Selection of drugs for the treatment of epilepsy

Antiepileptic drug selection is based on efficacy for specific seizure types and epileptic syndromes. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the drug of choice is valproate. Secondary generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single drug or combination of drugs. The drugs of choice for absence seizures are ethosuximide and valproate. For control of tonic-clonic seizures, any of the other major antiepileptic drugs can be effective. If valproate cannot be used, carbamazepine, phenobarbital, phenytoin, or primidone is effective, but ethosuximide or a benzodiazepine needs to be added to control associated absence or myoclonic seizures. The drugs of first choice for partial epilepsies with partial and secondarily tonic-clonic seizures are carbamazepine and phenytoin. Increasing evidence suggests that valproate may be a third alternative. Phenobarbital and primidone are second choice selections because of side effects. A combination of two of these five major antiepileptic drugs may be necessary for inadequately controlled patients. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, and alcoholic epilepsy require specific drug treatment. For all these seizure types and epilepsy syndromes, treatment ultimately must be selected to provide maximal efficacy and minimal adverse effect for each individual patient.     

Carbamazepine in the treatment of epilepsy in people with intellectual disability

Carbamazepine is a major antiepileptic drug which is primarily used to treat epileptic patients suffering from partial seizures with or without secondary generalization, but which also has applications in those suffering from primary generalized tonic-clonic seizures. Besides its antiepileptic effect, carbamazepine is also indicated in the treatment of trigeminal and occipital neuralgia, and in manic depressive disorders. Because of its minimal unwanted effects on cognition and behaviour, carbamazepine is an excellent drug for the treatment of people with intellectual disability and epilepsy. Carbamazepine is still one of the most commonly prescribed medications in the treatment of epileptic disorders.     

Carbamazepine--a double-blind comparison with phenytoin.

In a double-blind crossover study, carbamazepine and phenytoin were compared as single anticonvulsants in 47 patients with focal and major generalized seizures. Each drug provided superior seizure control in about half the patients, but significantly fewer patients had objective side effects while taking carbamazepine. Neuropsychologic testing showed improved performance in cognitive function and emotional status of patients while and carbamazepine. No hematotoxic complications arose, but vigilant follow-up is advised. Mean serum level of carbamazepine was 9.3 microng per milliliter with a suggested therapeutic range of 8 to 12 microng per milliliter reached by eventual doses of 16 to 20 mg per kilogram. Carbamazepine offers an independent choice of improved seizure control with a possibility of fewer side effects.     

Anticonvulsant drug actions on neurons in cell culture

Summary Two actions of clinically used antiepileptic drugs have been studied using mouse neurons in primary dissociated cell culture. The antiepileptic drugs phenytoin, carbamazepine and valproic acid were demonstrated to limit sustained high frequency repetitive firing of action potentials at free serum concentratons that are achieved in patients being treated for epilepsy. Furthermore, an active metabolite of carbamazepine also limited sustained high frequency repetitive firing while inactive metabolites of phenytoin and carbamazepine did not limit sustained high frequency repetitive firing. Phenobarbital and clinically used benzodiazepines limited sustained high frequency repetitive firing of action potentials, but only at concentrations achieved during the treatment of generalized tonic-clonic status epilepticus. Ethosuximide did not limit sustained high frequency repetitive firing even at concentrations four times those achieved in the serum of patients treated for generalized absence seizures. Phenobarbital and clinically used benzodiazepines enhanced postsynaptic GABA responses at concentrations achieved free in the serum during treatment of generalized tonic-clonic or generalized absence seizures. However, phenytoin, carbamazepine, valproic acid and ethosuximide did not modify postsynaptic GABA responses at therapeutic free serum concentrations. These results suggest that the ability of antiepileptic drugs to block generalized tonicclonic seizures and generalized tonic-clonic status epilepticus may be related to their ability to block high frequency repetitive firing of neurons. The mechanism underlying blockade of myoclonic seizures may be related to the ability of antiepileptic drugs to enhance GABAergic synaptic transmission. The mechanism underlying management of generalized absence seizures remains unclear.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Results of a Nationwide Veterans Administration Cooperative Study Comparing the Efficacy and Toxicity of Carbamazepine,Phenobarbital, Phenytoin,and Primidone

