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