Factors associated with high risk for recurrent seizures following discontinuation of therapy include EEG abnormalities, known structural lesions, abnormalities on neurological exam, and history of frequent seizures or medically refractory seizures prior to control. Conversely, factors associated with low risk for recurrent seizures include idiopathic epilepsy, normal EEG, onset in childhood, and seizures easily controlled with a single drug. The risk of recurrent seizures ranges from 12-66% (French and Pedley, 2008). Typically 80% of recurrences will occur within 4 months of discontinuing therapy. The clinician and patient must weigh the risk of recurrent seizure and the associated potential deleterious consequences (e.g., loss of driving privileges) against the various implications of continuing medication including cost, unwanted effects, implications of diagnosis of epilepsy, etc. Medications should be tapered slowly over a period of several months.
Simple and Complex Partial and Secondarily Generalized Tonic-Clonic Seizures
The efficacy and toxicity of carbamazepine, phenobarbital, and phenytoin for treatment of partial and secondarily generalized tonic-clonic seizures in adults have been examined in a double-blind prospective study (Mattson et al., 1985). Carbamazepine and phenytoin were the most effective agents. The choice between carbamazepine and phenytoin required assessment of toxic effects of each drug. Decreased libido and impotence were associated with all three drugs (carbamazepine 13%, phenobarbital 16%, and phenytoin 11%). In direct comparison with valproate, carbamazepine provided superior control of complex partial seizures (Mattson et al., 1992). With respect to adverse effects, carbamazepine was more commonly associated with skin rash, but valproate was more commonly associated with tremor and weight gain. Overall, the data demonstrated that carbamazepine and phenytoin are preferable for treatment of partial seizures, but phenobarbital and valproic acid are also efficacious.
Control of secondarily generalized tonic-clonic seizures did not differ significantly with carbamazepine, phenobarbital, or phenytoin (Mattson et al., 1985). Valproate was as effective as carbamazepine for control of secondarily generalized tonic-clonic seizures (Mattson et al., 1992). Since secondarily generalized tonic-clonic seizures usually coexist with partial seizures, these data indicate that among drugs introduced before 1990, carbamazepine and phenytoin are the first-line drugs for these conditions.
One key issue confronting the treating physician is choosing the optimal drug for initiating treatment in new onset epilepsy. At first glance, this issue may appear unimportant because ~50% of newly diagnosed patients become seizure free with the first drug, whether old or new drugs are used (Kwan and Brodie, 2000). However, responsive patients typically receive the initial drug for several years, underscoring the importance of proper drug selection. Among the drugs available before 1990, phenytoin, carbamazepine, and phenobarbital induce hepatic CYPs, thereby complicating use of multiple anti-seizure drugs as well as impacting metabolism of oral contraceptives, warfarin, and many other drugs. These drugs also enhance metabolism of endogenous compounds including gonadal steroids and vitamin D, potentially impacting reproductive function and bone density. By contrast, most of the newer drugs have little if any effect on the CYPs. Factors arguing against use of recently introduced drugs include higher costs and less clinical experience with the compounds.
Ideally, a prospective study would systematically compare newly introduced anti-seizure drugs with drugs available before 1990 in a study design adjusting dose as needed and observing responses for extended periods of time (e.g., 2 years or more), in much the same manner as that used when comparing the older anti-seizure drugs with one another as described earlier (Mattson et al., 1985).
Unfortunately, such a study has not been performed. Many of the studies referenced in description of newer drugs did compare a new with an older anti-seizure drug, but study design did not permit declaring a clearly superior drug; moreover, differences in study design and patient populations preclude comparing a new drug with multiple older drugs or with other new drugs. The use of recently introduced anti-seizure drugs for newly diagnosed epilepsy was analyzed by subcommittees of the American Academy of Neurology and the American Epilepsy Society (French et al., 2004a; French et al., 2004b); the authors concluded that available evidence supported the use of gabapentin, lamotrigine, and topiramate for newly diagnosed partial or mixed seizure disorders. None of these drugs, however, has been approved by the FDA for either of these indications. Insufficient evidence was available on the remaining newly introduced drugs to permit meaningful assessment of their effectiveness for this indication.
Ethosuximide and valproate are considered equally effective in the treatment of absence seizures (Mikati and Browne, 1988). Between 50% and 75% of newly diagnosed patients are free of seizures following therapy with either drug. If tonic-clonic seizures are present or emerge during therapy, valproate is the agent of first choice. French and others concluded that available evidence indicates that lamotrigine is also effective for newly diagnosed absence epilepsy despite the fact that lamotrigine is not approved for this indication by the FDA.
