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.     

Treatment of the Nonconvulsive Epilepsies

Summary: Eliminating seizures should be the first goal of therapy for non-convulsive epilepsies, but preventing seizures, i.e., guarding against head injuries and immunizing against agents that attack the nervous system, is the second goal. An accurate diagnosis of seizure type helps ensure that the appropriate medication for that particular form of epilepsy will be prescribed. Drug decisions should also be based on the risk:benefit ratio to the individual patient, and drug interactions should be considered when more than one drug is required. Frequent monitoring of drug serum levels is necessary in the case of multiple drug therapy or until seizures are controlled. Ethosuximide is considered the drug of choice in absence seizures, but valproic acid is equally effective. Although effective in controlling absence seizures, clonazepam is not favored in this indication because of a high incidence of side effects and the development of tolerance. Atonic seizures are generally refractory to treatment, but valproate, clonazepam, and occasionally carbamazepine represent the drugs of choice in management. Phenytoin continues to be a very popular drug for most types of seizures, but carbamazepine, used adjunctively until recently, is effective as monotherapy for the control of partial seizures, particularly those of the complex partial variety.     

Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.     

Levetiracetam in the treatment of epilepsy

Epilepsy is a common chronic disorder that requires long-term antiepileptic drug therapy. Approximately one half of patients fail the initial antiepileptic drug and about 35% are refractory to medical therapy, highlighting the continued need for more effective and better tolerated drugs. Levetiracetam is an antiepileptic drug marketed since 2000. Its novel mechanism of action is modulation of synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain. Its pharmacokinetic advantages include rapid and almost complete absorption, minimal insignificant binding to plasma protein, absence of enzyme induction, absence of interactions with other drugs, and partial metabolism outside the liver. The availability of an intravenous preparation is yet another advantage. It has been demonstrated effective as adjunctive therapy for refractory partial-onset seizures, primary generalized tonic-clonic seizures, and myoclonic seizures of juvenile myoclonic epilepsy. In addition, it was found equivalent to controlled release carbamazepine as first-line therapy for partial-onset seizures, both in efficacy and tolerability. Its main adverse effects in randomized adjunctive trials in adults have been somnolence, asthenia, infection, and dizziness. In children, the behavioral adverse effects of hostility and nervousness were also noted. Levetiracetam is an important addition to the treatment of epilepsy.     

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.     

Total or partial withdrawal of antiepileptic drugs

Total withdrawal of antiepileptic drugs leads to a mean relapse rate of approximately 50 p. 100 in adults and 25 p. 100 in children. The relapse rates are lowest in patients with benign epilepsies of childhood and epilepsies with absence seizures only and those with a short duration of epilepsy. Relapse rates are higher in patients with complex partial seizures, absences with generalized tonic-clonic seizures, juvenile myoclonic epilepsy, patients with several types of seizures, high seizure frequency prior to control, in patients with neurological, psychiatric or social handicaps and in those with emotional ambivalence towards the reduction. Guidelines for slow and safe withdrawal are given. Reduction should be actively encouraged only in patients with absence seizures or benign focal epilepsy and those with epilepsy of short duration. Slow partial withdrawal is recommended in uncontrolled epilepsy because in 80 p. 100 of the patients it results in a decrease in seizure frequency and side effects or both.     

