Efficacy assessment of phenobarbital in epilepsy: a large community-based intervention trial in rural China.

BACKGROUND: Many people with epilepsy need not experience further seizures if the diagnosis and treatment are correct. Most epilepsy patients have convulsions, which are usually fairly easy to diagnose. This study tested a model for treatment of people with convulsive forms of epilepsy at primary health-care level in rural areas of China. METHODS: Patients with convulsive epilepsy were identified at primary care level and provided with phenobarbital monotherapy. Local physicians, who were provided with special training, carried out screening, treatment, and follow-up. A local neurologist confirmed the diagnoses. Efficacy was assessed from the percentage reduction in seizure frequency from baseline and the retention of patients on treatment. FINDINGS: The study enrolled 2455 patients. In 68% of patients who completed 12 months' treatment, seizure frequency was decreased by at least 50%, and a third of patients were seizure free. 72% of patients who completed 24 months' treatment had reduction of seizure frequency of at least 50% and a quarter of patients remained seizure free. Probability of retention was 0.84 at 1 year, and 0.76 at 2 years. Medication was well tolerated and reported adverse events were mild; only 32 patients (1%) discontinued medication because of side-effects. INTERPRETATION: This pragmatic study confirmed that this simple protocol was suitable for the treatment of convulsive forms of epilepsy in rural areas of China. Physicians with basic training could treat epilepsy patients with phenobarbital, with beneficial effects for most patients with convulsive seizures. Few cognitive or behavioural adverse events were noted, but formal psychometric testing was not done.

[National demonstration project on epilepsy in Brazil]. / Projeto demonstrativo em epilepsia no Brasil.

Epilepsy is the most prevalent non-communicable serious neurological condition worldwide. Unfortunately, the majority of people with epilepsy in low-income countries do not receive appropriate treatment. Stigmatisation is the rule. In this setting, the World Health Organisation, the International League against Epilepsy and the International Bureau for Epilepsy launched the Global Campaign against Epilepsy in 1997. This entered its second phase in 2001 and as part of it has set up demonstration projects in the People's Republic of China, Zimbabwe, Senegal and, more recently, in Brazil. The objective of the demonstration projects is to show, through methodological evaluation, that it is possible to establish a model of treatment for people with epilepsy in primary health care settings. The Brazilian demonstration project has targeted regions in Campinas and S o Jose do Rio Preto, both in Sao Paulo State. A task force has been established to assess strategies to expand this project nationwide.

Differences in the use of health services among people with and without epilepsy in the United Kingdom: socio-economic and disease-specific determinants.

We aim to examine the socio-economic, demographic and disease-specific determinants in the use of health services by patients with epilepsy, compared to people without epilepsy. We used data from the fourth national survey of morbidity in general practice, carried out in 1991-1992. Overall mean annual number of consultations with general practitioners, home visits and referrals to secondary care per person were calculated for people with epilepsy, stratified by age, sex and socio-economic status. The proportion of patients consulting for certain diseases or disease groups were also calculated for patients with epilepsy. Results were compared to these in people without epilepsy, and rate ratios were calculated. Patients with epilepsy consulted twice as often, required three to four times more home visits, and were referred to secondary care three times more often than people without epilepsy, irrespective of age, sex and social class. Among patients with epilepsy, consultation rates and home visits were higher in females, older people and people from the manual social classes. A higher proportion of patients with epilepsy consulted for neoplasms, haematological and mental health disorders, dementia, stroke and gastrointestinal bleeding. Older age and low social class were less strongly associated with health service utilisation than in people without epilepsy, indicating that people with epilepsy lose much of the protective effect of young age and high social class on health. Factors contributing to the higher utilisation of health services in people with epilepsy need to be studied further and their effects taken into account in the organisation of health services for people with epilepsy.

The treatment of epilepsy in developing countries: where do we go from here?

Epilepsy is the most common serious neurological disorder and is one of the world's most prevalent noncommunicable diseases. As the understanding of its physical and social burden has increased it has moved higher up the world health agenda. Over four-fifths of the 50 million people with epilepsy are thought to be in developing countries; much of this condition results from preventable causes. Around 90% of people with epilepsy in developing countries are not receiving appropriate treatment. Consequently, people with epilepsy continue to be stigmatized and have a lower quality of life than people with other chronic illnesses. However, bridging the treatment gap and reducing the burden of epilepsy is not straightforward and faces many constraints. Cultural attitudes, a lack of prioritization, poor health system infrastructure, and inadequate supplies of antiepileptic drugs all conspire to hinder appropriate treatment. Nevertheless, there have been successful attempts to provide treatment, which have shown the importance of community-based approaches and also indicate that provision for sustained intervention over the long term is necessary in any treatment programme. Approaches being adopted in the demonstration projects of the Global Campaign Against Epilepsy--implemented by the International League Against Epilepsy, the International Bureau for Epilepsy, and the World Health Organization--may provide further advances. Much remains to be done but it is hoped that current efforts will lead to better treatment of people with epilepsy in developing countries.

