Introduction

Neurological disorders pose a large burden on worldwide health. The most recent estimates show that the neurological disorders included in the Global Burden of Disease (GBD) Study–Alzheimer’s and other dementias, Parkinson’s disease, multiple sclerosis, epilepsy, and headache disorders (migraine, tension-type headache [TTH], and medication-overuse headache [MOH])–represent 3 percent of the worldwide burden of disease. Although this is a seemingly small overall percentage, dementia, epilepsy, migraine, and stroke rank in the top 50 causes of disability-adjusted life years (DALYs) (Murray and others 2012).

Migraine and epilepsy represent one-third and one-fourth of this neurological burden, respectively (Murray and others 2012), and dementia and Parkinson’s disease are among the top 15 conditions with the most substantial increase in burden in the past decade. In 2010, neurological disorders constituted 5.5 percent of years lived with disability (YLDs), or 42.9 million YLDs; migraine, epilepsy, and dementia were among the top 25 causes of YLDs. Migraine leads the list of neurological disorders, representing more than 50 percent of neurological YLDs or 2.9 percent of global YLDs; epilepsy represents 1.1 percent of global YLDs (Vos and others 2012).

The neurological burden of disease is expected to grow exponentially in low- and middle-income countries (LMICs) in the next decade (Murray and others 2012). Despite the significant impact of neurological disorders on patients and societies, knowledge of their epidemiology, including variation in disease frequency across place and time and understanding of associated risk factors and outcomes, remains limited, particularly in LMICs. Patients with neurological disorders often require significant social and economic support because of physical, cognitive, and psychosocial limitations (WHO 2006). Despite the high prevalence of disability, there is increasing recognition that services and resources are disproportionately scarce, especially in LMICs (WHO 2004). In addition, knowledge of the cost-effectiveness of interventions to improve neurological care in these settings remains limited.

This chapter addresses three neurological disorders: epilepsy, dementia, and headache disorders. The chapter reviews current knowledge of the epidemiology, risk factors, and cost-effective interventions for these conditions. The focus is on interventions that provide meaningful reduction in the burden to the global population, with particular emphasis on applicability to LMICs. Neurological disorders are an emerging challenge to health care systems globally, requiring further study, government and social engagement, and improvements in health care infrastructure.

This chapter uses the World Health Organization (WHO) regions—African, the Americas, Eastern Mediterranean, European, South-East Asia, and Western Pacific—to describe the global burden of the highlighted neurological disorders.

Epilepsy

Definitions

Epilepsy is a brain disorder traditionally defined as the occurrence of two unprovoked seizures occurring more than 24 hours apart with an enduring predisposition to generate further seizures (Fisher and others 2014). In 2014, the International League against Epilepsy provided an enhanced definition of epilepsy (box 5.1).

Box 5.1

Definition of Epilepsy. A person has epilepsy if he or she meets any of the following criteria (Fisher and others 2014): At least two unprovoked (or reflex) seizures occurring more than 24 hours apart

Epilepsy is considered to be resolved if a person has an age-dependent syndrome that is now beyond the expected age for this syndrome, or if the individual remained seizure free for the past 10 years and was off anti-epileptic drugs for at least the past five years (Fisher and others 2014). Those who continue to have seizures despite an adequate trial of a regimen of two tolerated and appropriately chosen anti-epileptic drugs (AEDs), whether in monotherapy or polytherapy, are considered to be drug resistant. Epilepsy can be classified in three categories:

• Structural or metabolic epilepsies, for example, epilepsy caused by a remote stroke
• Epilepsies of genetic or presumed genetic origin, for example, juvenile myoclonic epilepsy
• Epilepsies of unknown causes (Berg and others 2010).

Examples of more common causes of epilepsy include brain tumors, infectious diseases, brain injury, stroke, and hippocampal sclerosis. Less frequent causes include genetic causes, autoimmune causes, and malformations of cortical development (Bhalla and others 2011). Perinatal and infection-related etiologies often predominate in LMICs.

