41° Congrès SENP
18-20 avril 2013
Manifestations de type autistique révélant ou
associées une maladie neurologique organique
P. Visconti
UOC NPI IRCCS Istituto delle Scienze Neurologiche
Bologna
 Autism first described by psychiatrist Leo
Kanner in 1943 in US
 Hans Asperger also described “autistic
psychopathology” in 1944 in Austria (1980
translated to recognize ‘Asperger syndrome’)
 Autism was once seen as a rare condition
 Form of schizophrenia
 Attributed to poor mothering- Bettleheim,
1960’s
 Today - Autism Spectrum Disorders (ASDs)
having a biologic basis and broad spectrum
Autism Spectrum Disorder or
Autistic Continuum
• Wing e Gould (1979): triad
a) Impairments in social interaction
b) Impairments
in
verbal
and
nonverbal
communication,
especially
regarded
to
communicational intent
c) Poor and stereotyped immagination.
• Several levels of mental retardation
• “Continuum” of clinical patterns  “Autism
Spectrum Disorder” (ASD) (Wing, L., 1988)
•
DSM-V
Proposed changes
1. from Pervasive Developmental Disorder
(introduced in DSM III-R, APA 1987) to
Autism Spectrum Disorder
2. Creation of a single diagnosis,
Autism Spectrum Disorder
3. Rett Disorder is eliminated due to the
identification of its molecular basis
DSM-V
Proposed changes
Lord et al, 2012
Is there an autistic epidemic?
The recent upward trend in estimates of prevalence cannot be
directly attributed to an increase in the incidence of the disorder.
Confounding factors:
•changes in diagnostic criteria;
•diagnostic substitution;
•increased efficiency over time in case identification;
•changes of age at diagnosis;
•changes in the policies for special education;
•the increased availability of service.
Epidemiology …
• 1970: 2-5/10000
• All PDDs: 60-70/10000 (=1/150) Fombonne, 2009
• AD: 20-60/10000 (4-30 times)
High incidence
(> dyabetes, > tumors, > HIV overall)
Autism Prevalence (per 1,000)
Comparison of Autism Prevalence
01
02
0
3
18
16
Kanner
14
Rutter
12
DSM-III
10
DSM-IIIR
8
ICD-10
6
DSM-IV
4
2
0
1960
1970
1980
1990
Year
2000
2010
2020
Points to remember
 No biological test to confirm diagnosis at
present
 Diagnosis based on developmental history
and observable behaviors and a specific
neurobehavioral assessment (Test and
scales)
 Presentation of autism changes with
development
Which are the relationships
among:
• Autistic features / Autistic clinical pattern
• Syndromic and Non Syndromic Autism
• Comorbidities
• Underlying Neurological Diseases
???
Comorbidity
Low-functioning
(QI 70 cut-off)
Intellectual Disability
High-functioning
Mood Disorders
Learning disabilities
Hyperactivity/ADHD
Anxiety Disorder
Gastrointestinal Disorders
Oppositional Defiant Disorder
Sleeping Disorder
Stereotyped Movement Disorder
Tics
Epilepsy
OCD
Rare Pathologies (Genetic and
Methabolic Disorder)
S. Tourette
Gillberg, 2010
Gillberg, 2010
Gillberg, 2010
Double Syndromes – ASD Center Sample 2000-2005
(255 pts)
N.
Genetic Syndromes (19)
6
Down
2
Inv-Dup 15
2
Rett-LiKe
2
FG
2
X-Fragile
1
Sotos
1
22 chr. Microduplication
1
Becker
1
Tuberous Sclerosis
1
Rubinstein-Taybi
Double Syndromes – ASD Center Sample 2000-2005
N.
Infections (2)
1
Rubella
1
Herpes simplex
Mixed comorbidity (9)
1
Celiac Disease
1
Congenital Megacolon
1
Blindness
1
Neurosensorial Deafness
3
Epileptic Encefalopathies
1
OCD
1
Tourette
Double Syndromes – ASD Center Sample (2000-2005)
Double Syndromes Sample: 255 pts.
