Advertisement
  • Loading metrics

Packages of Care for Epilepsy in Low- and Middle-Income Countries

  • Caroline K. Mbuba,

    Affiliation The Centre for Geographic Medicine Research (Coast), KEMRI, Kilifi, Kenya

  • Charles R. Newton

    cnewton@kilifi.kemri-wellcome.org

    Affiliations The Centre for Geographic Medicine Research (Coast), KEMRI, Kilifi, Kenya, Clinical Research Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom, Neurosciences Unit, Institute of Child Health, University College London, London, United Kingdom

Packages of Care for Epilepsy in Low- and Middle-Income Countries

  • Caroline K. Mbuba, 
  • Charles R. Newton
PLOS
x

This is the second in a series of articles highlighting the delivery of “packages of care” for mental health disorders in low- and middle-income countries. Packages of care are combinations of treatments aimed at improving the recognition and management of conditions to achieve optimal outcomes.

Summary Points

  • Epilepsy is the most common chronic neurological disorder, affecting over 65 million people worldwide, of whom 80% are estimated to live in low- or middle-income countries (LMICs).
  • Anti-epileptic drugs are very effective in controlling seizures, but most people with epilepsy in LMICs do not receive appropriate treatment.
  • This “treatment gap” is influenced by factors such as limited knowledge, poverty, cultural beliefs, stigma, poor health delivery infrastructure, and shortage of trained health care workers.
  • Several studies implementing interventions at the community level (for example, training programs for primary health care workers) have successfully improved the identification of people with epilepsy and reduced the treatment gap.
  • The sustainability of these interventions needs to be addressed, however, and efforts must be made to ensure a continuous supply of anti-epileptic drugs.

Introduction

Epilepsy is one of the most common and widespread neurological disorders. Recent estimates suggest that it accounts for 1% of the global burden of disease [1] and affects over 65 million people [2]. In addition, because the relatives and friends of people with epilepsy (PWE) also bear the burden of this condition, more than 500 million people are indirectly affected by epilepsy [3]. Thus, epilepsy imposes a large economic burden on global health care systems and is a major public health problem in low- and middle-income countries (LMICs) [1].

The World Health Organization (WHO) estimates that 80% of PWE live in LMICs. The incidence and prevalence of epilepsy are thought to be higher in LMICs than in high-income countries (HIC)—the median prevalence in LMICs is 9.5/1,000 compared to 8/1,000 in Europe, although the prevalence varies widely among countries [1],[2]. The incidence of epilepsy in LMICs is thought to be up to five times that in HICs, although there are fewer studies on which to base this estimate. Worldwide, mortality among PWE is two to three times higher than in the general population and it is thought to be higher in LMICs than in HICs although data are scarce [4]. The treatment gap, i.e., the difference between the number of people with active epilepsy and the number whose seizures are being appropriately treated, is high in many LMICs [1]. Overall, 56% (range 7%–98%) of PWE in LMICs remain untreated, with 73% remaining untreated in rural regions compared to 46% in urban settings [5].

The International Classification of Disease (ICD) 10 diagnostic criteria for epilepsy are given in Box 1 [6]. The definition of epilepsy has recently been revised by the International League Against Epilepsy (ILAE) [7], but the original classification of seizures (transient occurrences of signs and/or symptoms due to excessive or synchronous discharge of neuronal activity in the brain) as partial (focal), generalized, or unclassified remains useful [8]. Epilepsy has many different etiologies, with head trauma, central nervous system infections, perinatal problems, and cerebrovascular accidents most commonly identified [1], although in most cases a cause is not found. Focal epilepsies represent a greater proportion of epilepsies in LMICs than in HICs and risk factor analysis has identified many causes that are preventable.

Box 1. International Classification of Diseases 10 Criteria for Epilepsy [6]

“G40.0 Localization-related (focal or partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset

Benign childhood epilepsy with centrotemporal EEG spikes

Childhood epilepsy with occipital EEG paroxysms

G40.1 Localization-related (focal or partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures

Attacks without alteration of consciousness

Simple partial seizures developing into secondarily generalized seizures

G40.2 Localization-related (focal or partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures

Attacks with alteration of consciousness, often with automatisms

Complex partial seizures developing into secondarily generalized seizures

G40.3 Generalized idiopathic epilepsy and epileptic syndromes

Benign:

 Myoclonic epilepsy in infancy

 Neonatal convulsions (familial)

Childhood absence epilepsy

Epilepsy with grand mal seizures on awakening

Juvenile:

 Absence epilepsy

 Myoclonic epilepsy [impulsive petit mal]

Nonspecific epileptic seizures:

 Atonic

 Clonic

 Myoclonic

 Tonic

 Tonic-clonic

G40.4 Other generalized epilepsy and epileptic syndromes

Epilepsy with:

 Myoclonic absences

 Myoclonic-astatic seizures

Infantile spasms

Lennox-Gastaut syndrome

Salaam attacks

Symptomatic early myoclonic encephalopathy

West's syndrome

G40.5 Special epileptic syndromes

Epilepsia partialis continua

Epileptic seizures related to: alcohol, drugs, hormonal changes, sleep deprivation or stress

G40.6 Grand mal seizures, unspecified (with or without petit mal)

G40.7 Petit mal, unspecified, without grand mal seizures

G40.8 Other epilepsy

Epilepsies and epileptic syndromes undetermined as to whether they are focal or generalized

G40.9 Epilepsy, unspecified”

Although seizures are its most overt manifestations, epilepsy is associated with significant psychological [9] and psychiatric conditions [10], which have social consequences for everyday living [11]. Psychiatric disorders occur in 25%–30% of PWE [10], with depression being the most common, followed by anxiety disorders, psychoses, and personality disorders [12],[13]. Psychiatric comorbidity appears to be particularly common in some LMICs [14]. Stigma poses a major burden to PWE and their families, interfering with the opportunities that PWE have for employment and marriage [15]. Finally, women with epilepsy are particularly vulnerable to sexual exploitation, physical abuse, and extreme poverty [16].