The treatment gap in epilepsy: the current situation and ways forward.

This article is a summary of a workshop held by the ILAE concerning the issue of the epilepsy treatment gap in developing countries. The gap is defined in terms of those people with epilepsy who are not being appropriately treated and is the result of an array of medical, political, social, economic, and cultural factors. The situation regarding the treatment gap for various countries is reviewed, along with some of its causes. Although the overall gap is estimated to be large, a number of recent projects and interventions have been effective in delivering appropriate treatment to people with epilepsy in underresourced countries of the developing world. It is hoped that these may be transferable elsewhere and that, combined with the ILAE/IBE/WHO Global Campaign against Epilepsy and increased support from the worldwide epilepsy community, the treatment gap will begin to be bridged.

Comparing the cost of epilepsy across eight European countries.

To observe the degree to which prices for medical services and anti-epileptic drugs (AEDs) vary between eight European Union (EU) countries, to identify the factors that are likely to contribute to these variations and to consider the validity of international cost-of-illness comparisons. Cost-of-illness study methodology has been used to estimate the national cost of epilepsy in several developed countries. The validity of comparing these studies is unknown. Eight EU member countries were selected. Charges and prices were obtained for important aspects of medical care of patients with epilepsy including AEDs. The perspective taken was that of the major health care payer within each country. Prices were validated by a local panel of doctors expert in treating epilepsy. Prices for similar services were compared between countries. Charges and prices levied to health service payer vary widely between the eight countries considered. The cheapest and most expensive medical services vary by as much as 24 times, whereas the price of AED varies up to 4.4 times. These wide variations suggest that prices do not reflect the true cost of providing these important aspects of epilepsy treatment. International comparisons between national cost-of-illness estimates relying on such prices should be interpreted with caution.

[Analysis of cost minimization of monotherapy antiepileptic treatment in patients with recent diagnosed epilepsy : the situation in Spain]. / Análisis de coste-minimización del tratamiento antiepiléptico en monoterapia en pacientes con epilepsia de reciente diagnóstico: situación en España.

OBJECTIVE: To analyze the cost of monotherapeutic treatment of patients with newly diagnosed epilepsy. PATIENTS AND METHODS: We analysed the cost of treatment with lamotrigine (LTG), carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) using published data regarding the efficacy and tolerability of comparative clinical trials of monotherapy. We established a model of treatment for newly diagnosed patients during the first 12 months after diagnosis. A panel of doctors reached a consensus on the use of resources, costs and model of treatment in Spain. We made a cost minimization analysis for economic assessment of the data based on the fact that randomized trials indicated that CBZ, LTG, PHT and VPA ware of similar efficacy. Analysis was done as 'intention to treat'. Only direct medical costs were considered. RESULTS: In Spain treatment with LTG is twice or three times as expensive as treatment with the other drugs. Sensitivity analysis showed that variations in the interval of use of resources and of costs (defined by the panel of doctors) did not significantly alter the results. CONCLUSIONS: Treatment with LTG is more expensive than treatment with the classical drugs. In view of the methodological limitations of this study, further analysis is necessary, particularly of the methodology of cost-benefit, to evaluate the economic impact of the new antiepileptic drugs and determine whether their use is justified as drugs of first choice.

Cost minimization analysis of antiepileptic drugs in newly diagnosed epilepsy in 12 European countries.

A recent United Kingdom cost minimization analysis (CMA) of four antiepileptic drugs (AEDs) used to treat newly diagnosed adult epilepsy demonstrated that a new drug, lamotrigine (LTG), incurred higher costs than carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA), whose costs were similar. This analysis took account of each drug's side-effect and tolerability profile. The present analysis investigated the costs of treatment with LTG, CBZ, PHT, and VPA in 12 European countries. Data were derived from published sources and from a panel of locally based experts. When no published data were available, estimates were obtained using expert opinion by a consensus method. These data were incorporated into a treatment pathway model, which considered the treatment of patients during the first 12 months after diagnosis. The primary outcome considered was seizure freedom. Randomized controlled trials demonstrate that the drugs considered are equally effective in terms of their ability to achieve seizure freedom, and thus the most appropriate form of economic evaluation is a CMA. These trials provided data on the incidence of side effects, dosages, and retention rates. The economic perspective taken was that of society as a whole and the analysis was calculated on an "intent-to-treat" basis. Only direct medical costs were considered. In each country considered, LTG was twofold to threefold more expensive than the other drugs considered. A sensitivity analysis demonstrated that varying each of the assumptions (range defined by expert panels) did not significantly alter the results obtained.

