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Neurocysticercosis as an infectious acquired epilepsy worldwide
Seizure 52 (2017) 176–181
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Review
Neurocysticercosis as an infectious acquired epilepsy worldwide Doodipala Samba Reddy* , Randy Volkmer II Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA
A R T I C L E I N F O
Article history: Received 7 August 2017 Received in revised form 5 October 2017 Accepted 7 October 2017 Available online xxx Keywords: Neurocysticercosis Epileptogenesis Infestation Parasite Taenia solium
A B S T R A C T
Aside from brain injury and genetic causes, there is emerging information on brain infection and inflammation as a common cause of epilepsy. Neurocysticercosis (NCC), the most common cause of epilepsy worldwide, is caused by brain cysts from the Taenia solium tapeworm. In this article, we provide a critical analysis of current and emerging information on the relationship between NCC infection and epilepsy occurrence. We searched PubMed and other databases for reports on the prevalence of NCC and incidence of epilepsy in certain regions worldwide. NCC is caused by brain cysts from the T. solium and related tapeworms. Many people with NCC infection may develop epilepsy but the rates are highly variable. MRI imaging shows many changes including localization of cysts as well as the host response to treatment. Epilepsy, in a subset of NCC patients, appears to be due to hippocampal sclerosis. Serologic and brain imaging profiles are likely diagnostic biomarkers of NCC infection and are also used to monitor the course of treatments. Limited access to these tools is a key limitation to identify and treat NCC-related epilepsy in places with high prevalence of this parasite infestation. Overall, NCC is a common infection in many patients with epilepsy worldwide. Additional clinical and animal studies could confirm common pathology of NCC as a postinfectious epilepsy that is curable. © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction Epilepsy is a chronic disorder of the brain that causes seizures [1–4]. Genetic and acquired conditions are common risk factors for the development of epilepsy. The most common acquired conditions or risk factors for epilepsy are brain injuries, neurotoxicity, prolonged seizures, stroke and infection [5–7], but they vary from country to country [8–11]. Infections of the central nervous system (CNS) are common risk factors for acquired epilepsy, also known as postinfectious epilepsy. Viral meningitis and parasitic infections are the most widely observed causes of postinfectious epilepsy worldwide. Many viruses, such as Theiler’s murine-encephalomyelitis virus, are widely reported to cause encephalitis and sometimes even epilepsy. Neurocysticercosis is one of the major parasitic infection that is known to cause seizures
Abbreviations: BBB, blood brain barrier; CDC, Center for Disease Control and Prevention; CSF, cerebrospinal fluid; CNS, central nervous system; CT, computerized tomography; ELISA, enzyme-linked immunosorbent assay; ILAE, International League Against Epilepsy; IL, interleukins; MMP, metalloproteinases; MRI, magnetic resonance imaging; NCC, neurocysticercosis. * Corresponding author at: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, 2008 Medical Research and Education Building, 8447 Riverside Parkway, Bryan, TX 77807-3260, USA. E-mail address: [email protected] (D.S. Reddy).