In this article, we focus on the management of epilepsy in LMICs. We review the evidence from LMICs on the efficacy of treatments and delivery of interventions. Because that evidence is often limited, we also refer to systematic reviews, meta-analyses, and key trials from HICs where appropriate. On the basis of this review, we propose a package of care—a combination of interventions aimed at improving the recognition and management of conditions to achieve optimal outcomes—for epilepsy.

The Evidence on the Treatment of Epilepsy

The evidence for most aspects of the management of epilepsy is poor in both high- and low-income settings (Table 1).

Detection of Epilepsy

Much epilepsy in the world is not identified, particularly in LMICs, and thus PWE may not benefit from treatment. The diagnosis of epilepsy is based on clinical history alone, but since patients may become unconsciousness during seizures, an independent observer is often necessary. In HICs misdiagnosis occurs in 5%–30% of cases [17], and in LMICs this is likely to be higher. In HICs, clinical examination may identify the cause of epilepsy and help with prognosis [18]. For example, electroencephalography (EEG) may detect epileptic discharges, which support the diagnosis, but is not necessary for confirmation. Although this test lacks sensitivity and specificity [17], it is useful for classification of seizures and epilepsy syndromes. Video electroencephalography (telemetry) is particularly useful for management of intractable epilepsy. Various biochemical tests can help in differential diagnosis and can determine an underlying cause of epilepsy. Computerized tomography (CT) scanning is useful for demonstrating gross abnormalities, haemorrhages, and calcification and for detecting parasitic diseases, e.g., neurocysticercosis [19]. Magnetic resonance imaging (MRI) is more sensitive than tomography in identifying structural abnormalities [20]. It is recommended that patients with refractory epilepsy undergo functional neuroimaging. Finally, single-photon emission computer tomography and positron emission tomography may help locate ictal foci, and are particularly useful in identifying candidates for surgery [21]. Unfortunately, these investigations are rarely available in LMICs.

Anti-epileptic Drug Therapy

Because the cause of epilepsy is often undetermined, and in most cases the epileptogenic focus cannot be removed, anti-epileptic drugs (AEDs) are used to control seizures. In HICs, AEDs may be considered if the person has had seizures within the past 2–5 y (active epilepsy), but in many LMICs AEDs are only often recommended in PWE with a seizure in the past year. AEDs are very effective in controlling seizures: 75% of those treated may become seizure free; 20%–30% of PWE have spontaneous remission of seizures without treatment [22]. Phenobarbital is the least expensive and most widely used AED. It controls a range of seizure types and is on the essential drug list of 95% countries surveyed by the WHO; phenytoin, carbamazepine, and valproate (also first-line AEDs) are on the essential drug list in 86%, 93%, and 87% of countries, respectively [1]. Many other AEDs have been introduced to HICs but are not widely available in LMICs. Each of these AEDs has a profile of adverse events, which may influence their use.

Few randomized trials have compared the efficacy and effectiveness of these first-line AEDs, and most of these trials were conducted in HICs. In a recent review by the International League Against Epilepsy (ILAE), evidence for the efficacy and effectiveness of AEDs as initial monotherapy was found only in adults with partial-onset seizures (carbamazepine, phenytoin, and valproate), children with partial-onset seizures (oxcarbazepine), and elderly adults with partial-onset seizures (gabapentin and lamotrigine) [23]. In Cochrane reviews, no significant differences were documented in efficacy between phenobarbital, carbamazepine, phenytoin, or valproate in patients with generalized or partial-onset seizures [24][27]. In LMICs, carbamazepine was not shown to be better than phenobarbital in Ecuadorian [28] or Kenyan adults [29]. In Indian children, there was no difference in efficacy between phenobarbital and phenytoin [30]. However, questions have been raised about the suitability of phenobarbital because of its adverse events [31], and the ILAE has argued that the status of this drug is based on economic factors, rather than on efficacy and suitability [32].

Surgery

Surgical removal of the epileptic focus is the only cure for epilepsy. Palliative procedures can also be performed. Surgery requires a thorough evaluation to identify the epileptic focus and the relationship of this focus to other functionally important areas of the brain (for example, the speech centre). A recent meta-analysis identified factors associated with seizure remission following surgery (Table 1) [33]. Because surgery requires sophisticated facilities and specialized staff, it is usually only available in HICs. Nevertheless, surgery is increasingly being performed in LMICs [34].

Vagus Nerve Stimulation

This technique is proposed for the treatment of refractory epilepsy and for the treatment of PWE who are not candidates for surgical treatment. It is effective in treatment of epilepsy patients with partial seizures [35], but is not widely available in LMICs.

Lifestyle Changes

Although seizures cannot be prevented by lifestyle changes alone, PWE can nevertheless make changes that improve their lives and give them a sense of control. For example, although many PWE do not know the precipitants for their seizures, inadequate sleep, food allergies, alcohol, smoking, and flashing lights may trigger seizures in some patients and can be avoided. Similarly, exercise is important for many aspects of epilepsy [36], particularly to counteract the side effects of some AEDs. However, exercise can trigger seizures in some patients. Finally, dietary changes may prevent the adverse events of some AEDs—phenytoin interferes with vitamin D metabolism, for example. The ketogenic diet (high-fat, no-sugar, low protein diet) is indicated in specific epilepsy syndromes [37], but requires specialized nutritional support that is often not available in LMICs [38]. Other diets are unproven.

Psychosocial Therapy

Psychological interventions such as psychotherapy, individual, group, or family counseling, progressive relaxation therapy, and cognitive behaviour therapy have all been used in epilepsy (Table 1). However, the trials were small and were mainly conducted in HICs and a systematic review concluded that there was no reliable evidence to support the use of these treatments [39].

Delivery of Effective Interventions

Delivery of efficacious interventions in LMICs can only be achieved if PWE are correctly identified. Unfortunately, the symptoms of some types of epilepsy (for example, hallucinations) may not be recognized as part of an illness, particularly in LMICs where epilepsy is interpreted within traditional belief systems. Furthermore, in LMICs, trained personnel for the detection and management of epilepsy and facilities for investigations of underlying causes are scarce [1]. However, nurses, community health workers, and key informants such as teachers can improve the identification of PWE [29],[40], and these PWE can then benefit from various interventions (Table 2).

