS was made
and intra-venous methylprednisolone was given. Over the subsequent
years the clinical findings of relapses of MS recorded and immunmodulatory therapy was planned. Recent neurological examination at
age 44 showed brisk lower limb reflexes with flexor plantars
responses, spastic gait abnormality and impaired vibration sense in
the lower limbs. He had been diagnosed with anxiety depression
additionally. Routine haemotological and biochemical parameters
including serum B 12 levels, liver, renal, thyroid tests were normal.
Analysis of CSF could not be performed. Brain MRI showed periventricular white matter lesions. In detailed neuropsychological
assessment there was an evidence of mild cognitive impairment.
SPG4 locus was detected and a heterozygous one pair deletion in
exon 6 (c.310_311 insA) of the spastin gene has been found. This
mutation has been confirmed in one of the offspring with a clinical
phenotype of pure HSP.
Conclusion: We have described a patient who had clinical findings
clear cut relapses and remissions of relapsing remitting MS and HSP
caused by a deletion in exon 6 of the spastin gene. If this coexistence
is not coincidence the mutation in the spastin gene may be a strong
susceptibility locus for MS.
P435
Clinicopathological features of a fulminant case of acute
disseminated encephalomyelitis
L. Schirmer, C.L. Seifert, S. Pfeifenbring, S. Wunderlich,
C. Stadelmann, B. Hemmer
Klinikum rechts der Isar (Munich, DE); University Medical Centre
Göttingen (Göttingen, DE)
Acute disseminated encephalomyelitis (ADEM) is a rare and usually
monophasic demyelinating disease of the central nervous system.
Here we report the clinical course and pathological features of a
fulminant case of acute disseminated encephalomyelitis (ADEM). A
52-year-old woman presenting with subacute tetraparesis was initially
admitted with the diagnosis of a multi-focal glioma. MRI revealed
confluent bihemispherical and periventricular white matter lesions.
CSF analysis showed only a mild pleocytosis. A brain biopsy revealed
an inflammatory process rather than a malignant pathology. After the
biopsy the patient rapidly deteriorated with loss of consciousness and
decerebrate posturing. Cerebral MRI revealed progressive edema and
signs of a cerebral herniation. The patient was treated with high dose
steroids followed by plasma exchange. Follow-up CSF analysis
revealed a moderate pleocytosis and intrathecal immunoglobulin
synthesis. Cerebral vasculitis and Hashimoto’s encephalitis could be
ruled out, and paraneoplastic antibodies were not detectable. Additional histopathological stainings demonstrated active perivascular
demyelination with infiltration by macrophages and T cells confirming the diagnosis of ADEM. Furthermore, an accompanying axonal
damage with presence of APP positive spheroids was evident. Following plasma exchange, the patient’s condition improved, and she
regained consciousness. Clinical follow-up six months after disease
onset did not reveal any motor or sensory deficits, even though
moderate neuropsychological deficits were still evident accompanied
by a pronounced brain atrophy of both gray and white matter in the
MRI.
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P436
The spectrum of neuromyelitis optica associated
with aquaporine-4 antibodies: clinical and imaging
features of a cohort of 7 Caucasian patients
E. Coutinho, R. Taipa, R. Felgueiras, P. Pinto, A.M. Silva,
E. Santos, M.I. Leite
Hospital Santo António (Porto, PT); John Radcliffe Hospital
(Oxford, UK)
Introduction: Neuromyelitis optica (NMO) is an autoimmune,
inflammatory and demyelinating disease of the central nervous system that affects predominantly optic nerve and spinal cord, though
brain can also be involved. The detection of specific aquaporine-4
autoantibody (AQP 4 ab) has allowed us to diagnose the disease more
easily, recognize the large spectrum of the disease and treat promptly
most of our patients.
Objectives: To review clinical and imaging features of our patients
with AQP4ab mediated NMO followed in our Neuroimmunology
clinic.
Methods: Retrospective analysis of patient’s notes and MRIs.
Results: We identified seven Caucasian females with AQP4 ab
positive disease. Wide range of age at onset (13–76); mean disease
duration at last follow up was 6.6 years (interval 1–19). Initial
manifestations were myelitis in 4 patients and brainstem symptoms in
3 [(vomiting + hiccups + unsteadiness); (vomiting + ophthalmoparesis + limb motor deficit); (ophthalmoparesis + unsteadiness)]. At
some point of the disease, 6 patients had myelitis (transverse myelitis
in 2; partial myelitis in 4) and 3 had optic neuritis. Four had other
autoimmune diseases (2x myasthenia gravis, thyroiditis and lupus)
and six had anti-nuclear antibodies. Two of those patients that
presented with myelitis had longitudinal extensive lesions ([3 vertebral segments), one had a short lesion and the other had no lesions
in the initial MRI. All three patients that presented with brainstem
symptoms had matching MRI lesions. Treatment included intravenous and oral steroids, these associated with long-term immunosuppression.
One patient died due to respiratory insufficiency, two are wheelchair bound and the other four have minimal symptoms. The group of
patients with significant functional disability had a mean diagnosis
delay of 9.7 years while in the other patients the delay was 3.5 years.
Conclusion: We highlight the importance of considering this
diagnosis in some particular situations, such as: (1) beginning of
symptoms in very young or old patients; (2) patients with other
autoimmune diseases; (3) patients with brain stem symptoms as initial
manifestation; and also in patients with (4) partial myelitis/no optic
nerve involvement and (5) with normal first spine MRI.
P437
Neuromyelitis optica spectrum disorder:
the importance of NMO-IgG in clinical practice
M. Radaelli, V. Martinelli, L. Moiola, D. Privitera,
D. Dalla Libera, M. Rodegher, B. Colombo, R. Fazio,
R. Furlan, G. Comi
University Hospital San Raffaele Hospital (Milan, IT)
Background: Neuromyelitis Optica (NMO) is the first demyelinating
disease of the CNS in which a specific biomarker has been found. The
discovery of the antibody (NMO-IgG) has brought to consider NMO a
syndrome (NMO Spectrum Disorder) which includes also limited
forms of the disease such as Longitudinally Extensive Transverse
Myelitis (LETM) and Recurrent Optic Neuritis (rON). The aim of our
study was to characterize patients affected by optico-spinal diseases
and to investigate the prognostic value of the NMOsd classification.
Methods: We collected patients affected by recurrent myelitis,
rON or both with an onset brain MRI not fulfilling the criteria for MS.
Patients that at the end of the investigations reached a diagnosis of
MS or other alternative diagnosis were excluded by the study.
Results: We recruited 79 patients: compatible clinical findings and
NMO-IgG positivity led to a diagnosis of NMO Spectrum Disorder
(NMOsd) in 48 of these patients. The mean age of onset and the mean
disease duration were 36 years and 7.5 years respectively. Twenty
patients (42%) developed brain MRI lesions during the follow-up.
A LETM was present in 80% of patients. After 6 years from the onset
half of our patients showed a severe disability defined as an EDSS of
6 or a blindness in at least one eye. When we compared patients with
a defined NMO (n = 32) with patients with limited forms of the
disease (n = 16) we didn’t find any significant difference both in
terms of baseline characteristics and in the clinical outcome except
for an earlier age at onset. On the contrary when we compared our 48
patients with NMOsd with the other 31 patients of the original cohort
with recurrent myelitis or rON who didn’t satisfy the criteria for
NMOsd, we found that the first group presented a higher prevalence
of female gender and a higher frequency of extensive spinal cord
lesions. Moreover they showed a significant lower rate of response to
the first immunosuppressive drug, a higher ARR, and a higher rate of
severe disability.
Conclusion: Our study shows that limited forms of NMO such as
LETM and rON share the same unfavorable outcome of Definite
NMO and the use of NMO-IgG antibody allows identifying patients
with a worse prognosis at early stages of the disease. NMO-IgG
determination is strictly recommended in the presence of a first attack
of Myelitis or Optic Neuritis and in the presence of a positive status
an immunosuppressive therapy has to be start as soon as possible.
P438
Analysis of 103 Hungarian patients with neuromyelitis
optica spectrum disease
M. Banati, E. Koszegi, P. Csecsei, L. Bors, B. Hemmer,
A. Berthele, T. Molnar, T. Csepany, C. Rozsa, M. Simo,
G. Jakab, S. Komoly, Z. Illes
University of Pecs (Pecs, HU); Technical University (Munich, DE);
University of Debrecen (Debrecen, HU); Jahn Ferenc Teaching
Hospital (Budapest, HU); Semmelweis University (Budapest, HU);
Uzsoki Teaching Hospital (Budapest, HU)
Objectives: Neuromyelitis optica (NMO) is an antibody(Ab)-mediated immune disorder directed against aquaporin 4 (AQP4). In a part
of cases the clinical syndrome is incomplete, and only relapsing/
bilateral optic neuritis (RION/BON) or longitudinally extensive
transverse myelitis (LETM) are detected.
Methods: We compared 103 patients with NMO spectrum (37
NMO, 28 RION and 38 LETM) to 159 patients with relapsingremitting multiple sclerosis (RRMS) and 92 patients with non-NMO.
AQP4 molecules are also expressed in gastrointestinal (GI) tract.
Therefore we examined the presence of GI Abs in the sera of patients
with NMO spectrum and patients with MS.
Results: The percentage of females and age at onset were higher in
NMO spectrum compared to MS (p B 0.01). Relapse frequency was
higher in AQP4+ cases (p \ 0.001) and 22% of 125 relapses were
preceded by infections. Mean EDSS was higher after a shorter followup in NMO compared to RRMS. Non-NMO controls had no antiAQP4 Abs in contrast to NMO, LETM and RION (p B 0.001); titres
were similar in NMO, LETM and RION. Brain MRI was abnormal in
16% of NMO spectrum in contrast to 100% of RRMS and 67% of
123
S102
non-NMO (p \ 0.001); 88% of NMO had LETM. CSF was abnormal
in 49%: oligoclonal bands were present in 16% compared to 97% of
RRMS (p \ 0.001). Additional autoimmunity was associated with
36% of the NMO spectrum, commonly in females (40.9 vs. 18.2%).
Out of 329 relapses, 7% spontaneously improved and 18% were
steroid-resistant. The number of relapses treated with plasma exchange
(PE) was higher among seropositive patients (p \ 0.01). Only 4% of
RION relapses required PE, in contrast to 13% in NMO and 24% in
LETM. 64% of NMO, 53% of LETM and 29% of RION are chronically
immunosuppressed. The percentage of patients testing positive for antiSaccharomyces cerevisiae Abs (ASCA) IgG were higher in the
AQP4+ NMO spectrum, NMO and LETM groups compared to MS
group (14.3% and 15% vs. 3.5%, p \ 0.05; 20 vs. 3.5%; p = 0.01). The
percentage of anti-intrinsic factor (IF) IgG Ab was higher in LETM group
than in MS group (6.7 vs. 0%; p = 0.01). The most explicit differences
were observed in patients with LETM, where the percentage of antiparietal cell (PC) IgG Ab was also elevated compared to patients with
RION (21.6 vs. 3.7%; p \ 0.05). In contrast, in the case of patients with
RION lower positivities of Abs were found.
Conclusion: Based on our data, we propose differential diagnostic
and therapeutic algorithms of NMO spectrum.
P439
Is cognitive dysfunction in multiple sclerosis
and Neuro-Behçet’s disease similar?
A. Bingol, B. Topcular, S. Yildiz, P. Kaya, M. Tutuncu,
O. Demirci, D. Uluduz, S. Saip, A. Siva
Mayis Psychology Center (Istanbul, TR); Bakirkoy Prof. Dr. Mazhar
Osman Teaching and Research Hospital for Mental Health
and Neurological Disorders (Istanbul, TR); University Cerrahpasa
(Istanbul, TR)
Objective: Cognitive impairment is a common problem in Multiple
Sclerosis (MS), effecting 40-65% of patients according to literature,
attention and information processing speed, memory and executive
functions being the most commonly affected functions. Studies on the
impact of Neuro-Behcet’s disease (NBD) on cognitive functions
although limited reveal cognitive impairment in 33.3–46.1% of patients.
Studies document a pattern consisting of memory, attention and executive function impairment in NBD patients, a pattern similar to MS.
Comparative studies on severity and pattern of cognitive dysfunction in
MS and NBD are lacking. Therefore, we aimed to study severity and
compare patterns of MS and NBD related cognitive impairment.
Methods: Inclusion criteria were MS diagnosis according to
revised McDonald’s Criteria (Polmann et al 2005) and Behcet’s
Disease according to International Study Group for Behçet’s Disease
diagnostic criteria and NeuroBehcet’s Disease according to predefined criteria (Siva and Saip 2009);18-65 years of age, primary school
or higher education. Exclusion criteria were disease exacerbation or
pulse steroids within last 30 days and concomitant severe psychiatric
disorder. The neuropsychological battery included Paced Auditory
Serial Addition Test(3’’),Selective Reminding Test, Spatial Recall
Test,Symbol Digit Modalities,Word List Generation.
Results: Forty MS patients and 40 NBD patients were included.
There were 16 females, 24 males (F/M: 0.66) in NBD group, the mean
age was 38.09 ± 10.17. Mean age at disease onset was 24 ± 8. In the
MS group, the female/male ratio was 2.05. Mean age was
37.2 ± 9.80, mean age at disease onset was 25.3 ± 9.1. All MS
patients had a relapsing remitting course. There were no significant
differences in group demographics except gender. The cognitive
scores of NBD group were: PASAT 30.75 ± 26.11; SRT 35.8 ± 9
45/5.95 ± 2.67;
SPART
6.4 ± 3.2
/3.45 ± 2.67;SDMT
29.84 ± 19,50; WLG 12.8 ± 6.34. The cognitive scores for MS
123
group were PASAT 59.98 ± 20.19; SRT 47.7 ± 3.38/6.36 ± 1.28;
SPART 13.95 ± 1.69/2.35 ± 1.02;SDMT 29.54 ± 15.53; WLG
20.42 ± 6.01. MS group had higher test scores on PASAT, SRT,
SPART and WLG tests compared to NBD group (0.001;
\0.001; \0.001, 0.001; respectively) refering to sustained attention
and information processing speed, verbal and visuospatial memory
and executive functions respectively.
Conclusion: Results of this study reveal that MS and NBD patienst
have similar cognitive profiles, with NBD group being more significantly impaired.
P440
Cognitive dysfunction in Neuro-Behçet’s disease
B. Topcular, A. Bingol, P. Kaya, S. Yildiz, D. Uluduz,
A. Siva, S. Saip
Bakirkoy Prof. Dr. Mazhar Osman Teaching and Research Hospital
for Mental Health and Neurological Disorders (Istanbul, TR);
Mayis Psychology Center (Istanbul, TR); University Cerrahpasa
(Istanbul, TR)
Background and objective: Behcet’s Syndrome (BS) is a multi-system,
vascular-inflammatory disease of unknown origin, involving the nervous
system in a subgroup of patients. Studies on the impact of Neuro-Behcet’s
disease (NBD) on cognitive functions are limited. Therefore we aimed to
evaluate cognitive functioning in NBD patients.
Methods: Inclusion criteria were: Behcet’s Disease according to
International Study Group for Behçet’s Disease diagnostic criteria and
NBD according to predefined criteria (Siva and Saip 2009); 18–65 years
of age, primary school or higher education. Exclusion criteria were:
disease exacerbation or pulse steroids in the last 30 days and concomittant severe psychiatric disorder. The neuropsychological battery included
Selective Reminding Test, Spatial Recall Test, Symbol Digit Modalities,
Word List Generation, Paced Auditory Serial Addition Test(3’’).
Results: Forty patients with NBD were tested. There were 16 females,
24 males (F/M: 0.66). The mean age was 38.09 ± 10.17. Mean age at
disease onset and disease duration were 24 ± 8 and 9.3 ± 6.2 years
respectively. Cognitive Test scores were as follows: PASAT:
30.75 ± 26.11, SRT: 35.8 ± 9.45/5.95 ± 2.67, SPART: 6.4 ± 3.2 /
3.45 ± 2.67; SDMT: 29.84 ± 19.50, Word List Generation:
12.8 ± 6.34. Patients with test scores 2 SD below 50th percentile in at
least two tests were considered cognitively impaired. 31.4% of patients
were cognitively impaired. 60% of patients had depression according to
Beck Depression Inventory. Depression was more frequent in cognitively
impaired patients (76% in patients with cognitive impairment vs. 44% in
patients without cognitive impairment). Sustained attention and information processing speed (57.5%), visuospatial and verbal memory(38.09
and 33.3%, respectively) and executive functions(27.27%) were the most
commonly effected cognitive functions.
Conclusion: Results of this study reveals that cognitive impairment is a considerable component of Neuro-Behcet’s Disease and
must be taken into account when managing patients with NBD.
Neuro-oncology
P441
RTVP-1 regulates the migration and invasion of glioma
cells via interaction with N-WASP and hnRNPK
A. Ziv-Av, M. Barda-Saad, R. Sarid, S. Cazacu, H. Lee,
C. Xiang, S. Finniss, C. Brodie
Bar-Ilan University (Ramat-Gan, IL)
S103
Gliomas are characterized by increased infiltration into the surrounding normal brain tissue. We reported that RTVP-1 is highly
expressed in gliomas and that its expression is correlated with the
malignancy of astrocytic tumors and with poor prognosis. In addition,
RTVP-1 is involved in the regulation of migration of glioma and
glioma stem cells. To further delineate the molecular mechanisms
underlying RTVP-1 effects, we performed a pull down assay followed
by mass spectroscopy, and found that RTVP-1 was associated with
the actin polymerization regulator, N-WASP. The association of
RTVP-1 and N-WASP was further validated by co-immunoprecipitation and FRET analysis. We found that overexpression of RTVP-1
increased, whereas silencing of this protein decreased cell spreading
and migration of glioma cells. The effect of RTVP-1 was mediated by
N-WASP since silencing of N-WASP abolished RTVP-1 effects. In
addition, RTVP-1 increased podosome formation in glioma cells and
this effect was also mediated via its interaction with N-WASP.
Another protein that was found to interact with RTVP-1 by the pull
down assay is hnRNPK, which has been recently reported to associate
with and to inhibit N-WASP function, RTVP-1 decreased the association of N-WASP and hnRNPK, therefore suggesting that RTVP-1
may activate N-WASP by decreasing its association with hnRNPK. In
summary, we report that RTVP-1 regulates glioma cell spreading,
migration and invasion and that these effects are mediated via interaction with N-WASP and by interfering with the inhibitory effect of
hnRNPK on the function of N-WASP. Thus, RTVP-1 is a potential
therapeutic target for the inhibition of glioma cell and glioma stem
cell migration and invasion.
P442
Toll-like receptors and inflammatory cells in brain
tumours
D. Labunskiy, T. Fedotova, V. Poleshchuk, N. Plotnikova
University of Northern California (Santa Rosa, US); Tver State
Medical Academy (Tver, RU); Research Center of Neurology
(Moscow, RU); Mordovian State University (Saransk, RU)
Oligodendrogliomas are a type of glioma that rise from the oligodendrocytes of the brain or from a glial precursor cells.
Medulloblastomas are a highly malignant primary brain tumors that
originate in the cerebellum or posterior fossa. Meningiomas are the
second most common primary neoplasms of the CNS, arising from
the arachnoid ‘‘cap’’ cells of the arachnoid villi in the meninges.
Immune infiltration of advanced human gliomas has been shown,
but it is doubtful whether these immune cells affect tumor progression. It could be hypothesized that this infiltrate reflects recently
recruited immune cells that are immediately overwhelmed by a high
tumor burden. Toll-like receptors (TLRs) are a family of evolutionarily conserved molecules that directly detect pathogen invasion or
tissue damage and initiate a biological response. TLRs initiate the
potent proinflammatory response to infection, are essential for the
establishment and maturation of adaptive immunity, being a targets to
adjuvants.
Under our observation were 27 patients with oligodenrdrogliomas
(12 men and 15 women, 18–72 years old), 19 patients with medulloblastoma (7 men and 12 women, 23–81 years old), and 15 patients
with meningiomas (9 men and 6 women, 21–76 years old.) The
control group comprised by 51 neurologically healthy donors (18 men
and 33 women, 17–69 years old.) We studied monocytes and human
umbilical vein endothelial cells from all these patients and control
group in vitro by stimulation and blockage of inflammatory responses.
Cultured cells were treated with serum from all brain tumors patients,
showed a strong inflammatory response that was blocked when TLR2/
4 or cellular fibronectin (cFN) or HSP60 were blocked. The blockage
of medulloblastoma patients cells was considerably higher than in
cells from oligodendroglioma or meningioma patients. In control
group inflammatory response to TLR stimulation was not so marked.
Local TLR stimulation is an interesting way to induce anti-tumor
immunity. Experimental models of brain tumors could provide
insights into pharmacological correction using inflammatory cells and
TLR stimulation.
The immuno-stimulatory properties of TLRs are being used to
generate tumor-specific immune responses to CNS tumors while the
immuno-modulatory properties are being used to suppress damaging
inflammatory responses to cerebrovascular diseases. Hence, the TLRs
offer novel targets for the treatment of neurological diseases, and
some brain tumors particularly.
P443
Anti-SOX1 antibodies are markers of different tumour
types in paraneoplastic neurological syndromes
M. Tschernatsch, K. Sivamaran, P. Singh, T. Scheper,
M. Kaps, F. Blaes
Justus-Liebig-University (Giessen, DE); Euroimmun AG
(Lübeck, DE)
Objective: Antibodies against SOX1 have been described in patients
with paraneoplastic Lambert-Eaton-myasthenic-syndrome, in patients
with anti-Hu positive paraneoplastic neurological syndromes with
small cell lung cancer (SCLC) and in patients with SCLC alone,
respectively.
Methods: We analysed a total of 87 patients with paraneoplastic
neurological syndromes and a variety of underlying tumour types for
the presence of anti-SOX1-antibodies. Testing for anti-SOX1-antibodies was carried out suing SOX1-Immunoblot with the recombinant
human SOX1-protein. Anti-SOX1-antibodies were detectable in 46%
of all analysed patients, associated tumours varied from lung cancer
to prostate cancer and different gynaecological tumours. Anti-SOX1
antibodies are markers not only for LEMS and small cell lung cancer,
but are also associated with a variety of paraneoplastic neurological
syndromes and associated tumours. Therefore detection for antiSOX1-antibodies should not only be done when lung cancer is suspected, but included into general tumour work-up.
P444
The Ommaya Green Project at the University
of Texas-M.D. Anderson Cancer Center
S. Tummala, D. Blas-Boria, L. Brown, J. Walker,
D. Schultz, S. Lee-Kim, E. Lee, I. Tremont-Lukats
University of Texas-M.D. Anderson Cancer Centre (Houston, US)
Objectives: To make the Ommaya kits more user-friendly.
Methods: We involved physicians, Advanced Practice Nurses
(APNs), nurses, the Centre Business Manager, and the Centre
Administrative Director in the Brain & Spine Centre at our institution;
we ran a cause and effect analysis to determine the main issues, and
we collected baseline data from 19 consecutive patients attending the
Ommaya Clinics, to validate our hypothesis that Ommaya kits are
hard to use and mostly wasted. Our measurements were (1) Ease of
use as rated by staff satisfaction; (2) Percent of items wasted. Then,
we created a pilot kit working with the manufacturer of the Ommaya
kits to obtain the items we needed, assembled all its components, and
retested the same measurements used to collect the baseline data with
the conventional Ommaya kits.
123
S104
Results: With the Ommaya kits, our staff found it easy to use 21%
of the time, wasting 46% of its items. With the modified kits, staff
satisfaction increased from 21 to 68%. The staff could decrease waste
from 46 to 20%. We could not eliminate waste completely because
patients have different needs at time of procedure. The estimated
savings is US$ 9860 a year. So far, there have been no complications
from this modified Ommaya kits.
Conclusions: The housestaff could initiate and develop a quality
improvement project that yielded a positive result. This is likely to
result in changes to the Ommaya kits supplied to our institution. We
plan to roll this out to other services that use Ommaya kits, such as the
Melanoma, Leukemia, and Lymphoma services at the M.D. Anderson
Cancer Centre.
P445
Could helical tomotherapy do whole brain radiotherapy
and radiosurgery?
Y. Kirova, C. Chargari, S. Zefkili, F. Campana,
V. Die´ras, A. Fourquet
Institut Curie (Paris, FR)
Background: Whole brain radiotherapy (WBRT) remains the standard
management of breast cancer patients with brain metastases, allowing
for symptomatic improvement and good local control in most
patients. However, its results remain suboptimal in terms of both
efficacy and toxicity. In highly selected breast cancer patients, stereotaxic radiotherapy demonstrates a very good local control with a
low toxicity. With the purpose of improving the efficacy/toxicity
ratio, we report the association of integrated boost with WBRT in a
breast cancer patient with brain metastases.
Materials and methods: A 40-year-old female presented with
multiple brain metastases from breast cancer measuring 17 mm in
greatest dimension. She was deferred for Helical Tomotherapy (HT),
delivering 30 Gy using 6 MV photons, at 3 Gy per daily fraction, in
the whole brain for 14 days, concurrently with vinorebine. Integrated
synchronous boost treatments were used, in order to deliver 36 Gy in
the growth tumoral volumes.
Results: Six months after HT, the metastases were stable in size,
with intra-tumoral necrosis and rounded with an edema that accurately drew the shape of isodoses. Two and a half years after
completion of helical tomotherapy (HT), the patient experienced
clinical and radiological complete remission of her brain disease. No
delayed toxicity occurred and the patient kept her hair without need of
radiosurgical procedure.
Conclusion: The HT provided a high dosimetric homogeneity,
delivering integrated radiation boosts, and avoiding critical structures
involved in long-term neurological toxicity. Further assessment is
required and recruitment of breast cancer patients into clinical trials is
encouraged.
P446
Posterior reversible encephalopathy manifested
by refractory status epilepticus in two patients
under chemotherapy
H. Foreid, M.C. Pires, R. Peralta, C. Bentes, J. Pimentel,
L. Albuquerque
Hospital de Santa Maria (Lisbon, PT)
Introduction: Posterior reversible encephalopathy syndrome (PRES)
is a clinical-radiological syndrome characterized by brain symmetric
123
lesions of vasogenic edema without a clear vascular territory,
involving the white matter but also basal ganglia and cortex, preferentially in posterior topography. These usually reversible lesions may
be irreversible due to ischemia, showing restricted diffusion on the
diffusion-weighted imaging (DWI) and corresponding apparent
coefficient (ADC) map. Clinical manifestations include headache,
cortical blindness, seizures, focal signs and altered state of consciousness. The association between PRES and several chemotherapy
regimens is increasingly described. Several hypotheses for the
underlying pathophysiological mechanism are a direct toxic effect
with damage of the blood-brain barrier, the induction of vasospasm
and microthrombosis, or the result of a tumour lysis syndrome. The
safety in the re-administration of the same chemotherapic regimen is
controversial. We report two clinical cases of status epilepticus (SE)
and PRES in oncologic patients.
Clinical cases: A 19-year-old man with a Hodgkin lymphoma
under ABVD (Adriamicin, Vinblastine, Bleomicine, Dacarbazin),
and a 44-year-old woman under Docetaxel and Gemcitabine
because of a femoral sarcoma developed refractory SE. Brain MRI
depicted brain lesions compatible with PRES: the 1st patient presented bilateral paracentral parieto-occipital lesions with restricted
diffusion on DWI. The 2nd patient had frontal-parietal-occipital
symmetric lesions with no hydric restriction on ADC as well as
transient intracranial vasospasm in the Transcranial Doppler (right
middle and anterior cerebral arteries, and basilar artery). Both
patients recovered from SE under anticonvulsant treatment, blood
pressure control and nimodipine. Also, there was an improvement of
MRI abnormalities. The 1st patient repeated ABVD afterwards
without recurrence of PRES.
Conclusions:
– Clinical suspicion of PRES is required in patients with acute/
subacute neurologic dysfunction under chemotherapy.
– SE may be the first manifestation of PRES and its treatment may
include the control of blood pressure and vasospasm.
– PRES is an emergency which should be early recognised and
treated to avoid irreversible damage.
– It is important to report such cases in order to better clarify the
actual relation between chemotherapy, other concomitant conditions, and the development of PRES.
P447
Atypical teratoid/rhabdoid tumour in an adult
J. Marques, S. Costa, C. Firmo, L. Albuquerque,
E. Aronica, J. Pimentel
Portuguese Institute for Oncology (Lisbon, PT); Hospital Prof. Dr.
Fernando Fonseca (Amadora, PT); Hospital de Santa Maria (Lisbon,
PT); Academic Medical Centre (Amsterdam, NL)
Introduction: The Atypical Teratoid/Rhabdoid Tumor (ATRT) is a
highly malignant neoplasm, composed of elements of different nature,
occurring mainly in the pediatric age, with \30 cases described in
adults. It’s usually associated with hSNF5/INI1 gene mutation (a
tumor suppressor gene located in the 22q11.2 chromosome). Prognosis is dismal, usually less than a year survival in the general
population and nearly 21 months in adults.
Clinical case: 20-year-old male patient with progressively worsening headache in the previous 3 weeks. MRI showed an extensive
intra-axial fronto-temporal lesion, with gadolinium enhancement. A
macroscopic total resection of the tumor was performed. The neuropathologic exam was compatible with ATRT. Immunohistochemistry
for INI1, although positive in adjacent endothelial cells, was completely negative in the tumor cells. The adjuvant treatment consisted
S105
in focal radiotherapy and chemotherapy (ICE protocol) for 6 months.
He has been recurrence-free for 20 months.
Conclusions: We highlight that, despite its rarity, the ATRT should be
considered in the differential diagnosis of brain tumors in the adult population. The absent INI1 expression in the tumor cells supports this diagnosis.
Despite the dismal prognosis, some cases have been reported with a more
favourable outcome associated with a more aggressive treatment.
P448
A central nervous system germinoma presenting
as an inflammatory pituitary lesion
A. Merlini, G. Liberatore, L. Straffi, M. Terreni, M. Losa,
M. Rodegher, V. Martinelli, G. Comi
University Hospital San Raffaele (Milan, IT)
Objective: Description of a suprasellar germinoma with progressive
visual loss and panhypopituitarism masquerading as an inflammatory
pituitary lesion.
Methods: Observational case report.
Results: A 26-year-old man referred a 1-year history of progressive
visual loss. Right eye visual acuity was 1/10 and left eye acuity was 0/10.
Hormonal and osmolarity evaluations revealed panhypopituitarism with
diabetes insipidus. Suspecting an infundibular-hypophyseal pathology,
brain magnetic resonance (MRI) was performed and showed an enlarged
pituitary stalk and loss of the neurohypophyseal T1-hyperintensity. Optic
nerves displayed bilateral swelling, T2-hyperintensity and gadolinium
enhancement of the intracanalicular portion, while the intraorbital portions were both markedly atrophic. Cerebrospinal fluid (CSF) contained
less than 1 cell/ul and normal protein content. There was intrathecal IgG
synthesis with oligoclonal banding.
The patient refused a diagnostic biopsy of the lesion. MRI and CSF
findings suggested an inflammatory/granulomatous lesion and the patient
was treated with 10 monthly cycles of cyclophosphamide (CTX) at 1.4 g/
m2. After three infusions, MRI showed shrinkage of the thickened pituitary stalk and reduced enhancement of the optic nerves. After patient’s
decision to stop therapy, visual function further deteriorated and brain
MRI showed significant expansion of the suprasellar lesion, which had
inhomogeneous enhancement and cranially dislocated the optic chiasm,
and an enlarged, contrast-enhancing pineal gland. CSF analysis revealed
elevated b-chorionic gonadotropin. A transsphenoidal biopsy was finally
performed, which showed nodules of Oct-4 positive cells, the hallmark of
germ cell tumors. The patient underwent surgical exeresis of the lesion
followed by radiotherapy.
Conclusions: Suprasellar germinomas with simultaneous involvement
of optic nerve and suprasellar structures are rare and the diagnosis is
challenging, especially because germinomas are extremely immunogenic
and the inflammatory infiltrate could mask the underlying neoplastic
lesion. Biopsy should be readily performed to allow for adequate treatment, which is curative in most patients. Interestingly, in our patient the
outburst of the disease occurred after stopping CTX. Immunosuppressive
treatment might have altered the precarious balance between the tumor
cells and the inflammatory infiltrate, affecting only partially tumor
growth, while significantly reducing the immune response.
P449
Paraneoplastic cerebellar degeneration due
to a primary germinoma of the thymus
N. Solà-Valls, L. Gaba, E. Muñoz, B. Mellado, T. Ribalta,
A. Saiz, F. Graus
Clinic Barcelona (Barcelona, ES)
Introduction: Paraneoplastic cerebellar degeneration (PCD) is characterized by subacute pancerebellar ataxia mainly associated with
breast, ovarian and lung cancer. However, the association with germinoma is exceptionally rare. So far, only two patients have been
reported.
Objective: To describe a patient with PCD who improved after
treatment of an underlying thymic germinoma.
Case report: A 55-year-old man presented with difficulty on
walking for 1 month. On examination there was dysarthria, bilateral
horizontal nystagmus, dysmetria in both legs, and ataxic gait. Over
the ensuing 10 months, he became unable to walk alone. Additionally, he developed mild arm ataxia. Routine blood analysis, brain
MRI, and CSF examination were normal. Onconeural (Hu, Yo, Ri, Tr,
CV2, Ma2, amphiphysin), GAD, and anti-neuropil (NMDAR, AMPAR, GABAR, and CASPR2) antibodies were negative. Serum and
CSF did not show any specific immunoreactivity on rat brain sections
by an avidin-biotin immunoperoxidase technique. Whole body PET
scan with fluoro-desoxyglucose disclosed a positive nodule in the
thymus. A sonographic investigation of the testis showed a suspicious
lesion in the left testicle but no malignant infiltration was found after
orchiectomy. The thymic nodule was removed and the pathological
examination revealed a germinoma surrounded by a heavy infiltrate of
T and B lymphocytes. Gait ataxia clearly improved 2 weeks after
surgery. Further improvement was observed after three cycles of
chemotherapy and treatment with steroids. At last follow-up 6 months
after surgery, the patient only presents a minimal gait ataxia.
Conclusion: The relationship between germinoma and PCD has
been rarely described. Thymus has a specific role in the immune
system and the location of the germinoma in this gland could promote
the development of PCD. Our case illustrates that studies to rule out
an underlying tumor are mandatory in any patient with rapidly progressing cerebellar ataxia despite the absence of anti-neuronal
antibodies if there are no other causes that justify the cerebellar
syndrome.
P450
Pontine granular cell astrocytoma: a rare lesion in even
rarer localisation
A. Ferreira, O. Rebelo, H.P. Grebe
Hospital São Sebastião (Santa Maria da Feira, PT); Coimbra
University Hospital (Coimbra, PT)
Introduction: Granular cell astrocytoma (GCA) is a rare type of
malignant brain tumour with distinct morphologic features and poor
prognosis. The current World Health Organization (WHO) classification lists granular cells as a tissue pattern of glioblastomas. The few
published cases are essentially of hemispherical localization, with one
case each described in the cerebellum and in the spinal cord, none
primarily in the brainstem.
Case report: A 68-year-old male presented with gait instability and
paresthesias in the right half of the face and tongue as well as the left
body-half, which had developed within a month. Neurological
examination revealed right facial and tongue hypoesthesia, left
peripheral facial palsy, slight left hemiparesis and right dysmetria.
Magnetic resonance imaging showed a hyperintense, gadolinium
enhancing lesion affecting the pons, the right middle cerebellar
peduncle as well as the surrounding cerebellum and the right thalamus. Cerebrospinal fluid examination was inconclusive. A
stereotactic biopsy showed large Periodic-Schiff-Acid (PAS)-positive
cells surrounded by lymphocytes and was considered consistent with
CNS Whipple’s disease. Samples were collected for PCR testing for
Tropheryma whipplei and he started antibiotics. There was no clinical
improvement and test results were negative, so the treatment was
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stopped. The patient’s state deteriorated progressively, including
worsening hemiparesis, dysarthria and severe dysphagia, the latter
leading to recurrent respiratory infections. He died 8 months after
onset of symptoms. The autopsy confirmed a GCA (WHO grade III)
of the brainstem and cerebellum, extending to the cerebral hemispheres (diencephalon and internal capsules).
Discussion: GCA is a malignant brain tumour with only 60
published cases to our knowledge. They were mostly located in the
cerebral hemispheres. This is the first report with primary brainstem
localization. As in the present case, these tumours’ histological
features, including large cells with granular, PAS-positive cytoplasm, which can resemble histiocytes may lead, especially in small
samples, to difficulties in differential diagnosis with non-neoplastic
lesions. Although granular cell tumours in other localizations are
relatively benign, GCA has a poor prognosis, our patient’s course
is consistent with previous descriptions (mean survival time
9 months).
P451
Locally destructive growing glioblastoma multiform
presenting with trigeminal neuralgia: a case report
A. Tinchon, S. Oberndorfer, S. Pollanz, B. Calabek,
W. Grisold
Kaiser Franz Josef Hospital (Vienna, AT)
Objective: We report a rare case of glioblastoma multiforme (GBM)
with a locally destructive growth pattern through meninges, cranial
nerves, bone, as well as muscle and distant metastasis.
Methods: An analysis of the medical history was performed,
regarding cerebral imaging, clinical and histopathological findings.
Results: A 47-year-old male underwent surgery of a left temporal mass lesion in March 2009. Histologically a GBM was
diagnosed. Shortly afterwards, he was admitted due to left sided
neuropathic pain in the V2-segment of the trigeminal nerve and
abduction impairment of the left eye. He suffered from cluster like
headache, responsive to oxygen inhalation. MRI at this time showed
an infiltration of the cavernous sinus. The patient was treated
additionally with gabapentin and received a chemotherapy with
temozolomide according to the 5/28-day-schedule. Two months
later, he was admitted due to sustained face pain and headache. MRI
revealed a local destruction with origin in the left temporal lobe,
having destroyed the skull base and infiltrating the soft tissue of the
parapharyngeal region as well as the surrounding muscles of mastication. Furthermore, the left cavernous sinus was totally destroyed,
including the passing cranial nerves and the ventrally adjacent
paranasal sinuses. A breakthrough to the left orbital region clinically resulted in exophthalmos and optocinetic disorder of the left
eye. The patient received a second line chemotherapy with bevacizumab and radiotherapy of 30 Gy total dose in the target area.
Achieving slight pain reduction, he died in December 2009 as a
result of bilateral pneumonia and further tumor progression.
Autopsy revealed an extensive local destruction, as well as distant
metastases to lung, muscle, bone and diaphragm.
Conclusion: GBM rarely shows distant metastases or malignant
spinal cord compression in the course of the disease. In this case, post
mortem histology exhibited additional sarcomatous parts, which were
not even retrospectively reported in the first histological findings after
resection. These histological findings may be an explanation for the
aggressive biological behavior, resulting in extensive local destruction of the surrounding tissues. The pathophysiological mechanisms
of this phenomenon are not resolved at the moment, although genomic instability due to therapeutic intervention is discussed as possible
trigger.
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P452
Aggressive leptomeningeal gliomatosis
in neurofibromatosis type 1
D. Arkadir, E. Linetsky, E. Shalom, A. Lossos
Hebrew University-Hadassah Medical Center (Jerusalem, IL)
Objectives: To describe rare instances of aggressive leptomeningeal
gliomatosis in adult NF1 patients.
Methods: Case series of patients treated at our institution between
2009 and 2010.
Results: We have identified two adult Neurofibromatosis type 1
(NF1) patients with aggressive leptomeningeal gliomatosis. The first
patient was a 25-year-old woman with known familial NF1 who
presented with sub-acute headache and signs of increased intracranial
pressure. Magnetic resonance imaging (MRI) showed hydrocephalus
due to a space-occupying lesion in the right basal ganglia diagnosed
on a stereotactic biopsy as anaplastic astrocytoma WHO grade III.
Treatment with VP-shunt, steroids and a concomitant chemo-irradiation with temozolomide was followed by a monthly temozolomide
schedule with a significant clinical improvement and MR stabilization
over the next 6 months. Low back pain at this stage prompted MR
evaluation and diagnosis of extensive leptomeningeal seeding leading
within 3 months to progressive paraplegia and thereafter death despite
total neuro-axis irradiation and additional chemotherapy efforts. The
second patient was a 35-year-old woman with known familial NF1
and shunted hydrocephalus since childhood who developed sub-acute
nausea, cachexia and focal seizures. MRI revealed diffuse cerebral
and spinal leptomeningeal involvement associated with medullary
space-occupying lesion. CSF was uninformative but cerebral and
meningeal biopsy diagnosed leptomeningeal gliomatosis of high
grade glioma. Despite total neuro-axis irradiation and steroids, the
patient died 3 months after the diagnosis.
Conclusion: Aggressive leptomeningeal gliomatosis occasionally
occurs in adult NF1 patients and should be considered in the appropriate clinical and imaging setup.
P453
Dysembryoplastic neuroepithelial tumour: recurrence
as a different tumour after 22 years
A. Sousa, M.C. Pires, R. Roque, J. Pimentel
Hospital Santo António dos Capuchos (Lisbon, PT); Hospital de Santa
Maria (Lisbon, PT)
Objectives: To report the case of a patient who developed a glioma
histomorphologically different from the previous, macroscopic totally
resected, dysembryoplastic neuroepithelial tumor (DNET).
Methods: Case retrieved from the Laboratory of Neuropathology’
files with review of clinical and pathological aspects.
Results: 28-year-old woman with seizures since the age of 2 years.
At the age of 6 years, she underwent total resection of a left parietotemporal mass diagnosed as a malignant ependymoma. She was
subsequently treated with adjuvant radiation therapy but was lost for
follow-up. Twenty-two years later, the patient experienced an
increase in seizures frequency, and a MRI revealed a new mass at the
site of the previous surgery. The second surgery revealed a pilocytic
astrocytoma. Slides of the first surgery were reviewed and a diagnosis
of a DNET was performed.
Conclusion: DNETs have traditionally been viewed as benign
embryonal tumors widely considered curable with surgery alone,
without recurrence or malignant transformation. However, the natural
history of these tumors has not been fully elucidated and recently a
few case reports have described recurrences following subtotal or
S107
even total resection and malignant gliomas arising after irradiation.
The present case supports the scarce evidence that these tumors may
have a different, from the expected, evolution and provide new insight
into their long-term management.
P454
Cauda equina syndrome as the initial presentation
of intravascular lymphoma: a case report
P. Caroppo, A. Chiappella, V. Veglio, M. Bergui,
M. Croce, F. D’Agata, M. Caglio, U. Vitolo, P. Mortara
University of Turin (Turin, IT)
Intravascular lymphoma is a rare neoplastic pathology, characterized
by the proliferation of B-lymphoid cells in the lumen of the small
blood vessels. It usually has a poor prognosis and often the diagnosis
is made after the autopsy. The isolated neurological involvement is
rare and often mimics stroke episodes, multiple sclerosis or
polyradiculoneuritis.
We describe a case of a 74-old woman with progressive subacute
paraparesis started with low back pain, lower limbs paresthesias and
sphincter dysfunction. The lumbar MRI evidenced the fracture of L2
and a contrast enhancement of the radices of the cauda equina, that
well-suited with inflammatory meningoradiculitis. The brain MRI
evidenced multiple cerebral vascular lesions.
The CSF pattern evidenced a very low glucose level, elevated
proteins and elements. The cytology evidenced an inflammatory
pattern without neoplastic cells. On the basis of the glucose level and
CFS pattern the suspect of tuberculous meningo-radiculitis was formulated and the specific therapy was started. The clinical conditions
rapidly worsen with the occurrence of multiple cranial nerves paralysis. We repeated the lumbar puncture and the CSF showed the
presence of B-lymphoid cells consistent with the diagnosis of
B-lymphoma. The bone marrow biopsy was compatible with intravascular lymphoma. She died after 2 weeks from the diagnosis
despite the beginning of high intrathecal and intravenous dose
methotrexate chemotherapy.
