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"I don't understand it, and I don't like what I don't understand."― E.B. White, Charlotte's Web

There is a strong association between autism spectrum disorders (ASD) and epilepsy. However, the special relationship between ASD and epilepsy is not quite well understood.1

Autism and epilepsy are common neurological conditions with chronic disabilities and are increasingly prevalent. Leo Kanner was the first to describe the clinical and personality traits of children with autism and its association with seizures in his 1943 paper entitled, "Autistic disturbances of affective contact." He recognized this condition as being an innate disorder that needed further biomarkers.2

The biological association between the two and treatment and research gaps have been nicely summarized in a recent workshop report that was released by National Institute of Neurological Disorders and Stroke (NINDS) with support from the National Institute of Child Health and Human Development, Autism Speaks, and Citizens United for Research in Epilepsy.3

Chicken or egg? Does autism cause epilepsy or epilepsy cause autism?

  • Based on several meta-analysis studies and pooled data review, autism and epilepsy tend to co-occur in about 30% of individuals.
  • In children with ASD, intellectual disability (ID) is a major risk factor for developing epilepsy with an estimated risk of 8% for those without ID and as high as 20% in those with ID.4
  • Seizures may first begin in adolescence or adulthood.
  • Approximately 4-5 % of children with epilepsy will have ASD.5
  • It is becoming clear that ID is common whether we are dealing with children who develop autism first and then go on to develop epilepsy or children with early onset epileptic encephalopathies with autistic features such as tuberous sclerosis complex (TSC). Thus, there is a shared mechanism between autism, epilepsy, and ID.6

What are the underlying mechanisms for autism and epilepsy? Nature vs Nurture

  • Abnormal synaptic plasticity, imbalances in excitatory and inhibitory neurotransmitters, and disruptions in a developing brain can lead to autism, epilepsy, and ID.
  • Abnormal neurogenesis, neuronal migration and proliferation, cortical malformations, and dysplasias are common in both autism and epilepsy.
  • Low birth weights, prematurity, and advanced paternal or maternal age are also known contributors.
  • Recent advances in molecular genetics in certain known single gene disorders causing epilepsy with neuro-cognitive and behavioral consequences, such as Fragile X, TSC, and Rett syndrome, have helped us understand the molecular pathways and the effects involved in phenotypic genotypic interaction. Animal models have been developed in these conditions which have helped with advancing human clinical trials. There are now FDA approved drug trials in known genetic syndromes such as Rett and TSC.7

Is there a role for early intervention? What are some of the early biomarkers?

In a prospective longitudinal at risk cohort of 40 infants with TSC, Spurling Jeste and his colleagues looked for early developmental markers of ASD. 22 out of 40 (55%) infants were diagnosed with ASD. 95% of this cohort had epilepsy among which 65% had infantile spasms. These infants were identified to have early visually mediated delays resulting in poor social development, non-verbal communication, and subsequent global and cognitive deficits. The extent to which epilepsy, particularly infantile spasms, contributed to delays and to ASD diagnosis is unclear. The big question that remains to be answered is if autism can be prevented and if the overall developmental outcome improved by early targeted developmental intervention in some of these high risk groups with early onset epileptic encephalopathy.8,9

The utility of magnetic resonance imaging (MRI) of the brain with special sequences called the diffusion tensor imaging (DTI) for tracking down early white matter tract abnormalities is being explored.

Abnormal electroencephalogram (EEG) with epileptiform discharges without clinical seizures are often seen in ASD. These interictal epileptiform discharges (IED) are frontally dominant. Some clinicians believe this represents a “tip of an iceberg.” It is uncertain if the epileptiform discharges cause ASD or if the presence of IED indicates a dysfunctional brain. Presence of IEDs is thought to be harmful as they interfere with sleep, long term memory, learning, and cognition. Interventional strategies to eliminate or suppress this abnormal epileptiform activity in the absence of clinical seizures needs further study.

With collaborative efforts and ongoing research we are hopeful to better understand the complex relationship between autism and epilepsy that may further translate into improved clinical care and quality of life.

References

  1. Anne T. Berg, Sigita Plioplys. Epilepsy and Autism: Is there a special relationship? Epilepsy Behav. 2012 March; 23(3): 193–198.
  2. Kanner L. Autistic disturbances of affective contact. Nerv Child 1943; 2: 217-50.
  3. NINDS epilepsy and autism spectrum disorders workshop report. Neurology-2013;81:1630–163
  4. Roberto Tuchman .Autism and Cognition within Epilepsy: Social Matters. Epilepsy Curr. 2015 Jul-Aug; 15(4): 202–205.
  5. Berg AT, Plioplys S, Tuchman Risk and correlates of autism spectrum disorder in children with epilepsy: a community- based study. A, R J Child Neurol 2011; 26:540–547
  6. Brooks-Kayal A. Molecular mechanisms of cognitive and behavioral comorbidities of epilepsy in children. Epilepsia 2011;52(suppl 1):13–20
  7. Khwaja OS, Sahin M. Translational research: Rett syndrome and tuberous sclerosis complex. Curr Opin Pediatr 2011; 23:633–639
  8. Spurling Jeste S, Wu JY, Senturk D, Varcin K, Ko J, McCarthy B, Shimizu C, Dies K, Vogel-Farley V, Sahin M, Nelson CA III. Early developmental trajectories associated with ASD in infants with tuberous sclerosis complex. Neurology 2014;83:160–168
  9. S. J. Rogers, L. Vismara, A. L. Wagner, C. McCormick, G. Young, S. Ozonoff. Autism Treatment in the First Year of Life: A Pilot Study of Infant Start, a Parent-Implemented Intervention for Symptomatic Infants. Journal of Autism and Developmental Disorders, 2014, Volume 44, Number 12, Page 2981
  10. Gregory L. Holmes. What are more harmful, seizures or epileptic EEG abnormalities? Is there any clinical data? Epileptic Disord 2014; 16 (Suppl. 1): S12-S22

This content was created through a partnership between the Epilepsy Foundation and American Epilepsy Society.

Authored By: 
Anu Venkat MD
Authored Date: 
12/2016
Reviewed By: 
Joseph I. Sirven MD
on: 
Wednesday, December 14, 2016