Interventions to Ensure an Adequate Drug Supply

One of the factors contributing to the treatment gap in epilepsy in LMICs is the lack of a continuous and affordable supply of AEDs [31],[32]. Phenobarbital is most widely used in LMICs. Other available AEDs such as phenytoin, carbamazepine, and valproate are three, 11, and 16 times more expensive, respectively, than phenobarbital [1]; and are often not available and/or routinely prescribed in peripheral health facilities. Because only a 1–3-mo supply of AEDs is dispensed at any one time, PWE have to attend clinics frequently and the cost of these visits may interrupt adherence. Furthermore, the systems for providing a continuous supply of AEDs, particularly to rural clinics, often fail, which discourages attendance. Studies in Kenya and India have shown that programs that ensure a continuous supply of AEDs can improve adherence [29],[41], thereby reducing the treatment gap. Drug banks set up by nongovernmental organizations (NGOs) in some LMICs to supply hospitals when there is a shortage within the government sector can help to ensure adequate drug supplies but are difficult to sustain.

Interventions to Educate PWE and Caregivers about Epilepsy

Education of PWE and caregivers about epilepsy is important for several reasons. First, PWE with limited knowledge of epilepsy are at increased risk of the complications of seizures, such as fractures, burns, and accidental death [42],[43]. Second, one of the major conflicts in LMICs is the community's beliefs of the cause of epilepsy, and thus its treatment. In many societies, epilepsy is not thought to be caused by diseases of the brain, but is attributed to traditional beliefs such as spirits [44]. Finally, in LMICs, PWE often have cognitive impairment and psychiatric comorbidity, which impairs their understanding of epilepsy and the need to take AEDs daily. Thus, the care of PWE often falls onto family members and friends.

Although psychoeducational interventions tested in randomized controlled trials in HICs significantly improved knowledge and coping with epilepsy and decreased seizure frequency in HICs (Table 1), there have been no similar trials in LMICs, and the educational interventions required are likely to be different in these settings. There have been some programs that increased the knowledge of epilepsy in LMICs as part of a package of interventions but the components of these programs with the most significant effect on AED adherence, seizure outcome, and self-esteem among PWE are difficult to identify [45][47].

Patient support groups are found in many countries and play an important role in educating PWE and their caregivers, as well as in advocacy (http://www.ibe-epilepsy.org/links). In addition to education, PWE and their families may also benefit from targeted psychosocial interventions. For example, a study in a London out-patient clinic provided evidence that the provision of skilled counseling to patients with epilepsy in addition to “routine” therapeutic intervention is useful [48]. Counseling helps to deal with many of the problems associated with epilepsy that are not related to the medical or technical aspects of seizure control. Unfortunately, the resources needed for counseling PWE and their caregivers are often not available in LMICs and the provision of such services competes with other health needs.

Community-Based Interventions to Improve Awareness

Public education is generally advocated as the best method to reduce the stigma attached to conditions such as epilepsy, but interventions need to be based upon qualitative and quantitative assessments to identify the causes of stigma in each region [15]. Information, education, communication, and social marketing are needed to enhance compassion and reduce blame [49]. Community programs to achieve these aims must be based on the local perceptions of epilepsy and needs and must consider social and cultural conditions in the region. To date, community programs have met with some success in Kenya [29], Ecuador [28], Malawi [50], Ethiopia [51], and India [41]. Community-based studies in Kenya and India that supplied free AEDs reported low rates of withdrawal and good adherence and response to therapy [29],[41]. In Ethiopia, community awareness and a regular supply of phenobarbital increased the number of patients attending the clinic [51]. In Malawi, the model tested included publicity of accessible services, adequate supplies of AEDs, setting up of mobile clinics, and frequent follow up by health workers [50]. Unfortunately, most of these programs do not appear to have been sustained since they relied on external funds. Thus, epilepsy care needs to be integrated into primary health care delivery, perhaps with patients providing some of the cost of AEDs to enhance sustainability [45].

The Global Campaign Against Epilepsy, a partnership between the WHO, ILAE, and the International Bureau for Epilepsy was launched in 1997 to improve the acceptability, treatment, services, and prevention of epilepsy worldwide [52]. Several demonstration projects are currently underway under the auspices of this Campaign that aim to reduce the treatment gap and the physical and social burden of epilepsy through community-level interventions. The most successful is the Chinese project, which started with a media-based education program to create awareness about epilepsy and to convey the message that epilepsy is treatable. The program provided free phenobarbital at local health centres and patients were followed up by primary health care physicians who had received basic training in the diagnosis and management of epilepsy [53]. Lectures and group discussions for PWE and their families were arranged and community leaders and teachers were given information about epilepsy. This project improved adherence to AEDs and significantly decreased the treatment gap from 63% to 50% [53].

Interventions to Train Health Care Providers

There are few specialists, particularly neurologists, in LMICs [1] and health care providers are often ignorant about epilepsies, particularly about their causes, diagnosis, treatment, and psychosocial aspects. Interventions to train health care workers should, therefore, equip them with the knowledge and skills needed to diagnose and manage epilepsy, to counsel PWE, and to make appropriate referrals. It should promote strategies to ensure adherence and follow-up care [46]. Training facilities often cannot be established in LMICs because of the expense [1]. Thus, the training of health care providers in such countries requires the production and distribution of educational materials, including standard guidelines for diagnosis and care of PWE. Our review indicates that educational interventions that targeted health care providers in Zimbabwe and Ethiopia greatly improved the diagnosis and management of epilepsy [45],[51].

Interventions to Involve Traditional Healers

Despite important advances in the understanding and treatment of epilepsy, many communities in LMICs still believe that epilepsy is supernatural or sacred and is associated with possession, impurity, contagion, heredity, and madness. In many parts of Africa and Asia, notions about epilepsy are rooted not in a medical model but in a spiritual model [54]. Often these beliefs involve external factors and so PWE seek a contextually relevant cure from a traditional healer that removes the alien factor from the body rather than seeking preventative or biomedical treatment.