Summary: : In 1985 a 5-year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double-blind prospective study design. A total of 622 patients, either previously untreated or undertreated, were entered into the study. Strict exclusion criteria limited confounding factors such as drug or alcohol abuse. Results showed that each of the four drugs used as monotherapy were similarly effective in the treatment of generalized tonic-clonic seizures, but carbamazepine was significantly more effective in the treatment of complex partial seizures as measured by 100% control. When the results for all four drugs were combined, the data showed that approximately 80% of the patients were adequately managed on monotherapy. Differences in toxicity were the most significant factor that discriminated between these four drugs. Both carbamazepine and phenytoin were associated with significantly lower incidences of intolerable side effects than were primidone or phenobarbital. A behavioral toxicity battery was performed whenever possible prior to administration of any antiepileptic drug and at 1, 3, 6, and 12 months after initiation of monotherapy. Significant differences in performance on all subtests of the battery were found between patients with epilepsy and a control group matched by age, sex, and education. When the differential effects of all four drugs on behavioral toxicity were compared, few statistically significant differences emerged. However, carbamazepine consistently produced fewer adverse effects on tests of attention/concentration and motor performance than did the other three antiepileptic drugs.     

Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial.

Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs, utilised as monotherapy in newly diagnosed epileptic patients. Between 1981 and 1987 243 adult patients aged 16 years or over, newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission. The overall outcome with all of the four drugs was good with 27% remaining seizure free and 75% entering one year of remission by three years of follow up. No significant differences between the four drugs were found for either measure of efficacy at one, two, or three years of follow up. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomised drug, was 10%. For the individual drugs phenobarbitone (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures, the choice of drug will be more influenced by considerations of toxicity and costs.     

Phenytoin: effective but insidious therapy for epilepsy in people with intellectual disability

Phenytoin (5,5-diphenylhydantoin), which has been in use for 60 years, is still an important antiepileptic drug. Its primary mechanism of action is modulation of the sustained repetitive firing of neurones by direct inhibition and blockage of voltage-gated sodium channels in the neuronal cell membrane, and by delay of cellular reactivation. The plasma protein binding of phenytoin is normally between 90% and 95%. The drug is rapidly distributed from the blood to the tissues and is almost completely metabolized in the liver. The plasma phenytoin concentration normally reaches the steady-state level within 1-2 weeks. The half-life of phenytoin is less than 20 h in low doses, but is prolonged in high doses, newborn infants and elderly people. The half-life is shortened when phenytoin is given concomitantly with an enzyme-inducing drug, such as phenobarbital or carbamazepine. Phenytoin is effective for treating generalized tonic-clonic seizures, partial seizures with or without generalization, and convulsive status epilepticus. Over the years, many new, and even serious, adverse effects of phenytoin have been recognized. Phenytoin encephalopathy, manifesting as cognitive impairment and a cerebellar syndrome, is an important adverse neurological effect, the development of which depends on the saturation kinetics of phenytoin, individual differences in phenytoin metabolism, an inhibitory effect of certain drugs on phenytoin metabolism, or the ability of certain drugs to displace phenytoin from plasma proteins, leading to an increase in the plasma level of unbound phenytoin. Because of its potentially adverse effects, phenytoin is not recommended as the first choice for treating epileptic seizures, except as a co-drug for managing convulsive status epilepticus. In patients with epilepsy who also have intellectual disability, and are susceptible to balance disturbances and cognitive dysfunction, it is wise to replace phenytoin with another drug, such as carbamazepine or oxcarbazepine. The long-term use of phenytoin is not recommended for patients with loss of locomotion, marked cognitive impairment, or symptoms and signs of cerebellar disease. The prevention of phenytoin intoxication, with the subsequent development of phenytoin-induced encephalopathy, depends on careful observation of the patients and frequent monitoring of plasma levels of phenytoin and other concomitantly administered antiepileptic drugs.     

Refractory idiopathic absence status epilepticus: A probable paradoxical effect of phenytoin and carbamazepine

PURPOSE: To compare the frequency of seizures and status epilepticus and their response to first-line drugs in patients with idiopathic generalized epilepsies receiving carbamazepine or phenytoin to those receiving other drugs or no treatment. METHODS: We performed a retrospective chart review of all cases of idiopathic generalized epilepsies treated by the authors between 1985 and 1994. We compared seizure frequency and mean intravenous benzodiazepine dose required to control absence status epilepticus, intraindividually in subjects on carbamazepine or phenytoin before and after discontinuation of these compounds, and interindividually to subjects without treatment or receiving other drugs. RESULTS: Bouts of absence or tonic-clonic status epilepticus and seizures in subjects treated with phenytoin or carbamazepine at therapeutic concentrations were considerably more frequent and proved intractable to treatment with valproic acid or benzodiazepines, compared with a cohort of subjects also with idiopathic generalized epilepsies, but naive to, or receiving subtherapeutic or therapeutic doses of other agents. CONCLUSIONS: Our observations strongly suggest that therapeutic concentrations of phenytoin and carbamazepine exacerbate idiopathic generalized epilepsies. Subjects in whom absence is one of the seizure types seem at a particularly high risk for responding paradoxically. These findings underscore the value of accurate classification of seizures and particularly the syndromic approach to diagnosis and point to the potential for iatrogenic complications with indiscriminate use of antiseizure drugs.     

