Neuroscience Day 2011
Amanda Rabquer - Screening Laboratory Studies in the Initial Evaluation of Peripheral Neuropathy
Introduction: The initial evaluation of the patient presenting with symptoms and signs consistent with a neuropathy
can be daunting at first given the multiple available diagnostic tests, both laboratory and electrodiagnostic. Clinical
uncertainty exists about which specific tests should be performed in the initial evaluation of patients presenting for
symptoms consistent with peripheral neuropathy. The ANN guideline statement regarding the initial evaluation of
distal symmetric neuropathy, did not address the many of the tests, including rheumatologic studies and thyroid
function tests, which are frequently ordered in evaluation of this condition. Given the current health care climate,
which places a premium on cost-effective medicine, further studies are needed to determine which tests should be
performed.
Methods: We performed a retrospective cross sectional analysis. Patients, whose presenting complaint was
peripheral neuropathy were identified and demographic information was collected. In addition, we obtained
information on suspected etiology, the presence or absence of pain, weakness on examination, demyelinating
features on electrodiagnostic testing, any nerve conduction study abnormality, any electromyography evidence of
denervation outside of the foot attributed to the neuropathy, history of thyroid or rheumatic disease, and
signs/symptoms of thyroid or rheumatologic disease. Information on characteristics suggestive of more rare
neuropathy subtypes (so called warning signs of other neuropathy subtypes other than DSP) were collected
including: acute or relapsing onset, motor predominant symptoms, non-length dependent symptoms, prominent
autonomic features and asymmetry of symptoms. Those patients who had blood tests for thyroid and rheumatologic
conditions were identified and the results were documented as normal or abnormal. If abnormal, we documented
whether the test changed the suspected etiology or management of the patient. Based on the small numbers of
abnormal results of the patient population that we reviewed, we were unable to perform any mutlivariate models or
univariate analysis.
Results: Screening thyroid function studies were rarely abnormal in our study (7.8%). When the results were
abnormal, the suspected etiology of the peripheral neuropathy was not changed based on the abnormal result. In
contrast, screening rheumatologic studies were frequently abnormal in our study (45.9%), but only occasionally
changed the suspected etiology of the peripheral neuropathy or patient management (3.1%). The most frequently
abnormal rheumatologic laboratory studies were: ESR (29.2%), CRP (28.1%), ANA (14.5%) and ANCA (13.0%).
Discussion: We found that thyroid studies were frequently checked, but rarely abnormal, and when abnormal did not
change the suspected etiology of the patient’s neuropathy. In comparison, rheumatologic screening laboratory
studies were frequently abnormal in the cohort, but when the results were abnormal, the management of the patients
was affected in only a small percentage. Based on the results of our study, we would not suggest ordering screening
thyroid or rhematological laboratory studies in the initial evaluation of DSP.
Anthony Wang –
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Less than 5% of patients
survive more than 2 years and new therapeutic strategies are desperately needed. The Notch signaling pathway
plays a crucial role in regulation of multi-potent stem cells in the development of the human central nervous system.
In addition, it has been shown that GBMs contain a sub-population of cancer stem cells (CSCs) that demonstrate
elevated Notch activity. However, it is as yet unknown whether Notch pathway blockade could target CSCs in GBM.
Recent studies have shown that primary cultures of GBM propagating as neurospheres more accurately replicate the
infiltrating growth patterns seen in the native brain tumor, and contain CSCs with stem-like multi-potent capacity.
Among solid tumors, brain CSCs are by far the mostly well-studied. This is due, at least in part, to the well-developed
neurosphere culture systems. We have obtained four GBM neurosphere lines from Dr. Angelo Vescovi. Other GBM
models we study include several lines of primary patient-derived GBMs engrafted intracranially in
immunocompromised mice obtained from Dr. Sean Morrison, as well as three primary low-passage GBM cultures.
Finally, we have obtained a p53-/-;NF1-/- transgenic mouse GBM model from Dr. Yuan Zhu, which shows elevated
Notch activity and propagates as neuroshperes in vitro. We are, therefore, well positioned to further address this
exciting new area of cancer biology.
In the current application, we propose a series of studies using these models, focusing on targeting GBM CSCs by
Notch pathway inhibition (gamma secretase inhibitor-18), both in vitro and in vivo. We will begin by examining the
mechanism by which the Notch signaling pathway regulates these brain CSCs, and design a realistic combination
therapeutic regimen to facilitate its clinical translation. Specific Aim #1 is to determine effects of Notch pathway
inhibition on CSCs in GBM in vitro and in vivo. Specific Aim #2 is to identify the target genes that mediate the effects
of Notch inhibition on GBM CSCs. Specific Aim #3 is to examine the effects of Notch inhibition in combination with
Akt inhibition and/or common chemo-radiation therapies on GBM CSC-derived mouse tumor models. Success in the
current proposal will not only enhance our understanding CSC biology in general, but also has the potential for direct
translational impact on GBM treatment in our patients.
Daniel Orringer - The Application of Coherent Raman Imaging to Brain Tumor Surgery
Introduction: Achieving a maximal, safe tumor cytoreduction is the central goal of all brain tumor resections.
However, surgeons lack a uniform, objective method for determining when all safely resectable tumor has been
removed. Here, we describe the ex vivo and in vivo application of coherent Raman imaging, an innovative, non-toxic,
stain- and label-free modality capable of delineating the tumor-brain interface on a cellular level.
Methods: Coherent anti-Stokes Raman microscopy and stimulated Raman scattering microscopy were employed to
evaluate the histologic borders of the tumor-brain interface fresh specimens from the following models: 9L gliomas,
MDA-MB-211 implanted breast cancer metastases, and human glioblastoma xenografts. Subsequently, brain tumor
window animals were used to image brain tumor margins in vivo. Imaging conditions were tuned to detect CH2 and
CH3 molecular vibrations and hemoglobin autoflorescence. Coherent Raman imaging data were compared to
corresponding hematoxylin and eosin-stained specimens.