Zonisamide: Review of Recent Clinical Evidence for Treatment of Epilepsy

Zonisamide is an orally administered antiepileptic drug that was first approved for clinical use in Japan in 1989. Since then, it has been licensed in Korea for a broad spectrum of epilepsies in adults and children, and in the USA for adjunctive therapy of adults with partial seizures, and in Europe for monotherapy of adults with newly diagnosed partial seizures and adjunctive therapy of adults and adolescents and children aged ≥6 years with partial seizures with or without secondary generalization. Zonisamide is a benzisoxazole derivative with a unique chemical structure, predictable dose‐dependent pharmacokinetics, and multiple complementary mechanisms of action. Treatment with zonisamide is well tolerated and is not known to be associated with clinically significant drug–drug interactions, including with oral contraceptives or other antiepileptic drugs. There have been >2 million patient‐years of experience with zonisamide for treatment of epilepsy, and this drug has International League Against Epilepsy level A evidence for efficacy/effectiveness as initial monotherapy for adults with partial‐onset seizures. This review presents the evidence for zonisamide across the spectrum of epilepsy, with emphasis on real‐world clinical practice and special populations of patients (children, elderly patients, and women of childbearing age) who are likely to be treated in daily clinical practice.     

Juvenile absence epilepsy exacerbated by valproic acid

Valproic acid is commonly and effectively used in the treatment of idiopathic generalized epilepsies, including juvenile absence epilepsy. Although several adverse effects are associated with this drug, it has only rarely been known to exacerbate seizures. Similar to antiarrhythmic drugs aggravating particular arrhythmias, antiepileptic drugs can paradoxically induce new seizure types or exacerbate existing ones. This reaction is better known with carbamazepine and phenytoin, but is less common with broad-spectrum antiepileptic drugs such as valproic acid. This report describes a case of paradoxical, intravenous valproic acid-induced seizure exacerbation in a child with juvenile absence epilepsy, documented by video-electroencephalography.     

Seizure Risk in Offspring of Parents with Generalized Versus Partial Epilepsy

Genetic factors are commonly assumed to play a more important role in generalized than in partial epilepsy. This study tested this hypothesis by comparing risks of unprovoked seizures in offspring of individuals with generalized versus partial epilepsy. Overall, seizure incidence was no higher in offspring of persons with generalized epilepsy than in offspring of those with partial epilepsy. The number of affected offspring was about three times that expected from population incidence rates, regardless of whether the parent had partial or generalized epilepsy. For the subgroup of generalized cases with absence seizures, however, seizure incidence in offspring was about three times as high as for partial cases. The higher incidence in offspring of absence cases was only partly explained by a higher proportion of absence than partial cases with two factors associated with high risk in relatives, namely early age at onset and idiopathic epilepsy. Offspring of absence cases had higher risk than offspring of other cases not only for absence seizures, but for other seizure types as well, suggesting that absence epilepsy is not genetically distinct from other seizure types of epilepsy. These results suggest that the higher incidence sometimes observed in relatives of patients with generalized epilepsy is due to a small proportion of generalized cases with extremely high familial risks--most generalized epilepsies are no more likely than partial epilepsies to have a genetic basis.     

Sodium Valproate: Monotherapy and Polytherapy

Summary: Of the 605 patients seen since 1973, 336 patients have been treated with sodium valproate (VPA) alone or in combination with drugs other than carbamazepine (CBZ). Of these 336, 240 have been on monotherapy, of whom 200 are seizure-free. Follow up has been longer than 3 years in 78%. Complete control of seizures has been achieved in more than 80% of patients with absence, myoclonic, and primary tonic-clonic seizures, in 72% of those with photosenstivie epilepsy including eyelid myoclonia, and in 47% of partial epilepsies, for which carbamazepine was the initial drug of choice. Only 21% of those with myoclonic astatic epilepsy have become free from seizures. At first VPA was given twice daily, but in recent years it was given once daily, as this was more effective. Reasons for failure of VPA therapy are given. Side effects in 436 patients (100 more patients were added for this assessment only) were uncommon, though where they did occur, weight increase was the most frequent. Platelets were reduced without clinical problems. There were no severe hepatic disorders. Serum levels were assessed in seizure-free patients, and the optimum level was between 60 and 120 mg/L (most patients received between 20 and 30 mg/kg). VPA was given during 30 pregnancies, and there was no evidence of teratogenicity on monotherapy. VPA is most effective in primary generalized epilepsy, especially if given as the sole antiepileptic drug. If the daily dose does not exceed 40 mg/kg or 2.5 g, it is singularly free from serious side effects.     