in Asian and African countries. This article provides a critical analysis of current and emerging information on neurocysticercosis as an infectious cause of acquired epilepsy. We reviewed clinical reports and articles on the prevalence of this parasitic infection and the incidence of epilepsy in endemic regions worldwide. 2. Neuropathology of neurocysticercosis 2.1. Introduction Neurocysticercosis (NCC) is one of the more thoroughly researched causes of CNS infection. It has a documented correlation to increased epilepsy prevalence in many countries, accounting for up to 30% of epileptic seizures in certain areas of Central and South America [12,13]. NCC is caused by Taenia solium, a parasitic helminth worm [13]. Specifically, T. solium belongs to the Platyhelminthes phylum which is the tapeworm subcategory of the helminth parasites [13]. The life cycle of T. solium is illustrated by the Center for Disease Control and Prevention (CDC) (Fig. 1). The initial infection of T. solium occurs from the ingestion of eggs, which are found in the feces of a human host that is inundated with T. solium infection, or by the consumption of undercooked pork that contains the larval cysts (cysticerci) [13,14]. While in the process of travelling through
https://doi.org/10.1016/j.seizure.2017.10.004 1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
D.S. Reddy, R. Volkmer / Seizure 52 (2017) 176–181
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Fig. 1. The CDC illustration of the lifecycle of Taenia solium and Taenia saginata, the suspected parasites for the infectious cause of epilepsy worldwide. According to U.S. Centers for Disease Control and Prevention (CDC), cysticercosis is a parasitic tissue infection caused by larval cysts of the tapeworm Taenia solium. These larval cysts infect brain, muscle, or other tissue, and are a major cause of adult onset seizures in some countries. A person gets cysticercosis by swallowing eggs found in the feces of a person who has an intestinal tapeworm. Eating undercooked pork can result in intestinal tapeworm infection if the pork contains larval cysts. Pigs become infected by eating tapeworm eggs in the feces of a human infected with a tapeworm. Pigs serve as intermediate reservoirs for larval and egg forms. Source: U.S. Centers for Disease Control and Prevention (CDC).
the gastrointestinal tract, the ingested larva eventually attach to the intestinal wall, and ultimately mature into egg-producing adult tapeworms [14,15]. Pigs are usually the intermediate host for the tapeworm infection, and humans are usually definitive hosts [14]. It is the ingestion of the eggs by exposure to egg-containing human or pig stools, and not consumption of the larval infected pork meat, that causes onset of NCC [14]. Once ingested and in the intestines, the eggs hatch into oncospheres (embryos) that cross the intestinal wall where they are transported by blood to various body tissues in which they form the larval cysts [14,15]. These larval cysts are usually destroyed by the host’s immune system, leading to what is typically an asymptomatic disease [14]. However, if the oncospheres form cysts in an immunologically privileged site (impervious to major immune response) such as the CNS, symptomatic features of NCC will appear [14]. These larvae usually infect the brain tissue via route of the blood [13]. Once there, they stimulate an immune response that will induce both granuloma formation as well as perilesional edema around the granuloma [13]. Later on, after the cyst degenerates, the lesion undergoes a further immunologic process in which there is a deposition of fibrotic
material and the cyst eventually hardens and turns into a calcific nodule [13]. 2.2. Immunopathology A large part of the pathology associated with NCC is due to the host’s immunologic response to the T. solium larval cysts [13]. The immunopathology of T. solium infection is largely due to the balanced response of the Helper T-cells: Th1 and Th2 [13,16]. IL-2, a cytokine that is produced by Th1, has been found in human cerebrospinal fluid (CSF) in individuals with symptomatic NCC, and was originally thought to be the major culprit of NCC symptomology [13]. Yet in more recent studies, symptomatic NCC immune response has also been found to be associated with high levels of Th2 cytokines such as IL-4 (increases IgE production) and IL-5 (chemokine for eosinophil recruitment) [15–17]. In one murine model where mice were infected with Taenia crassiceps cysts (a tapeworm closely related to T. solium), Th1 cells were found to release IL-2 and interferon-g and were associated with the dying of the T. crassiceps cysts [18]. Cytokines that are present in the