Results: Coherent Raman imaging provides subcellular resolution of brain tumor tissue. The difference in cellularity,
nuclear to cytoplasmic ratio and vascularity between tumor tissue and normal brain is readily apparent with coherent
Raman imaging. On this basis, coherent raman imaging is useful for delineating brain tumor margins both ex vivo and
in vivo. Histologic and biochemical differences between tumor and normal brain imaged with coherent Raman
imaging mimic those demonstrated by traditional hematoxylin and eosin staining. There was no adverse effect of
coherent Raman imaging on tissue histology or the well being of the animals being imaged.
Conclusions: Coherent Raman Imaging is a safe and effective method for delineating tumor tissue from normal brain
on the cellular level in animal brain tumor models. Translational studies designed to integrate coherent Raman
imaging into brain tumor surgery are warranted. Coherent Raman imaging may ultimately become the basis of a
method to objectively judge the completeness of a brain tumor resection on a cellular level.
Dustin Nowacek - The Prognostic Implications of Elevated Parathyroid Hormone in Amyotrophic Lateral Sclerosis
Introduction: Over the past several years, an association between elevated parathyroid hormone and amyotrophic
lateral sclerosis (ALS) has been described. It is unclear whether this is an epiphenomenon of disease or a part of the
pathophysiology of ALS. In order to better understand this association we present a cohort of ALS patients, and
report the frequency of elevated intact parathyroid hormone (iPTH) levels and primary hyperparathyroidism in this
group. Furthermore, we assessed whether or not elevated iPTH levels were associated with altering the survival of
ALS subjects.
Methods: A retrospective chart review of patients diagnosed with ALS from September 1994 to December 2009 was
undertaken. This study was approved by the local institutional review board with a waiver of informed consent. To
be included in this study, an iPTH level must have been drawn at the time of initial diagnosis at our institution and the
subjects were deceased at the time of our chart review. ALS subjects with renal disease or elevated glomerular
filtration rate (GFR) were excluded. A Cox proportional hazards regression model was used to assess the
relationship between serum iPTH levels and survival. The same regression model was then adjusted for variables
known to be associated with poor ALS survival, specifically age and bulbar onset symptoms.
Results: 113 ALS patients were identified who met the inclusion and exclusion criteria. The median age was 61
years, 50% (56) were female, 66% (75) had limb-onset disease, and the median time from symptom onset to
diagnosis was 377 days. Of the 113 patients, 12 (11%) had elevated iPTH levels. Calcium levels were available in
112 of these patients. Out of these 112 patients, 4 had elevated calcium levels (3 of which also had elevated iPTH
levels). Therefore, 2.7% of ALS patients in our cohort had serum markers consistent with primary
hyperparathyroidism. Interestingly, elevated iPTH levels were associated with a trend towards reduced survival with
a hazard ratio (HR) of 1.25 (95% CI 0.99, 1.58). After adjusting for age and bulbar-onset symptoms, this association
persisted with a HR of 1.21 (95% CI 0.96, 1.52) and 1.20 (95% CI 0.95, 1.52), respectively.
Discussion/Conclusions: Although just missing statistical significance, we found a clear trend between elevated iPTH
levels and decreased ALS survival, which persisted when adjusting for age and bulbar-onset symptoms. Thus, it may
be possible that elevated iPTH levels adversely alter the ALS disease course. Interestingly, experiments assessing
human motor nerve, axonal organelle trafficking have demonstrated a similar pattern of abnormal organelle trafficking
in both motor nerve axons exposed to PTH and human ALS motor nerve axons. Further investigations are needed to
better assess the relationship between elevated iPTH levels and ALS pathophysiology.
Our study was not without limitations. Unfortunately, not every patient diagnosed with ALS at our institution had an
iPTH level drawn. In our patient population, it is also unclear if the elevated iPTH level with normal calcium was
secondary to a mild primary hyperparathyroidism, or secondary hyperparathyroidism for another process, such as
vitamin D deficiency.
Emily Lehmann - Deep Brain Stimulation in the Central Nucleus of the Amygdala Decreases Consumption of
Sucrose Pellets in a Reversible Manner
Deep brain stimulation (DBS) is a technique that may be used to modulate the function of a target nucleus. In studies
of DBS in the VIM thalamus, high frequency stimulation (HFS) has been found to block the function of the target,
while low frequency stimulation (LFS) has been shown to activate the target (1). We evaluated the effect of DBS in
the central nucleus of the amygdala (CeN) on consumption of sucrose. This nucleus participates in the control of
feeding, and is believed to be involved in processing the reward value of food, particularly food containing fat or sugar
(2,3). We hypothesize that inactivation of the CeN will lead to decreased sucrose pellet consumption.
Sprague-Dawley rats (N=2) were stereotactically implanted with bilateral stimulating electrodes in the CeN. The
animals were tested in an instrumental-response paradigm in which a lever pressed by the animal delivers sucrose
pellets. The animals underwent 45 minute trials of stimulation of varying frequencies: 0 Hz (baseline), 20 Hz (LFS),
and 130 Hz (HFS). The numbers of lever contacts, sucrose pellets delivered, and pellets consumed were recorded.
Video of the trials was analyzed to evaluate for motor and behavioral changes.
Animals undergoing stimulation in the CeN consumed fewer sucrose pellets, compared to no stimulation. Both pellet
consumption and lever contacts quantitatively decreased with stimulation, though there was no change between high
and low frequency. Cage crosses, an indication of locomotor activity, did not decrease with stimulation. Upon
cessation of stimulation, animals immediately returned to baseline levels of lever pressing and pellet consumption.
Additional testing and statistical assessment is in progress.
Stimulation in the CeN quantitatively decreased consumption of sucrose in a reversible manner, without causing
changes in other observed behavior.
Emily Rainey-Barger - Superimposed viral infection recruits CD8+ T cells to the CNS that exacerbate EAE
Epidemiological data support a link between viral infection and multiple sclerosis (MS), but the underlying cellular and
molecular mechanisms through which such infections might initiate or alter the disease remain unknown. Likewise,
few studies have examined the effects of a superimposed viral infection on experimental autoimmune
encephalomyelitis (EAE), an important mouse model of MS. We find that an otherwise asymptomatic alphavirus
infection introduced directly into the brains of mice during the pre-clinical phase of active immunization EAE
significantly accelerates disease progression compared to sham-inoculated controls. While peripheral T cell
responses and the proportions of CD4+ T cells in spinal cords of infected and sham-inoculated EAE mice are similar,
the CD8+:CD4+ ratio and the total number of CD8+ T cells increase in the spinal cords of infected EAE hosts.