Traditional healers live within the community and know the communities' perceptions of ill health. Their concentration is much higher in many populations than medical staff [55], and they provide explanations that members of the community believe. They can also provide psychosomatic support, spend longer with their clients than medical staff, and will accept flexible payment systems [56]. But as a group of health care providers, their training, expertise, and beliefs are very variable, and their activities rarely regulated. Nevertheless, because they are frequently consulted in many LMICs, involving traditional healers in the management of epilepsy might be a useful intervention.

Interventions to Integrate Epilepsy Care into Existing Health Services

Acceptance of epilepsy treatment may be markedly improved by integrating it into existing health care services. Mental health services are particularly important in LMICs since there are more psychiatrists than neurologists and PWE often have considerable psychiatric comorbidity. Experience in both Kenya and Malawi has shown that although epilepsy care can be successfully provided in LMICs, it is much harder to sustain it when it is not integrated into such services [29],[50]. Programs that address epilepsy alone are unlikely to be sustained, and there is a compelling argument that such programs should be incorporated into mental illness or chronic disease services. The sustainability of these programs depends on community participation in planning, implementation, and evaluation as well as integration into primary health care [31]. A study conducted in Ethiopia illustrated how an existing health care infrastructure developed for treatment of infectious diseases could be adapted to deal with epilepsy [51]. An Indian study showed that management of epilepsy should be set within the context of rehabilitation and incorporated into wider programs aimed at the alleviation of poverty [57]. In addition, a commitment needs to be made to deal with the many preventable causes of epilepsy in LMICs such as poor perinatal care, head trauma, and parasitic infections, by integrating epilepsy into wider public health programs [31].

Epilepsy services could also be improved in the community through approaches such as “extension services” (satellite clinic model) of apex institutions and collaboration with other organizations (Table 2). Satellite clinics facilitate the provision of services to the neglected populations of rural areas by reducing the distances travelled by PWE to attend health facilities. Similarly, the creation of partnerships between governmental, private, and voluntary agencies, has proved a useful, cost-effective, and sustainable way to improve the identification and management of PWE [41],[46]. More specifically, in two studies in India where workers in NGOs that were already involved in community-based health care received training in case ascertainment and in informing communities about epilepsy, the epilepsy service continued after the studies ended because it was integrated into existing health care provision [41],[57].

Packages of Care for Epilepsy in LMICs

Epilepsy, one of the most common neurological conditions, is under-resourced and undertreated in LMICs. A large number of people have significant morbidity and mortality because of the failure to identify cases, difficulties with infrastructure, and the unavailability of suitable AEDs. Education of the community and of health care workers will improve the identification of PWE and thus reduce the treatment gap, provided inexpensive and reliable supplies of AEDs are available. Governments in LMICs need to recognize the burden of epilepsy and need to develop packages of care to reduce the disability associated with this condition in an efficient, sustainable, and equitable manner. We propose two packages of care based on the availability of resources (Table 3). Ideally, the delivery of these packages should be integrated into existing primary health care with the help of NGOs and other nonmedical staff involved in community-based and mental health care.

Acknowledgments

This paper is published with permission of the Director of Kenya Medical Research Institute.

Author Contributions

ICMJE criteria for authorship read and met: CKM CRN. Agree with the manuscript's results and conclusions: CRN. Wrote the first draft of the paper: CRN. Contributed to the writing of the paper: CKM CRN.

