Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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About 80% of persons with epilepsy inhabit low and middle income countries (LMICs). Studies have shown that up to 70% of newly diagnosed children and adults with epilepsy are successfully treated with antiepileptic drugs. In lower income regions, up to 75% of people with epilepsy may not receive the treatment they need. The treatment gap in these regions needs to be narrowed to decrease morbidity and mortality due to epilepsy.
Of the 35 to 40 million people with epilepsy who live in low-income countries, approximately 56% to 85% receive no treatment at all (14; 35; 17; 08). As a consequence, they are at increased risk for excess morbidity and mortality from seizures and the psychosocial consequences of stigma and discrimination. Regrettably, most of these people—many of whom are children—could have their seizures completely controlled and could return to a normal life by taking a single daily dose of a drug that costs less than (£1.50; €2.20) each year (15). Conducting clinical trials in resource-restricted countries is difficult, contributing to wide treatment gaps, which result from lack of resources and trained personnel, and knowledge gaps in these countries (21).
The earliest detailed account of epilepsy resides in the British Museum in London. It is part of a Babylonian text on medicine, Sakikku, written over 3000 years ago. The Babylonians provided descriptions of many of the seizure types (miqtu), including what are now called “tonic-clonic seizures,” “absences,” “drop attacks,” “focal impaired awareness or focal aware seizures,” “gelastic seizures,” and “focal motor (Jacksonian) seizures.” The supernatural view has dominated thinking about epilepsy since then and even now remains a deeply rooted negative social influence in many parts of the world.
The supernatural basis was challenged by the school of Hippocrates in the fifth century BC Greece, which first suggested that the brain was the seat of this disorder; however, this concept was later replaced by supernatural causes in much of the world (35). By the seventeenth and eighteenth centuries, the Hippocratic concept of epilepsy as a brain disorder began to resurface. During these 2 centuries, efforts was made to separate “nervous disorders” from “mental disorders,” which led to the beginnings of modern neurology in the nineteenth century. Many treatises during this era covered convulsive diseases and also included hysteria, tetanus, tremors, rigors, and other paroxysmal movement disorders. The latter were gradually separated from epilepsy in the nineteenth century.
The understanding of the basis of epilepsy among poorly educated people in the developing world varies widely, and the supernatural and mental illness concepts remain the understanding for many. Even now, many who live with epilepsy in low and middle income countries believe the cause of their disease to be related to fever, demonic power, curses, beatings, witchcraft, and God (25).
Fortunately, modern treatments are sometimes available. In recent decades, many new drugs have been developed, some of which are available in developing countries.
It is estimated that around 80% of people with epilepsy live in low and middle income countries (WHO 2019). The incidence rate of epilepsy in low-middle income countries was found to be 61 per 100,000 person-years, with a lifetime prevalence of 7.6 per 1,000 people (09). There were further increased rates in those living in rural areas, up to 15 per 1000, whereas in high income countries (HICs) it was found to be 5 per 1000. In South Africa, incidence rate was found to be as high as 180 to 250 per 100,000, whereas in high income countries was found to be 45 per 100,000 (08). Incidence and prevalence rates of epilepsy in people of low socioeconomic status in high income countries, however, are comparable to those observed in low income countries (13). This could be explained by shared risk factors and limited resources despite country of residence. Additionally, premature mortality is higher in this population, as well as deaths specifically relating to the disease (05). Those deaths directly attributable to epilepsy, based on population studies, were shown to be at 27%, with causes including status epilepticus and SUDEP. Additionally, deaths indirectly related to epilepsy, at 20%, included causes such as drowning, burns, head injury, and falls. Death rates in people with epilepsy in low and middle income countries are estimated to be 2.6 times higher than in the general population in low and middle income countries (16).
Higher incidence rates in LMICs are thought to be attributable to parasitosis (particularly neurocysticercosis, but also falciparum malaria, schistosomiasis, and paragonimiasis), HIV-AIDS, trauma, perinatal morbidity, and consanguinity. The higher incidence is difficult to interpret because of methodological issues, particularly the lack of age adjustment, which is important because epilepsy has a bimodal peak with age. The prevalence of active epilepsy in developing countries has been found to be fairly uniform at 4 to 10 per 1000 in a large number of studies, but higher prevalence has been reported in sub-Saharan Africa and Central and South America; this is possibly due to methodological differences, or increased risk factors as noted above, or both, which are particularly different in rural areas (12; 22). Ascertainment may also be confounded by the ability to group and classify epilepsy in these regions.