Furthermore, this infection does not exacerbate EAE symptoms compared to sham inoculation in CD8-deficient
hosts. These findings suggest that CD8+ T cells activated by a superimposed alphavirus infection promote
autoimmune mechanisms that drive EAE pathogenesis, possibly via production of pro-inflammatory cytokines or
cytotoxic molecules. Our dual disease paradigm will allow us to determine how acute viral infection influences
peripheral and central nervous system (CNS) immune responses during EAE as well as to clarify the role of CD8+ T
cells in autoimmune CNS demyelination.
Eric Adelman - Gender differences in the primary prevention of stroke with aspirin
Aspirin is used to prevent ischemic stroke and other types of cardiovascular disease (CVD). Seven trials of aspirin
for primary prevention of stroke and other cardiovascular events have been performed, but three of these did not
include women. Data from these trials, and one meta-analysis, suggest that aspirin prevents myocardial infarction
(MI) in men and stroke in women, although the findings in women were driven by the results of a single large study
and a subsequent meta-analysis did not find a gender difference. The reasons for the possible gender differences in
aspirin’s effectiveness are not entirely clear.
Gary Gallagher - Asymmetry of Peripapillary Retinal Nerve Fiber Layer Thickness and Motor Symptoms in Parkinson
Disease
Background: Idiopathic Parkinson’s disease (PD) commonly presents asymmetrically. Visual symptoms are common
among the non-motor phenomena in PD and may relate to post-mortem findings of retinal pathology. Visual function
loss, including impaired contrast sensitivity, color discrimination, motion perception abnormality and temporal
sensitivity are partially modulated by dopamine. With recent technologic advancements, quantitative morphology of
gross retinal histology in humans can be measured in vivo using time domain optical coherence tomography (OCT).
There is little information about retinal thinning in PD in relationship to the asymmetry of clinical motor symptoms. We
hypothesized that RNFL thinning is related to clinical asymmetry of parkinsonian motor symptoms.
Methods: Nineteen patients clinically diagnosed with PD (13M/6F, mean age 63.5 ± 5.7 (range 53-74), Mean UPDRS
motor score: 21.9 ± 10.4 (range 8-50) underwent near infrared Fourier-domain OCT (RTvue, Optovue, Inc; Fremont,
California) and tonometry. Using the RNFL scan protocol, four circular scans at a diameter of 3.45mm were targeted
around the optic nerve head. The clinically most affected body side was determined on the basis of the UPDRS
examination and clinical history. The RNFL of the side corresponding to the clinically most affected body side was
compared to the RNFL of the contralateral eye.
Results: Nine patients had predominant left-sided body involvement and ten patients had predominant right-sided
body involvement. There was a modest difference in RNFL thickness, significant in the temporal segment, of the eye
corresponding to the clinically most affected (thinner) versus the least affected body side (P=0.03, uni-tailed). RNFL
ipsilateral to the most affected body site had significant correlations with the UPDRS rigidity (R=-0.49, P=0.03) but not
with tremor, bradykinesia or axial scores. A subgroup analysis on less severely affected patients, suggested a more
pronounced difference.
Conclusion: Findings suggest a modest relationship between asymmetry in peripapillary retinal nerve fiber layer
thickness and motor symptoms in PD. Processes underlying asymmetric neurodegeneration in PD may also be
present in parkinsonian retinopathy.
Jared Mott - Knowledge of Epilepsy Among Elementary School Teachers
Epilepsy is relatively common among Elementary School aged children. It is therefore important that teachers have
ready access to information about epilepsy. In the past 10 years there have been only a few studies in the United
States addressing teachers’ knowledge of epilepsy, with an emphasis on attitudes toward students with epilepsy.
There have been no studies published that specifically address teachers’ confidence in their knowledge of epilepsy,
or from where they obtain information. We conducted a survey of Washtenaw County Elementary School teachers
to learn about their self-reported confidence in their knowledge about epilepsy, factors that might influence the degree
of confidence, where they have obtained information about epilepsy in the past, and from where they would prefer to
obtain information. Results are pending data collection (Survey went out March 28,2011).
Jennifer Strahle - Effect of amusement park rides on programmable shunt valve settings
Introduction:
Programmable valves may be susceptible to environmental factors such as magnetic fields and g-forces.
Passengers on an amusement park ride may be subjected to elevated g-forces and newer rides may impart a
magnetic field through the use of linear induction motors (LIMs) and magnetic brakes.
Methods:
Two different magnetically programmable valves (type A, n=10; type B, n=9) of varying resistance settings were
tested in 2 trials on 6 rides (2 with LIMs, 2 with magnetic brakes and 2 without magnetic technology). A control ride
with maximum g- force less than 2 g was also tested. Magnetic fields were measured on all rides using a
magnetometer.
Results:
The setting of valve type A changed in 7.5% (3/40) of trials on rides without magnets and in 2.5% of trials (2/80) on
rides with magnetic technology. Valve type B changed 2.7% (1/36) of the time on rides without magnets and 5.5%
(4/72) of the time on rides with magnets. There was a total change of 4.2% for valve type A and 4.6% for valve type
B on rides with g-forces ranging 3.7-4.6 g compared with a 0% change for both valves on a control ride with
maximum g-force less than 2 g. The maximum measured magnetic field on all rides ranged from 0.5 to 0.9 guass
and was negligible.
Conclusion:
An amusement park ride with a large g-force may change the setting of a magnetically programmable valve and is
independent of magnetic technology.