Tot. 30
11,7 %
low-functioning
Brain MRI abnormalities – ASD Center Sample 2000-2005
255 pts.
N.
Type (40)
7
Cerebell. Vermis Hypoplasia (rare Cerebell.
Hemispheres)
13
Periventricular White Matter Hyperintensity
5
Arnold-Chiari 1
3
Size Ventricular Asimmetry
4
Dysplasias (Hyppocampus and Parietal Region)
3
Delay or not completed Myelination
5
Other
Brain MRI abnormalities
ASD Center Sample 2000-2005
Abnormalities
Sample: 255 pts.
Tot. 40
15,7%
low-functioning
Diagnostic Assessment
Neurological Evaluation Protocol
• Objective neurological examination
• Family Anamnesis
• Steps in psychomotor development Anamnesis
• Remote and recent Pathological Anamnesis
Hematic Laboratory Examinations:
• Routine screening (blood count, glycemia etc..)
• electrolytes
• ceruloplasmin, ammonium, uric acid, lactic acid, pyruvic
acid
• CPK, LDH
• immunoglobulins
AGA, EMA, antitransglutaminase
• TSH, FT3, FT4
Neurological Evaluation Protocol
Urinary Laboratory Examination:
uricosuria
electrolytes
O. R. L. Examination:
es. audiometric, otoemissioni, es. impedenziometrico
Ophthalmic Evaluation
Neurogenetic Screening:
Serum and urinary amino acids
Lysosomial leukocytary enzymes
Oligosaccharides, Mucopolisaccharides and glycosaminoglycans
Neurophysiological Examination:
EEG (awake/aspleep)
ABR and other evoked potentials, if indicated
Neurological Evaluation Protocol
Genetics:
- Clinical evaluation
-
X Fragile (Fra-X A and E)
If indicated, high resolution karyotype
MECP2
Focused investigation on specific pathologies (S. di Angelman)
Array-CGH
Radiological examination and diagnosis thorough
Images:
- Rx for the bone age evaluation
- Cerebral MRI
Epilepsy and autistic spectrum
disorders (ASD) often occur together
The prevalence of epilepsy in all children is 2-3%
Prevalence of epilepsy in autism from 5 to 42%
(Rosman and Bergia, 2013)
Frequency in HF ASD lowest at 11% (Tuchman and
Rapin, 1997)
Frequency in LF ASD is highest at 39% (Kawasaki et al.1997)
Epilepsy
Autism
• Mouridsen SE et al, 2011: epilepsy prevalence
was greater in association with severity of
ID
  34% of epilepsy in Pts with autism and
IQ< 50
  27% of epilepsy in Pts with autism and IQ
50-69
  9% of epilepsy in Pts with autism and IQ>
70
Autism
Epilepsy
Several small series report the occurrence of autism
or autistic features
in patient with selected types of epilepsy:
•Infantile spasms
•Tuberous sclerosis with mutation in TSC2 gene
•Dravet syndrome
•Epilepsy in female with mental retardation in
PCDH19
Intellectual disability is the main and possibly the only reason
that studies find a higher-than-expected level of autism in
children with epilepsy
Absent ID, the
overlap is no greater
than expected by
chance alone
. The question is:
Above and Beyond any
contribution from ID
Have ASD and Epilepsy
a special relationship ?
?
• Might there be common
underlying
pathophysiological
mechanisms that can
explain the frequent cooccurrence of these two
conditions?
ASD and epilepsy  disorders of synaptic plasticity
that result in imbalances of excitation and inhibition in
the developing brain
•Fragile X
•Rett syndrome
•CDKL5 mutations
• tuberous sclerosis
complex (TSC)
• neuroligin mutations
•“interneuronopathies”
resulting from anstalessrelated homeobox, Xlinked (ARX) and
Neuropilin 2 (NRP2) gene
mutations.
Regression
Regression is noted usually at 18-24 months with particular loss
of verbal and nonverbal communication.