P455
Abducens nerve palsy as a symptom of clivus metastasis
in two patients with prostate carcinoma
S. Pollanz, A. Tinchon, B. Calabek, S. Oberndorfer,
R. Pöhnl, B. Horvath-Mechtler, W. Grisold
Sozialmedizinische Zentrum Süd (Vienna, AT)
Metastasis to the clivus is rare and has been previously described in
some case studies.
Here we report two patients with prostate carcinoma with metastasis to the clivus causing abducens nerve palsy.
Case 1: A 52-year-old man with prostate carcinoma diagnosed
2 years before with multiple metastases to the skeletal system,
including vertebra, pelvis and tibia, presented with left abducens
nerve palsy and lumbar radiculopathy with drop foot on the left side.
CSF cytology revealed no malignant cells.
Magnetic resonance imaging and computed tomography of the
head showed an abnormal intensity mass located in the clivus,
responsible for the abducens nerve palsy. Other metastases were
found in the right orbit and the occipital bone. The MRI scan of the
spine disclosed compression of the nerve roots by the tumor masses as
cause of the lumbar radiculopathy.
After the patient underwent radio- and chemotherapy (11 cycles
docetaxel and 1 cycle second line chemotherapy with carboplatin /
etoposid), a subsequent radiotherapy of the clivus region and palliative chemotherapy with mitoxantrone was performed. Disease
progression led to deterioration of the patient0 s general condition and
he died 3 months later.
Case 2: A 80-year-old man with metastatic prostate carcinoma
diagnosed 9 years before, presented with right abducens nerve palsy
and hypaesthesia of the right face. MRI scan of the brain showed
malignant mass involving the clivus, the right cavernous sinus region
and the right cavum Meckeli. The patient underwent radiotherapy
with transient improvement in his clinical presentation and symptoms.
4 months after irradiation the patient presented with worsening of
diplopia again and bilateral abducens nerve palsy. MRI scan showed a
massive progression of the tumour mass infiltrating the parasellar
region and both cavernous sinuses. Therefore chemotherapy with
docetaxel and a further radiotherapy was initiated.
Cranial nerve lesions are rare complications of cancer. In literature, 35 case studies of metastases located in the clival bone were
found with prostate cancer as the most common primary tumour.
Because of its close location to the clivus and the cavernous sinuses a
metastatic lesion to the clivus can be responsible for unilateral or
bilateral abducens nerve palsy and should be considered in differential diagnosis to meningeal carcinosis.
P456
Multiple meningiomas with venous sinus invasion
manifested by intracranial hypertension
H. Foreid, N. Simas, P. Costa, L. Ganança, R. Mendes,
M. Moitinho, G. Guerreiro, L. Guedes, C. Barroso,
L. Albuquerque
Hospital de Santa Maria (Lisbon, PT); Hospital Amato Lusitano
(Castelo Branco, PT); Hospital de Faro (Faro, PT)
Introduction: Multiple meningiomas is an uncommon meningeal
proliferation defined by simultaneous or sequential appearance of two
or more meningiomas spatially separated. The incidence of multiple
intracranial meningiomas in different series varies from 1 to 10% of
all meningiomas. The pathophysiology of multiple meningiomas is
unclear and two main hypotheses are a clonal origin with subsequent
spreading of tumor cells via the cerebrospinal fluid versus the existence of independent and cytogenetically distinct tumors. Multiple
meningiomas are more often associated with neurofibromatosis type 2
(NF2) and occur less frequently in sporadic cases. Clinical manifestations are heterogeneous and depend on the localization and size of
the lesions. Brain MRI characteristic features are extra-axial masses
originating from the meninges with a ‘‘dural tail’’.
Clinical case: A 59-year-old woman presented with bilateral
papilledema. Besides decreased visual acuity she had no other
symptoms and the neurological examination was otherwise unremarkable. Brain MRI showed diffuse meningeal thickening and
gadolinium enhancement, and scattered nodular foci in the lateral
aspect of cerebel tentorium, parafalcial occipital topography and
frontal convexity. Angio-MRI showed the invasion of several venous
sinuses, namely the right lateral sinus, sigmoid sinus, longitudinal
superior sinus and bilateral cavernous sinus. Lumbar puncture
revealed an opening CSF pressure of 380 mm H2O. Cytochemical and
cytological examination of CSF were normal. A meningeal biopsy
was done and the neuropathological examination of a meningeal
specimen identified a clear cell meningioma (WHO grade 2). A
ventriculo-peritoneal shunt was performed, leading to improvement
of papilledema and visual acuity.
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Conclusion: Multiple meningiomas may have an insidious
asymptomatic growing until fully disseminated along the meninges
and dural sinuses. Brain imaging may be misleading suggesting other
diffuse infiltrative meningeal disorders.
P457
Anaplastic ganglioglioma in adults: a report of two
cases and a review of the literature
L.L. Guilloton, J.L. Lamboley, L. Quesnel,
N. Streichenberger, A. Drouet, J. Guyotat
Army Instruction Hospital Desgenettes (Lyon, FR);
Neurological Clinic (Lyon, FR)
Introduction: The gangliogliomas (GG) are rare tumors of the CNS,
consisting with both neuronal and glial elements. Usually with a slow
progression and a pediatric predilection, anaplastic GG (AGG) are
possible in adults.
Observation: The authors report the case of 2 patients 33, and
27 years old, in whom an AGG was diagnosed following the occurrence of a generalized seizure: this epilepsy revealed the disease for
the first patient and complicated the evolution of a WHO grade 2 GG,
diagnosed 2 years ago. MRI showed a left temporal tumor with cystic
lesion and a contrast enhancement; there was a complication with
temporo-occipital intratumoral hemorrhage and meningeal spread for
the second patient. Surgical resection associated with additional
treatment was decided: radiotherapy combined with temozolomide
(Stupp protocol) was proposed for the first patient authorizing complete remission after 16 months. A stereotaxic biopsy followed by
chemotherapy with nitroso urea was decided for the second patient:
the evolution was unfortunately negative, the patient dying after
3 months of follow-up.
Discussion: A review of the literature on 32 cases of AGG in
adults is proposed; this tumor can occur in adults patients, aged
18–77 years with a sex ratio of 1:6. Temporal localization is usually
observed and tumor is most often reveled by seizure. The interest of
immunohistochemical analysis, is stressed in the neuropathological
tumor diagnosis (CD34 and neurofilament positivity for neuronal
component; p53 or GFAP positivity for glial element) with anaplasia
for the glial component (28/32). The treatment is most often surgical;
adjuvant treatment is discussed with radiotherapy and/or chemotherapy: nitroso urea or more recently temozolomide are used.
Conclusion: Rare in adults, the AGG are most often inaugural or
can complicate the evolution of a WHO grade 2 GG; their surgical
treatment is supplemented by treatment with radiotherapy and
chemotherapy
P458
T-cell acute lymphoblastic leukemia presenting
with facial diplegia
T. Kasikci, S. Bek, O. Oz, H. Akgun, S. Tasdemir,
G. Yozgatli, Z. Odabasi
Gulhane Medical Faculty (Ankara, TR)
Objective: Bilateral facial paralysis is a rare clinical entity. It is
usually seen as a sign of systemic diseases’. The most common reasons of bilateral facial paralysis are Lyme disease, Guillain–Barre’s
syndrome, leukemia, sarcoidosis, meningitis, leprosy, Moebius’ syndrome, infectious mononucleosis and cranium fractures. Fifteen
percent of acute lymphoblastic leukemias is consisted of T-cell acute
lymphoblastic leukemia (ALL). Its prognosis is benign with early
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diagnosis and treatment. Central nervous system (CNS) involvement
can be seen 5% of ALL patients.
Case: Twenty-one year old male referred to our department with
the complaints of unable to closing eyelids and moving his lips, with
speech difficulty. In his neurological examination bilateral peripheral
facial paralysis, loss of corneal and glabellar reflexes, reduction of
tastes’s sense, and horizontal nistagmus were detected. The left eye
could not adduct by convergence. He had also right submandibular
and postauricular lymphadenopathy. His brain magnetic resonance
imaging with contrast was normal. In the thoracoabdominopelvic
computed tomography upper and anterior mediastinal mass was
found. Biopsy of submandibular lymph node was compatible with T
cell ALL. Partial improvement in symptoms was observed after
chemotherapy.
Conclusion: Leukemic cell infiltration, concomitant infections
during treatment, adverse effects of chemotherapy are the main reasons of neuronal dysfunction. Patients with bilateral facial paralysis
neoplastic diseases have to be investigated.
P459
Meningeal carcinomatosis presenting as acute onset
of hypoacusia in rapidly evolving non-small cell lung
cancer
G. Pavan, B. Colombo, D. Dalla Libera, V. Martinelli,
A. Secchi, G. Comi
University Hospital San Raffaele (Milan, IT)
Objectives: To report an unusual case of occult Non-Small Cell Lung
Cancer (NSCLC) presenting with acute hypoacusia.
Methods: Observational case report.
Results: A 47-year-old man with a no relevant past medical history
presented with a 2-months history of rapid and severe bilateral
hearing loss and a progressive asthenia with weight loss. Recent brain
Magnetic Resonance Imaging (MRI) revealed symmetrical bilateral
acoustic nerve thickening associated with enhancement inside internal
auditory meatus and postcontrast T1-weighted unusual ventricular
ependymal hyperintensity, findings initially interpreted as inflammatory. On admission he was in good general conditions and
neurological examination showed severe bilateral hypoacusia and
mild ataxic gait. Preliminary examinations performed included chest
X-ray and abdominal ecography (both negative except for two focal
hepatic lesions). Lumbar puncture was performed and cerebrospinal
fluid (CSF) proteins were markedly increased (355 mg/dL), CSF
glucose was decreased (18 mg/dL) and pleocytosis (leukocyte count:
53/mcl) was present, Link index was normal with negative IEF.
Cytological analysis was positive for malignant cells, strongly suggestive for meningeal carcinomatosis (MC). Serum measurement of
tumor markers revealed neuron-specific enolase increase (21.2 ug/L).
Further investigations were done to assess his clinical status: total
body CT scan showed multiple pulmonary lesions and two liver
masses, indicative of metastasis, and thoracic diffuse lymphadenopathies, especially in right axillary region. Fine needle aspiration
biopsy was diagnostic for Non-Small Cell Lung Cancer. Clinical
conditions rapidly worsened and the patient died 2 weeks after
diagnosis.
Conclusions: Sensorineural hearing loss has rarely been reported
as an initial manifestation of MC. Previous data showed only two
cases of hypoacusia in MC respectively in malignant melanoma and
lung cancer. In conclusion, meningeal carcinomatosis must be considered in the differential diagnosis in patients with acute bilateral
sensorineural hearing loss, even when no further systemic or neurological symptoms are associated.
S109
P460
Lung metastasis in anaplastic meningioma
D. Blas-Boria, L. Brown, I. Tremont-Lukats
University of Texas-M.D. Anderson Cancer Centre (Houston, US)
Objective: To describe a patient with lung metastasis from an anaplastic meningioma.
Methods: Case report
Results: 61-year-old woman with grade III meningioma since
December 2008, treated initially with gross total resection and adjuvant radiotherapy. She had recurrent disease in November 2009
presenting with expressive aphasia; the tumor was resected again, and
its analysis showed grade III meningioma with an MIB-1 index of
44.7%. We treated her with hydroxyurea, sunitinib, and stereotactic
radiosurgery for 6 months, but in June 2010 a surveillance MRI
showed recurrence. We admitted her for cycle 1 of ifosfamide, carboplatin, and etoposide. Her course was complicated by symptomatic
hyponatraemia and seizures with postictal aphasia and right hemiparesis. A chest X-ray showed a mass in the right lung not present
before, and a CT-guided biopsy revealed a malignant neoplasm with
epithelioid cells arranged in a syncytial pattern exhibiting focal areas
of whorling. Immunohistochemical studies demonstrated that tumor
cells were positive for the epithelial membrane antigen (EMA),
focally positive for CD56 and negative for chromogranin, synaptophysin and CK7, a pattern consistent with metastatic meningioma.
Our patient did not respond to treatment, even after we added bevacizumab on a compassionate basis. The disease progressed in the
brain and the single lung mass increased in size, but was always
asymptomatic. She was referred to hospice and died 4 months later
from intracranial disease.
Conclusion: In patients with history of grade III meningioma, a
new lung mass could indicate a distant metastasis from this primary
brain tumor; this finding can be incidental in advanced or recurrent
disease, and the patient may not have respiratory symptoms at all.
P461
Whole-brain radiation therapy in breast cancer
patients with brain metastasis previously treated
with bevacizumab-based chemotherapy
C. Chira, J. Jacob, M. Bollet, N. Derhem, F. Campana,
R. Dendale, V. Marchand, J. Pierga, A. Fourquet, Y. Kirova
Institut Curie (Paris, FR)
Purpose: To report preliminary experience and early neurological
toxicity of Bevacizumab based chemotherapy (BBCT) followed by
whole brain radiotherapy (WBRT) in breast cancer patients (pts) with
multiple metastases to the brain.
Methods and materials: A retrospective study of seven metastatic
breast cancer pts treated at the Institut Curie with at least 1 course of
BBCT before WBRT, with a delay of B12 months between the two
treatments. Toxicities were scored according to the Common Terminology Criteria for Adverse Events (v4. 2010).
Results: Median age was 56 years (range 41–65). Median followup starting from day 1 of radiotherapy (RT) was 5.9 months (range
0.4–24.6). The median dose of bevacizumab was 12.5 mg /kg (range
10–15 mg/kg) once every 14 days. Median number of administered
cycles was 6 (range 1–11). Various chemotherapy regimens were
used, the most common association being Paclitaxel (90 mg/m2 Days
1, 8, 15)-Bevacizumab (10–15 mg/kg, days 1, 15). Median time
between Bevacizumab administration and WBRT was 7 months
(range 1–12 months). RT delivered 30 Gy in ten fractions for 2 weeks
to the whole brain in five patients (71.4%) and 20 Gy in 5 fractions
and 1 week in 2 pts (28.6%).One patient underwent stereotactic
radiosurgery after WBRT (16–20.8 Gy). Brain magnetic resonance
imaging evaluation prior and after RT was available in 5 pts. For the
others only CT scan evaluations were available for comparison. No
patient received BBCT during RT. Most common reported side
effects were nausea (n = 6), vomiting (n = 4), headache (n = 3) and
vertigo (n = 3). All patients presented mild or moderate grade B2
neurologic toxicity. For one patient, there was missing clinical data as
she left the hospital before completion of WBRT and after signed
consent, currently being lost to follow-up. There were no radiological
signs of neither necrosis nor cerebral ischemia, as previously reported
in other series.
Conclusion: BBCT prior to WBRT was not associated with severe
(grade C 3) brain toxicity. Because of limited number of pts as well
as important delays between the two treatments these results need to
be validated in the setting of a clinical trial.
Peripheral neuropathy
P462
ACE gene polymorphism in Romanian patients
with diabetic neuropathy
A. Stoian, C. Banescu, C. Duicu, M. Stoian, G. E. Buicu,
C. Crisan, A. Cif, C. Feier, A. Schiopu, V. G. Osan
University of Medicine and Pharmacy (Targu Mures, RO); Mures
County Hospital (Targu Mures, RO); Mediab Medical Center (Targu
Mures, RO)
Background: Neuropathy is one of the most common complication
that affects diabetic patients. It has been reported that the genetic
susceptibility may be an important factor in the development of
nephropathy in diabetic patients, but the genes responsible for the
predisposition to diabetic neuropathy are not known.
Objective: To investigate the relation between the angiotensinconverting enzyme (ACE) gene I (insertion)/D (deletion) polymorphism and diabetic neuropathy in Romanian patients.
Methods: We performed a case–control study with 23 patients
with diabetic neuropathy confirmed through electrophysiology study
and 19 healthy controls. Genomic DNA was extracted from whole
blood sample, ACE I/D gene polymorphism was examined by polymerase chain reaction–restriction fragment length polymorphism
(PCR–RFLP) analysis and agarose gel electrophoresis.
Results: Subjects were consisted of 23 patients with diabetes mellitus
and male to female ratio was 1.3:1, mean age 62.17 years. ACE genotypes in whole population were 43.5% DD genotype, 43.5% ID genotype
and 13% II genotype. A significantly higher frequency of ACE I allele
was observed in the diabetic neuropathy patients.
Conclusion: Our results indicate that ACE I allele may play a
significant role in individual’s susceptibility to the disease. Due to the
small number of studied cases we consider it necessary to extend the
lots in order to obtain conclusive data.
P463
Congenital hypomyelinating neuropathy due to a novel
MPZ gene mutation
T. Sevilla, R. Sivera, V. Lupo, L. Bataller, N. Muelas,
F. Palau, E. Rivas, J.J. Vilchez, C. Espinos
University Hospital La Fe (Valencia, ES); Institute for Biomedicine
(Valencia, ES); Hospital Virgen del Rocio (Sevilla, ES)
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Background: Congenital hypomyelinating neuropathy (CHN) is a
severe neuropathy with neonatal or early infancy onset, reduced nerve
conduction velocity, and severe hypomyelination on sural nerve
biopsy.
Case report: The patient was cesarean born and required superficial reanimation upon birth. Seven months later he developed acute
respiratory insufficiency and was admitted in the hospital with
respiratory support. Clinical examination showed severe axial weakness and hypotonia, being unable to turn in bed or to raise his head.
Nerve conduction studies revealed severely slowed nerve conduction
velocities. Pathologic findings of the sural nerve revealed a characteristic picture of nonmyelinated and poorly myelinated axons.
Nowadays, he is nearly 4 years old and is completely bed-bound, with
no productive muscle movement in limbs, invasive ventilation and
enteral feeding.
Results: Genetic analysis revealed that the propositus was a heterozygous carrier of a novel mutation, p.S121F, in the MPZ gene. In
silico analysis using SIFT and PolyPhen softwares predicted that the
MPZ p.S121F mutation is probably pathological. Finally, the colocation studies showed that the mutant protein loses its correct
location and is mainly expressed in the cytosol.
Conclusions: in this study we report a novel missense p. S121F
mutation in the MPZ gene in a patient with probably the most severe
form of congenital hypomyelinating neuropathy described with
molecular genetic study.
This work was supported by the Fondo de Investigación Sanitaria
(Grants number PI08/90857, PI08/0889, CP08/00053 and PS09/
00095) and co-funded with FEDER funds.
P464
Conduction blocks in Charcot–Marie–Tooth 1A
Y. Parman, E. Kocasoy-Orhan, Z. Matur, P. OflazerSerdaroglu, E. Battaloglu, M. Poyraz, F. Deymeer
Istanbul University (Istanbul, TR); Bogazici University (Istanbul, TR)
Objectives: Charcot–Marie–Tooth Disease (CMT) is the most commonly inherited disease of the peripheral nervous system. CMT type 1
(CMT1) is the demyelinating dominant form characterized by distal
weakness and atrophy of the extremities with reduced nerve conduction velocities (\38 m/s). In demyelinating forms, nerve
conduction velocities (NCV) slowing is uniform and diffuse. We
report two CMT1A patients who showed conduction blocks (CB).
Methods and patients: Forty-four years old woman was seen
because of numbness in the right 4. and 5. fingers and in the right 5.
toe. On neurological examination, strength was full. A mild pes cavus
was present. Deep tendon reflexes were unobtainable in the lower
extremities. She had markedly diminished vibration sense and
hypoalgesia below the ankles. She had an affected son, sister, niece
and nephew. The second patient was a 27-year-old woman, who
complained of paresthesiae of all limbs during her pregnancy. After a
febrile episode, she started to have unsteady gait. Neurological
examination showed distal weakness and hypoalgesia with diminished vibration sensation. Deep tendon reflexes were hypoactive in
the upper, abolished in lower limbs. She had pes cavus. Her mother
and one brother showed similar symptoms and signs. Both patients
had CMT1A duplication
Results: NCVs of the first patient revealed a median motor nerve
conduction velocity of 22 m/s and a distal latency of 8.6 ms. There
were CBs involving median, bilateral ulnar, and peroneal nerves. The
second patient had prolonged distal motor latencies and pronounced
slowing of motor conduction velocities: 9.5 m/s for median and 12 m/
s for ulnar nerve. The evoked motor responses were relatively
123
preserved in amplitude on distal stimulation but were reduced and
dispersed on the proximal stimulations suggesting CBs.
Conclusion: CBs are characteristic features of acquired demyelinating neuropathies. Uniformity of conduction slowing in all nerves
was emphasized in demyelinating forms of CMT. Although nonuniform conduction was rarely observed with some mutations, like
MPZ and GJB1. It is clinically important to recognize the different
electrodiagnostic patterns of demyelinating hereditary neuropathies.
P465
Gait patterns and clinical correlation in adults
with Charcot–Marie–Tooth disease
C. Marchesi, M. Ferrarin, G. Bovi, M. Rabuffetti,
P. Mazzoleni, A. Montesano, E. Pagliano, A. Marchi,
I. Moroni, D. Pareyson
C. Besta Neurological Institute (Milan, IT); Don Gnocchi Foundation
(Milan, IT)
Objectives: To explore whether objective assessment of locomotor
functions through gait analysis (GA) may be a good outcome measure
for Charcot–Marie–Tooth disease (CMT). We found that GA is
highly reliable in adults and children and observed three gait patterns
in CMT1A children (pseudonormal, footdrop, footdrop and push-off
deficit). Goal of this study was to identify typical walking patterns in
a group of adult CMT subjects and to study their correlation with
clinical status.
Methods: Thirty adult CMT subjects and 20 age-matched healthy
controls were recruited. We evaluated walking at natural and
increased speed, toe- and heel-walking, stair ascending and
descending, employing a nine TV cameras SMART system, two force
plates and a wireless 8-channel EMG system (marker set in accordance with LAMB full body protocol). We evaluated time course of
kinematic, kinetic and EMG signals, and computed a set of parameters related to specific clinical signs (foot drop, plantar flexor failure,
joint ROM and their changes during heel- and toe-walking, compensatory movements at hip and knee during swing). Clinical
measures were: CMT Neuropathy Score (CMTNS) and Examination
Score (CMTES); strength of foot dorsiflexion and plantar flexion
assessed with a myometer; overall neuropathy limitations scale
(ONLS); 10-meter timed walking (T10-MW); Walk-12; SF-36 health
related quality of life questionnaire.
Results: We recruited 11 CMT1A, 9 CMTX, 2 CMT1B, 1
CMT2A, 4 CMT2 J, and 3 CMT2 (with undetermined gene defect)
patients (age range 18–68 years, mean 43). CMTES range was 3–18
(mean 9.2). According to values of ankle range of motion during
swing (A-ROM) and ankle positive work we indentified different gait
patterns: (1) 1 pseudo-normal patient (PN), similar to controls; (2) ten
patients showing only foot-drop (FD); (3) 17 patients with FD and
push-off deficit (FD&POD); (4) two patients with prevailing push-off
deficit (POD). Gait pattern was independent from CMT type.
FD&POD patients were older and had slightly more severe disease
than FD patients. When pooling the data with 20 CMT1A children we
found correlation of gait indexes with clinical severity (e.g., A-ROM
and toe-heel ankle flexion with CMTES and ONLS).
Conclusion: Gait patterns in CMT adults are similar to those
already identified in children but have a different distribution in
accordance with disease progression. Key indexes of gait abnormality
correlated with clinical severity in the whole series of CMT adults and
children.
Funded by the Italian Ministry of Health and Telethon-UILDM
(GUP10010).
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P466
Central nervous system demyelination
in a Charcot–Marie–Tooth type 1A patient
C. Koros, E. Andreadou, D. Pandis, M. Evangelopoulos,
P. Davaki
Athens National University (Athens, GR)
Charcot–Marie–Tooth (CMT) disease represents a heterogeneous
group of inherited neuropathies associated with peripheral nervous
system (PNS) demyelination. A central nervous system (CNS)
involvement either in the form of clinical symptoms or magnetic
resonance imaging (MRI) white matter lesions has occasionally been
reported mainly for the X-linked type of CMT.
Objectives: Herein, we present the case of a 28-year-old man with
a history of CMT1A who developed CNS demyelination mimicking
multiple sclerosis. The CMT1A diagnosis had been confirmed 4 years
ago, by means of electrophysiological and molecular evaluation
[peripheral myelin protein 22 gene (PMP-22) duplication]. However,
his family history was negative.
Results: The patient was referred to us because of an episode of
double vision. He also reported an episode of right hemibody dysaesthesias 2 weeks ago, with spontaneous remission. Neurological
examination revealed an ataxic gait, distal weakness and atrophy of
the lower limbs, absent tendon reflexes, bilateral pes cavus and
decreased vibration sensation. Examination of the cranial nerves
showed a right intranuclear ophthalmoplegia with dissociative nystagmus along with right abducens nerve paresis. Blood investigations
including serum vitamin B12 and antinuclear antibodies were normal.
Cerebrospinal fluid studies showed a mild increase in protein level
(52 mg/dl, normal \ 45) without pleocytosis and a marginal IgG
index (0.65 normal \ 0.65) without oligoclonal bands. Brain MRI
revealed multiple hyperintense lesions on FLAIR and T2-weighted
images in the periventricular and subcortical white matter bilaterally
although no lesions could be traced in the brainstem. Additionally,
cervical MRI showed an area of increased signal at the level of C2.
The patient was started on corticosteroids with complete remission
within 2 weeks.
Conclusion: Clinical, imaging and laboratory findings suggest an
autoimmune CNS demyelination. Although the simultaneous existence of CMT1A and multiple sclerosis could be coincidental, the
individual prevalence of each disorder is relatively low. On the other
hand, despite the fact that PMP-22, the target protein in CMT1A, is
expressed selectively in the PNS, it shares a partial homology with
other CNS proteins like the proteolipid protein (PLP). It is possible
that PMP-22 overexpression might influence the immunological self
tolerance to CNS proteins via molecular mimicry, leading to a CNS
autoimmune demyelinating disorder.
P467
Genetic heterogeneity of X-linked dominant
Charcot–Marie–Tooth disease
B.-O. Choi, G. Lee, E. Park, H.-K. Jung, J. Hyun,
J. Park, S.-H. Kim
Ewha Womans University (Seoul, KR)
Objectives: Charcot–Marie–Tooth disease (CMT) is a heterogeneous
disorder of hereditary motor and sensory neuropathies characterized
by progressive distal muscle weakness, sensory loss, and areflexia.
X-linked Charcot–Marie–Tooth disease (CMTX) is the second most
frequent form after CMT1 with a frequency of approximately 20%.
Although connexin 32 (Cx32) gene expression is not limited to the
peripheral nervous system, Cx32 mutations are only associated with
CMT. In the present study, we evaluated the Cx32 mutations in
Korean CMTX patients, and clinical and genetic features were
investigated in patients with Cx32 mutations.
Methods: We enrolled 1,526 individuals (affected 940; unaffected
586) from 527 unrelated CMT families of Korean ancestry. A group
of 200 healthy Korean controls was recruited. We performed a
mutation analysis of Cx32 by direct sequencing of the coding
sequence.
Results: Mutational analysis revealed 23 Cx32 mutations from
28 Korean CMTX families of 527 unrelated CMT families, and of
them, 11, 4 and 13 mutations were found in the demyelinating,
axonal, and intermediate type, respectively. All families except six
sporadic cases revealed well co-segregation of the mutations with
affected members, which were compatible with X-linked dominant
inheritance. Nine mutations were not reported previously: Gly5Ser,
Ser26 fs, Val37Leu, Thr86Ile, Val152 fs, Phe153Cys, Asp178X,
Ala197Val, and Ile214Asn. The extracellular domain 2 (EC2) of
Cx32 protein was the hot spot mutation domain in 44% of Koreans.
Transmembrane domain 4 (TM4) was rarely affected in Koreans
(4%), compared with 14% of Europeans. The EC1 and intracellular
domain (IC) was not affected in Koreans, although they were frequently affected in Europeans. This study revealed that the
frequencies of CMTX with Cx32 mutations are different ethnic
group specifically.
Conclusion: The frequency of CMTX (5.3%) caused by Cx32
mutation in Koreans is similar to those in Asians, but lower than those
in Europeans. In addition, we found nine novel Cx32 mutations that
have not been reported. This study suggests differences between
CMTX patients with Cx32 mutations and ethnic background.
P468
Mononeuritis multiplex as a paraneoplastic
syndrome—a case report
E. Aldeia, A. Sousa, L. Medeiros
University Hospital of Central Lisbon (Lisbon, PT)
Objective: To describe a clinical case of a mononeuritis multiplex
(MM) as the first sign of a tumor of unknown origin.
Methods: We reviewed the clinical history, spinal magnetic resonance imaging (MRI), scintigraphy, positron emission tomography
(PET), the electrophysiological study and all laboratory work up
needed in the diagnosis of the tumor.
Results: A 52-year-old patient, smoker, with progressive asymmetric lower limbs weakness and paresthesias since September 2010,
diagnosed with an expansive/lytic lesion of the left iliac bone 2
months later. The electrophysiological study showed an asymmetric,
axonal, sensory-motor polyneuropathy, suggestive of MM. Serum
protein electrophoresis and immunofixation revealed a monoclonal
gammopathy IgG/lambda. Other laboratory data were normal,
including anti-neuronal and anti-ganglioside and sulfatide antibodies.
Scintigraphy bone scan and PET confirmed a solitary lytic lesion in
the left pelvis, and thoracic, abdominal and pelvic MRI showed no
other abnormalities. Three bone biopsies were made, the first two
were inconclusive, and the third one showed infiltration of the bone
by neoplastic plasma cells CD138 + with monoclonal expression of
lambda light chains which confirmed the diagnosis of plasmacytoma.
Conclusion: Frequently paraneoplastic neurologic syndromes
manifest before a cancer diagnosis and MM as a paraneoplastic
syndrome is a very rare one, more frequently associated with lymphoma and lung cancer. Their timely recognition may lead to
detection of an otherwise clinically occult tumor at an early and
treatable stage. The authors accentuate the importance of recognition
of these rare neurological syndromes.
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P469
Long-term follow-up of 76 chronic dysimmune
demyelinating neuropathies
C. Ganino, D. Sabbatini, S. Balestrini, V. Cameriere,
F. Lupidi, P. Di Bella, F. Logullo
University Hospital of Ancona (Ancona, IT)
Objective: chronic dysimmune demyelinating neuropathies (CDDN)
are an etiologically heterogeneous entity with different clinical presentations and variable course. CDDN mainly encompass three forms:
chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and serum paraproteins neuropathies.
We conducted a retrospective study of patients with CDDN who were
followed up at our department from 2000 to 2010.
Methods: 76 patients were included in this study. The diagnosis
was made according to EFNS/PNS criteria. 49 of the patients were
male (64.47 %) and 27 female (35.52%). Age at onset ranged from 13
to 78 years, with mean age of 52.9 years.
Results: In our population, 20 patients (26.31%) developed
classical CIDP from the onset or later in the course, 11 patients
(14.47%) presented atypical CIDP: six multifocal acquired demyelinating sensory and motor (MADSAM), two focal presentation and
three central nervous system involvement. Neuropathies associated to
serum paraproteins accounted for 51.31% of cases (20 with anti-MAG
IgM monoclonal gammopathy, 16 with IgM monoclonal gammopathy
without anti-MAG antibodies and 3 with POEMS). MMN was
observed in nine patients (11.84%). Nine patients received only
corticosteroids (three cases of CIDP and six cases with polyneuropathy associated with IgM monoclonal gammopathy). Eighteen
patients received only intravenous immunoglobulins (IVIg) (five
cases of CIDP, seven cases of MMN, five cases with polyneuropathy
associated with IgM monoclonal gammopathy and 1 case of
POEMS). Twenty-two patients underwent to polytherapy (1 case of
MMN, 15 cases of CIDP and 6 cases of polyneuropathy associated
with IgM monoclonal gammopathy). Bone marrow transplantation
was performed in 1 patient with POEMS. 6 patients were treated only
with symptomatic therapy for pain (1 case of POEMS and 5 painful
predominantly sensory demyelinating polyneuropathy cases associated with IgM monoclonal gammopathy). Therapy was not required
in 15 patients because of mild disease or clinical stability (1 MMN, 11
polyneuropathy associated with IgM monoclonal gammopathy and 3
CIDP). Two patients died: 1 further to disease macroglobulinaemia
and one further to acute myocardial infarction. Five patients were lost
in follow-up.
Conclusion: This study shows epidemiological features of a
CDDN population collected at a single center and it can be a valid
contribution to analyse the heterogeneous clinical, diagnostic, prognostic and therapeutic aspects of these neuropathies.
P470
Vasculitic neuropathy successfully treated
with mycophenolate mofetil
G. Genc, S. Bek, T. Kasikci, O. Oz, Z. Odabasi
Gulhane Military Medical Academy (Ankara, TR)
Introduction: Vasculitides are heterogeneous group of disorders
affecting various diameters of vessels and organs. Vasculitic neuropathies are rare seen neuropathies. Early diagnosis and aggressive
approach with combined steroids and cytostatic agents especially
cyclophosphamide are important because of the treatable life-threatening organ failure. We report a patient with vasculitic neuropathy
123
diagnosed as clinically, electrophysiologically, pathologically, and
successfully treated with mycophenolate mofetil.
Case Presentation: A 29-year-old woman was admitted to our
hospital with severe pain spreading down first left than right knee,
rash on the lower parts of the legs, and weakness in feet for 3 days.
Her examination revealed painful erythematous rash in lower limbs,
bilateral lower limb stock-like hypoesthesia, bilateral absent Achilles
reflex, and weakness of ankle dorsiflexion and plantar flexion. Sedimentation rate was 90 mm/h. Nerve conduction studies showed
severe symmetrical sensorimotor axonal polyneuropathy findings and
pseudo-conduction blocks in lower extremities. Antinuclear antibody
test was positive. Sural nerve biopsy revealed necrotizing vasculitis
involving small and medium vessels. Vasculitis involving small and
medium-sized arteries was found in skin biopsy, and morphological
findings were compatible with polyarteritis nodosa. Cyclophosphamide 1 g/m2 iv and 60 mg of oral prednisolone therapies were
initiated. Also gabapentin, carbamazepine, tramadol, alprazolam,
fentanyl transdermal patches were used because of the severe pain. At
her first and sixth month control follow-up, there was no improvement
in her neurological examination whereas she was pain-free. Mycophenolate mofetil at 2 mg dose was initiated. At her ninth month
control follow-up, it was observed that her weakness of ankle dorsiflexion, gait and balance were improved markedly.
Conclusion: Vasculitic neuropathy should be considered in painful
mononeuropathy or asymmetric polyneuropathy with acute or subacute onset and, presence of the pseudo-conduction blocks in nerve
conduction studies. Mycophenolate mofetil should be taken into
account as an alternative treatment beside combined corticosteroid
and cyclophosphamide treatment because of the high potential benefit
from immunosuppressive therapies.
P471
Vasculitic neuropathy after Hansen disease:
coincidence or cause?
P. Pita Lobo, T. Evangelista, R. Silvestre, I. Conceição
Hospital de Santa Maria (Lisbon, PT)
Background and objective: Etiology of vasculitic neuropathy comprises a heterogeneous group of causes, namely genetic, toxic,
metabolic, infectious and auto-immune systemic or primary vasculitis. We describe a case of subacute vasculitic neuropathy, developed
33 years after successfully treated lepromatous leprosy.
Methods and results: Case report investigation and discussion: We
report a 68-year-old woman, with a past history of Hansen Disease at
15 years old, treated with rimfapicine, dapsone and thalidomide
during 2 years and with dapsone during 20 years. The patient was
referred for neurological assessment complaining about a symmetric
and progressive numbness and pain affecting feet and hands, with 1
year of evolution. Neurological examination revealed glove and sock
hypoesthesia, diminished postural and vibratory sense in feet, fingers
and bilateral hallux paresis (four on the MRC scale) and severe axonal
loss normal deep tendon reflexes. Dermatological evaluation disclosed multiple sequelar lesions of Hansen Disease, without nervous
trunk enlargement. Electromyography revealed a moderate axonal
sensory neuropathy. Laboratory studies showed high erythrocyte
sedimentation rate (60 mm/h) and were unremarkable for systemic
vasculitis, antiganglioside, antineuronal antibodies, antisulfatide and
antigliadin autoantibodies. Cryoglobulins, b-2 microglobulin, protein
immunoelectrophoresis, urine protein and serological tests for HIV,
HCV, HBV and CMV were also negative. Perivascular inflammatory
infiltrates composed of T and B lymphocytes and severe axonal loss
were present in sural nerve biopsy, compatible with vasculitis.
Mycobacteria Fite-Faraco staining was negative in sural biopsy. The
S113
patient was started on oral prednisolone with clinical and neurophysiological improvement.
Conclusion: In this case, we admit the presence of an isolated
vasculitis of peripheral nervous system, and speculate that the trigger
mechanism of the vasculitis is a late immunological process secondary to previous and persistent mycobacterium antigen exposition.
P472
Prognostic factor associated with rapid recovery
in patients with Guillain–Barré syndrome
H.W. Shin, Y.C. Youn, K.Y. Park, J.Y. An, S.W. Ahn
Chung-Ang University Hospital (Seoul, KR); Catholic University
Hospital (Suwon, KR)
Objectives: We aimed to study epidemiological, clinical, laboratory,
and electrophysiological features and correlation of these parameters
with prognosis in Guillain–Barré syndrome (GBS) patients with good
outcome.
Methods: The 22 patients with GBS were enrolled, who were hospitalized and followed up at a tertiary hospital center during January
2005–October 2010. We described age, gender, antecedent infections,
presenting symptoms, clinical severity with GBS disability scale, cranial
nerve involvement, presence of respiratory distress, laboratory, electrophysiological findings and treatment, and analyzed the correlation
between the data and prognosis in all patients with good outcome.
Results: Cerebrospinal fluid (CSF) protein level (correlation
coefficient; 0.554, p = 0.007), clinical severity (GBS disability scale,
correlation coefficient; 0.870, p \ 0.001) and the timing of intravenous immunoglobulin G (IVIgG, correlation coefficient; 0.519,
p = 0.013) treatment were strongly associated with recovery of illness. Ten patients with normal CSF protein rapidly improved to GBS
disability scale 0 or 1 within 1 month, whereas other 12 patients with
high CSF protein showed slow recovery. Additionally, the patients
with low GBS disability scale or early IVIgG therapy rapidly
improved, as contrasted with the other patients with high GBS disability scale or delayed IVIgG therapy.
Conclusion: The current study revealed significant prognostic
factors in recovery of GBS, although the favorable prognostic factor
in GBS patient calls for further large studies surveying biochemical
analysis of CSF and longitudinal changes involving biochemical
markers in extended GBS patients. Normal CSF protein, low GBS
disability scale and early IVIgG therapy are strongly associated with
rapid recovery in GBS patients with consequently good outcome.
P473
Posterior reversible encephalopathy syndrome
and Guillain–Barré syndrome: diagnostic
and therapeutic challenge
F. Sousa, J. Pinho, J. Rocha, M. Rodrigues, C. Ferreira,
R. Mare´
Hospital of Braga (Braga, PT)
Introduction: The autonomic dysfunction with fluctuating blood
pressure is a common complication of Guillain–Barré syndrome
(GBS). In turn, Posterior Reversible Encephalopathy Syndrome
(PRES) is precipitated by hypertensive crisis and clinically characterized by encephalopathy, seizures, headaches, impaired vision, and
symmetrical vasogenic edema observed preferentially in the posterior
regions. A rare and reversible association of GBS / PRES has been
described in the literature.
Case report: 67 years old woman, with background history of
polyarthritis, observed by acute onset of malaise, anorexia and low
back pain followed by vomiting and diarrhea, vision impairment, and
disorientation beginning 1 day before admission. Objectively, she
presented time and space disorientation, blindness and hypertension.
Cerebral CT scan revealed questionable bilaterally occipital hypodensities. The cerebrospinal fluid (CSF) was normal and the
electroencephalogram presented moderate encephalopathy. She was
admitted in Neurology Department and treated with prednisolone
(50 mg) for control of inflammatory arthropathy. Four days after
admission she had left peripheral facial paresis and flaccid areflexic,
predominantly proximal and of lower limbs, tetraparesis. New CSF
showed elevated protein level, starting immunoglobulins. Marked
hemodynamic instability with frequent hypertensive peaks was
recorded. Magnetic Resonance Image showed marked cortico-subcortical signal abnormalities, involving occipital, parietal and frontal
lobes, bilaterally, characteristic of vasogenic edema. The patient
completed 5 days of treatment with immunoglobulin and methylprednisolone, without clinical response. By day 11, deterioration of
consciousness occurred with correspondent increased extent of the
imaging abnormalities. Steroids were restarted, without improvement.
In day 15 she was admitted in the Intensive Care Unit for sudden
respiratory failure, with apnea periods and respiratory arrest. The
patient died on day 20.
Conclusions: This case raises two distinct important issues that
requires our attention and without clear solution: a rare presentation
of GBS with PRES, assuming that this usually reversible association
is a consequence of autonomic dysfunction, and in other hand, the
secondary increase of cerebral edema with therapy (immunoglobulins
and steroids) also related with development of PRES.
P474
Asymptomatic posterior reversible encephalopathy
syndrome-like brain MRI in a case of Guillain–Barré
syndrome
C. Parmentier, Y. Vandermeeren, P. Laloux, E. Mormont
University Clinics of Mont-Godinne (Yvoir, BE)
Background: Posterior reversible encephalopathy syndrome (PRES)
was first reported in 1996 and consists of a reversible vasogenic
oedema predominating in the cerebral posterior white matter. There
are several known causes of PRES, including hypertension and
intravenous immunoglobulin (IVIg) therapy. We report the case of an
asymptomatic PRES during the course of a Guillain–Barré syndrome
(GBS).
Case-report: A healthy 28-year-old woman presented with dysesthesias of the hands and feet which occurred two days after an upper
respiratory tract infection. Initial examination revealed moderate
distal sensory loss and proximal weakness of the four limbs, tachycardia and de novo hypertension (160/100 mmHg). Initially,
cerebrospinal fluid (CSF) analysis and electrophysiological examination were normal. A brain MRI showed extensive bilateral frontoparieto-occipital hyperintensities of the white matter and cortex in
FLAIR and T2-weighted images. A second CSF analysis revealed
elevated protein level with a normal cell count; a second electrophysiologic study demonstrated an axonal neuropathy, consistent with
the diagnosis of axonal GBS. A neuromuscular biopsy showed only
an axonal neuropathy. IVIg were infused for 2 days only because of
an allergic reaction. The blood pressure was managed appropriately
and was never higher than 160/100 mmHg. A new brain MRI performed 8 days after the first one showed near complete resolution of
the signal abnormalities. One month after discharge, the neurological
examination revealed a moderate sensory loss of the four limbs, no
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muscle weakness, normal heart rate and normal blood pressure. The
patient still complained of neuropathic pain of the extremities.
Discussion: MRI findings were consistent with a posterior
reversible encephalopathy syndrome (PRES), which has already been
described in association with GBS or IVIg treatment in a few cases.
However, in this case, the patient never presented the common
manifestation of this syndrome, such as encephalopathy, seizures,
headache or visual disturbance. Therefore, we suggest that PRES-like
cerebral vasogenic oedema and transient extensive brain lesions can
occur without symptom. Brain MRIs should be performed prospectively before and after IVIg therapy for GBS, particularly in case of
dysautonomia, to determine the incidence of PRES-like images during the course of GBS and to explore the different possible etiological
factors.