References

  1. 1. World Health Organisation (WHO) (2005) Atlas: epilepsy care in the world. Geneva: WHO. World Health Organisation (WHO)2005Atlas: epilepsy care in the worldGenevaWHO
  2. 2. Ngugi AK, Bottomly C, Kleinschmidt I, Sander JW, Newton CR (2009) Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia. AK NgugiC. BottomlyI. KleinschmidtJW SanderCR Newton2009Estimation of the burden of active and life-time epilepsy: a meta-analytic approach.EpilepsiaIn press. In press.
  3. 3. Kale R (2002) Global Campaign Against Epilepsy: the treatment gap. Epilepsia 43: 31–33.R. Kale2002Global Campaign Against Epilepsy: the treatment gap.Epilepsia433133
  4. 4. Diop AG, Hesdorffer DC, Logroscino G, Hauser WA (2005) Epilepsy and mortality in Africa: a review of the literature. Epilepsia 46: Suppl 1133–35.AG DiopDC HesdorfferG. LogroscinoWA Hauser2005Epilepsy and mortality in Africa: a review of the literature.Epilepsia46Suppl 113335
  5. 5. Mbuba CK, Ngugi AK, Newton CR, Carter JA (2008) The epilepsy treatment gap in developing countries: a systematic review of the magnitude, causes, and intervention strategies. Epilepsia 49: 1491–1503.CK MbubaAK NgugiCR NewtonJA Carter2008The epilepsy treatment gap in developing countries: a systematic review of the magnitude, causes, and intervention strategies.Epilepsia4914911503
  6. 6. WHO (2007) Diseases of the nervous system. International classification of diseases and related health problems. Geneva: WHO. pp. G00–G99.WHO2007Diseases of the nervous system. International classification of diseases and related health problemsGenevaWHOG00G99
  7. 7. Fisher RS, van Emde BW, Blume W, Elger C, Genton P, et al. (2005) Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46: 470–472.RS FisherBW van EmdeW. BlumeC. ElgerP. Genton2005Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE).Epilepsia46470472
  8. 8. ILAE (1981) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 22: 489–501.ILAE1981Proposal for revised clinical and electroencephalographic classification of epileptic seizures.Epilepsia22489501
  9. 9. Fisher RS, Vickrey BG, Gibson P, Hermann B, Penovich P, et al. (2000) The impact of epilepsy from the patient's perspective I. Descriptions and subjective perceptions. Epilepsy Res 41: 39–51.RS FisherBG VickreyP. GibsonB. HermannP. Penovich2000The impact of epilepsy from the patient's perspective I. Descriptions and subjective perceptions.Epilepsy Res413951
  10. 10. LaFrance WC Jr, Kanner AM, Hermann B (2008) Psychiatric comorbidities in epilepsy. Int Rev Neurobiol 83: 347–383.WC LaFrance JrAM KannerB. Hermann2008Psychiatric comorbidities in epilepsy.Int Rev Neurobiol83347383
  11. 11. Baker GA (2002) The psychosocial burden of epilepsy. Epilepsia 43: Suppl 626–30.GA Baker2002The psychosocial burden of epilepsy.Epilepsia43Suppl 62630
  12. 12. Devinsky O (2003) Psychiatric comorbidity in patients with epilepsy: implications for diagnosis and treatment. Epilepsy Behav 4: Suppl 4S2–S10.O. Devinsky2003Psychiatric comorbidity in patients with epilepsy: implications for diagnosis and treatment.Epilepsy Behav4Suppl 4S2S10
  13. 13. Gaitatzis A, Trimble MR, Sander JW (2004) The psychiatric comorbidity of epilepsy. Acta Neurol Scand 110: 207–220.A. GaitatzisMR TrimbleJW Sander2004The psychiatric comorbidity of epilepsy.Acta Neurol Scand110207220
  14. 14. Nubukpo P, Preux PM, Houinato D, Radji A, Grunitzky EK, et al. (2004) Psychosocial issues in people with epilepsy in Togo and Benin (West Africa) I. Anxiety and depression measured using Goldberg's scale. Epilepsy Behav 5: 722–727.P. NubukpoPM PreuxD. HouinatoA. RadjiEK Grunitzky2004Psychosocial issues in people with epilepsy in Togo and Benin (West Africa) I. Anxiety and depression measured using Goldberg's scale.Epilepsy Behav5722727
  15. 15. Baskind R, Birbeck GL (2005) Epilepsy-associated stigma in sub-Saharan Africa: the social landscape of a disease. Epilepsy Behav 7: 68–73.R. BaskindGL Birbeck2005Epilepsy-associated stigma in sub-Saharan Africa: the social landscape of a disease.Epilepsy Behav76873
  16. 16. Birbeck G, Chomba E, Atadzhanov M, Mbewe E, Haworth A (2007) The social and economic impact of epilepsy in Zambia: a cross-sectional study. Lancet Neurol 6: 39–44.G. BirbeckE. ChombaM. AtadzhanovE. MbeweA. Haworth2007The social and economic impact of epilepsy in Zambia: a cross-sectional study.Lancet Neurol63944
  17. 17. Chowdhury FA, Nashef L, Elwes RD (2008) Misdiagnosis in epilepsy: a review and recognition of diagnostic uncertainty. Eur J Neurol 15: 1034–1042.FA ChowdhuryL. NashefRD Elwes2008Misdiagnosis in epilepsy: a review and recognition of diagnostic uncertainty.Eur J Neurol1510341042
  18. 18. Dooley JM, Gordon KE, Wood EP, Camfield CS, Camfield PR (2003) The utility of the physical examination and investigations in the pediatric neurology consultation. Pediatr Neurol 28: 96–99.JM DooleyKE GordonEP WoodCS CamfieldPR Camfield2003The utility of the physical examination and investigations in the pediatric neurology consultation.Pediatr Neurol289699
  19. 19. Bernal B, Altman NR (2003) Evidence-based medicine: neuroimaging of seizures. Neuroimaging Clin N Am 13: 211–224.B. BernalNR Altman2003Evidence-based medicine: neuroimaging of seizures.Neuroimaging Clin N Am13211224
  20. 20. Wieshmann UC (2003) Clinical application of neuroimaging in epilepsy. J Neurol Neurosurg Psychiatry 74: 466–470.UC Wieshmann2003Clinical application of neuroimaging in epilepsy.J Neurol Neurosurg Psychiatry74466470
  21. 21. Duncan JS (2002) Neuroimaging methods to evaluate the etiology and consequences of epilepsy. Epilepsy Res 50: 131–140.JS Duncan2002Neuroimaging methods to evaluate the etiology and consequences of epilepsy.Epilepsy Res50131140
  22. 22. Kwan P, Sander JW (2004) The natural history of epilepsy: an epidemiological view. J Neurol Neurosurg Psychiatry 75: 1376–1381.P. KwanJW Sander2004The natural history of epilepsy: an epidemiological view.J Neurol Neurosurg Psychiatry7513761381
