Subclinical epileptiform discharges in atypical cognitive development and a Review of Antiepileptic Drugs
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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 Subcategory Language Regression Fluctuations Learning Fluctuations Memory Fluctuations Paroxysmal Seizure 50% 20% 7% 20% % of All Patients 68% 4.5% 14% 23% 4.5% 18% 9% 18% 4.5%
Specific Developmental Cognitive Profile
% of Subcategory Attention Problems Mild ADD/ADHD Autism Symptomatology Echolalia Mild PDD PDD-NOS HFASD Speech or Language Disorder No Paroxysmal Symptoms Subtle Symptoms Staring 53% 89% 25% 75% 8% 46% 23% 8% % of All Patients 73% 18% 55% 59% 4.5% 27% 14% 4.5% 91% 77% 41% 36%
Location of Epileptiform Discharges IS NOT Consistent Probably Not Specific to Disorder Discharges on at least two EEGs Focal Discharges on two EEGs Consistent Lateralization Consistent Localization 86% 95% 53% 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 2 100% 6 67% 4 50%
PDD ADHD RD
Bilateral 0% 16% 25%
Right 0% 16% 25%
Treated with AED Carbamazepine Valproic Acid Oxcarbazepine Ethosuximide Lamotrigine Levetiracetam IVIG
91% 31% 19% 19% 8% 8% 4% 4%
AED treatment Improves Symptoms
Improvement within One Clinic Visit Improvement with Increasing AED Limited Dose Improvement No Improvement 70% 10% 5% 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 Improvement with Increasing AED Limited Dose Improvement No Improvement
72% 9% 9% 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 Channels
Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca++: Ethosuximide Valproic acid Na+: For general tonic-clonic and partial seizures Ca++: For Absence seizures
Enhance GABA Inhibit EAA Transmission Transmission
Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence Felbamate Topiramate
Antiepileptic Drugs
Classical
• • • • • • • Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Trimethadione
Newer
• • • • • • • • Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam
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 (StevensJohnson 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 ?
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 Subcategory Language Regression Fluctuations Learning Fluctuations Memory Fluctuations Paroxysmal Seizure 50% 20% 7% 20% % of All Patients 68% 4.5% 14% 23% 4.5% 18% 9% 18% 4.5%
Specific Developmental Cognitive Profile
% of Subcategory Attention Problems Mild ADD/ADHD Autism Symptomatology Echolalia Mild PDD PDD-NOS HFASD Speech or Language Disorder No Paroxysmal Symptoms Subtle Symptoms Staring 53% 89% 25% 75% 8% 46% 23% 8% % of All Patients 73% 18% 55% 59% 4.5% 27% 14% 4.5% 91% 77% 41% 36%
Location of Epileptiform Discharges IS NOT Consistent Probably Not Specific to Disorder Discharges on at least two EEGs Focal Discharges on two EEGs Consistent Lateralization Consistent Localization 86% 95% 53% 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 2 100% 6 67% 4 50%
PDD ADHD RD
Bilateral 0% 16% 25%
Right 0% 16% 25%
Treated with AED Carbamazepine Valproic Acid Oxcarbazepine Ethosuximide Lamotrigine Levetiracetam IVIG
91% 31% 19% 19% 8% 8% 4% 4%
AED treatment Improves Symptoms
Improvement within One Clinic Visit Improvement with Increasing AED Limited Dose Improvement No Improvement 70% 10% 5% 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 Improvement with Increasing AED Limited Dose Improvement No Improvement
72% 9% 9% 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 Channels
Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca++: Ethosuximide Valproic acid Na+: For general tonic-clonic and partial seizures Ca++: For Absence seizures
Enhance GABA Inhibit EAA Transmission Transmission
Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence Felbamate Topiramate
Antiepileptic Drugs
Classical
• • • • • • • Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Trimethadione
Newer
• • • • • • • • Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam
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 (StevensJohnson 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 ?