P475
Informative value of the diagnosis of ‘‘microvasculitis’’
of the peripheral nervous system—insides form
a clinical cohort
S. Gollwitzer, S. Schwab, D. Heuss
University Hospital Erlangen-Nuremberg (Erlangen, DE)
Objectives: Nonsystemic vasculitic neuropathy (NSVN) is an immune
mediated inflammatory disease restricted to vessels of the peripheral
nervous system. Compared to systemic vasculitis, the prognosis is
relatively benign. In this retrospective follow-up study we analyzed
the clinical course and response to therapy depending on different
kinds of vasculitis according to morphological criteria.
Methods: All diagnostic nerve biopsies from patients without signs
for systemic disease performed over 18 years were reviewed. Nerve
biopsies diagnostic for vasculitc neuropathy were classified into three
groups: definite vasculitis, probable vasculitis or microvasculitis. The
clinical findings of the patients at onset and follow-up and the therapeutic regimens were analyzed.
Results: A cohort of 28 patients out of 142 biopsies diagnostic for
vasculitic neuropathy could be assembled: necrotizing vasculitis
n = 4, probable vasculitis n = 11, microvasculitis n = 13. 71% of
the patients suffered painful neuropathy, 64% had sensory-motor
symptoms. Neurologic disability at follow-up was not significantly
different between the three groups. All Patients with necrotizing
NSVN had been treated with steroids in combination with a cytoreductive medication, such as azathioprine, methotrexate,
cyclophosphamide or cyclosporin. All of them improved significantly.
52% of patients with probable vasculitis and microvasculitis deteriorated under therapy, only 48% improved. Adjunction therapy did not
show better results than steroids alone. Three patients with microvasculitis were not treated at all, two of these improved
spontaneously.
Conclusion: Necrotizing NSVN always shows therapeutic
response to adjunction therapy and should therefore be treated in that
way. With regard to outcome, patients suffering microvasculitic
NSVN do not differ from those suffering necrotizing NSVN. Microvasculitis and probable vasculitis do not respond to
immunosuppressive treatment in principle. In this respect microvasculitis may not be vasculitis in fact, but may be a concomitant
phenomenon of another disorder. Alternatively, assumed ineffectiveness of therapy could be due to possible spontaneous remission,
substantiated by the casual morphological finding of healing vessels
without any treatment. 50% of these patients did respond to therapy,
adjunction therapy not being superior to steroid monotherapy.
Therefore steroid treatment by way of trial is justified in
‘microvasculitis’.
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P476
Seronegative Wegener’s granulomatosis with a cranial
polyneuropathy presentation
S. Machado, N. Inácio, J. Alves, L. Biscoito, J.P. Farias,
A. Pinto
Hospital Prof. Dr. Fernando Fonseca (Amadora, PT); Hospital de
Santa Maria (Lisbon, PT)
Introduction: Wegener’s Granulomatosis (WG) is systemic vasculitis
of unknown etiology that can be seen in almost any system. It classically affects the upper airways, lungs and kidneys but neurological
involvement is hardly seen. We present a case of palsy of the lower
cranial nerves as the initial presentation of a seronegative WG.
Case report: A 59 years old woman was in her usual state of good
health. In October 2009, she recurred to our ER with a 1-month
history of right otalgy followed by an right facial palsy, gait disturbance, dysphagia and dysphonia. There was low grade fever since the
beginning but no other accompanying symptoms. On the neurological
examination we only found peripheral paresis of the VII, IX, XI and
XIth right cranial nerves. A brain MRI found out a round in the
jugular foramen. The angioMRI supported a possible jugular glomus.
In this context, a conventional angiography was realized and the
suspicion of glomus was not confirmed but an occlusion of the right
internal jugular vein was identified. The laboratory data disclosed
a modest elevation of the sedimentation rate, leucocytosis and
microhematuria. The prothrombotic screening was completely normal
(including ANA and ANCA). A thoracic CT scan found multiple
millimetric bilateral pulmonary nodules. During the hospital stay
there was a subtle improvement in the deficits and she was discharged.
In April 2010, she returned to our department with a week course of
severe headache and difficulty in the verbal articulation de novo. On the
examination there was only a XIIth right cranial nerve palsy with no
meningeal signs or other remarkable deficits. A MRI and a new adjacent
meningeal enhancement was found. A lumbar puncture was done with
pleocytosis (42 cells, mononuclear). The diagnosis of seronegative WG
was made. Corticotherapy was then initiated and after 1 month course of
prednisolone 1 mg/kg PO all the clinical symptoms vanished, a MRI was
repeated with no meningeal enhancement, and the LCR evaluation was
entirely normal. This case represents a disseminated form of WG and
cyclophosphamide was started.
Conclusion: The diagnosis and treatment of WG is of paramount
importance as it is well known that without therapy it is uniformly
fatal. Corticosteroids and cytotoxic agents as cyclophosphamide are
the mainstay of treatment. This entity should thus be considered in
cranial multiple neuropathies or aseptic meningitis when there is also
renal and respiratory tract involvement.
P477
Anti-ganglioside antibodies in gluten neuropathy
patients
S. Kopishinskaya, A. Gustov, A. Repin, T. Kolchanova,
M. Kolchanova, V. Antonova, N. Kondratieva, L. Dmitrieva
Nizhny Novgorod Medical Academy (Nizhny Novgorod, RU);
Nizhny Novgorod Diagnostic Center (Nizhny Novgorod, RU)
Objectives: Celiac disease is an autoimmune enteropathy triggered by
the ingestion of gluten in genetically susceptible individuals. Celiac
disease is common, affecting 1–2% of the population. Antiganglioside
antibodies (AAb) have been described in sera of celiac disease with
peripheral neuropathy. The aim of the present study was to assess the
occurrence frequency of AAb in gluten neuropathy patients.
S115
Methods: We surveyed three groups of patients. There were 35
gluten neuropathy patients in the first group. The second group contained 20 patients with diabetic neuropathy. 32 patients who had
reflux-esophagitis according to endoscopy results made up the third
control group. All patients were tested for AAb using the kit ‘‘Ganglioside-Profile 2 Euroline IgM and IgG’’ .
Results: In the group of gluten neuropathy patients we revealed higher
frequency of AAb GM1 IgM, GD1b IgG and GT1b IgG—25.7, 34.3 and
37.1%, respectively. It was also revealed that 54.3% of the first group
patients, 35.0% of the second group patients and 25.0% of the third group
have at least one antibody type. We revealed statistically significant
reliability of distinctions (Ð \ 0.05) of detecting most often occurring
AAb between three groups. According to our data the occurrence frequency of GM1 IgM in gluten neuropathy patients is 25.7%. In the group
of gluten neuropathy patients, the 34.3% occurrence frequency of GD1b
IgG has significant distinctions from the occurrence frequency of this
antibody of 10.0% in the second group (P = 0.036). Also in the first
group the occurrence frequency of GD1b IgG antibody has significant
distinctions from the occurrence frequency of this antibody of 3.1% in the
third group (P = 0.004). The same significant distinction is revealed for
antibody GT1b IgG.
Conclusion: Frequency rates of detecting AAb GM1 IgM, GD1b
IgG, GT1b IgG or at least one type of antibodies in the first group
were significantly different from the rates of the second, and the third
groups. Thus we revealed the high occurrence frequency of GM1
IgM, GD1b IgG and GT1b IgG antibodies in gluten neuropathy
patients which could be a new diagnostic criterion for this autoimmune disease.
P478
Small-fibre involvement in the hands of patients
with systemic sclerosis
N. Solà-Valls, J. Casanova-Molla, M. Morales,
J. Valls-Sole´
Clinic Barcelona (Barcelona, ES)
Introduction: Neuropathic pain is not a common manifestation in
patients with systemic sclerosis (SSc). Although entrapment neuropathies are the most commonly reported, the involvement of small
fibers as a distal sensory neuropathy should be considered. We report
here a form of neuropathy involving the hands in two patients with
SSc.
Objective: To describe the clinical, electrophysiological and histopathological characteristics of the small fibres at the hands in two
patients with SSc. Patients and Methods. Patients were two men (70
and 40 years old) with confirmed diagnosis of SSc, who complained
of pain in the palm of their hands during some daily living activities
such as holding keys or scrunching a paper. We carried out conventional nerve conduction studies and recorded the contact heat cerebral
evoked potentials (CHEPs) to stimuli applied to the dorsum and the
palm of the hand in the two patients and in 6 age-matched healthy
volunteers. In patients, we also took a skin biopsy from the inner side
of the index finger. Samples were sectioned at 50-mcm thick and
stained with the panaxonal marker PGP 9.5. We performed double
fluorescent staining with the PGP 9.5 and the myelin basic protein
(MBP) to identify unmyelinated and myelinated endings using confocal fluorescent microscopy.
Results: Data on nerve conduction tests were normal in both patients.
CHEPs to the dorsum of the hand were abnormally reduced (21 and 14
mcV) and delayed (526 and 481 ms) in comparison to the mean values
of healthy subjects (46 ± 14 lV and 386 ± 51 ms). CHEPs to the palm
of the hand were of shorter latency than normal (514 and 491 ms in the
patients and 539 ± 93 ms in healthy control subjects). The mean
latency difference between palm and dorsum was 177 ms in controls
subjects and -16 ms in patients (U Mann–Whitney, p \ 0.001). Skin
biopsy revealed a borderline significant reduction of intraepidermal
nerve fibre density (6.7 and 5.2 fibres/mm, respectively) and dermal
nerve fibres length (1.6 and 1.5 DNFL/mm, respectively). There were
axonal morphological abnormalities such as fragmentation that included
the myelinated fibres from Meissner corpuscles.
Conclusions: Our results are compatible with the existence of a
small fibre neuropathy that affects both, myelinated and unmyelinated
fibres in hands of patients with SSc. The presence of axonal damage
and possible abnormalities in skin thickness may by factors contributing to neuropathic pain in these patients.
P479
Rituximab treatment in non-malignant inflammatory
sensory polyganglionopathy
A. Zekeridou, J. Kleeberg, A. Menetrey, T. Kuntzer
Lausanne University Hospital (Lausanne, CH)
Non-malignant inflammatory sensory polyganglionopathy (NISP) is the
most common form of acquired ganglionopathies, a rare and distinct
subgroup of peripheral nerve diseases characterized by a primary
degeneration of sensory neurons in dorsal root ganglia. There is a
rational for the use of immune modifying agents (IMA) in NISP since an
underlying auto-immune process is demonstrated or suspected. However, commonly used IMA such as corticosteroids, azathioprine,
methotrexate or IVIG do not prevent disease’s progression in the
majority of patients. The use of newer IMA, especially those directed
against B-cells, may be a therapeutic alternative. An interesting candidate is rituximab, a mouse-human chimeric anti CD20 antibody that
specifically eliminates B-cells and B-cells precursors.
Objectives: This is a prospective open label pilot study to determine the efficacy of rituximab treatment in NISP patients, who did
not respond to commonly used IMA.
Methods: Five patients (40% male) with a mean age of 55 years
(range 49–67), diagnosed with NISP after extensive work-up, were
treated (schema used for one cure: 2 9 1gr within 15 days interval).
Neurological scores (NIS, ISSS, ODSS) and B cell counts were
assessed at baseline and during clinical follow-up at 2 and 6 months
to assess treatment efficacy.
Results: The treatment was generally well tolerated. Minor
adverse events reported were transient arterial hypotension during the
infusions in two patients and intermittent mild leucopenia in one
patient. Clinical evolution during the follow-up period was characterized by a stability of the functional scores in four patients (80%)
and the continuation of disability progression of one patient (20%).
CD4 cells disappeared in all patients after the second infusion, an
effect that lasted until the follow up at 6 months.
Conclusion: The preliminary results of this pilot study indicate
that rituximab is generally well tolerated and prevents progression of
disability during the 6-month observation period in NISP patients.
Inclusion of additional patients and extending of the follow-up period
are intended to further investigate the efficacy of rituximab in NISP.
P480
Two cases of brachial plexopathy after total
laparoscopic hysterectomy
J.Y. An, S.W. Ahn, M.S. Park
The Catholic University of Korea (Suwon, KR); Chung-Ang
University of Medicine (Seoul, KR); Yeungnam University
(Daegu, KR)
123
S116
Introduction: Brachial plexopathy is the second most common
peripheral neuropathy associated with general anesthesia. and it has
been described in a wide range of surgical settings. We described here
two cases of brachial plexopathy in middle-age women who underwent total laparoscopic hysterectomy under general anesthesia for
myoma uteri on the same day.
Case: During the operation, the patients were in the Trendelenburg
position with 15 of head down tilt and shoulder braces were placed
over the bilateral acromioclavicular joints. One patient had weakness
of left arm and hypesthesia over the lateral side of the left arm and
both forearms and right thumb. The other patient had weakness of left
arm and hypesthesia over the lateral side of both arms. The two
patients were treated by conservative treatment. At 1 month later after
discharge, both patients showed significant recovery of their neurological dysfunctions.
Conclusion: we describe here two patients who experienced
asymmetric bilateral brachial plexopathy, which mainly involved the
upper trunk, and this was most likely due to the improper use of
shoulder braces and the head-down position. To minimizing the
occurrence of brachial plexopathy during operations, physicians in the
operating room must give more attention to the extent of the headdown tilt and the amount of time the patient is placed in this position,
and the use of shoulder braces should be avoided whenever possible.
P481
Somatic and autonomic small-fibre neuropathy induced
by bortezomib therapy: an immunofluorescence study
R. Liguori, M. Giannoccaro, C. Gomis Perez, W. Borsini,
V. Di Stasi, V. Donadio
University of Bologna (Bologna, IT); University of Florence
(Florence, IT)
Objectives: Bortezomib, a new agent approved for the treatment of
multiple myeloma (MM), is known to cause a peripheral lengthdependent sensory axonal neuropathy. Autonomic symptoms have
been reported although autonomic neuropathy has never been characterized. The aim of this study is to characterize, by means of
immunofluorescence, the involvement of autonomic skin nerve fibers
in patients treated with bortezomib.
Methods: we studied three women affected by MM, two treated
with bortezomib and one with bortezomib and thalidomide. All
patients had symptoms of peripheral neuropathy whereas two complained also of autonomic symptoms like gastrointestinal disturbances
and cutaneous hyperemia. Patients underwent to neurologic examination and nerve conduction study (NCS). A punch biopsy was taken
from the distal leg and thigh to visualize epidermal and autonomic,
cholinergic and adrenergic, innervation. Epidermal nerve fibre density
(ENFs) was calculated per linear millimetre of epidermis. Autonomic
innervation was graded from 0 (no innervation) to 4 (normal innervation pattern and density) by a semi quantitative scale. Fifteen agematched healthy subjects (62 ± 9 years) without clinical signs of
neurological dysfunction served as controls.
Results: NCS demonstrated a sensory axonal neuropathy in two
patients. In all patients, skin biopsy showed a significant ENFs reduction
in thigh (5 ± 2; n.v. 23.8 ± 4.5) and leg (2.5 ± 1.3; n.v. 15.9 ± 3.9)
associated with a significant reduction of adrenergic and cholinergic
innervation both in thigh (mean adrenergic fibers 2.1 ± 0.7; n.v.
3.8 ± 0.4; mean cholinergic fibers 2.5 ± 0.5; n.v.3.8 ± 0.4) and leg
(mean adrenergic fibers 1.6 ± 1, n.v. 3.4 ± 0.5; mean cholinergic fibers
2 ± 0.8, n.v. 3.4 ± 0.5).
Conclusions: Bortezomib may cause a neuropathy involving
somatic as well as autonomic small fibres with a length-dependent
pattern.
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P482
Injection with corticosteroids at the elbow (ultrasound)
in patients with an ulnar neuropathy: feasibility study
C.L. Alblas, V. van Kasteel, K. Jellema
Medical Centre Haaglanden (The Hague, NL)
Introduction: Unlike carpal tunnel syndrome, little is known about
injection with corticosteroids in patients with an ulnar neuropathy.
The purpose of this feasibility study is to see if injection with corticosteroids is safe in patients with an ulnar neuropathy and whether
there are grounds to launch a prospective placebo controlled study of
the effect of corticosteroids.
Methods: Patients with clinical symptoms of ulnar neuropathy and
abnormal EMG or thickened ulnar nerve at the elbow by ultrasonography were included. Neurological examination was performed at
baseline and after 3 months. After 3 months, the EMG and ultrasound
was repeated and a clinical outcome determined.
Results: Eight patients with nine ulnar neuropathies were included.
Improvement of symptoms occurred in five patients. In three patients,
there was no improvement and one patient deteriorated. Overall there
was no significant improvement in the thickness of the ulnar nerve,
nor was there significant EMG improvement. Complications of the
injection did not occur.
Conclusion: Ultrasound guided injection of corticosteroids in
patients with an ulnar neuropathy is safe. There was an improvement
of the subjective symptoms in five patients. Because injection with
corticosteroids is safe, a larger prospective placebo controlled study is
started.
P483
Ulnar nerve compression in hereditary spastic
paraplegia type 17
F.A.P. Nijhuis, A. Verrips, J. Meulstee, E.J. Kamsteeg
Canisius Wilhelmina Hospital (Nijmegen, NL); Radboud University
Hospital (Nijmegen, NL)
Objectives: Hereditary spastic paraplegia (HSP), in which the predominant feature is spastic gait, is associated with genetic
heterogeneity and different phenotypes are described. The autosomal
dominant hereditary spastic paraplegia associated with BSCL2
mutation is usually characterized by a distal amyotrophy, starting and
predominately in the hands, and spasticity in the legs. We present a
patient with the HSP type 17 with an asymmetric presentation of
motor weakness who had a compression ulnaropathy.
Methods: A 16 years old, right-handed male was referred with a
gait disorder, progressive motor weakness, muscular atrophy and a
claw hand. Neurological examination revealed a stappage (or neuropathic) gait, foot deformities, contractures and atrophy of the
intrinsic hand muscles. Sensory examination was normal and reflexes
were brisk with flexor plantar reflexes. His father had similar neurological findings, with a left Babinski and a right indifferent plantar
reflex. During follow- up the deterioration of right hand function in
the index patient became more prominent. Repeated electromyography (EMG) and genetic analysis were done.
Results: EMG showed an axonal polyneuropathy with motor
deficits more prominent than sensory deficits. In the father, a predominant motor axonal polyneuropathy was found as well. Genetic
analysis of the MFN2 gene revealed normal wildtype alleles. In both
the patient and father the heterozygote mutation p.Asn88Ser in the
BSCL2 gene was found confirming the diagnosis autosomal dominant
HSP type 17. Repeated neurological examination after 1 year showed
a marked asymmetric deterioration of the right hand function with
S117
severe wasting of interosseus muscles and absence of pain or sensory
abnormalities. EMG findings were compatible with ulnar nerve
compression at the sulcus ulnaris. Neurolysis of the right ulnar nerve
was performed and during the procedure entrapment of the nerve was
confirmed. After surgery, no further deterioration occurred.
Conclusion: We diagnosed autosomal dominant HSP type 17 with
BSCL2 gene mutation in our patient. EMG revealed a predominant
motor axonal neuropathy, and in follow-up a right sided ulnar nerve
compression at the sulcus. The incidence of nerve entrapment syndromes in HSP is not described in the literature. Fast and asymmetric
disease progression, in the view of normally slow symmetric progression in HSP, can point to a treatable nerve entrapment disorder.
P484
Mandibular nerve palsy due to dental amalgam
K. Demirkaya, OM. Akgun, H. Akgun, O. Oz, M. Yucel,
Z. Odabasi
Gulhane Medical Academy (Ankara, TR)
Introduction: Amalgam is a restorative material that commonly used
in dentistry for more than 150 years. It contains a mixture of mercury
with at least one other metal such as silver (Ag), copper (Cu), tin (Sn)
metals mercury (Hg). The purpose of this paper is to discuss a case of
mandibular nerve palsy due to partial leakage of amalgam filling.
Case: A 35-year-old female admitted to neurology clinic with
complaints of numbness in the left lip. In clinical examination, no
abnormality was detected except hypoesthesia in the front section of
the left lip and chin. Trigeminal somatosensorial evoked potentials
was performed and latency prolongation was found on the left side.
The patient was thought to be affected locally and referred to Dentistry Department. Panoramic dental radiograph revealed metallic
image in the inferior alveolar canal on the left side. Her medical
history revealed, extraction of her 3rd molar tooth 10 days before and
the 1st and 2nd molar teeth were filled on the same session. The
metallic image detected in radiograph related to leakage of amalgam
and the findings occurred due to mandibular nerve compression of the
material.
Conclusion: Detailed patient history and examination should be
done in patients who admitted to neurology department complaining
of mandibular nerve paralysis, because this situation can result from
dental treatment that applied short time ago. Extraction and filling
should not be performed at same session due to the risk of leakage of
filling material.
P485
The effectiveness of triamcinolone acetonide
with repetitive procaine HCL injection
in the management of carpal tunnel syndrome
O. Karadas, O. Koroglu, F. Tok, L. Gul, U. Ulas,
Z. Odabasi
Gulhane Military Medical Academy (Ankara, TR); Kartal Education
and Research Hospital (Istanbul, TR)
Background and aim: Corticosteroid injection into the carpal tunnel is
frequently used for the treatment of symptomatic carpal tunnel syndrome (CTS) and is known to be safe and effective. Steroids are
usually mixed with local anesthetics, which have positive effects that
can aid the treatment of CTS by inhibiting the spontaneous discharge
ability of excitable nerves . The aim of this study was to determine the
efficacy of triamcinolone acetonide with repetitive procaine HCl
injection in the treatment of CTS
Materials and method: This prospective clinical trial followed-up
patients for 2 months. 22 patients (37 median nerves) with clinical
and electrophysiological evidence of CTS were included in the study.
All patients received both 40 mg of triamcinolone acetonide for once
and 4 ml of 1% procaine HCl twice a week for 2 weeks with the same
technique. Clinical, functional, electrophysiological and ultrasonographic evaluations were performed at the study onset, and 2 months
after the last injection.
Results: Distal motor latency (DML), compound muscle action
potential (CMAP) amplitude, sensory nerve conduction velocity
(SNCV), sensory latency (DSL), compound sensory action potential
(CSAP) amplitude, ultrasonographic findings (median nerve anterior–
posterior diameter, transverse diameter and cross sectional area in the
proximal carpal tunnel and volar bulging,) VAS scores, Boston carpal
tunnel symptom and function assessment scale improved significantly
in all patients (P \ 0.05).
Conclusion: Corticosteroid injection with repetitive procaine HCl
injection effectively reduced the symptoms of CTS, improved the
Boston carpal tunnel symptom and function assessment scale (BCTQ)
and also electrophysiological and ultrasonographic findings.
P486
Ultrasound in diagnosis of carpal tunnel syndrome
D. Azman, J. Bosnjak, M. Dikanovic, G. Lojen,
M. Bitunjac, V. Demarin
General Hospital ‘‘Dr. Josip Bencevic’’ (Slavonski Brod, HR);
University Hospital ‘‘Sestre Milosrdnice’’ (Zagreb, HR)
Objectives: Carpal tunnel syndrome (CTS) is the most frequent
entrapment neuropathy. While the diagnosis is based on clinical
parameters, current gold standard for confirmation of CTS in most
institutions are neurophysiological methods—electroneurography or
electromyography. Recent studies show that some parameters of
median nerve on ultrasound (US) can be used in diagnosis of CTS.
Aim of this study was to evaluate suitability of US in confirmation of
CTS, by comparing it with neurophysiological methods.
Methods: An ultrasound device Aloka A10 with a high-frequency
transducer of 13 MHz and a custom preset was used for imaging.
Different parameters of the median nerve (MN) were measured using
built-in functions. Cross-sectional area (CSA) of MN was assessed at
the inlet and in the middle of the carpal tunnel and flattening ratio was
calculated. Patient group consisted of 20 consecutive patients, with
bilateral or unilateral CTS symptoms, which were subjected to
neurophysiological testing prior to ultrasound examination. Control
group had 25 asymptomatic patients and did not undergo examination
in an electrophysiological lab.
Results: Bilateral symptoms of CTS were present in 75% of
patients. Compared to control group, patients with CTS had higher
average CSA (9.7 vs. 13.9 mm2, respectively). By using current
standard cut-off value for diagnosing CTS of 10 mm2, sensitivity of
91.2% and specificity of 86,1% was established. EMNG correctly
detected 92.8% of symptomatic CTS with specificity of 86,7%.
Correlation between semiquantitative values of symptoms and EMG
findings was 0.39.
Conclusion: Our findings show comparable sensitivity and specificity of US and EMNG in detection of CTS, using CSA at carpal
tunnel inlet as key parameter. By not causing any discomfort in
patients, and with an advantage of offering data on possible visible
etiology of neuropathy inside carpal tunnel, ultrasound could prove to
be a convenient method in diagnostic work-up of this condition.
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S118
Cerebrovascular disorders: clinical features
of stroke II
P487
Persistent akinetic mutism with manipulation
behaviours. An ultimate dysexecutive syndrome
after bilateral thalamopolar artery stroke
A. Carota, P. Calabrese, C. Cereda, C. Bassetti
Hildebrand Clinic (Brissago, CH); Neurocenter (Lugano, CH)
Objectives: The aim of this study is to report the outcome of a patient
with bilateral anterior thalamic stroke.
Case report: A 46-year-old male patient was admitted in the
emergency room with fever, meningism and hypoacousia, without
cognitive and motor deficits. The diagnosis, through neuroimaging
and LCR analysis, were right mastoiditis and pneumococcal meningitis. Mastoidectomy was performed and intravenous antibiotic
started. 48 h later, the patient showed sudden coma without lateralized
signs. This clinical picture, as confirmed by MR-DW images, was
related to bilateral ischemic stroke in the territories of thalamopolar
arteries (involving anterior thalamic nuclei and mammillothalamic
tracts). Acute and follow-up neuroimages did not show any cortical
lesion. The workup excluded other causes of stroke (i.e. endocarditis)
besides meningeal vessels inflammation.
Follow-up: The patient recovered to a normal sleep-waking cycle
within 4 weeks but he showed no sign of improvement for the following
12 months. Over this period he remained in a state of akinetic mutism. He
spent all the waking time with the eyes open without any initiative. He
was mute, had no vocalizations and was unable to respond to relevant
stimuli. He showed an unceasing grasping (clothes, urinary and enteral
tubes) with unrestrained manipulation of whatever object the examiner
placed in the personal space. He did not show finalistic movements, even
for feeding and sphincter functions. Corticospinal pathways were intact.
The patient remained upright (with support) with the head and four limbs
flexed. Repeated EEGs showed diffuse theta bisynchrone rhythms with
weak reactivity to stimulation. This clinical picture, at 12 months followup, remained unchanged despite several pharmacological trials (dopamine, amantadine, acetylcholineesterase inhibitors).
Conclusions: The anterior thalamic nuclei receive projections
from the mamillothalamic tract and have dense reciprocal connections
with the extended limbic system and the medial and lateral prefrontal
cortex. Only very few reports in literature provided data on long-term
functional outcome of bilateral thalamopolar artery strokes. This
single report suggests that thalamic anterior nuclei are fundamental
relays that sustain motivation and purposeful behaviours. Their
bilateral interruption might result in a persistent apathetic and
extremely severe dysexecutive syndrome (akinetic mutism, unceasing
grasping and total environmental dependency).
P488
Phenotypical classification of ischaemic stroke
in patients receiving intravenous fibrinolytic therapy
A. Carrilho Romeiro, P. Santos, M. Rodrigues,
R. Guerreiro, R. Matos, J. Pinto Marques
Hospital São Bernardo (Setúbal, PT)
Introduction: Ischaemic Stroke is a clinically heterogeneous disorder.
From several classification of Stroke, A-S-C-O (A-atherothrombosis,
S-small vessel disease, C-cardioembolism, O-other causes) incorporates better clinical and pathological aspects, defining the most likely of
123
several causes, but still allowing more than one cause. Our goal was to
apply the A-S-C-O classification and evaluate each phenotype at discharge according to recovery, haemorrhage and mortality.
Methods: Retrospective, observational, cohort study with patients
admitted to a Stroke Unit receiving intravenous fibrinolysis, between
January 2007 and November 2010. Probability grades 1 and 2 were
aggregated to define ‘‘A’’, ‘‘S’’, ‘‘C’’, ‘‘O’’ phenotypes. Patients
without subsequent evidence of stroke were excluded.
Results: There were 167 patients receiving intravenous fibrinolytic
therapy, with ages ranging 18–90 years (average = 69.8, standard
deviation = 11.1), 55% of them male. ‘‘C’’ phenotype was the most
frequent (49.4%) and ‘‘O’’ was the less frequent (2.5%). The ‘‘S’’ and
‘‘A’’ phenotypes occurred in 21% and 19% of the patients, respectively.
Two patients were not classified due to insufficient information. The ‘‘C’’
phenotype patients were on average 7.8 years older than the ‘‘S’’ phenotype patients (p = 0.001). The ‘‘S’’ phenotype had less severe stroke
on admission, with a median NIH stroke scale difference of 9.5 to ‘‘A’’
and 9 to ‘‘C’’ (p \ 0.001). When evaluating each phenotype at discharge,
there was less haemorrhage (24%, p = 0.03) and mortality (9.3%,
p = 0.04) in the ‘‘S’’ phenotype. ‘‘C’’ phenotype had poorer recovery
(54.5%, p = 0.02), more haemorrhage (85.7%, p = 0.02) and more
mortality (86.8%, p = 0.01).
Conclusions: The application of A-S-C-O classification overcomes
the limitations imposed by other systems, by establishing a probability relation between the involved mechanisms. The phenotypes
seem to associate with different outcomes, which is relevant to
prognosis. Prospective application of this classification is justified
since in a retrospective evaluation the information can be insufficient
to fulfil the reference criteria for each grade.
P489
Blink reflex and somatosensory evoked potentials
in acute brainstem infarcts
U. Meenakshisundaram, R. Patel
Sri Ramachandra University (Chennai, IN)
Objectives: To find out abnormalities in electrically elicited blink
reflex, median and tibial SSEPs in clinical and MRI proven brainstem
infarction and correlate with the site of infarction.
Methods: Thirty-one consecutive patients admitted with brainstem
infarcts (clinical and MRI) between August 2008 and August 2011
were evaluated.The electrophysiological studies were done within a
week of onset of acute stroke.
Results: In all,77.4% of patients had abnormal blink reflex.84.6% of
patients with lateral medullary infarction had abnormal blink reflex. Blink
reflex abnormalities were also noted in midbrain infarction but were not
seen in patients with medial medullary infarction. In all, 38.7% of patients
had abnormal median SSEPs.Pontine infarcts were more likely (61.5%) to
cause abnormal median SSEPs. In all, 35.5% of patients had abnormal
trigeminal SSEPs. As expected, it was more likely in pontine lesions but
also seen in 66.66% of midbrain infarcts. Asymptomatic trigeminal SSEP
abnormalities were seen 1n 18.18% of pontine infarcts.
Conclusions: The electrophysiological abnormalities indicate that
the sensory pathways in the brainstem are quite intricate and extensive and lesions in the brainstem are very likely to involve them.
P490
Cerebral venous thrombosis as a complication
of neurosarcoidosis
I. Cordeiro, H. NZwalo, F. Sá, F. Ferreira, C. Bası´lio
Hospital of Faro (Faro, PT)
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Introduction: Having a wide range of clinical presentations, a highly
variable mode of onset and very different imagiological findings,
cerebral venous thrombosis (CVT) is an uncommon condition which
mimics a variety of other neurological disorders. With only a few
cases described in literature, CVT is a very rare complication of
neurosarcoidosis. Although the exact mechanism of thrombus formation in sarcoidosis is not yet known, venous stasis secondary to
lymph node compression, local tissue thrombophilia in involved
organs, and granulomatous phlebitis are potential causes.
Case report: A 42-year-old male was presented to the emergency
room with paresthesias of the upper right extremity and a 15-day
history of headache. His past medical history was significant for
sarcoidosis (stage II) and deep venous thrombosis of the upper and
lower right extremities in the last 2 years. The patient was currently
on corticotherapy. He denied drug or tobacco use and his family0 s
history for thrombosis was negative. Physical examination was
unremarkable and the neurological examination revealed right astereognosia. Brain CT and MRI findings were suggestive of extensive
cerebral venous thrombosis, associated with multiple infarcts. The
metabolic study, that included autoimmunity markers and serum
angiotensin converting enzyme, was unremarkable. He was started on
continuous heparin infusion and later switched to warfarin. Aside
from an episode of simple partial seizure, he had a very good
recovery, and was discharged from the hospital 2 weeks later,
asymptomatic, on warfarin treatment (INR 2–3).
Conclusion: This case alerts for the possibility of neurological
complications in sarcoidosis, particularly CVT, even in patients with
minor neurological complaints or neurological signs. We believe that
similar cases should promptly require neurological evaluation in order
to facilitate early diagnosis and treatment.
P491
Geographical distribution of stroke mortality, stroke
mortality rates, and the Human Development Index
correlation in the city of São Paulo. A Brazilian stroke
mortality study
A. Kaup, G. Silva, A. Cypriano, B. Santos
Hospital Israelita Albert Einstein (São Paulo, BR)
Objectives: To analyze the stroke mortality rates (SMR), the stroke
mortality distribution (SMD), and to study a possible correlation
between stroke mortality rates and geographical distribution with the
human development index (HDI) in the city of São Paulo, the largest
city of Brazil, with an estimated population of 11 million people. The
city is divided in 96 districts.
Methods: The death register of the city of São Paulo was verified
to all stroke related codes of International Code of Diseases 10,
I60–69 groups, between 2004 and 2008. Higher SMR was considered
for the regions where the SMR was at least 50% higher than the
observed mean for the age-strata’s 0–14, 15–29, 30–44, 45–59,
60–74, 75 and more, during at least 3 years of the period observed.
HDI is a worldwide used index by United Nations that is composed by
financial income per capita, life expectancy, and school attainment,
was applied to each one of the 96 districts. A geographical analysis of
SMD was realized in order to see if differences could be observed
concerning the geographical distribution of stroke mortality. A Pearson’s correlation test was done to study the correlation between SMR
and HDI.
Results: 34 out of 96 neighborhood district were considered as
having a high SMR in at least 3 out of 5 years observed, characterizing a consistent geographical SMD . Localized most in extreme
regions far from the most developed neighborhoods. The mean HDI
for the city of São Paulo is 0.841, but an individualized HDI was
applied for each one of the 96 neighborhood district of the city,
ranging between 0.701 and 0.961 confirming a known socio-economic inequality. A Pearson’s correlation test showed a consistent
negative correlation between HDI and SMR.
Conclusion: It is well known that stroke incidence and mortality
can be influenced by economic and social variables. We identified a
geographical pattern of high SMR areas in our city that showed to be
related, at least in part, to socio-economic differences, observed when
using the HDI. These findings will allow us to look carefully for the
most affected places concerning stroke occurrence and mortality, and
to plan different actions towards to reduce the burden of stroke.
P492
Clinico-imagistical study of vertebral and basilar artery
abnormalities in stroke patients
M. Sabau, A. Comanescu, I. Popa
University of Oradea (Oradea, RO); Medicine and Pharmacy
University ‘‘Iuliu Hatieganu’’ (Cluj-Napoca, RO)
Material and method: 3D TOF MRA was performed in 113 patients
with ischemic and hemorrhagic stroke, pathological aspects of VA
and BA and their structural implication in cerebral vascular pathology
were analyzed. Hypoplasia was defined by an arterial diameter
\2 mm for VA, \3 mm for BA. Megavessel was defined by a
diameter over 10 mm for VA and over 45 mm for BA.BA was considered dolichovessel when over 29.5 mm length and/or over 10 mm
deviation of one of its segments towards the others.
Results: VA findings: absence of signal in 14 cases (12.50%), VA
hypoplasia in 25 cases (19.64%). Structural changes were limited to
VA and/or BA in 13 cases (11.60%) and were extended to segments
of Willis circle in 12 cases (10.71). Mega VA, mega BA and AVM of
BA was present in 1 patient (0.89%). VA aneurysm and contralateral
VA hypoplasia was found in 1 patient (0.89%). BA structural changes
were found in 12 cases (10.71%): segmental BA hypoplasia associated with VA hypoplasia and a clinical picture of TIA in the
vertebrobasilar arterial system in 1 patient (0.89%), entire BA
hypoplasia associated with bilateral VA hypoplasia in three patients
(2.67%), mega BA and AVM-1 case (0.89%), segmental dedublation
in two cases (1.78%), out of which one case had two segments of
dedublation, dolichoBA in five cases (4.46%), aneurysmal dilatation
of BA in two cases (1.78%).
Discussion and conclusion: We found an increased incidence of
VA hypoplasia as compared to other reports.Vertebrobasilar arterial
system abnormalities are a common cause of stroke.
Keywords: vertebral artery (VA), basilar artery (BA), arteriovenous malformation (AVM) MRA
P493
Internal carotid artery thrombus in a case of acute
carbon monoxide intoxication
T. Teodoro, R. Geraldes, T. Pinho e Melo
Hospital de Santa Maria (Lisbon, PT)
Background: There are few reports on the association between carbon
monoxide intoxication and both arterial/venous trombo-embolic
events.
Case report: We report the case of a previously healthy 46 yearold Pakistani women, who was found unconscious in the bathtub after
the explosion of gas water heater. At the Emergency Department, the
patient had an altered state of consciousness (GCS 10), forced left
gaze deviation and right hemiparesis and hyperreflexia. The Carbon
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Oxide Haemoglobin (COHb) was 18.4% of total Hb. The admission CT
and ECG were unremarkable. The working diagnoses were stroke and
carbon-monoxide intoxication. Acetylsalicylic acid and statin were
started and a session of hyperbaric oxygen therapy was done and followed
by invasive mechanical ventilation with hyperoxigenation. In the following days, there was neurological deterioration (GCS 3). She repeated
the CT scan, which showed a malignant infarction in the left anterior and
middle cerebral arteries territories. Manitol was started with clinical
improvement. On day 6, the patient was weaned off from the ventilator,
was awake, with a global aphasia, right hemianopsy, hemiparesis and
hemihypoaesthesia. Cervical arteries ultrasound showed a thrombus at
the level of the left common carotid bifurcation, occluding the left
internal carotid artery (ICA). There was complete ICA recanalization
3 days later. Laboratory investigation, including coagulation, Hb electrophoresis, vasculitidis and prothrombotic states screening was normal.
Discussion and conclusions: We report a case of a woman with a
reversible ICA thrombus in the context of carbon monoxide intoxication. The temporal coincidence between the two events suggests a
possible etiological role of carbon monoxide intoxication in arterial
thrombosis. The existence of previous case reports of deep venous,
pulmonary, cardiac, mesenteric and cerebral thrombosis after carbon
monoxide intoxication reinforce our conviction. A cardio-embolic
source cannot be excluded: myocardial hypoxia induced by CO
intoxication might have caused a transient cardiac dysrhythmia, with
thrombus formation. We speculate that carbon monoxide might
induce thrombosis by a direct effect on endothelia and/or platelets.
P494
Embolic stroke due to left ventricular metastatic
sarcoma
S. Nunes de Oliveira, J. Toste, M. Nave, J. Ferro
Hospital da Luz (Lisbon, PT)
Introduction and case report: Intracardiac sarcoma metastases are rare
and usually affect the right atrium and ventricle. Left chamber metastatic
involvement is due to hematogenous dissemination or spread from lung
lesions and is unusual. We describe the case of an 86-year-old female
with an acute ischemic frontal subcortical lesion due to embolism of
metastatic heart tumour. Nine months earlier a diagnosis of sarcoma of
the left thigh had been made. At the time of the diagnosis the disease was
widespread with hepatic and pulmonary involvement. Palliative radiotherapy and chemotherapy was started and the patient remained with
minimal symptoms except for occasional thigh pain and fatigue. On the
day of referral to our clinic the patient presented with acute left paresthesia and hemiparesis lasting for 2 min with full recovery. The
neurological exam was unremarkable except for a left Babinski sign. A
brain MRI revealed a small acute ischemic lesion in the middle cerebral
artery territory. Subsequent echocardiography showed two masses in the
left ventricle compatible with metastatic intracardiac lesions. Oral anticoagulation was started and palliative chemotherapy was continued.
Surgery was not attempted due to adverse prognosis.
Conclusions: Intracardiac metastatic disease is a rare and severe
cause of stroke that must be considered in oncologic patients with
widespread disease. It is probably an undiagnosed condition estimated
in 10–25% of patients with terminal cancer.
P495
Amnesic syndrome after infarction of the rostrum
corpus callosum and anterior fornix
S. Nunes de Oliveira, A. Brás, J. Ferro
Hospital da Luz (Lisbon, PT)
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Introduction and case report: Amnesic strokes due to strategically
located lesions of the genu and rostrum of the corpus callosum and
anterior fornix are extremely rare. We report the case of a previously
healthy 80-year-old female that presented with sudden onset amnesic
syndrome caused by an ischemic stroke involving the rostrum of the
corpus callosum and fornix pillars. Examination of the patient
revealed severe anterograde episodic amnesia with inability to retain
new information affecting verbal, visual and spatial information.
Short-term memory was also impaired. Old memories were intact.
Semantic memory was also preserved. The patient was anosognosic
and no repetitive questioning was present. No language, calculation,
attention, visuospatial, executive, emotional or other significant
cognitive deficits were apparent. Cranial MRI revealed an acute
ischemic lesion of the rostrum of the corpus callosum and anterior
fornix, with involvement of the left hypothalamic region. In 48 h, the
patient regained partial insight in to her memory deficits. However,
significant memory loss persisted. Three weeks after hospital discharge, a significant improvement was noted although the patient
remained partially dependent in her everyday activities.
Conclusions: Robust evidence on the prognosis of amnesic strokes
due to infarcts of the anterior fornix and adjacent structures are
lacking due to the small number of patients reported. In our case,
partial recovery was possible. Early recovery of meta-memory may be
an indicator of better prognosis.
P496
Why did we perform a lumbar puncture in a young
patient with ischaemic stroke?
R. Geraldes, A.C. Fonseca, P. Canhão, T. Pinho e Melo
Santa Maria Hospital (Lisbon, PT)
Objectives: It is generally accepted that a lumbar puncture (LP)
should be performed in suspicion of central nervous system (CNS)
infection or vasculitides but its role in the etiological investigation of
an ischemic stroke is unclear. We aimed to determine the frequency
of LP performed in the investigation of ischemic stroke of young
patients, the reasons that lead to its performance, cerebrospinal fluid
(CSF) analysis results and their implication to etiological diagnosis.
Methods: We performed a retrospective descriptive study of
patients between 18 and 55 years old that were admitted to our Stroke
Unit from May 2007–December 2009. Patients were investigated
according to a standardized protocol that includes brain CT and/or
MRI, electrocardiogram, laboratorial evaluation with vasculitis and
infection screening (HIV, hepatitis, VDRL), cervical arteries and
transcranial ultrasound transtoracic/ transesophagic echocardiogram
and 24-h-ECG Holter. The decision to perform digital subtraction
angiography and LP was individually discussed. Etiological diagnoses
were made according to TOAST classification.
Results: From the 143 young stroke patients admitted during the
study period, in 36 (25.2%) a lumbar puncture was performed. Reasons that led to LP were (1) infection suspicion (1 HIV+, 2 VDRL+,
1 endocarditis), (2) central nervous system vasculitis suspicion
(4 ANAs+, 1 antiphospholipid+, 6 with intracranial stenosis), (3)
Identifying the cause of stroke in patients with otherwise negative
investigation (9) or with a PFO as the only identified cause (8). In four
patients LP was done in the initial differential neurological diagnosis
(ex. unconcious patients). CSF was normal in 29 patients. In three
patients, there was [5 cells /ml, CSF proteins [ 50 mg/dl in 6
patients, matched CSF oligoclonal bands were present in 1 patient,
CSF VDRL was positive in 1 patient. LP only confirmed stroke etiology in one case (syphilis).
