Transcript Toxicity / Side Effects

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
7%
20%
Fluctuations
20%
Fluctuations
50%
Learning
Memory
Paroxysmal
Seizure
% 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
25%
75%
8%
46%
23%
8%
No Paroxysmal Symptoms
Subtle Symptoms
Staring
% of All
Patients
73%
18%
55%
59%
4.5%
27%
14%
4.5%
91%
77%
53%
89%
41%
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
PDD
ADHD
RD
Spike Localization
N
Left
2
100%
6
67%
4
50%
Bilateral
0%
16%
25%
Right
0%
16%
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 Dose 10%
Limited Improvement
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 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AEDs were withdrawn in three patients.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? 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
Enhance GABA
Transmission
Na+:
Phenytoin,
Carbamazepine,
Lamotrigine
Topiramate
Valproic acid
Ca++:
Ethosuximide
Valproic acid
Benzodiazepines
(diazepam, clonazepam)
Barbiturates
(phenobarbital)
Valproic acid
Gabapentin
Vigabatrin
Topiramate
Felbamate
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
Inhibit EAA
Transmission
Felbamate
Topiramate
Antiepileptic Drugs
Newer
Classical
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Phenytoin
Phenobarbital
Primidone
Carbamazepine
Ethosuximide
Valproic Acid
Trimethadione
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Lamotrigine
Felbamate
Topiramate
Gabapentin
Tiagabine
Vigabatrin
Oxycarbazepine
Levetiracetam
Phenytoin
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Slow, incomplete and variable absorption.
Extensive binding to plasma protein.
Complicated Kinetic
Can be Difficult to Manage in Children
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Toxicity / Side Effects
Dose related vestibular/cerebellar effects
Behavioral changes
Gingival Hyperplasia
GI Disturbances
Sexual-Endocrine Effects:
Osteomalacia, Hirsutism, Hyperglycemia
Valproic Acid
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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
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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)
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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
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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 ?