  23. 23. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, et al. (2006) ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 47: 1094–1120.T. GlauserE. Ben-MenachemB. BourgeoisA. CnaanD. Chadwick2006ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.Epilepsia4710941120
  24. 24. Taylor S, Tudur SC, Williamson PR, Marson AG (2001) Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev CD002217.S. TaylorSC TudurPR WilliamsonAG Marson2001Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures.Cochrane Database Syst RevCD002217
  25. 25. TudurSmith C, Marson AG, Williamson PR (2001) Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev CD001769.C. TudurSmithAG MarsonPR Williamson2001Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures.Cochrane Database Syst RevCD001769
  26. 26. TudurSmith C, Marson AG, Clough HE, Williamson PR (2002) Carbamazepine versus phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev CD001911.C. TudurSmithAG MarsonHE CloughPR Williamson2002Carbamazepine versus phenytoin monotherapy for epilepsy.Cochrane Database Syst RevCD001911
  27. 27. TudurSmith C, Marson AG, Williamson PR (2003) Carbamazepine versus phenobarbitone monotherapy for epilepsy. Cochrane Database Syst Rev CD001904.C. TudurSmithAG MarsonPR Williamson2003Carbamazepine versus phenobarbitone monotherapy for epilepsy.Cochrane Database Syst RevCD001904
  28. 28. Placencia M, Sander JW, Shorvon SD, Roman M, Alarcon F, et al. (1993) Antiepileptic drug treatment in a community health care setting in northern Ecuador: a prospective 12-month assessment. Epilepsy Res 14: 237–244.M. PlacenciaJW SanderSD ShorvonM. RomanF. Alarcon1993Antiepileptic drug treatment in a community health care setting in northern Ecuador: a prospective 12-month assessment.Epilepsy Res14237244
  29. 29. Feksi AT, Kaamugisha J, Sander JW, Gatiti S, Shorvon SD (1991) Comprehensive primary health care antiepileptic drug treatment programme in rural and semi-urban Kenya. Lancet 337: 406–409.AT FeksiJ. KaamugishaJW SanderS. GatitiSD Shorvon1991Comprehensive primary health care antiepileptic drug treatment programme in rural and semi-urban Kenya.Lancet337406409
  30. 30. Pal DK, Das T, Chaudhury G, Johnson AL, Neville BG (1998) Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India. Lancet 351: 19–23.DK PalT. DasG. ChaudhuryAL JohnsonBG Neville1998Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India.Lancet3511923
  31. 31. Scott RA, Lhatoo SD, Sander JW (2001) The treatment of epilepsy in developing countries: where do we go from here? Bull World Health Organ 79: 344–351.RA ScottSD LhatooJW Sander2001The treatment of epilepsy in developing countries: where do we go from here?Bull World Health Organ79344351
  32. 32. ILAE (1985) Availability and distribution of antiepileptic drugs in developing countries. III and IV Commissions on Antiepileptic Drugs of the International League Against Epilepsy. Epilepsia 26: 117–121.ILAE1985Availability and distribution of antiepileptic drugs in developing countries. III and IV Commissions on Antiepileptic Drugs of the International League Against Epilepsy.Epilepsia26117121
  33. 33. Tonini C, Beghi E, Berg AT, Bogliun G, Giordano L, et al. (2004) Predictors of epilepsy surgery outcome: a meta-analysis. Epilepsy Res 62: 75–87.C. ToniniE. BeghiAT BergG. BogliunL. Giordano2004Predictors of epilepsy surgery outcome: a meta-analysis.Epilepsy Res627587
  34. 34. Asadi-Pooya AA, Sperling MR (2008) Strategies for surgical treatment of epilepsies in developing countries. Epilepsia 49: 381–385.AA Asadi-PooyaMR Sperling2008Strategies for surgical treatment of epilepsies in developing countries.Epilepsia49381385
  35. 35. Ben-Menachem E (2002) Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol 1: 477–482.E. Ben-Menachem2002Vagus-nerve stimulation for the treatment of epilepsy.Lancet Neurol1477482
  36. 36. Arida RM, Cavalheiro EA, da Silva AC, Scorza FA (2008) Physical activity and epilepsy: proven and predicted benefits. Sports Med 38: 607–615.RM AridaEA CavalheiroAC da SilvaFA Scorza2008Physical activity and epilepsy: proven and predicted benefits.Sports Med38607615
  37. 37. Kossoff EH (2008) International consensus statement on clinical implementation of the ketogenic diet: agreement, flexibility, and controversy. Epilepsia 49: Suppl 811–13.EH Kossoff2008International consensus statement on clinical implementation of the ketogenic diet: agreement, flexibility, and controversy.Epilepsia49Suppl 81113
  38. 38. Seo JH, Kim HD (2008) Cultural challenges in using the ketogenic diet in Asian countries. Epilepsia 49: Suppl 850–52.JH SeoHD Kim2008Cultural challenges in using the ketogenic diet in Asian countries.Epilepsia49Suppl 85052
  39. 39. Ramaratnam S, Baker GA, Goldstein LH (2008) Psychological treatments for epilepsy. Cochrane Database Syst Rev CD002029.S. RamaratnamGA BakerLH Goldstein2008Psychological treatments for epilepsy.Cochrane Database Syst RevCD002029
  40. 40. Mielke J, Adamolekun B, Ball D, Mundanda T (1997) Knowledge and attitudes of teachers towards epilepsy in Zimbabwe. Acta Neurol Scand 96: 133–137.J. MielkeB. AdamolekunD. BallT. Mundanda1997Knowledge and attitudes of teachers towards epilepsy in Zimbabwe.Acta Neurol Scand96133137
  41. 41. Mani KS, Rangan G, Srinivas HV, Srindharan VS, Subbakrishna DK (2001) Epilepsy control with phenobarbital or phenytoin in rural south India: the Yelandur study. Lancet 357: 1316–1320.KS ManiG. RanganHV SrinivasVS SrindharanDK Subbakrishna2001Epilepsy control with phenobarbital or phenytoin in rural south India: the Yelandur study.Lancet35713161320
  42. 42. Beghi E (2005) Injuries in patients with epilepsy. Lancet Neurol 4: 71–72.E. Beghi2005Injuries in patients with epilepsy.Lancet Neurol47172
  43. 43. Josty IC, Narayanan V, Dickson WA (2000) Burns in patients with epilepsy: changes in epidemiology and implications for burn treatment and prevention. Epilepsia 41: 453–456.IC JostyV. NarayananWA Dickson2000Burns in patients with epilepsy: changes in epidemiology and implications for burn treatment and prevention.Epilepsia41453456
