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Follow-up reports by The Johns Hopkins University School of Medicine and Galen Press on research presented at the 2001 meeting of the American Epilepsy Society

Antiepileptic drugs and seizure aggravation

The observation that antiepileptic drugs (AEDs) may precipitate seizures or worsen seizure control was first made in the 1960s, but recently this possibility has become the focus of increasing attention, according to Emilio Perucca, MD, PhD, professor of medical pharmacology at the University of Pavia in Italy. Although no precise incidence data are available, the literature suggests that seizure exacerbation by AEDs is relatively common, especially for children (Perucca E et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia. 1998;39[1]:5-17). The clinical manifestations of AED-induced seizure aggravation that have been identified include (1) the emergence of new seizure types that are not present in a patient's history, (2) an increase in the severity or frequency of preexisting seizure types, and (3) status epilepticus.

AED intoxication

Based on an extensive review, Dr Perucca distinguishes between two primary types of AED-related seizure exacerbation: intoxication and selective aggravation. Overdose with "virtually any AED," he says, can cause seizures even for people who do not have epilepsy. For patients with epilepsy, "AED intoxication can increase the frequency of preexisting seizure types," and "at times a change in seizure severity, the appearance of new seizure types, and even the precipitation of convulsive or nonconvulsive status epilepticus may be seen."

Dr Perucca says that the mechanisms for this type of seizure aggravation are often multifactorial and may include "facilitation of paroxysmal activity secondary to sedation, superimposition of AED actions not usually operating at lower dosages, and the contribution of ancillary pharmacologic actions." This last mechanism may be drug-specific -- for example, hyponatremia associated with carbamazepine or oxcarbazepine treatment. Although many patients present with other symptoms of intoxication, such as ataxia and stupor, for some patients exacerbation of seizures may be the only symptom, and in such cases, accurate diagnosis is difficult.

Most of the early reports of seizure aggravation through AED intoxication pertain to patients treated with phenytoin, but Dr Perucca points out that this preponderance might be due to that drug's more extensive use during the years when many of these observations were made. Development of intoxication may be more common with phenytoin as a result of the drug's nonlinear pharmacokinetics. Intoxication-related seizure aggravation has subsequently been reported with other drugs -- including carbamazepine, tiagabine, and valproate (Perucca et al, 1998). In the case of valproate, Dr Perucca cautions that seizure exacerbation may be "an important sign heralding severe hepatotoxicity" or may occur within the context of toxic encephalopathy even without high serum levels of the AED. "Overly aggressive polytherapy" may lead to worsening of seizure control, he observes, "regardless of plasma levels of the individual agents." For patients on polytherapy, toxicity may relate more to total drug load than to the dosage and serum levels of individual drugs.

Selective aggravation

In contrast to intoxication-induced exacerbation (which results when the AED dosage is too high for a particular patient), selective aggravation most often occurs when the wrong AED is prescribed for a specific type of epilepsy. According to Dr Perucca, this situation is thought to occur when "the primary pharmacologic action(s) of the administered AED adversely affects seizure generation or propagation in specific epileptic syndromes," particularly idiopathic generalized epilepsies with absence or myoclonic seizures. Selective seizure aggravation is generally more predictable than exacerbation due to AED intoxication.

The vast majority of reports of AED-induced selective aggravation of seizures revolve around carbamazepine and pediatric patients with generalized seizures. The drug has been reported to exacerbate or precipitate typical and atypical absences as well as atonic, tonic, and myoclonic seizures, at times with severe consequences, including status epilepticus. But Dr Perucca warns that there may be a "strong selection bias" in these retrospective reports and points out that no randomized prospective studies have addressed the issue of drug-induced seizure exacerbation. He also observes that spontaneous fluctuation or evolution of the disease process and the effect of discontinuing previous medication complicate interpretation of findings.

Selective aggravation is also common for patients treated with other sodium-channel blocking agents besides carbamazepine (oxcarbazepine, phenytoin) and drugs (such as gabapentin, tiagabine, and vigabatrin) that act through the gamma-aminobutyric acid (GABA) system. Generally, broad-spectrum AEDs are less likely to cause selective seizure aggravation, although Dr Perucca says that physicians should always bear in mind "the possibility of specific syndromes being made worse by any kind of drug treatment."

Occasionally selective aggravation may occur even when an AED is prescribed for a type of seizure for which it is usually effective. Many patients with juvenile myoclonic epilepsy appear to benefit from treatment with lamotrigine, but for some this drug may fail to control, or may indeed aggravate, myoclonic seizures (Biraben A et al. Exacerbation of juvenile myoclonic epilepsy with lamotrigine. Neurology. 2000;55[11]:1758). Dr Perucca explains that this varying response may reflect "pathophysiological heterogeneity" within this syndrome. For patients with severe myoclonic epilepsy of infancy, in contrast, lamotrigine has been found to cause more consistent aggravation. In one series of 21 patients with this rare disorder, the vast majority showed aggravation of at least 1 seizure type after being given adjunctive therapy with lamotrigine. Eventually, 19 of these patients discontinued the drug, with consequent clinical improvement for 18. Because lamotrigine dose needs to be titrated upward slowly, seizure deterioration developed insidiously and in some cases it was not readily recognized by the treating physicians (Guerrini R et al. Lamotrigine and aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39[5]:508-512).

Avoiding AED-induced seizure aggravation

According to Dr Perucca, the ability of AEDs to cause deterioration of seizures is often overlooked by the treating physician, who is therefore reluctant to remove the causative agent even when the patient or relatives have identified the relationship. "Doctors should learn how to listen carefully to their patients and be prepared to accept that in many situations removal of an AED or a reduction in its dosage may paradoxically help in bringing seizures under better control."

Correct identification of seizure types and syndromes is a key step in minimizing the risk of AED-induced seizure exacerbation. When it is not possible to diagnose a syndrome before treatment, Dr Perucca says that careful follow-up, including repeated EEG recordings when appropriate, may help establish the diagnosis and identify changes that might predict deterioration. In a study of 59 children with epilepsy who were given carbamazepine and had long-term follow-up with serial EEGs, of 33 who had an unchanged, improved, or minimally modified EEG during therapy, the vast majority did well and no one required discontinuation of the drug due to seizure exacerbation. On the other hand, of 26 children whose EEG showed deterioration with appearance or increase of epileptiform activity while taking carbamazepine, almost one half had to discontinue the drug because of seizure worsening, and most of those that continued on carbamazepine required polypharmacy (Talwar D et al. EEG changes and seizure exacerbation in young children treated with carbamazepine. Epilepsia. 1994;35:1154-1159).

Carbamazepine, phenytoin, and the GABAergic drugs should preferably be avoided for patients with syndromes known to be associated with absence seizures, and carbamazepine and the GABAergic drugs should be avoided for syndromes with myoclonic manifestations, such as juvenile myoclonic epilepsy. Dr Perucca says that juvenile myoclonic epilepsy is "probably underdiagnosed" and that patients may not report early morning myoclonus without specific prompting. He also recommends that carbamazepine be used with caution when seizure types are mixed.

Although patients with drug-resistant epilepsy and/or multiple seizure types may benefit from polypharmacy, Dr Perucca exhorts physicians to remember that greater drug loads not only carry increased risk of toxicity but also may worsen seizure control for some patients.