Conclusion: In our series, LP was performed in a high percentage
of patients but did not contribute to etiological stroke classification in
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most of the cases. There was no additional information when the
objective was to determine stroke cause in patients with a negative
investigation, reinforcing the recommendation that LP should be
performed only in suspicion of infection or CNS vasculitides.
P497
Involuntary leg movements in acute stroke patients
E. Tufanoiu, A.M. Corfu
Fundeni Clinical Institute (Bucharest, RO)
Many of the described involuntary movements, except hemiballismus
are not commonly seen in acute stroke patients.
Between the years 1998 and 2007, we have observed involuntary
movements appeared in stroke patients. Of all the patients, four
presented hemiballismus with poor prognostics (hemorrhagic stroke).
The subject of this presentation is another type of movements,
seen in five patients, with lesions present at the level of the basal
ganglia, especially lenticular nucleus. All the patients were submitted
to physical and neurological examination, blood tests, CT scans and
periodical fallow-ups every 3 months. The movements were captured
on camera.
These movements were observed periodically, during 2 or 3 min.
They were spontaneous, or induced by verbal, sensitive or sensorial
stimulation. The movement had two components: a rapid one, consisting of dorsal flexion of the leg and the maintenance of that posture
for 20 or 30 s, and a slow one, during which the leg came back to the
initial posture. The patients also presented hemiparesis with pathological reflexes and spasticity on the same side as the involuntary
movement. On the moment of appearance of those movements the
patients were somnolent or comatose.
The initial CT scan was normal. We repeated the CT scan after 24
h and it revealed a low density area present in the lenticular nucleus,
on the opposite side of the involuntary movement.
The evolution was favourable under treatment.
One year after the stroke, none of the patients presented movement, cognitive, sensitive or neuropsychological deficit.
P498
Features of stroke in patients with atrial fibrillation
I. Macavei, I. Huza, S. Morar, D. Pop-Ionasiu, A. Treaba,
A. Macavei, I. Macavei
University Hospital (Targu Mures, RO); University of Medicine
and Pharmacy (Targu Mures, RO); Clinical County Hospital
(Targu Mures, RO)
Objectives: Frequency estimation, assessment of risk factors, of major
clinical and imaging features of stroke in patients with atrial fibrillation (AF), primary and secondary prevention measures,
understanding the preventive measures by patients.
Methods: The study included 973 stroke cases admitted to the
Neurology Clinic Tg-Mures, during 1st January–31st December 2010.
The following factors were taken into account: age, sex, environment,
type of AF, risk factors, risk stratification, clinical expression of
stroke onset, primary and secondary prevention, incidence of complications and clinical outcome. Evaluation consisted of medical
history, neurological examination, laboratory tests, electrocardiogram, computed tomography, heart ultrasound and Doppler
ultrasound.
Results: Ischemic stroke patients with AF accounted for 23.39% of
all ischemic stroke. Stroke was more common over age of 65
(62.32%), in female patients (59.06%) and patients from rural areas
(59.54%). Most common type of AF was chronic AF (82.33%).
Hypertension was the most important associated risk factor (90.69%),
followed by age over 75 years (56.74%), diabetes mellitus (20.93%),
history of stroke or transient ischemic attack (20%). In terms of risk of
embolism, 22.32% of patients had a low clinical score, 54.88% had a
moderate score and 22.79% had an increased score. Major neurological disorders seen in the study group include motor deficits
(85.58%), followed by speech and language disorders (51.16%).
Lesions on admission CT were absent in 32.09% of cases. A 23.72%
rate of disabling injuries were present, an ischemic lesion was found
in 33.02% of cases and lacunar infarction occurred in 11.88% of
cases. 87.5% of patients had evidence of carotid or vertebrobasilar
atheromatous changes, and 12.5% had no such changes. As far as
regarding primary prevention, 48.17% of patients did not attend any
treatment and 44.51% were taking antiplatelet therapy and/or oral
anticoagulant therapy. Also, 21.56% of patients did not take any
secondary prevention treatment. At discharge, 94.88% of patients had
an improved neurological condition and a favorable outcome.
Conclusions: AF is a major, but modifiable risk factor for ischemic
stroke. Severity of a stroke occurred in a patient with AF is higher in
all age groups, as compared with other etiology. AF is sometimes
underdiagnosed or undertreated. Thus, AF should be sought in elderly
patients with imaging features suggestive for cardioembolism.
P499
Clinical presentation, aetiology and long-term
prognosis in patients with atraumatic convexal
subarachnoid haemorrhage
T. Gattringer, C. Enzinger, M. Beitzke, G. Wagner,
K. Niederkorn, F. Fazekas
Medical University Graz (Graz, AT)
Objective: To systematically investigate clinical symptomatology,
aetiology and long-term prognosis in patients with nontraumatic
convexal subarachnoid hemorrhage (cSAH).
Methods: For a 6-year period, we searched our radiologic database
for patients with non-traumatic, non aneurismal, subarachnoid hemorrhage (n = 132) and amongst those identified 25 patients with
cSAH as defined by intrasulcal bleeding restricted to the hemispheric
convexities. Subsequent data collection was done by a review of the
medical records and standardized interpretation of neuroimaging
studies. Follow up data after a mean of 32 months (range
1–61 months) were obtained by telephone or a clinical visit whenever
possible.
Results: The 25 patients with cSAH had a mean age of 70 years
(range 37–88 years) and 13 (52%) were women. 21 patients (84%)
were [60 years. The majority of patients (n = 11, 44%) presented
with partly recurrent transient sensory or motor symptoms. Seizures
were the presenting symptom in five patients. Headaches were indicated by 11 patients (44%), with only four experiencing thunderclap
headaches. Symptoms were not typical of a SAH in almost all
patients [60 years. MRI revealed a high frequency of previous
bleedings and their pattern was often suggestive of cerebral amyloid
angiopathy. In five patients, cSAH was associated with acute ischemic
lesions. Fourteen patients (61%) had an unfavorable outcome (modified Ranking Scale score 3–6) at follow-up with five deaths.
Unfavorable outcome was associated with age [60 years and evidence for multiple bleedings. Recurrent cSAH was not observed.
Conclusions: cSAH often mimics transient ischemic attacks and
thus may be an under recognized disorder. In older patients, it shows a
high association with cerebral amyloid angiopathy and carries a bad
prognosis.
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P500
Vascular thalamic confusional state
H. Nicolae, M. Comanescu, R. Borindel, R. Gurgu,
C. Panea
Elias University Hospital of Emergency (Bucharest, RO)
Background: The acute confusional state is characterized mainly by
an alteration of consciousness and by prominent disorders of attention
and perception, which interfere with the speed, clarity, and coherence
of thinking, the formation of memories, and the capacity for performance of selfdirected and commanded activities. Strokes are frequent
causes of delirium. Lesion loci associated with acute confusional
states include thalamic lesions that affect Papez circuit (anterior
nucleus, fornix, mammillothalamic tract).
Case-reports: Case 1: A 38-year-old right-handed man with no
relevant medical history and unknown vascular risk factors is referred
to hospital for loss of consciousness, intense occipital cephalalgia,
paresthesias of right limbs. At admission: somnolence, lack of
cooperation, mild right hypoesthesia, mild right central facial paresis.
After 12 h: dysarthria, right hemiparesis, ataxia of right limbs, right
hemihypoesthesia, right Babinski sign. Routine blood tests, Doppler
examination of extra and intracranial blood vessels, ECG, echocardiography, EEG were within normal limits.. Brain imaging (CT and
MRI) showed a left thalamic infarction. Case 2: A 60-year-old righthanded woman, with history of hypertension without constant treatment was referred to hospital after being found lying on the ground,
unresponsive to questions. Initial evaluation showed no neurological
focal signs, somnolence, minor language disorder with verbal stereotypy and a blood pressure of 210/110 mmHg. One hour later the
patient developed divergent strabismus of the right eye, left hemiparesis, bilateral miosis, bilateral Babinski sign. Paraclinic workup
showed dyslipidemia and mild carotidian atheromatosis. The CT scan
revealed right thalamic primary (hypertensive) hemorrhage with
ventricular fraction.
Discussions: Thalamic confusion, consisting of agitation, disorientation, language disorders of expressive type (reduction in
language, slowness in response,verbal paraphasias) and affected
verbal memory may be explained by lesions of the paramedian nuclei
and by frontal lobe dysfunction from interruption of thalamofrontal
projections. The aim of our paper is to underline the importance of
this clinical manifestation which may be the only one present at the
initial evaluation of a patient in the Emergency Department.
P501
Stroke in Malta
M. Mallia, P. Dingli, L. Azzopardi, D. Vassallo,
J. Aquilina, N. Vella, A. Galea Debono
Mater Dei Hospital (B Kara, MT)
Objectives: The aim of the study was to benchmark the quality of
local stroke practice.
Methods: All stroke patients admitted to Mater Dei Hospital were
recruited prospectively over 6 weeks in 2008. A questionnaire based
on the Royal College of Physicians (RCP) National Sentinel Stroke
Audit was used. The results were compared to the RCP 2008 national
sentinel stroke audit.
Results: 63 patients were admitted with a diagnosis of stroke of
which 42 were confirmed. 50% were male. Ages ranged between 37
and 93, with an average age of 75.7 years. 47.6% presented within 3
h. 31% were under the care of a consultant neurologist and 26.2%
spent [50% of their stay in the dedicated neurology ward. The
average length of stay was 9 days (range 1–30 days). 81% were
123
discharged alive. Of these 44.1% went home, 26.5% went to a rehab
unit, while 20.6% were transferred to a long-term care facility. All
patients underwent CT scanning of the brain within 24 h, with 62% of
scans being performed within 3 h of presentation. 85.7% had at least
one co-morbidity, the commonest being hypertension (73.2%), previous CVA/TIA (43.9%), diabetes mellitus (39%) or evidence of
vascular disease (39%). Concomitant past cerebrovascular events and
diabetes was present in 38.1%. 94% received aspirin within 48 h.
Nutrition was started within 72 h for 90.5%. At 24 h from admission,
54.7% of patients were not screened for swallowing. 47.6% of
patients were not assessed by occupational therapist. 81% of patients
were assessed by physiotherapy at 72 h of admission. None of the
patients had rehabilitation goals agreed upon by a multi-disciplinary
team. If thrombolysis was available, 16.7% would have been eligible.
The commonest contraindications were: presentation [ 3 h of onset
of symptoms (52.4%), age [ 80 years (35.7%), blood pressure [
185/110 (26.2%) and significant stroke severity (19%).
Conclusion: Local results compared well to the RCP 2008 results
in initiation of aspirin, imaging, and nutrition. However, there is need
for improvement in the assessment of swallowing, mood and cognitive function as well as involvement of a multidisciplinary team.
Ways in which adherence to international guidelines can be improved
include the introduction of a stroke unit, delivery of thrombolysis, a
dedicated multidisciplinary service and the use of local guidelines for
stroke. A follow up audit is currently underway to assess implementation of these recommendations.
P502
Diabetic uraemic syndrome: a case report
M. Senol, E. Cengiz, T. Dogan, S. Alay, M. Saracoglu
GATA Haydarpasa Training Hospital (Istanbul, TR)
Objective: In patients with uremia can be changes in consciousness
and hyperkinetic movement disorders, parkinsonism can also be
found next. In this study, we followed-up for diabetic uremic syndrome and a patient with bilateral basal ganglia damage was
evaluated.
Materials and methods: 74-year-old male patient who have diabetes mellitus for 11 years, be followed hypertension and diabetic
nephropathy for 9 years and the surgical management of prostate ca
9 years ago, who had difficulty speaking, was admitted with complaints of difficulty in choosing words.
Results: Neurological examination; the cooperative, but distorted
orientation, paraphasia and parkinsonism revealed. Serum urea and
creatinine levels were increased. In the patient’s cranial MR imaging,
T2 and FLAIR sequences involving there were widespread diffuse
hyperintense signal changes in both the lentiform nucleus and there
were not in diffusion limitations. The patient received dialysis therapy. Levodopa/carbidopa 125 mg 3 9 1 was added him therapy.
Follow-up findings of the partial regression were observed in
parkinsonism.
Conclusion: Diabetic uremic patients associated with acute bilateral basal ganglia damage is a rare syndrome. Clinically, the findings
also are common in parkinsonism. Imaging associated with clinical
findings, but may not show reversible changes. Diffusion-weighted
images were shown primarily vasogenic edema.
P503
Epileptic seizures in stroke patients
D. Kuljic-Obradovic, S. Medic
Clinical Hospital Centre ‘‘Dr. Dragisa Misovic’’ (Belgrade, RS)
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Objective: The objective of our study was to determine the frequency
of the episodic loss of consciousness (epileptic seizures or other
disorders of consciousness) and to identify the prognostic factors for
recurrent epileptic seizures.
Methods: We studied 1,050 first-ever acute stroke patients, age range
39–82. Among these patients 80 had episodic disturbances of consciousness, and were divided in two groups according to the presence of
epileptic seizures and other disturbances of consciousness (syncope,
faintness). The patients with episodic disturbances of consciousness were
evaluated 3 months later. Standard protocol included: medical history,
neurological and cardiological examination, brain CT and/or MRI and
EEG within 7 days of the stroke and after 3 months.
Results: Among stroke patients 7.6% had some episodic disturbances of consciousness. The first epileptic seizures in onset of stroke
was more frequent than other disorders of consciousness 5.2 versus
2.4%. There was no significant difference in types of stroke between
observed groups: single ischemia 5.9 versus 5.0% multiple ischemic
brain lesions 9.3 versus 8.7%, SAH 7.1 versus 8.0%, hemorrhage 5.3
versus 5.5% with hemorrhage with seepage into the ventricular system 6.8 versus 6.0%. Focal epileptic seizures were more prevalent
27.3% simple focal seizures, 23.8% complex focal seizures, 14.9%
secondarily generalized and 24.8% generalized seizures. The most
common EEG patterns were localized epileptiform patterns (44%) in
patients with epileptic seizures and normal patterns (48%) in patients
with other disorders of consciousness. The frequency of localized
slow waves and changes of amplitude was nearly similar. After 3
months recurrent epileptic seizures occurred in 4.6% of stroke
patients. The vast majority of these patients had epileptic seizure early
in the course of stroke(74 vs. 26%), had multiple ischemic brain
lesions and localized epileptiform patterns on EEG.
Conclusions: The frequency of epileptic seizures in the onset of stroke
was 5.2%. The majority of the seizures were focal in onset with or without
secondary generalization (p \ 0.001). The most common EEG patterns
were localized epileptiform patterns in patients with epileptic seizures
(p \ 0.05). The prognostic factors for recurrent epileptic seizures were
ischemic stroke associated with epileptic seizures in firs days of stroke,
and epileptiform EEG pattern (p \ 0.05).
P504
Carotid occlusion without parenchymal ischaemic
lesion
S. Machado, C. Conceição, L. Santos
any parenchymal ischemic lesions. The present case report illustrates
the crucial role of the collateral vessels in the prognosis of this
clinical entity.
Clinical neurophysiology
P505
Sensitivity of tibial somatosensory evoked potentials
in diagnosing patients with relapsing–remitting form
of multiple sclerosis
V. Djuric, V. Milosevic, S. Ljubisavljevic, J. Stamenovic,
G. Djordjevic, A. Prazic
Clinical Centre Nis (Nis, RS)
Background: Multiple sclerosis (MS) is mostly diagnosed clinically,
but the diagnosis has significantly improved through the use of brain
magnetic resonance imaging (MRI), testing of cerebrospinal fluid, and
multimodal evoked potentials (MEPs). Even though MRI is the
superior method in diagnosing this illness, MEPs remain important
because they can detect clinically silent lesions in the sensory and
motor pathways of the central nervous system (CNS).
Aim: The aim of the study is to test the diagnostic sensitivity of
MEPs and MRI and the ratio of their sensitivity in patients with MS.
Materials and methods: The study subjects included 249 patients with
relapsing–remitting (RR) MS. All patients were subjected to an MRI
brain scan, visual evoked potentials (VEPs), median somatosensory
evoked potentials (SEPs), tibial somatosensory evoked potentials (SEPs),
and auditory evoked potentials (AEPs). Abnormal Findings Included:
changed wave morphology, interside difference in wave amplitude,
absolute and interwave latency increased by 2.5 SD as compared with the
control group. The control group comprised of 35 healthy subjects.
Results: In this study the most abnormal findings were tibial SEPs,
median SEPs, and VEPs. Our results suggest different sensitivity of
MEPs in MS patients. In RR-MS the sensitivity of tibial SEPs was
significantly greater (Fischer’s exact probability test) as compared to
other evoked potential modalities. Similarly VEPs were more sensitive as compared to AEPs. There was no significant difference in the
sensitivity of MRI and MEPs in the RR form of MS.
Conclusion: Tibial SEPs produce the most abnormal results and
the highest sensitivity in the RR-MS. We propose that this test as
useful criterion for the diagnosis of MS.
Hospital Prof. Dr. Fernando Fonseca (Amadora, PT);
Hospital Centre of Central Lisbon (Lisbon, PT)
Introduction: The carotid dissection is a frequent cause of stroke in young
individuals being totally asymptomatic in 5% of cases. There are some
well established precipitating factors namely the hyperextension of the
neck and the sudden rotation of the head. One can diagnose it after trivial
movements such as those present during vomiting.
Case report: 38 years old woman with otherwise unremarkable
past medical illness except being on hormonal contraception. She
recurred to a Neurologist after an episode of vomiting and headache
with subsequent asymmetrical eyelids and pupils. On the neurological
examination only a right Horner’s sign was observed. There were no
bruits in the carotid areas and the entire general examination was
unremarkable. A cerebral MRI with angiographic study was done
with the identification of a right carotid occlusion without any
parenchymal ischemic lesions. The patient was then medicated with
acetylsalicylic acid and nowadays remains clinically stable without
any new neurological signs.
Conclusion: The carotid occlusion can remain totally asymptomatic and if there is an efficient collateral circulation it may not result in
P506
Autonomic dysfunction in Klinefelter’s syndrome
M. Yucel, O. Oz, A. Taslipinar, H. Akgun, U. Ulas, E. Bolu,
Y. Kutukcu, Z. Odabasi
Gulhane Military Medical Academy (Ankara, TR)
Objective: This study was planned to investigate the function of the
autonomic nervous system in patients with Klinefelter’s Syndrome
(KS) with those of healthy controls using sympathetic skin response
(SSR) and RR interval variation (RRIV) studies.
Methods: The study group was consisted of 29 patients with KS and
the control group was composed of 26 age and sex matched healthy
subjects. Patients and controls underwent SSR and RRIV tests in our
electrophysiology laboratory. RRIV recorded at rest was termed R% and
the one recorded during hyperventilation was termed as DR%. Beginning
latencies and amplitudes of median and tibial SSRs obtained from
patients compared with those obtained from controls. R% and DR%
values were compared among patients and controls.
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Results: The latencies of SSRs recorded from palm (median) and
sole (tibial) of KS patients were not statistically different from control
subjects (P = 0.482, P = 0.435, respectively). Additionally the mean
amplitude of SSR recorded from palm and sole were not statistically
different from control subjects (P = 0.571, P = 0.053). The RRIVs
obtained from Acromegalics at rest and during hyperventilation were
significantly increased from control group (P \ 0.001, P \ 0.001).
Conclusion: In conclusion the present study suggests that a parasympathetic cardiovagal autonomic dysfunction exists in patients with
KS. This may be documented by means of RRIV.
P507
Sympathetic autonomic dysfunction in young male
patients with idiopathic hypogonadotropic
hypogonadism
M. Yucel, O. Oz, A. Taslipinar, H. Akgun, U. Ulas, E. Bolu,
Y. Kutukcu, Z. Odabasi
Gulhane Military Medical Academy (Ankara, TR)
Objective: There is little data available regarding the effects of male
sex hormones on autonomic function. This study was planned to
investigate the function of the autonomic nervous system in young
male Idiopathic Hypogonadotropic Hypogonadism (IHH) patients
with those of healthy controls using sympathetic skin response (SSR)
and RR interval variation (RRIV) studies.
Methods: The study group was consisted of 41 male patients with
IHH (mean age 22.2 ± 3.5 years) and the control group was composed of 26 age and sex matched healthy subjects (mean age
21.4 ± 2.8). Patients and controls underwent SSR and RRIV tests in
our electrophysiology laboratory. RRIV recorded at rest was termed
R% and the one recorded during hyperventilation was termed as
DR%. Beginning latencies and amplitudes of median and tibial SSRs
obtained from patients compared with those obtained from controls.
R% and DR% values were compared among patients and controls.
Results: The latencies of SSR recorded from palm (median) and
sole (tibial) of IHH patients were significantly longer than healthy
subjects (P \ 0.001, P \ 0.001). The mean amplitude of SSR recorded from palm (median) and sole (tibial) were not statistically
different from control subjects (P = 0.571, P = 0.053). RR interval
variation obtained from IHH patients even at rest or during deep
breathing, was insignificant when compared to control group values
(P = 1.000, P = 0.294).
Conclusion: In conclusion the present study suggests that a
sympathetic sudomotor dysfunction exists in patients with IHH. This
may be documented by means of SSR.
P508
Investigation of the presence of polyneuropathy
in pre-diabetic patients
S. Gudul, U. Emre, N. Ayhan, A. Unal, H. Atasoy
Zonguldak Atatürk State Hospital (Zonguldak, TR); Zonguldak
Karaelmas University (Zonguldak, TR); Artvin State Hospital
(Artvin, TR); Namik Kemal University (Tekirdag, TR)
Objectives: Prediabetic state (impaired fasting glucose (IFG) and
impaired glucose tolerance (IGT)), described as early dibabetic stage,
is an important clinical entity. There is a limited number of studies in
which polineuropathy, an important clinical problem was evaluated in
prediabetic patients. In this study, our purpose was to determine the
presence of polineuropathy with using nerve conduction studies
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(NCS), and define the patient characteristics with clinical and laboratory datas, in prediabetic patients.
Methods: Fifty patients (38 IFG, 12 IGT) who are diagnosed as
prediabetic patients and 25 healthy controls have been included the
study. NCS and laboratory parameters are recorded in all gorups,
diabetic neuropathy symptom score (DNS) and diabetic neuropathy
examination score (DNE) are recorded in the patient group.
Results: According to the NCS, there was no statistically significant
difference between the patient group and the control group. There was no
significant correlation between electroneuromyography (ENMG) abnormalities and DNS and DNE scores, but there was a significant relationship
between right sural/radial sensory neural action potential ratio (SRAR) and
DNS scores (p = 0.041), and a significant relation between right
(p = 0.035) and left (p = 0.018) sural nerve sensory neural action
potentials (SNAP), right median motor amplitude (p = 0.032), right ulnar
motor conduction velocity (p = 0.048), right (p = 0.000) and left tibial
nerve motor amplitude (p = 0.001) was found. The subjects that have
abnormal ENMG findings, have higher body mass index levels
(p = 0.038). Similarly, the subjects that have metabolic syndrome, are
more likely to have EMG abnormalities. (p = 0.047).
Conclusion: The neurologic examination and history are found to
be sensitive to determine the presence of neuropathy in prediabetic
patients. The subjects that have metabolic syndrome, are more likely
to have EMG abnormalities. Studies with larger population are needed for the electrophysiologic findings that we found in pre-diabetic
patients, to be considered as neuropathy.
P509
Absence of cutaneous silent period changes in a patient
with stiff person syndrome
A. Mekideche, I. Kuzmanovic, C. Sottas, A. Truffert
Geneva University Hospital (Geneva, CH)
Objectives: to report a case of stiff person syndrome (SPS) with
electrophysiological data suggesting cortical, rather than spinal motor
neuron hyperexcitability.
Methods: In a 62 years old woman with SPS (increased anti-GAD
antibodies), both the cutaneous silent period (Cu-SP) after sural nerve
electrical stimulation, and the silent period of motor evoked potentials
(MEPs) after transcranial magnetic stimulation (MEP-SP) were
recorded from the contracting tibialis anterior muscle. The Cu-SP is
thought to reflect spinal motor neurons excitability, while the MEPSP assesses cortical motor neurons excitability.
Results: Latency and duration of the Cu-SP was within the normal
range of our laboratory reference values. By contrast, the MEP-SP
was markedly shortened, as usually described in SPS. Under benzodiazepine (lorazepam) treatment, the MEP-SP duration was normal.
Lower limbs MEPs were of normal amplitudes and latencies and
decreased thresholds.
Conclusion: The issue of the site of motoneuronal hyperexcitability in SPS is still a matter of debate. Our finding of normal CuSP
in our patient suggests a normal excitability of spinal motor neurons
in SPS. Moreover, the shortened duration of the MEP-SP, reversible
under specific benzodiazepine treatment further supports the
hypothesis of a cortical motor neuron hyperexcitability in SPS.
P510
Ultrasound-guided needle positioning in sensory nerve
conduction study of the saphenous nerve
M. Evangelopoulos, S. Humpert, A. Weck, K. Rösler
University of Athens (Athens, GR); University of Berne (Berne, CH)
S125
Conduction studies of the saphenous nerve are rarely done, because
the nerve may be difficult to localize, responses are generally small,
and techniques have not been standardized. Surface electrode
recordings have the disadvantage of small response amplitudes, while
needle recording electrodes may be difficult to place, thus sometime
missing the nerve.
In this study, we identified the saphenous nerve using ultrasound
imaging, and compared sensory nerve action potentials (SNAPs)
recorded by surface electrodes and needle electrodes, both optimally
placed under ultrasound guidance.
Ultrasound imaging identified the saphenous nerve in all 20
healthy subjects (mean age 30 ± 5.8 years, 10 males), some
5.5–7.0 cm distally from the edge of the medial articular surface,
behind the medial border of the tibia in close proximity to the
saphenous vein. The mean nerve diameter and cross-sectional area
were 0.17 ± 0.22 cm and 0.014 ± 0.0.02 cm2, respectively. Orthodromic conduction was measured by distal supramaximal nerve
stimulation and proximal recording, using both, needle and surface
recording electrodes. Surface electrodes recorded responses in 17 of
20 subjects, while ultrasound guided needles recorded responses in 19
of 20 subjects. In all subjects, SNAPs recorded by ultrasound guided
needle electrodes were significantly larger than those obtained by
surface electrodes (5.85 ± 3.01 vs. 1.98 ± 1.37 lV, p \ 0.0001).
Needle recorded SNAP amplitudes correlated inversely linear with
the nerve diameter (p \ 0.0001, r = -0.476). Conduction velocities
were identical with both recording methods, and nerve distance from
the body surface did not influence the results.
Conclusion: The use of ultrasound helps identifying saphenous
nerve and significantly improves sensory conduction studies of the
saphenous nerve.
Supported by ENS Fellowship.
P511
Clinical electromyography correlation in patients
admitted to a university hospital, Curitiba, Brazil
C.S. Kay, R.H. Scola, P.J. Lorenzoni, L.C. Werneck
Paraná Federal University (Curitiba, BR)
Objectives: The aim of the study was to correlate clinical suspicion
with results of electromyography (EMG) in patients admitted to the
HC-UFPR within 1 year to evaluate the contribution of the examination in the diagnosis of the patient.
Background: An examination of EMG is an extension of the
neurological examination, but its contribution to the diagnosis and
management of inpatients is not often reported in the literature.
Design/methods: A retrospective analysis of 406 examinations
performed in 2007, in hospitalized patients in the HC-UFPR, disclosed 210 EMG performed in 204 inpatients that were studied
correlating suspect(s) clinic(s) and outcome. Such correlation was
classified as a confirmatory, new diagnosis, incidental findings,
inconclusive or normal. When necessary, medical records were
reviewed for additional information.
Results: The sample consisted of 204 patients (81 female and 123
males), aged between 4 months to 91 years, with mean age of
38 years. Five patients repeated EMG (one repeated twice) in the
same year because the initial clinical suspicion in four was myasthenia gravis with first exam normal, and one did chemotherapy. The
clinical suspicions was sorted by topography with 14% for motor
neuron involvement, 14% nerve root, peripheral nerve 40%, 8%
neuromuscular junction and 24% by muscle involvement. Correlation
was considered confirmatory in 61%, new diagnosis in 9%, incidental
5%, inconclusive 3% and normal 22%. Motor neuron diseases were
most often confirmed by EMG (73%) and neuromuscular junction
diseases had more normal result (53% normal result and 29% was
confirmatory). Examinations performed for suspected peripheral
neuropathy was confirmatory in 64% and had normal results in 17%,
mainly in patients under investigation by ataxia and when prevailed
pain manifestation.
Conclusions: This study showed that perform EMG is important in
the evaluation of inpatients, mainly when suspected motor neuron
disease. Although the EMG is an extension of neurological examination, 9% had a new diagnosis. The commonest technical of EMG
contributes little to painful neuropathy.
P512
How should the cortical area for activation of muscles
with transcranial magnetic stimulation be defined?
M. Thordstein, K. Berglund, G. Pegenius, M. Elam
Sahlgrenska University Hospital (Gothenburg, SE)
Introduction: Transcranial magnetic stimulation (TMS) can be used to
define the cortical areas from which different muscles are controlled.
When this is done as part of the pre operative investigation before
neurosurgery, optimal precision is needed. The new TMS-equipments; navigated TMS, often called Navigated Brain Stimulation
(NBS), use the patients’ own three dimensional MR image to guide
for the stimulation. The potential of these systems to improve precision has not been fully investigated.
Objective: To study effects of varying stimulation intensity and
varying target muscles on response characteristics in terms of resting
motor threshold (RMT) and defined area of activation.
Methods: With NBS equipment, the above mentioned parameters
were determined in healthy adult volunteers using three different
stimulation intensities (100, 110 and 120% of RMT defined in electric
field strength) in four muscles; m abductor pollicis brevis (APB),
extensor digitorum communis (EDC), biceps brachii (BB) and tibialis
anterior (TA). The limit for response amplitude was set to 20 lV and
the quantification of area for activation was made in the Freesurfer
environment.
Results: The RMTs for all muscles differed between individuals
(up to 46% difference) whereas the intraindividual differences
between muscles were smaller (up to 12% difference). The area for
activation increased for all muscles in all individuals as the stimulation intensity was increased. However, the degree to which this took
place differed between muscles intra- and interindividually.
Conclusions: Using optimal stimulation in healthy adults, reproducible responses smaller than 50 lV are reliable. The activation area
and the steepness of its ‘‘stimulus response curves’’ varies between
and within individuals. Thus, people and parts of the motor system are
different. This should be taken into account when results of motor
mapping are reported. The current recommendations concerning
stimulus parameters may need to be changed.
P513
Contact heat evoked potential stimulation spinal cord
conduction velocity values in normal controls
and in patients with sensory loss are significantly faster
with lumbar than with cervical stimulation
B. Smith, M. Ross, B. Goodman
Mayo Clinic (Scottsdale, US)
Objectives: In addition to using Contact Heat Evoked Potential
Stimulation (CHEPS) to evaluate spinothalamic scalp response
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amplitude and latency, spinal A delta fibre conduction velocity (CV)
can be approximated by stimulating axial sites with CHEPS. In order
to assess A delta fibre spinal cord CV values from the lumbar and
cervical spinal sites in normal controls and in patients with sensory
loss CHEPS was employed.
Methods: Individuals with normal sensation (neuropathy impairment score-sensory subscore [NISS] B 2) and those with abnormal
sensation (neuropathy impairment score-sensory subscore
[NISS] [ 2) from a variety of peripheral and/or central disorders
underwent neurology examination, detailed neurophysiologic assessment, and CHEPS over the torso (L1 and C7 spine), recording over
the central scalp. At each site 14 stimuli were delivered to produce a
single averaged scalp response.
Results: In controls (n = 4) the spinal cord A delta fibre CV
values (range; standard deviation) were (in m/s): L1 spine 1.34
(0.99–1.71; 0.32) and C7 spine 0.73 (0.54–0.83; 0.13). In patients
with sensory loss and elicitable CHEPS responses (n = 12), the spinal
cord A delta fibre CV values (range; standard deviation) were (in
m/s): L1 spine 1.49 (1.08–1.91; 0.29) and C7 spine 0.64 (0.41–0.91;
0.13). In both cohorts spinal A delta fibre CV values were more rapid
from lumbar versus cervical spinal sites, on average being approximately twice as fast from the low back as from the neck.
Conclusions: (1) Adult median spinal A delta fibre CV values from
4 control and 12 patients with sensory loss are reported. (2) There
appears to be a significant A delta fibre CV gradient comparing
lumbar with cervical stimulation sites at close to a 2:1 ratio. (3)
Possible explanations for the greater A delta fibre CV values from the
lumbar versus cervical spinal cord include: (a) larger diameter axons
in lumbar versus cervical A delta pathways, (b) greater myelin
thickness in lumbar versus cervical A delta nerve fibres, and
(c) longer myelinated internodes in lumbar versus cervical A delta
pathways.
This work is supported by a grant from Mayo Foundation,
Rochester, Minnesota USA.
P514
Facial nerve conduction in diabetic neuropathy
C.U. Velmurugendran
Sri Ramachandra Medical College and Hospital (Chennai, IN)
Neuropathy is one of the most common complications of diabetes
mellitus. It is more likely to affect the nerves of the extremities than
the cranial nerves. In some cases the facial nerve conduction is
delayed though there is no facial palsy in established diabetic
peripheral neuropathy.
Aims and objectives: To study the facial nerve conduction in
patients with established clinical and electrophysiological neuropathy.
Material and methods: The study was conducted in a group of 30
diabetic neuropathic patients who had electrophysiologically confirmed conduction delay in peripheral nerves. Patient who had clinical
facial neuropathy were excluded in the study. The clinical nerve
conduction studies were performed by using Nihon Kohden (EMG/
EP/NCS Equipment) at normal room temperature. The latency and the
amplitudes of the facial nerve were recorded using surface electrodes.
Results: The facial nerve conduction studies in 30 patients with
diabetic neuropathy shows abnormality in facial nerve conduction in
14 patients (46.6%). Out of these 12 patients showed reduction in
amplitude, CMAP \ 2, the normal value being 2 in our lab. The
remaining two patients showed prolonged latency and reduced
amplitude.
Discussion: This study has shown that the facial nerve is affected
in peripheral neuropathic patients, who had no clinical facial palsy.
The reduction in amplitude possibly favours Axonopathy. During the
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1 year follow up these patient did not develop clinical facial palsy or
other cranial nerve palsy.
Conclusion: This study shows that there is subclinical involvement
of facial nerve in 46.6% of patients with diabetic neuropathy possibly
due to axonopathy which might be metabolic in nature.
P515
Differential diagnosis of optic neuritis in neuromyelites
optica and multiple sclerosis: are VEPs useful?
L. Straffi, M. Radaelli, M. Bianco, V. Martinelli, G. Comi,
L. Leocani
University Hospital San Raffaele (Milan, IT)
Objectives: The aim of our study was to investigate whether the
presence of a different pattern of response at visual evoked potentials
(VEPs) in patients affected by neuromyelites optica (NMO) and
multiple sclerosis (MS) with optic neuritis (ON).
Methods: We retrospectively evaluated VEPs in patients within 1
week after a first ON episode and who were given a diagnosis of MS
of NMO after a follow-up of (4 ± 3 years). Latency and presence
of VEPs response over the affected and unaffected eyes were
determined.
Results: Thirty-seven patients were included in the study, of whom
19 with a subsequent diagnosis of NMO and NMO-IgG positivity
(female 17; age 35 ± 16); 18 patients with MS and NMO-IgG negativity (females 17, age 29 ± 8). Bilateral ON was present in 4/19
(21%) NMO patients and 1/18 (5%) MS patients. No significant group
difference was found in mean visual acuity in affected eyes:
4/10 ± 3.1 in NMO patients and 5/10 ± 3.2 in MS patients. A
measurable VEP response was detected in all unaffected eyes. NMO
patients had a higher frequency of VEPs absence in the affected eye
(73 vs. 35%; p = 0.03 Fischer). A measurable cortical VEP response
was recorded in 6 NMO patients and 10 MS patients, respectively. A
significant higher P100 latency was observed in MS patients (MS:
143 ± 14 ms; NMO: 126 ± 13 ms; ANOVA p = 0.04). No significant group difference was found on VEPs latencies in the unaffected
eye.
Conclusions: Visual evoked responses after ON were more frequently absent in patients who subsequently developed NMO
according to serologic and clinico-radiologic criteria. Our findings are
consistent with the view of a different pathological substrate underlying MS and NMO, the characterized by a more frequent and severe
axonal involvement. This findings also suggest that VEP may help in
differentiating MS and NMO already at the first episode of optic
neuritis.
P516
Is hemifacial spasm accompanied by haemodynamic
changes detectable by ultrasound?
F. Perren, M.R. Magistris
University Hospital of Geneva (Geneva, CH)
Introduction: Hemifacial spasm (HFS) is a rare condition characterized by weakness, synkinesis and involuntary, intermittent, spasmodic
contractions of hemifacial muscles innervated by the facial nerve.
Usually, an arterial tortuosity of the posterior circulation compressing
the facial nerve as it exits from brainstem induces the ephaptic axonoaxonal cross-talk that sparks HFS. MR angiography, the actual gold
standard, does not always clearly show the ‘‘vascular-nerve conflict’’.
We sought if a noninvasive method such as color-coded duplex flow
S127
imaging (CDFI) of these arteries might detect hemo-dynamical
changes in HFS.
Methods: Nine successfully treated (botulinum toxin) patients
have been examined prospectively. Color-coded duplex flow imaging
(extra- and transcranial using 7.5 and 2 MHz devices) has been performed by a sonographer who was blinded to the presence of an HFS.
Blood flow velocities [including mean blood flow velocities (MFV)]
of the vertebral (VA), posterior inferior cerebellar (PICA) and anterior inferior cerebellar (AICA) arteries were measured and side-toside comparison was performed for all of them.
Results: Nine patients (5 men; mean age 53.4 years) were studied.
Whereas there was no significant association between MFV elevation
of the VA and HFS (Fisher’s exact p = 0.523), an elevation of MFV
of the PICA and AICA was found on the side of the HFS in the seven
patients (in whom these vessels could be detected by the method
(Fisher’s exact p = 0.0285; 2-tailed).
Conclusion: Despite the limited number of HFS patients studied,
we found a significant association between elevation of MFV of the
PICA and AICA and the side of HFS. Therefore, HFS seems to relate
not only to an unfortunate ‘‘malposition’’ of an artery over the root
exit zone of the facial nerve, but also to hemodynamic changes
detectable by CDFI. Ultrasound techniques may become an additional
tool in the detection and evaluation of the ‘‘vascular-nerve’’ conflict
of HFS.
P517
Brainstem reflexes in porphyria variegata
G. Barraza, T. Serranova, C. Herrero, J. Casanova-Mollá,
J. Herranz, J. To-Figueras, J. Valls-Sole´
University Hospital (Barcelona, ES)
Objectives: Porphyria Variegata is a form of porphyria that is known
to present mainly with an acute predominantly proximal motor neuropathy. However, the involvement of the cranial nerves has received
less attention. Our aim was to assess cranial nerves function in two
patients (mother and son) with Porphyria Variegata who presented
with neuropathy involving the face.
Methods: The propositus was a 37 years old man who presented
an acute episode of abdominal pain, delirium, proximal tetraparesis
with predominant upper limb involvement and bilateral facial weakness. Biochemical analysis showed a marked increase of deltaaminolevulinic acid, porphobilinogen and total porphyrins in the
urine, and also a marked increase of total porphyrines, coproporphyrin
and protoporphyrin in the stools. Plasma fluorescence emission was
highly suggestive of Porphyria Variegata (625 nm). The propositus’
mother was a 70 years old woman who presented a chronic weakness
in four limbs and face. After the diagnosis in her son, she was also
tested and found positive for Porphyria Variegata. Apart from conventional electromyogaphy and nerve conduction tests, we examined
the blink reflex to electrical stimuli of the trigeminal and peripheral
nerves, the jaw jerk and the masseter inhibitory reflex.
Results: Similar observations were made in both patients. Nerve
conduction studies showed normal conduction velocity in motor and
sensory fibers. Needle EMG showed loss of functional motor units in
proximal muscles, whereas EMG activity was strictly normal in distal
muscles. The blink reflex to electrical stimuli of the supraorbital nerve
showed absence of late responses, with perfectly normal R1 to
stimulation in both sides. The blink reflex was also absent to stimuli
applied to peripheral nerves. Responses to auditory stimuli were
present but of small amplitude. The jaw jerk was normal. The masseter inhibitory reflex showed reduced inhibition in the second phase.
Conclusion: Normal R1 responses ruled out a trigeminal nerve
neuropathy and a lesion in the upper pons. Normal jaw jerk indicates
absence of a lesion in the trigeminal mesencephalic nucleus. No
evidence for involvement of long tracts was present and, therefore,
the lesion is more likely to be central than lateral in the brainstem.
This, together with the abnormal R2 responses of the blink reflex and
the second phase of the masseteric inhibitory reflex, are compatible
with lower pontine and upper medulla involvement.
P518
Spatial discrimination of contact heat thermal stimuli
in healthy volunteers
O. Grau, E. Selvi, L. León, J. Casanova-Molla,
J. Valls-Sole´
University Hospital of Barcelona (Barcelona, ES)
The size of the cortical evoked potentials (EPs) to nociceptive stimuli
is determined by stimulus-related factors, such as intensity and salience and subject-related factors, such as attention and novelty. These
factors influence also the conscious perception of nociceptive inputs
but the precise relationship between perception and EP size is not
known. We investigated how well healthy subjects are able to discriminate between two spatially and temporally separate thermal
stimuli through an analysis of conscious perception and EP
characteristics.
The study was carried out in nine healthy volunteers. We used two
different thermal stimulators (Pathway, Medoc, Israel) to apply single
stimuli through independent thermodes attached with a distance
between centers of 5 cm at the proximal 1/3 of the left forearm.
Subjects could receive in random order either a single stimulus or a
pair of stimuli separated by 0, 50, 100, 150, 200, 300 or 500 ms.
Contact heat evoked potentials (CHEPs) were recorded from Cz with
reference to the earlobe. After each trial, subjects were asked to state
whether they received one or two stimuli and to score their pain
sensation in a 0 to 10 numerical rating scale.
The mean percentage of correct discrimination trials was about
chance at short intervals (0–150 ms) and increased up to 80% at long
interval (300–500 ms). The mean pain score with a single stimulus
was 4.2 ± 0.6 and it tended to increase as the intervals increased
achieving its highest value at 250 ms (6.3 ± 0.9) and then slowly
decreased with longer intervals. CHEPs were present to the second
stimulus at all intervals, even in trials in which subjects stated that
they felt only one stimulus. The percentage suppression of the second
CHEPs was 51 % at the interval of 50 ms and increased to 89% at
250 ms.
The mechanisms responsible for sensory discrimination of nociceptive inputs involve functions beyond cortical generation of
CHEPs. Although the ‘first come first serve’ theory may govern both
events, physiological mechanisms responsible for the size of the
evoked potentials may be more stimulus-dependent, including
refractoriness and synaptic amplification) while those responsible for
conscious perception may depend more on psychophysiological
properties such as gating, spatio-temporal summation and attention
masking.
P519
Clinical improvement of secondary dystonia after deep
rTMS performed with H-coil. A case report
F. Spagnolo, M.A. Volonte´, R. Chieffo, L. Straffi, E. Coppi,
M. Bianco, L. Ferrari, D. Dalla Libera, S. Velikova,
A. Nuara, G. Di Maggio, G. Comi, L. Leocani
University Hospital San Raffaele (Milan, IT)
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Introduction: Dystonia represents one of the most disabling movement disorders, characterized by involuntary, sustained or repetitive
contractions of opposing muscles, causing twisting movements and
abnormal postures, with severe long-term effects. Treatment is manly
symptomatic as the pathogenesis of most dystonias is still poorly
understood. Therapeutic options include physical and occupational
therapy, oral medications, botulinum toxin, and surgery. A common
reported abnormality in dystonic condition is a reduced inhibition of
motor areas, which results in excessive muscular activity. Deep
repetitive Transcranial Magnetic Stimulation (rTMS) performed with
H-coil can be used to modify neural circuits and potentially to restore
cortical excitability.