Julie M Rumble - G-CSF plays a critical role in EAE by driving granulocyte expansion in the bone marrow and
mobilization into the circulation
Experimental autoimmune encephalomyelitis (EAE) is a murine model of neuroinflammatory demyelination that is
frequently used as a model for multiple sclerosis (MS). We have previously shown that CXCR2+ granulocytes are
critical for blood-brain-barrier (BBB) breakdown and the development of neurological deficits in MOG-immunized
mice. However, pathways controlling the mobilization and recruitment of granulocytes to the CNS remain unclear. In
the current study we investigated the mechanisms by which granulocytes are regulated during EAE. EAE is induced
in C57BL/6 mice by active immunization with an epitope of myelin oligodendrocyte glycoprotein (MOG35-55)
combined with adjuvants. Bordetella pertussis toxin (PT) administration at days 0 and 2 post-immunization (p.i.) is
required for clinical manifestation of disease. Serum levels of granulocyte-colony stimulating factor (G-CSF), a
granulocyte growth and mobilization factor, were measured by ELISA, and cell numbers in blood and bone marrow
were assessed by flow cytometry.
We found that granulocytes expanded dramatically in the bone marrow and bloodstream by day 3 p.i., which was
preceded by a spike in systemic levels of G-CSF. Sustained expression of G-CSF and accumulation of circulating
monocytes and granulocytes only occurred in mice given PT, suggesting that this accumulation was mechanistically
linked to disease. In addition, treatment of actively immunized mice with an antagonistic G-CSF receptor-Fc fusion
protein prevented clinical EAE. We postulate that induction of G-CSF by active immunization drives the expansion
and mobilization of bone marrow derived granulocytes that ultimately mediate BBB breakdown, thereby facilitating
CNS infiltration by leukocytes. Our findings are consistent with the observation that individuals with MS experienced
severe exacerbations upon the administration of recombinant G-CSF following bone marrow transplantation.
Furthermore, this suggests granulocyte growth and mobilization factors may be novel therapeutic targets in
autoimmune demyelinating disease.
Katiuska Molina - Luna The physiological basis of Ataxia
How does cerebellar dysfunction contribute to the development of ataxia? We use a mouse model deficient in
caytaxin to address this question. Caytaxin is a protein encoded by the Atcay gene and expressed in neural tissue.
Caytaxin deficiency in humans causes a rare form of ataxia termed Cayman ataxia. In mice, mutations in the Atcay
homolog can result in ataxia. Atcayswd/swd mice are easily recognizable because they are smaller than their wild
type counterparts; they have a pronounced ataxic phenotype that is detectable as early as day 10, and are unable to
reach adulthood dying of dehydration and starvation at around day 21. Brain morphology in these mice is normal
suggesting a defect in brain function underlies the motor phenotype. We used the patch-clamp technique to record
from Purkinje neurons in the cerebellum and have observed three different patterns of intrinsic firing in Purkinje cells
of the Atcayswd/swd mice. Roughly 70% of cells lack spontaneous firing in spite of exhibiting a normal membrane
potential. These cells also fail to maintain repetitive spiking in response to injected current. Approximately fifteen
percent of cells show a reduced spontaneous firing frequency. These cells too, are unable to sustain repetitive firing
following depolarizing current injections. Fifteen percent of Purkinje neurons have a firing pattern similar to that of wild
type neurons. These neurons exhibit repetitive firing of reduced amplitude following current injection. Sodium
channels are critical for initiation and propagation of action potentials in neurons. Voltage-gated sodium channels α
subtypes Nav1.6 located in the initial segments of Purkinje cells, have been suggested to mediate repetitive firing in
Purkinje neurons. We hypothesized that the abnormalities in Purkinje cell firing in the Atcayswd/swd mice reflect an
alteration in Nav1.6 channel expression. Preliminary results of Western blot analysis and immunofluorescence
studies indicate that a reduction in expression of the Nav1.6 channels in Purkinje Cells of Atcayswd/swd mice. We
suggest that the etiology of ataxia in the Atcayswd/swd mice is secondary to a defect in Purkinje neuron firing due to
reduced levels of Nav1.6 channels.
Katherine Wilson - Assessment for Sleep Disordered Breathing in Children with Cleft Palate Repair
Background: Children with a history of cleft palate repair (CPR) may be at increased risk for sleep disordered
breathing (SDB), but how to screen or assess for SDB among these patients has not been well studied.
Objectives: To examine among children with CPR both the frequency of SDB and the effectiveness of a symptombased questionnaire screen for SDB.
Methods: Children aged 5-16 years with CPR were recruited from a tertiary care university hospital craniofacial
anomalies clinic. Parents completed a validated 22-item Pediatric Sleep Questionaire (PSQ) SDB scale. A score
≥0.33 (one-third of symptom-items endorsed) identifies increased risk for SDB in children with no history of CPR.
Subjects underwent overnight PSG including esophageal pressure (Pes) monitoring, and SDB was defined by an
apnea-hypopnea index (AHI) >1 or a minimum Pes ≤ -20 cm H2O.
Results: Thus far, 31 children with CPR have been studied, with a mean age of 9.9 ±3.1 years, including 16 boys
(52%). Among the 31 children, 17 (55%) screened positive for SDB on the PSQ-SDB scale. Of these 17 children, 13
(76%) had AHI>1, another 2 (12%) had a minimum Pes worse than -20 cm H2O, and the remaining 2 did not have
SDB. However, among the 14 children who screened negative for SDB, 10 (71%) had SDB on PSG. In total, 25 of
31 children (81%) had PSG-defined SDB (n=23 [74%] with AHI>1). Sensitivity and specificity of the PSQ-SDB scale
for PSG-defined SDB were 60 and 67%, respectively.
Conclusion: In this initial sample from a craniofacial anomalies clinic, the PSQ-SDB scale did not show good
sensitivity or specificity for PSG-defined SDB. In this setting, different thresholds for the PSQ-SDB scale may show
improved utility, but evaluation by PSG should be considered for all patients because more than 80% may have some
level of SDB.
Khoi Than - Perioperative Management of a Neurosurgical Patient Requiring Antiplatelet Therapy: Case Report
BACKGROUND AND IMPORTANCE: In patients who undergo neurovascular stent placement with postoperative
dual antiplatelet therapy to prevent in-stent thrombosis, there is currently no protocol for balancing the risk of acute
stent thrombosis and bleeding when subsequent urgent neurosurgical procedures are required. We detail
perioperative management of dual antiplatelet therapy in a patient with a recently placed neurovascular stent
requiring an urgent neurosurgical procedure.
