Role of valproate across the ages. Treatment of epilepsy in children

In June 2005 a team of experts participated in a workshop with the objective of reaching agreement on the place of valproate use in the treatment of paediatric epilepsy patients. A general 'consensus of the meeting' was that the initiation of antiepileptic drug (AED) treatment should be based on a seizure-syndromic approach in children. Participants of the meeting also agreed that valproate is currently the AED with the broadest spectrum across all types of seizures and syndromes. Its superiority has been shown over almost 40 years of clinical experience. The best results are seen in idiopathic generalized epilepsy with or without photosensitivity, idiopathic focal and symptomatic generalized tonic–clonic seizures (GTCS). Evidence supports the use of valproate, ethosuximide and lamotrigine in absence epilepsies and the use of carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate and phenobarbital for primary GTCS. For new AEDs trials have been undertaken to define their therapeutic role but studies comparing their role to 'old' broad-spectrum drugs in specific syndromes are missing. Experts concluded that intravenous (i.v.) valproate is a useful agent in the treatment of non-convulsive status epilepticus (SE). There is an easy transition to oral treatment following i.v. valproate use. The discussion also concluded that, despite the lack of studies, valproate is an interesting, underutilized alternative in convulsive SE but more controlled studies are needed. The side effects of valproate use are well documented. Its effect on cognition and behaviour is more favourable than many of the other AEDs which is an important consideration in children. Overall, the clinical consensus of the meeting was that valproate's well established therapeutic properties far outweigh the negative side effects. Contraindication or withdrawal should be assessed individually.     

Epilepsy in the Elderly: The Use of Tiagabine

Summary: The incidence of epilepsy increases sharply in patients older than 60 years. There is a clear need for clinical trials designed specifically for this age group, as elderly patients differ from younger patients with epilepsy with respect to seizure etiology, coexisting diseases, concomitant drug therapy, and drug disposition. The new antiepileptic drugs (AEDs) are often associated with fewer side effects than are the traditional AEDs and may be particularly useful in the elderly. The pharmacokinetics of tiagabine (TGB) are not significantly modified in elderly patients, although elimination is more rapid in the presence of enzyme-inducing AEDs. Efficacy and tolerability data on TGB in elderly patients is currently limited, and a formal trial of TGB monotherapy in this age group is needed.     

Therapy insight: clinical management of pregnant women with epilepsy

In pregnant women with epilepsy who are being treated with antiepileptic drugs (AEDs), careful clinical management is vital because seizure frequency can change during pregnancy, and both seizure activity and AED treatment can have consequences for the developing fetus. Complications of epilepsy and AED treatment include stillbirths, prematurity, low birth weight, major and minor malformations, and cognitive delay later in life. Certain AEDs probably have more adverse effects than others; data from prospective studies indicate that phenobarbital and valproate are associated with significant increases in major malformations, and retrospective studies show lower verbal IQs and greater need for extra assistance in school for children whose mothers received valproate during pregnancy. Monitoring of AED levels and dosage adjustment are warranted throughout pregnancy, and vitamin K(1) at a dose of 10 mg/day should be given in the last month, particularly when cytochrome P450 enzyme-inducing AEDs are being administered. In the postpartum period, breastfeeding is recommended; however, there is differential transfer of individual AEDs in breast milk, and the infant should be observed clinically. For all women of reproductive age, preconceptual counseling is important, and includes optimization of the AED regimen and advising the mother to take supplemental folic acid.     

Seizures and therapy in adolescents with uncomplicated epilepsy.