The Absence Epilepsies

Four syndromes comprise the absence epilepsies. Each is classically associated with the absence seizure, although other syndromes also have absence attacks as part of their repertoire. The most common syndrome is childhood absence epilepsy; it usually occurs in the age range of 6–7 years. The absence seizures may occur many times daily, and the electroencephalographic (EEG) characteristics are the most typical of the absence epilepsies. The second form of absence epilepsies is juvenile absence epilepsy; it begins near puberty and may represent a continuum from the childhood form. Myoclonic seizures are more common than in the childhood form, and the spike-wave discharges in the EEG are often faster than that seen in childhood absence epilepsy. The third form of absence epilepsy is juvenile myoclonic epilepsy, characterized especially by myoclonic jerks in the morning; these attacks occasionally progress to generalized tonic-clonic seizures. The final form of absence epilepsy is epilepsy with myoclonic absences, a rare disorder with a specific form of absence seizures. The absence seizure itself is observed to a greater or lesser extent in all of these syndromes. This seizure is a curious event, and its causes are poorly explained by current knowledge of the fundamental mechanisms of the epilepsies. Although the etiology of the absence seizure at a biochemical level is unknown, some studies suggest that certain low-threshold calcium ion currents (T currents), which are partially controlled by GABA-B mechanisms, may activate burst firing of thalamic neurons, initiating an absence seizure. The evidence of a genetic predisposition for the absence epilepsies is overwhelming. Although the nature of the genetic abnormality remains unclear, promising investigations may soon reveal the location and the nature of the genetic defect.     

Photosensitivity in epileptic syndromes of childhood and adolescence.

PURPOSE: Photosensitivity, a reaction of the brain to external photic stimulation, can be graded from 1 to 4, and is most frequently seen in the first decades of life. This study investigated photosensitivity in children with epilepsy. METHODS: A retrospective study performed in the neuropaediatric department of the largest paediatric hospital in Kiel, treating patients at all medical care levels. The clinical data and EEG records of 566 patients with the most common epileptic syndromes were analyzed, in particular regarding photosensitivity. Their EEGs included application of intermittent light stimulation using standard techniques at twice the minimum. RESULTS: The proportion of photosensitive patients was significantly higher in the paediatric cohort than in adult patients, as published in the literature: 46% of patients with generalized epilepsies showed photosensitivity as compared to 20% with focal epilepsies. Photosensitivity was more common in idiopathic generalized epilepsy (IGE), (epilepsy with grand mal on awakening, 74%; juvenile absence epilepsy, 56%; juvenile myoclonic epilepsy, 50%; childhood absence epilepsy, 44%) than in focal types (idiopathic partial - Rolandic epilepsy, 23%; symptomatic/cryptogenic type of epilepsy, 16%), while in patients who experienced occasional seizures (neonatal/febrile seizures), this ranged between 40% and 23%, respectively. The generalized photoparoxysmal response, (PPR), grades 3 and 4 were found significantly more often in patients with IGE (92%) than in patients with focal epilepsies. Finally, the female preponderance was confirmed (37% to 27% of all epilepsies). CONCLUSIONS: Photosensitivity can be detected both in patients with IGE, with idiopathic and symptomatic/cryptogenic types of focal epilepsies, and with epileptic (occasional) seizures. PPR grades 3 and 4 are the most common in IGE.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Sultiame revisited: treatment of refractory absence seizures

Sultiame is recommended for the treatment of benign epilepsy of childhood with centrotemporal spikes, electrical status epilepticus during slow‐wave sleep, as well as other genetic (idiopathic) focal epilepsies. Sultiame is not traditionally considered a treatment choice for idiopathic generalised epilepsy, and it does not appear on the list of drugs recommended for treatment of absence seizures. We report the efficacy of sultiame in treating three children with drug‐resistant absence seizures and discuss the potential use of sultiame beyond the idiopathic focal epilepsies.     

