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The Effect of AED’s upon Cognition: What we Know
Cynthia Smith, PhDProgram Director, Division
of NeuropsychologyThe Brain & Spine Institute
AED’s suppress seizures and do not “cure” them
AED success rate 50% to 70%
Academic Performance & Epilepsy
Contributing FactorsIdiopathic vs sympathicAge at first seizurePresence of >1 Status EpilepticusFrequency of seizuresSingle versus polytherapyMood stateFamily organization and quality of function
Aggression and hyperactivity more common in children than depression in adults
Children with epilepsy 5 times more likely to have behavior or other mental health problems than adults with epilepsy
Children w/ epilepsy 2.5 more likely than other children to have psychiatric difficulties
Cumulative effect of learning interference Majority of childhood seizures are nocturnal.
Poor sleep quality effect upon cognition?
The most prevalent of the CNS adverse effects observed during AED therapy are sedation, somnolence, distractibility, insomnia and dizziness. Sedation, in particular, is associated with most of the commonly used AED therapies. CNS Drugs 2009; 23 (2): 121-137
Testing Models
Vast majority of studies on adult men
Vast majority of animal studies on adult males
Seizure type, clinical and electroencephalographic phenotype, syndrome, and etiology are often quite different in children with epilepsy than in adults. Despite these age-related unique features, drugs used in children are generally the same as those in adults.
Holmes GL, Zhao Q. Choosing the correct antiepileptic drugs: From animal studies to the clinic. Pediatr Neurol 2008; 38:151-162
Adult studies suggest improvement of cognitive dysfunction with cessation of AED and seizures.
Normal CNS Function
Excitation Inhibition
glutamate,aspartate
GABA
Modified from White, IGES, 2001
Excitation
Inhibition
GABA
glutamate,aspartate
Abnormal excitation
Modified from White, IGES, 2001
Excitation Inhibition
AEDs Act By Restoring Balance
Reduce excitationPHT, CBZ, VPA, FBM,LTG, TPM, OCBZ, ZNS,
Increase inhibitionPB, BDZ’s, VPA, FBM,TPM, ZNS, TGB, VGB
Modified from White, IGES, 2001
Bromides
Phenobarbitol
Phenytoin
Ethosuximide
Carbamazepine
Valproate
Vigabatrin
Lamotrigine
Gabapentin
Topiramate
Oxcarbamazepine & Levetriacetam
1857 1912 1938 1960 1965 ‘76 ‘89 ‘91 ‘93 ‘96 ‘97 ‘99 ’00 ‘05 ‘09 ‘10
Tiagabine
ZonisamidePregabalin
Lacosamide, Retigabine, Rufinamide
Brivaracetam
Felbamate
AEDs Spectrum of ActivityGeneralized Onset
Absence Myoclonic Atonic Tonic Tonic-Clonic
Ethosuximide Benzodiazepines
Partial Onset
Simple Complex
CarbamazepinePhenytoin GabapentinOxcarbazepinePregabalin
PhenobarbitalValproateLamotrigineLevetiracetamTopiramateZonisamide
FDA-Approved Indications
PartialSeizure
Gen.Seizure
LGS StatusEpilepticus
Phenobarbital XX XX XX XXPhenytoin XX XX XX XXCarbamazepine XX XX XXValproic acid XX XX XXFelbamate XX XXGabapentin XXLamotrigine XX XX XXLevetiracetam XX XXOxcarbazepine XXPregabalin XXTopiramate XX XX XXZonisamide XX
French et al, Epilepsia 45, 2006
AAN guidelines for new AEDs in newly diagnosed epilepsy
French et al, Epilepsia 45, 2006
AAN guidelines for new AEDs in refractory epilepsy
AED: Cognitive Side Effects Low
Gabapentin Lamotrigine Levetiracetam Pregabalin
Intermediate Carbamazepine Oxcarbazepine Phenytoin Valproic acid Zonisamide
High Topiramate Zonisamide Phenobarbital
CarbamazepineBenign Rolandic Seizure (J Child Neurol 1999;14:716-
723).