  44. 44. Jilek-Aall L (1999) Morbus sacer in Africa: some religious aspects of epilepsy in. Epilepsia 40: 382–386.L. Jilek-Aall1999Morbus sacer in Africa: some religious aspects of epilepsy in.Epilepsia40382386
  45. 45. Adamolekun B, Mielke JK, Ball DE (1999) An evaluation of the impact of health worker and patient education on the care and compliance of patients with epilepsy in Zimbabwe. Epilepsia 40: 507–511.B. AdamolekunJK MielkeDE Ball1999An evaluation of the impact of health worker and patient education on the care and compliance of patients with epilepsy in Zimbabwe.Epilepsia40507511
  46. 46. Gourie-Devi M, Satishchandra P, Gururaj G (2003) Epilepsy control program in India: a district model. Epilepsia 44: Suppl 158–62.: 58–62.M. Gourie-DeviP. SatishchandraG. Gururaj2003Epilepsy control program in India: a district model.Epilepsia44Suppl 15862.: 58–62
  47. 47. Olley BO (2004) Psychosocial and seizure factors related to depression and neurotic-disorders among patients with chronic epilepsy in Nigeria. Afr J Med Med Sci 33: 39–44.BO Olley2004Psychosocial and seizure factors related to depression and neurotic-disorders among patients with chronic epilepsy in Nigeria.Afr J Med Med Sci333944
  48. 48. Usiskin SC (1993) The role of counselling in an out-patient epilepsy clinic: a three year study. Seizure 2: 111–114.SC Usiskin1993The role of counselling in an out-patient epilepsy clinic: a three year study.Seizure2111114
  49. 49. Weiss MG, Ramakrishna J (2006) Stigma interventions and research for international health. Lancet 367: 536–538.MG WeissJ. Ramakrishna2006Stigma interventions and research for international health.Lancet367536538
  50. 50. Watts AE (1989) A model for managing epilepsy in a rural community in Africa. BMJ 298: 805–807.AE Watts1989A model for managing epilepsy in a rural community in Africa.BMJ298805807
  51. 51. Berhanu S, Alemu S, Prevett M, Parry EH (2009) Primary care treatment of epilepsy in rural Ethiopia: causes of default from follow-up. Seizure 18: 100–103.S. BerhanuS. AlemuM. PrevettEH Parry2009Primary care treatment of epilepsy in rural Ethiopia: causes of default from follow-up.Seizure18100103
  52. 52. Reynolds EH (2000) The ILAE/IBE/WHO Global Campaign against Epilepsy: bringing epilepsy “out of the shadows”. Epilepsy Behav 1: S3–S8.EH Reynolds2000The ILAE/IBE/WHO Global Campaign against Epilepsy: bringing epilepsy “out of the shadows”.Epilepsy Behav1S3S8
  53. 53. Wang W, Wu J, Dai X, Ma G, Yang B, et al. (2008) Global campaign against epilepsy: assessment of a demonstration project in rural china. Bull World Health Organ 964–969.W. WangJ. WuX. DaiG. MaB. Yang2008Global campaign against epilepsy: assessment of a demonstration project in rural china.Bull World Health Organ964969
  54. 54. Whyte SR (1995) Constructing epilepsy: images and contexts in East Africa. In: Whyte SR, Ingstad B, editors. Disability and culture. Berkeley: University of California Press. pp. 226–245.SR Whyte1995Constructing epilepsy: images and contexts in East Africa.SR WhyteB. IngstadDisability and cultureBerkeleyUniversity of California Press226245
  55. 55. Baskind R, Birbeck G (2005) Epilepsy care in Zambia: a study of traditional healers. Epilepsia 46: 1121–1126.R. BaskindG. Birbeck2005Epilepsy care in Zambia: a study of traditional healers.Epilepsia4611211126
  56. 56. Kendall-Taylor N, Kathomi C, Rimba K, Newton CR (2008) Traditional healers and epilepsy treatment on the Kenyan coast. Epilepsia 49: 1638–1639.N. Kendall-TaylorC. KathomiK. RimbaCR Newton2008Traditional healers and epilepsy treatment on the Kenyan coast.Epilepsia4916381639
  57. 57. Pal DK, Das T, Sengupta S (2000) Case-control and qualitative study of attrition in a community epilepsy programme in rural India. Seizure 9: 119–123.DK PalT. DasS. Sengupta2000Case-control and qualitative study of attrition in a community epilepsy programme in rural India.Seizure9119123
  58. 58. Corey LA, Kjeldsen MJ, Solaas MH, Nakken KO, Friis ML, et al. (2009) The accuracy of self-reported history of seizures in Danish, Norwegian and U.S. twins. Epilepsy Res 84: 1–5.LA CoreyMJ KjeldsenMH SolaasKO NakkenML Friis2009The accuracy of self-reported history of seizures in Danish, Norwegian and U.S. twins.Epilepsy Res8415
  59. 59. Reutens DC, Howell RA, Gebert KE, Berkovic SF (1992) Validation of a questionnaire for clinical seizure diagnosis. Epilepsia 33: 1065–1071.DC ReutensRA HowellKE GebertSF Berkovic1992Validation of a questionnaire for clinical seizure diagnosis.Epilepsia3310651071
  60. 60. Cockerell OC, Goodridge DM, Brodie D, Sander JW, Shorvon SD (1996) Neurological disease in a defined population: the results of a pilot study in two general practices. Neuroepidemiology 15: 73–82.OC CockerellDM GoodridgeD. BrodieJW SanderSD Shorvon1996Neurological disease in a defined population: the results of a pilot study in two general practices.Neuroepidemiology157382
  61. 61. Hauser WA, Annegers JF, Kurland LT (1991) Prevalence of epilepsy in Rochester, Minnesota: 1940–1980. Epilepsia 32: 429–445.WA HauserJF AnnegersLT Kurland1991Prevalence of epilepsy in Rochester, Minnesota: 1940–1980.Epilepsia32429445
  62. 62. Placencia M, Sander JW, Shorvon SD, Ellison RH, Cascante SM (1992) Validation of a screening questionnaire for the detection of epileptic seizures in epidemiological studies. Brain 115: 783–794.M. PlacenciaJW SanderSD ShorvonRH EllisonSM Cascante1992Validation of a screening questionnaire for the detection of epileptic seizures in epidemiological studies.Brain115783794
  63. 63. Preux PM (2000) [Questionnaire in a study of epilepsy in tropical countries]. Bull Soc Pathol Exot 93: 276–278.PM Preux2000[Questionnaire in a study of epilepsy in tropical countries].Bull Soc Pathol Exot93276278
  64. 64. Sawhney IM, Lekhra OP, Shashi JS, Prabhakar S, Chopra JS (1996) Evaluation of epilepsy management in a developing country: a prospective study of 407 patients. Acta Neurol Scand 94: 19–23.IM SawhneyOP LekhraJS ShashiS. PrabhakarJS Chopra1996Evaluation of epilepsy management in a developing country: a prospective study of 407 patients.Acta Neurol Scand941923