EEG abnormalities occur in 20-40% with autism and regression
and in 6-30% of those with autism without regression
(Kagan-Kushnir T, 2005)
Rates of epileptiform discharges are influenced by the types of
EEGs performed with highest rates in studies using overnight
recordings or include at least some sleep state recording
Autism and Metabolic Diseases (1)
Inherited metabolic disease (IMD) with isolated ASD as a prominent
feature or as a first sign (Schiff et Al, 2011)
•
•
PKU + behavioural disorder (BD), epilepsy, severe ID
HCY (Homocystinuria) + lens subluxation, vascular thrombosis, skeletal
abnormalities
•
treatable
treatable
Mucopolysaccharidosis type III (MPS III, San Filippo Disease) +
severe BD, slowly progressing developmental impairment, speech regression, loss
of toilet training → severe encephalopathy
•
Urea Cicle Disorder (Ornithine transcarbamylase deficiency) + BD,
ataxic gait, epatho-digestive abnormalities
•
treatable
Cerebral Creatin Deficiency Syndrome (CCTD) + ID, Oral Dyspraxia,
speech delay
Autism and Metabolic Diseases (2)
•
Adenylosuccinase Deficiency (autosomal recessive error of purine
synthesis) + developmental delay, seizures, agitation (Vincent e Jackson, 1997;
Sempere et Al, 2010)
•
X-linked Adreno-leukodystrophy (Schilder Disease) (Rosman and
Bergia, 2013)
•
Metachromatic leukodystrophy (Rosman and Bergia, 2013)
CCTD screening
100 Autistic Pts
(Newmeyer et al., 2007)
No pathogenetic (“silent”) mutation
290 pts with X-linked ID
Prevalence: 2.1% (6/288)
2004)
(Rosenberg et al.,
•
•
•
•
•
Is an Autistic phenotype ?
9 y.boy with no medical or psychiatric history
Acute onset of secondary generalized seizure
Speech and swallowing difficulties
10 days later agitated catatonic state with
opisthotonic posturing, tonic posturing of limbs,
insomnia, dyskinesia.
+ Oligoclonal bands in CSF, treatment for Atypical
child. Epilepsy (CT spikes)
• 1 month later: Robotic state, complete
mutism and negativism
Final «organic» diagnosis
• Marked deterioration, catatonia, a normal
development up to at least 5 years of age
suggest an ORGANIC CAUSE
• Slightly raised anti-NMDA-receptor Ab in
serum and highly raised in CSF
Conclusion
Taking in account to investigate metabolic disorders and/or syndromic
Autism Spectrum Disorder in presence of these clinical signs:








Seizures
Dysmorphic features
Skin abnormalities
Vomiting
Ataxia
Micro/macrocephaly
Cataract
Developmental delay and/or ID
Children with Autistic Spectrum Disorder who have lower cognitive
function are more likely to have specific neurological disorder or
epilepsy
“Autistic Phenotype” or Comunication-Social
Impairment in Moderate/Severe ID ?
• Learning disabilities
• Absent understanding of
environmental requests
• Attentional deficits
• Degree of delay
Autistic features both in low and high functioning ADS pts
are caused by an early insult on developing brain
BUT
In low functioning ADS pts the pathological impact causing
the disruption of neurodevelopment trajectories is global
and wide, affecting different cortical developing networks
In high functioning ADS pts it is more specific on networks
subserving social/communication functions
What’s the role of the genetic underlying condition?
Could autistic phenotype in low functioning pts depend on
or be linked to the ID, and not to a specific condition?
Is Autism phenotype specific “per se” or is the common
final pathway of different pathogenetic mechanisms?
Reduced frontal-posterior cortical connectivity.
Common finding (Kana et al., 2009);
It represents a constraint on the capacity of cortical
networks to coordinate information processing (Kana et
al., 2006)
Disturbances in integrative information processing as the
basis for the clinical deficits that define autism.
A specific and detailed neurobehavioral
and neurological assessment is needed:
•
•
•
CARS,
ADI, ADOS
Core autistic features
Neurobehavioral and dimensional profile
(language, IQ, executive function, visual-motor
integration, adaptive and playing behavior…)
Homogeneous ASD subgroups to drive genetic
research
Un Saluto da Bologna!