Loss of taste and carbamazepine

Carbamazepine is the drug of choice for many partial and generalized seizures. Neurotoxic manifestations are the most common side effect. We present an unrecognized neurological complication associated with carbamazepine occurring probably as an idiosyncratic event.     

How to Initiate and Maintain Carbamazepine Therapy in Children and Adults

Summary: Appropriate use of carbamazepine for the treatment of epilepsy is based on correct identification of the patient's seizure type. Carbamazepine is effective against partial seizures and against generalized tonic-clonic seizures. Therapy should begin gradually, with initial doses increased slowly over 1 or 2 weeks, as tolerated. Side effects include fatigue, dizziness, ataxia, double vision, nausea, and vomiting. Most practitioners agree that, because of carbamazepine's relatively short half-life, the total dosage should be administered in at least two divided doses. This avoids too high a peak blood level that would occur with a single dose. Carbamazepine therapy is associated with the development of two hematologic conditions. Leukopenia, which may be transient or persistent, requires careful monitoring but is not cause for immediate discontinuation of therapy. Aplastic anemia occurs rarely but is potentially fatal, and therefore diligent monitoring of hematologic function is indicated. Aplastic anemia is an idiosyncratic, non-dose-related side effect that is most likely to occur within the first 3 or 4 months of initiating therapy. Once seizures are controlled, plasma levels of carbamazepine should be measured to establish optimum levels for individual patients being treated with this drug.     

Clinical Science

Pregabalin Drug Interaction Studies: Lack of Effect on the Pharmacokinetics of Carbamazepine, Phenytoin, Lamotrigine, and Valproate in Patients with Partial Epilepsy Martin J. Brodie, Elaine A. Wilson, David L. Wesche, Christine W. Alvey, Edward J. Randinitis, Edward L. Posvar, Neil J. Hounslow, Nicola J. Bron, G.L. Gibson, and Howard N. Bockbrader Pregabalin (Lyrica) is a new drug that has been approved in the EU as add‐on treatment for partial seizures, and as treatment of peripheral neuropathic pain, in adults. Because many patients with partial seizures require more than one antiepileptic drug (AED) to achieve the best seizure control they can, it is important to determine whether new drugs for treating partial seizures may interact with commonly used AEDs. This paper reports the results of several drug–drug interaction studies of pregabalin and commonly used AEDs. In these studies, pregabalin was given to patients who were each taking one AED, either valproate, phenytoin, lamotrigine, or carbamazepine, to treat their epilepsy. Adding pregabalin to monotherapy with valproate, phenytoin, lamotrigine, or carbamazepine had no effect on the concentrations in the blood of any of these four drugs. Likewise, when concentrations of pregabalin in the blood were measured in these same patients, the concentrations were similar to those seen in the blood of subjects from earlier studies who had received pregabalin by itself. These findings indicate that pregabalin does not interact with any of these four common AEDs. The combinations of pregabalin with either valproate, phenytoin, lamotrigine, or carbamazepine were generally well tolerated by the patients in these studies, and when side effects did occur, they were typically mild to moderate and resolved quickly. Together, these studies demonstrate that pregabalin may be safely added to therapy with valproate, lamotrigine, phenytoin, or carbamazepine without concern for drug–drug interactions.     