Interventions

Population-Based Interventions

Targeting Epilepsy Risk Factors

Although genetic causes of epilepsy cannot be prevented, the more common structural or metabolic causes can be the target of primary prevention through public health policies. For example, helmet use for motorcyclists and laws against drinking and driving can reduce the risk of traumatic brain injury, a common risk factor. Improved perinatal care, particularly in rural areas, can reduce the incidence and subsequent prevalence of epilepsy. In one Tanzanian community-based, case-control study, adverse perinatal events were present in 14 percent of children with epilepsy but absent in all controls (Burton and others 2012). A population-based cross-sectional and case-control study in Ghana, Kenya, South Africa, Tanzania, and Uganda reported an association between abnormal antenatal period and active convulsive epilepsy (Ngugi and others 2013). Although abnormal delivery and home delivery did not reach statistical significance, there was a trend for these to be associated with active convulsive epilepsy.

Policies to control neurocysticercosis, a common risk factor in LMICs, would be an effective way to reduce epilepsy worldwide. An extensive eight-year public health and educational intervention program aimed at reducing symptomatic epilepsies (particularly those caused by perinatal insults and neurocysticercosis) was implemented in rural Salama, Honduras, starting in 1997 (Medina and others 2011). The program included education and media campaigns, animal husbandry training for pig farmers, construction of water projects and proper sewage disposal, deworming of school students, ongoing taeniasis surveillance, and other initiatives (Medina and others 2011). The proportion of epilepsy caused by neurocysticercosis was reduced from 36.9 percent in 1997 to 13.9 percent in 2005 (Medina and others 2011). The overall cost of this study was US$1.33 million, although an economic analysis was not conducted to determine if it was cost-effective.

A smaller-scale study examined the efficacy of teaching methods to prevent epilepsy caused by neurocysticercosis in western Kenya (Wohlgemut and others 2010). The authors found that knowledge improved significantly using this teaching method. Whether this program reduced the incidence of epilepsy caused by taenia solium was not examined, but the findings represent a positive step. The expert consultation report on foodborne infections, such as taeniasis/cysticercosis, proposes some approaches to ensure sustainable prevention and control of this often endemic agent. These approaches are listed in box 5.2; however, the report did not define the costs of implementing these approaches (WHO 2011).

Box 5.2

Approaches to Ensure Sustainable Prevention and Control of Neurocysticercosis. Preventive chemotherapy of human taeniasis through mass or targeted treatment of humans Mass treatment and vaccination of pigs

Anti-Stigma Interventions

Civil rights violations, such as unequal access to health and life insurance or prejudicial weighting of health insurance provisions, are common. Discrimination in the workplace and restricted access to education are frequent. School teachers often have poor knowledge and negative attitudes toward children with seizure disorders (Akpan, Ikpeme, and Utuk 2013). Stigma is associated with social and economic consequences. Persons with epilepsy may not seek treatment or convey related health concerns to their care providers, further widening the treatment gap.

Improved knowledge about epilepsy is associated with positive attitudes and reduced stigma, but the sustainability and impact remain to be determined (Fiest and others 2014). A broad approach is needed to target stigma at the population level through legislation and advocacy. In addition, education and information provision to dispel myths and enhance seizure management among employers and teachers should empower those with epilepsy to seek treatment and encourage them to be more actively engaged in their communities. The cost-effectiveness of interventions to reduce stigma has not been formally assessed.

Legislation

One of the greatest contributors to the epilepsy treatment gap in LMICs is the lack of availability of anti-epileptic drugs. The second-generation medications are not available in the majority of countries, and even the older anti-epileptic drugs are only available sporadically. Investigators in Zambia who surveyed 111 pharmacies found that 49.1 percent did not carry anti-epileptic drugs. Pediatric syrups that are extensively used in HICs were universally unavailable (Chomba and others 2010). Regrettably, personal communications with epilepsy care providers in other LMICs suggested that this problem may be widespread (Chomba and others 2010).

Clearly, policies are warranted to guarantee the ongoing availability of affordable and efficacious anti-epileptic drugs to patients worldwide. Few countries have a separate budget for epilepsy services, and national funding support for epilepsy care is needed. Out-of-pocket expenses are the primary source of financing epilepsy care in 73 percent of low-income countries, including many countries in Africa, the Eastern Mediterranean, and South-East Asia, where the burden is highest (WHO 2011). Disability benefits do not exist in many regions, and patients are unable to receive monetary support.

