41° congrès senp 18-20 avril 2013
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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 - PowerPoint PPT PresentationTRANSCRIPT
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41° Congrès SENP18-20 avril 2013
Manifestations de type autistique révélant ou associées une maladie neurologique organique
P. Visconti
UOC NPI IRCCS Istituto delle Scienze NeurologicheBologna
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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
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• Wing e Gould (1979): Wing e Gould (1979): triadtriad a)a) Impairments in social interactionImpairments in social interactionb)b) Impairments in verbal and nonverbal Impairments in verbal and nonverbal
communication, especially regarded to communication, especially regarded to communicational intent communicational intent
c)c) Poor and stereotyped immagination. Poor and stereotyped immagination. • Several levels of mental retardation Several levels of mental retardation • ““Continuum” of clinical patterns Continuum” of clinical patterns “Autism “Autism
Spectrum Disorder” (ASD) Spectrum Disorder” (ASD) (Wing, L., 1988)(Wing, L., 1988)
•
Autism Spectrum Disorder or Autistic Continuum
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DSM-VProposed 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
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DSM-VProposed changes
Lord et al, 2012
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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.
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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)
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1960 1970 1980 1990 2000 2010 2020
Au
tism
Pre
vale
nce
(p
er 1
,000
)
Year
Comparison of Autism Prevalence
Kanner
Rutter
DSM-III
DSM-IIIR
ICD-10
DSM-IV
0102
03
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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
Points to remember
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Which are the relationships among:
• Autistic features / Autistic clinical pattern
• Syndromic and Non Syndromic Autism
• Comorbidities
• Underlying Neurological Diseases
???
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Comorbidity
Intellectual Disability Mood Disorders
Learning disabilities
Stereotyped Movement Disorder Tics
Epilepsy OCD
Rare Pathologies (Genetic and Methabolic Disorder) S. Tourette
Low-functioning High-functioning(QI 70 cut-off)
Gastrointestinal Disorders
Sleeping Disorder
Anxiety Disorder
Hyperactivity/ADHD
Oppositional Defiant Disorder
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Gillberg, 2010
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Gillberg, 2010
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Gillberg, 2010
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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
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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
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Double Syndromes – ASD Center Sample (2000-2005)
Double Syndromes Sample: 255 pts.
Tot. 30 11,7 %
low-functioning
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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
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Brain MRI abnormalitiesASD Center Sample 2000-2005
Abnormalities Sample: 255 pts.
Tot. 40 15,7%
low-functioning
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Neurological Evaluation ProtocolNeurological Evaluation Protocol• Objective neurological examination• Family Anamnesis • Steps in psychomotor development Anamnesis• Remote and recent Pathological Anamnesis Hematic Laboratory ExaminationsHematic 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
Diagnostic Assessment Diagnostic Assessment
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Neurological Evaluation ProtocolNeurological Evaluation Protocol
Urinary Laboratory Examination:Urinary Laboratory Examination:uricosuriaelectrolytes
O. R. L. Examination:O. R. L. Examination:es. audiometric, otoemissioni, es. impedenziometrico
Ophthalmic EvaluationOphthalmic Evaluation
Neurogenetic Screening:Neurogenetic Screening:Serum and urinary amino acidsLysosomial leukocytary enzymesOligosaccharides, Mucopolisaccharides and glycosaminoglycans
Neurophysiological Examination:Neurophysiological Examination:EEG (awake/aspleep)ABR and other evoked potentials, if indicated
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Neurological Evaluation ProtocolNeurological Evaluation Protocol
Genetics: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 Radiological examination and diagnosis thorough Images:thorough Images:- Rx for the bone age evaluation- Cerebral MRI
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Epilepsy and autistic spectrum disorders (ASD) often occur together
The prevalence of epilepsy in all children is 2-3%
Frequency in HF ASD lowest at 11% (Tuchman and Rapin, 1997)
Prevalence of epilepsy in autism from 5 to 42% (Rosman and Bergia, 2013)
Frequency in LF ASD is highest at 39% (Kawasaki et al.1997)
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• 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
Epilepsy Autism
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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
Autism Epilepsy
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Intellectual disability is the main and possibly the only reason that studies find a higher-than-expected level of autism in
children with epilepsy
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Absent ID, the overlap is no greater
than expected by chance alone
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. The question is:
Above and Beyond any contribution from ID
Have ASD and Epilepsy a special relationship ?
?
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• Might there be common underlying
pathophysiological mechanisms that can
explain the frequent co-occurrence of these two
conditions?
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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 anstaless-related homeobox, X-linked (ARX) and Neuropilin 2 (NRP2) gene mutations.
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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
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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 treatable
• HCY (Homocystinuria) + lens subluxation, vascular thrombosis, skeletal abnormalities 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
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• 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)
Autism and Metabolic Diseases (2)
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CCTD screening
100 Autistic Pts (Newmeyer et al., 2007)
No pathogenetic (“silent”) mutation
290 pts with X-linked ID
Prevalence: 2.1% (6/288) (Rosenberg et al., 2004)
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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
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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
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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
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“Autistic Phenotype” or Comunication-Social Impairment in Moderate/Severe ID ?
•Learning disabilities
•Absent understanding of environmental requests
•Attentional deficits
•Degree of delay
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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?
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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.
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A specific and detailed neurobehavioral and neurological assessment is needed:
• CARS,
• ADI, ADOS
• Neurobehavioral and dimensional profile (language, IQ, executive function, visual-motor integration, adaptive and playing behavior…)
Homogeneous ASD subgroups to drive genetic research
Core autistic features
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Un Saluto da Bologna!