41° Congrès SENP 18-20 avril 2013

1. 41° Congrès SENP18-20 avril 2013 Manifestations de type autistique révélant ou associées une maladie neurologique organiqueP. ViscontiUOC NPI IRCCS Istituto delle Scienze NeurologicheBologna

2. 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

3. Autism Spectrum Disorder or Autistic Continuum • Wing e Gould (1979): triad • Impairments in social interaction • Impairments in verbal and nonverbal communication, especially regarded to communicational intent • Poor and stereotyped immagination. • Several levels of mental retardation • “Continuum” of clinical patterns  “Autism Spectrum Disorder” (ASD) (Wing, L., 1988)

5. 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

6. DSM-V Proposed changes Lord et al, 2012

7. Is there an autistic epidemic? • The recent upward trend in estimates of prevalencecannot 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.

8. 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)

10. 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

11. Which are the relationships among: • Autisticfeatures / Autisticclinical pattern • Syndromic and Non SyndromicAutism • Comorbidities • UnderlyingNeurologicalDiseases ???

12. Comorbidity Low-functioning High-functioning (QI 70 cut-off) Hyperactivity/ADHD Anxiety Disorder Gastrointestinal Disorders Oppositional Defiant Disorder Sleeping Disorder

13. Gillberg, 2010

14. Gillberg, 2010

15. Gillberg, 2010

16. Double Syndromes – ASD Center Sample 2000-2005 (255 pts)

17. Double Syndromes – ASD Center Sample 2000-2005

18. Double Syndromes – ASD Center Sample (2000-2005)

19. Brain MRI abnormalities – ASD Center Sample 2000-2005 255 pts.

20. Brain MRI abnormalities ASD Center Sample 2000-2005

21. 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

22. 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

23. 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

24. 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)

25. 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

26. Autism Epilepsy • Several small series report the occurrence of autism or autistic features • in patient withselected types of epilepsy: • Infantile spasms • Tuberous sclerosis with mutation in TSC2 gene • Dravet syndrome • Epilepsy in female with mental retardation in PCDH19

27. Intellectual disability is the main and possibly the only reason that studies find a higher-than-expected level of autism in children with epilepsy

28. Absent ID, the overlap is no greater than expected by chance alone

29. . The question is: Above and Beyond any contribution from ID Have ASD and Epilepsy a special relationship ? ?

30. Might there be common underlying pathophysiological mechanisms that can explain the frequent co-occurrence of these two conditions?

31. 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.

32. 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

34. 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 Autism and Metabolic Diseases (1)

35. 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) Metachromaticleukodystrophy (Rosman and Bergia, 2013) Autism and Metabolic Diseases (2)

36. 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) CCTD screening

40. 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

41. Final «organic» diagnosis • Markeddeterioration, catatonia, a normaldevelopment up to atleast 5 years of agesuggest an ORGANIC CAUSE • Slightlyraisedanti-NMDA-receptor Ab in serum and highlyraised in CSF

42. 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 Conclusion

43. Learning disabilities Absent understanding of environmental requests Attentional deficits Degree of delay “Autistic Phenotype” or Comunication-Social Impairment in Moderate/Severe ID ?

44. 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?

45. 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.

46. 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

47. Un Saluto da Bologna!