Autism & Epilepsy: Which Comes First?

December 6, 2011

Roberto Tuchman, M.D. Director, Autism and Neurodevelopment Program

Miami Children’s Hospital Dan Marino Center Clinical Professor of Neurology and Psychiatry

Herbert Wertheim College of Medicine, FIU

American Epilepsy Society | Annual Meeting

Disclosure

Name of Commercial

Interest

Type of Financial

Relationship

American Epilepsy Society | Annual Meeting

No Disclosures

Learning Objectives

• Shifting Perspectives & Common Mechanisms

• Which comes first Autism or Epilepsy

• Clinical and Research Synergies

American Epilepsy Society | Annual Meeting

Autism and Epilepsy

Autism and Epilepsy: Shifting Perspectives

Neurodevelopmental Disorders Happe, F., et al. (2006). "Time to give up on a single explanation for autism." Nat Neurosci Berg, A., Scheffer I. (2011). "New concepts in classification of the epilepsies: Entering the 21st century." Epilepsia

Epilepsy, like autism, is increasingly being described as a spectrum disorder

Jensen, F. E. (2011). "Epilepsy as a spectrum disorder: Implications from novel clinical and basic neuroscience." Epilepsia

multiple etiologies variable clinical symptoms variable outcomes

Epilepsy and Autism Commonly Co-exist

Mouridsen, S. E., et al. (2011). "A longitudinal study of epilepsy and other central nervous system diseases in individuals with and without a history of infantile autism." Brain Dev

Clark DF, et al. (2005) The prevalence of autistic spectrum disorder in children surveyed in a tertiary care epilepsy clinic. Epilepsia

Matsuo, M., et al. (2010). Frequent association of autism spectrum disorder in patients with childhood onset epilepsy Brain Dev

Sansa, G., et al. (2011). "Medically refractory epilepsy in autism." Epilepsia

Increased morbidity and mortality

Danielsson, S., et al. (2005). "Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood” Epilepsia

Gillberg, C., et al. (2010). "Mortality in autism: a prospective longitudinal community-based study." J Autism Dev Disord

Sillanpaa, M. and S. Shinnar (2010). "Long-Term Mortality in Childhood-Onset Epilepsy." New England Journal of Medicine

Pickett, J., et al. (2011). "Mortality in Individuals with Autism, with and without Epilepsy." J Child Neurol

Autism, Epilepsy, and Intellectual Disability: Common Mechanisms

Brooks-Kayal, A. (2011). "Molecular mechanisms of cognitive and behavioral comorbidities of epilepsy in children." Epilepsia

Fassio, A., et al. (2011). "SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function." Human molecular genetics

Tsai, P. and Sahin M. (2011). "Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex." Current opinion in neurology

Wegiel, J., et al., (2010). The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol

Common Mechanisms: Common Number Variants (CNVs)

Common recurrent microdeletions associated with generalized epilepsy seen at a frequency of 1% at 15q13.3, 16p13.11, and 15q11.2 These three regions have been tied to multiple neurobehavioral phenotypes including epilepsy, autism, intellectual disability, and schizophrenia

Mulley, J. C. and H. C. Mefford (2011). "Epilepsy and the new cytogenetics." Epilepsia

Intellectual Disability

Epilepsy

Autism Spectrum Disorders

SHARED MECHANISMS

Risk Factors: risk genes Risk Process: (Epileptogenesis-Sociogenesis) Altered neuronal excitation/inhibition (interneuron) Altered neuronal networks Altered pattern of interaction between child and environment

INTERVENTION

mTOR pathway

Behavioral

specific synaptic or other molecular pathways

Which comes first

Definitions: Autism Deconstructed

RRBIs

Language

Intellectual

Disability

Social

Interaction

Motor

Social

Which comes first: Joint Attention

capacity of individuals to coordinate attention with a social partner in relation to some object or event

begins to emerge by 6 months of age

early and critical foundation

language & social cognition

After 6 months…… ASD group shows a rapid decline in

eye contact social smiling examiner-rated social responsiveness

Ozonoff, S., et al. (2010). "A prospective study

of the emergence of early behavioral signs of autism." J Am Acad Child Adolesc Psychiatry

By 12 months…..

Not Responding to Name by 8 to 12 months

Pointing or Gestures by 12 months

Responding to Joint Attention by 12 to 18 months

Repetitive Actions

Unusual Sensory Responses

Zwaigenbaum, L., et al. (2009). "Clinical assessment and management of toddlers with suspected autism spectrum disorder: insights from studies of high-risk infants." Pediatrics Zwaigenbaum, L., et al. (2011). "The NeuroDevNet Autism Spectrum Disorders Demonstration Project." Seminars in pediatric neurology

Epilepsy in Children with ASD Tuchman, et al. (1991). "Autistic and dysphasic children. II: Epilepsy." Pediatrics

1.0

0.8

0.6

0.4

0.2

0 5 10 15 20 25

AGE AT TIME OF SEIZURE (Years)

30

Infantile Spasms

ongoing neurological process

Epileptic Encephalopathy

In a meta-analysis of 24 reports on autism and epilepsy published from 1963 to 2006:

Pooled prevalence of epilepsy

21.4% in 1485 individuals with autism and intellectual disability

versus

8% in 627 persons with autism without intellectual disability

Amiet, C. et al., Epilepsy in autism is associated with intellectual disability and gender: evidence from a meta-analysis. Biol Psychiatry 2008

Autism spectrum disorders in children with seizures in the first year of life - a population-based study. Epilepsia 7% with ASD all with intellectual disability Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life. Epilepsia

Overall 14% with ASD

ASD in 46% of those with Infantile Spasms

ASD in 69% of those whose seizures were associated

with brain insults

Saemundsen, E., P. Ludvigsson, et al. (2007) Saemundsen, E., P. Ludvigsson, et al. (2008).

Berg, A, et al. (2011). "Risk and correlates of autism spectrum disorder in children with epilepsy: a community-based study." J Child Neurol

5% met criteria for ASD 10% of those whose seizures start in the first 2 years of life

met criteria for ASD 13.8 % in those with IQ less than 80 met criteria for ASD 2.2 % with normal cognitive abilities met criteria for ASD

West syndrome (Infantile Spasms) (30% with ASD), intellectual impairment, male sex independently associated with ASD Younger age (of seizures) at onset did not contribute independently to ASD

Clinical and Research Synergies

ILAE-AS Task Force

AS-CURE-ILAE: Scientific Research Synergies from a Global Perspective: Key Points Brooklyn December 10, 2010

– Key Points

• Identify infants with seizures at risk for autism and those with autism at risk for epilepsy

• Identify genetic and environmental risk factors common to epilepsy-autism

• Explore the underlying mechanisms of convergence between autism and epilepsy

AS-CURE-ILAE: Scientific Research Synergies from a Global Perspective: Key Points Brooklyn December 10, 2010

– Key Points

• Coordinate tissue and brain banking efforts in epilepsy-autism

• Develop treatment models behavioral and pharmacological in infants with epilepsy-autism (or at risk for autism)

The NINDS , in conjunction with Autism Speaks and CURE, will host a workshop in the spring of

2012

Research Agenda

Coordination of Resources

Common Mechanisms

Treatment approaches