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beginning stages of cyst (active, non-calcific lesion) formation were once thought to cause the seizures classically seen with NCC, but murine models of mice with T. crassiceps induced brain lesions have proven this not to be the case [18,19]. Granuloma formation, which is a classic finding in chronic parasitic infection, was found in the same murine research experiment to be directly correlated with increased levels of interferon-g and could be related to the early pro-inflammatory response caused by Th1 [13,18]. Beyond cytokines, metalloproteinases (MMP) have been found in increased amounts in both mice and humans with symptomatic NCC [15,20,21]. MMPs are usually secreted by cells belonging to the monocyte lineage and have the capacity to degrade various extracellular matrix components and have been shown to degrade and increase the permeability of the blood-brain barrier in individuals with NCC [15,20–22]. 2.3. Diagnosis One of the most definitive ways in which NCC can be diagnosed is by neuroimaging. MRI and CT scanning can be used to identify the calcific, granulomatous “ring enhancing” lesions found in the brain [14]. However, each is not without its own limitations. CT scan has a strong sensitivity to picking up the classic NCC lesions, but has been found to be less than optimal at identifying lesions located in brain tissue that reside in the posterior fossa of the skull [14,23]. MRI is better in its ability to portray NCC lesions, but the sheer cost of this type of scan makes it a very limited and inaccessible resource in regions of the world where NCC is endemic [23]. Serologic testing can also be utilized in the diagnosis of NCC. Enzyme-linked immunoelectrotransfer blot assay can be used to detect antibodies that have been formed against T. solium cysts [24,25]. This form of serum testing has been shown to have a very high specificity for T. solium infection, but does not have a very strong sensitivity for only one brain lesion, which makes it problematic for diagnosing NCC [24]. Enzyme-linked immunosorbent assay (ELISA) testing is also used for detection of T. solium antibodies but has been shown to have both poor sensitivity and specificity [24]. Serum testing is useful in helping rule in or out parasitic infection of the host, but is limited in its ability to establish location of the parasitic infection. Antibody testing of the
CSF gives a better indication of whether or not parasitic cysts are located in the CNS, but is not used as widely due to both the difficulty and painfulness of the procedure used to obtain a sample [26]. It has also been documented that serum and CSF antibody testing has very little capacity to identify inactive, calcific lesions of the brain which are prominent in later stages of NCC [26]. 3. Neurocysticercosis as infectious cause of epilepsy 3.1. Prevalence of NCC in developing countries NCC has been identified as what is mainly a problem in developing countries and communities that have low levels of sanitation and repeated exposure to pigs and pig feces [27] (Table 1). In one study that examined the CT scans and serology for NCC in people located in the Vellore district of southern India, it was found that there was a prevalence rate of 1.02 people with NCC per 1000 individuals for the rural areas of south India and a prevalence of 1.28 people with NCC per 1000 individuals for the urban areas [28,29]. Compared to the previous southern Indian study, the prevalence rate of NCC in rural northern India in the Dehradun district was found to be 3.48 people with NCC per 1000 individuals, although it is possible that the study underestimated the actual total of NCC cases since only subjects with some degree of a seizure disorder were examined by a neural CT scan [30]. In a study conducted in West Cameroon (sub-Saharan Africa) that utilized both serology as well as neural CT scans to identify the presence of NCC infection after receiving a positive test result for T. solium antibodies in the serum, the prevalence rate of NCC was found in 2.6 people per 1000 individuals [31]. Results of the NCC prevalence in the Cameroon study could be underestimated, due to both the death and dropping out of subjects found to be seropositive before they could be tested for neural lesions via CT scanning [31]. Subjects in each of the aforementioned studies (southern India, North India, Cameroon) had extensive exposure to pigs and pig feces, which consequently led to the high prevalence rates of NCC as compared to a country such as the United States, which has an estimated NCC prevalence of 0.2 to 0.6 per 100,000 people in the general population [32]. It is due to a higher prevalence of NCC that makes developing countries a more appropriate subject for analysis of NCC and its relation to epilepsy.