Methods: Here we describe the case of a 33-year-old man, suffering from a severe left hemi-dystonia since the age of 3, after a
cryptogenic ischemic stroke had disrupted his right deep grey nuclei
circuits. He was still able to walk autonomously, but the voluntary use
of his left upper limb was precluded to him. Moreover severe
involuntary twisting of his left arm obliged him to continuously block
the dystonic limb with the contralateral arm, worsening his social
embarrass. After the inefficacy of the commonly used oral therapies
and of botulinum injections, he was referred to our TMS centre,
where he underwent a 2 weeks protocol (4 sessions/week) of low
frequency (1 Hz) rTMS performed with H-coil. Inhibitory stimulation
was applied to the Motor Cortex of his affected hemisphere (right)
and to the Prefrontal Cortex (PF) bilaterally, every session of stimulation lasting about 40 min (900 total pulses delivered to every site).
Results: Since the third session of treatment inhibitory rTMS produced an improvement in patient’s motor condition, with a reduced
severity and frequency of upper limb involuntary movements. The
patient felt more confident in public during the day and was able to sleep
properly during the night thanks to a reduction of obliged postures (see
video for detail). Follow up of the patient will be provided.
Conclusions: This very preliminary, single case observation, open
the possibility of using deep rTMS to treat dystonia. Further appropriate clinical trials are needed.
P520
Effects of l-opioid receptor agonist on saccadic
refixations
P. Walecki, W. Lason, J. Feit, E.J. Gorzelanczyk
Jagiellonian University Medical College (Cracow, PL); Nicolaus
Copernicus University Medical College (Bydgoszcz, PL); Polish
Academy of Sciences (Warsaw, PL)
Objective: The goal of this study was to assess an impact of l-opioid
receptor agonists on eyeball movements (saccades). In various diseases saccadic disorders are observed. In the nervous system, the
natural ligands of opioid receptor agonists are endogenous peptides:
endorphins, enkephalins and dynorphins. Opioid receptors are present
in the cerebral cortex (layer III and IV), in the thalamus and with the
greatest density in striatal striosomes.
Participants and methods: 23 people were examined. The study
included persons involved in the substitution therapy for people
addicted to opiates. The researchers applied a non-invasive method of
eye movements measurement using a Saccadometr (Ober Consulting
Poland, Advanced Clinical Instrumentation, Cambridge, UK),
allowing the measurement of eye position with 1 ms (1,000 Hz) time
resolution. Before the administration of methadone (l-opioid receptor
agonist) two saccadic tests were carried out: Latency Test (LT) and
Antisaccades Test (AT). Each test consisted of 20 trials for calibration, and 50 actual study measurements. In total, each person made
140 responses to stimuli. Both tests were repeated after approximately
1.5 h after administration of methadone.
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Results: Results of LT and AT showed that after a single dose of
methadone the duration (5%) and latency (18%) increased, and the
amplitude (-5%) and peak velocity (-8%) decreased. Statistical
analysis of Wilcoxon matched-pairs signed-ranks test showed that
changes are statistically significant (p \ 0.05). After administration of
methadone the number of correct responses increased, and the number
of incorrect responses decreased significantly statistically (p \ 0.05).
Conclusions: The results show significant inhibitory effects of
l-opioid receptor agonist. These effects suggest that the location of
opioid receptors in the brain is associated with the oculomotor pathway.
P521
Differences of saccadic refixations in ADHD/HKD
and non-ADHD individuals
P. Walecki, E.J. Gorzelanczyk
Jagiellonian University Medical College (Cracow, PL); Polish
Academy of Sciences (Warsaw, PL)
Objective: The goal of this study was to assess the differences in eyeball
movements (saccades) between ADHD/HKD individuals and healthy
subjects. The study analyzed the following saccadic parameters: duration,
amplitude, average velocity, peak velocity, sharpness, and skewness.
Participants and methods: Saccadic dynamics change with age,
therefore in the study a person from a homogeneous age group, i.e.
from 18 to 20 years took part. Based on the results of psychological
tests: TOVA (Test Variables of Attention) and CAARSTM-S:L
(Conners’ Adult ADHD Rating Scales) group of 35 people who had
the highest score in the ADHD/HKD scales was distinguished. The
control group consisted of 75 persons. In this study, we made use of a
head-mounted oculometer Jazz (Ober Consulting Poland) which
measures parameters related to eyeball movement in response to
stimuli displayed on the monitor screen.
Results: The results showed a significant mean difference between
two groups in the Mann–Whitney U test (p \ 0.05) in the following
saccadic parameters: duration (for saccades with amplitude 5, 15
and 20), peak velocity (10, 15 and 20) and sharpness (15 and
20). ADHD/HKD individuals had shorter duration, higher velocity
and sharpness of 15 and 20 saccades than those in the control group.
Conclusions: Some areas of the brain, such as basal ganglia and
dorsolateral prefrontal cortex, related to a saccadic control are also
involved in the pathogenesis of ADHD/HKD. Therefore, examination
of problems of eyeball movements may constitute an effective
neurophysiological diagnosis of ADHD/HKD.
Neuro-rehabilitation
P522
The Upper Limb Assessment in Daily Living:
construction and validation
M. Rousseaux, H.Y. Bonnin Koang, B. Darne´, P. Marque,
B. Parratte, A. Schnitzler, C. Delleci, N. Bradai,
J.M. Viton, W. Daveluy, B. Perrouin Verbe, A. Yelnik,
M. Zadikian, C. Benaı̈ m
University Hospital (Lille, FR); University Hospital (Nimes, FR);
Monitoring Force (Paris, FR); University Hospital (Toulouse, FR);
University Hospital (Besancon, FR); Public Health Assistance
(Garches, FR); University Hospital (Bordeaux, FR); Public Health
Assistance (Paris, FR); University Hospital (Marseille, FR);
University Hospital (Nantes, FR); Merz Pharma France (Paris, FR);
University Hospital (Dijon, FR)
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Objectives: Many scales have been constructed to assess the functionality of the upper limb in testing conditions. More recently other
scales have been developed in order to evaluate the use in everyday
life, though they essentially assess active and distal functions, i.e.
object manipulation. Our aim was to build a new scale (upper limb
assessment in daily living, UL-ADL) that both explores the use in
daily living and capacities in a test situation, following a proximaldistal progression and the integration of passive and active functions.
Methods: A group of experts built-up a scale consisting in 17
items corresponding to specific activities of daily living for which it
was possible to present a questionnaire (Q) and a test (T). The 17-item
UL-ADL scale follows a proximal-distal progression and includes
passive and active functions. Each item corresponds to a specific
activity of daily life. Each item is quoted between 0 (cannot perform)
and 100 (perform with no difficulty). Internal consistency was
assesses with the Cronbach’s a coefficient. Intra-rater and inter-rater
reliabilities were assessed with the intraclass correlation coefficient
(ICC) and the Bland and Altman method. UL-ADL was also compared to the arm movement section of the Rivermead Motor
Assessment scale (RMA).
Results: Overall, 49 stroke patients were rated over 7 days by 21
physicians leading to 142 ratings. Total time of UL-ADL was 16 ± 8
min compared to 9 ± 5 min for RMA. The Cronbach a was 0.95 and
0.97 for Q and T, respectively. Global UL-ADL scores were slightly
higher at second rating, especially Q score. Intra-rater ICC was 0.65
(95% CI [0.44-0.79) and 0.97 [0.95-0.98] for the Q and T steps,
respectively. Inter-rater ICC was of 0.95 for the Q and T steps. Bland
and Altman method showed good intra- and inter-rater reliabilities
with no systematic trend. Correlation with RMA was [0.80 with Q
and with T.
Conclusion: The UL-ADL has fair metrological properties and
seems suitable for stroke patients with all levels of upper limb
impairment.
P523
Including relatives as clients into the rehabilitation
process after stroke: related ethical issues as perceived
by relatives and patients
A. Rochette, E. Racine, H. Lefebvre, J. Lacombe, J. Bastien
University of Montreal (Montreal, CA); McGill University (Montreal,
CA); Montreal Clinical Research Institute (Montreal, CA);
Rehabilitation Institute Gingras-Lindsay (Montreal, CA)
Objective: To document perceptions about ethical issues of relatives
and individuals with a first stroke with respect to including the relative into the rehabilitation process as a client.
Methods: Qualitative design with a phenomenological orientation.
In-depth interviews were realised using an interview guide validated
by experts. Open-ended questions focused on perceptions of actual
services received by relatives versus ideals services, involvement in
decision making regarding date of discharge and discharge destination as well as relationships with medical staff. Data were collected
more than 3 weeks following discharge from acute care or from inpatient rehabilitation services. Audio content was transcribed verbatim and analysed rigorously by two team members. NVivo software
was used for data analysis and management.
Results: Sample was composed of 25 relatives (mean age
53.4 ± 12.7 and women n = 21/25) and of 16 individuals with a first
stroke (mean age = 55.7 ± 11.2 and women n = 7/16). Main themes
emerging from preliminary analysis include respect–openness to
communication where participants mentioned how busy they felt the
medical staff to be and at the same time felt respect most of the time
when they did ask questions or sought information; positive and
negative attitudes from medical personnel ‘‘I would go anywhere on
the ward, use their kitchen, no one never told me that I could not, on
the contrary, I could go to heat my meals and they would help me to
use the micro-wave’’ or ‘‘… it is not normal to feel that way. I take
away part of their tasks when I bath my father, I help him to eat and I
don’t even feel comfortable to ask them question as if I am bothering
them…’’;, legitimacy to receive services as a relative where relatives (and individuals with stroke) mentioned relative’s needs for
information, education and support but did not perceived themselves
as clients which detrimentally impacted autonomy in decision
making.
Conclusion: Although it is now recommended by best practices to
systematically offer services to relatives post-stroke and that relatives
do identify needs in terms of information, education and support, both
individuals with stroke and their relatives are not fully aware of relatives ‘rights’ to receive such services.
Funded by an operating grant from Canadian Institutes of Health
Research.
P524
Mirror training and cortical network changes adressed
by TMS
C.H. Läppchen, E.M. Frittgen, R. Lange, C. Weiller,
F. Hamzei
University Medical Center (Freiburg, DE); Moritz-Klinik (Bad
Klosterlausnitz, DE); University Medical Center (Jena, DE)
Introduction: Several recent studies have provided evidence that
‘‘mirror therapy’’ represents a promising tool for exercising hemiparetic stroke patients. In this therapy a mirror is positioned
orthogonally in front of the patient, who performs motor exercises
with the non-affected limb while watching the mirror. We used
transcranial magnetic stimulation (TMS) and excitatory thetaburst
stimulation (iTBS) to address these mechanisms.
Methods: 30 right handed healthy subjects were divided in three
groups. Group 1 mirror group (MG) and group 2 (MG_iTBS) trained
through a mirror with its right hand over 4 days. Group 3 (control
group; CG) traind with a board instead of the mirror. MG_iTBS
received iTBS over the right PMd every day before starting training
session. The right PMd was individually stimulated (fMRI, neuronavigator). TMS was performed before and after the training.
Results: All three groups showed a significant improvement of the
tests of the left hand (paired t test baseline vs. post: p \ 1.2 x 10-6).
Test results at time point baseline did not differ between groups. At
time point post the test results of the left hand were significantly better
in MG than in CG (p = 0.02) and MG_iTBS (p = 0.001). TMS: In
CG the ICF on the left side was significantly stronger after training
(p = 0.02). In MG the ICI on the left side was significantly stronger
after training (p = 0.01), whereas the ICI on the right side was significantly lower (p = 0.04). Only the ICI changes on the left side was
close correlated with the test results of the left hand (r = 0.6;
p = 0.01). In MG_iTBS the ICI decreased on the right side
(p = 0.03) while the ICF increased on both sides (p = 0.04).
Discussion: The close correlation between ICI changes in left
motor cortex (M1) and the improvements of the motor test may show
that the left hand has more access to the left M1 as a consequent of
mirror training. This is supported by enhanced fMRI activation in the
left sensorimotorcortex after mirror training. While in MG the ICI
within left M1 was stronger after training, in MG_iTBS ICI showed
no change and ICF increased. Consequently, while the training with
the right hand in the mirror induced a reduction of excitability within
left M1, an increased excitability was induced with iTBS over right
PMd.
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This PMdright-M1left interaction might be balanced by an
inhibitory effect, rather than an excitatory one. Whether further
regions are involved in this interaction warrants further investigation.
P525
Is oral feeding a sign of consciousness or can it occur
in the vegetative/unresponsive state?
A. Vanhaudenhuyse, M.A. Bruno, A. Maudoux,
O. Gosseries, C. Schnakers, C. Chatelle, A. Demertzi,
G. Moonen, S. Laureys
University of Liège (Liège, BE)
Objectives: There is no consensus regarding whether or not oral
feeding can occur in the vegetative/unresponsive state. We here
assessed feeding (oral vs. artificial) in patients with chronic disorders
of consciousness occurring after coma.
Method: We studied feeding in 164 vegetative/unresponsive
patients (age range 19–88 years). Diagnosis was based on standardized Coma Recovery Scale-Revised (CRS-R) assessments. Etiology
was traumatic in 53 and non-traumatic in 111 patients (i.e., anoxic
encephalopathy (n = 48), ischemic or hemorrhagic stroke (n = 36),
metabolic encephalopathy (n = 19), intoxication (n = 2), mixed
etiology (n = 6)). Mean interval since insult was 4 months
(SD = 11 months).
Results: 162 patients had artificial hydration and nutrition via
gastrostomy, 2 patients were orally fed: a 34-year-old man with
anoxic encephalopathy assessed 20 years after cardiac arrest and a
35-year-old man with anoxic encephalopathy assessed 19 years after
cardiac arrest. In both patients repeated CRS-R examinations concluded the diagnosis of vegetative/unresponsive state and brain MRI
revealed major diffuse cortical atrophy and ex-vaquo hydrocephalus.
Positron Emission Tomography (PET) showed global decreased
cerebral hypometabolism with preserved activity in brainstem and
cerebellum and significant widespread frontoparietal cortical dysfunction. Both patients showed preserved chewing and swallowing of
manually inserted mashed food in the mouth. Without any form of
artificial tube feeding or hydration both showed correct nutritional
status over the past 36 months.
Conclusion: The vast majority of vegetative/unresponsive patients
(99% in the present cohort) need artificial enteral tube feeding for
hydration and nutrition. The presented case reports, however, show
that exceptionally some ‘‘vegetative’’ patients without higher-order
cortical brain function can satisfactorily feed by mouth. Oral feeding
consequently seems no necessary sign of consciousness.
P526
EM-line! Project: a cognitive rehabilitation programme
for patients with multiple sclerosis
J. Gich, L. Ramió-Torrentà, J. Freixanet, R. Garcı´a,
K. Vilanova, D. Genı´s
Hospital of Girona (Girona, ES); University of Girona (Girona, ES);
Clinic Girona (Girona, ES)
Background: Cognitive impairment is a frequent symptom in Multiple
Sclerosis (MS) that can be present from the onset of the disease and
can present independently of the physical disability. While patients
preserve daily life activities, cognitive rehabilitation is often delayed
due to the difficulty in attending sessions whilst continuing to work
normally. The idea of the programme of cognitive rehabilitation in
MS, called ‘‘EM- line!’’, began in 2005, after the publication of
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studies demonstrating neuroplasticity in the early phases of MS before
the appearance of cognitive deterioration. This evidence, together
with the detection of a gap in the cognitive treatment until patients
start neurorahabilitation for the physical problem, showed the need to
develop a more specific programme which patients could start using
right from the onset of their disease.
Objective: To develop a cognitive rehabilitation programme for
patients with MS, which can be used from the early stages of the
disease without interfering with daily life activities.
Methods and results: In order to develop an efficient and attractive
programme, and faced with the need to include material of varying
characteristics, a multidisciplinary team was set up (20 mathematicians, 4 engineers, 1 speech therapist, 1 linguist, 1 architect, 1
photographer and neuropsychologists). Three types of material with
different levels of difficulty have been either developed or adapted: 1/
Written (450 mathematical problems, 150 problem-resolving exercises, 115 crossword-type questions, 344 word, number and image
puzzles); 2/ Manipulative (paper folding with colour photos and
intermediate steps, two-handed coordination movements, threedimensional manipulation and reasoning games); and 3/ Informatics
(virtual reality to stimulate memory functions—380 questions, virtual
galleries of the Thyssen Museum in Madrid—150 questions, 4
working memory games, 40 computer games (language, speed processing, planning, memory and reasoning games). Clues are supplied
to solve problems to improve treatment adherence (errorless
learning).
Conclusions: The EM-line! project is a cognitive rehabilitation
programme to improve the main cognitive deficits related with MS to
perform at home from the early stages of the disease without interfering in daily life activities. This programme is aimed at filling the
current gap in cognitive rehabilitation between the time of diagnosis
and the start of full integrated neurorahabilitation.
We recieved funding from pharmacological industries (Biogen
idec, Bayer Health Care, Merck Serono and TEVA) and grants from
Caja Madrid, La Caixa, Acadèmia de Ciències Mediques de Girona
and Mutual Medica.
P527
Rearrangement of metabolism and cerebral
haemodynamics in ischaemic stroke patients
during rehabilitation: age peculiarities
V. Kuznietsov, D. Schulzenko
Academy of Medical Sciences of Ukraine (Kiev, UA)
Purpose: To study correlations between metabolism and cerebral
hemodynamics as a function of age in ischemic stroke patients.
Subjects and methods: The study included 263 patients with an
ischemic stroke in the internal carotid artery (ICA) area who were
divided into two age groups: middle-aged (n = 198) and elderly
(n = 65). Cerebral hemodynamics was inferred from duplex scanning
using Sonoline Elegra (Siemens) and metabolism of the brain from
the in vivo H1 MR spectroscopic data (1.5 T Magnetom Vision Plus,
Siemens).
Results: The middle-aged post-stroke patients versus age-matched
control subjects displayed more pronounced decrease of LBFV and
volumetric blood flow rate in the damaged (55.3 and 19.2%,
respectively) and intact ICA (32.4 and 10%, respectively) and MBA
(respectively 47.7 and 39%; and 36.4 and 29.3%) and the higher
frequency of hypoechogenic atherosclerotic plaques (49.5% in middle-aged and 24.1% in elderly). At the same time the gray and white
matter NAA content in elderly patients was statistically lower than in
elderly control subjects (18.2 ± 0.9 and 24.1 ± 0.8 nominal units,
respectively). Dissociation between degree of changes in cerebral
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hemodynamics and NAA metabolism level is conditioned by that in
elderly patients the influence of hemodynamics on NAA content on
damaged basin vessels is more pronounced. Thus NAA content of the
occipital gray matter in middle-aged patients correlated with volumetric blood flow rate in intact ICA (K = 0.74) and VA (K = 0.81),
while in the elderly it correlated with hemodynamics in homolateral
MBA (K = 0.69). In elderly patients, changes of cerebral hemodynamics and metabolism were more marked with right hemispheric
stroke localization (white matter NAA content was 21.74 ± 0.52
from the right and 21.50 ± 0.54 from the left; gray matter NAA
contents were respectively 21.13 ± 0.62 and 23.58 ± 0.93) than with
left hemispheric stroke localization (white matter NAA content was
23.43 ± 0.5 from the right and 23.37 ± 0.57 from the left; gray
matter NAA contents were respectively 22.78 ± 0.99 and
24.91 ± 0.87).
In conclusion, cerebral hemodynamics changes were more pronounced in middle-aged patients and metabolic changes were more
marked in elderly post-stroke patients. Therefore such age peculiarities should be considered while choosing proper tactics for their
pharmacological rehabilitation.
P528
Syndrome of the trephined: 4 case reports
and literature review
J. Flores Alves dos Santos, A. Tanga, A. Schnider,
B. Leemann
University Hospital Geneva (Geneva, CH)
Object: The syndrome of the trephined (ST), also known as the
‘‘syndrome of the sinking skin flap’’ (SSSF) or ‘‘motor trephined
syndrome’’, is defined as a neurological deterioration following craniectomy. It may arise within weeks to months after the craniectomy,
but rapidly improved after cranioplasty. The ST is often misdiagnosed, related symptoms being associated with initial brain lesions
and complications. We report the cases of 4 patients who developed
the ST and clearly improved their neurological status upon cranioplasty. In one of them, a provisory synthetic sucking cranial device
allowed clinical progress.
Methods: We performed a comparative analysis of clinical, neurobehavioral and radiological data of the 4 patients prior to and
following cranioplasty. A literature review was conducted, using the
PubMed databases on the history and the different pathophysiological
theories of the ST.
Results: In three patients, symptoms occurred in upright position,
showing an aggravation of the hemiparesis. In two patients, we also
observed a worsening of the hemineglect. All 3 patients showed an
improvement of these symptoms when a horizontal position was
adopted. All three cases showed a clear recovery upon cranioplasty
and this orthostatic effect has completely disappeared. In one of them,
the cranioplasty was removed due to post-operative infection, with
resurgence of neurological symptoms. In this case, a provisory suction-cup helmet was used, allowing a partial recovery. In one patient,
we did not observe an orthostatic effect but, 2 months after craniectomy, he suffered three episodes of sudden hemiplegias. EEG and
CT-scan showed no abnormalities and an anticonvulsant treatment
did not avoid the recurrence of the episodes. After cranioplasty, the
neurological status was stable even after anticonvulsant treatment has
been stopped. The literature evokes atmospheric/intracranial pressure
gradient, cerebral blood flow changes, cerebrospinal fluid hydrodynamics modifications and cellular metabolism alterations as the
processes implicated in the pathophysiology of ST.
Conclusion: The diagnosis of ST is not usually evoked and not
easy to assess, even if it seriously disturbs the patients’ rehabilitation
due imposed supine position on awaiting cranioplasty. A suction-cup
helmet constitutes an interesting alternative in this situation. Finally,
there is a need for a unified and integrative theory of mechanisms
leading to the ST.
P529
Differences in instructional conditions for an imagery
task are not related to M1 excitability
S. Shimizu, T. Kawakami
Kitasato University (Kanagawa, JP)
Objective: Mental practice may activate the primary motor cortex
(M1) and promote functional recovery following stroke. It is necessary to create an accurate image of the task to do mental practice
effectively; therefore, good instructions are important for obtaining
optimal results. However, differences between the effects of mental
practice according to the method of instruction have not been clearly
demonstrated. We tested three methods for communicating instructions to study participants to investigate whether the type of
instructions changed M1 excitability.
Methods: Twelve healthy volunteers participated in this study. The
imagery task used was the opening and closing movement of scissors
with the right hand with a metronome. The instructions for the
imagery task were delivered in (1) Language condition 1, in which
the instructions for the imaging task were communicated using only
language and subjects were instructed only to imagine opening and
closing of scissors; (2) Language condition 2, in which subjects were
instructed to imagine that they cut the line drawn on cardboard with
scissors; and (3) Motor observation condition, in which subjects were
instructed to observe a video of a person performing the opening and
closing movement of scissors and to imagine that they performed the
movement. Single pulse transcranial magnetic stimulation (TMS) was
performed using a Magstim 200 stimulator (Magstim, Gwyneth,
Dyfed). Muscle evoked potentials (MEPs) were obtained from the
first dorsal interosseous muscles of the dominant hand in each condition and at rest. Subjects were asked to evaluate the distinction of
the imagery after mental practice in each condition using a visual
analogue scale (VAS). The result of the MEP amplitude value and
VAS were analyzed using a one-way analysis of variance. All subjects gave informed written consent prior to participation.
Results: In all conditions, MEP amplitudes were increased relative
to rest. There were no significant differences in the magnitude of
MEPs between instructional conditions. There were no significant
differences in VAS scores between conditions.
Conclusion: The image task used in this research was a common
daily movement that was easy to imagine. During mental practice
there was an increase in M1 excitability; however, the influence of the
different instructional conditions on M1 excitability remains unclear.
P530
Education of multiple sclerosis patients to lifetime
physical exercise
S. Kersten, C. Haas, G. Wydra, M. Mahli, C. Lutz
Saarland University (Saarbrücken, DE); Hochschule Fresenius
University of Applied Science (Idstein, DE)
Objectives: It is well known that multiple sclerosis (MS) patients
benefit from physical exercise like endurance- or strength-training.
However, it is also known that various exercise-effects are not sustainable. On might explain this phenomenon by patients’ nescience
about physical functions or training principles leading to negative
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interactions between every day behavior and training related physiological adaptations (e.g. inadequate rest periods). Therefore the aim
of this study was on one hand to realize an exercise program and on
the other hand to instruct and educate patients regarding principles of
physical exercise and physiological adaptation processes, etc. We
hypothesized about a positive transfer of patients’ basic physiological
knowledge to an adequate and autonomous management of training
and every day behavior.
Methods: 15 MS patients were analyzed pre and post a 12-week
intervention phase in a 6 min walk test (6 MW), Timed-Up-And-Go
test (TUG), Fatigue-Severity Scale (FSS) and SF 36. The average age
of the patients was 48.1 (±9.2) years, and MS was diagnosed on
average in 1999 (±7.7 years). The mean EDSS Score was 4 (±1.5)
and the Scripps Score 78.2 (±10.22). The first 6-week intervention
phase consisted of a training and education program regarding
coordination-, endurance-, strength-training, rest periods and regeneration time, and related management and knock-out criteria. In the
second phase (6 weeks) patients planned and realized their exercise
program autonomously.
Results: Performance in the 6 MW and the TUG improved highly
significant (p \ 0.001) by 15.4 and 23.3%, respectively. Fatigue
(FSS) decreased by 10.9% (p = 0.119) and the SF 36 showed a
statistical trend in physical role (p = 0.05) and significant improvements in vitality (p \ 0.01). Besides these results, all patients were
able to manage and assess their own training and every-day behavior,
successfully. Interviews confirmed increased self-confidence and selfefficacy concerning sports and daily life.
Conclusion: This study shows that MS patients are able on one
hand to acquire good knowledge about basic physiological functions
and training principles and on the other hand to apply this knowledge
training successfully in the training management. We believe that
these competences (self-competence, empowerment) are pre-conditions not only for realizing the training program effectively but also to
coordinate training and every-day challenges and finally to assure
sustainable effects.
P531
Reliability of a new clinical device to measure muscle
tone in spastic muscles
J. Gäverth, M. Sandgren, P. Lindberg, A.-C. Eliasson
Karolinska Institute (Stockholm, SE); Danderyd University Hospital
(Stockholm, SE)
Objective: The aim of this study was to investigate intra- and interevaluator reliability of a new clinical device for quantification of
wrist and finger muscle hypertonus after stroke. In a clinical setting, it may be difficult to differentiate between spasticity and
stiffness in muscle and tissue or contractures. Therefore, a biomechanical device was constructed incorporating a mathematical
model that allows differentiation between neural (reflex) and nonneural (muscle and tissue) components of muscle hypertonus after
stroke.
Methods: Muscle hypertonus was measured using the device
which produces slow and fast isokinetic passive wrist extensions.
Joint position and resistance to passive movement is recorded for offline analysis where neural and non-neural components of the resistance is calculated. The method has been validated in a previous study
and has shown content and concurrent validity. A convenience sample
of 22 persons with chronic ([6 months) stroke were evaluated using
the device by two evaluators on 1 day. Persons with sufficient passive
range of movement of the wrist (i.e. C40 wrist extension with fingers
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extended) or with modified Ashworth score of [0 or \4 in finger or
wrist flexors were included. Intra- and inter-evaluator reliability was
calculated in a two-way random effects model single measure reliability giving an intraclass correlation coefficient (ICC2.1).
Results: These results are preliminary and the aim is to include, in
total, 30 persons. In this sample, the participants showed a wide range
of muscle hypertonus. Reliability for the device was high for both
intra- and inter-evaluator measurements for both neural (ICC [ 0.9)
and non-neural (ICC [ 0.70) components.
Conclusions: The results indicate that the device is reliable for
quantification of both neural- and non neural components of muscle
hypertonus, i.e., spasticity, in persons with chronic stroke. Future
studies will be focused on responsiveness and clinical application.
Supported by Karolinska Institutet Health Care Sciences Postgraduate School, VINNOVA/VINN-verification, Stiftelsen Promobilia
and Stroke Riksförbundet.
P532
The efficacy of a multidisciplinary in-patient approach
to treating functional neurological disorders:
a retrospective series
T. Saifee, P. Kassavetis, I. Parees, J. Foong, G. Price,
E. Joyce, M. Edwards
University College (London, UK); The National Hospital
for Neurology and Neurosurgery (London, UK)
Objective: Establish the long-term outcomes and efficacy of a multidisciplinary in-patient approach to treating functional neurological
disorders.
Background: Functional neurological disorders are common, disabling and difficult to treat. There is little consensus on the best
approach to management. A multidisciplinary in-patient approach is
employed in some centres but its efficacy has not been widely
reported. In particular, the long-term outcomes are uncertain.
Methods: We conducted a retrospective study using questionnaires completed by patients who were treated at a specialised
multidisciplinary in-patient program at the National Hospital for
Neurology and Neurosurgery, Queen Square, London. Patients who
were admitted to this centre between 2006 and 2008 were consecutively recruited. Questionnaires were sent by post at least 2 years
after discharge.
Results: We contacted 34 patients and 26 responded (mean age
47 years, 58% female) to the questionnaire. The majority had
symptoms for 3 or more years prior to in-patient admission and
54% had attended an out-patient clinic with the multidisciplinary
team of the hospital prior to admission. 58% of patients reported
significant benefit from the in-patient program on discharge. This
benefit to quality of life and function as judged by patients was
sustained over the 2-year follow-up period although return to
work or cessation of disability benefits was uncommon even in
those who had improved. 63% of those questioned stated they
would recommend the treatment program to others with similar
symptoms.
Conclusions: Our data suggest that the multidisciplinary in-patient
program at our centre offered to patients with functional neurological
disorders provides self-reported benefit that is sustained in the longterm. This benefit occurred prior to specialist treatment in an outpatient setting. Prospective analysis of such interventions and the
determinants of benefit need to be assessed in order to improve
the service and target those patients with the best chance of
improvement.
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P533
The hemiplegic’s shoulder. Analysis of the potential
contribution of the scapula’s position on the upper limb
spastic pattern and glenohumeral subluxation
during three exercises for arm elevation
A.C. Vidal, A.G. Pascoal, S.A. Pinto, A.C. Sequeira
Thecnical University of Lisbon (Lisboa, PT); Hospital Garcia de Ortal
(Almada, PT); Health School Egas Moniz (Almada, PT)
During the rehabilitation process of hemiplegic/hemiparetic subjects
after stroke a special attention is putted on the affected upper limb in
order to avoid spastic pattern and glenohumeral subluxation by controlling arm position at the glenohumeral joint. However, those
patterns could also be conditioned by the scapular position. In this
study the scapular position during arm rehabilitation exercises was
analyzed in order to understand it contribution on arm spastic and
subluxation patterns.
The affected shoulder of 11 patients with stroke (female = 7;
age = 58.5 ± 12.5 years) was study during three exercises used on
the rehabilitation of hemiplegic/hemiparetic arm elevation: oriented
movement (OM), where the arm motion is oriented by the therapist;
isolated movement (IM), where the patient performs arm movement
alone; and the contra-lateral assisted movement (CT) where the
contra-lateral upper limb assists the affected limb. At the end-range of
arm motion, the scapular 3D position was recorded by means of an
electromagnetic tracking device (100 Hz) and compared between
exercises using a Friedman test for paired samples (p \ 0.05). Joint
angles were calculated and expressed as Euler angle decompositions.
To obtain this, the local coordinate systems for each segment
(humerus, thorax and scapula) was defined based on standard bony
landmarks and a specific Euler rotation order, following the shoulder
ISB standardization protocol [1]. Scapular rotations were defined with
respect to the thorax as protraction, lateral-rotation and spinal tilt.
On OM exercise, the scapular protraction angle was significantly
higher (OM = 68 ± 48; CT = 28 ± 78; IM = 0.3 ± 78) while the
lateral-rotation angle was lower (OM = 11 ± 5; CT = 228 ± 88;
IM = 238 ± 98), i.e., the glenoid face more forward and downwardly. On all exercises scapula assumed a posterior tilted position
and no differences were observed between exercises (OM = 38 ± 38;
CT = 38 ± 48; IM = 28 ± 68).
An increased scapular protraction angle was previously associated
with humeral internal position, which can enhance the arm spastic
pattern, while a downward scapular position was associated with
shoulder subluxation. These findings suggested that on the IM and CT
exercises the scapular position seems to be more protective for arm
spastic pattern and glenohumeral subluxation.
1. Wu G. et al. (2005) J Biomech. 38, 981-992.
P534
A new biomechanical model for the estimation of neural
and non-neural contributions to spasticity
P. Lindberg, J. Gäverth, M. Islam, A. Fagergren, J. Borg,
H. Forssberg
Karolinska Institute (Stockholm, SE)
Objectives: Spasticity is a common symptom after stroke and is often
evaluated according to the modified Ashworth score. However, the
validity and reliability of this score has been questioned in many
studies. Another disadvantage is that the modified Ashworth score
only measures the total force and does not allow separation of the
neural and non-neural components. The aim of this study was
therefore to validate a new method for quantification of muscle tone
in the hand after stroke.
Methods: A simple biomechanical model of the neural and nonneural components contributing to passive movement resistance of
the wrist was constructed, consisting of (i) inertia, (ii) elastic
resistance (length-dependent), (iii) viscous resistance (velocitydependent) and (iv) reflex mediated muscle contractions (neural
component, NC, velocity-dependent). We measured resistance and
EMG during 508 passive wrist extension across four controlled
velocities (5, 71, 142, and 2368/s) in chronic stroke patients with
varying degree of spasticity and healthy subjects. In a subgroup of
patients, repeated measures before and after ischemic nerve block
were obtained.
Results: The model was validated in three ways: (1) NC decreased
drastically after the ischemic nerve block; (2) NC correlated strongly
to the EMG activity, both in the same subject during the ischemic
nerve block procedure and in the patient group; (3) NC was also
velocity dependent. In the majority of patients the NC was the main
contributor of passive movement resistance. Only in some patients
was elasticity found to contribute substantially. NC correlated negatively with clinical measures of upper limb function.
Conclusions: The results suggest that the model can accurately
measure the neural component of increased muscle tone in chronic
stroke patients. The method may be developed to be used clinically to
measure muscular and neural components of muscle spasticity.
P535
Mental training based on cognitive prediction
paradigms as alternative approach to improve motor
functions
E. Binder, K. Hagelweide, L.E. Wang, K. Kornysheva,
C. Grefkes, G.R. Fink, R.I. Schubotz
University Hospital Cologne (Cologne, DE); Max Planck Institute
for Neurological Research (Cologne, DE); The University of Hong
Kong (Hong Kong, CN); University College London (London, UK);
Research Centre Jülich (Jülich, DE)
Objectives: It has often been suggested that motor performance might
be improved by means of mental strategies like motor imagery. Motor
imagery is widely used in the field of competitive sports and also in
the neurological rehabilitation of patients with stroke-induced motor
impairments. Neuroimaging studies have shown that the imagination
and execution of an action share common neural substrates, among
others in premotor areas. However, the quality of how well motor
imagery is performed is difficult to assess by means of objective measures, and can in its own right be disturbed in stroke
patients. Therefore we designed a novel mental training paradigm
based on the serial prediction task (SPT) (Schubotz 1999) as an
alternative way of activating premotor circuits in order to improve
motor performance.
Methods: A total of 39 right handed healthy volunteers participated in the study. 18 participants (11 male; mean 26.1 years) were
allocated to the SPT-training and 21 (10 male; 25.6 years) to a control-training based on a working memory task (serial-match-tosample). The training was conducted on five consecutive days for 1 h
each day. The task was presented on a computer screen and had
increasing levels of task difficulty adapted to the individual performance of the subjects. On the 2 days directly before and after the
mental training performance in four different motor tasks was
assessed. Two of these tasks accounted for specific transfer effects on
motor performance (rhythm-synchronization finger tapping task and
finger pointing task), whereas the other two (Jebsen Taylor Hand
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Function Task and goal-directed joystick task) investigated a more
general transfer of training effects into everyday motor functions.
Results: The SPT-group showed significant improvements
(p \ 0.05) in a complex visuomotor timing task (synchronization of
finger tapping to a visually presented rhythm) compared to the group
that received the control-training, indicating a specific transfer effect
of the respective mental training on motor performance. By trend
(p \ 0.1) the SPT-training also resulted in greater improvements in
the ability of visuomotor coordination (pointing task).
Conclusion: A mental training based on the serial prediction
task can improve motor performance in a group of young healthy
participants. Therefore, the SPT task seems to be a promising
approach in a neurorehabilitative setting for patients suffering from
motor deficits.
P536
Clinical rehabilitation exercise programmes
and principles of training
C. Haas, M. Fröhlich, O. Marcus, R. Thietje
Hochschule Fresenius - University of Applied Sciences (Idstein, DE);
Saarland University (Saarbrucken, DE); Trauma Hospital Frankfurt
(Frankfurt, DE); Trauma Hospital Hamburg (Idstein, DE)
Objectives: Non-use effects like muscular atrophy, deficits in
strength, endurance, or coordination are characteristic symptoms in
various neurological patients. The aim of exercise programs (EP) is
typically to improve the components of physical condition as well
as coordination in order to assure a high degree of day to day
functions. However, from basic research it is well known that
success in training and motor learning depend on the consideration
of so-called ‘‘principles of training’’, i.e. the intensity and order of
exercises, repetition of training stimuli, duration of rest-periods, etc.
Consequently we evaluated clinical EP with respect to these
principles.
Methods: EP were analyzed in 12 incomplete spinal cord injury
patients that were in stationary care in two different clinical rehabilitation units. The order of the realized exercises was documented
and classified (strength, endurance or coordination) using expert ratings and patient interviews. Patients were asked further more for their
perceived exertion after each training exercise using the modified
Borg-scale.
Results: EP are characterized on average by a huge volume and
various types of exercises. Exercises with predominantly coordinative
goals were realized in 45%. 40% of the training program consisted of
strength-exercise and 10% of endurance-exercises. Exercises with
mixed goals were performed in 5%. Intensities of the training were
high on average, i.e. after 31% of all exercises the perceived exertion
was C15 points on the Borg scale and 47% of coordinative exercises
led to 15 or more points. Rest periods were frequently short. No rest
period between different exercises occurred in 26% and only in 11%
the rest took more than 2 h.
Conclusion: Since the exercise programs are characterized by
huge volumes and high intensities they seem effective to improve
components of physical condition like strength or endurance, and
furthermore effective to counteract developing non-use deficits.
However, coordinative adaptations and motor learning is highly
associated with adequate training intensities and rest periods. The
evaluated programs did respect these training principles only slightly.
Consequently, high fatigue occurred frequently which might disturb
an optimal neurotrophic factor release. To enhance exercise efficiency
it seems necessary to implement a goal setting strategy in order to
avoid conflicts in adaptations processes resulting from multivariate
exercises.
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P537
Comparative study of neurodevelopment treatment
with or without BTX-A (Dysport) injection
in the management of spasticity of hemiplegic patients
R. Abolfazli, G. Olyaei, S. Talebian, N. Ansari, M. Sheikh,
S. Samadzadeh
Tehran university of medical science (Tehran, IR)
Spasticity is one of the motor disorders of upper motor neuron that it’s
mechanisms, assessment and treatment are usually troublesome.
Different methods of treatment have been presented for control of
spasticity. One of them is treatment according to Bobath’s method
(NDT). Recent studies show that injection of BTX-A (Dysport) into
spastic muscles can reduce spasticity. The aim of this study was to
compare the effect of neurodevelopment treatment (NDT) with BTXA injection and NDT alone in reduction of spasticity and improvement the quality of movement patterns of lower limb in hemiplegic
patients.
Twenty hemiplegic patients (9 female, 11 male) with age ranging
from 41 to 78 years participated in this study. They were in spastic
phase and could have been walked with or without assistive device.
Severity of spasticity according to original ashworth scale (OAS) was
between 1 and 3. In group 1, patients were treated by NDT method
and in group 2 patients were treated by NDT and BTX-A injection.
Baseline assessments consisted of: spasticity severity in plantar
flexor’s muscles according to OAS, active and passive range of
motion of ankle joint and quality of movement patterns of lower limb
in standing position according to NDT. Injection of BTX-A was
performed in gastrocnemius muscle (200 u in 4 sites of medial and
lateral heads), soleus muscle (75 u in 2 sites) and tibialis posterior
muscle (50 u in 2 sites). NDT in two groups was performed by 10
sessions.
In two groups, decreasing of OAS, increasing of active and passive
range of motion and quality of movements patterns were seen. All of
this changes were more significant in group 2. In each group, severity
had been significant correlation with recovery according to OAS and
quality of movement patterns.
NDT with inhibition of abnormal patterns, fascilitation of normal
responses and increasing the ability of patient to perform discrete
movements in spite of presence of synergic movement patterns can
reduce spasticity, increase range of motion and quality of movement
patterns. Direct effect of BTX-A on muscle tone and reduction of
spasticity can increase the effectiveness of neurodevelopment
treatments.
P538
Chemodenervation of the antagonist muscle
T.A. Gaber, A. Azer, B. Basu, S. Mannemela
Taylor Rehabilitation Unit (Manchester, UK);
Directory of Social Change (Wirral, UK)
Introduction: The standard model of using chemodenervation for the
management of local spasticity hypothesise that local spasticity is
mainly due to concentric contraction of the agonist muscle or group of
muscles. This hypothesis is certainly true in most cases as proving by
routine practice in managing local spasticity leading to common
deformities such as elbow flexion or spastic foot drop. From a
physiological standpoint, muscles can contract concentrically or
eccentrically. In concentric muscle contraction the muscle shortens as
it contracts whilst in eccentric contraction the muscle lengthens as it
contracts. Eccentric contraction is used as a means of decelerating a
S135
body part or object, or lowering a load gently rather than letting it
drop.
Case report: A 68-year-old male patient presented with left sided
hemiparesis after suffering from a cerebro-vascular accident (CVA)
8 months earlier. The patient was able to walk independently using a
stick but he had recurrent falls. Clinical assessment showed that the
falls were mainly secondary to extensor left knee spasms. Neurological examination showed moderate increase in muscle tone
especially affecting the left hamstrings group of muscles. EMG
studies were performed mainly on the left quadriceps and hamstrings
muscles while the patient stood to simulate the biomechanical position when the spasms often happen. The EMG showed evidence of
spasticity mainly in the hamstrings and a decision to carry out
chemodenervation to the hamstrings was duly taken. The patient
response was dramatic with significant reduction in the frequency and
severity of the extensor spasms and subsequently the number of falls.
Comments: In normal subjects: The hamstrings’ eccentric contraction produces significantly smaller signals than quadriceps
concentric contractions. This observation encouraged us to interpret
our subject’s EMG changes as sufficient evidence indicating significant spasticity of the left hamstrings group of muscles which might be
the main culprit leading to the extensor spasms. It is difficult to
establish how common our observation is in the general population
suffering from an upper motor neurone (UMN) syndrome. The limited evidence available suggests that in an UMN lesion extended leg,
the EMG activity recorded from the quadriceps muscles were dominant. However, we feel that the routine assumption of a primary role
of the concentrically contracted agonist muscles in the treatment of
muscle spasms is unjustified.