PURPOSE: This study aimed to describe seizures and their therapy among Swedish adolescents, aged 13-22, with active but uncomplicated epilepsy. METHOD: The adolescents answered questionnaires (158/193). Data were also obtained from medical records. RESULTS: Epileptic seizure types could be specified in 92.1% of the cases. Predominant types were Primary Generalised Tonic-Clonic Seizures and Partial Complex Seizures with Secondary Generalisation. Clinical diagnoses by physicians were unspecified in 25.8%. Ninety percent were on antiepileptic drugs (AEDs), most commonly valproate and carbamazepine. New AEDs were used in 9.3% of the cases and polytherapy in 13.9%. More than 40% of the respondents had seizures despite AED treatment. Side effects of AEDs were experienced by 61%, most commonly tiredness, concentration difficulties and headache. Patients on polytherapy experienced significantly more side effects. The choice of a new AED over a traditional one was not related to seizure type or seizure control. CONCLUSIONS: Many adolescents had persistent seizures despite treatment at a specialist regional epilepsy centre. This, plus the high reported rate of side effects of AED treatment, suggests that treatment is not optimal for the group studied. As traditional AEDs strongly dominated treatment possibly newly marketed AEDs are underused in this group.     

Teratogenicity of antiepileptic medications

Antiepileptic drugs (AEDs) are frequently used to treat several conditions that are common in women of childbearing age, including epilepsy, headaches, and mood disorders. Moreover, as in the case of epilepsy and severe psychiatric disease, clinicians frequently do not have the option of stopping these medications or switching to another class of drugs. Overall, AEDs have been associated with an increased risk of major congenital malformations, minor anomalies, specific congenital syndromes, and developmental disorders seen in childhood. However, the differential effects of individual AEDs remain uncertain. Data are accumulating which strongly suggest that these risks are highest in patients receiving polypharmacy and valproate. There is also modest evidence to suggest an increased risk for phenobarbital. While other older AEDs appear to carry some teratogenic risk, there is not adequate evidence to further stratify their risk. Clinical and basic science research regarding newer AEDs suggests equivalent, if not safer, profiles compared with older AEDs, but these data are inconclusive. Management of women with epilepsy should include a discussion of these risks, prophylactic treatment with folic acid, and the minimal use of polypharmacy and valproate needed to maintain optimum seizure control.     

The choice of antiepileptic drugs in newly diagnosed epilepsy: a national French survey.

The choice of an antiepileptic drug (AED) in patients with epilepsy is mainly based on efficacy and safety of each drug. However, these criteria of drug selection should be further evaluated according to the epileptic syndromes, and adjusted to the sex and age of the patient. Unfortunately, very few studies have been conducted based on these latter criteria. We conducted a survey on the management of epilepsy treatment in adults. This survey was undertaken in France, and led to the establishment of a French consensus on antiepileptic drug treatment in adult patients with newly diagnosed epilepsy. Patients were grouped into 18 categories according to the epileptic syndrome (absence epilepsy, juvenile myoclonic epilepsy, undetermined idiopathic generalized epilepsy, symptomatic or cryptogenic partial epilepsy and unclassified epilepsy), and to the patient's gender and age. Our survey suggests that there is a consensus among French epileptologists for the choice of AEDs, mainly based on the epilepsy syndrome. Gender also plays a crucial role. Sodium valproate and lamotrigine are the two drugs of choice for generalized epilepsies, as well as for undetermined epilepsies. Lamotrigine is often prefered for women of childbearing age. First line AEDs in partial epilepsy are carbamazepine (particularly for men), lamotrigine (particularly for women), and gabapentin (in the elderly). In cases of failure and/or intolerance to one of these AED, the principal alternatives are oxcarbazepine, sodium valproate and topiramate.     

Quality of life in seizure-free patients with epilepsy on monotherapy

Epilepsy is a multifaceted chronic disorder which has diverse and complex effects on the well-being of the patient. Although it is evident that seizure type and frequency play a critical role in the quality of life (QOL) of patients with epilepsy, it is less clear what the major determinants are that influence QOL in seizure-free patients receiving monotherapy. The aim of this study was to evaluate demographic, clinical, and socioeconomic factors influencing the QOL of seizure-free patients receiving monotherapy. All participants were patients from four medical centers who had epilepsy, were on monotherapy, and had been seizure-free for at least 1 year. Responders completed three questionnaires on demographic and clinical information, QOL, and antiepileptic drug (AED) side effects during routine follow-up visits in the epilepsy clinics. We present the data of 103 patients: 59 females (57.3%), mean age 37.75+/-13.66 years. Treatment side effects and unemployment (p<0.0001, p=0.037, respectively) were significant predictors for poor overall QOL, whereas age, gender, education, family status, comorbidity, seizure type, age of seizure onset, and epilepsy duration did not significantly affect overall QOL. There was no significant difference in side effects and QOL between patients receiving older versus newer AEDs. Ninety-four (92.2%) patients reported experiencing at least one side effect of AEDs when queried about specific symptoms, while only 11 (10.7%) patients replied affirmatively when asked whether they experienced "any" side effects. The most common side effects involved the central nervous system. In conclusion, this study reveals that the most significant factor influencing the QOL in seizure-free patients on monotherapy is AED side effects. QOL is a crucial component in the clinical care of patients with epilepsy, and physicians should take the time to ask specific questions on side effects of AEDs.     

