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