P539
Botulinum toxin in the management of hitchhiker’s toe
T.A. Gaber, B. Basu, J. McFarlane, S. Salam, R. Singh,
D. Shakespeare
Taylor Rehabilitation Unit (Manchester, UK); Walkergate Park
Centre for Neurological Rehabilitation (New Castle, UK); Northern
General Hospital (Sheffield, UK); Preston Neurological
Rehabilitation Unit (Preston, UK)
Introduction: Hyperextension of the extensor hallucis longus (EHL)
muscle is a well recognised disabling sequel of either pyramidal or
extrapyramidal lesions causing what is known as striated or hitchhiker’s toe. Surgery was the only effective strategy to manage EHL
hyperextension before botulinum toxin’s use to manage muscular
dystonia and spasticity became widely popular.
Methods: A multicentre retrospective study. A standard proforma
was sent to specialists in neurological rehabilitation dealing routinely with this problem. The data was analysed using descriptive
statistics.
Results: Four consultants and two trainees representing five separate neurological rehabilitation services agreed to participate in the
study. Full data was available from the 29 proformas completed. The
subjects were 15 females with an age range between 20 and 78 years
(mean 58.7). Stroke was the primary diagnosis in 18 subjects. Four
subjects had bilateral involvement. 16 subjects had either an associated foot drop or equino varus deformity. Dysport was used in 15
subjects with an average dose of 170 units per injection and Botox in
the other 14 with an average dose of 65 units. The treatment was
effective in 24 subjects (83%). All patients receiving Dysport
responded to the treatment. Whilst 5 Botox treated patients failed to
respond to it (35% failure rate). Most of the non respondents seemed
to receive insufficient doses of Botox (below 60 units). Surgical
management was successful in 3 out of the 5 non respondent cases.
Conclusion: Botulinum Toxin is an effective and safe method to
manage hitchhickers toe. In our study the conversion ratio between
Dysport and Botox was 2.5:1. Third of the patients receiving
Botox failed to respond to the treatment most probably due to
insufficient doses used.
P540
Presenting the vibratory stimulus
as a neurorehabilitation tool - a tolerability test
V. Tedim Cruz, V. Ferro Bento, J.P. Cunha, P. Coutinho
Hospital São Sebastião (Santa Maria da Feira, PT);
University of Aveiro (Aveiro, PT)
Objectives: To perform a tolerability test on a new device aimed at
intensive ambulatory proprioceptive stimulation early after stroke.
Methods: A wearable device was conceived and developed for
long term ambulatory use. Its main function is to provide external
vibratory stimuli as a source of proprioceptive input to the central
nervous system (CNS). These stimuli can be programmed both in
intensity and duration. The tolerability test was designed to access
easiness of use and comfort provided by the device when delivering
stimuli during a 5-h period to patients that had their first ever medial
cerebral artery (MCA) ischemic stroke. Data on vital parameter,
motor and sensitive performance, spontaneous motion quantification,
anxiety scores, global medical questionnaire and physical examination was recorded and analyzed.
Results: Five patients, three male and two female, aged between
43 and 71 years old were enrolled. Three had a left MCA ischemic
stroke. The test occurred between 5 and 14 days after admission.
Motor deficits dominated and were severe, but were not hemiplegia
(NIHSS between 11 and 14). Two patients had visual and sensitive
neglect. All patients were able to locate tactile and vibratory stimulus
on both sides at the beginning of the study. The device remained in
place throughout the study. There were no records of pain, discomfort, cardiovascular instability or extreme anxiety. The analogical
anxiety scores were low at baseline, and did not increase during the
experiment except for one patient with a 1 point increase in a 9 point
scale. Patients were able to locate the stimulus appropriately and
discriminate between different intensities and stimulation intervals.
Visual attention towards the affected side immediately upon stimulation was recorded in four patients. A subjective but clear increase in
global awareness was recorded in two patients during stimulation, as
assessed by the neurologic examination.
Conclusions: There were no major complications to report during
a five hour use of the device in an early post-stroke setting. Most
interestingly the majority of patients increased their attention to the
affected side during stimulation and two were reported as clearly
more awake during the test. These findings will be further analyzed
under functional MRI control and on long term use, during the
ensuing pilot trial. The device tested is under patent protection.
Supported by Fundação para a Ciência e Tecnologia, PTDC/
SAU_NEU/102075/2008.
P541
Effects of left-sided STN stimulation on saccadic
refixations
E.J. Gorzelanczyk, M. Michalak, P. Walecki, M. Harat
Polish Academy of Sciences (Warsaw, PL); Kazimierz Wielki
University (Bydgoszcz, PL); Jagiellonian University Medical College
(Krakow, PL); Nicolaus Copernicus University Collegium Medicum
(Bydgoszcz, PL)
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Objective: The goal of this study was to assess changes of saccadic
refixations parameters in case of left-sided Deep Brain Stimulation
(DBS) of the subthalamic nucleus (STN) in Parkinson’s disease (ICD10; G20).
Participants and methods: Based on the subjective test, questions, and
additional tests including neuroimaging and neuropsychological tests,
the patient was qualified for surgery (ICD-10; 02.931, 00.36, 86.95):
implantation of stimulating electrodes (model 3387 Medtronic, Minneapolis) to the STN on the left side. Before and after treatment, the patient
was examined using a Saccadometer (Ober Consulting Poland,
Advanced Clinical Instrumentation Cambridge UK), allowing the measurement of eye position with the time resolution of 1 ms (1,000 Hz).
Results: Before surgery the patient showed an asymmetry of the
dynamics of fast eyeball movements (saccades), depending on the
direction of movement of the eyes. After the surgery saccadic
parameters have changed. The latency of left saccades was reduced
by 14%, right was reduced by 7%. The duration of left saccades was
increased by 5%, and right has not changed. The standard deviation of
right saccades duration has declined by about 55%. The amplitude of
left saccades has fallen by 9.5%, and right was increased by 29%. The
standard deviation of right saccades amplitude has declined by about
50%. The peak velocity of left saccades was reducuced by 19% and
right was reduced by 6%. The standard deviation of right saccades
peak velocity has declined by about 66%. The ratio of peak velocity
to the amplitude of left saccades was decreased by 10%, and right was
decreased by 27%. The standard deviation of right saccades peak
velocity has declined by about 76%.
Conclusions: The results show that left DBS-STN significantly
impacts on the saccadic refixations, in particular its asymmetry
depending on the direction of eye movement. This study shows that the
STN plays an important role in the control of eyeball movement. Its
function is probably related to the determination of contralateral range of
motion (amplitude) and velocity, as well as the ipsolateral latency.
P542
Efficacy of a cognitive rehabilitation programme
for patients with multiple sclerosis: ‘‘EM-line! Project’’
J. Gich, L. Ramió-Torrentà, R. Menendez, J. Freixanet,
R. Garcia, K. Vilanova, D. Genı´s
Hospital of Girona (Girona, ES); University of Girona (Girona, ES);
Clinic Girona (Girona, ES)
Objective: To present the cognitive results of the pilot study into the
efficacy of the ‘‘EM-line! project’’.
Methods: A simple blind, randomized and controlled 24-week
study was conducted. Patients were randomized to an experimental
group (cognitive rehabilitation with EM-line! programme for two 60
min sessions every week) or a control group (no cognitive rehabilitation). All patients were given the following tests before starting
and on completion of the study: (1) Neurological examination
including Expanded Disability Status Scale. (2) Neuropsychological
assessment including the following tests: Brief Repeatable Battery of
Neuropsychological Tests: Selective Reminding Test (SRT), 10–36
Spatial Recall Test (10/36 SPART), Symbol Digit Modalities Test
(SDMT), Paced Auditory Serial Addition Test (PASAT), Word List
Generation (WLG). We also added Phonetic Fluency (FAS), Boston
Naming Test (BNT), Trail Making Test (TMT), Frontal Assessment
Battery (FAB), Letter & Number and Digits of Wechsler Adult
Intelligence Scale III Ed. (WAIS-III). (4) Radiological assessment:
Conventional sequences and MRIf with three paradigms. The statistical methodology included: a descriptive analysis of the
demographic and clinical characteristics of the sample and a
covariance analysis.
123
Results: Forty-three randomised patients (22 experimental group;
21 control group). Stratified randomisation was used (control variable:
level of cognitive deterioration). No significant differences were
observed in the following variables: age, sex, years of evolution of the
disease, years since the diagnosis, level of cognitive deterioration, professional activity, EDSS, treatment received during the study, and type of
Multiple Sclerosis. Covariance analysis revealed significant improvement in 10–36 SPART (p = 0.0002), WLG (p = 0.0123), letters and
numbers of WAIS III (p = 0.0413), BNT (p = 0.0007) and TMT
(p = 0.01) for the group of patients with EM-line! programme.
Conclusions: The preliminary results of the study of the efficacy of
the EM-line! project show a significant improvement in processing
speed, attention, visual memory, naming ability and executive functions (fluency ability and working memory). Furthermore, a tendency
towards significance is found in variables that evaluate verbal memory and planning ability as well as manipulative praxis. The results
obtained are promising and suggest a clear tendency to the efficacy of
EM-line! with regards to the main cognitive deficits related to Multiple Sclerosis.
We received funding from pharmacological industries (Biogen
idec, Bayer Health Care, Merck Serono and TEVA) and grants from
Caja Madrid, La Caixa, Acadèmia de Ciències Mediques de Girona
and Mutual Medica.
P543
Supported living accommodations for people in need
of intensive assistance: first results of a new housing
project in Germany
K. Wolf-Ostermann
Alice Salomon University of Applied Sciences (Berlin, DE)
Objectives: In 2009, the Donnersmarck Foundation (FDST) launched
a new housing project for people with (multiple) severe disabilities
caused by brain injuries in Germany. In this project people in need of
intensive assistance will be able to organize their lives in a completely
private setting with the option of an individual 24 h support. Residents
from a permanent residential living are offered the opportunity to
move into two newly built supported living accommodations (SLA).
The core aim of the presentation is to provide an overview of the
relocation process and the impact on residents0 primary outcome
parameters.
Methods: In a longitudinal design residents from a permanent
residential living facility are surveyed for 2 years (12/2009–11/2011)
using self- and proxy-rating instruments. Residents are assessed at the
time shortly before moving into the SLA as well as 6, 12 and 18
months later (t1–t4). We investigated social aspects as well as health
outcomes including day to day functioning (WHODAS II), ADL
functioning (Extended Barthel-Index), needs of assistance (Metzler
H.M.B.-W), quality of life (WHOQoL-Bref, EQ-5D), anxiety and
depression (HADS), life goals and additional social factors.
Results: 40 persons (65% male) were recruited into the longitudinal study. At baseline the average age of the residents was
46.2 years. In a classification indicating levels of needed help from 0
to 5 (no to intensive help needed) 12.5% of the participants belong to
level 3,82.5% to level 4 and 5% to level 5. The total score of the
WHODAS II indicated an intermediate mean level of day to day
functioning. Quality of life reached a moderate level, significant
differences between age, sex and level of need could not be observed.
At t2, 15 persons have already moved into a SLA 6 months ago, 14
are soon moving and 11 persons will remain in permanent residential
living. No significant differences in quality of life, functioning and social
participation could be shown between the groups at this point of time (t2).
Further results of the longitudinal analysis will be presented.
S137
Conclusion: The first results concerning social and health-related
outcomes did not show significant effects 6 months after relocating.
Further analysis will indicate whether SLA could help to improve the
situation of people in need of intensive assistance in the long term and
offer them the chance to bear a self-determined life and to participate
actively in new social networks.
P544
Ultrasound-guided injection of Botulinum toxin type
A in the treatment of upper limb spasticity in children
with cerebral palsy
F. Frascarelli, G. Di Rosa, E. Castelli
Children Hospital Bambino Gesù (Rome, IT)
Objectives: Cerebral Palsy (CP) is the most common upper motor neuron
disorders in children. The children with hemiplegic CP usually acquire
the ability to walk and to perform most activities of daily living with one
arm. Management of upper limb spasticity in children with congenital
hemiplegia has received increased attention in the last few years due to
the impact of this type of impairment on activity daily life and on care of
oneself. In the last few years, botulinum toxin type A (BoNT-A) has been
widely used in the management of spasticity in children with acquired or
congenital brain injury in order to reduce hypertonicity and improve
functional outcomes enhancing motor skill development. One important
factor influencing the treatment outcome is the accuracy in delivering the
toxin to the target muscle. In general, manual needle placement is considered to be an acceptable technique for delivering the toxin to large,
superficial muscles, but not to small, deeply seated muscles of upper limb.
Also, the appropriate number of injection sites usually depends on the
size of the muscle. In this study we describe an ultrasound-guided technique (UGT) for the intramuscular injection of BoNT-A to treat spasticity
of the upper limb muscles.
Methods: BoNT-A injections was injected with UGT into the
affected upper limb muscles of 10 hemiplegic CP. The needle was
inserted into the muscle at an angle of 45 along the longitudinal axis.
Outcome assessments, evaluated before and 3 months after the
injection, included: Melbourne Scale, QUEST, Modified Ashworth
Scale (MAS) and Passive Range of Motion.
Results: In all children, the upper limb muscles were easily
identified and both superficial and the deep muscles were injected.
Introduction of the needle and drug injection were entirely carried out
under ultrasonographic guidance. Children had significantly greater
reduction in spasticity (MAS, p \ 0.01), which explains an
improvement in upper limb function and quality movement measured
with the functional scales (p \ 0.01).
Conclusions: The UGT for BTX-A treatment of upper limb
muscles spasticity allows the operator to verify the position of the
needle before the injection. So, the position of the needle can also be
continuously monitored during the injection and incorrect needle
placement can be excluded as possible causes of nonresponse. This
technique can improve the pharmacological effect of the BoNT-A to
facilitate functional use of upper limb in motor performance.
P545
Botulinum toxin injection for pathological lower limb
flexion in hemiplegic patients
M. Rousseaux, W. Daveluy, J. Paquereau, O. Kozlowski,
F. Beaucamp
Hopital Swynghedauw (Lille, FR)
Objectives: Hemiplegic patients can show lower limb spasticity in a
flexion scheme at the hip and knee. This causes pain, impairs passive
functions and significantly hampers standing and locomotion. Reducing
lower limb flexion is an important goal for care, but conventional oral
treatments and physiotherapy have modest effects. We present an open
label study suggesting that botulinum toxin injections (BTI) can be
effective on pain and passive functions, including bed positioning.
Methods: Ten patients were included after a severe stroke (eight
cases) or traumatic brain injury (two cases). Mean age was 60. All
were impaired in daily living by severe hip and knee flexion, and
possibly by hip rotation and/or adduction. BTI (300–400U Botox)
were systematically performed in the iliacus and hamstring muscles
and, when necessary, in the hip adductors and/or rotators and ankle
plantar flexors. Evaluations were performed before (D-15, D 1) and
after (Week 6–10; W 21–26) treatment.
Results: The benefit on spasticity (Ashworth score) was modest
and there was no change in motor control. But we found a significant
gain (p \ 0.05) on the passive range of motion in hip and knee
extension and on the spontaneous lower limb position when the
patient was supine or standing with support. Locomotion was always
impossible or difficult and was not improved, except in one case.
Conversely, a significant effect was found on passive functions,
including cleaning and dressing, bed facilities, passive transfers, and
pain. Efficacy was more evident at week 6–10 but was still present at
week 21–26. Tolerance was fair, with transient pain during iliacus
muscle injection. Patients were satisfied and reinjection was considered in each case after a 5-month period.
Conclusion: Pathological lower limb flexion can occur in patients
with severe encephalic lesions and definitely impairs daily living. Our
results suggest that after a stroke or a TBI, BTI is able to improve
comfort, passive functions and pain, with fair satisfaction.
P546
The use of gabapentin in visual hallucinations
with no visual pathway impairment
M. Tanaka Gutiez, B. Papps, A. Saulat, R. Luff
Kings College Hospital (London, UK)
Objectives: Gabapentin has been used for the treatment of Charles
Bonnet Syndrome, however its use in patients with no visual
impairment has not been documented previously to our knowledge.
We describe a patient with schizoaffective disorder with severe visual
hallucinations that interfered with rehabilitation who was commenced
on gabapentin for dysaesthesia, resulting in a resolution of his
hallucinations.
Methods: Using the well validated Cardiff Anomalous Perceptions
Scale (CAPS) which assessed for distress, distractibility, and frequency, we compared a subjective account of his visual hallucinations
before and after titration with gabapentin.
Results: After increasing the gabapentin dose from 100 mg three times
daily to 300 mg three times daily to control his dysaesthesia, we were able
to see an almost complete resolution of his reported hallucinations.
Conclusion: The CAPS is an appropriate reliable tool to assess
perceptual anomalies when identifying the effectiveness of a therapeutic regime in a rehabilitation setting. Also, the use of gabapentin
could be successful in treating visual hallucinations in patients with
no impairment of the visual pathways. Importantly, the targeted use of
gabapentin in patients experiencing visual hallucinations may facilitate the process of engagement in inpatient neurorehabilitation
therapy. Lastly, Gabapentin may be a safe drug for the treatment of
visual hallucinations in a patient who is already on a high dose of
antipsychotics.
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P547
Outcomes of inpatient rehabilitation of patients
with multiple sclerosis
T.A. Gaber, W. Oo, V. Gautam, L. Smith
Taylor Rehabilitation Unit (Manchester, UK)
Background: Several trials have demonstrated improved outcomes
following inpatient rehabilitation for Multiple Sclerosis patients. Two
populations were studied: patients in relapse and patients with no
active medical problems recruited from the community. In every day
practice, most admissions for MS inpatient rehabilitation aim to
improve function following sudden deterioration. The outcomes of
inpatient rehabilitation for this population were never studied.
Method: Retrospective case note analysis of consecutive admissions of MS patients from 2005 to 2009 to a specialist neurological
rehabilitation unit.
Results: 41 cases were identified. 26 were females. Age 25–71
(mean 52 ± 12). Disease duration 0–39 years (mean 13 ± 11). 20
patients were admitted from the community and 21 were transferred
from acute hospital beds. Length of stay ranged between 11 and
152 days (mean 49 ± 36). Mean length of stay for wheelchair
dependent patients was approximately double ambulatory patients.
Improving mobility, transfer or posture were the primary cause of
admissions in 37 cases. 16 out of 21 ambulatory patients (76%)
attained 100% mobility goals. Only 4 out of 20 wheel-chair bound
patients (20%) achieved 100% mobility goals (P 0.002). Neither the
type of MS nor the duration of it influenced the overall outcome.
Conclusion: Our results suggest that MS patients admitted for
rehabilitation following deterioration secondary to a medical or surgical cause show the same favourable outcome that was demonstrated
with MS stable patients or in relapse. Baseline mobility, but not type
and duration of MS, seems to have a significant impact on the rehabilitation outcome in terms of goal achievement.
Epilepsy: management
P548
Study of the circadian pattern of seizures in patients
with mesial temporal lobe epilepsy in ambulatory care
R. Duarte Ferreira, R. Peralta, C. Bentes
University of Lisbon (Lisbon, PT); Santa Maria University Hospital
(Lisbon, PT)
Some studies suggest that epileptic seizures have a circadian rhythm
depending on the epileptogenic region and that in mesial temporal
lobe epilepsy (MTLE) the majority of the seizures occur in the
afternoon. However, studies conducted so far concerned heterogeneous groups of patients and were based on data gathered during
hospital admission, therefore subjected to the daily routine changes
imposed by admission and the cessation of anti-epileptic medication.
Goals: To characterize the circadian pattern of epileptic seizures in
patients with refractory MTLE in ambulatory care and to correlate it
with their sleep/wake cycles. With this essay we intend to present the
preliminary results of this on-going study.
Methods: Patients with lesional and refractory MTLE, regularly
followed at our epilepsy clinic were consecutively recruited. All
patients filled in a diary with their sleep, seizure and medication hours
for 30 consecutive days. Variables analysed: number of seizures/hour;
number of seizures in intervals of 4, 6, 8 and 12 h; number of seizures
while asleep and awake. Statistic tests used: Wilcoxon and Friedman,
p B 0.05.
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Results: 87 seizures from a total of 10 patients (average age:
45.42) with MTLE were analyzed. The average number of seizures
per patient was 8.70 ± 6. The hourly distribution was statistically
different (p = 0.035). A greater number of seizures were registered
between noon and 11 pm than between midnight and 11 am
(p = 0.049). The distribution of seizures in periods of 4, 6 and 8 h
was not statistically different. The number of seizures while awake
was greater than while asleep (p = 0.005). The total number of h of
sleep in days with and without seizures did not reveal significant
differences (p = 0.197).
Conclusions: In outpatient care, the afternoon and evening are
the most likely periods for the appearance of seizures in patients
with refractory MTLE, as it had already been demonstrated during
inpatient care. Furthermore, the seizures are reported mainly while
the patients are awake, not coinciding with eventual afternoon naps.
This data may eventually have localizing value for determining ictal
onset zones, and would improve the planning of complementary
exams and medication regimes. Also, by decreasing the unpredictable character of epileptic seizures, this knowledge would account
for a significant improvement in the safety and quality of life of
these patients.
P549
GEFS + syndrome in a large Gypsy/Roma family
S. Zhelyazkova, I. Tournev, M. Radionova,
V. Guergueltcheva, B. Morar, D. Azmanov,
D. Angelicheva, I. Scheffer, L. Kalaydjieva, J.W. Sander
Medical University (Sofia, BG); The University of Western Australia
(Perth, AU); The University of Melbourne (Victoria, AU); University
College (London, UK)
Objectives: The aim of our study is clinical and genetic characterization of a large highly consanguineous Roma/Gypsy family with
multiple members affected by epilepsy.
Methods: We collected extensive pedigree analysis, interviewed [ 30 family members, and performed clinical, electrophysiological and neuroimaging investigations on 18 affected
subjects. A linkage analysis is in progress using high density SNP
genotyping data (Affymetrix 5.0).
Results: Inheritance was consistent with autosomal-dominant
mode. Early development, current cognitive performance and neurological examination were normal in all but one patient. Generalized
tonic clonic seizures began in early childhood and persisted into
elderly adult life. Febrile seizures (FS) with onset at age 5 month to
3 years and offset by 5 years were reported in four subjects. Another
two individuals were classified as febrile seizures plus (FS+). The
affected older individuals in the family reported the late appearance
of focal seizures mostly characterized by oroalimentary and motor
automatisms, often evolving to bilateral convulsive seizures. Three
patients had atypical features. Interictal EEGs showed abnormalities
in most cases. Antiepileptic treatment was given intermittently and
for short periods and usually consisted of low-dose carbamazepine or
sodium valproate.
Conclusions: The phenotype is compatible with GEFS+ , with
some unusual features (e.g. GTCS persisting into late adult life and
high frequency of focal epilepsy). Identification of this family will
contribute to better definition of the full clinical spectrum of
GEFS+ in epilepsy patients of different countries and ethnic
groups
This study was supported by grant 458736 of the National Health
and Medical Research Council of Australia to LK.
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P550
Bidirectional relation between schizophrenia
and epilepsy: nationwide population-based case–control
study
Y.T. Chang, I.C. Chou, I.J. Tsai, P.C. Chen
China Medical University Hospital (Taichung, TW)
Objective: Several studies have found higher prevalence of schizophrenia-like psychosis in patients with epilepsy, as compared with the
general population. We proposed that schizophrenia and epilepsy may
share susceptibility and examined a bidirectional relation between
both disorders.
Methods: Data used in this population-based cohort study came
from the Taiwan National Health Insurance Research Database. We
identified study subjects from medical claims during 1999–2008 and
performed two separate analyses. Analysis 1 included 5,195 patients
with an initial diagnosis of schizophrenia and 20,776 randomly
selected non-schizophrenia comparison controls. Analysis 2 included
11,527 patients newly diagnosed with epilepsy and 46,032 randomly
selected non-epilepsy comparison subjects. For both analyses, the
comparison group was matched for age, sex and calendar year. We
used Cox proportional hazards regression models to assess the risk of
elevated incidence of schizophrenia associated with epilepsy in
analysis 1 and reversely, the excess risk of epilepsy incidence in
patients with schizophrenia in analysis 2.
Results: In analysis 1, patients with schizophrenia were at increase
risk of developing epilepsy [adjusted hazard ratio (HR) = 5.88, 95%
confidence interval (CI) = 4.71–7.36), as compared with the nonschizophrenia comparison subjects. In analysis 2, the adjusted HR of
incidence of schizophrenia were 7.65 (95% CI = 6.04–9.69) for
epilepsy patients. The effect of schizophrenia on subsequent epilepsy was greater for women, but the association between epilepsy
and elevated incidence of schizophrenia was more pronounced in
men.
Conclusion: We found a strong bidirectional relation between
schizophrenia and epilepsy. Patients with epilepsy are at greater risk
of developing schizophrenia, patients with schizophrenia at higher
risk of developing epilepsy. These two conditions may share common
genetic or environmental causes. Further studies on the mechanism
are required.
P551
Symptomatic epilepsy after stroke in adults
I. Marinkovic, S.T. Ristic, D.T. Ristic, G. Djordjevic,
M.D. Zivkovic
University of Nis (Nis, RS); Institute for Pulmonary Disease (Nis, RS)
Purpose: Cerebrovascular diseases are significant aetiological factors
of epilepsy. Seizures may appear in acute phase of the insult,or during
the reconvalescence. Our goal was to analyse the frequency and
correlation between epileptic seizures and the type and size of cerebrovascular lesion.
Methods: In this prospective study, we evaluated patients with
stroke who were hospitalised at the Department of Neurology in Nis,
between January and December 2010. Witnessed epileptic seizures
occured in 112 patients. Patients with a previous history of epilepsy
and pulmonary diseases were excluded. Patients were evaluated and
had the same investigations with anamnestic, clinical, neurological,
EEG and neuroimaging (CT, MRI) variables which were compared.
Patients were treated with regular anti-oedematous and vasoactive
therapy. After seizure appearance patients were instantly put on an
anti-epileptic drug treatment.
Results: Of the 1231 patients with stroke who were admitted to the
hospital, 430 (34.93%) had haemorrhagic stroke, and 801 (65.07%)
had ischemic stroke. Mean age was 52 ± 30 years. Of a total of 112
patients with witnessed epileptic seizures,71 were male and 41
female. 37 (33.04%) patients with haemorrhagic and 75 (66.96%)
patients with ischemic stroke developed seizures after 14 days of the
stroke. Partial motor seizures (PMS) were registered in 63 (56.25%)
patients, partial seizures with secondary tonic-clonic generalisation
(GTC) in 34 (30.36%) patients and primary GTC seizures in 15
(13.39%) patients. Status epilepticus (SE) was registered in 11
patients. 35 (31.25%) patients had EEG pathological changes (spike
or sharp-waves) and 27 (24.11%) patients had focal or diffuse Theta–
Delta waves. Normal EEG patterns were registered in seven patients.
Conclusion: Patients with ischaemic stroke and cortical lesions are
at a higher risk of developing seizures. Partial motor seizures and
partial seizures with secondary tonic-clonic generalisation are a
dominant feature. Our results differ from the ones in literature, in
which patients with haemorrhagic stroke are more likely to develop
seizures. It may be the consequence of the fact that the mortality in
haemorrhagic stroke patients is higher.
P552
Depression in women with epilepsy
A. Ilic
Health Center (Kraljevo, RS)
Purpose: to assess the prevalence and the predictors and risk factors
for depression in women with epilepsy
Method: Women with epilepsy and on antiepileptic drug treatment
and a control group of women without epilepsy were included. All
subjects were assessed for symptoms of depression with Beck
depression inventory (BDI). Quality of life was assessed with the
PESOS-Scales. All subjects were tested during a 1-year period, in
2-month intervals.
Results: The two groups did not differ in age and education level.
Each group consisted of 90 women (aged from 18 to 60 years).
Depression was increased compared to the population of women
without epilepsy. Depression values were in 16% of the women with
epilepsy and in 7% of the control group. Depression correlated significantly with perceived restrictions due to epilepsy and with the
global quality of life. Important predictors for depression are tolerability and efficacy of antiepileptic drug therapy, financial situation
and education.
Conclusion: The prevalence of depression in our patients is considerably higher than in the general population. Perceived restrictions
due to epilepsy and due to antiepileptic drug therapy, as well as the
financial situation, are significant predictors of depression.This study
should lead to further investigations addressing the issue of the timecourse of psychiatric comorbidity in epilepsy and also to the development of specific therapeutic strategies.
P553
A community-based door-to-door study of epilepsy
among children in the Roma district of Kyustendil,
Bulgaria
P. Antimov, I. Tournev, J.W. Sander
Medical University (Sofia, BG); University College (London, UK)
Objectives: Epilepsy is the commonest serious neurological disorder.
Epidemiological studies suggest that there is considerable geographical variation in prevalence of the condition which may be related to
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genetic and socio-economic factors. An increase in the prevalence of
epilepsy amongst the Roma community in Bulgaria has been
suggested.
Aim: To ascertain the prevalence of epilepsy in children aged
0–19 years in a specified area.
Methods: A door-to-door survey of the population in the Roma
district of Kyustendil, South West Bulgaria using a screening questionnaire for epileptic seizures. Trained field workers screened the
population followed by case examination by the field neurologist. Setup: The survey was performed in four stages. The first stage included:
precise limitation of the target area collecting demographic and
healthcare data; collecting previous data concerning epidemiology of
epilepsy in Bulgaria and in the Roma minority in Bulgaria; sociocultural workshop, which consists of establishing focus groups of
Roma representatives and organizing a discussion among the focus
group members about cultural context of epilepsy; determining the
local health seeking strategies; developing a screening tool, and
validating it. In the second stage the population of the Roma district
was screened. In the third stage screen positives were clinically and
electrophysiologically examined. The fourth stage consisted of data
analysis.
Results: A prevalence of 17.3/1,000 was found in the 71% of the
children received no treatment and had not previously been diagnosed. 90% of people identified resided in the part of the district with
the lowest socio-economic conditions.
Conclusion: The prevalence in this age group seems to be higher
than in other part of Europe were prevalence rates of 3.6–5.3/1,000
have been reported for this age group. Probable reasons for the higher
prevalence may include: increase rate of genetic conditions, a high
rate of brain trauma, unsatisfactory socio-economic conditions; higher
prevalence of infections and parasitic diseases; and more frequent
perinatal mishaps. Roma people with epilepsy often go untreated. The
next step will be to establish a correlation between this high prevalence of epilepsy possible risk factors. Population-based door-to-door
epidemiological studies in epilepsy are particularly expedient to
establish the magnitude of the treatment gap.
P554
Symptomatic epilepsy (histiocytosis X with CNS
involvement)
H. Nicolae, R. Sima, R. Borindel, D. Bumbacea, R. Popoiu,
G. Vulpe, C. Panea
Elias Emergency University Hospital (Bucharest, RO); National
Institute of Pneumophtisiology ‘‘M. Nasta’’ (Bucharest, RO)
Background: Histiocytosis-X is a disease of the lymphoreticular
system characterized by histiocytic infiltration of one or more tissues.
It is a complex disease that includes Letterer–Siwe disease, Hand–
Schuller–Christian disease, and eosinophilic granuloma. It is a nonneoplastic chronic disease of granulomatous nature which chiefly
affects the reticuloendothelial system. The basic disorder is proliferation of histiocytes of unknown etiology.
Case report: We present a case of a 43 years old right handed
woman, diagnosed with Histiocytosis X with pulmonary involvement
since 1998 (clinic, radiologic, bronchoalveolar lavage, biopsy), and
without known vascular risk factors, referred to our hospital for
recurrent paresthesias and mild weakness on right side of the body
lasting for seconds. Neurological examination was normal. Cerebral
MRI showed multiple round-oval areas with hyperintensity on T2
weighted images with variable dimensions(up to 13 mm) and variable
locations (subcortical, periventricular, deep in the basal ganglia,
midbrain) and with mild contrast enhancement in pons localization
lesion; there was a left thalamic lesion with restricted diffusion;
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Doppler examination of extra and intracranial blood vessels, ECG
were normal; EEG showed no focal lesion. Biologic assessment
excluded prothrombotic status and vasculitis (pANCA, cANCA and
specific systemic lupus erythematosus antibodies were negative); CSF
examination (cell count, protein and glucose levels) was normal.
Neurological course was favorable under antiepileptic treatment.
Discussion: The most common CNS manifestation is infiltration of
the hypothalamic pituitary region by Langerhans cell histiocytosis
(LCH) granuloma, frequently leading to diabetes insipidus and anterior pituitary hormone deficiency. Neurodegenerative changes, the
second most frequent pattern, comprise mostly bilateral symmetric
lesions in the cerebellum and basal ganglia of variable signal quality
on MRI, depending on site and stage of the lesion. Less frequently
lesions in the extraaxial spaces, i.e. the meninges, pineal gland and
choroid plexus, are observed. The particularity of case is the limited
neurological manifestation -only right focal sensory seizure- in a
patient with histiocytosis X with multiple brain determinations.
P555
Benign parietal lobe epilepsy with vestibular
disturbance: an under-recognised form of epilepsy?
R. Hewett, M. Guye, M. Gavaret, F. Bartolomei
University Hospital (Edinburgh, UK); Univesity Aix-Marseille II
(Marseille, FR)
Objectives: Parietal epilepsies are generally not recognized as constituting clinical syndromes in adults, but are regarded as a
heterogeneous aetiological group. In this study we describe a series of
adolescent and adult patients that share the electroclinical characteristics of a non-lesional, pharmacoresponsive epilepsy presenting with
prominent vestibular disturbance suggesting a parietal origin.
Methods: We retrospectively reviewed a data base of consecutive
patients referred to the epilepsy clinic over a 10-year period on the
following criteria: Recurrent episodes of paroxysmal vestibular
symptoms, including true vertigo and loss of balance, normal MRI
and interictal EEG changes over the posterior regions.
Results: Fourteen patients were finally selected (10 males, 4
females). Mean age of onset was 26.5 (range 12–59). Four patients
had a family history of epilepsy, though none with a first degree
relative. The diagnosis of epilepsy was usually delayed until after
cardiology and/or otorhinolaryngology work-up. The predominant
features on interictal scalp EEG were abnormalities over the posterior
areas. All patients responded well to antiepileptic medication.
Conclusion: We propose that, though it needs further characterization to constitute a syndrome, it is an under diagnosed form of
epilepsy which merits recognition.
P556
Post-stroke epilepsy
M. Ozturk, D. Yildiz, S. Oncel, A. Dirican, H. Kucukoglu,
S. Baybas
Bakirkoy Research and Training Hospital for Neurologic
and Psychiatric Diseases (Istanbul, TR)
Objectives: The aims of this study were to assess the occurrence of
poststroke epilepsy in patients with stroke. We analyzed the characteristics of the seizures, the rate and management of treatment.
Methods: Out of the 1,355 patients admitted for a first-ever stroke
to our department between 2005 and 2010, we retrospectively studied
the data of all patients with a first-ever seizure and analyzed their
evolution. 97 (7.2%) of the patients had seizure. Vascular risk factors
S141
for stroke types of epilepsies,EEG findings, ‘early-onset’ seizures
(\14 days) and ‘late-onset’ ones ([14th days) and localizations of
lesions were evaluated.
Results: 54 (55.7%) were female and 43 (44.3%) were male
patients. Patients between the ages of 22 and 91 years old and mean
age of them was 62.9 ± 15.8. 88 (87.6%) patients were ischemic, 9
(9.3%) were hemorrhagic stroke. We define as early seizure those
occurring within 15 days after stroke and late seizures those developing beyond 15 days. 48 patients(49.5%) had early seizure.23
(23.7%) patients had simple partial seizures, 2 patients (2.1%) had
complex partial seizures, 68 patients (70.1%) had seconder generalised seizures, 4 patients (4.1%) had generalised seizures. According to
the Oxfordshire Community Stroke Project classification, 41 patients
(48.8%) had PACI, 24 patients had (27.2%) TACI, 13 patients
(15.5%) had POCI, 5 patients (6%) had LACI and 2 patients (2.1%)
had POCI + PACI. Three patients had venous infarct. Etiologically,
30 (30.9%) of cases had big vessel disease, 29 (29.9%) of cases had
cardioembolic disease, 11 (11.3%) had small vessel disease, 2 patients
had rare ethiologies and 13 patients were not classified. 85 (87.6%) of
lesions were cortical and 12 (12.4%) of lesions were subcortical
infarcts. Oxcarbazepine, NA valproat, carbamazepine, levetiracetam
or phenytoin used for monotherapy but polytherapy was needed to
give for ten patients. No treatment was given to seven patients and
they did not have seizure yet. 80 patients with monotherapy and 4
patients with polytherapy were seizure free.
Conclusion: Patients with cortical ischemic lesions had higher rate
for poststroke epilepsy.Most of these seizures were partial and
patients had good response to treatment.
P557
Premonitory symptoms in generalised idiophatic
epilepsy
A. Massano, R. Teotónio, L. Letra, C. Bento, F. Sales
University Hospital of Coimbra (Coimbra, PT)
Objectives: Currently, in epilepsy, one of the topics of greatest
interest is the ability to anticipate seizures and the development of
strategies to avoid them before they start. EEG and imaging studies
have suggested the existence of a pre-ictal state before the onset of
seizures. Clinically, many patients report premonitory symptoms,
which are often categorized in auras (starting in the 30 min prior to
the crises) or prodromal (which appear more than 30 min before), as
well as the ability to avoid these episodes by using several strategies.
These kinds of studies were predominantly made in patients with
focal epilepsy and not in those with a generalized form. Our goal was
to characterize possible premonitory symptoms in a group of patients
followed in our outpatient for idiopathic generalized epilepsy.
Methods: telephone surveys applied to a group of patients with
idiopathic generalized epilepsy.
Results: In this sample of 62 patients, 48.4% don’t have premonitory symptoms. Of the remaining 32 patients, seven report the
existence of prodromal symptoms, which began up to 6 h before the
crisis, consisting mainly of changes in mood and cognitive-behavioral
complaints with a continuous and stereotyped nature. 24 patients (38.7%)
reported auras, also stereotyped (only three patients did not always feel
the same), in which the predominant symptoms were cognitive difficulties, anxiety, headache and dizziness, but there also motor and sensory
changes. Faced with this symptom, 54.17% of patients think they are able
to avoid at least some crises, and the most widely used technique for doing
that, is distraction with other activities.
Conclusions: Approximately, half of the patients reported some
kind of premonitory symptoms, mostly auras. This number, relatively
high compared to other similar studies may result from bias introduced by
methodology, based only on patients’ memory and not on the register of
the events when they occur. However it seems relevant the number of
auras in patients with generalized epilepsies, and deserves further characterization, since they can function as an ‘‘alarm’’ for patients and allow
therapeutic interventions in that pre-ictal phase.
P558
Emotional and pilomotor seizures in a patient
with non-paraneoplastic voltage-gated potassium
channel antibody-associated limbic encephalitis
G. Liberatore, A. Merlini, S. Sartori, M. Deriu,
F. Minicucci, G. Comi, V. Martinelli
University Hospital San Raffaele (Milan, IT)
Objective: We describe the case of a male patient who had a nonparaneoplastic voltage-gated potassium channel antibody-associated
limbic encephalitis with a rare type of limbic seizure.
Methods: Observational case report.
Results: A 72-year-old man was admitted to our department for
subacute progressive short term memory deficits, agitation, irritability
and paroxystic confusional episodes associated with orofacial rhythmic movements. On admission, brain MRI revealed T2 and FLAIR
hyperintensity and T1 hypointensity in both hippocampi with contrast
enhancement, the right one being more affected than the left. The
EEG revealed posterior activity at 9 Hz and two critical activities
with onset on frontal areas were recorded. The patient was promptly
started on iv acyclovir, iv immunoglobulins and Levetiracetam. The
cerebrospinal fluid PCR for neurotropic viruses were negative. To
rule out a paraneoplastic etiology of the limbic encephalitis, the
patient underwent a total-body CT and a PET-CT as well as testicular
and thyroid ecography, which reported no neoplastic lesions. Tumor
markers and paraneoplastic autoantibodies were negative. The search for
non-paraneoplastic autoantibodies associated with limbic encephalitis
was positive for voltage-gated potassium channel (VGKC) autoantibodies. The patient was then treated with Carbamazepine,
Benzodiazepines, Valproic acid and intravenous Methylprednisolone
with normalization of EEG parameters and a reduction of the hippocampal enhancement at MRI. During the following weeks, frequent
seizures re-emerged with snorting followed by tonic contractions of
facial muscles and bilateral piloerection on upper limbs; these symptoms
were associated with generalized fear, anxiety and grimaces. Ictal EEG
showed rhythmic spiking in the right temporal area with controlateral
diffusion. After re-assessment of the antiepileptic drugs, emotional and
pilomotor seizures gradually subsided. Subsequently, the patient started
monthly iv cyclophosphamide and showed a progressive improvement of
memory impairment.
Discussion: In our patient, VGKC limbic encephalitis was associated with emotional and pilomotor seizures. Ictal pilomotor erection
is typically but not exclusively associated with temporal lobe epilepsy
and can be evoked by stimulation of insula, hippocampus, amygdala
or hypothalamus. Given the prominence of fear and grimaces, a
central role of amygdala in the clinical presentation of patient’s seizure could be suspected.
P559
Sturge–Weber syndrome with an unusual onset
in the sixth decade: a case report
L. Ferrari, E. Coppi, F. Caso, R. Santangelo, L. Politi,
V. Martinelli, G. Comi, G. Magnani
University Hospital San Raffaele (Milan, IT)
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Background: Sturge–Weber Syndrome (SWS) is a neurocutaneous
syndrome, often diagnosed in childhood, defined by the association of
a facial capillary malformation (port-wine stain) with vascular malformation of the eye, and/or vascular malformation of the brain
(leptomeningeal angioma). This definition is referred to the complete
form, however there are two more types of SWS: type 2, involving a
facial angioma and the possibility of glaucoma, but no evidence of
intracranial disease, and type 3, characterized by leptomeningeal
angioma, with no cutaneous and/or ocular involvement.
Case report: We report the case of a 56 years male with a history
unremarkable except for a few episodes of loss of contact during the
last 2 months, who was admitted to our hospital because of a secondary generalized seizure, starting from right arm. Neurological and
physical examination, blood tests and electroencephalography (EEG)
revealed no abnormalities. The brain magnetic resonance imaging
(MRI) put in evidence, after gadolinium injection, a pial enhancement
along cortical sulci of left cerebral hemisphere, consistent with a
leptomeningeal angioma. In the same locations, the head computed
tomography (CT) pointed out gyriform calcifications. Imaging data,
associated with epileptic manifestations, allowed us to make diagnosis of SWS type 3. We started anticonvulsivante therapy with
phenobarbital 125 mg/die and prophylactic antiaggregant therapy. At
the moment, 1 year after, the patient is still free from seizures.
Conclusions: There are no studies to date reporting the case of a
patient who receives his first diagnosis of SWS in the sixth decade.
Some authors hypothesized that presentation of SWS variants at an
older age than classical form was due to a less extensive insult to
vascular development, that would result in milder impairment in brain
development and function. We can assume that, in our case,
involvement of the meninges only, with sparing of skin and eye, is
indicative of a less extensive vascular insult, and has allowed the
absence of seizures and normal development of the brain until such an
advanced age.
P560
Seizures and tics with a similar motor phenomenology
D. Neutel, R. Peralta, A. Valadas, M. Coelho, C. Bentes
Hospital de Santa Maria (Lisbon, PT)
Introduction: Tics are sudden, fast, recurrent, arrhythmic, stereotyped,
irresistible motor movements or vocalizations, partly dependent on
one’s will. They can be primary or secondary. Tics have been
described after epilepsy surgery, but not in patients with symptomatic
epilepsy sharing characteristics of ictal semiology.
