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

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

• 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

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

DSM-VProposed 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)

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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

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

Which are the relationships among:

• Autistic features / Autistic clinical pattern

• Syndromic and Non Syndromic Autism

• Comorbidities

• Underlying Neurological Diseases

???

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

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

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 – 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 abnormalitiesASD Center Sample 2000-2005

Abnormalities Sample: 255 pts.

Tot. 40 15,7%

low-functioning

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

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

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

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)

• 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

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

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 co-occurrence 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 anstaless-related homeobox, X-linked (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 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

• 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)

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)

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

• 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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