Self-Management

Self-management is empowering patients to participate more actively in managing their care. Patients are likely to improve their understanding, adopt healthier lifestyles, and improve adherence to treatment (Fitzsimons and others 2012). Self-management can help those with epilepsy better identify and manage their seizure triggers, which can reduce frequency and decrease health services utilization and health care costs (Fitzsimons and others 2012). A few studies have examined the effectiveness of self-management education programs in adults and children and demonstrated some evidence of benefits; future research is needed to examine the cost-effectiveness of such programs in LMICs (Bradley and Lindsay 2008; Lindsay and Bradley 2010).

Pharmacological Interventions

The decision to initiate treatment with anti-epileptic drugs can be challenging. Analysis of the Multicentre trial for Early Epilepsy and Single Seizures suggests little benefit in initiating treatment for those who present with a single seizure, with no known neurological disorder, and normal electroencephalograms (EEGs) (Kim and others 2006). However, medical management should be considered in those who are at moderate to high risk, defined as more than two to three seizures at presentation, underlying neurological disorders, and abnormal EEGs (Kim and others 2006). More than 60 randomized control trials (RCTs), mostly in HICs, have examined the efficacy of anti-epileptic drugs, but there continues to be a lack of well-designed RCTs examining the efficacy of these medications for patients with generalized epilepsy syndromes and for children (Glauser and others 2013). Newer AEDs tend to be better tolerated, with fewer long-term side effects, but otherwise their superiority has not been proven.

Studies comparing the cost-effectiveness of anti-epileptic drugs in new onset epilepsy have not been conducted. A recent systematic review summarizes the evidence regarding their efficacy as initial monotherapy in those with epilepsy. Monotherapy with any of the standard anti-epileptic drugs (carbamazepine, phenobarbital, phenytoin, and valproic acid) should be offered to children and adults with convulsive epilepsy. Several lower-quality studies have demonstrated efficacy for phenobarbital in adults and children with partial onset seizures and generalized onset tonic-clonic seizures (Glauser and others 2013). Given the acquisition costs, phenobarbital should be offered as a first option if availability can be ensured. If available, carbamazepine should be offered to children and adults with partial onset seizures (WHO 2009b). Using the lowest possible dose should minimize side effects, improve seizure outcomes, and decrease the treatment gap. Valproic acid and ethosuximide have been shown to be most effective in the management of absence seizures, especially in children, although valproic acid is recommended, as it is on the list of essential medicines. Ethosuximide is available as a complementary medication. However, the medication should be avoided, when possible, in women of childbearing potential because of its higher association with major congenital malformations and poorer neurodevelopmental outcomes. Although newer therapeutic agents that are not metabolized by the liver are available, such as levetiracetam, the cost-effectiveness of such therapies has not been studied in LMICs.

Unfortunately, in LMICs, the availability and affordability of standard medications are poor and constitute barriers to treatment. One study found that the average availability of generic medications in the public sector is less than 50 percent for all medicines, except diazepam injection. The private sector availability of generic oral medications ranged from 42 percent for phenytoin to 70 percent for phenobarbital. Public sector patient prices for generic carbamazepine and phenytoin were 5 and 18 times higher than international reference prices, respectively; private sector patient prices were 11 and 25 times higher, respectively. For both medicines, originator brand prices were about 30 times higher. The highest prices were observed in the lowest-income countries (Cameron and others 2012). Ensuring a consistent supply at affordable prices should be a priority.

Approximately 60 percent of patients in Sub-Saharan Africa do not have access to AEDs, increasing the risk of seizures, accidents related to seizures, and status epilepticus, a significant cause of morbidity and mortality in patients with epilepsy (Ba-Diop and others 2014). Some of the best patient-related strategies to avoid status epilepticus include adherence to treatment and avoidance of other seizure triggers. On a population level, the best way to avoid the morbidity and mortality associated with status epilepticus is through health policy to increase the availability of and access to AEDs, and through health professional education such that health professionals are aware that time is brain. Aggressive treatment of status epilepticus should be implemented after five minutes, not after 30 minutes of ongoing seizures, in accordance with the current operational definition of status epilepticus (Lowenstein and others 2001).