Tiagabine-induced absence status in idiopathic generalized epilepsy.

Several medications such as baclofen, amitriptyline and even antiepileptic drugs such as carbamazepine or vigabatrin are known to induce absence status epilepticus in patients with generalized epilepsies. Tiagabine (TGB) is effective in patients with focal epilepsies. However, TGB has also been reported to induce non-convulsive status epilepticus in several patients with focal epilepsies and in one patient with juvenile myoclonic epilepsy. In animal models of generalized epilepsy, TGB induces absence status with 3-5 Hz spike-wave complexes. We describe a 32-year-old patient with absence epilepsy and primary generalized tonic-clonic seizures since 11 years of age, who developed her first absence status epilepticus while treated with 45 mg of TGB daily. Administration of lorazepam and immediate reduction in TGB dosage was followed by complete clinical and electroencephalographic remission. This case demonstrates that TGB can induce typical absence status epilepticus in a patient with primary generalized epilepsy.     

Diagnosis of Childhood Seizure Disorders

Summary: Convulsive epilepsies are generally unmistakable. Absence epilepsies, which are easily recognized by the provocation of an episode during hyperventilation and by the typical features of the EEG, can be overdiagnosed, especially in the child who daydreams in class and has scattered, asymptomatic, epileptogenic EEG changes. As in adults, complex partial seizures in children can be difficult to distinguish from certain behaviors. Several types of benign childhood epilepsies need to be distinguished from the more intractable and lesional childhood epilepsies. Two common examples, benign rolandic epilepsy and benign occipital epilepsy, can be recognized by their unique EEG changes and clinical features. Juvenile myoclonic epilepsy generally does not remit spontaneously but should be recognized because it appears to respond to valproate. Some recurrent nonepileptic events seen in children can be mistaken for seizures, including shuddering attacks, paroxysmal vertigo, breath-holding spells, cardiogenic syncope, night terrors, and movement disorders, such as paroxysmal kinesigenic choreoathetosis.     

Efficacy of the ketogenic diet: Which epilepsies respond?

We report the efficacy of the ketogenic diet in refractory epilepsies focusing on outcomes with regard to epilepsy syndromes and etiology in children and adults with refractory epilepsy. Sixty-four consecutive children and four adults were prospectively enrolled from 2002 to 2009; seven were excluded from analysis. The classical ketogenic diet was initiated on an inpatient basis with dietary ratios ranging from 2:1 to 4:1 fat to carbohydrate and protein. Patients were classified according to syndrome and etiology using the 1989 and more recent 2010 International League Against Epilepsy (ILAE) classification systems. Responders were defined as >50% reduction in seizure frequency compared to baseline. Syndromes included symptomatic generalized (52), genetic (idiopathic) generalized (7), and focal epilepsies (2) and etiologies included structural (24), genetic (18), and unknown (19). Twenty-nine (48%) of 61 patients were responders at 3 months. Two children became seizure-free: one with focal epilepsy of unknown etiology and another with refractory childhood absence epilepsy. Responsive syndromes included migrating partial epilepsy of infancy, childhood absence epilepsy, focal epilepsy, epilepsy with myoclonic-atonic seizures, and Dravet syndrome. Children with lissencephaly and hypoxic ischemic encephalopathy had surprisingly good responses. The ketogenic diet is an effective treatment for children and adults with refractory epilepsy. The response is predicted by type of epilepsy syndrome. Accurate characterization of the electroclinical syndrome is an important factor in decisions about timing of initiation of the ketogenic diet.     

