Richard E. Frye, M.D., Ph.D.Assistant Professor of Pediatrics and Neurology

University of Texas Health Science Center

Subclinical epileptiform discharges in atypical cognitive development, and

a Review of Antiepileptic Drugs.

22 children 1 - Atypical cognitive development 2 - Subclinical epileptiform discharges on EEG3 - Two or more EEG Studies.

Subject Population

Age: Average: 5 years 11 monthsRange: 1 year 11 months to 11 years 1 month

MRI:26% Abnormal

80% Left Hippocampus Abnormalities20% Cortical Dysplasias

% of Subcategory

% of All Patients

Language 68% Regression 7% 4.5% Fluctuations 20% 14%

Learning 23% Fluctuations 20% 4.5%

Memory 18% Fluctuations 50% 9%

Paroxysmal 18% Seizure 4.5%

Presenting Symptoms.FEW WITH REGRESSION OR FLUCTUATIONS

% of Subcategory

% of All Patients

Attention Problems 73% Mild 25% 18% ADD/ADHD 75% 55%

Autism Symptomatology 59%

Echolalia 8% 4.5% Mild PDD 46% 27% PDD-NOS 23% 14% HFASD 8% 4.5%

Speech or Language Disorder 91%

No Paroxysmal Symptoms 77%

Subtle Symptoms 53% 41%Staring 89% 36%

Specific Developmental Cognitive Profile

Discharges on at least two EEGs 86%

Focal Discharges on two EEGs 95%

Consistent Lateralization 53%

Consistent Localization 27%

Location of Epileptiform Discharges IS NOT ConsistentProbably Not Specific to Disorder

Magnetoencephalography (MEG)

Magnetically-shielded room

“Recording neuromagnetic signals is like listening for the footsteps of an ant in the middle of a rock concert”

Dewar filled with helium

VectorView system Neuromag

Does Discharge Lateralization on MEG?

Only Consistent across two MEGs in 66%

Lateralization of MEG match EEG in 40%

Spike LocalizationN Left Bilateral Right

PDD 2 100% 0% 0%ADHD 6 67% 16% 16%RD 4 50% 25% 25%

Lateralization of MEG Spikes May Match Cognitive Symptoms but Sample Size Small

Treated with AED 91%

Carbamazepine 31%

Valproic Acid 19%

Oxcarbazepine 19%

Ethosuximide 8%

Lamotrigine 8%

Levetiracetam 4%

IVIG 4%

Improvement within One Clinic Visit 70%

Improvement with Increasing AED

Dose

10%

Limited Improvement 5%

No Improvement 15%

AED treatment Improves Symptoms

Could this be due to Chance or Placebo Effect?

50% of patients were followed for several months to years before starting AED treatment

Improvement within One Clinic Visit 72%

Improvement with Increasing AED

Dose

9%

Limited Improvement 9%

No Improvement 9%

Does Discontinuing Medication Result in Regression ?

AEDs were withdrawn in three patients.

This resulted in regression.

Reinstitution of AED Improved Cognitive Function

Children with subclinical discharges and developmental delays

1)Represent a specific phenotype? YesLanguage, Learning or Memory Difficulties

Regression not typicalCurrent of History of Speech of Language DisorderADHD and mild symptoms of PDD common

2) Do Specific EEG findings that correlate with symptoms? NoAppears to be a True EncephalopathySharp waves on EEG without specific

or consistent lateralization or localization

3) Is this syndrome treatable? YesGood Response to AEDs

Action on Ion Channels

Enhance GABA

Transmission

Inhibit EAA

TransmissionNa+:

Phenytoin, Carbamazepine, Lamotrigine

Topiramate

Valproic acid

Ca++:

Ethosuximide

Valproic acid

Benzodiazepines

(diazepam, clonazepam) Barbiturates (phenobarbital)

Valproic acid

Gabapentin

Vigabatrin

Topiramate

Felbamate

Felbamate

Topiramate

Na+:

For general tonic-clonic and partial seizures

Ca++:

For Absence seizures

Most effective in myoclonic but also in tonic-clonic and partial

Clonazepam: for Absence

Mechanism of Action for Antiepileptic Drugs

Classical• Phenytoin• Phenobarbital• Primidone• Carbamazepine• Ethosuximide• Valproic Acid• Trimethadione

Newer• Lamotrigine• Felbamate• Topiramate• Gabapentin• Tiagabine• Vigabatrin• Oxycarbazepine• Levetiracetam

Antiepileptic Drugs

Phenytoin• Slow, incomplete and variable absorption.• Extensive binding to plasma protein.• Complicated Kinetic• Can be Difficult to Manage in Children

Toxicity / Side Effects• Dose related vestibular/cerebellar effects• Behavioral changes• Gingival Hyperplasia • GI Disturbances• Sexual-Endocrine Effects:

Osteomalacia, Hirsutism, Hyperglycemia

• Effective for a wide spectrum of seizure types.• Effective for subclinical discharges and LKS• Effective for behavior & psychiatric disorders• Requires Monitoring Blood Tests

• Liver, Pancreas and Blood Counts

Valproic Acid

Fulminate hepatic failure. Most common in children < 2 yo. Cotreat w/ L-Carnitine to Protect the Liver

PancreatitisAnemia, Thrombocytopenia

Toxicity / Side Effects

• Effective for Absence seizures

• Long Half-life

Ethosuximide

Toxicity / Side Effects

Gastric distress—pain, nausea, vomiting. Weight LossBehavior ChangesChanges in Blood Counts.

Oxcarbazepine (Trileptal)• Good for Partial (Focal) seizures• Unlike Carbamazapine it has linear kinetic• Effective for behavior & psychiatric disorders

• Usually Mild Side Effects• Behavioral and Cognitive Problems• CAN MAKE SOME SEIZURES WORSE• Hyponatremia

Toxicity / Side Effects

• Effective against generalized seizures• Wide Spectrum of Effectiveness.• Effective for behavior & psychiatric disorders• Possibly Cognitively Enhancing in bipolar disorder• NEED TO INCREASE SLOWLY

Lamotrigine

• Side Effects Mild• Potentially life-threatening Rash (Stevens-

Johnson Reaction) in 1-2% of pediatric patients. This depends on the initial rate of increase in the dose. SO GO SLOW

Toxicity / Side Effects

• Reportedly very effective on multiple seizure types but too soon to know specifics effectiveness

• Minimal Drug Interactions• IV and Liquid Formulation• Extended Release Formulation

Levetiracetam (Keppra)

Toxicity / Side Effects• Side Effects Mild• Behavioral Side Effects Potentially Severe in

a small number of patients. May respond to B6

• Effective for a Wide Range of Seizure Types• Effective in Neonatal Seizures.• Effective for behavior & psychiatric disorders• Very Effective for Migraine Headaches

Topiramate (Topomax)

Toxicity / Side Effects• Psychomotor slowing and concentration prob• Speech Difficulties • Metabolic Acidosis• Weight Loss, Appetite Suppression• Glaucoma, Oligohidrosis, Nephrolithiasis

Questions ?

Subclinical epileptiform discharges in atypical cognitive development, and

a Review of Antiepileptic Drugs.