CLINICAL PRESENTATION: A 66-year-old man with a dolichoectatic aneurysm of the basilar artery was treated with
Pipeline stent. Postoperatively, he was placed on aspirin and clopidogrel to prevent in-stent thrombosis. One month
after the procedure, his neurological status declined secondary to obstructive hydrocephalus. His condition
necessitated urgent placement of a ventriculoperitoneal shunt, despite needing dual antiplatelet therapy for the flowdiverting Pipeline stent.
Aspirin and clopidogrel were discontinued 7 days prior to the planned shunt placement. To minimize time off
antiplatelet therapy, aspirin was immediately replaced with ibuprofen. Eptifibatide was then started 3 days prior to
surgery. The ibuprofen/eptifibatide bridge was discontinued at midnight prior to surgery. Aspirin was restarted on the
first postoperative day and clopidogrel was restarted on the second postoperative day.
The patient tolerated shunt placement without excess bleeding or hemorrhagic complication. During the remainder of
his hospital course, no evidence of stent thrombosis or intracranial hemorrhage was noted.
CONCLUSION: Management of antiplatelet prophylaxis for neurovascular stent thrombosis in patients requiring
urgent neurosurgical procedures can be successfully achieved by bridging aspirin and clopidogrel with ibuprofen and
eptifibatide in the preoperative period.
Kyle Sheehan – Levetiracetam versus phenytoin for seizure prophylaxis in subarachnoid hemorrhage
It is standard of care to treat patients with subarachnoid hemorrhage with anti-seizure medications to decrease the
risk of early post-hemorrhage seizures. Phenytoin has a number of undesirable characteristics including multiple drug
interactions, may induce fever, therapeutic-level monitoring. Additionally, there is some data that suggests the use of
phenytoin has a negative impact in out-come following subarachnoid hemorrhage. Alternatively, levetiracetam
(Keppra) does not require serum monitoring or have significant pharmacokinetic interactions. In this study, the
frequency of seizures, vasospasm and modified Rankin scores were compared in patients treated with either
phenytoin or levetiracetam.
Methods Data were retrospectively collected in 159 consecutive subarachnoid cases treated at the University of
Michigan. Of those patients, 112 patients were treated with levetiracetam monotherapy and 67 were treated with
phenytoin monotherapy. The cases were reviewed for evidence of radiographic or clinical vasospasm , seizure
during hospitalization, recurrent hemorrhage and modified Rankin score at time of discharge.
Results
There were no significant changes in the incident of vasospasm, recurrent hemorrhage, seizure or Modified Rankin
score at time of discharge. Levetiracetam and phenytoin and equally effective in preventing early onset seizures
following subarachnoid hemorrhage with equal incidence of vasospasm, recurrent hemorrhage and no significant
effective on modified Rankin score at time of discharge.
Lindsey De Lott - Mycophenolate mofetil as initial immunotherapy for ocular myasthenia gravis
Background: Ocular myasthenia gravis (OMG) may produce debilitating diplopia or ptosis leading to significant visual
disability. Symptomatic treatment with pyridostigmine is frequently ineffective and immunosuppressive therapy with
corticosteroids can have serious side-effects. Mycophenolate mofetil (MMF), a steroid-sparing agent, has been used
in generalized MG. We present 19 cases of OMG treated with MMF as a first-line agent.
Methods: We performed a retrospective analysis of 19 patients with isolated OMG treated with MMF as first-line
therapy. Diagnosis was confirmed by either single fiber electromyography (SFEMG) or elevated acetylcholine
receptor antibody (AchR-Abs) titers. Patients with prior or concurrent use of other immunomodulating therapies were
excluded. All were treated with 1000-3000mg total daily. Response to therapy was assessed using the Myasthenia
Gravis Foundation of America post-intervention status scale.
Results: Mean age was 65 years (range 33-84 years). Fifteen were men and 4 were women. Five were diagnosed by
SFEMG and 14 by AchR-Abs. None had thymoma. Average total follow up time was 18 months (range 6-61 months).
All patients improved (mean=4.8 months; range 1-10 months). Eight patients (44%) reached pharmacologic remission
(PR), 7 (39%) were minimal manifestations (MM)-1, and 3 (17%) were MM-3. In total, 15 (83%, both PR and MM-1
groups) patients improved to the degree that they were no longer symptomatic, eye misalignment could only be
detected on examination, and pyridostigmine was no longer necessary. There were no complications related to MMF.
Conclusion: Corticosteroids can have serious side-effects and many older patients and physicians are reluctant to
use steroids for OMG. We found no published series of the use of MMF as an initial immunotherapy agent in OMG.
Most of our patients improved with MMF to the point that they were no longer symptomatic and pyridostigmine was
not necessary. When eye misalignment was present, it could only be detected on detailed neuro-ophthalmologic
examination. Therefore, MMF may be effective as initial immunotherapy in patients with disabling OMG.
Matthew Hastings – A SURVEY OF ELECTROMYOGRAPHERS' ALTERATION OF NEEDLE EMG EXAMINATION
PRACTICES IN RESPONSE TO THE PERCEPTION OF PATIENTS' PAIN
Introduction: Pain is frequently cited as a cause of incomplete or inconclusive needle electromyography (EMG)
studies. Little is known about what methods are commonly used to alleviate pain or how often studies are truncated
due to physicians’ perceptions of patients’ pain.
Objectives: To determine the frequency with which electromyographers alter their EMG practices because of patients'
pain.
Methods: A ten question survey was sent electronically to approximately 3500 members of the American Association
of Neuromuscular and Electrodiagnostic Medicine (AANEM). Physicians were asked the frequency at which they
limit, avoid, and/or abort an EMG secondary to patients’ pain, and what strategies they use to limit this pain. Logistic
regression analysis was used to ascertain which demographic variables influence the alteration of an EMG.
Results: Of the 417 electromyographers responding, 67.1% limit or alter their standard EMG practice, 57.4% avoid
specific muscles, and 43% abort an examination early in at least 10% of studies due to the perception of patients’
pain. Most responders use a pre-examination explanation of what to expect, conversational distraction, or verbal
encouragement during EMGs. A minority of physicians use other methods to decrease pain, and these physicians do
not have a significantly different rate of altering studies. Physicians are less likely to limit studies with increasing years
of experience.