  65. 65. Murthy JM, Yangala R, Srinivas M (1998) The syndromic classification of the International League Against Epilepsy: a hospital-based study from South India. Epilepsia 39: 48–54.JM MurthyR. YangalaM. Srinivas1998The syndromic classification of the International League Against Epilepsy: a hospital-based study from South India.Epilepsia394854
  66. 66. Mohamed Y, Alias NN, Shuaib IL, Tharakan J, Abdullah J, et al. (2006) Referral of epileptic patients in North East Coast of West Malaysia an area with poor MRI coverage: an analysis. Southeast Asian J Trop Med Public Health 37: 1199–1208.Y. MohamedNN AliasIL ShuaibJ. TharakanJ. Abdullah2006Referral of epileptic patients in North East Coast of West Malaysia an area with poor MRI coverage: an analysis.Southeast Asian J Trop Med Public Health3711991208
  67. 67. Banu SH, Jahan M, Koli UK, Ferdousi S, Khan NZ, et al. (2007) Side effects of phenobarbital and carbamazepine in childhood epilepsy: randomised controlled trial. BMJ 334: 1207.SH BanuM. JahanUK KoliS. FerdousiNZ Khan2007Side effects of phenobarbital and carbamazepine in childhood epilepsy: randomised controlled trial.BMJ3341207
  68. 68. Wang WZ, Wu JZ, Ma GY, Dai XY, Yang B, et al. (2006) Efficacy assessment of phenobarbital in epilepsy: a large community-based intervention trial in rural China. Lancet Neurol 5: 46–52.WZ WangJZ WuGY MaXY DaiB. Yang2006Efficacy assessment of phenobarbital in epilepsy: a large community-based intervention trial in rural China.Lancet Neurol54652
  69. 69. Radhakrishnan K (2009) Epilepsy surgery in India. Neurol India 57: 4–6.K. Radhakrishnan2009Epilepsy surgery in India.Neurol India5746
  70. 70. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, et al. (2008) The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 7: 500–506.EG NealH. ChaffeRH SchwartzMS LawsonN. Edwards2008The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial.Lancet Neurol7500506
  71. 71. Helgeson DC, Mittan R, Tan SY, Chayasirisobhon S (1990) Sepulveda Epilepsy Education: the efficacy of a psychoeducational treatment program in treating medical and psychosocial aspects of epilepsy. Epilepsia 31: 75–82.DC HelgesonR. MittanSY TanS. Chayasirisobhon1990Sepulveda Epilepsy Education: the efficacy of a psychoeducational treatment program in treating medical and psychosocial aspects of epilepsy.Epilepsia317582
  72. 72. Snead K, Ackerson J, Bailey K, Schmitt MM, Madan-Swain A, et al. (2004) Taking charge of epilepsy: the development of a structured psychoeducational group intervention for adolescents with epilepsy and their parents. Epilepsy Behav 5: 547–556.K. SneadJ. AckersonK. BaileyMM SchmittA. Madan-Swain2004Taking charge of epilepsy: the development of a structured psychoeducational group intervention for adolescents with epilepsy and their parents.Epilepsy Behav5547556
  73. 73. Helde G, Bovim G, Brathen G, Brodtkorb E (2005) A structured, nurse-led intervention program improves quality of life in patients with epilepsy: a randomized, controlled trial. Epilepsy Behav 7: 451–457.G. HeldeG. BovimG. BrathenE. Brodtkorb2005A structured, nurse-led intervention program improves quality of life in patients with epilepsy: a randomized, controlled trial.Epilepsy Behav7451457
  74. 74. Liu L, Yiu CH, Yen DJ, Chou MH, Lin MF (2003) Medication education for patients with epilepsy in Taiwan. Seizure 12: 473–477.L. LiuCH YiuDJ YenMH ChouMF Lin2003Medication education for patients with epilepsy in Taiwan.Seizure12473477
  75. 75. Lundgren T, Dahl J, Melin L, Kies B (2006) Evaluation of acceptance and commitment therapy for drug refractory epilepsy: a randomized controlled trial in South Africa–a pilot study. Epilepsia 47: 2173–2179.T. LundgrenJ. DahlL. MelinB. Kies2006Evaluation of acceptance and commitment therapy for drug refractory epilepsy: a randomized controlled trial in South Africa–a pilot study.Epilepsia4721732179
  76. 76. Dahl J, Melin L, Lund L (1987) Effects of a contingent relaxation treatment program on adults with refractory epileptic seizures. Epilepsia 28: 125–132.J. DahlL. MelinL. Lund1987Effects of a contingent relaxation treatment program on adults with refractory epileptic seizures.Epilepsia28125132
  77. 77. Adamolekun B, Mielke J, Ball D, Mundanda T (2000) An evaluation of the management of epilepsy by primary health care nurses in Chitungwiza Zimbabwe. Epilepsy Res 39: 177–181.B. AdamolekunJ. MielkeD. BallT. Mundanda2000An evaluation of the management of epilepsy by primary health care nurses in Chitungwiza Zimbabwe.Epilepsy Res39177181
  78. 78. Mani KS, Sidharta P, Pickering C (1994) Educational aspects in the education of health workers, patients, and the public. Viewpoints from south India, Indonesia and Kenya. Trop Geogr Med 46: S34–S36.KS ManiP. SidhartaC. Pickering1994Educational aspects in the education of health workers, patients, and the public. Viewpoints from south India, Indonesia and Kenya.Trop Geogr Med46S34S36
  79. 79. Mani KS, Subbakrishna DK (2003) Perspectives from a developing nation with special reference to rural areas. Epilepsia 44: Suppl 155–7.: 55–57.KS ManiDK Subbakrishna2003Perspectives from a developing nation with special reference to rural areas.Epilepsia44Suppl 1557.: 55–57
  80. 80. Pal DK, Das T, Sengupta S, Chaudhury G (2002) Help-seeking patterns for children with epilepsy in rural India: implications for service delivery. Epilepsia 43: 904–911.DK PalT. DasS. SenguptaG. Chaudhury2002Help-seeking patterns for children with epilepsy in rural India: implications for service delivery.Epilepsia43904911
  81. 81. Olley BO, Osinowo HO, Brieger WR (2001) Psycho-educational therapy among Nigerian adult patients with epilepsy: a controlled outcome study. Patient Educ Couns 42: 25–33.BO OlleyHO OsinowoWR Brieger2001Psycho-educational therapy among Nigerian adult patients with epilepsy: a controlled outcome study.Patient Educ Couns422533