The results of studies on the causes of epilepsy have implications for decision-making about the development of locally relevant strategies for prevention and management, education of primary healthcare workers and community physicians, and further research. Perinatal causes have been reported among the most important etiologies of epilepsy in all income categories except high-income countries (35).
The top 4 most frequently reported etiologies of epilepsy (trauma, central nervous system infections, perinatal risk factors, and cerebrovascular disorders) are often modifiable (30). Multidisciplinary efforts focusing on the risk factors, such as reduction of head trauma incidence through enforcement of traffic regulations; immunization against relevant communicable diseases; and public health measures to reduce exposure to parasites could substantially decrease the incidence of epilepsy.
Epilepsy specialists provide care to people with epilepsy in 88.6% of high-income countries, but they are present in only 55.6% of low-income countries and are available without charge in about 67% of these low-income countries (35). CT scanning is available in 70.5% of low-income countries. MRI is much more useful in the evaluation of epilepsy, but is available in only 29.6% of low-income countries. Similarly, long-term video-EEG monitoring is available in 21.7% of low-income countries, as compared to 77.1% of high-income countries (35). The availability is often limited to high income people in these countries, however, and relatively inaccessible to the poor. Neuropsychological services are less available, with availability in 37% of low-income countries and available free of charge in about one third of these countries.
The median number of professionals per 100,000 population who are members of an organization of epilepsy specialists is 0.17 in southeast Asia and Africa, 0.31 in the Western Pacific, 0.33 in the Eastern Mediterranean, and 0.35 in the Americas, compared with 2.15 in Europe (11). Professional organizations of epilepsy specialists do not exist in 64.6% of low-income countries, compared with 22.9% of high-income countries (20). Also, the median number of professionals per 100,000 population who are members of an organization of epilepsy specialists varies across different income groups of countries, with 0.19 in low-income countries, compared to 1.83 in high-income countries (35).
A consensus definition of the “treatment gap” was adopted by international experts sponsored by the International League Against Epilepsy (ILAE): “The difference between the number of people with active epilepsy and the number whose seizures are being appropriately treated in a given population at a given point in time, expressed as a percentage” (18). The treatment gap has been shown to be 75% in low income countries and 50% in middle income countries (19). It is important to note, additionally, that rural areas are more affected than urban and suburban areas. A study in India showed a treatment gap of 40% to 90% in rural areas versus 22% to 50% in suburban/urban regions (08). Lack of access has been identified as a major barrier to adequate treatment in both high-income and low-income countries. The attributed causes with the highest medians have been related to the health systems: inadequately skilled personnel, lack of available drugs, and excessive cost of treatment. Improved training of the health workers providing first level of contact in case detection, initiation of treatment with antiepileptic drugs, follow-up, and monitoring for compliance and adverse effects might be the most cost-effective ways to decrease the treatment gaps in the majority of countries. Both cultural and structural factors affect the treatment gap (28), and cultural values affect health-seeking strategies. If people believe epilepsy has non-medical causes, then treatment through Western medicine may not be sought (18). In many developing countries, epilepsy is perceived as a manifestation of supernatural forces (32; 23; 28). In such situations, the family and the patient first consult the traditional healers and follow their recommendations; this treatment may be followed for a long period of time (24; 23; 28). Reports have identified this period as lasting 6 to 14 years (23; 28; 29). This depends on the area of residence (urban or rural), impact of cultural beliefs, and financial means.
There is wide disparity in the availability of treatment modalities in different parts of the world. The reasons for these inequalities are multifactorial. They may include both “hardware” factors (eg, availability of technologies and a reliable drug supply) and “software” factors (eg, availability of expertise and access to health care), which are often dictated by economic constraints (35). Phenobarbital has the lowest cost among the antiepileptic drugs and can be reliably supplied to rural areas. Phenytoin, carbamazepine, and sodium valproate can also be accessed in most countries. In low-income countries, inclusion of first-line antiepileptic drugs in the lists of essential drugs varies (10). Phenobarbital is included in 96%, carbamazepine in 82.6%, phenytoin in 68.2%, and valproic acid in 62.5% of the countries. The median cost in international dollars for the first-line antiepileptic drugs is variable across World Health Organization regions. The cost of carbamazepine and sodium valproate in Europe and the Western Pacific is almost half that of other regions. The cost of phenobarbital is 2.7 times higher in southeast Asia than in Europe (35). Even so, the use of newer antiepileptic drugs is increasing even in resource-limited settings, particularly among those in the upper income strata of their societies.