Management of Infectious Etiologies of Epilepsy

Neurocysticercosis is a common cause of epilepsy in LMICs. Recent evidence-based guidelines are available to guide the treatment of parenchymal neurocysticercosis (Baird and others 2013). These guidelines suggest that therapy with albendazole, with or without corticosteroids, along with AEDs, is likely to be effective in improving outcomes (Baird and others 2013).

Evidence-based guidelines were published to guide the selection of anti-epileptic drugs for people with HIV/AIDS, because concomitant AED-antiretroviral administration may be indicated in up to 55 percent of people (Birbeck and others 2012). The guidelines state that it may be important to avoid enzyme-inducing AEDs in people on antiretroviral regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, because pharmacokinetic interactions may result in virologic failure. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure the efficacy of the antiretroviral regimen (Birbeck and others 2012).

Surgical Management

The probability of achieving one-year seizure freedom after trying up to three anti-epileptic drugs occurs in the majority of cases (70 percent in those presenting with new onset epilepsy). However, drug resistance occurs in up to 40% of patients overall, particularly in those with focal epilepsy (Berg and others 2009; Kwan and Brodie 2000; Schiller and Najjar 2008; Semah and others 1998). In those who have failed three anti-epileptic drugs, attempting to treat with additional anti-epileptic drugs is unlikely to achieve sustained seizure freedom (Jette, Reid, and Wiebe 2014). Experts generally agree that those who are drug resistant and have failed two appropriate AED trials should be considered for a surgical evaluation (Jette, Reid, and Wiebe 2014; Kwan and others 2010; Wiebe and Jette 2012). Other patients who should be referred to a comprehensive epilepsy program for a surgical evaluation include children with complex syndromes, patients with stereotyped or lateralized seizures or focal findings, and children with a magnetic resonance imaging lesion amenable to surgical resection regardless of seizure frequency (Jette, Reid, and Wiebe 2014; Wiebe and Jette 2012). Strategies for surgical therapy of epilepsies in resource-poor settings have been proposed, and epilepsy surgery is increasingly performed in LMICs, with excellent outcomes (Asadi-Pooya and Sperling 2008).

Alternative Therapies

Proposed alternative therapies for epilepsy include dietary therapies, medical marijuana, and acupuncture; only dietary therapies have been subjected to randomized trials. The ketogenic diet can improve seizure outcome in those with drug-resistant epilepsy, but is difficult to tolerate, particularly in adults (Levy, Cooper, and Giri 2012). The Atkins diet was associated with improved seizure control in one observational study, but future studies are required to examine its benefit and the benefit of other dietary therapies, such as the modified Atkins diet and the low glycemic index diet (Levy, Cooper, and Giri 2012). Despite their increased use, dietary therapies are resource intensive, costly, and remain largely limited to HICs (Cross 2013). Cost-effective and simpler means of implementing these therapies in LMICs are needed. The efficacy of oral cannabinoids and acupuncture for the treatment of epilepsy remains uncertain (Cheuk and Wong 2014; Koppel and others 2014).

Interventions to Optimize Health Care Delivery

The treatment gap is defined as the number of people with active epilepsy who need appropriate anti-epileptic treatment but do not receive adequate medical therapy. Regrettably, those living in LMICs, where the burden of epilepsy is extensive, are the most affected by the epilepsy treatment gap (Jette and Trevathan 2014). The treatment gap is more than 75 percent in low-income countries, more than 50 percent in many LMICs and upper-middle-income countries, and less than 10 percent in most HICs (figure 5.1) (Meyer and others 2010).

Figure 5.1

Epilepsy Treatment Gap and Standard Errors Calculated from Lifetime Prevalence Estimates.