Benefit of combination therapy in epilepsy: a review of the preclinical evidence with levetiracetam

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad-spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug-resistant patients.     

Aggravation of epilepsy by anti-epileptic drugs

The possibility that so-called anti-epileptic drugs (AEDs) may aggravate epilepsy must always be borne in mind by the clinician. Many reports of such aggravation of seizures have been published. Most such reports are anecdotal and speculative, and suggest that many such reactions are idiosyncratic. However, for some there is a sufficient body of evidence to suggest that some AEDs used in certain epilepsies may consistently cause worsening of seizures. Seizure aggravation may include increase in the frequency or severity of existing seizures, emergence of new types of seizure, or the occurrence of status epilepticus. The pathophysiology of seizure aggravation is poorly understood including non-specific effects such as those associated with sedation, drug-induced encephalopathy, and paradoxical or inverse pharmacodynamic effects. For some epilepsies the choice of AEDs may be inappropriate, and although the mechanism of seizure aggravation is not clear, its occurrence may be fairly predictable. This is best documented for the use of carbamazepine in idiopathic generalized and myoclonic epilepsies. Most other AEDs have been reported occasionally to cause seizure aggravation. The lowest risk of seizure aggravation appears to be with valproate. Risk factors for worsening of seizures are epileptic encephalopathy, polytherapy, high frequency of seizures, and cognitive impairment. Advances in pharmacogenomics may in the future enable such adverse effects to be predicted for individual patients. Meanwhile, a systematic approach to reporting AED-induced seizure aggravation should be developed.     

Treatment of juvenile myoclonic epilepsy

Drug treatment of juvenile myoclonic epilepsy (JME) is mainly based on clinical experience and prospective and retrospective studies, with little evidence from randomized clinical trials. There are almost no head-to-head comparisons between old and new antiepileptic drugs (AEDs). Valproate is the drug of the first choice in men with JME. In women, lamotrigine (LTG) should be preferred regarding teratogenicity and side effects of valproate. Levetiracetam (LEV) is also effective. Recent data suggest that it may soon be used as first line treatment. Some AEDs can aggravate JME. In addition to AEDs, nonpharmacological treatments are important in JME. JME usually requires lifelong treatment because seizures nearly always return after withdrawal of therapy.     

Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis

PURPOSE: To survey the characteristics of epilepsy in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and determine the antiepileptic drug (AED) treatment most suitable for these patients. METHODS: The study included 60 patients with JNCL; their mean age was 16.5 years (range 5-33). The age at onset of epilepsy, type of seizures, effect of the first AED on seizures, and the current seizure frequency and AED therapy were studied. The side effects of the AEDs were also clarified. RESULTS: Fifty of the 60 patients had epilepsy. Patients' first epileptic seizure occurred at a mean age of 10.0 years (range 5-16), the most common type being generalized seizures. As the first AED tried, valproate (VPA) and lamotrigine (LTG) appeared equally effective, with 80% of the patients responding to these AEDs. During the study year, the median seizure frequency was four seizures a year (range 0-120), and 72% of the patients had good or satisfactory seizure control (0-6 seizures a year). In the different AED therapy groups, the proportion of patients with good or satisfactory seizure control ranged from 25% to 100%. LTG in monotherapy or in combination with clonazepam (CZP) was superior to other AEDs or combinations, but VPA also seemed effective. Adverse effects leading to the discontinuation of an AED were observed in 25% of the patients, most frequently in patients receiving phenobarbital (PB). No patient receiving LTG had to discontinue the drug due to adverse effects. CONCLUSION: Epilepsy in JNCL can usually be successfully treated with the current AEDs. In Finnish patients with JNCL, treatment is based on LTG, or, secondarily, VPA. In combination therapy, CZP seems a valuable add-on AED.     