Conclusion: Electromyographers often alter EMGs due to their perception of patients’ pain, but employ few methods
to alleviate this pain. Further investigation of effective pain management during EMG is needed to minimize the
number of altered EMGs.
Neena Jamwal - SPECTRUM OF EEG ABNORMALITIES IN ANGELMAN SYNDROME
Introduction: Angelman syndrome is a rare genetic disorder characterized by developmental delay, severe mental
retardation, paroxysmal laughter, craniofacial dysmorphism, EEG abnormalities and epilepsy. The diagnosis of
Angelman syndrome is confirmed by identification of a deletion of maternally derived 15q11-13 chromosome.
Epilepsy is common in children with this condition, and characteristic EEG findings have been described in the
literature in Angelman syndrome
Case Reports: We present 3 patients with genetically confirmed Angelman syndrome with characteristic EEG
features.
Case 1: A 6 year old girl with developmental delay, was diagnosed with Angelman syndrome at 34 months of age
following a positive methylation PCR study. She was seen for episodes concerning for seizures. Her EEG showed
high amplitude, rhythmic, 3-4 Hz activity, > 200uv, prominent in the bioccipital regions with spikes. There were
prolonged runs of high amplitude rhythmic 2 Hz activity, > 200uv over bifrontal region.
Case 2: A 25 month old girl presented with developmental delay and occasional episodes of staring. She was
diagnosed with Angelman syndrome on the basis of positive methylation PCR study at 21 months of age. EEG
showed runs of high amplitude rhythmic 3-4 Hz activity, >200uv in the bioccipital regions with spikes.
Case 3: A 4 year old girl with developmental delay, Angelman syndrome and epilepsy, was seen for increased
frequency of seizures. She had been diagnosed with Angelman syndrome on the basis of positive methylation PCR
study and FISH analysis at 15 months of age and developed epileptic seizures at 19 months of age. EEG showed
runs of generalized, high amplitude rhythmic notched slow waves, 2 Hz in frequency. There were brief runs of
rhythmic, medium to high amplitude sharply contoured delta at 3 Hz over occipital regions.
Discussion: The EEG findings of Angelman syndrome are characteristic interictal findings, and should not be
considered as ictal patterns. Additionally, such EEG findings may help identify patients who present with
developmental delay and epilepsy, and suggest an etiologic diagnosis that can then be confirmed with genetic
testing. .
Rahul Karamchandani - Choice of anticonvulsant prophylaxis and incidence of delayed seizures, delayed cerebral
ischemia, and poor outcome after aneurysmal subarachnoid hemorrhage
Background
Anticonvulsant prophylaxis is widely used following aneurysmal Subarachnoid Hemorrhage (aSAH). Various
retrospective studies report the rate of seizures after aSAH as 4-18%1. The risk of delayed or in-hospital seizures
may be even lower when anticonvulsant prophylaxis is used2. It is not known whether the choice of anticonvulsant
used for prophylaxis may have an impact on subsequent risk of seizures or poor outcomes after aSAH.
Objective
To compare the incidence of in-hospital seizures, delayed cerebral ischemia, poor neurological outcomes, and death
in patients with aneurysmal subarachnoid hemorrhage exposed to anticonvulsant prophylaxis with Levetiracetam and
Phenytoin.
Methods
The medical records of patients with SAH admitted to the University of Michigan Neurosurgical Intensive Care Unit
between January 2005 and April 2009 were reviewed. Patients with non-aneurysmal etiology, age <18 years, nonavailability of CT scan within 24 hours of onset, modified Fisher grade 0-1, and those who died within 72 hours, were
excluded. The incidence of in-hospital seizures, delayed cerebral ischemia (DCI), poor functional outcomes, and
death in patients treated with Phenytoin versus Levetiracetam for anticonvulsant prophylaxis in patients with aSAH
were compared. The modified Rankin scale (mRS) was used to assess functional outcome at follow-up. Follow-up
was assessed between 6 weeks and 6 months from discharge or from date of last contact and carried forward. Poor
neurological outcome was defined as a mRS>2 at follow up. Chi-square or Fishers Exact test were used to identify
the presence of a univariate association between categorical patient variables and the outcomes of interest.
Univariate associations of continuous patient variables with a normal distribution were assessed with the independent
sample 2-tail Student t-test and continuous variables with non-normal distributions were assessed with the MannWhitney U test. Significant (P<0.05) univariate variables were included in a multivariate logistic regression model to
identify the independent variables associated with the outcomes of interest.
Results
The records of 148 patients with aneurysmal SAH were reviewed. The mean age was 56 years (SD 13 years). There
were 112 (76%) women and 36 (24%) men. Of the 136 patients who did not have a seizure prior to initiation
anticonvulsant prophylaxis, 113 patients (83%) received Phenytoin, while 101 (74%) received Levetiracetam. Only 3
of 148 (2%) patients had a seizure following initiation of anticonvulsant prophylaxis. Two patients were on Phenytoin
only and one had been switched to Levetiracetam from Phenytoin. There was no statistically significant difference in
the number of patients receiving Levetiracetam (1/101, 1%) and Phenytoin (2/113, 2%) who had an in-hospital
seizure (p=1.00). Fifty-two of 148 (35%) patients had delayed cerebral ischemia. Neither treatment with Phenytoin
(DCI in 43 of 125 exposed to Phenytoin versus 9 of 23 not exposed to Phenytoin, p=0.8) nor treatment with
Levetiracetam (39 of 106 exposed to Levetiracetam versus 13 of 42 not exposed to Levetiracetam, p=0.6) were
statistically significant risk factors for the development of DCI. Of 148 patients, 61 (41%) had poor functional
outcome (mRS>2) at follow up. Forty-three of 106 patients (40%) treated with Levetiracetam versus 18 of 42 patients
(43%) never treated with Levetiracetam had mRS>2 at follow up (p=0.94). Forty-six of 125 patients (37%) treated
with Phenytoin versus 15 of 23 patients (65%) never treated with Phenytoin had mRS>2 at follow up (p=0.02).
