Vigabatrin is useful in the treatment of infantile spasms, especially when associated with tuberous sclerosis. The drug is also effective against focal seizures. The half-life is approximately 6–8 hours, but the pharmacodynamic activity of the drug is more prolonged and not well correlated with the plasma half-life because recovery from the drug requires synthesis of replacement GABA-T enzyme. In infants, the dosage is 50–150 mg/kg/d. In adults, vigabatrin is started at an oral dosage of 500 mg twice daily; a total of 2–3 g/d may be required for full effectiveness. The most important adverse effect of vigabatrin is irreversible retinal dysfunction. Patients may develop permanent bilateral concentric visual field constriction that is often asymptomatic but can be disabling. Minimal evidence also suggests that vigabatrin also can damage the central retina. The onset of vision loss can occur within weeks of starting treatment or after months or years. Other adverse effects are somnolence, headache, dizziness, and weight gain. Less common but more troublesome adverse effects are agitation, confusion, and psychosis; preexisting mental illness is a relative contraindication.
Seven benzodiazepines play roles in the treatment of seizures and epilepsy (see also Chapter 22). All produce their functional effects by positive allosteric modulation of GABAA receptors; however, subtle structural differences among the benzodiazepines result in differences in their pharmacokinetic properties. Certain benzodiazepines are the first-line acute treatment for seizures, either in status epilepticus or acute repetitive seizures (seizure clusters). However, two prominent aspects of benzodiazepines limit their usefulness in the chronic therapy of epilepsy. The first is their pronounced sedative effects; however, in children, there may be a paradoxical hyperactivity, as is the case with other sedative agents such as barbiturates. The second problem is tolerance, in which seizures may respond initially but recur within a few months. As a result of these limitations, benzodiazepines are infrequently used in the chronic treatment of epilepsy.
Diazepam given intravenously is a first-line treatment for status epilepticus. It is also used in a rectal gel formulation for the treatment of acute repetitive seizures (seizure clusters). The drug is occasionally given orally on a long-term basis, although it is not considered very effective in this application, because of the development of tolerance. Lorazepam is more commonly used in the treatment of status epilepticus because it has a more prolonged duration of action after bolus intravenous injection. There is evidence that intramuscular midazolam, which is water soluble, is preferred in the out-ofhospital treatment of status epilepticus because the delay required to achieve intravenous access may be avoided. Clonazepam is a long-acting benzodiazepine that on a milligram basis is one of the most potent antiseizure agents known. It has documented efficacy in the treatment of absence, atonic, and myoclonic seizures. As is the case for all benzodiazepines, sedation is prominent, especially on initiation of therapy; starting doses should be small. Maximal tolerated doses are usually in the range of 0.1–0.2 mg/kg/d, but many weeks of gradually increasing daily doses may be needed to achieve these dosages in some patients. Nitrazepam is not marketed in the USA but is used in many other countries, especially for infantile spasms and myoclonic seizures. Clorazepate dipotassium is approved in the USA for the treatment of focal seizures. Drowsiness and lethargy are common adverse effects, but as long as the drug is increased gradually, dosages as high as 90 mg/d can be given. Clobazam is described earlier in this chapter under atonic seizures.