Lamotrigine therapy of epilepsy with Angelman's syndrome

PURPOSE: Angelman syndrome (AS) is a neurogenetic disorder characterized by developmental delay and a frequently refractory epileptic condition. Valproate, clonazepam and/or phenytoin are said to be the most effective antiepileptic drugs (AEDs) against the seizures in AS. Experience with the newer AEDs is very limited despite their better safety profile and tolerability. Considering its favorable side effect profile and its effectiveness against both partial and generalized seizures, we hypothesized that lamotrigine (LTG) might be more efficacious and better tolerated. METHODS: Potential patients for this retrospective study were identified from the epilepsy clinics at Notre-Dame, Sainte-Justine, and Yale New Haven hospitals. Patients were included in the study if they had AS along with refractory seizures. The medical record of each patient was reviewed with interest on seizure types, previous AEDs and response to LTG. RESULTS: Five patients (2M, 3F) were included in this study. Age at LTG ranged from 10 to 33 years old. All had >or=2 seizure types, mainly generalized tonic-clonic, myoclonic seizures, and atypical absences. Previously tried AEDs included valproic acid (5), benzodiazepines (5), phenytoin (4), carbamazepine (3), and topiramate (1). One patient had pancreatitis on phenytoin, one had worsened seizures on carbamazepine, and one developed hepatic encephalopathy on valproic acid. Three patients became seizure-free with LTG (9, 20, and 36 months FU), one was seizure-free for 1 year with subsequent loss of efficacy, and one showed >50% reduction in myoclonic seizures (20 months FU). No side effects were reported. CONCLUSION: LTG can be efficacious and well tolerated in patients with AS.     

Use of antiepileptic drugs in the treatment of epilepsy in people with intellectual disability

The main principles of antiepileptic drug treatment of epilepsy in patients with intellectual disability are basically the same as for other patients with epilepsy. However, some specific issues need to be taken into account These are primarily associated with the diagnostic difficulties of epilepsy in this population. In addition, a number of other relevant issues, including the degree and location of brain lesion, the nature of the underlying disease, the higher frequency of difficult-to-treat epilepsies, the additional intellectual impairment caused by inappropriate antiepileptic medication, or by frequent and prolonged seizures, the appropriate use of monotherapy versus rational polytherapy, and the use of broad-spectrum antiepileptic drugs will be discussed in the present paper. Although the goals of treatment are to keep the patient seizure-free and alert while preventing possible mental deterioration, we have to accept compromises between these primary goals in many cases. Some people with epilepsy and intellectual disability are very vulnerable to insidious neurotoxic effects; for example, sedative effects caused by phenobarbital, or cognitive and/or cerebellar dysfunction caused by long-term phenytoin, especially together with other drugs. Because of the adverse effects of phenobarbital and phenytoin, these drugs are no longer recommended as a first-choice drugs when long-term antiepileptic medication is required. In primary generalized tonic-clonic seizures, valproate, oxcarbazepine/carbamazepine and lamotrigine are recommended in this order of preference. The corresponding recommendations are: in typical absences, valproate, ethosuximide and lamotrigine; in atypical absences, valproate and lamotrigine; in juvenile myoclonic epilepsy, valproate, lamotrigine and clobazam; in infantile spasms vigabatrin, ACTH and valproate; in Lennox-Gastaut syndrome, valproate, lamotrigine and vigabatrin; in atonic seizures, valproate and lamotrigine; in simple and complex partial seizures with or without secondary generalization, oxcarbazepine/carbamazepine, valproate/ vigabatrin and lamotrigine; and in status epilepticus lorazepam, diazepam and clonazepam together with phenytoin or fosphenytoin. In cases of poor response to the monotherapy recommended above, the following combinations may be indicated: in primary generalized tonic-clonic epilepsy, valproate and oxcarbazepine/ carbamazepine, or valproate and lamotrigine; in typical absences, valproate and lamotrigine, or valproate and ethosuximide; in juvenile myolonic epilepsy, valproate and lamotrigine, or valproate and clonazepam; and in partial epilepsies, add to the monotherapy one of the following drugs, vigabatrin, lamotrigine, gabapentin, tiagabine, topiramate, zonisamide or clobazam. So far, the order of preference of these new drugs remains undetermined. More data are needed on the efficacy and adverse effects of the new drugs based on controlled studies on patients with intellectual disability and epilepsy.     

Effects of carbamazepine, clonazepam, and phenytoin on seizure threshold in amygdala and cortex

This experiment was designed to determine whether or not the stronger effect of anticonvulsants on cortex than on amygdala focal seizures was due to a greater elevation of cortex seizure threshold. The effects of several doses of carbamazepine, clonazepam, and phenytoin were examined on the threshold for electrically induced afterdischarge in amygdala and cortex in 71 rats. All three drugs were found to be effective in increasing the seizure threshold with greater effects being produced in the cortex than in the amygdala. Carbamazepine produced the largest threshold increase in both foci, and clonazepam produced the weakest effects. These data are comparable to previous data on drug action against focal or partial seizures, and suggest that anticonvulsants may control partial attacks through their action on the local seizure threshold. This theory of anticonvulsant drug action adds to the common belief that carbamazepine and phenytoin act primarily by blocking seizure spread.     