Table 1 An overview of clinical reports of neurocysticercosis (NCC) and epilepsy in various countries. Place
Number of subjects
Measurements Detection method: NCC (CT or Serology)
Prevalence general population: NCC
Prevalence general population: EP
Southern India (Vellore district)
50, 617 (38, 105 rural/12,512 urban)
NCC and Epilepsy
Both
Urban: 6.23 per 1000 55/162 Subjects with EP + NCC/ Rural: 3.04 per 1000 Total Subjects with EP
[29]
Northern India (Dehradun district) West Camaroon Zambia
14, 086
NCC and Epilepsy
Both
Urban: 1.28 per 1000 Rural: 1. 02 per 1000 3.48 per 1000
10 per 1000
[30]
4, 993 49
NCC NCC
Both Both
Mozambique
151
NCC
Both
Burkina Faso
32
NCC
Both
Ecuador
19
NCC and Epilepsy
Both
Peru
48
NCC and Neural Symptoms
Both
Prevalence
clinical subgroup
49/141 Subjects with EP + NCC/ Total Subjects with EP
2.6 per 1000
9.4 per 1000
188 per 1000
18/49 Subjects with EP + NCC/ Total Subjects with EP 85/151 Subjects with EP + NCC/ Total Subjects with EP 12/32 Subjects with EP + NCC/ Total Subjects with EP 5/19 Subjects with EP + NCC/Total Subjects with EP 8/48 Subjects with neural symptoms + NCC/Total Subjects with NCC
Reference
[31] [40] [41] [42] [27]
[47]
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Under-diagnosis of NCC is a potential issue given the limitations of the types of testing (serologic and neuroimaging) that are predominately used to diagnose it [14,23,24]. Depending on where the NCC lesion is located in the brain, such as within the parenchyma or within the ventricles, and even whether the cyst is active or inactive, either MRI or CT scanning should be used to more accurately to identify the lesion in question [33]. Whether it is within research studies or in the clinic, under-identification could occur due to the lack of utilizing both types of neural scanning (MRI/CT) because of either a lack of accessibility or a lack of financial means to carry out both diagnostic methods. It has also been documented that neuroimaging techniques are limited in their ability to illuminate neural NCC lesions under a certain size, which makes it increasingly difficult to diagnose the CNS infection altogether [34]. NCC lesions identified on neural scanning have the capacity to be misdiagnosed [35]. In particular, NCC lesions have the potential to be confused with tuberculoma, bacterial abscesses, fungal abscesses, brain tumors, or congenital arachnoid cysts [35]. All of these factors, both by themselves and/or coupled to one another, could directly contribute to a misrepresentation of the actual prevalence of NCC. 3.2. Incidence of epilepsy in NCC cohorts Based on the site of the neural lesion caused by NCC, infection can manifest itself through many different neurologic signs or syndromes such as headaches, confusion, ataxia, meningismus, and/or seizures [36,37]. In particular, the onset of seizures is the most commonly associated clinical feature of NCC [36,37]. It is thought that certain stages of cyst formation and degeneration are associated with varying risk of seizures, though this theory has not been proven experimentally [13,38]. Specifically, the inactive, calcific lesions that form after the cyst has degenerated have a higher propensity for inducing seizures than the earlier, activeedematous cystic stage [13]. Prevalence of epilepsy in patients with NCC is a heavily researched and contested area of study [39] (Table 1). In the rural and urban southern Indian population, 55 out of the 162 patients with epilepsy that underwent CT testing were found to have NCC [29]. The criteria for epilepsy diagnosis was based on whether or not the patient had two or more seizures in their life, one of which must have happened at least 5 years before the study was performed [29]. NCC in the rural northern Indian population was found in 49 of the 141 people with epilepsy that had further CT testing, and epilepsy was diagnosed by analysis via EEG and CT scan and was in accordance with ILAE criteria [30]. Upon examination of an epileptic population of people in Zambia, which was highly endemic for NCC, it was found that 28.6% of the subjects had neural lesions that were either highly suggestive or definite for NCC [40]. Epilepsy in this study was defined as having had seizures within the last two years or having been on antiepileptic medication at one point in their life [40]. Another study conducted in an epileptic, rural population in Mozambique that was highly endemic for T. solium infections showed that 56% of the subjects with epilepsy had NCC lesions seen on CT scan [41]. The diagnostic criteria for this study was in accordance with the ILAE definition of epilepsy [41]. In a study performed in an epileptic population in Burkina Faso, a country in sub-Saharan Africa, calcific lesions indicative of NCC were found in 12 of the 32 participants that were screened via CT [42]. In rural Ecuador, a study over the proportion of NCC in epileptic individuals was found in 5 of the 19 total individuals [43]. The criteria used to diagnose epilepsy was based on whether or not the individual had two or more seizures in their lifetime [43]. Over all of these studies, in the developing world, NCC was consistently found in around 37.6% of individuals with epilepsy or seizure disorders (Table 1). This rate is comparable to
