Subclinical epileptiform discharges

in atypical cognitive development, and

a Review of Antiepileptic Drugs.

Richard E. Frye, M.D., Ph.D.

Assistant Professor of Pediatrics and Neurology
University of Texas Health Science Center
 Subject Population

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

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

MRI:
26% Abnormal
80% Left Hippocampus Abnormalities
20% Cortical Dysplasias
 Presenting Symptoms.
FEW WITH REGRESSION OR FLUCTUATIONS

% of % of All
Subcategory 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%
 Specific Developmental Cognitive Profile
% of % of All
Subcategory 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%
 Location of Epileptiform Discharges IS NOT Consistent
Probably Not Specific to Disorder

Discharges on at least two EEGs 86%

Focal Discharges on two EEGs 95%

Consistent Lateralization 53%

Consistent Localization 27%

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

Dewar filled with helium

Magnetically-shielded room

VectorView system Neuromag

 Does Discharge Lateralization on MEG?

Only Consistent across two MEGs in 66%

Lateralization of MEG match EEG in 40%

Lateralization of MEG Spikes May Match

Cognitive Symptoms but Sample Size Small

Spike Localization
N Left Bilateral Right
PDD 2 100% 0% 0%
ADHD 6 67% 16% 16%
RD 4 50% 25% 25%
Treated with AED 91%

Carbamazepine 31%

Valproic Acid 19%

Oxcarbazepine 19%

Ethosuximide 8%

Lamotrigine 8%

Levetiracetam 4%

IVIG 4%
AED treatment Improves Symptoms

Improvement within One Clinic Visit 70%

Improvement with Increasing AED 10%

Dose Improvement
Limited 5%

No Improvement 15%
 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 9%

Dose Improvement
Limited 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AEDs were withdrawn in three patients.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

3)Represent a specific phenotype? Yes

Language, Learning or Memory Difficulties
Regression not typical
Current of History of Speech of Language Disorder
ADHD and mild symptoms of PDD common

2) Do Specific EEG findings that correlate with symptoms? No

Appears to be a True Encephalopathy
Sharp waves on EEG without specific
or consistent lateralization or localization

3) Is this syndrome treatable? Yes

Good Response to AEDs
 Mechanism of Action for Antiepileptic Drugs

Action on Ion Enhance GABA Inhibit EAA

Channels Transmission Transmission
Na+: Benzodiazepines Felbamate
Phenytoin, (diazepam, clonazepam) Topiramate
Carbamazepine, Barbiturates
Lamotrigine (phenobarbital)
Topiramate Valproic acid
Valproic acid Gabapentin
Ca++: Vigabatrin
Ethosuximide Topiramate
Valproic acid Felbamate
Na+: Most effective in
For general tonic-clonic myoclonic but also in
and partial seizures tonic-clonic and partial
Ca++: Clonazepam: for Absence
For Absence seizures
 Antiepileptic Drugs
Classical Newer
• Phenytoin • Lamotrigine
• Felbamate
• Phenobarbital
• Topiramate
• Primidone • Gabapentin
• Carbamazepine • Tiagabine
• Ethosuximide • Vigabatrin
• Valproic Acid • Oxycarbazepine
• Levetiracetam
• Trimethadione
 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
 Valproic Acid
• 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
Toxicity / Side Effects
Fulminate hepatic failure.
Most common in children < 2 yo.
Cotreat w/ L-Carnitine to Protect the Liver
Pancreatitis
Anemia, Thrombocytopenia
 Ethosuximide
• Effective for Absence seizures
• Long Half-life

Toxicity / Side Effects

Gastric distress—pain, nausea, vomiting.
Weight Loss
Behavior Changes
Changes in Blood Counts.
 Oxcarbazepine (Trileptal)
• Good for Partial (Focal) seizures
• Unlike Carbamazapine it has linear kinetic
• Effective for behavior & psychiatric disorders

Toxicity / Side Effects

• Usually Mild Side Effects
• Behavioral and Cognitive Problems
• CAN MAKE SOME SEIZURES WORSE
• Hyponatremia
 Lamotrigine
• Effective against generalized seizures
• Wide Spectrum of Effectiveness.
• Effective for behavior & psychiatric disorders
• Possibly Cognitively Enhancing in bipolar disorder
• NEED TO INCREASE SLOWLY

Toxicity / Side Effects

• 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
 Levetiracetam (Keppra)
• Reportedly very effective on multiple seizure types
but too soon to know specifics effectiveness
• Minimal Drug Interactions
• IV and Liquid Formulation
• Extended Release Formulation

Toxicity / Side Effects

• Side Effects Mild
• Behavioral Side Effects Potentially Severe in
a small number of patients. May respond to
B6
 Topiramate (Topomax)
• Effective for a Wide Range of Seizure Types
• Effective in Neonatal Seizures.
• Effective for behavior & psychiatric disorders
• Very Effective for Migraine Headaches

Toxicity / Side Effects

• Psychomotor slowing and concentration prob
• Speech Difficulties
• Metabolic Acidosis
• Weight Loss, Appetite Suppression
• Glaucoma, Oligohidrosis, Nephrolithiasis
 Subclinical epileptiform discharges
in atypical cognitive development, and
a Review of Antiepileptic Drugs.

Questions ?