Research in Epilepsy: Development Priorities for Developing Nations

Authors


Address correspondence and reprint requests to Dr. E. S. Krishnamoorthy at T. S. Srinivasan Institute of Neurological Sciences and Research, Public Health Centre, 114, Lake View Road, West Mambalam, Chennai 600033, India. E-mail: krish@ttsh.com.sg

Abstract

Summary:  Purpose: To identify research priorities in epilepsy for developing nations.

Methods: A panel discussion with audience participation at the Indo-U.K. Workshop on Epilepsy. This included short presentations by panelists, the presentation of a research proposal, and debate on research priorities.

Results: The need to focus on primary-care populations; to use a multi-centre random block design; to incorporate rural areas and a service component; to study incidence, natural history, and aetiology; to focus on problems, such as cysticercosis, and to adopt a comprehensive public health–centred approach in doing so; to study disorders of local interest, such as hot water epilepsy; to pilot both pharmacological and nonpharmacological interventions; to incorporate comprehensive measures of cognition, behaviour, and psychosocial outcome in all studies; and to examine the role of novel diagnostic tools (imaging for example) and therapy (surgery for example) on cost were all outlined as priority areas.

Discussion: There is a felt need for greater and better-quality research output from the developing world. The development of uniform research protocols, the twinning of developed and developing nations for research, and training of developing nations' personnel are likely to increase research output in the years that come.

Epilepsy is a common neurologic disorder with prevalence ranging from 5 to 10 per 1,000, depending on sampling criteria and the population surveyed (1). Although no inherent differences between developed and developing countries with regard to the biological and clinical aspects of epilepsy are well known, differences in incidence, etiology, social, cultural and economic factors, and systems of health care delivery and treatment have been reported. However, as developing countries do not have organized health care systems, record keeping is poor, and research is minimal, few accurate scientific data are available (2).

In general, findings from developing countries show higher incidence rates than do those from developed countries. Whereas this may in part reflect the populations being of younger age, poorer general health, and poorer socioeconomic status, a significant component of this difference may be attributable to differences in etiology. It has been suggested that chronic central nervous system (CNS) infections, cysticercosis in particular, may be responsible for the higher incidence of epilepsy in developing countries (2,3).

Studies of etiology in the developing world are limited by the following:

  • 1The nonavailability of neuroimaging/the high cost of neuroimaging, leading to noninclusion of these techniques in community-based studies, or their application to a small proportion of the population studied.
  • 2The descriptive rather than analytic nature of these studies, in which the clinician decides a particular factor is responsible for epilepsy in the given case; the lack of rigid and standardized definitions of seizures (provoked versus unprovoked) and etiologic factors; and the lack of a control group in most studies.
  • 3The use of hospital rather than community-based populations, leading to significant bias (2). Those analytic case–control studies that have been carried out (4,5) have involved small populations and have failed to demonstrate the role of infections as a risk factor for epilepsy, which is not in keeping with common clinical experience.

There have been >20 published epidemiologic studies of epilepsy in India in the past three to four decades (6). None of these has formally examined etiologic factors by using both gold-standard methods of investigation and ascertainment, and a cohort/case–control design. With organized epilepsy services in the primary care setting being few and far between, little is known about health service use in epilepsy. However, studies in primary care have shown that a significant treatment gap exists and that although many patients try antiepileptic medications (AEDs), few continue to take them (7). As epilepsy is highly stigmatized in these cultures (8) and psychiatric comorbidity can significantly add to the stigmatisation and disability posed by the condition, population-based estimates of psychiatric comorbidity in epilepsy also are essential. Little is known about the impact of etiology on psychiatric comorbidity, the impact of these factors on disablement, and the barriers to health service use in epilepsy, in the Indian setting.

With its being estimated that there will be 5.5 million people with epilepsy in India in 2001, and ∼4.1 million of these will not be in receipt of appropriate treatment (6), systematic population-based research addressing these issues is both important and essential.

An Indo-U.K. Workshop on epilepsy was held between September 1 and 3, 2000, in Chennai (formerly called Madras), the largest metropolis in south India. Organized by the T. S. Srinivasan Department of Clinical Neurology and Research and the T. S. Srinivasan Neurosciences Trust, this educational workshop was held under the aegis of the International League Against Epilepsy, Commission on Developing Countries. The aim was to bring together experts from representative developed and developing nations, the United Kingdom (U.K.) and India, respectively, to debate clinical and research issues in epilepsy across the cultural divide. The themes of discussion were epidemiology; etiology; pathophysiology, and clinical manifestations; diagnosis and management; and the organization and delivery of epilepsy services in primary care. This attempt at generating debate among experts across cultures was reflected in the workshop's theme, “Transcultural Perspectives in Epilepsy.”

An important academic component of this workshop was a panel discussion involving experts from the U.K. and India, entitled “Research in Epilepsy: Development Priorities for Developing Nations.” A summary of viewpoints put forward by panelists and the research priorities identified therein are summarized.