Proposed mechanisms for the epilepsy treatment gap can be divided into two broad categories: health care system and patient-related reasons (Cameron and others 2012; Kale 2002; Mbuba and others 2008). Health care system issues include lack of availability of anti-epileptic drugs, missed or delayed diagnosis, wrong treatment prescribed, treatment not offered to patients, and lack of resources and personnel (Cameron and others 2012; Kale 2002; Mbuba and others 2008). Epilepsy diagnosis is predominantly based on clinical history, and primary care physicians can be trained to provide basic treatment. Patient-related potential mechanisms for the treatment gap include cultural beliefs, stigma, fear of side effects, the hassle factor, and cost of treatment (Cameron and others 2012; Kale 2002; Mbuba and others 2008). All these reasons for the epilepsy treatment gap should be considered as potential targets for evaluation and action.

One study examined the availability, price, and affordability of anti-epileptic drugs in 46 countries (Cameron and others 2012). The study found that not only is the availability of these medications lower in LMICs, but their costs are highest where the treatment gap is the greatest (Cameron and others 2012). This study supports the view that availability and affordability of anti-epileptic drugs are likely major drivers in resource-poor countries. Box 5.3 provides a summary of the potential targets for evaluation and action to improve the epilepsy treatment gap.

Box 5.3

Potential Targets to Improve the Epilepsy Treatment Gap. Health Care System Improve access to anti-epilectic drugs

Two of the most impactful approaches to target the treatment gap are legislative and anti-stigma interventions. Unfortunately, their cost-effectiveness has not been evaluated.

Dementia

Dementia poses a unique burden to those affected, their families, and societies. Substantial projected increases of patients with dementia in LMICs will pose additional economic and social burdens. Dementia is often erroneously considered an unavoidable part of aging or a condition for which nothing can be done; limited understanding and the persistence of stigma and discrimination limit help-seeking. Consequently, timely diagnosis is the exception rather than the norm; most people are not diagnosed and have limited access to adequate health or social care. Because pharmacotherapy and psychological and psychosocial interventions that can ameliorate symptoms and lessen the impact on family members and caregivers are often unavailable, the treatment gap remains very large, particularly in countries where cultural and infrastructure barriers persist.

Epidemiology and Burden of Dementia

The most significant risk factor of dementia is increasing age; the incidence doubles with every five-year increment after age 65 (WHO 2015). The graying of societies in all global regions is expected to increase the number affected substantially. In 2015, approximately 47 million people had some form of dementia; 63 percent of those were in LMICs. This figure will nearly double to 76 million in 2030 and to 145 million by 2050. The majority (71 percent) of new cases will occur in LMICs (figure 5.2) (Prince and others 2015; WHO 2015). The steepest projected increases in numbers of people with dementia are expected in these settings because of rapid demographic changes. A new dementia case is diagnosed every four seconds in the world, leading to 7.7 million new cases per year; nearly 50 percent of new cases occur in Asia (WHO 2015).

Figure 5.2

Projected Growth in Number of People with Dementia in All Income Groups, 2010–50.

In community-based samples, the prevalence of dementia varies from 38 to 400 per 100,000 inhabitants, with an increasing incidence over 55 years. Frontotemporal dementia (9.7 percent), alcohol-related dementia (9.4 percent), traumatic brain injury (3.8 percent), and Huntington’s disease (3 percent) are more frequently present in early-onset dementia (EOD) compared with late-onset dementia (Picard and others 2011). Although dementia is more common in older age, some people develop symptoms at a younger age compatible with EOD, a poorly understood and frequently underdiagnosed condition.

Independent of the age at onset, most patients are cared for at home by close relatives. Need for one-on-one care starts early, becomes increasingly intense, and may change significantly throughout the natural history of the disease. Mood and behavioral changes, memory impairment for recent events, and spatiotemporal disorientation, as well as problem-solving deficits that characterize the early stage, may expose people with dementia and their families to stressful situations well before the clinical diagnosis is made. Later, mood and behavioral disorders further increase the burden of the disease.

The later stages are characterized by diffuse involvement with psychological and behavioral symptoms, including repetitive behaviors, hallucinations, aggression, and wandering (Kales and others 2014). In contrast to cognitive deficits, these symptoms are strongly related to institutionalization (Richardson and others 2013). Caring for persons with dementia is associated with increasing physical and emotional stress. Studies show that caregivers often have feelings of isolation, anxiety, and depression that reduce the quality of life and may impact the quality of care they provide (Reitz, Brayne, and Mayeux 2011). The cumulative distress of caregivers constitutes a central component of the dementia burden (Donaldson and Burns 1999).