Slow processing
Impaired verbal memory
Partial or Generalized TC (Epilepsy & Behavior 14 (2009) 522–528)
Overall decline from baseline
Information processing speed and Attention
RemacemidePartial or Generalized TC (Epilepsy & Behavior 14 (2009)
522–528)
Overall decline from baseline
Information processing speed and Attention
Valproate Mild to Moderate slowing in psychomotor
speed and mental speed
Decreased verbal memory retrieval
Decreased visuospatial skills
Vigabatrim Visual field restriction
Behavioral problems
Conflictual findings
OxcarbazepineNo changes six and twelve months post
Lamotrigine Contrasted with topiramate
Less impairment with phonemic fluency
Less impairment with coding
GabapentinNo known cognitive side effects
TiagabineNo known cognitive side effects
As an add on therapy, can improve motor speed, reading speed, attention and verbal fluency
TopiramateDecline in verbal fluency and verbal
working memory
LevetiracetamImproved reaction time and motor speed
ZonisamideInitial impaired memory and verbal
learning in dose/concentration manner. Recovery to baseline after 12 weeks
ADHD and Epilepsy 20% of children with epilepsy have ADHD 3% to 7% typical children have ADHD The overall ADHD population has a greater
incidence of electroencephalography abnormalities (5.6-30.1% vs. 3.5%)
Methylphenidate treatment is equally efficient in children with isolated attention-deficit hyperactivity disorder and in children with attention-deficit hyperactivity disorder and epilepsy (70%-77%). (Kaufmann, Journal of Child Neurology, Volume 24 Number 6, June 2009 727-733)
ADHD and Epilepsy
Significantly impacts quality of life
Executive system dysfunction predictor of poor quality of life
Use of Psychostimulants no concern for children with controlled
seizures
Some concern for children with uncontrolled seizures. Seizure frequency can increase
BECTS: Longitudinal Study
Six children with Benign Epilepsy with Central-Temporal Spikes (BECTS) were evaluated for longitudinal neuropsychological abilities (memory, attention, visuospatial skills, receptive and expressive language, and executive system) using a within-patient repeated measures design.
Subject No. Gender AgeDuration of
EpilepsyFSIQ Medication
1 M 10 2 97 CBZ
2 F 11 2 109 CBZ
3 M 11 2 105 VPA
4 F 7 1 116 None
5 F 11 3 107 CBZ
6 M 9 3 137 CBZ
7 M 11 5 95 Unk
BECTS: Longitudinal Study
The children (ages 7-11 yrs) previously diagnosed with BECTS underwent repeated neuropsychological assessment following EEG recordings for 2-3 sessions at 1-2 month intervals. All patients demonstrated impaired performance (at least one standard deviation below the normative mean) on four or more of the cognitive measures.
BECTS: Longitudinal Study
Impaired performance was not associated with spike frequency rates or focus. All patients demonstrated some variability of performance (greater than one standard deviation of change) between sessions. Five of the six patients’ performance on the Test of Variables of Attention was consistent with the presence of Attention Deficit/Hyperactivity Disorder.
BECTS: Longitudinal Study
In particular, fluctuation was observed on measures of visual and auditory attention, executive system abilities, visual and verbal memory, and visuospatial organization.
BECTS: Longitudinal Study
EEG recordings revealed spike activity that was not correlated with cognitive performance. EEG recordings differed from session to session.
Sub ject
EEG #1 EEG #2 EEG #3 Consistency
Spike
Count
Async
Foci
Slow Wav
e Focu
s
Spike
Count
Async
Foci
Slow Wav
e Focu
s
Spike
Count
Async
Foci
Slow Wav
e Focu
s
≥5 vs. ≤6/min
≥10 vs. <10/
Async
Foci
Slow Wav
e Focu
s
1 NA NA NA 11.5 N Y 0 N Y N N Y N
2 NA NA NA 0 N N 0 N Y Y Y Y N
3 0 N N 4.2 N N NA NA NA Y Y Y Y
4 2.3 N Y 0 N N 4.8 N Y Y Y N N
5 0.8 Y N 3.8 Y N 0.8 N N Y Y Y Y
6 0.7 N Y 0.2 N Y 0.8 N Y Y Y Y Y
7 8.5 Y Y 28.6 Y Y NA NA NA Y N Y Y
BECTS: Longitudinal Study
Children with BECTS experience fluctuating EEG recordings and cognitive abilities on repeated measures over a two to three month period of time (1SD or greater difference) in attention, memory, visuospatial skills and executive system abilities, that can adversely affect their development and education