A survey of a novel epilepsy clinic

The management of a group of epilepsy patients from primary care, in a geographical area with clear epilepsy management guidelines and secondary care clinics is surveyed. Suggestions are made to improve liaison between primary and secondary care as well as epilepsy management in primary care.All 42 local primary care practices were invited to take part in this project. A study day providing a broad overview of epilepsy management was held. Those attending were expected to identify all patients in their practice with epilepsy using diagnostic codes and prescribing data.Nine of the invited 42 practices took part in the project, and identified 506 patients prescribed anti-epilepsy drugs (AEDs). Three hundred and three patients were invited for review by their practice nurse, following exclusion of those prescribed AEDs for other conditions, children and those already under specialist review. One hundred and sixteen patients attended for review. Seventy-one patients were identified as requiring specialist review and a consultant neurologist, epilepsy nurse specialist and clinical assistant completed them. Of the 71 patients 31 had experienced no seizures for 5 years, 40 had experienced seizures in the past 5 years, of whom 32 had experienced seizures in the last year. Sixteen were suffering at least one seizure per month, and a few had poorly controlled epilepsy.Patients were taking mainly Phenytoin, Carbamazepine and Sodium valproate. Twenty were taking polytherapy and one no treatment.Fifty-two patients reported side effects and 15 poor compliance.Many patients reviewed were considered to be taking unnecessary medication and suffering unnecessary side effects.There is a need for improved epilepsy management in primary care and better liaison between primary and secondary care.     

Managing epilepsy in pregnancy

There are close to one and half million women with epilepsy (WWE) in reproductive age group in India. WWE have several unique gender-specific problems in the biological and social domains. Women experience more social stigma from epilepsy and have more difficulty with education and employment. They have more difficulty to get married and sustain successful family life. Reproductive hormones like estrogen and progesterone have opposing effect on seizure threshold. WWE have increased risk of infertility. About 10% of their babies may have major congenital malformations. Most of the adverse biological outcomes for WWE are related to adverse effects of antiepileptic drugs (AEDs). Traditional AEDs like phenobarbitone and sodium valproate are probably associated with increased risk of fetal malformations or other adverse fetal outcomes. Polytherapy and use of high dose of any AED is associated with higher risk fetal complications. It is very important that all WWE have a preconception evaluation done by a neurologist, when the need to continue AEDs or possibility of reducing AED load could be assessed. All WWE need to take folic acid 5 mg daily during preconception period and pregnancy. They should undergo a detailed screening for fetal malformations between 12 and 18 weeks of pregnancy. The neurologist, gynecologist, imageologist and pediatrician need to work as a team while managing pregnancy in WWE. It is important to reassure WWE and their relatives that pregnancy is safe in WWE and their children are healthy in more than 90% instances.     

Pharmacodynamic interaction studies with topiramate in the pentylenetetrazol and maximal electroshock seizure models.

There is emerging evidence to support the efficacy of some antiepileptic drug (AED) combinations in refractory epilepsy. Definitive clinical studies are, however, difficult to perform. Experimental seizure models can be employed to identify potentially useful combinations for subsequent clinical evaluation. We have investigated the anticonvulsant effects of topiramate (TPM) in combination with 13 other AEDs in the pentylenetetrazol (PTZ) and maximal electroshock (MES) seizure models. Single drugs and combinations were administered by intraperitoneal injection and anticonvulsant effects determined at 1-hour post-dosing. TPM was without significant effect in the PTZ test. In contrast, phenobarbital, primidone, ethosuximide, sodium valproate, felbamate and tiagabine all increased the latency to the first generalised seizure. Combinations of TPM and active adjunctive drug were universally effective. Combinations of TPM with clobazam, lamotrigine and levetiracetam were also anticonvulsant, despite the inactivity of the constituent compounds when administered alone. TPM reduced the incidence of MES-induced seizures in a dose-dependent manner, as did phenobarbital, phenytoin, primidone, carbamazepine, sodium valproate, clobazam, lamotrigine, felbamate and tiagabine. All combination treatments were similarly effective. These findings suggest that combinations of TPM with lamotrigine and levetiracetam may demonstrate anticonvulsant synergism and merit further investigation in additional model systems and with recourse to more quantitative mathematical analysis.     