RESEARCH PRIORITIES

It was pointed out that with a population of 1 billion served by 500 neurologists, most in large centers, the conduct of research and identification of priority areas was difficult. The diversity of environmental factors and gene pools was further identified as making difficult the extrapolation of results to other populations within a large country like India. Thus, to be truly effective, studies would have to be multicentric and sample subjects in randomised blocks from different corners of the country. Further, with limited resources available, the need to set priorities in research efforts toward the identification of specific patterns of disease seen in India and to focus on both prevention and treatment was highlighted.

Further, it was pointed out that the vast majority of Indians still live in the villages and that there was a significant rural/urban divide in epilepsy services, with the vast majority of neurologists being concentrated in major cities. The need to focus research efforts on rural primary care populations was identified. The development of a primary care–based service was identified as being crucial to the conduct of such research. “In a developing nation there can be no research without service,” opined panelist the late Professor K. S. Mani, well known for his contributions in primary care research and service in rural India.

With >20 prevalence studies of epilepsy having been completed in India, it was pointed out that there was now a felt need for high-quality data on incidence and analytic epidemiology. The difficulties of studying the incidence of epilepsy in a large and diverse country with parallel healthcare systems ranging from that offered by the state, private practitioners, practitioners of traditional systems, Ayurveda, Siddha, and homeopathy, to name a few, was explicitly acknowledged. It was pointed out that the development of a friendly, responsive, and well-accepted local service would help greatly in ensuring that the vast majority of incident cases were identified. That the role of primary care health workers was invaluable in the establishment of such a service and in the conduct of such research was emphasized.

That the etiology of epilepsy had not been formally investigated by using gold-standard methods of ascertainment and control populations in the Indian setting (and seldom elsewhere in the developing world) was pointed out. This was particularly important in the developing nation setting, given the higher incidence of CNS infections, brain injury around the time of birth, high levels of consanguinity especially in certain communities, and reports citing higher prevalence rates, especially small and poorly controlled studies.

The role of tuberculosis and cysticercosis as etiological factors in epilepsy was highlighted. Single enhancing lesions on computer tomography (CT) are the most common radiological abnormality in Indian patients with new-onset partial seizures. In some patients these lesions may be “tuberculoma,” but histopathological studies have shown that neurocysticercosis is responsible in the vast majority (9).

Further, the sequelae of such infection, focal cortical-subcortical calcifications (FCSCs) (10) and their relationship to seizures merit further investigation in the community setting.

As cysticercosis was by its very nature a public health problem, it was felt that an effective and wide ranging study would have to examine several public health factors, such as diet; hygiene and sanitation; water supply arrangements; cooking arrangements; and so on. In addition, its biological antecedents and conventional neurological factors would have to be studied, given that the regional specificity of this disorder, not fully explained by empirical observations about diet and sanitation, merited a search for genetic factors and susceptibility.

The need to involve public health experts in the organisation and conduct of such research was emphasised. Concerns were also expressed about the collection of blood samples and about performing imaging on control populations. Previous experience in other Indian settings had been that there could be difficulties in doing this in community studies, and there may be a risk of alienating the populace. It was pointed out that the establishment of an efficient primary care service locally might mitigate these difficulties to some extent. Sensitivity to local cultural issues in establishing these research projects was emphasised as an essential prerequisite, as also was some piloting of the feasibility of such projects.

The importance of a geographically specific epilepsy syndrome prevalent in south India, the syndrome of “hot water epilepsy,” was pointed out. The syndrome (11) is reported frequently from south India, but rarely from other parts of the world.

There is a positive family history in 7–23% of cases. The question as to whether this was a situation-related seizure, a variant of febrile seizures persisting into adulthood, or whether the clustering in south India and family history indicated a genetic basis, were identified as areas that needed to be addressed.

That research should be directed towards the development of effective and affordable community-based interventions was pointed out. From the pharmacological viewpoint, given that local experts found phenobarbitone effective (see Professor Mani's article on primary care in this volume, pp. 55–57), the potential for widespread use of this drug in primary care was emphasised. However, it was pointed out that this drug had been demonstrated to have several cognitive and behavioural adverse effects in western settings, but not in India (12). The need to systematically investigate these differential adverse effects across cultures, and whether these differences were a reflection of differential beliefs and expectations across cultures, rather than a reflection of true biological variation, was identified as a priority. Further, a study of their impact on performance and quality of life in different social groups was identified as a research priority.

Apart from such pharmacological interventions, it was suggested that there was a need for nonpharmacological, community-based interventions that would help reduce the stigma of epilepsy and break down barriers to effective care. It is common experience that subjects in community studies start taking antiepileptic drugs and experience remission of symptoms when these are first prescribed, only to subsequently discontinue AED therapy and suffer a relapse (see also articles in this volume by J. M. K. Murthy, pp. 38–42, and K. S. Mani, pp. 55–57).