Neurocysticercosis and epilepsy in developing countries.

Neurocysticercosis is a disease of poverty and underdevelopment. Little is known about the natural history of the infection in humans, but some of the mechanisms whereby the parasite remains silent and evades the host immune response are understood. Symptomatic neurocysticercosis usually results from host inflammatory response after parasite death, and the clinical manifestations can be diverse. There is no evidence that cysticidal treatment does more good than harm in addition to conventional antiepileptic treatment. Population control measures involving immunisation or mass treatment have not shown long term effectiveness.Epilepsy, similarly to neurocysticercosis, is a largely unrecognised but increasing burden on the welfare and economies of developing countries. The technology of drug treatment and psychosocial rehabilitation is well known but requires widespread and effective dissemination at low cost. There is little epidemiological data on risk factors for epilepsy in developing countries on which to base prevention strategies. The public health prioritisation of chronic disorders such as epilepsy remains a challenge for policy and practice in developing countries. For both neurocysticercosis and epilepsy, there is a dilemma about whether limited public resources would better be spent on general economic development, which would be expected to have a broad impact on the health and welfare of communities, or on specific programmes to help individual affected people with neurocysticercosis and epilepsy. Either approach requires detailed economic evaluation.

An economic appraisal of carbamazepine, lamotrigine, phenytoin and valproate as initial treatment in adults with newly diagnosed epilepsy.

We undertook an economic appraisal of four drugs used in monotherapy during the first 2 years of treatment for newly diagnosed patients with epilepsy: carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), and valproate (VPA). We adopted the cost-minimization model because, although no single trial compares all four drugs directly, the clinical trials comparing two or more of these drugs in newly diagnosed cases show no significant difference in efficacy between the drugs in terms of seizure frequency. Considered in the cost analyses were frequency of side effects, retention rates, medical consultations, inpatient and accident and emergency costs, laboratory investigations, and drug changes. A Delphi panel provided the treatment pathways, including frequency of clinical consultations, second-line monotherapy, and side-effects management. A sensitivity analysis was performed, varying the assumptions on which the calculations were based. Analysis was completed for a prospective, intention-to-treat perspective and also for those patients continuing the initial drug. The direct medical costs of 2-years therapy (intention-to-treat analysis) calculated for each trial were pound sterling 795-829 for CBZ, pound sterling 1,525-2,076 for LTG, pound sterling 736-768 for PHT, and pound sterling 868-884 for VPA. A sensitivity analysis provided similar relative estimates. We found that LTG for newly diagnosed patients is significantly more expensive in direct health service costs incurred. This analysis incorporated seizure control, side effects, and tolerability. We recommend that a similar type of analysis be considered as part of all clinical trials of antiepileptic drugs in which efficacy of outcome is similar as a guide to assess optimal cost effectiveness.

Circumstances of death in sudden death in epilepsy: interviews of bereaved relatives.

OBJECTIVES: To study the circumstances of death in sudden death in epilepsy. METHODS: Self referred bereaved relatives of patients with epilepsy who had died suddenly were interviewed with information obtained substantiated through other sources-namely, coroners' officers' reports, postmortem reports, previous medical records, and EEG reports. RESULTS: Of 34 cases, 26 were classified as sudden unexpected deaths in epilepsy (SUDEP). Twenty four of 26 cases of SUDEP were unwitnessed. Evidence indicative or suggestive of a seizure was found in most. In 11 of 26 the position of the head was such that breathing could have been compromised. Cases included both localisation related and idiopathic primary generalised epilepsy. Only three were in remission at the time of death. Most relatives expressed the view that they would have preferred to have known that epilepsy could be fatal. CONCLUSIONS: Although the deaths in question were largely unwitnessed, the available evidence suggested that most cases of SUDEP represented ictal or postictal seizure deaths, occurring in people with a history of generalised tonic clonic seizures, and in both primary generalised and localisation related epilepsy. These interviews highlight the needs of bereaved relatives and their sense of isolation in the face of an entirely unexpected and apparently unexplained loss.

New antiepileptic drug trials in developing countries: are they necessary?