Case-report: A 40-year-old man with a past history of traumatic
brain injury in childhood and epileptic seizures since 5. The seizures
begin with a smell ‘‘as in the hospital’’, followed by loss of consciousness, right head rotation, oroalimentary and manual automatic
movements, predominantly on the left side, lasting 30–60 s followed
by post ictal confusion, hunger and amnesia for the event. The seizures were not controlled under treatment with Levetiracetam
1,000 mg/day and Sodium Valproate 2,000 mg/day. He also displays
stereotyped movements of lateral contraction of the nose and bilateral
blinking, partly controlled by will and exacerbated with hyperpnia,
followed by a sense of relief, and arising particularly in situations of
distractibility. MRI shows right mesial temporal sclerosis and a small,
nodular, neocortical, lesion in the right parietal convexity. VideoEEG shows seizures beginning with blinking and lateral contraction
of the nose, similar to the previously described tics, followed by
manual and oroalimentary automatisms and predominantly right
cephalic version. Ictal scalp EEG changes begin in the fronto-temporal and right inferior temporal regions, 15–30 s after clinical onset.
Back-average analysis didn’t show any cortical correlate for the tics.
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Discussion: We present a case of symptomatic epilepsy associated
with simple motor tics, in which seizures and tics have a similar
phenomenology. The analogy between ictal motor patterns and
parasomnias has been associated with activation of central motor
generators by different mechanisms. This case suggests that tics may
also share motor patterns with seizures, probably related to subcortical activation. Future studies should assess the frequency of tics in
patients with epilepsy.
P561
An estimation of the 2010 incidence
of hyperammonaemic encephalopathy related
to endovenous valproate seen at a level II Hospital
in Catalonia, Spain
E. Peral, M. Martinez-Corral, C. Serrano-Munuera
Hospital of Martorell (Martorell, ES)
Objectives: ev VPA is an antiepileptic drug of common use. HE is a
well known adverse event (AE) of VPA, especially when used with
old age patients, known liver disease, polytherapy and endovenously.
Our target is to estimate the incidence of this AE in our daily practice.
Methods: We retrospectively reviewed the clinical files of all the
in-patients who had been under treatment with ev VPA throughout
2010 (January to December) at our hospital; a level II (150 beds and
with specialist in formation occasionally) hospital of the Spanish
Public Health System.
Results: During 2010, 33 in-patients (18 male/14 female, median
age (MA) 68.6 years, 93% under polytherapy) received ev VPA. VPA
was started for the first time in 26 patients. Of those; 3 patients (11%,
2 male/1 female, MA 75 years) developed an HE. The maximum
ammonium levels were 105, 70, 90 lmol/L (n: 9–33). All of them
received other drugs. 2 did have known liver disease and showed
hyperammonemia without impairment of other markers of liver
function (AST, ALT, GGT, FA). 1 patient did not have known liver
disease and showed significant impairment of markers of liver function. All patients did normalize their ammonium levels when VPA
was retired. All patients improved substantially their level of consciousness (1 complete recovering) when VPA was discontinued.
Conclusions: Our estimate annual incidence of HE has been relatively high (11%). We think VPA is an excellent first line
antiepileptic drug, but we have to be careful when using ev VPA,
specially when dealing with patients of old age, under polytherapy,
and known liver disease.
P562
Progressive myoclonic epilepsy: searching for a genetic
diagnosis
J. Pinho, S. Rocha, R. Mare´, E. Lourenço
Hospital of Braga (Braga, PT)
Introduction: Progressive Myoclonic Epilepsies (PME) are a group of
diseases of which the majority have a genetic cause, with variable age
of onset, classically characterized by myoclonic seizures, tonic–clonic
seizures, ataxia and cognitive decline. Although myoclonus is the
predominant manifestation, age of onset and association with other
neurological and non-neurological symptoms and signs help to guide
aetiological investigation.
Methods and results: We describe two siblings (absent consanguinity in the family): a 29-year-old man and a 31-year-old woman
with multifocal myoclonus which began at age 16 and 19,
S143
respectively, present during action and posture, sensitive to light, with
progressive worsening, refractory to anticonvulsants, leading to
inability to walk unaided 5 years later. During follow-up a pancerebellar syndrome gradually developed, action dystonia of distal upper
limbs was observed in the woman, the man developed generalized
tonic-clonic seizures and no cognitive decline or ophthalmological
abnormalities were present. Video-EEG monitoring revealed a normal
background activity, myoclonus without EEG correlation and generalized myoclonic seizures with epileptiform discharges. Brain MRI
was normal. Enzyme studies were normal (N-acetyl neuraminidase,
b-galactosialidase), as were urinary oligosaccharides. Skin and muscle pathology were normal (including electronic microscopy,
periodic-acid-Schiff staining, and absent red ragged fibers). Genetic
study for MERRF mutations and CAG expansion in DRPLA gene
were negative. Finally, CSTB repeat expansion was also negative.
Discussion: Pedigree suggests an autosomal-recessive pattern of
inheritance and phenotype is similar to the one observed in Unverricht–Lundborg Disease (ULD), even though investigation was
negative for CSTB repeat expansion and other PME causes. While a
homozygous mutation expansion is found in about 90% of patients
with ULD, its absence does not exclude the diagnosis, since a recent
study provides evidence for genetic heterogeneity in patients with
ULD phenotype.
P563
Epileptic seizures precursor of cerebral haematomas
A. Antunes, R.G. Gouveia, L. Albuquerque, R. Peralta,
I.P. Martins, C. Bentes
Hospital Santa Maria (Lisbon, PT); Hospital da Luz (Lisbon, PT)
Objective: To demonstrate that the relationship between epilepsy and
cerebrovascular disease is not restricted to post-stroke epilepsy, but also
involves the concept of ‘‘vascular precursor epilepsy’’. These heralding
seizures are usually related with ischemic stroke but a few cases of primary cerebral hemorrhage have been reported in the literature.
Method: Case report and literature review.
Results: We report a case of 82-year-old female, without previous
neurological complaints, who presented transient episodes (lasting
\24 h) of left hemiparesis, homonymous hemianopsia and inattention
to the hemi-space. Afterwards, she evolved to paroxystic episodes of
clonic and dystonic position of the left arm, sometimes with secondary generalization, and post-critical left hemiparesis and
inattention to the hemi-space. These episodes led to the introduction
of anti-epileptic therapy. She also had two episodes of prolonged
confusional status, which responded to anti-epileptic regime modification, regarded as non-convulsive status epilepticus. EEGs showed a
right hemispheric dysfunction and focal slow activity with very frequent epileptiform discharges in right temporal, posterior temporal,
parietal and occipital leads. Several cranial CT scans and CSF were
unremarkable. A 0.5T brain MRI was performed, as the patient had a
metal prosthesis, but it was not conclusive because she was not
cooperative. Two and a half years later, a new episode of prostration
and a left hemiparesis led to a new cranial CT scan, which showed a
right anterior frontal cortico-subcortical haematoma. Traumatic and
hypertensive cause were excluded and CT angiography did not show
cerebral aneurysms, arteriovenous malformations and abnormal
venous drainage. The EEG revealed bilateral independent epileptiform discharges on right temporal and left fronto-temporal regions.
Two months later, she was admitted with seizures and persistent right
hemiparesis and an extensive left temporo-parietal haematoma was
diagnosed. The EEG disclosed bilateral independent epileptiform
activity on right frontal, temporal and posterior temporal and left
frontal regions. The patient died 1 month later.
Conclusion: This case exemplifies the concept of ‘‘vascular precursor epilepsy’’. The investigation suggested the diagnosis of
probable cerebral amyloid angiopathy as a cause of recurrent lobar
hemorrhages. This support the hypothesis that pathological changes
are also related to the previous epileptic events.
P564
Epilepsy in focal cortical dysplasia—clinical
characterisation
R. Teotónio, F. Sá, C. Bento, F. Sales
Coimbra University Hospital (Coimbra, PT);
Hospital of Faro (Coimbra, PT)
Objective: Malformations of cortical development (MCD) are a heterogeneous group characterized by structural abnormalities of the
cerebral cortex. Within this group we have Focal Cortical Dysplasia
(FCD), an entity that results from an error during cortical cell proliferation and differentiation. First recognized in 1971 as an
epileptogenic lesion, FCD has been recognised as a major cause of
refractory epilepsy, especially in children. Our aim is to characterize
the group of patients with epilepsy and FCD followed in our neurology department.
Methods: We reviewed the Brain MRI and Clinical Files of all
patients followed in our outpatient clinic and Epilepsy Monitoring
Unit. Then we selected those who had an image consistent with FCD.
Results: We found 45 patients with MCD and 32 (71%) with FCD.
Of these, 23 were women (71.8%) with an average age of 33.45 years
old. The average age of epilepsy onset was 12.7 years. The majority
(55%) had at least weekly seizures and 34% had daily seizures. About
80% of the patients were receiving polytherapy, with 62% taking at
least three antiepileptic drugs. Two patients had dual pathology, more
precisely mesial temporal sclerosis associated with ipsilateral temporal dysplasia. Most patients (84%) had an extra-temporal
localization.
Conclusion: As already noted by many other authors, epilepsy
associated with FCD is usually refractory. It’s interesting to note that
as in other reviews, we found that when dysplasia is associated with
mesial sclerosis, it tends to be located in the temporal lobe. It’s
important to remember the bias inherent to the limitations of current
diagnostic methods regarding the detection of dysplasia in more
innocent histological patterns, which will correlate with more discrete
imaging abnormalities and a potentially more benign clinical
presentation.
P565
Amniotic fluid embolism: report of a case presenting
as status epilepticus
A. Veiga, P. Guimarães, M. Correia, M. Silva
University Hospital of Trás os Montes e Alto Douro (Vila Real, PT)
Introduction: Amniotic fluid embolism is one of the most catastrophic
complications of pregnancy. Although its rarity, it is one of the differential diagnosis of seizures occurring during labor.
Case report: A healthy, 35 years old, 40 weeks pregnant woman
developed generalized tonic-clonic status epilepticus, during the
labor, evolving to bradycardia and respiratory arrest. An emergent
cesarean section was performed resulting in a healthy newborn. After
surgery patient was found to be in cardiogenic shock (peripartum
cardiomyopathy confirmed by ultrasound) and multiple organ dysfunction, namely respiratory, hepatic, hematological (without
thrombocytopenia or coagulation abnormalities), and metabolic.
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Neurological examination revealed no other abnormalities. Phenitoin
ev, fluids resuscitation, ventilatory and aminergic support were started
at intensive care unit. Brain MRI showed post-critical vasogenic
edema. No further seizures occurred. Patient experienced quite salutary recovery, allowing her to be vanished from critical support in a
few days, and discharged to an outpatient therapy in Cardiology 2
weeks latter, with no other abnormalities besides echocardiography
determination of systolic function of the left ventricle in the lower
limit of normal.
Conclusion: Status epilepticus in a non epileptic individual is
usually related with acute symptomatic conditions. In pregnant
women, cerebral venous thrombosis and amniotic fluid embolism
are etiologies to taking into account. Considering its potential
fatal outcome, early recognition and with prompt intervention in
this latter condition is of paramount importance. Its management
is resuscitative, geared toward maintaining vital signs and
treating hemodynamic and coagulopathic derangements as they
occur.
Neuro-ophthalmology/neuro-otology
P566
Visual exploration of dynamic real-world scenes
in patients with hemispatial neglect
B. Machner, J. Gablentz, v.d., A. Sprenger, M. Dorr,
E. Barth, W. Heide, C. Helmchen
University Hospital (Lübeck, DE); Harvard University (Boston, US);
University Lübeck (Lübeck, DE); General Hospital (Celle, DE)
Visual exploration of everyday scenes requires shifts of attention
performed by the use of saccadic eye movements. We do know
that patients with hemispatial neglect show profound deficits in
the exploration of static scenes and in visual search paradigms
using abstract stimuli. However, little is known about their scanning behaviour in dynamic scenes, in particular when the moving
real-world stimuli are presented in a visual search context. Given
that visual attention is largely driven by the salience of visual
targets and that motion is one of the strongest (most salient) cues,
we wondered whether neglect patients’ exploratory eye movements differ between naturalistic dynamic scenes and static
images.
Using a remote eye tracking system at the bedside, we examined 19 patients with spatial hemineglect following acute right
hemisphere stroke, 14 right-brain damaged patients without neglect
and 21 healthy control subjects. Real-world scenes were presented
as static photographs, dynamic scenes and in a visual search
context.
We analyzed global saccade parameters such as saccadic amplitude and fixation duration, the spatial distribution of fixations as well
as physical scene properties (local motion, colour and contrast).
Preliminary results indicate that the pathological attentional rightward
shift in neglect patients can be overcome by objects in the left hemifield that are of higher interest and saliency (motion, contrast) than the
right-sided objects. The cue ‘‘motion’’ reduced the neglect behaviour
even in the complex visual search task, in which left-sided targets
were more likely to be found when they were moving. In the
future, the use of modified real-world movies may be an interesting
complement to current therapy schemes using static and abstract
stimuli for the rehabilitation of neglect and associated visuo-spatial
disorders.
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P567
Body position and direction of moving object modulate
visual motion perception
J. Claassen, S. Bardins, R. Spiegel, E. Schneider, R. Kalla,
K. Jahn, M. Strupp
Ludwig-Maximilians University (Munich, DE)
Introduction: A recent study showed that perception of visual motion
diminishes in normal subjects when an object moves at lower
velocities. Patients with bilateral vestibulopathy have higher motion
coherence thresholds (MCT) than normal subjects. Their thresholds
are also higher at low velocities. This was hypothesized to indicate a
compensatory mechanism for reducing oscillopsia caused by head
movements. In the current study healthy subjects were examined to
determine if the direction of the moving object and gravity influence
visual perception and thus MCT.
Methods: Nine healthy subjects (four males, ages 26–35 years,
mean 28.8 ± 2.8 years) were examined using a random dot pattern in
which variable percentages of dots moved in a particular direction,
i.e., upwards or downwards at random. Participants were asked to
indicate in which of the two possible directions they perceived the
coherent motion. Vertical planes were tested at speeds of 0.1–25/s
when the subjects were upright or lying on their sides.
Results: (1) When upright, subjects had a significantly higher
MCT for dots moving upwards than for those moving downwards
across all velocities (p = 0.049). Conditions with a higher velocity
had a lower MCT for all directions (p \ 0.0001). There was a significant interaction between direction and velocity (p \ 0.0001). Posthoc Bonferroni test revealed a significant difference between the
upward and the downward condition as regards MCTs at low velocities (0.1, 0.2, 0.4/s; p \ 0.05); lower MCTs were found for the
downward-moving dots. (2) When lying on their sides, subjects did
not exhibit any significant effect of the direction on the MCT
(p = 0.813). High velocities corresponded to low MCTs (p = 0.002).
Post-hoc Bonferroni test did not reveal any significant difference
between the two directions for each velocity.
Conclusion: This study demonstrates that the perception of slowly
moving objects depends on the direction of the vertically moving
object as well as on the position of the body. Our observation that the
direction of vertically moving objects has an influence only when the
subject is upright supports the view that gravity affects visual motion
perception. Objects moving in the direction of gravity are easier to
detect, perhaps because vestibular and visual inputs are then
congruent.
P568
Visual field deficits and pituitary adenomas:
not always related
N. Kale, D. Kuscu, M. Colak, D. Kirbas
Bakirkoy Neuro-Psychiatry Training and Research Hospital
(Istanbul, TR)
Objectives: Anterior ischemic optic neuropathy is the most common
form of optic neuropathy in the elderly. The presentation is the end
result of thrombosis of the optic nerve vascular supply due to risk
factors including hypertension, diabetes and ischemic heart disease.
The patients present with loss of visual acuity, color perception,
afferent pupillary defect and visual field defects that respect the
horizontal meridian. In this abstract we would like to discuss a patient
with nonarteritic anterior ischemic optic neuropathy and pituitary
adenoma and further discuss the possible mechanisms that lead to
bilateral altitudinal visual field deficits.
S145
Methods: We present a 60-year-old male with a previous history
of vision loss in his right eye that partially resolved.15 years following the initial presentation patient presented with vision loss in the
contralateral eye. The neuro-ophthalmologic exam showed bilateral
decreased visual acuity, color perception and Humphrey visual field
exam revealed bilateral altitudinal visual field deficit involving the
inferior meridians. The fundus exam revealed palor in both optic
nerves. Cranial magnetic resonance imaging (MRI) of the patient
revealed a 6 mm pituitary adenoma.
Results: The differential diagnosis of the patient with the presentation
of a bilateral visual field deficit included pituitary adenoma affecting the
afferent visual system and optic neuropathies. The neuro-ophthalmological exam revealed decreased visual acuity and color, however no
afferent pupillary defect was observed due to bilateral involvement of the
optic nerves. The visual field defect respected the horizontal meridian
suggesting an optic nerve involvement.
Conclusion: This case report aims to discuss the pathologies that
might lead to visual field deficits involving optic nerves, prechiasmal,
chiasmal and postchiasmal lesions.
P569
Recurring meningoencephalitis in sinusitis-associated
acute posterior multifocal placoid pigment
epitheliopathy under prednisone tapering
H. Joswig, C. Flückiger, A. Infanger, B. Tettenborn,
A. Felbecker
Cantonal Hospital St. Gallen (St. Gallen, CH)
Objectives: Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE) is a rare cause of bilateral visual loss and might be
associated with severe neurological complications.
Methods: We describe a case of APMPPE with recurrent neurological complications under prednisone tapering.
Results: A 24-year-old man suffered from recurrent acute sinusitis
based on chronic pansinusitis for 6 months and received recurrent
antibiotic treatment before he experienced subacute bilateral visual
loss. Based on the typical fundoscopic findings, APMPPE was diagnosed. During the further course of the disease recurrent episodes of
meningitis and encephalitis occurred, once tapering of prednisone was
attempted. Secondary to encephalitic lesions, the patient developed
partial epileptic seizures, which made an anti-convulsive medication
necessary. Because we considered the sinusitis to be an etiological factor
of the underlying autoimmune process, the patient underwent surgical
intervention of the sinusitis. Due to the prolonged and complicated course
we decided to start long-term immunosuppressive therapy with azathioprine under which the patient remained stable. Now prednisone could be
tapered successfully over a period of 6 months.
Conclusion: Neurological complications of APMPPE are rare.
Nevertheless, this illustrative case demonstrates that long-term
immunosuppressive treatment might be necessary to prevent recurrent
neurological complications in some cases.
P570
Early magnocellular dysfunction following a first optic
neuritis episode
A.-C. Viret, C. Cave´zian, O. Coubard, V. Vasseur, N. Raz,
N. Levin, C. Vignal, O. Gout, S. Chokron
Ophthalmologic Fondation Rothschild (Paris, FR); University Pierre
Mendès (Grenoble, FR); Hadassah Hebrew University Hospital
(Jerusalem, IL)
Introduction: Following visual acuity recovery after an optic neuritis
episode, several patients report visual discomfort despite normal
scores on various ophthalmologic examinations. Besides, it has been
shown that visual analysis starts with an extraction of basic information such as spatial frequencies typically segregated as Low and
High Spatial Frequencies (LSF and HSF).
Objective and methods: To better characterize patients’ visual
abnormalities, detection and categorization tasks of images filtered (in
LSF or HSF) or not were presented to 16 healthy controls and 8
patients recovering from a first optic neuritis episode.
Results: In healthy controls, response times to HSF-images were
longer than for LSF or non-filtered images which reflect the classic
coarse-to-fine time course of spatial frequency processing. However,
when they completed the tasks with their (previously) pathologic eye,
optic neuritis patients showed lower accuracy than control individuals
or than with their healthy eye for LSF-images only. Conjointly,
response time was longer with the pathologic eye than with the
healthy eye (or than controls) regardless of the type of images and to a
greater extent in the categorization task than in the detection task.
Conclusion: Altogether, our results suggest that even when
patients show a complete ophthalmologic recovery (visual acuity,
contrast sensitivity,…), optic neuritis alters LSF processing. The
present data confirm the hypothesis of a magnocellular pathway
alteration in optic neuritis.
This research was supported by the Edmond and Benjamin de
Rothschild Foundations (Geneva and New York).
P571
The presentation of optic neuropathy and posterior
scleritis in the setting of systemic immune-mediated
conditions
M. Ozerden, N. Kale, N. Sakalli, D. Kirbas
Bakirkoy Neuro-Psychiatry Training and Research Hospital
(Istanbul, TR)
Objectives: The spectrum of orbital inflammatory disease (OID)
ranges broadly from specific disease diagnoses including Wegener’s
granulomatosis, sarcoidosis and connective tissue disorders to nonspecific inflammation which may involve one or multiple structures of
the orbit. These immune mediated conditions might also lead to optic
neuropathy with disc edema. In this abstract we would like to present
a patient with optic neuropathy and posterior scleritis in the setting of
a possible rheumatologic disease.
Methods: 37-year-old female presented with acute onset headache
and blurry vision on the right eye (OD). The patient did not have any
history of previous diseases. On admission the neuro-ophthalmologic
exam revealed chemosis OD. The visual acuity was 40/20 OD and
20/20 OS. Fundus exam showed edema in the optic disc and macula
with posterior scleritis. The cranial magnetic resonance imaging
(MRI) and angiography were normal, orbital MRI revealed a right
hyperintense optic nerve. Lumbar puncture was performed, opening
pressure and CSF analysis was within normal limits.
Results: The patient’s symptoms resolved after the application of
high dose corticosteroid treatment followed with oral prednisone
tapering. The last follow-up exam revealed that the chemosis OD
resolved, blurry vision and visual acuity improved (20/20 OU). The
fundus exam showed that the edema in the optic disc and macula
resolved. The serological and immunological panel revealed
increased dsDNA results and patient was referred to rheumatology for
follow-up with the possible diagnosis of systemic lupus
erythematosus.
Discussion: The differential diagnosis for optic neuropathies with
disc edema must be considered in a comprehensive exam to rule out
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possible ischemic and demyelinating events. The presentation may be
secondary to an underlying systemic inflammatory disease, or may
represent localized pathologic processes without systemic involvement. A systemic evaluation is necessary for an accurate diagnosis
and for developing therapeutic strategies.
P572
Inflammatory and idiopathic optic neuritis:
the baseline profile of 40 Portuguese patients
C. Andrade, P. Barros, M.J. Sá, J. Guimarães
Hospital de S. João (Porto, PT)
Introduction: The optic neuropathies are a heterogeneous group of entities with different etiologies and clinical patterns. The optic neuritis (ON)
of inflammatory etiology is a subgroup often related to multiple sclerosis
(MS). The establish clinical profile seen in literature is manly based in the
Optic Neuritis Treatment Trial (ONTT), in which an American population is analyzed. Such prospective studies carried out in patients with ON
have concluded that the initial clinical pattern [like no light perception,
severe optic disc edema, absence of pain in the setting of no magnetic
resonance imaging (MRI) lesions] and the imagiological and cerebrospinal fluid (CSF) findings allow to stratify the risk of MS and possibly
adopting different therapeutic strategies.
Objectives: Assessment of baseline characteristics of patients with
inflammatory optic neuritis in a Portuguese population.
Patients and methods: A 6 years period (2004–2009) was selected
to conduct a retrospective study of all patients admitted at the inpatient Department of Neurology with the diagnosis of possible
inflammatory optic neuritis. Demographic, semiological, analytical
and MRI data were collected.
Results: On a sample of 52 patients admitted at the Department of
Neurology, 12 patients were excluded due to optic neuropathies of
other etiologies (6 non-arteritic anterior ischemic, 1 toxic-related; 1
infection by Mycoplasma pneumonia, 1 neurobrucellosis; 1 neuroBehçet; 2 neuroretinitis of undetermined etiology). In the final sample
of 40 patients, demographic characteristics were: mean age of
31.5 years (14–56 years) and 75% were female. Initial clinical pattern: 60% had ocular pain and 52.5% had changes of the optic disk
(bilateral - 10%); 21 patients had other symptoms (manly frontal
headaches). Initial visual acuity was available only in 25 patients, 14
of whom had 1/10 or less. Brain MRI, performed in 39 patients,
showed 2 or more demyelinating lesions in 17 patients, 94.1% of
whom have now the diagnosis of MS. Complete CSF study was made
in 37 patients revealing a mean of 4 cells (0–28), 0.43 g/dL proteins
(max. 0.7) and positive oligoclonal bands in 40.5% cases, 80% of
whom have MS. Thus, 16 new cases of MS were diagnosed after this
initial evaluation.
Conclusion: Our results suggest that this population of Portuguese
patients with inflammatory ON differs from the literature for the
lower frequency of ocular pain (60 vs. 92% in ONTT) and of retrobulbar ON (47.5 vs. 64.7%).
P573
Peripapillary retinal nerve fibre layer thickness
in patients with Parkinson’s disease and multiple
system atrophy
Y. Balash, T. Gurevich, M. Naftaliev, E. Naftaliev,
H. Shabtai, A. Rosenberg, A. Ezra, D. Klepiko, A. Korczyn,
N. Giladi, A. Kesler
Tel Aviv Medical Center (Tel Aviv, IL)
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Background: Retinal nerve fiber layer (RNFL) is composed of axons
originating in retinal ganglion cells that eventually form the optic
nerves. A thinning of the RNFL, in particular in the inferior quadrant,
has been shown in small sample of patients with Parkinson’s disease
(PD). It was also described in multiple system atrophy (MSA-C)
patients in one, small-sample study.
Objective: Quantitative assessment and comparison of thickness of
RNFL of a larger group of patients with moderate-advanced PD
versus MSA patients versus healthy controls.
Methods: Mean RNFL thickness of 89 eyes of 45 PD patients
(HY stages 2–3; 31 male; age 55.9 ± 9.2 years; PD duration
11.2 ± 5) was compared with 11 eyes of six patients with MSA (3
MSA-P; 3 MSA-C; age 55.9 ± 9; mean disease duration 5.3 years)
and 27 eyes of healthy controls (age 66.6 ± 11.2). Thickness was
acquired using OCT 3 according to a protocol with the fast RNFL
procedure. In each eye, average RNFL thickness measurements
were obtained in temporal, superior, nasal and inferior quadrants.
RNFL thickness differences between PD, MSA patients and controls
were evaluated by one way ANOVA, p \ 0.05 considered
significant.
Results: The mean RNFL thickness was reduced in both PD and
MSA groups compared to controls (89.6 ± 12.2, 90.1 ± 10.5 vs.
95.3 ± 9.9, respectively). While the reduction was more prominent
in PD compared to MSA, the difference was not statistically significant (in per-quadrant calculations as well as overall). Nasal
quadrant: RNFL in PD versus controls—65.9 ± 21.1 vs. 78 ± 25.8
(p = 0.01); MSA versus controls 72.5 ± 16 versus 78 ± 25.8
(p = 0.5); inferior quadrant: PD 113.7 ± 26.5 versus controls
126 ± 19.4 (p = 0.02); MSA 119 ± 18.2 versus controls
126.2 ± 19.4 (p = 0.4); superior quadrant: PD 104.9 ± 23 versus
controls 114. 9 ± 16.6 (p = 0.03); MSA 108.6 ± 14.7 versus
controls 114. 9 ± 16.6 (p = 0.4). No differences were observed in
the temporal quadrant. Disease duration had no effect on the RNFL
thickness in both groups.
Conclusions: Our data shows that RNFL thinning and the quadrants affected are similar between PD and MSA, in PD being more
prominent, though not statistically significant. Further, large-scale
studies may confirm this trend that might reflect the different pathophysiological mechanisms of the two diseases.
P574
Comparison of peripapillary retinal nerve fibre layer
thickness in patients with Parkinson’s disease, carriers
and non-carriers of mutations in the LRRK2 or GBA
genes
T. Gurevich, H. Shabtai, E. Naftaliev, M. Neudorfer,
Y. Balash, A. Rosenberg, A. Mirelman, A. Bar-Shira,
Z. Gan-Or, A. Orr-Urtreger, A. Kesler, N. Giladi
Tel Aviv Medical Center (Tel Aviv, IL)
Background: Retinal nerve fiber layer (RNFL) is composed of axons
originating in retinal ganglion cells that eventually form the optic
nerves. Thinning of RNFL, in particular in the inferior quadrant, has
been shown in Parkinson’s disease (PD). The effect of genetic status
on RNFL thickness in PD patients with and without mutations in the
LRRK2 or GBA genes has never been reported.
Objective: Quantitative assessment and comparison of RNFL in
PD with different genotypes.
Methods: Mean peripapillary RNFL thickness of 9 eyes of 5 PD
patients, LRRK2 G2019S mutation carriers (mean H&Y stage 2.4;
age 61.8 ± 9.2 years; mean PD duration 7 years) was compared to 13
eyes of PD patients carriers of GBA mutations (mean H&Y stage 2;
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age 53.1 ± 3.9; disease duration 6 years), 27 eyes of PD patients
without these mutation (PD-Nom) (mean H&Y stage 2; age
55.6 ± 9.7; disease duration 5 years) and 27 eyes of healthy controls
(age 66.6 ± 11.2). The thickness was acquired using optical coherence tomography (Startus OCT 3) according to fast RNFL protocol.
In each eye, average RNFL thickness measurements were obtained in
temporal, superior, nasal, and inferior quadrants.
Results: Mean RNFL thickness was reduced in PD-LRRK2 and
PD-Nom in comparison to controls (85.6 ± 23.6 lm,
89.6 ± 10.2 lm vs. 95.3 ± 9.9 lm, respectively). In patients with
mutations (LRRK2 or GBA), RNFL thickness was reduced in comparison with PD-Nom in the nasal quadrant: 56.6 ± 20.5 lm
(LRRK2) and 59.9 ± 33.3 (GBA) versus 68.9 ± 18.9 lm (P \ 0.05).
In the inferior and superior quadrants, PD-LRRK2 showed lowest
RNFL thickness in comparison to GBA and PD-Nom: superior
quadrant—90.3 ± 19.1 lm versus 112.7 ± 18.2 lm (p = 0.02) versus 104.8 ± 23.8 lm, respectively; inferior quadrant - 102.5 ± 51.5
lm versus 122.3 ± 21.4 lm versus 113.06 ± 23 lm. In PD-GBA
patients, average and in vertical quadrants’ RNFL thicknes was
reduced slightly with no significant differences from controls.
There were no differences in the RNFL thickness in the temporal
quadrants. Age and disease duration had no effect on the RNFL
thickness.
Conclusions: Differences in RNFL thickness and in the quadrants
affected were found in PD with different genotypes. PD carriers of the
LRRK2 G2019S mutation demonstrated the lowest RNFL thickness.
Further studies in larger cohorts of patients are needed to confirm
these findings.
P575
Migraine and benign paroxysmal positional vertigo
N. Tevzadze, M. Janelidze, R. Shakarishvili
S. Khechinashvili University Clinic (Tbilisi, GE);
P. Sarajishvili Institute of Neurology (Tiblisi, GE)
Objective: Migraine and BPPV are common disorders in general
population and it has been proposed that they might occur together in
the same patient purely by chance alone or they might have causal
relationship.
Methods and results: During 2009–2010 year 18 patients (14
women, 4 men) with migraine and BPPV were evaluated in our clinic.
Age range was 22–35 years. Migraine was confirmed according to the
IHS criteria, BPPV according the Lempert criteria. A positive DixHallpike test with a typical positional nystagmus beating towards the
undermost ear confirms the BPPV diagnosis. Previously, before
appearing of BPPV attacks, all patients suffered from migraine for
5–10 years. Personal histories indicated that 10 of the patients
experienced motion sickness in their childhood, in seven cases
patients had familial history of migraine. None of the patients had
head trauma or vestibular neuritis, BPPV attacks occurred 2–3 days
after the migraine episodes. None of patients received preventive antimigraine therapy, in 10 cases migraine attacks responded to nonsteroid antinflammatory drags (NSAIDs), in eight cases tryptans were
used. All the patients were successfully treated with repositioning
maneuvers, with 100% effectiveness.
Conclusions: Emerging of BPPV directly after migraine attacks
give opportunity for suggestion that BPPV and migraine share certain
pathophysiological features. While this link could not be simply
explained by neurovascular concept, commonly accepted for migraine
attacks. It should be supposed that either certain neurotransmitters
and metabolic defect or genetically determined channelopathy
under definite circumstances cause emerging of migraine attacks and
BPPV.
P576
Vestibular-somatosensory interaction: a near-infrared
spectroscopy study
M. Iida
Tokai University School of Medicine (Isehara, JP)
Introduction: The aim of the present study using near-infrared spectroscopy (NIRS) is to evaluate the correlation of the vestibulo-ocular
reflex (VOR) and the somatosensory input. We have reported previously that VOR is affected by somatosensory stimulation. It was
suggested that somatosensory input during active-somatosensory
stimulation may relate to the central vestibular mechanism.
Subjects and method: Five healthy young adults (4 male, 1 female,
all right handler) participated in this study. Caloric stimulation was
achieved in the subjects by irrigating the left external ear canals with
20 ml of cold water for 5 s, while the subjects lay in a supine position
with eyes closed. During the unilateral caloric stimulus, relative
changes of total cerebral hemoglobin were measured by NIRS bilaterally and simultaneously. During the nystagmus occurrence, activesomatosensory stimulation was given to the subjects with putting a
foot board against the soles. The total cerebral hemoglobin changes
before, in the middle and after the somatosensory stimulation were
calculated by using NIRS.
Results: As a result of the present study, a rapid phase in the
nystagmus (RPEV) was suppressed during somatosensory stimulation. In the NIRS study, the amount of oxygenated hemoglobin
increased on the parieto-temporal lobe during active-somatosensory
stimulation.
Discussion: Our present study justified the usefulness of NIRS for
confirming the existence of neural linkage between the peripheral
vestibular organ and somatosensory input. Omnipause neurons
(OPNs) are thought to control a number of oculomotor behaviors,
especially saccades and rapid-phase VOR. It was suggested that OPNs
inhibition originates from the superior colliculus (SC). The excitatory
effects from the SC are concealed by inhibitory input from OPNs and
the SC activation is disclosed when this inhibition is removed by a
pause in OPN activity at the beginning of saccades. The saccadic
signals and the rapid-phase eye movement from the SC to bursterdriving neuron (BDN) may be augmented by vestibular signals.
According to the present study, it is suggested that the activesomatosensory influenced RPEV, which may enhance the activity of
SC, OPN via the central vestibular cortex, and inhibit the RPEV.
Conclusion:
1. Active-somatosensory input may influence to the central vestibular cortex.
2. SC and OPNs may be related to the somatosensory inputs.
P577
Oculographic findings differentiate between
parkin-linked and idiopathic Parkinson’s disease
W. Heide, B. Machner, A. Sprenger, P. Baumbach,
P. Pramstaller, C. Helmchen, C. Klein
General Hospital Celle (Celle, DE); University of Lübeck
(Lübeck, DE); Central Hospital (Bozen, IT)
Objective: To investigate, if cerebral hemispheric eye movement
disorders help to differentiate between Parkinsonian patients with
Parkin mutations and those with idiopathoic Parkinson’s disease (PD).
Background: Parkin gene mutations are the most common cause of
early-onset parkinsonism. Patients with Parkin mutations may be
clinically indistinguishable from patients with idiopathic Parkinson’s
123
S148
disease (PD). At present, there is no specific clinical feature that
clearly distinguishes this monogenic form from idiopathic PD. Eye
movement disorders can help to differentiate parkinsonian syndromes, but have never been systematically looked for in Parkin
mutation carriers.
Design/Methods: Eye movements were recorded in symptomatic
(n = 9) and asymptomatic Parkin mutation carriers (n = 13), idiopathic PD patients (n = 14) and age-matched control subjects
(n = 27) during established oculomotor tasks.
Results: Both PD patients and symptomatic Parkin mutation carriers showed hypometric prosaccades towards visual stimuli, as well
as deficits in suppressing reflexive saccades towards unintended targets (antisaccade task). When directing gaze towards memorized
target positions, PD patients exhibited hypometric saccades, whereas
symptomatic Parkin mutation carriers showed normal saccades. In
contrast to PD patients, the symptomatic Parkin mutation carriers
showed impaired tracking of a moving target (reduced smooth pursuit
gain). The asymptomatic Parkin mutation carriers did not differ from
healthy control subjects in any of the tasks.
Conclusions/relevance: Although clinically similarly affected,
symptomatic Parkin mutation carriers and idiopathic PD patients
differed in several oculomotor tasks. This finding may point to distinct anatomical structures underlying either condition, namely
damage to cortical areas involved in smooth pursuit (V5, frontal eye
field) in Parkin-linked parkinsonism and greater impairment of basal
ganglia circuits in idiopathic PD.
Study supported by the Lübeck Research grant E-32-2008.
Multiple sclerosis: markers
P578
Does APOE-epsilon4 have a detrimental effect
in multiple sclerosis?
A. Martins Silva, A. Bettencourt, A. Gonçalves, C. Pinto,
E. Santos, I. Moreira, A. Tavares, E. Coutinho, F. Gomes,
P. Costa, B.M. Silva, S. Cavaco
University Hospital of Porto (Porto, PT); University of Porto (Porto,
PT); Hospital de Santo Antonio (Porto, PT); National Health Institute
Dr. Ricardo Jorge (Porto, PT)
Background: The role of apolipoprotein E (APOE) polymorphism, in
particular the epsilon4 allele, has been well recognized in various
neurodegenerative diseases (e.g., Alzheimer’s disease). However, the
literature has provided conflicting findings regarding a putative
association between APOE e4 and cognitive functioning in multiple
sclerosis (MS) patients.
Objective: To explore, in a large Portuguese cohort, the association between APOE epsilon 4 and clinical manifestations of MS, both
physical and cognitive.
Methods: A total of 339 MS patients (216 females, mean age
40.5 ± 10.9 years, mean age at onset 29.9 +/ 9.4 years, mean disease
duration 10.7 ± 8.4 years, mean EDSS 3.1 +/2.2 and mean MSSS 3.9
+/ 2.7) from CHP-Porto Neuroimmunology Clinic were genotyped for
the APOE gene and underwent a neurological and a comprehensive
neuropsychological assessment (Attentive Matrices-AT, Digit SpanDS, Corsi Block-Tapping Test-CB, Auditory Verbal Learning TestAVLT, Sentence Repetition-SR, Category Fluency-CF, Letter Word
Fluency-LWF, Trail Making Test-TMT, Wisconsin Card Sorting
Test-WCST, Nine-Hole Peg test-NH, and Hospital Anxiety and
Depression Scale-HADS). Mini-Mental State Examination was used
to detect patients in the dementia spectrum. Non-parametric tests (i.e.,
Mann-Whitney and Chi-Square) were applied to analyse the data.
123
Results: The genotyping revealed that 66 MS patients (16.97%)
carried the epsilon4 allele. There were no significant differences
between carriers and non-carriers regarding demographic (i.e., age,
gender and education) and clinical (i.e., age at onset, disease
course, disease duration, EDSS, MSSS) variables. No significant
group differences were found in the neuropsychological assessment. The incidence of dementia, as measured by Mini-Mental
State Examination did not differ between epsilon4+ and epsilon4groups.
Conclusions: The findings suggest that APOE-epsilon4 allele does
not have a negative impact on the physical and cognitive manifestations of MS disease. These observations are consistent with recent
reports (Ghaffar et al. 2010; Portaccio et al. 2009).
P579
Outcome of pregnancy in MS patients - mother’s point
of view
P. Hradilek, O. Zapletalova, I. Woznicova, M. Petzel,
O. Simetka
University Hospital (Ostrava, CZ)
Backgrounds: Multiple sclerosis (MS) is a disease affecting young
women with child-birth potential. Generally pregnancy is known to be
as period of immunotolerance and the risk of relapse is generally low.
On the other hand, postpartum period brings higher risk of relapse or
change of disease course into progressive one due to vast hormonal
changes after delivery.
Objective: To determine relapse rate and EDSS change in patients
with relapsing–remitting MS before and during pregnancy and after
delivery according to type of treatment.
Methods and results: We reviewed history of 68 pregnancies of
MS women (11 were treated with b-interferons at early stage of
pregnancy, 22 with Copaxone and other 35 patients did not take
disease modifying drugs (DMD) therapy at early stage of pregnancy).
Relapse rate in the year before pregnancy was similar in all groups
(0.6 vs. 0.6, vs. 0.7). The highest rate of relapses during pregnancy
and 6 months after delivery was found in Copaxone treated group
(27% of patients had relapse during pregnancy and totally 19 relapses
in 22 patients occurred during 6 months after delivery), whereas there
was no significant difference between other two groups (18% of
patients with relapse during pregnancy in interferons group and 17%
in the group without DMD treatment, and 6 relapses in 11 patients
during 6 months after delivery in interferon group and 15 relapses out
of 35 in the group without DMD). Average EDSS was same before
pregnancy and 6 months after delivery in all groups (1.4 vs. 1.4 in the
group without DMD, 2.5 vs. 2.5 in interferon group and 1.6 vs. 1.6 in
Copaxone group).
Conclusions: In our study we found slightly higher relapse rate
during pregnancy and during 6 months after delivery in patients
treated with Copaxone at early stage of pregnancy comparing to
patients without DMD therapy or treated with interferons b. In
accordance with literature we did not observe any influence of
pregnancy and delivery to average EDSS in any group.
P580
Serum antibodies to tubuline b class III in relation
to number of relapses in first 2 years of multiple
sclerosis and clinical disease course
I. Cihelková, M. Vyhnálek, P. Jinoch, M. Bojar
Charles University (Prague, CZ); Vidia (Prague, CZ)
S149
Background: Neuromarkers are a potential tools for diagnostic and
monitoring of Multiple Sclerosis /MS/. Serum IgM and IgG antibodies to tubuline b class III. /antiTBIII/ are good available. We
proved in last studies on 0.05 significance: their decrease after half
and 1 year on DMD, more IgG after glatirameracetate /GLA/ and
higher IgG and IgM in MS patients with depression and positive
correlation on involution of plagues on conventional MRI to
decreasing of both antiTBIII. Aim of this study was to investigate
mainly relation of antiTBIII: to number of relapses in first 2 years /
one predictor of worse MS course/ in MS patients on worse disease
course in DMD therapy to EDSS, to disease duration and to age for
confirm our older studies.
Methods: 53 MS patients 39 women and 13 men, with MS
according McDonalds criteria on glatirameracetate therapy, were
assessed for IgG and IgM serum antiTBIII. by ELISA method on
Vidia, s.r.o. sets. All patients had not medicaments causing a
depression, relapse or methylprednisolon in last 3 months, they had
disease duration to 7 years and GLA from 14 to 63 months, are not
older than 48 years, EDSS to 5.0. Nonparametric correlation of antiTIBIII. titers to number of relapses in first 2 years of MS, to EDSS,
to age and to disease duration were done.
Results: No correlation on 0.05 significance both in IgM and IgG
antiTBIII titers to number of relapses in first 2 years of disease, to age,
to EDSS and to disease duration were proved MS patients, which had
were treated by GLA.
Discussion: No differences in antiTBIII: according disease course
we proved. There is for further analyses, if it is the neuroprotective
effect of GLA therapy or it is not detectable dependency of umber of
relapses in first 2 years of MS to detection of serum antiTBIII. No
relation of antiTBIII. to age, disease duration and EDSS we confirmed
our last results.
P581
Prevalence of anti-JCV antibodies in a cohort
of multiple sclerosis patients from Italy
L. Moiola, F. Sangalli, V. Martinelli, S. Bucello,
L.M. Grimaldi, D. Baroncini, A. Ghezzi, A. Pace,
D. Paes, M. Subramanyam, G. Comi
University Hospital San Raffaele (Milan, IT); San Raffaele Hospital
A. Giglio (Cefalù, IT); San Antonio Abate Hospital (Gallarate, IT);
Biogen Idec Inc (Weston, US)
Objectives: To assess factors associated with anti-JCV antibody
prevalence in a cohort of natalizumab-treated MS patients in Italy.
