1. 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.

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

3. % of Subcategory % of All Patients Language68% Regression7%4.5% Fluctuations20%14% Learning23% Fluctuations20%4.5% Memory 18% Fluctuations50%9% Paroxysmal18% Seizure4.5% Presenting Symptoms. FEW WITH REGRESSION OR FLUCTUATIONS

4. % of Subcategory % of All Patients Attention Problems73% Mild25%18% ADD/ADHD75%55% Autism Symptomatology59% Echolalia8%4.5% Mild PDD46%27% PDD-NOS23%14% HFASD8%4.5% Speech or Language Disorder 91% No Paroxysmal Symptoms77% Subtle Symptoms53%41% Staring89%36% Specific Developmental Cognitive Profile

5. Discharges on at least two EEGs86% Focal Discharges on two EEGs95% Consistent Lateralization53% Consistent Localization27% Location of Epileptiform Discharges IS NOT Consistent Probably Not Specific to Disorder

6. 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

7. Does Discharge Lateralization on MEG? Only Consistent across two MEGs in 66% Lateralization of MEG match EEG in 40% Spike Localization NLeftBilateralRight PDD2100%0% ADHD667%16% RD450%25% Lateralization of MEG Spikes May Match Cognitive Symptoms but Sample Size Small

8. Treated with AED91% Carbamazepine31% Valproic Acid19% Oxcarbazepine19% Ethosuximide8% Lamotrigine8% Levetiracetam4% IVIG4%

9. Improvement within One Clinic Visit70% Improvement with Increasing AED Dose10% Limited Improvement5% No Improvement15% AED treatment Improves Symptoms

10. 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 Visit72% Improvement with Increasing AED Dose9% Limited Improvement9% No Improvement9%

11. Does Discontinuing Medication Result in Regression ? AEDs were withdrawn in three patients. This resulted in regression. Reinstitution of AED Improved Cognitive Function

12. Children with subclinical discharges and developmental delays 1)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

13. Action on Ion Channels Enhance GABA Transmission Inhibit EAA Transmission Na + : Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca ++ : Ethosuximide Valproic acid Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate 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

14. Classical Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Trimethadione Newer Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Antiepileptic Drugs

15. 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

16. 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 Pancreatitis Anemia, Thrombocytopenia Toxicity / Side Effects

17. Effective for Absence seizures Long Half-life Ethosuximide Toxicity / Side Effects Gastric distress—pain, nausea, vomiting. Weight Loss Behavior Changes Changes in Blood Counts.

18. 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

19. 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

20. 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

21. 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

22. Questions ? Subclinical epileptiform discharges in atypical cognitive development, and a Review of Antiepileptic Drugs.