Chronic management of seizures in the syndromes of idiopathic generalized epilepsy

As a group, idiopathic generalized epilepsies (IGEs) have the highest rates of complete seizure control with medication. However, there are little evidence-based data to guide drug choice for treatment. Examples of IGE include absence epilepsy, generalized tonic-clonic epilepsy, and juvenile myoclonic epilepsy. Generalized epilepsies seem to be particularly vulnerable to seizure aggravation, and medications that are primarily effective against partial seizures are more commonly involved in seizure aggravation than other medications. A review of current research has shown that only a few medications can control IGE without potentially causing seizure aggravation. Broad-spectrum antiepileptic drugs such as valproate (VPA), lamotrigine, and topiramate are extremely effective at controlling a variety of seizures without causing excessive seizure aggravation. Among these drugs, VPA has the longest clinical experience history and the largest body of published data.     

Focal epilepsies: Update on diagnosis and classification

Correctly diagnosing and classifying seizures and epilepsies is paramount to ensure the delivery of optimal care to patients with epilepsy. Focal seizures, defined as those that originate within networks limited to one hemisphere, are primarily subdivided into focal aware, focal impaired awareness, and focal to bilateral tonic–clonic seizures. Focal epilepsies account for most epilepsy cases both in children and adults. In children, focal epilepsies are typically subdivided in three groups: self-limited focal epilepsy syndromes (e.g., self-limited epilepsy with centrotemporal spikes), focal epilepsy of unknown cause but which do not meet criteria for a self-limited focal epilepsy syndrome, and focal epilepsy of known cause (e.g., structural lesions—developmental or acquired). In adults, focal epilepsies are often acquired and may be caused by a structural lesion such as stroke, infection and traumatic brain injury, or brain tumors, vascular malformations, metabolic disorders, autoimmune, and/or genetic causes. In addition to seizure semiology, neuroimaging, neurophysiology, and neuropathology constitute the cornerstones of a diagnostic evaluation. Patients with focal epilepsy who become drug-resistant should promptly undergo assessment in an epilepsy center. After excluding pseudo-resistance, these patients should be considered for presurgical evaluation as a means to identify the location and extent of the epileptogenic zone and assess their candidacy for a surgical procedure. The goal of this seminar in epileptology is to summarize clinically relevant information concerning focal epilepsies. This contributes to the ILAE's mission to ensure that worldwide healthcare professionals, patients, and caregivers continue to have access to high-quality educational resources concerning epilepsy.     

Monday July 3, 200619:30–21:00Hall 1Sanofi-Aventis Satellite SymposiumManagement of epilepsy across the ages

¹ A. Arzimanoglou (   ¹ University Hospital Robert Debré, Paris, France )
Idiopathic Generalised Epilepsies (IGE) account for nearly one third of all epilepsies and the majority of cases have an onset in childhood or adolescence. When treated with the appropriate AEDs the majority of IGE patients will become seizure-free and will benefit from fully normal schooling and societal life. Consequently, individual tolerance of the chosen drug is of primary importance. Age-related and gender issues must also be taken into consideration. Whenever possible, drugs with an eventual impact on learning and language abilities or behaviour should be avoided. Drugs like carbamazepine, oxcarbazepine, vigabatrin, gabapentine and pregabalin must be avoided as they can aggravate, or sometimes even induce, myoclonic seizures and cannot control absence seizures.
Some of the IGE syndromes, like childhood absence epilepsy, will definitely resolve by adolescence, resulting in AED discontinuation. For patients with photosensitive epilepsies, treatment with AEDs is not always necessary as measures to avoid environmental stimuli may be sufficient. Juvenile myoclonic epilepsy is one of the most AED-dependent syndromes since discontinuation of all AEDs usually leads to recurrence of seizures.
Valproate is the only AED available that has the potential to control all three types of seizures encountered in the category of idiopathic generalized epilepsies (typical absences, myoclonias and generalized tonic–clonic seizures). Ethosuximide can be active for the control of typical absences and sometimes myoclonias. From the newer AEDs only levetiracetam, topiramate and lamotrigine can be used. Combination of two drugs may prove to be very useful in intractable cases or when a smaller dose is needed to avoid an undesirable effect.