While the cost of AED therapy (affordability) may be one explanation for this, other explanations such as accessibility, acceptability, and availability of AEDs need to be considered. This knowledge, combined with information about barriers to epilepsy care, may be used to develop effective community-based interventions. Recent examples of such community-based interventions were discussed. That such activity was promoted by nongovernmental organisations (NGOs) in India was acknowledged and the need to operationalise such activity and to research its efficacy in breaking down the barriers to care accepted.

The need to have a greater understanding about the natural history of epilepsy in India and the factors influencing prognosis and outcome was identified by the panellists as being an important development priority. Indeed, with a large untreated population, especially in rural areas, the unique research opportunities that India and other similar developing nations offered in this regard were emphasised. It was also observed that with several laboratories in India now having co-competency in genetic research (following on from the Human Genome Project), combining genetic studies with a population-based exploration of risk factors was entirely feasible. In this regard, the need for developed and developing nations to twin with each other for research was emphasised.

The growing role of magnetic resonance imaging in the diagnosis of epilepsy was emphasised. The need to set up cheap and robust imaging services was pointed out. The importance of examining health improvements with the use of such technology was identified as a priority area for a developing nation. The role of surgery in the management of epilepsy was emphasised, and the need of a skilled multidisciplinary team outlined. The cost-effectiveness of surgical intervention was identified as an area that merited research in the setting of a developing nation.

Psychiatric co-morbidity in epilepsy is in general an under-researched area, and there is little agreement even about whether psychiatric disorders are more common in epilepsy. The available evidence suggests that while common mental disorders are not more common in epilepsy than in populations matched for disability, there is a significant over-representation of major mental illness, psychoses in particular, in epilepsy (13). A majority of population-based studies of psychiatric co-morbidity have however come from the west, studies in developing nations being few and far between. Further, while studies in clinic populations (14) do suggest a high burden of psychiatric co-morbidity in patients with epilepsy, this has never been examined in the community-based setting, although population-based studies in children have been reported (15).

The study of cognitive and behavioural problems in epilepsy and the differentiation of those due to disease and those due to drugs were identified as a research priority. The relationship between anxiety and epilepsy and the impact of environmental and psychosocial factors on quality of life were considered to merit exploration in the Indian setting.

That the neuropsychiatric epidemiology of epilepsy was poorly understood worldwide, and in developing nations in particular, was also acknowledged. Further, the role of neurocysticercosis per se in the development of co-morbid cognitive and behavioural problems may merit further investigation (16) (see also article by Trimble and Krishnamoorthy, pp. 21–24).

The benefits of research were widely acknowledged. The possibility of genetic studies in the future, the expected improvements in neurological and mental health care in general, and epilepsy care in particular that would accompany such activity, and the improvements in community awareness that such activity would bring, were all widely acknowledged. Community-based research projects carried out in Yelandur in Karnataka (7) and Kerala (8) were identified as sterling examples of how research could lead to greater understanding of the barriers to epilepsy care.

Over 250 physicians attended this workshop. The ratio between trainee doctors and consultants was ∼2:3. No doubt the exchange of ideas and the critical discussions will help shape future progress. However, at least as important has been the interaction between physicians and scientists interested in the problems associated with epilepsy from the developed and developing world.

Acknowledgment:

  • 1The Sponsors: The Wellcome Trust, U.K., through its Non-Communicable Diseases (NCD) initiative; The TS Srinivasan Department of Clinical Neurology and Research, Chennai, India
  • 2The Panel (aside from the authors of this paper): Prof. S. D. Shorvon, Professor and Chairman, University Department of Clinical Neurology, Institute of Neurology, Queen Square, London, U.K. (Chair); Prof. Nadir Bharucha, Professor of Neuroepidemiology, Bombay Hospital, Mumbai, India; Professor J. Duncan, Professor of Clinical Neurology, Institute of Neurology, Queen Square, London; Prof. Gourie-Devi, vice-chancellor and Professor of Neurology, NIMHANS (Bangalore, India); Late Prof. K. S. Mani, Retired Professor of Neurology, NIMHANS, Bangalore, Independent Consultant Neurologist and Epileptologist in Primary Care; Professor J. M. K. Murthy, Professor and Chairman, Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India; Professor V. Rajashekar, Professor of Neurosurgery, Christian Medical College and Hospital, Vellore, India; Professor M. R. Trimble, Professor of Behavioural Neurology, Institute of Neurology, Queen Square, London, U.K.; Professor C. U. Velumurugendran, Professor and Head, Department of Neurology, Sri Ramachandra Medical College, Chennai, India; Prof. N. H. Wadia, Professor & Chairman, Department of Neurology, Jaslok Hospital and Research Institute, Mumbai, India.
  • 3National Neuroscience Institute of Singapore (support for E.S.K. during period of authorship).

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