Prospective study of seizures in the elderly in the Marshfield Epidemiologic Study Area (MESA)

PURPOSE: To assess the incidence, etiology, antiepileptic drug (AED) use, and quality of life in patients having their first seizure at age 50 years or older. METHODS: All patients in the Marshfield Epidemiologic Study Area (MESA) aged 50 years or older having their first seizure between July 1, 1996, and June 30, 1998, were identified through the diagnostic coding system. Patients were followed up for 12 months for recurrent seizures. Etiologies, drug treatments, magnetic resonance imaging (MRI), computed tomography (CT), or EEG results and medication adverse effects were recorded. Those patients who reached 1-year follow-up received a quality of life (QOLIE-31) survey. RESULTS: Forty-eight patients having a first seizure were identified (162 of 100,000). Twelve patients had had recurrent seizures, and 36 had a single seizure at the time of study entry. Fourteen of these 36 had had an abnormal MRI, CT, or EEG. The remaining 22 had a single seizure and normal imaging and EEG. Six of these had one or more subsequent seizures, and all six were in the group with normal tests. Etiologies included vascular, neoplasm, trauma, dementia, metabolic, and unknown. Seventy-five percent of the patients achieved seizure control with phenytoin, carbamazepine, and/or valproate. Twenty-seven percent experienced adverse side effects. None had been given second-generation AEDs as an initial treatment. Thirty-one patients received the QOLIE-31 survey; 20 did not complete the survey for various reasons. The mean QOLIE-31 scores for those completing the survey were significantly higher than those of the reference cohort. CONCLUSIONS: The incidence of first seizure in MESA is high in the elderly and increases with advancing age. As in other studies, vascular causes accounted for the largest etiology. Use of new AEDs was uncommon. There was a high incidence of untoward side effects related to the traditional AEDs. High morbidity and mortality unrelated to seizures limits follow-up analysis in the elderly. Quality-of-life analysis via QOLIE questionnaires is problematic in this population.     

Treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy

Drug treatment of Juvenile myoclonic epilepsy (JME) is mainly based on clinical experience and prospective and retrospective studies, with little evidence from randomized clinical trials. There are no head-to-head comparisons between old and new antiepileptic drugs (AEDs) and no drugs licensed specifically for JME. Valproate is unquestionably the drug of the first choice in men with JME. In women, lamotrigine should be preferred regarding teratogenicity and side effects of valproate. In addition, levetiracetam and topiramate are effective and can be use in combination or as second line treatment. Some AEDs can aggravate JME. In addition of AEDs, non-pharmacological treatments are important in JME. JME usually require lifelong treatment because seizures nearly always return after withdrawal of therapy.     

Epileptic fits and epilepsy in the elderly: general reflections, specific issues and therapeutic implications

Seizures and epilepsy are commonly encountered in the elderly. Diagnosis is not always straightforward as reliable history is often difficult to obtain and EEG findings can be non-specific. When to treat and how may be difficult choices as adequate studies in elderly are rather scarce. Treatment should be based on careful assessment and comparison of risk/benefit profiles of various anti-epileptic drugs (AEDs) in this specific elderly population. Since most AEDs are effective in terms of seizure control in the elderly, the choice of treatment is often determined by tolerability, pharmacokinetic profile and drug interactions of AEDs. As recently introduced AEDs have a better safety profile compared to older agents it seems logical to initiate treatment in the frail elderly patient with those more modern AEDs. In this review some distinctive clinical features of epilepsy in the elderly are discussed in three sections (general issues, special issues and selected treatment options with special reference to medicinal treatment).