Methods: A novel, two-step assay was used to detect anti-JCV
antibodies in blood obtained from 376 natalizumab-treated
MS patients from three Italian hospitals. A Chi-square test was
used to assess bivariate associations between factors and antiJCV antibody prevalence. A multiple logistic regression analysis
was also performed to adjust for potential confounding among
factors.
Results: Consistent with previous reports that anti-JCV antibody
prevalence is between 50 and 60%, a prevalence rate of 56.9% (95%
CI 51.7–62.0%) was observed in this cohort, with lower rates
occurring in females (51.6 vs. 67.7%, P = 0.003). While prevalence
tended to increase with age: \30 years (51.6%), 30–39 years
(56.0%), 40–49 years (62.2%), 50–59 years (64.7%), and C60 years
(37.5%), these differences were not statistically significant
(P = 0.360). Prevalence of anti-JCV antibodies was also not significantly different in patients who had prior immunosuppressant (IS) use
(61.3%) compared to those with no prior IS use (55.2%), P = 0.283),
or in patients with increasing natalizumab treatment duration
(P = 0.116 for linear association). Multivariate results were consistent, with only gender demonstrating a significant association with
anti-JCV antibody prevalence (gender P = 0.005, age P = 0.357, IS
use P = 0.398, treatment duration P = 0.288).
Conclusions: These data estimate a prevalence of anti-JCV antibodies in Italy of approximately 57%, which is consistent with
previous observations in Europe. Also similar to previous studies,
prevalence was lower in females. Prevalence was not found to be
significantly associated with age, prior IS use, or natalizumab treatment. Large-scale, clinical studies are underway to determine antiJCV antibody prevalence in a broad MS population, and determine
the potential utility of this two-step assay for PML risk stratification.
Supported by Biogen Idec, Inc. and Elan Pharmaceuticals, Inc.
P582
Value of tumour necrosis factor-a and interleukin
6 polymorphisms as prognostic marker of efficacy
of interferon b-1b in relapsing–remitting multiple
sclerosis
A.L. Guerrero, J.A. Garrote, D. Pe´rez, A. Mendoza,
J.T. López-Alburquerque, J.C. Morán, A.B. Guerrero,
D. Bernardo, A.B. Caminero, J. Martı´n-Polo, S. Merino,
H. Alonso, C. Jime´nez, J.J. Ruı´z, E. Arranz on behalf
of the GENPROCLEM Group
Objectives: Cytokine gene polymorphisms are known to influence
susceptibility and disease course of many autoimmune diseases, and it
has been suggested a role for some of these genes in susceptibility to
multiple sclerosis (MS). Current approach to modify natural history of
MS is the use of immunomodulatory agents, as Interferon B-1b
(IFNB1b). Nevertheless, therapeutic response is highly variable, and
genetic heterogeneity may be a factor contributing to this variability,
as has been previously shown with some cytokine-coding genes. We
aim to assess whether Tumour Necrosis Factor-a (TNFA) and Interleukin 6 (IL6) polymorphisms might have a prognostic value as
markers of response to treatment with IFNB1b.
Methods: We conducted an open, multicentric, prospective,
observational study, in seven hospitals belonging to SACYL Public
Health Network (Castilla y León Autonomous Community, Spain).
Inclusion criteria were diagnosis of relapsing–remitting MS
(RRMS), age above 18, Expanded Disability Status Score (EDSS)
of 0–6.5, two or more relapses in the previous 3 years, and naı̈ve
status beginning treatment with IFNB. Polymorphisms of TNFA
(transition G-A in position -238 and G-A in position -308 of its
promoter) and IL6 (transition G-C in position -174 and G-A in
position -565) were determined. After 2 years follow-up, patients
were classified as responders or non-responders based upon clinical
criteria, relied on the presence of relapses, increase of disability, or
both. Correlation between responding status with each polymorphism was tested.
Results: 24 patients (14 females, 10 males, ratio 1:4) were included. Mean age was 35.4 ± 9.6 years (range 22–54). 60.9%
were considered responders (neither relapse nor disability increasing).
We observed increases in the A allele of TNF-308 (OR 9.61, p 0.05)
and in the A allele of IL6-565 (OR 5, p 0.05) in the non-responders
group.
Conclusion: These results in a small, but clinically homogeneous
population indicate that polymorphic variations of pro-inflammatory
cytokines TNFA and IL6 might play a role as a prognostic marker of
efficacy of IFNB1b in RRMS.
Study supported by a grant from Bayer Schering Pharma.
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P583
The timed 25-foot walk as an outcome measure
for clinical trials in multiple sclerosis: further evidence
that a 20% change is clinically meaningful
J. Hobart, A. Blight, F. Lynn, N. Putzki
Peninsula School of Medicine and Dentistry (Plymouth, UK); Acorda
Therapeutics, Inc (Hawthorne, US); Biogen Idec (Maidenhead, UK);
Biogen Idec (Zug, CH)
Objective: The timed 25-foot walk (T25FW) is often measured in
multiple sclerosis (MS) clinical trials. Meaningful interpretation of
these studies requires a clear understanding of what change in
walking speed (WS) is clinically important for people with MS.
Although 5 studies have suggested this value is C20%, none has
examined the relationship between change in WS and change in a
rating scale measuring self-reported walking ability. This relationship
can now be studied using 2 phase 3 trials of prolonged-release (PR)
fampridine (dalfampridine in the US) which concurrently measured
WS (T25FW) and a self-reported ability questionnaire (12-item MS
Walking Scale [MSWS-12]) off and on treatment.
Methods: MS patients were randomly assigned to PR fampridine
10 mg (n = 343) or placebo (n = 190) twice daily for 9–14 weeks.
T25FW was measured 4 times pre-treatment and 4 times on-treatment. The MSWS-12 was completed by patients twice pre-treatment
and 4 times on-treatment. We computed T25FW and MSWS-12
change scores from mean pre- to mean on-treatment. A 6-pt change
on the MSWS-12 was used as the threshold for clinically meaningful
change as this was a conservative estimate derived from seven
independent studies.
Results: First, we examined change data for everyone (n = 533).
People who walked C20% faster (n = 138) had a mean MSWS-12
improvement of 8.4 points. People who didn’t walk 20% faster
(n = 395) had a mean MSWS-12 worsening of 0.1 points
(p \ 0.001). Next, we examined the mean MSWS-12 change score
when people were grouped by change in walking speed using 10%
increments (e.g. C0 to \10% change) from -20 to +40%. Increased
walking speed was associated with a step-wise increase in mean
MSWS-12 change score for these groups. The meaningful mean
MSWS-12 change [6 points was first seen in the group of patients
who had a C20% to \30% increase in walking speed. Finally, we
examined the treatment groups. More people randomized to prolonged-release fampridine (33%) than placebo (14%) had a C20%
increase in WS (p \ 0.001).
Conclusions: Improvements C20% in objectively measured
walking speed were associated with clinically meaningful (C6-point)
improvements in subjectively measured walking ability. These data
provide further evidence that a change in walking speed of C20% on
the T25FW is clinically meaningful for people with MS. They also
provide evidence that clinically meaningful benefits in walking were
observed in 33% of people treated with prolonged-release fampridine.
Funding for this study was provided by Acorda Therapeutics,
editorial support by Biogen Idec.
P584
Evaluation of a multiple sclerosis disease progression
composite in AFFIRM patients
L. Balcer, A. Zhang, R. Hyde
University of Pennsylvania (Philadelphia, US); Biogen Idec Inc.
(Weston, US)
Objectives: To evaluate a composite measure of sustained disability
progression in multiple sclerosis (MS) patients.
123
Methods: While the Expanded Disability Status Scale (EDSS) is
currently the most widely used measure of disability in MS clinical
trials, it may not capture all aspects of disability and typically requires
a large study to detect treatment effects. The MS Functional Composite (MSFC) and low-contrast letter acuity (LCA) assess changes in
ambulation, upper limb function, cognition, and vision. Use of a
composite including EDSS, MSFC, and LCA may provide a more
complete measure of disability and require a smaller study. This post
hoc analysis used data from the 2-year, placebo-controlled AFFIRM
trial of natalizumab monotherapy in relapsing MS (n = 627 for natalizumab; n = 315 for placebo). Progression was defined as EDSS
progression, C1.0-point increase from a baseline EDSS score C1.0 or
a C1.5-point increase from a baseline EDSS score of 0 sustained for
3 months; MSFC individual component progression, C15% worsening sustained for 3 months; and visual function progression, 7-letter
reduction in LCA (2.5% contrast) sustained for 3 months. A log-rank
test of equality of survival curves was used for sample size
calculations.
Results: In AFFIRM, natalizumab reduced the risk of 3-month
sustained EDSS progression by 42% (HR = 0.58; 95% CI = 0.43,
0.77; P \ 0.001). Cumulative probability of EDSS progression at
2 years was 17% (natalizumab) versus 29% (placebo). On the basis of
these EDSS results, demonstration of treatment effect in a 1:1 study
with 90% power would require 524 total patients. Natalizumab also
reduced the risk of 3-month sustained composite progression (EDSS,
MSFC, and LCA) by 33% (HR = 0.67; 95% CI = 0.56, 0.80;
P \ 0.001). The cumulative probability of composite progression at
2 years was 51% (natalizumab) versus 67% (placebo). On the basis of
these results, a 1:1 study using a composite measure with 90% power
would require 380 total patients. A similar pattern was observed for
6-month sustained outcome.
Conclusion: While the estimated effect is different than that for
EDSS progression alone, a composite measure of sustained disability
progression (including EDSS, MSFC components, and LCA) continued to demonstrate the effect of natalizumab treatment. Such a
composite measure may provide a more complete assessment of
disability and also allow for the use of a smaller sample size in future
MS studies.
This study was supported by Biogen Idec Inc. and Elan Pharmaceuticals, Inc.
P585
Predictive value of short-term clinical outcomes
on long-term mortality in multiple sclerosis: data
from the interferon b-1b 21-Year long-term follow-up
study
D. Goodin, G. Cutter, A. Reder, G. Ebers,
M. Kremenchutzky, J. Oger, D. Langdon, K. Beckmann,
M. Rametta, V. Knappertz
University of California (San Francisco, US); University of Alabama
(Birmingham, US); University of Chicago (Chicago, US); John
Radcliffe Hospital (Oxford, UK); London Health Sciences Centre
(Ontario, CA); University of British Columbia (Vancouver, CA);
University of London (Surrey, UK); Bayer Schering Pharma AG
(Berlin, DE); Bayer HealthCare Pharmaceuticals (Wayne, US); Bayer
HealthCare Pharmaceuticals (Montville, US)
Objective: To examine the predictive value of short-term (2 years)
clinical trial outcomes on all-cause mortality in the 21-year long-term
follow-up (21Y-LTF) study, which investigated the fate of patients
21 years after their participation in the original randomized controlled
trial (RCT) of interferon b-1b (IFNB-1b) in multiple sclerosis (MS).
S151
Methods: The vital status of patients who participated in the RCT
was determined. Clinical and MRI variables at Year 2 of the RCT
were examined in unadjusted and adjusted Cox proportional hazard
regression models as potential predictors of mortality.
Results: At a median of 21.1 years after RCT enrolment, 98.4%
(366/372) were identified and 81 deaths recorded (21.8%). As previously reported, those originally randomized to IFNB-1b had a
significant reduction in all-cause mortality over LTF compared with
placebo [hazard ratio (HR) = 0.560, P = 0.0272]. In the unadjusted
explorations, change in EDSS score from baseline to Year 2, annualised relapse rate (ARR) at Year 2, and MRI T2 activity at Year 2
were significantly associated with a prolongation of the time from
pivotal trial randomization to death (P = 0.0383, P = 0.0359, and
P = 0.0236, respectively). In addition, some baseline clinical and
MRI disease parameters were predictive of the time from pivotal trial
randomization to death, although neither change in T2 burden of
disease from baseline to Year 2 nor change in MRI third ventricular
width size from baseline to Year 2 were significantly associated with
mortality outcome. In the adjusted Cox models (ie, each covariate
plus treatment), the IFNB-1b treatment effect on mortality was
retained (HR range 0.46–0.63). Here again, the change in EDSS score
from baseline to Year 2 significantly contributed to the prediction of
the time to death after pivotal trial randomization. Neither this variable nor the ARR at Year 2, however, significantly modified the
observed treatment-related effect of IFNB-1b on mortality outcome.
Conclusions: Because IFNB-1b is known to impact short-term
clinical outcomes and is itself associated with reduced mortality,
some association between the 2-year on-study variables and mortality
is anticipated. However, the important point here is that these associations were additive to the impact of therapy. Thus, over and above
any impact of IFNB-1b, greater disease activity and greater disease
progression during the RCT was associated with a lower likelihood of
being alive at the time of the 21Y-LTF study.
This study was supported by Bayer HealthCare Pharmaceuticals,
Montville, NJ, USA.
P586
Predictive factors for multiple sclerosis in patients
after isolated optic neuritis
I. Yazici, N. Kale, J. Agaoglu, E. Idiman, Y. Zorlu
Izmir Tepecik Educational and Research Hospital (Izmir, TR);
Istanbul Bakirkoy Educational and Research Hospital (Istanbul, TR);
Istanbul Apex Hospital (Istanbul, TR); Izmir Dokuzeylul University
(Izmir, TR)
Objective: Identifying the factors that determine multiple sclerosis
(MS) development in clinically isolated syndromes (CIS) is of great
importance with regards to a disorder such as MS which has a high
risk of developing chronic and neurological disability.
Method: In our study, we have investigated MS-conversion
properties appertaining to patients applied due to isolated optic neuritis (ON), based on neurological examination, laboratory, MRI,
visual evoked potential (VEP) and cerebrospinal fluid (CSF)
examinations.
Results: 41 patients without any autoimmune, neurological or
comorbid diseases are included in our study. 27 of 41 patients applied
due to isolated ON (65.9%) have converted to definitive MS
according to Mc Donald’s criteria. It was found out that risk of MS
development after isolated ON had been in evident rise in the first
2 years (34.1%), then this risk was sustained with decrease. In VEP
examinations, it was detected that increased latencies of P100
response supported MS diagnosis. In cranial MRI examination, it was
observed that 24 patients (88.9%) diagnosed with lesion in both T2
and FLAIR incisions converted to MS. MS conversion have occurred
in six patients (54.5%) with a number of lesion lesser than three,
and in 18 patients (100%) with a number of lesions higher than three
or above. In this respect, it was found out in Cranial MRI examination that presence and excessiveness of white matter lesions in
T2/FLAIR dominated incisions were one of the factors to anticipate
conversion from ON to MS. In our study, 17 of 20 patients diagnosed oligoclonal bands (OCBs) positive in CSF (85%), and 2 of 8
patients diagnosed OCBs negative (25%) have converted to definitive MS. This finding has suggested that OCBs examination in CSF
may be considered as one the factors that will determine MS conversion beforehand.
Conclusion: Identifying prognostic factors that determine MS
development in isolated ON and other CIS is of great importance.
Therefore, patient selection for early treatment, and consideration of
early immunomodulatory and other treatment options at first for
identifying those prognostic factors may be required.
P587
MS-like white matter lesions: what is multiple sclerosis
really—and what is it not?
L. Ramió-Torrentà, R. Robles, J. Gich, A. Quiles,
G. Laguillo, D. Genı´s
Dr. Josep Trueta University Hospital (Girona, ES)
Introduction: The widespread use of MRI in medicine has led to an
increased awareness of the number of patients with incidental white
matter pathology in the central nervous system (CNS). Some of these
patients are asymptomatic whereas others have unspecific neurological symptoms. The evolution of such patients with respect to their
risk of developing multiple sclerosis (MS) is unclear.
Objective: To perform MRI and other studies on a cohort of
subjects with CNS white matter lesions referred to our MS Unit and
describe the wide range of clinical presentations. To follow-up their
clinical and radiological evolution over a 2-year period.
Methods: Clinical examination, MRI, CSF, evoked potentials,
right-left shunt studies and the evolution of these patients.
Results: Fifty-three subjects were analysed (11 men) with a mean
age of 45.6 years. Eight patients were asymptomatic or consulted for
headaches. Nineteen patients had a history of migraine. 15% had no
Barkhof-Tintore MR criteria, 15% had C 3 criteria and 70% had 1 or
2 criteria. Of the 37 patients on whom a lumbar puncture was performed, only two were found to have positive oligoclonal bands in the
CNS. Right-left shunt was detected in 15 (45%) of 33 subjects on
whom transcranial Doppler and echocardiography were performed.
Extensive blood analyses were conducted without any systemic or
neurological immune diseases being detected. During the follow-up
(mean 2.5 years) one patient was diagnosed as having MS and
another as having acute disseminated encephalomyelitis. The
remaining 51 patients did not fulfil either clinical or radiological time
dissemination criteria to diagnose MS.
Conclusion: Most patients with MS-like white matter lesions have
an MRI indicating a low risk of conversion to multiple sclerosis.
Some patients are asymptomatic whereas others have unspecific
neurological symptoms. The high proportion of cases associated with
migraine and right-left shunt may indicate another pathological
mechanism for these lesions. Very few cases had positive oligoclonal
bands. The vast majority of our cohort remained stable during the
short 2-year period in which their evolution was followed and there
were no MS criteria for dissemination in time. In the absence of a
specific surrogate marker to differentiate between benign MS and no
MS, the diagnosis and evolution of these patients will only become
clear over time.
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P588
Progression of brain atrophy over 10 years and its
relationship to disability change in patients
with multiple sclerosis
A. Giorgio, M.L. Stromillo, M.L. Bartolozzi, F. Rossi,
M. Battaglini, A. Blandino, L. Guidi, P. Maritato,
A. Federico, N. De Stefano
University of Siena (Siena, IT); Hospital of Empoli (Empoli, IT)
Objective: To evaluate in patients with multiple sclerosis (MS) the rate of
brain atrophy, regarded as an important marker of disease progression,
and its relationship with change in clinical disability over 10 years
Methods: As part of an ongoing project, we studied here 47
clinically definite MS patients, 32 females and 15 males,
age = 37.3 ± 10 years, with a relapsing–remitting (RR) (n = 40),
secondary progressive (SP) (n = 5) and primary progressive (n = 2)
course, disease duration = 4.7 ± 6.1 years. Seven normal controls
(NC), 5 females and 2 males, age = 39.7 ± 5.6 years, were also
included. Percent Brain Volume Change (PBVC) between the two
time points was computed using SIENA, part of FSL.
Results: In MS patients, EDSS was 2.5 ± 1.7 at baseline and
3.4 ± 2.2 at follow-up (p \ 0.001). Disease course turned into SP in 3
RR subjects. Relapses over 10 years were 3.8 ± 3.6, with a relapse rate
of 0.4 ± 0.4. T2-lesion volume was 5.4 ± 5 cc at baseline and 8 ± 7 cc
at follow-up (p \ 0.001). PBVC over 10 years was higher (p = 0.03) in
MS patients (-5% ± 2.2%) than in NC (-3% ± 1.2%). This value was
higher in patients with relapse rate C 0.5 (n = 14) than in those with
relapse rate \0.5 (n = 33) (-6.1% ± 2.5% versus -4.3% ± 1.9%,
p = 0.02). In all patients, PBVC correlated with EDSS change (r = 0.30, p = 0.04). This correlation was closer in patients with an EDSS
change C0.5 (r = -0.57, p = 0.001).
Conclusion: This study represents the first report of a long-term
follow-up on brain atrophy in MS. Decrease in global brain volume
over 10 years was on average -5% in MS patients and -3% in NC.
The rate of brain atrophy was related to clinical progression, particularly in those patients with higher frequency of relapses and
progressing disability. Overall, these data suggest that long-term
global brain atrophy changes may provide a valuable outcome of
longstanding clinical disability and progression in patients with MS.
P589
Brain atrophy and fatigue in relapsing–remitting
multiple sclerosis patients: a 3T study
A. Bisecco, A. Gallo, R. Sacco, M. Della Corte, R. Docimo,
M. Cirillo, D. Corbo, L. Lavorgna, S. Cirillo, S. Bonavita,
F. Esposito, G. Tedeschi
Second University of Naples (Naples, IT); Magnetic Resonnance
Imaging Research Centre (Naples, IT)
Background: Fatigue is a frequent complaint of patients with multiple
sclerosis (MS) but little is known about the origins of MS-associated
fatigue. Recent evidences suggest that MRI measures of Gray Matter
(GM) damage could be the best predictor of fatigue in MS.
Objectives: the aim of the present study was to explore the relationship between 3T MRI markers of brain tissue loss and fatigue complaints
in a population of relapsing–remitting MS (RRMS) patients.
Methods: We studied 52 RRMS patients and 30 healthy controls
(HCs), matched for age, gender and education. All subjects underwent a
clinical evaluation including the Expanded Disability Status Scale
(EDSS) and Fatigue Severity Scale (FSS). The patients were subdivided
in two groups on the basis of their average FSS score: the low-fatigue MS
123
(LF-MS) group (FSS B 4) and the high-fatigue MS (HF-MS) group
(FSS C 5). Conventional T2 and FLAIR images as well as 3D highresolution T1 images were acquired on a 3T scanner within 2 weeks of the
clinical evaluation. T2 lesion load (LL) was computed by means of a
semiautomatic method (MIPAV, freesoftware). Brain and GM atrophy
were computed using SIENAX. For the statistical analysis we considered
two whole brain atrophy measures, the Brain Parenchymal Fraction
(BPF) and the Normalized Brain Volume (NBV) as well as two regional
brain atrophy measures, the Normalized Peripheral Gray Matter Volume
(NPGMV) and the Normalized Gray Matter Volume (NGMV).
Results: All atrophy measures were significantly reduced in
RRMS patients when compared to HCs. Significant differences were
also found when comparing LF-MS group versus HF-MS group with
lower values in NBV (p = 0.03) and NGMV (p = 0.04) in the HFMS group. There was no correlation between fatigue and NBV as well
as NGMV in the HF-MS group.
Conclusion: The results of the present study further support the
role of GM damage in MS-associated fatigue. Our data suggest that a
crucial role could be played by the deep GM, since NGMV but not
NPGMV was significantly reduced in HF-MS group. Larger studies
with a longitudinal design are warranted to further clarify the most
relevant MRI-measures associated to fatigue in MS.
P590
Added prognostic value of early cervical cord MRI
in patients with CIS and multiple sclerosis
A. Kronenberger, S. Haufe, E. Thomae, J.-P. Schneider,
F. Then Bergh
University of Leipzig (Leipzig, DE)
Objectives: Clinically silent white matter lesions on cranial magnetic
resonance imaging (MRI) provide prognostic information. The extent
to which this is true for cervical spinal cord lesions is unknown. We
sought to determine the added prognostic value of cervical cord MRI
in patients with clinically isolated syndrome (CIS) or early Multiple
Sclerosis (MS).
Methods: 76 patients with CIS or clinically definite MS underwent
cervical spinal cord MRI at initial evaluation, within 1 year from first
symptoms. After a mean follow-up of 2.8 ± 1.7 years, we recorded
disease evolution and current disability (EDSS; 9-HPT, timed 25-ftwalk in 31 patients). Progression index (PI: EDSS at follow-up
divided by years from first symptoms) was chosen as the primary
outcome variable, and sample size estimate based on this variable.
Results: 35 patients had cervical cord lesions (CCL+), 41 had no
lesions (CCL-) at baseline. The distribution of known predictors for
disease progression (gender, initial symptoms, presence of cranial and
especially infratentorial MRI lesions, CSF oligoclonal bands) did not differ
between groups. At follow-up, CCL+ patients were significantly more
severely affected than CCL- patients (EDSS 2.7 ± 1.9 vs. 1.2 ± 1.5;
p = 0.001, ANOVA), had progressed faster (PI 0.97 ± 0.79 vs.
0.49 ± 0.74; p = 0.004), and had a higher MS Severity Scale (MSSS)
score (5.34 ± 2.34 vs. 2.80 ± 2.76; p \ 0.001). In the subset evaluated
by MSFC, CCL+ patients were slower in the timed 25-foot walk (median
9.7 s, IQR 2.7, vs. 7.4 s, IQR 1.1; p = 0.017, Kolmogorov–Smirnov); there
was trend of slower dominant (p = 0.081) and a non-significant difference
in nondominant (p = 0.216) hand function. When subdivided according
to onset symptoms with known prognostic power, CCL+ patients fared
worse in ‘‘optic neuritis’’, ‘‘sensory’’ or ‘‘other’’ onset, although this
reached statistical significance only in the latter group.
Conclusions: Early cervical spinal cord MRI can add prognostic
information in CNS demyelination and thus facilitate counselling and
treatment decisions.
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P591
Frequency of spinal cord lesions and correlation
with clinical presentation of multiple sclerosis
in Latvian patients
L. Elsone, A. Platkajis, G. Karelis, M. Murzina
Riga Stradins University (Riga, LV); Latvian Maritime Medicine
Centre (Riga, LV)
Objectives: The clinical and pathological manifestations of multiple
Sclerosis (MS) are due to areas of demyelination which occur
throughout the white matter of the central nervous system. Aim of this
study was to analyze areas of high T2 signal characteristic of
demyelination in spinal cord and correlation with clinical manifestation of spinal disturbances.
Methods: Retrospective data of 150 patients (103 female, 47 male)
from Latvian MS data base with clinically definite MS according to
McDonald criteria were analyzed. Only patients with whole spinal
cord scanned and existence of spinal cord lesions in MRI were
included. MRI system of GE SIGNA was operated with magnets at
field strength 1.0 T, using standardized protocols for spinal cord
investigation. Clinical characteristics were analyzed and compared
with radiological findings.
Results: Median age at onset of MS was 31.05 years (total), onset
of spinal manifestation 30.37 years. Duration of spinal MS presentation at the time of MRI examination ranged from \1 month to more
than 10 years (25.2%- \ 6 months, 10.8% within 6 months to 1 year,
14.4% [10 years). Spinal cord lesions before clinical manifestation
were found in 6.3% of cases. Total of 54.8% showed only 1, but
38.26% at least 2, and 6.96% [ 3 episodes of spinal disturbances pre
MRI. In cases where only 1 clinical episode of spinal manifestation
was noted duration to MRI was: \ 6 months 33.4%, \1 year
46.1%, [5 years 26.9%. MRI duration [ 1 year: at least 2 spinal
episodes—48.5%, MRI duration [ 10 years and only 1 spinal
relapse- 4 cases. High T2 signal was seen in 88.7% of cervical (C),
58.7% of thoracic (Th), and 50% of combination of both (C,Th) cords
scanned. Each patient displayed from 1 to 16 lesions, for a total of 701
loci, with average 9.4 lesions/patient, total of C lesions 434, with
average 5.86 lesions/ patient, Th lesions- 267, average 3.58 lesions/
patient. From all lesions 2% were distributed in C2, 12% C3, 10% C4,
9% C5, 9% C6, 7% C7, 4% Th1, 4% Th2, 4% Th10, and 4% Th11
level. The 58% of all patients showed C3, 48% C2, 46% C4, 19.3%
Th2, 18.7% Th11, 17.3% Th10, 20% C1, 8.7% Th6, and 5.3% L1
lesions. Total of 49.2% patients having 1 spinal relapse showed 2-4,
11.1%- more than 8 cord lesions, with average amount 4.9 lesions/
patient.
Conclusions: More frequently lesions were located in C cord rather
than Th cord. Most of the patients having spinal cord lesions have had at
least one clinical episode showing spinal cord dysfunction.
P592
Early brain MRI activity may predict disability
progression after 5 years in relapsing–remitting
multiple sclerosis patients treated
with immunomodulatory treatments
M. Romeo, V. Martinelli, E. Perego, F. Sangalli,
G. Liberatore, M. Rodegher, M. Sormani, G. Comi
University Hospital San Raffaele (Milan, IT); University of Genoa
(Genoa, IT); University Vita-Salute San Raffaele (Milan, IT)
Objectives: In multiple sclerosis (MS) clinical practice our main
objective is the early identification of patients who will not benefit of
a first-line immunotherapy (non-responders). Many attempts have
been made to identify reliable predictive factors of response to
immunomodulatory therapy (IMT), but so far none has been validated
by a long-term follow-up (f-up). The aim of the present study is to
investigate the value of early brain MRI as a possible predictor of
long-term clinical disability progression.
Methods: This is an observational single-center study carried out
on a large cohort of relapsing–remitting multiple sclerosis (RR-MS)
patients treated with IMT at the MS Center of the San Raffaele
Institute in Milan between 1996 and 2005. All patients were treated
with one of the different types of b-interferon (IFN) or with Glatiramer Acetate (GA) for at least 5 years. The patients were evaluated
every 3 months, while brain MRI was performed 6–12 months after
starting the IMT, and afterward every 1–2 years in most patients. We
defined as ‘‘non-responder’’ the patients with an EDSS confirmed
progression of C1.5 point at 5-year f-up. The patients without a
clinical relapse and disability progression \ 1.5 have been considered
as ‘‘responder’’. Finally ‘‘partial responders’’ were defined the patients
without any significant EDSS worsening (EDSS changes lower than
1.5 point), who had at least one relapse.
Results: Six hundred sixty-eight patients of a total of 864 patients
completed 5-year f-up. Brain MRI was performed 6–12 months after
starting IMT in 396 patients. 61 patients (15.4%) presented 3 or more
‘‘active’’ lesions (new T2 or T1 Gd+) at brain MRI scan, when
compared with baseline MRI. The presence of more than two
‘‘active’’ lesions was associated with a higher risk of disability progression after 5-year f-up [Odds Ratio (OR) non-responder vs.
responder 4.0; 95% CI 1.6–10, p = 0.003]. The risk increases 2.6
times comparing partial and non-responders versus responders
(p = 0.006).
Conclusions: Brain MRI performed 6–12 months after starting
IMT may be a useful and sensitive tool in predicting the response to
treatment and for the early identification of patients who will develop
long-term disability progression. An alternative treatment should be
early considered in patients with ‘‘active’’ MRI, before the occurrence
of irreversible neurological disability.
P593
Evidence for resource allocation of the brain
to preserve cognitive function with progression
of relapsing–remitting multiple sclerosis—Insights
from a longitudinal fMRI study
M. Loitfelder, F. Fazekas, E. Aspeck, M. Jehna, S. Ropele,
S. Fuchs, M. Wallner-Blazek, A. Pichler, K. Petrovic,
R. Vollmann, C. Neuper, R. Schmidt, C. Enzinger
Medical University Graz (Graz, AT); Karl Franzens University Graz
(Graz, AT)
Objectives: Cognitive dysfunction is common in multiple sclerosis
(MS). While cerebral reorganization has been shown to at least partially limit deficits in the sensorimotor system in MS, it has been
suggested only recently that similar processes might occur in cognitive domains (Loitfelder et al. Neurology 2011 in press). However,
these conclusions are based on an extrapolation from cross-sectional
observations in different phenotypes of MS. We here set out to use
functional MRI (fMRI) and a cognitive paradigm to address this
question more directly, by repeatedly assessing changes in cerebral
activation patterns over time in MS patients and relating these findings to healthy controls.
Methods: Fifteen relapsing–remitting MS patients (age: x = 30.9
years, SD = 9.8, min–max = 17–49, EDSS: x1 = 1.7, SD1 = 1.4,
min–max1 = 0–3.5; 92 = 1.1, SD2 = 1.2, min–max2 = 0–3.5) and
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15 healthy controls (HC; age: x = 26.3 years; SD = 4.7; min–
max = 20–37; p = 0.122) twice underwent a stimulus-response discrimination task of varying difficulty at 3.0 T, separated by a time
interval of at least 12 months (9months = 19.8; SD = 1.4; min–
max = 14–23), at a 3.0 T magnet. All subjects underwent initial
extensive neuropsychological testing including the Brief Repeatable
Battery of Neuropsychological Tests (BRB-N) and the Wisconsin
Card Sorting Test (WCST); with patients being assessed also at follow-up.
Results: Consistent with own previous work in a different cohort,
we observed stable network activation in both groups in bilateral
mesial and dorsolateral frontal, parietal, insular, basal ganglia, and
cerebellar regions at baseline. Patients and HC did not differ significantly regarding cognitive function at baseline concerning all
subtests of the BRB-N and the WCST. On baseline fMRI, patients
versus HC showed increased activation in the insula, the precuneus,
the anterior cingulate, the supramarginal gyrus, and the cerebellum.There was no significant deterioration in cognitive function over
time in the patients. Nonetheless, while brain activation patterns were
constant in HC, patients demonstrated a shift of activation from left
parietal default network ‘‘activation’’ at rest to the task within the left
parietal lobe at follow-up.
Conclusion: In the absence of behaviorally detectable cognitive
changes, we here provide evidence for cerebral reorganization in
cognitive domains at baseline and for resource allocation over time in
patients with mild RR-MS, changes that are not present in controls.
P594
Combination of magnetic resonance lesions
and relapses as a perfect surrogate for disability
in interferon-treated relapsing–remitting multiple
sclerosis
M. Sormani, D. Li, B. Stubinski, P. Cornelisse, S. Rocak,
N. De Stefano
University of Genoa (Genoa, IT); University of British Columbia
(Vancouver, CA); Merck Serono S.A. (Geneva, CH);
University of Siena (Siena, IT)
Objective: In multiple sclerosis (MS), the ultimate aim of therapies is
to prevent the accumulation of irreversible disability. This may be
difficult to assess given the short time course of clinical trials.
Magnetic resonance imaging (MRI) outcomes and relapses are often
used as surrogates of disability progression in MS studies, but their
validity remains controversial. We sought to validate, at the individual-patient level, the number of MRI active lesions and clinical
relapses as surrogate endpoints for worsening of disability measured
over the course of MS clinical trials.
Methods: Individual-patient data from a large placebo-controlled
clinical trial of subcutaneous interferon b-1a in patients with
relapsing–remitting (RR) MS [the Prevention of Relapses and
Disability by Interferon b-1a Subcutaneously in Multiple Sclerosis
(PRISMS) study] were analysed. The four Prentice criteria were
applied to evaluate surrogacy of MRI active lesions and relapses
assessed in the shorter term (1 year) for disability worsening
[measured as Expanded Disability Status Scale (EDSS)] over the
follow-up (2 years).
Results: All Prentice criteria were satisfied. Treatment reduced by
31% the proportion of patients with EDSS worsening over 2 years,
reducing the number of MRI active lesions by 61%, and the number
of relapses by 36% over 1 year. Both 1-year MRI lesion activity and
relapses, when considered independently, accounted for more than
60% of the treatment effect on EDSS worsening over 2 years.
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A combination of 1 year MRI lesion activity and relapses explained
100% of the treatment effect on EDSS worsening over 2 years.
Conclusion: A combined measure of shorter-term changes in MRI
active lesions and relapses over the first year of interferon therapy
fully estimated the corresponding effect on worsening of disability
over 2 years in patients with RRMS, and appears to be a perfect
surrogate for clinical disability progression over a longer term when
evaluating the therapeutic effect of interferon.
This work was supported by Merck Serono S.A.
P595
Cognitively preserved MS patients demonstrate
functional differences in processing neutral
and emotional faces
M. Jehna, C. Langkammer, M. Wallner-Blazek, C. Neuper,
M. Loitfelder, S. Fuchs, M. Khalil, F. Fazekas, C. Enzinger
Medical University Graz (Graz, AT); Karl-Franzens University Graz
(Graz, AT)
Background: The recognition of emotional facial expression is crucial
for adequate social behaviour. Previous studies suggested deficits in
multiple sclerosis (MS) patients in emotion recognition, but it was not
clear if this was due to separate emotional processes or dependent on
cognitive abilities. In addition abnormal recognition processes of
neutral facial stimuli per se might also cause deficits in the recognition of emotional expressions. We here set out to further explore these
open questions using functional MRI (fMRI) in MS patients testing
whether functional differences are distinct for separate emotions, and
assessing the relationship to cognitive (attentive) working processes.
Methods: Fifteen low disability relapsing-remitting MS patients
(5 m/10f, mean age 29.5 ± 9.6 years, mean education 13.8 ± 2.9
years, median EDSS 2.0) and 15 age-, gender, and educational-level
matched healthy controls (HC) underwent behavioural and clinical
assessments, structural MRI, and fMRI including presentation of
neutral, scrambled, angry, disgusted, and fearful faces, and houses.
Results: In absence of differences in the neuropsychological performance and the ability to accurately recognize emotional facial
expressions, MS patients relative to HC demonstrated excess fMRI
activations during facial recognition. These concerned the occipital
fusiform gyri and the anterior cingulate cortex for neutral faces versus
houses and the posterior cingulate cortex (PCC) and precuneus for
anger and disgust contrasted to neutral faces.
Conclusions: These results suggest that in the context of MS
pathology excess activation including the attentive network (PCC)
might be important for accurate processing of higher order visual
stimuli suggesting dependence between emotional and cognitive
working processes.
P596
Comparison of MRI lesion location in multiple sclerosis
patients with and without oligoclonal bands
in the cerebrospinal fluid
V.D. Karrenbauer, R. Prejs, K. Imrell, A. Glaser,
T. Masterman, J. Hillert
Karolinska University Hospital (Stockholm, SE)
Nordic multiple sclerosis (MS) patients are in 95% of cases positive
for oligoclonal IgG bands (OCB) in the cerebrospinal fluid (CSF).
OCB+ and OCB patients are similar with regard to clinical characteristic- and indistinguishable with regard to fulfillment of the
S155
Barkhof criteria on brain MRI-but differ in MRI lesion distribution
patterns. Intriguingly, OCB MS is not associated with the best known
MS risk factor-the HLA class II allele DRB1*15-but rather with the
HLA-DRB1*04 allele. Greer et al. (2008) have shown that carriage of
HLA-DRB1*04 is correlated with MRI lesions in the brainstem and
cerebellum, owing to T-cell immunoreactivity to specific epitopes of
myelin antigens. In 2009, Huttner et al. reported that 11 OCB cases
differed from 22 OCB+ cases, with the former group displaying a
higher frequency of juxtacortical lesions and a lower frequency of
infratentorial lesions than the latter group.
Objectives: To compare fulfillment of the Barkhof criteria, singly
and cumulatively, in OCB+ and OCB MS patients. To investigate the
influence of HLA alleles on MRI lesion location in OCB + and OCB
MS patients.
Methods: For this retrospective case–control study, 40 OCB and
60 OCB+ MS patients attending Stockholm MS Center were selected
according to the following criteria: (1) they had been examined
with brain MRI according to the ‘‘STOP MS’’ protocol; (2) their
OCB status was known; and (3) they had been genotyped for
HLA-DRB1*15 and HLA-DRB1*04. HLA-DRB1 was genotyped
by sequence-specific PCR using a commercial kit. Hyperintense
T2-weighted lesions on MRI were assessed manually by a blinded
clinical neuroradiologist in assigned neurotopographical locations:
juxtacortical, subcortical, deep white matter, periventricular or infratentorial. The total number of gadolinium-enhanced lesions,
hypointense T1 lesions was quantified. Chi-squared and Fisher’s exact
tests were used to evaluate associations between the categorized
variables.
Results: The OCB and OCB + MS patient groups were similar
with regard to demographical variables (mean and median age at
MRI; and male/female ratio). Preliminary results revealed no differences with regard to fulfillment of the Barkhof criteria between the
OCB and OCB+ groups. Statistical analysis is ongoing in order to
address our remaining objectives.
Conclusion: This study will provide new insight into a better
understanding of the influence of immunological and genetic profiles
on MRI lesion location in MS patients.
This work has been supported by financial grant from Karolinska
institute and Stockholm County Council.
P597
Internal jugular vein stenosis cannot be found
in patients with relapsing-remitting multiple sclerosis
G. Panczel, K. Kovacs, R. Horvath, C. Rozsa
Peterfy Sandor University Hospital (Budapest, HU);
Jahn Ferenc Hospital (Budapest, HU)
Objectives: The idea that chronic cerebrospinal venous insufficiency
(CCSVI) may cause multiple sclerosis (MS) has been proposed.
Angiography and angioplasty of the internal jugular veins (IJV) of
MS patients has been performed in several angiological centers. Our
goal was to determine if hemodynamically significant stenosis of IJVs
of MS patients could be demonstrated.
Methods: 62 patients with RR-MS (mean age 36 years; 18 male,
44 female) were examined by duplex ultrasound in two centers.
Morphologic and hemodynamic parameters were measured in the
proximal (near to skull base), middle and distal parts (just above the
subclavian vein junction) of IJVs both sides.
Results: Mean cross-sectional area in the proximal part of IJV was
0.39 and 0.33 cm2 (right and left side respectively), the medial part
0.5 and 0.48 cm2, the distal part 1.12 and 0.82 cm2, the latter values
differed significantly (p \ 0.001). Time averaged mean velocities
(TAMV) in the proximal part were 16.6 and 16.3; the middle part 16.3
and 16.2; the distal part 13.5 and 15.9 cm/s. Volume flows (VFs) in
the proximal part were 352 and 305; the middle part 429 and 380; the
distal part 815 and 591 ml/min, the latter values differed significantly
(p = 0.01). Only in 1 patient was the maximal VF as low as 116 ml/
min, all other patients had substantially higher values. Reflux was
observed in the distal part near the venous valves (136 and 116 ms)
and in few cases in the middle part (98 and 115 ms) of IJV but not in
the proximal part. We have not found correlation between Tr and VF.
The IJVs were scanned in color and power mode from the most
proximal part to the distal part just below the junction of subclavian
vein: no hemodynamically significant stenosis has been found.
Conclusion: Doppler sonography is a suitable method for the
investigation of IJV. We have not found any hemodynamically significant stenosis. Although about 50% lumen reduction was detected
in two patients secondary to venous valve intrusion, the VF
was [300 ml/min both cases proving sufficient venous outflow
despite the moderate morphological stenosis. No correlation was
found between Tr and VF suggesting that reflux is not an indicator of
venous insufficiency but the consequence of venous valve movement.
Based on these results catheter-dilatation does not seem to be a
rational approach in the treatment of MS.
P598
EEG background activity is correlated to a measure
of cognitive speed in multiple sclerosis
M. Hardmeier, I.K. Penner, Y. Naegelin, R. Zimmermann,
F. Hatz, L. Kappos, C. Schindler, S. Rueegg, P. Fuhr
University Hospital Basel (Basel, CH); University of Basel
(Basel, CH)
Objective: In neurodegenerative diseases, slowing of the EEG background activity has been shown to correlate with cognitive decline.
Cognitive symptoms and fatigue can have a serious impact on quality
of life in MS patients. Quantification is based on neuropsychological
testing and questionnaires. An objective and quantitative measure
would be desirable.
Methods: 62 subjects (42 patients) were assessed on cognition
with the paced auditory serial addition task (PASAT), the Multiple
Sclerosis inventory cognition (MUSIC) and the symbol digit modalities test (SDMT), and on fatigue applying the fatigue scale for
motor and cognitive functions (FSMC). EEG was recorded from 256
electrodes. The peak and mean frequency in the 6.0–14.0 Hz band
was analysed in 2 9 13 frontal and 2 9 15 parieto-occipital electrodes (spectral resolution 0.25 Hz). Group differences and
correlations were tested non-parametrically at a significance level of
p \ 0.05. Median values are reported.
Results: Patients had a median EDSS of 2.5 (range 1.0–4.0), and
mostly relapsing-remitting disease (93%). Median age was 40.5
(range 23.4–50.0) in patients, and 39.6 (range 20.0–48.0) in healthy
controls. Groups differed significantly, with patients having a slower
frontal mean frequency (8.9 vs. 9.3 Hz), higher scores in the FSMC
(50 vs. 31 total score) and lower perfirmance in the SDMT (51 vs. 65).
Frontal mean frequency was significantly correlated to SDMT
(r = 0.28), whereas correlations to the MUSIC, PASAT, fatigue or
clinical measures were not significant.
Conclusion: This preliminary analysis points to a potential role of
spectral EEG