In recent times, antiepileptic drug (AED) development has expanded with at least seven new AEDs being marketed in a variety of countries. However, in this same period there have been very few trials of new AEDs in the developing world where the majority of people with epilepsy reside. There are many problems with the extrapolation of results from AED trials in developed countries, thus underlining the need for new AED trials in developing countries. This, however, presents a number of ethical and logistical problems, as the majority of people with epilepsy in developing countries are inadequately treated with established drugs. Additionally, there are further problems involving the cost of treatment and the allocation of sparse resources. If trials of new AEDs are to take place in developing countries, strict ethical guidelines must be adhered to, the trials must not be purely marketing exercises, and there must be the continued availability of the new AED to those in the trials who have benefited.

The cost of epilepsy in the United Kingdom: an estimation based on the results of two population-based studies.

Epilepsy has important socio-economic costs to a population. It is important to assess these costs so that health care priorities can be set. We assessed the burden of illness of epilepsy at the community level, and from this we were able to estimate costs for an individual and the cost to the United Kingdom (UK) as a whole. Cost analysis was based on two different populations of patients with epilepsy, a prevalent and an incident population. Patients with established epilepsy (n = 1628), who were identified from general practices throughout the UK as part of the National Epilepsy Survey (NES), and patients with newly diagnosed epilepsy (n = 602), from the National General Practice Study of Epilepsy (NGPSE), which is a prospective longitudinal cohort study of epilepsy. Indirect and direct costs were assessed in the NES, and direct costs in the NGPSE. A longitudinal cost profile of epilepsy was calculated, with an average initial direct costs of 611 pounds (US$917) per patient per annum which decreased after eight years of follow up to 169 pounds (US$254) per patient per annum. The cost to the UK of newly diagnosed epilepsy in the first year of diagnosis was 18 million pounds (US$27 million). The total annual cost of established epilepsy to the UK was estimated at 1930 million pounds (US$2895 million), over 69% of which was due to indirect costs (unemployment and excess mortality). The cost of active epilepsy per patient was approximately 4167 pounds (US$6251), and of inactive epilepsy 1630 pounds (US$2445) per patient per annum. Methodological issues in cost studies of epilepsy are reviewed.

Antiepileptic drug treatment in a community health care setting in northern Ecuador: a prospective 12-month assessment.

The results of a prospective assessment of antiepileptic drug treatment carried out over a 12-month period, in the context of existing community health care in a rural area of a developing country (a highland region of northern Ecuador), are reported. A house to house survey defined all patients in the area with a history of epileptic seizures, and 192 patients with active epilepsy were recruited into the programme. These patients were randomised to treatment with carbamazepine or phenobarbital, and 139 completed the assessment. Treatment was carried out by health visitors and rural doctors, monitored by a team of neurologists, and standard treatment regimens were used. Treatment was effective in controlling seizures, 53% of the patients were rendered entirely seizure free in the second 6 months of therapy, and a further 14% had a 50% or more reduction in seizures. These results were similar to those reported in hospital based studies in developed countries. No significant differences were found between the efficacy and safety of phenobarbital or carbamazepine. Antiepileptic drug levels were monitored during the study, and ranges similar to those found in developed countries were recorded. Compliance was good. In view of the successful treatment in this community control programme, we would recommend that community programmes for the control of epilepsy in rural settings should be given a higher priority in the planning of health care provision than is commonly the case. Finally, the programme afforded the opportunity to study the efficacy of treatment in patients with chronic long-standing epilepsy, who had not been previously treated, and the results of this treatment were good.

An assessment of serum and red blood cell folate concentrations in patients with epilepsy on lamotrigine therapy.

Lamotrigine (LTG) is a new antiepileptic drug which is effective in refractory epilepsy and which has been shown to have weak antifolate properties in vitro. The effect of LTG on serum folate and red cell folate (RBC) concentrations was assessed in a series of 14 patients on short-term LTG treatment during a placebo-controlled double-blind study. A further 14 patients who had been treated with LTG for up to 5 years were also assessed. In the short-term double-blind study the baseline mean serum folate concentration was 2.7 ng/ml and mean RBC folate concentration was 295 ng/ml. After 12 weeks of LTG therapy mean concentrations were 3.3 ng/ml and 339 ng/ml respectively and corresponding levels after 12 weeks of placebo were 2.4 ng/ml and 288 ng/ml. Patients on chronic LTG therapy showed no significant difference in RBC folate concentrations compared to those prior to LTG therapy (346 compared to 407 ng/ml). Other biochemical and haematological parameters were unaltered by LTG therapy. Thus, neither short-term nor chronic LTG therapy appears to be associated with significant changes in serum or RBC folate concentrations.