Aggravation of partial seizures by antiepileptic drugs: is there evidence from clinical trials?
OBJECTIVE
To assess clinical trials for evidence that antiepileptic drugs (AED) aggravate partial seizures. To determine if the methodology used to examine drug efficacy can also be used to examine seizure aggravation.


BACKGROUND
It is widely accepted that AED aggravate epilepsy in some patients. However, there is little published objective or quantitative evidence. Most reports concern generalized epilepsies.


METHODS
Pharmaceutical companies responsible for the development of five of the new AED were asked to provide data concerning seizure increases during randomized placebo-controlled, add-on clinical trials in patients with uncontrolled partial seizures. Seizure frequency in individual patients taking drug or placebo was compared with the baseline pretreatment seizure frequency. The counterpart of the 50% reduction used in efficacy analyses is a 100% increase, because both represent a twofold change. A dose-response relationship was also explored.


RESULTS
More than 40% of subjects in clinical trials of tiagabine (TGB), topiramate (TPM), and levetiracetam (LEV) experienced an increase in seizures while taking a placebo. Seizure increases were no more likely to occur when taking any of the three drugs than taking placebo. A doubling or more of seizure frequency was less likely to occur with TPM or LEV than with placebo but more likely with TGB. However, for TGB, this did not reach significance. There was some evidence for a dose-response effect with TGB but a negative effect with TPM (aggravation less likely with increasing dose). Data on gabapentin and lamotrigine were not provided.


CONCLUSIONS
Many patients with partial seizures experience an increase in seizures when a new AED is added to their therapy. However, it occurs no more frequently when taking drug than placebo. It probably represents the spontaneous fluctuation of seizure frequency. When a patient who has started a new AED deteriorates, this is not necessarily a drug effect.
Somerville
Ernest R
ER
Epilepsy Unit, Westmead Hospital, Sydney, Australia. e.somerville@staff.usyd.edu.au
D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects*; D004828:Epilepsies, Partial / Q000139:chemically induced*; D004829:Epilepsy, Generalized / Q000188:drug therapy*; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D000077287:Levetiracetam; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D010889:Piracetam / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D000078308:Tiagabine; D000077236:Topiramate
D000927:Anticonvulsants; D009557:Nipecotic Acids; D000077236:Topiramate; D005632:Fructose; D000077287:Levetiracetam; D000078308:Tiagabine; D010889:Piracetam