Increasing age, higher Hunt and Hess grade, modified Fisher grade, presence of intracerebral hematoma, and nonuse of phenytoin were found to be significant (P<0.05) univariate associations with poor functional outcome. When
these factors were included in a multivariate logistic regression analysis, age (OR 1.06, 95% CI 1.03-1.10, p=0.0008),
Hunt & Hess grade 1 (OR 0.20, 95% CI 0.04-0.93, p=0.04), presence of intracerebral hematoma (OR 3.13, 95% CI
1.15-8.5, p=0.02), and non-use of Phenytoin (OR 3.05, 95% CI 1.04-8.93, p=0.04) were found to be statistically
significant associations with poor functional outcome at follow-up. In contrast, early anticonvulsant exposure alone
(Phenytoin compared to Levetiracetam) was not independently associated with improved functional outcome (OR
1.56, 95% CI 0.68-3.67).
Conclusions
In-hospital seizures are rare when anticonvulsant prophylaxis with Phenytoin or Levetiracetam is used after
aneurysmal subarachnoid hemorrhage. The choice of anticonvulsant does not influence the risk of delayed cerebral
ischemia but the use of Phenytoin may be associated with better functional outcomes at follow-up compared to the
use of Levetiracetam alone. Prospective, randomized, placebo-controlled trials are required to determine the value of,
and optimal agent (if any), for anticonvulsant prophylaxis after aneurysmal subarachnoid hemorrhage.
Rani Singh - Long-term outcome of epilepsy surgery patients with intracranial electroencephalography monitoring
Objective: In this observational study we assess the long-term outcome of epilepsy patients who had intracranial
electroencephalography monitoring to localize the epileptogenic zone.
Methods: We retrospectively reviewed the clinical data for 92 adult patients who underwent intracranial subdural
electrode monitoring sessions between 1991 and 2006.
Results: The mean age at onset of epilepsy was 14±10 years. The mean age at surgery was 39±10 years, with a
mean duration of epilepsy of 19±11 years. The mean duration of monitoring was 10±4 days. Seventy-two patients
(78%) had discrete lesions identified on magnetic resonance imaging, 55 (60%) of which were temporal. Resections
included a) lesionectomy (n=38; 41.3%), b) lesionectomy and resection of additional epileptogenic zone (n=15;
16.3%), c) limited resection of lesion (n=13; 14.1%), and d) resection of epileptogenic zone in nonlesional patients
(n=15; 16.3%). Eleven patients (12%) did not have a surgical resection, six of whom seizure onset was not
localizable. There were no deaths and seven (8%) major complications: three hematomas, three infections, and one
infarction. The mean duration of follow up was 67±54 months. Thirty eight patients (41%) were seizure-free (Engel
Class I) after surgical resection: 33 lesional and five nonlesional.
Conclusions: Patients who undergo intracranial electroencephalography monitoring represent a distinct group of
intractable epilepsy patients. The epileptogenic focus can be identified in the majority (93%) of patients. Although
surgical resection may be limited by eloquent cortex, many patients experience a significant reduction in seizure
frequency, with a higher rate in lesional patients.
Rob Pace
The identification of biomarkers in multiple sclerosis may lead to further insight into pathogenesis, improved risk
stratification, and the development of novel therapeutics. IL-21 has been indicated as a biomarker for the
development of autoimmunity in relapsing-remitting multiple sclerosis patients treated with alemtuzumab (Campath1H)1. Specifically, higher levels of IL-21 were demonstrated in patients who went on to develop autoimmunity
following treatment with alemtuzumab than in those who did not. We propose that IL-21 levels may be altered in
response to disease activity. In this study, serum samples of patients were obtained from relapsing-remitting multiple
sclerosis patients and normal volunteers on a monthly basis. These patients had serial neurologic exams and brain
MR with gadolinium to assess for disease progression. IL-21 levels were evaluated in the serum using ELISA. The
results were compared between patients whom had active disease and those who did not, as well as between
individuals at the time of active disease and periods of disease quiescence. In this small case-series, there were no
statistically significant differences between serum IL-21 levels between patients or in individual patients with regards
to disease activity. Although this suggests that IL-21 is not a reliable biomarker of disease activity in relapsingremitting multiple sclerosis, larger studies with increased sample sizes may be warranted.
Saju Abraham - Medication withdrawal after epilepsy surgery at U of M
The postsurgical medication withdrawal policy was retrospectively reviewed for 30 adults and children (inclusion
criteria included those aged 16-80) who had epilepsy surgery from 2000-2006. The patients included in this study
were rendered seizure free for at least 3 years after the surgery. Data was obtained purely from medical records. For
1 year after surgery, 70% of the patients were still maintained on the same number of medications. For 2 years after
the surgery, 50% of the patients were maintained on the same amount of medications. Three years after the surgery,
16% of the patients were still maintained on the same amount of medications as they were initially started on. 26% of
patients had their medications dropped by 1 by the first year; 33% by their second year, and 53% by the third year.
3% of patients were discontinued off 2 medications by the first year out from their surgery; 10% of patients by the 2nd
year; and 23% by the 3rd year. These results suggest that appropriate discretion is used for weaning patients who
underwent epilepsy surgery.
Sarah Berini - Evaluating the Effect of Conference Attendence and Evaluations of Medical Knowledge on Residency
In-Service Training Examination Scores in Neurology Residents over the past 4 years
This projects aim is to determine if conference attendence and scores for medical knowledge
on clinical evaluations corrolate with performance on the Neurology Resident In-Service Training examination.
Within ACGME, conference attendence is highly valued and a greater than 70% conference attendence is required.
It is uncertain if this attendence, specifically in the Neurology Department at the University of Michigan
affects performance on the inservice examination. In addition, clinical evaluations are an important part of
resident evaluation and it is uncertain if these evaluations which specifically rate a resident's medical
knowledge corrolate with the in service examination scores. Dr. London, the residency program director,
has access to de-identified compiled scores from the Residency In-service Training Examination for the
past 3 years. In addition, our program assistant has access to resident's clinical evaluations over the past 3 years.
No personal identifiers are present on the Resident In-Service Exam information.
The resident evaluation data has been de-identified prior to the PI's review. In addition,
Dr. London has access to conference attendence over the past 3 years. This information will have
all identifiers removed and will be presented as a class average percentage to the PI.