Global Burden of Dementia

Dementia has become a significant economic burden across the world (figure 5.3). The disease is the leading cause of dependence in older adults in all world regions; up to 50 percent of older adults who need care have dementia. According to the 2010 GBD report, the DALYs attributable to Alzheimer’s disease and other dementias doubled in the past 20 years, and dementia is estimated as the major driver of DALYs in late life among all chronic diseases by virtue of its strong association with mortality and dependence. The dementia-attributable DALYs may increase further in LMICs, where life expectancy is increasing, and resources for the provision of health care for older adults are limited or unavailable.

Figure 5.3

Distribution of the Total Societal Costs of Dementia Care, by World Bank Income Level.

In HICs, the level of care needed is the single strongest predictor of institutionalization of older adults. In LMICs, institutionalization is less likely; people with dementia tend to stay in their homes through the very advanced stages of the disease, cared for by informal caregivers, who are almost invariably close relatives and women.

The direct costs include health service use, health care, and institutionalization; the indirect costs include those associated with cutting back on work to provide care. Both pose significant financial burdens on individuals, families, and societies.

The global economic cost in 2013 was US$604 billion, approximately 1 percent of the global gross domestic product (WHO 2015). The direct and indirect costs are proportionally higher in HICs. Moreover, the distribution of costs across medical, societal, and informal care varies strikingly across regions and health system organizations. Hospital inpatient costs contributed 70 percent of the direct costs for prevalent dementia, mainly related to psychiatric care (Leibson and others 2015). The indirect costs of informal care likely go far beyond foregone income. There are potentially pernicious repercussions on families and social ties, caused by caring for persons with dementia, particularly in settings where there are false beliefs about the causes and course.

Headache Disorders

The three headache disorders of particular public health importance are migraine, TTH, and MOH. Collectively, these three are the third most common cause of disability in populations throughout the world (Murray and others 2012; Steiner and others 2015; Stovner and others 2007; Vos and others 2012).

Headache disorders are the most frequent cause of consultation in primary care and neurology practice; it prompts many visits to internists; ear, nose, and throat specialists; ophthalmologists; dentists; psychologists; and proponents of a wide variety of complementary and alternative medical practices (WHO 2011). Headache is a common presenting symptom in emergency departments. The consequences of recurring migraine include pain, disability, diminished productivity, financial losses, and impaired quality of life. Therefore, although headache rarely signals serious underlying illness, its causal association with personal burdens of pain, disability, and diminished quality of life makes it a major contributor to ill health.

Conclusions and Recommendations

Epilepsy, dementia, and headache disorders represent a significant burden on global health. Not only are these conditions prevalent, but they are associated with significant disability, poor psychosocial outcomes, and substantial economic costs.

Innovative health care management approaches are required in LMICs because of the lack of specialist care. Some of these approaches are discussed, but few have been subjected to cost-effectiveness evaluations. Further data collection is needed in many areas of global neurology, including epidemiological studies, needs assessments, and cost-effectiveness analyses.

For all three of these conditions, pharmacotherapies have advanced considerably in the past two decades, but these options are regrettably limited in LMICs. Indeed, the treatment gap for these conditions is substantial, driven by patient and health system factors, which are unlikely to improve without education of the public and health care professionals, legislation, and anti-stigma interventions. Fortunately, attitudes and knowledge about the burden of epilepsy, dementia, and migraine are starting to improve, and such progress can help reduce the treatment gap and enhance psychosocial outcomes for those suffering from these conditions. Ultimately, however, increased financial investments and legislative changes are required to improve neurological care in LMICs.

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Footnotes

World Bank Income Classifications as of July 2014 are as follows, based on estimates of gross national income (GNI) per capita for 2013:

• Low-income countries (LICs) = US$1,045 or less
• Middle-income countries (MICs) are subdivided:
  a) lower-middle-income = US$1,046 to US$4,125
  b) upper-middle-income (UMICs) = US$4,126 to US$12,745
• High-income countries (HICs) = US$12,746 or more.