Valproic acid is the drug of choice for myoclonic seizures in the syndrome of juvenile myoclonic epilepsy, in which myoclonic seizures often coexist with tonic-clonic and absence seizures. Levetiracetam also has demonstrated efficacy as adjunctive therapy for refractory generalized myoclonic seizures.
Two to four percent of children experience a convulsion associated with a febrile illness. From 25-33% of these children will have another febrile convulsion. Only 2-3% become epileptic in later years, a 6-fold increase in risk compared with the general population. Several factors are associated with an increased risk of developing epilepsy: preexisting neurological disorder or developmental delay, a family history of epilepsy, or a complicated febrile seizure (i.e., the febrile seizure lasted > 15 minutes, was one-sided, or was followed by a second seizure in the same day). If all of these risk factors are present, the risk of developing epilepsy is ~10%.
The increased risk of developing epilepsy or other neurological sequelae led many physicians to prescribe anti-seizure drugs prophylactically after a febrile seizure. Uncertainties regarding the efficacy of prophylaxis for reducing epilepsy combined with substantial side effects of phenobarbital prophylaxis (Farwell et al., 1990) argue against the use of chronic therapy for prophylactic purposes (Freeman, 1992). For children at high risk of developing recurrent febrile seizures and epilepsy, rectally administered diazepam at the time of fever may prevent recurrent seizures and avoid side effects of chronic therapy.
Seizures in Infants and Young Children
Infantile spasms with hypsarrhythmia (abnormal inter-ictal high amplitude slow waves and multifocal asynchronous spikes on EEG) are refractory to the usual anti-seizure agents. Corticotropin or the glucocorticoids are commonly used and repository corticotropin (h.p. acthar gel) was designated as an orphan drug for this purpose in 2003. A randomized study found vigabatrin (γ-vinyl GABA; sabril) to be efficacious in comparison to placebo (Appleton et al., 1999). Constriction of visual fields has been reported in a high percentage of patients treated with vigabatrin (Miller et al., 1999). The potential for progressive and permanent vision loss has resulted in vigabatrin being labeled with a black-box warning and marketed under a restrictive distribution program. The drug received orphan drug status for the treatment of infantile spasms in the U.S. in 2000 (and was FDA-approved in 2009 as adjunctive therapy for adults with refractory complex partial seizures). Ganaxolone also has been designated as an orphan drug since 1994 for the treatment of infantile spasms and completed a phase II clinical trial for uncontrolled partial-onset seizures in adults in 2009.
The Lennox-Gastaut syndrome is a severe form of epilepsy which usually begins in childhood and is characterized by cognitive impairments and multiple types of seizures including tonic-clonic, tonic, atonic, myoclonic, and atypical absence seizures. Addition of lamotrigine to other anti-seizure drugs resulted in improved seizure control in comparison to placebo in a double-blind trial (Motte et al., 1997), demonstrating lamotrigine to be an effective and well-tolerated drug for this treatment-resistant form of epilepsy. Felbamate also was found to be effective for seizures in this syndrome, but the occasional occurrence of aplastic anemia and hepatic failure have limited its use (French et al., 1999). Topiramate has also been demonstrated to be effective for Lennox-Gastaut syndrome (Sachdeo et al., 1999).
Status Epilepticus and Other Convulsive Emergencies
Status epilepticus is a neurological emergency. Mortality for adults approximates 20% (Lowenstein and Alldredge, 1998). The goal of treatment is rapid termination of behavioral and electrical seizure activity; the longer the episode of status epilepticus is untreated, the more difficult it is to control and the greater the risk of permanent brain damage. Critical to the management is a clear plan, prompt treatment with effective drugs in adequate doses, and attention to hypoventilation and hypotension. Since hypoventilation may result from high doses of drugs used for treatment, it may be necessary to assist respiration temporarily. Drugs should be administered by the intravenous route only. Because of slow and unreliable absorption, the intramuscular route has no place in treatment of status epilepticus. To assess the optimal initial drug regimen, a double-blind, multicenter trial compared four intravenous treatments: diazepam followed by phenytoin; lorazepam; phenobarbital; and phenytoin alone (Treiman et al., 1998). The treatments had similar efficacies, with success rates ranging from 44-65%. Lorazepam alone was significantly better than phenytoin alone. No significant differences were found with respect to recurrences or adverse reactions.