The information will be statistically analyzed in order to determine if Neurology Residents' conference
attendence and medical knowledge scores on clinical examinations corrolate with performance on
the Neurology In Service Examination Scores over a 3 year period. Other factors, such as program size,
faculty size, length of specific rotations such as EEG and EMG will also be assessed in order
to determine if these changes corrolate with changes on the Neurology In-Service Training Examination Scores.
Shawn Hervey-Jumper - Detection of glioma associated microRNA in patient serum and their inhibitory role in
glioma cell proliferation and tumor formation
Introduction. Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Even with optimal
therapy, more than 70% of GBM patients will die within 2 years of diagnosis. MicroRNAs (miR) are important
regulators of gene expression through posttranscriptional silencing of target mRNA. MicroRNA roles in cell
proliferation, invasion, angiogenesis, and glioma stem cell activity are little known. In this study, we focus on the
expression and function of microRNAs in human gliomas and show that microRNAs are present in bodily fluids
representing new effective biomarkers.
Methods. Using RNA extracted from 15 GBM patient samples and serum collected from 2 glioma patients, miR 338
and miR 542 expression, relative to normal brain and control serum, was examined using RT PCR. Regional miR
expression within a single tumor was identified. A DNA fragment containing the hsa-miR-338-3p and miR-542-5p loci
were amplified and cloned into a lentiviral vector, then transduced into GBM neurosphere lines. MicroRNA and their
downstream target, expression was assessed by RT PCR and western blot. GBM neurosphere growth was examined
in vitro.
Results. Over-expression in miR 338-3p and 542-5p in human GBM neurospheres and primary patient sample was
associated with decreased cell proliferation and neurosphere formation. MiR 338-3p showed increased expression at
the tumors invading periphery, while playing an inhibitory role cell invasion and migration assays. MicroRNA 542-5p
is detectable in the serum of glioma patients and its level is decrease by 50% after tumor removal (relative to the
tumor’s core), remaining low throughout treatment until tumor recurrence.
Conclusions. MicroRNA 338-3p and 542-5p inhibit glioma cell proliferation, migration, and neurosphere formation in
vitro. MicroRNAs are present in bodily fluids and may represent new effective biomarkers in glioma patients.
Sterling Malish - New Parents, Sleep Disruption and Driving: A population at risk?
Introduction
Sleep disturbance is associated with increased risk of motor vehicle accidents (MVAs). New parents experience
significant sleep disturbance, however, the relationship between poor sleep and risk of MVAs or near-miss accidents
has not been studied in this population. This study aims to determine the frequency of motor vehicle-related incidents
in parents of infants and the association of such events with disturbed sleep.
Methods
An anonymous survey was administered to parents of infants <12 months presenting at well-baby visits beginning in
February 2011. The survey elicited demographic data, medical problems, and sleeping habits of parents and infants.
Measures of current parental sleep disturbance included the General Sleep Disturbance Scale (GSDS) and typical
duration of nighttime sleep. The survey also queried driving habits and frequency of sleepy driving, MVAs, and nearmiss accidents (NMAs) since the infant’s birth. Sleepy drivers were defined as subjects reporting driving while sleepy
frequently in the past month.
Results
Of 29 participants thus far, all but one were female, 41% self-identified as sleepy, and half of these reported
sleepiness only since their infants’ birth. NMA’s were reported by 31%. There was no significant difference in
demographics, or total time spent driving between subjects reporting NMAs and those not reporting NMAs.
Unsurprisingly, sleepy drivers were more likely to have shorter sleep duration at night (5.7±1.1 hours vs. 6.8±1.3
hours, p=0.03) and poor sleep quality (100% vs. 60%, p=0.02) compared to non-sleepy drivers. Sleepy drivers were
more likely to have had a NMA (78% vs. 26%, p=0.017). In separate logistic regression models, both sleep duration
and self-reported sleepy driving were independently predictive of NMA (R2=0.21, p<0.05 and R2=0.3, p<0.02).
Conclusion
Almost half of new parents report driving while sleepy and this is strongly associated with having a near-miss
accident. New parents may be a high-risk population for drowsy driving.
Vikas Kotagal - Amyloid and Acetylcholinesterase PET Imaging in Parkinson's disease and reported dream-enacting
behavior
Background: REM sleep behavior (RBD) or dream-enacting behavior is common in Parkinson's disease (PD) but its
pathophysiology remains poorly understood. RBD has been suggested to be a risk factor of dementia in PD. There
have been variable reports regarding abnormal amyloid deposition in patients with Parkinson disease and
Parkinson’s disease with dementia. Our investigation aimed at investigating the association of amyloid deposition,
cholinergic denervation and RBD in a group of Parkinson’s disease patients.
Methods
74 patients with Parkinson’s disease and no to mild cognitive impairment (mean age 65.07.0, range 50-82, 15
males, 16 females; mean Montreal Cognitive Assessment Test score of 26.02.3, range 21-29) underwent
acetylcholinesterase imaging using the [C-11]PMP ligand (18 mCi). A subset (n=21) underwent also dynamic betaamyloid brain PET imaging with Pittsburgh compound B (18 mCi [C-11]PIB), PET studies were performed on a
Siemens ECAT HR+ tomograph in 3D. PIB PET data were analyzed using the Logan graphical method and the
cerebellum as reference region to determine global cortical PIB DV. PMP hydrolysis rates were estimated using the
Nagatsuka method with the striatum as input function. Symptoms of RBD were assessed using the Mayo Sleep
Questionnaire.
Results
29 out of 74 subjects reported positive symptoms of RBD. Those individuals who reported RBD symptoms showed
significantly decreased cortical AChE activity compared to subjects without RBD (0.02250.0038 vs. 0.02450.0026,
t=3.3, P=0.0016) as well as thalamic AChE activity (0.05120.0058 vs. 0.05620.0061, t=3.2, P=0.0019). There
were no significant differences in cortical PIB binding (1.170.18 vs. 1.120.09, t=0.7, ns).
Conclusions
The presence of RBD in PD correlates with cortical and subcortical (thalamic) cholinergic denervation but not
significantly with comorbid amyloidopathy. A PSG correlation study is underway.
Research Support: NIH P01 NS015655