Alternative single anticonvulsant drug therapy for refractory epilepsy

Fifty-nine patients with chronic generalized tonic-clonic or partial seizures refractory to the maximally tolerated daily dosage of single-drug therapy with carbamazepine, phenytoin, phenobarbital, or primidone subsequently received single-drug therapy with another one of these primary anticonvulsant drugs. Alternative single-drug therapy resulted in complete seizure control or more than 75% seizure reduction for 18 patients (31%). Side effects disappeared in 16 patients (27%). Patients with a good therapeutic response often had epilepsy of recent onset. Alternative single-drug therapy is beneficial for chronic refractory epilepsy and should be considered before a second drug is permanently added.     

Protease inhibitor-induced carbamazepine toxicity

Neurologic manifestations of HIV infection are quite diverse and can develop into seizures. Because new drug therapies have been developed, it is important to know the interactions between antiretroviral and antiepileptic agents. A 36-year-old patient with HIV developed a set of progressive left hemiparesis and secondarily generalized partial seizures related to progressive multifocal leukoencephalopathy. Phenytoin and carbamazepine were necessary to control the seizures. Instead of diverse antiretroviral therapies, the viral load was increased. Protease inhibitors (ritonavir and saquinavir) were added to the treatment and the patient developed progressive ataxia related to carbamazepine toxicity. Carbamazepine was discontinued and the patient remained asymptomatic. The patient was diagnosed with carbamazepine toxicity related to the introduction of ritonavir. Ritonavir is a potent inhibitor of hepatic cytochrome P450, mainly the CYP3A4 isoform. Carbamazepine is metabolized by this subsystem. Ritonavir acted as a CYP3A4 inhibitor, diminishing carbamazepine metabolism and provoking an increase in serum levels and clinical toxicity. We present a case of interaction between ritonavir and carbamazepine. Interaction between antiepileptic and antiretroviral agents is an emergent problem caused by the increasing association of the two therapies. We recommend strict monitoring of serum antiepileptic drug (AED) levels to avoid toxicity and inadequate seizure control.     

Aspects of antiepileptic drug therapy in children

During the past 10 years, better results in the treatment of epilepsy have been obtained through the application of pharmacokinetic data to drug therapy of epilepsy. However, pediatric drug therapy is complicated by the continuous change in body weight and body composition with the growth and development, especially during infancy. Younger children require a higher dose per kilogram of body weight than older children in order to achieve comparable plasma concentrations. Plasma levels and seizure control were investigated in a prospective randomized study when phenytoin, carbamazepine (CBZ) or sodium valproate (VPA) was given as a single drug to pediatric patients with several types of epileptic seizures. Studies on newly referred, previously untreated children suggest that both partial and generalized tonic-clonic seizures can be prevented by each of the three drugs. No significant differences in clinical efficacy were found among the three drugs, when optimum plasma concentration ranges were maintained with blood level monitoring. Clonazepam (CZP) may be effective in partial seizures. However, as a wide range of plasma levels was associated with complete freedom from seizures, it was not possible to define a therapeutic range for CZP. Any patient who receives multiple-drug therapy is at risk to develop a drug-drug interaction. Simultaneous administration of VPA was associated with a raised plasma level of carbamazepine-10,11-epoxide (CBZ-E), a major metabolite of CBZ, relative to the CBZ dose, whereas the plasma CBZ level remained unaltered. High plasma concentration of CBZ-E may be responsible for side effects in some patients. Drug-protein binding interactions are another source of side effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phenobarbital still has a role in epilepsy treatment

Phenobarbital, the oldest of the currently available antiepileptic drugs, has lost its popularity in this era of multiple new drugs and is seldom used after infancy in developed countries. We report a group of patients with generalized epilepsy in whom phenobarbital proved to be the drug of choice. Phenobarbital monotherapy was given to 20 patients with idiopathic generalized epilepsy beginning in childhood but persisting into adulthood. All the patients have normal intelligence and neurologic status. The electroencephalogram has either been normal or showed generalized spike-wave discharges. All patients' seizures are fully controlled on once-a-day low-dose phenobarbital with no side effects. Attempts to discontinue the medication have led to recurrence of seizures. We believe that in patients with mild generalized tonic-clonic seizures phenobarbital could still be the drug of choice since it is cheap, safe, convenient, and effective.