Treatment of Children With Autism Spectrum Disorders and Epileptiform EEG With Divalproex Sodium

Epilepsy and epileptiform EEG abnormalities are common co-morbidities in Autism Spectrum
Disorders (ASD) that can be considered important biomarkers of cortical dysfunction in these
disorders. They may represent a measure of the excitatory-inhibitory imbalance posited to be
involved in the pathogenesis of the disorder. Treatment of epilepsy is always indicated, but
treatment of isolated epileptiform EEG (i.e. in the absence of clinical seizures) is frankly
controversial. Since data suggest that these epileptiform discharges are associated with
deficits in attention, language and behavior, the investigators believe that they may
represent an important and novel treatment target in this population. The proposed study
brings together a group of investigators long interested in this problem in order to
investigate the efficacy of using an anticonvulsant medication with spike suppression
capabilities (VPA in the form of divalproex sodium) to treat children with ASD and isolated
epileptiform EEGs. Recruiting from 3 large autism centers (Boston Children's Hospital (BCH)
and Vanderbilt University (VU) and University of Louisville (U of L)) with very large
pediatric epilepsy units, the investigators propose a 26 week randomized placebo controlled
cross over study of VPA in 4-8 year old children with ASD with frequent epileptiform EEG
discharges.

Inclusion Criteria:

1. Male or female patients aged 4 to 10 years.

2. Diagnosis of with ASD (Autistic Disorder, Asperger's Disorder, or pervasive
developmental disorder (PDD-NOS).

3. Frequent epileptiform discharges on EEG (defined as spikes, spike wave, and sharp
waves occurring at greater than 15 events per hour).

4. Intelligence quotient (IQ) range 40 to 100.

5. Weight > or = 12.5 kg.

6. English speaking families

Exclusion Criteria:

1. History of epilepsy, known neurogenetic disorder or chromosomal abnormalities with
high rates of epilepsy (15q duplication syndrome, 16p deletion/duplication syndrome,
Fragile X, tuberous sclerosis complex), or structural brain lesion (prior stroke,
migrational defects, brain malformations).

2. The presence of a severe epileptiform EEG on the sleep EEG referred to as electrical
status epilepticus in sleep (ESES) in sleep

3. Previous treatment with divalproex sodium that is any one of the following:

- of greater than 6 months duration

- within the last 12 months

- that was associated with significant side effects leading to termination of
treatment

4. Children who have had general anesthesia within the six months or sedation within 2
weeks of study enrollment.

5. Recent (less than two months prior to study entry) initiation of a behavioral therapy
program or new psychotropic medication, or the plan to change or start a new therapy.

6. Presence of medical condition, such as carnitine deficiency, urea cycle disorder or
other metabolic disorder that would be a contraindication to divalproex sodium usage.

7. Presence of a significant untreated medical problem (obstructive sleep apnea,
restless legs syndrome, GERD, etc.) which may have significant impact on sleep study
measures.

8. Renal, hepatic, pancreatic, or hematologic dysfunction as evidenced by values above
upper limits of normal for BUN/creatinine, or values twice the upper limit of normal
for serum transaminases (ALT/SGPT, AST/SGOT), values twice the upper limit of normal
for serum lipase and amylase, platelets <80,000 /mcL, WBC<3.0 103 /mcL.

9. Concomitant use of medication contraindicated with divalproex sodium including
topiramate, lamotrigine, and drugs that inhibit cytochrome p450 enzymes.

10. Behavioral management issues (e.g. self-injury, aggressiveness) severe enough to be
of safety concerns (to subject and/or staff).

11. Absence of primary care physician.