Valproate Has a Benign Effect on Cognition and Possibly for Myoclonic Status Epilepticus

abstracts & commentary

Sources: Dikmen SS, et al. Neuropsychological effects of valproate in traumatic brain injury: A randomized trial. Neurology 2000;54:895-902; Sheth RD, Gidal BE. Intravenous valproic acid for myoclonic status epilepticus. Neurology 2000; 54:1201.

Valproate already enjoys a reputation of being an anticonvulsant that has the fewest cognitive effects. It is difficult to obtain hard data that confirms this. Put briefly, anticonvulsants may improve cognitive function in the epileptic by controlling seizures, yet worsen baseline cognitive function as the attacks subside. Indeed, few large studies have specifically examined the cognitive effects of anticonvulsants in the absence of clinically expressed seizures. Dikmen and colleagues report the neuropsychological outcome of 279 nonepileptic patients randomized to receive anticonvulsant treatment vs. placebo following traumatic brain injury. Patients were randomized to three arms of the study: 1) one week of phenytoin; 2) one month of valproate; or 3) six months of valproate. After completing treatment, patients in the first two groups received placebo until six months after injury. Patient outcome and neuropsychological testing after one month and six months constituted the primary measures of treatment effect. As this population experienced few seizures—of 279 patients, there were a total of five seizures in the first month and seven in the subsequent five months distributed randomly across treatments—the cognitive effects of anticonvulsants were not confounded by treatment of frequent seizures.

Dikmen et al found no significant change in cognitive function between treatment groups tested one month and six months after injury. Patients taking valproate for one or six months fared no worse or better than patients taking phenytoin (Dilantin; Parke-Davis) for one week followed by placebo. Valproate produced no additional cognitive impairment. In contrast, there was a trend toward higher mortality in both of the valproate-treated groups (P = 0.07) when compared to the phenytoin-treated group. These investigators conclude that valproate neither prevented post-traumatic seizures, nor did it worsen cognitive function.

A series of recent case reports document the first experience with intravenous valproic acid in the treatment of nonconvulsive status epilepticus. The latest of these communications—a letter from Sheth and Gidal—reports the first intravenous use of valproate in two patients with juvenile myoclonic epilepsy. Both patients presented initially with a subacute impairment of mentation accompanied by myoclonic jerks and paroxysmal changes on electroencephalogram (EEG) despite ongoing treatment with appropriate doses of lamotrigine in one patient, and of phenytoin in the other. Both patients received 500 mg valproic acid intravenously over 30 minutes. Almost immediately upon completion of the valproate infusion, both patients returned to their pre-seizure baseline mental status.

Commentary

More experience with intravenous valproate is necessary before it can be accepted as first-line treatment for nonconvulsive status epilepticus. Primary generalized epilepsies, especially juvenile myoclonic epilepsy, however, often respond well to valproate. In patients whose underlying epilepsy is known to be sensitive to valproate, intravenous valproic acid may provide an effective treatment of myoclonic status epilepticus without risk of sedation. In cases of nonconvulsive status epilepticus in which the underlying seizure disorder is known to respond to valproate, clinicians should consider the risks of sedation or other side effects from first-line anticonvulsants. As a start, one could compare benzodiazepines or phenytoin against the potential benefit and side effects of intravenous valproate. But, a note of caution should appear. As with phenytoin, intramuscular injection of valproate can cause tissue necrosis. Furthermore, since valproate inhibits the metabolism of lamotrigine, physicians should adjust the latter’s dosage if valproate is added to the daily regimen. —fal

Following traumatic brain injury, treatment with valproic acid was associated with:

a. increased mortality at six months.

b. increased incidence of myoclonic status epilepticus at six months.

c. improved cognitive function at six months.

d. cognitive impairment in nonepileptic patients.

e. worsened cognitive function at six months.