Services provided by epilepsy specialists vary among countries with regard to provision of surgical therapy. The outcome of epilepsy surgery in LMICs is comparable to that of HICs in terms of quality of life and rates of seizure freedom. It is difficult to know how widely epilepsy surgery is offered in LMICs, but it appears that this has increased in availability in Latin America and Asia. One review found mention of epilepsy surgery in only 22% of LMICs, with the most common procedure being temporal lobectomy (31). Surgery can provide a significant improvement in quality of life for many of the 30% of people with epilepsy who continue to have seizures while taking appropriate medication. However, epilepsy surgery is not available in a majority of low-income countries. Availability of epilepsy surgery requires a knowledgeable team consisting of an epileptologist and neurosurgeon, and technical services, including MRI and video-EEG (07; 26; 02).
Whereas the treatment gap for epilepsy is of considerable concern in the developing world, there is a marked treatment gap with respect to epilepsy surgery even in industrialized countries, where perhaps only 5% of potential surgical candidates are ever referred to an epilepsy surgery center. This is largely attributed to misinformation about the risks and benefits of surgery, particularly with respect to recent advances in diagnostic and surgical approaches that have greatly improved safety and efficacy. Until recently, epilepsy surgery was not available in countries with limited resources, but epilepsy surgery programs are now found widely Brazil, China, India, and Turkey and are being developed in many other countries with limited resources where it is recognized as a more cost-effective treatment for surgically remediable syndromes than continued pharmacotherapy (06; 33). The success of epilepsy surgery depends on the accurate identification of good surgical candidates, and then selecting the best candidates based on the available resources and technologies without jeopardizing safety (Engel et al 2005; 26; 02).
Although the World Health Organization has made significant progress in defining the magnitude of the problem of epilepsy and identifying the likely etiological factors, our understanding of the epidemiology of epilepsy in developing countries is still incomplete. The problem is particularly compounded in areas where patients with epilepsy do not have access to neurologists, or even to physicians, and where diagnostic methods such as CT scans and electroencephalography (EEG) are not available. Other difficulties include the complexity of diagnosis in epilepsy.
The causes of epilepsy in low-middle income countries differs from those in high-income countries; however, some of the etiological factors in LMICs may be preventable with appropriate public health measures (01; 27). Prenatal factors and intracranial infections are of particular importance in LMICs because nutrition, improvement in hygiene, and vaccination can have major impacts. Epilepsy and other long-term sequelae of intracranial infections can be minimized by early detection and prompt treatment.
The treatment gap is substantial in LMICs, but many of the causes could be addressed by effective government, infrastructure improvement, and public health schemes. The financial burden to most people in most low-middle income countries is considerable, because patients must pay directly for their healthcare. This situation differs from high-income countries, nearly all of whom have government or privately funded insurance mechanisms to provide healthcare for those at low income levels. This financial burden results in further inequity, with underutilization of medical services in low-income countries. This situation could be improved if countries in every region took collective and cohesive effort toward the management of epilepsy (04). Developing effective national programs will go a long way in reducing the treatment gap in epilepsy in the poor regions of the world.
Certain interventions, such as creating a standardized application EpiPick for choosing appropriate antiepileptic drugs (03), may reduce the treatment gap by providing guidance to practitioners who lack expertise in epilepsy management. Additionally, education regarding risks of death from epilepsy along with improving access to treatment could decrease premature mortality in this disease (16).
Michelle Braslavsky DO
Dr. Braslavsky of Thomas Jefferson University Hospital in Philadelphia has no relevant relationships to disclose.See Profile
Michael R Sperling MD
Dr. Sperling of Thomas Jefferson University in Philadelphia received research contracts from SK Life Science, UCB, Takeda, Neurelis, Engage Therapeutics, Medtronic, Eisai, Cerevel, Xenon, and Janssen; consulting fees from Medtronic and Johnson & Johnson; and speaker honorariums from Eisai.See Profile
John M Stern MD
Dr. Stern, Director of the Epilepsy Clinical Program at the University of California in Los Angeles, received honorariums from Eisai, Jazz Pharmaceuticals, LivaNova, Neurilis, SK Life Sciences, and UCB Pharma as an advisor and/or lecturer.See Profile
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