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those that have previously been determined from other studies that have examined populations in the developing world as well [44,45] (Table 1). Caution should be used when examining the prevalence rates of research studies in this area, as not all of them utilize the same diagnostic criteria and techniques used to identify NCC and could thus misrepresent the actual proportion of individuals with NCC [44]. For example, certain studies utilized serum AG-ELISA to test for NCC antigen while others used serum antibody testing to determine T. solium infection [41,43]. These test results were then subjectively weighted and diagnoses were made, based on the preferences of the researchers and their respective diagnostic criteria. Furthermore, some studies have different definitions of epilepsy that could potentially lead to individuals being inappropriately included or excluded for NCC presence investigation, when in fact their neurological disorder is something else entirely, thus distorting the subsequent data. The ILAE definition of epilepsy states that the seizures must have been more than 24 h apart, and certain studies have been found to disregard that timeline in their subject recruitment [29,40,43]. Many studies that examine the relationship between rates of NCC in populations with epilepsy utilize prevalence as the quantitative value to analyze the correlation between the two [44]. Prevalence represents the simultaneous presence of both epilepsy and NCC present at a single point in time. This strategy diminishes the capacity to determine whether or not NCC occurred in the subjects before or after the onset of epilepsy [44,46]. Inability to estimate time of NCC occurance as it relates to epilepsy onset greatly takes away from the conclusions that are made regarding the causative correlation of NCC to epilepsy. Another major limitation to most studies that investigate NCC as a major cause of epilepsy lies in the sole investigation of populations of people that have epilepsy or other seizure disorders. Emphasis should also be put on the prevalence of seizure symptoms in people with NCC, so as to better understand the likelihood that an individual with NCC will develop epilepsy or epilepsy like syndromes. A study that was conducted in a highly NCC endemic population in rural Peru found that out of 48 people with NCC lesions in their brain, 40 of them reportedly never had any neurologic history of seizure or recurring headaches [47]. Research in this area is very limited which is likely due to the cost inefficiency of performing neural scans on a general population. However, further studies must be conducted to better estimate the true prevalence of seizure disorders in patients with NCC. Beyond the variations of the studies themselves, there is disagreement in this field of research as to whether or not the seizure disorder induced by NCC should be classified as epilepsy [39,44]. The ILAE definition of epilepsy includes that the seizures in question must be “unprovoked” to be eligible for epilepsy diagnosis [2,44]. It was determined in one study that transient inflammation and subsequent edema surrounding a calcific NCC lesion was associated with recurrence of seizures [48,49]. This raises the question as to whether NCC is a direct cause of epilepsy development, or is a causative agent of symptommatic seizures that are provoked by the inflammation or damage to the brain tissue that is caused by the NCC lesions [44]. 3.3. Animal models of NCC infection Although NCC has been recognized as a common helminthic infection of the brain caused by the larval form of the tapeworm T. solium, there are few experimental studies to link the NCC as a major cause of seizures and epilepsy in animal models [50]. In experimental models, the term ‘epileptogenesis’ is used to describe the complex plastic changes in the brain that, following a precipitating insult or injury, convert a normal brain into a brain
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Fig. 2. A model for neurocystocercosis-induced epilepsy development. It is likely that NCC infection may act as an initial insult or inciting lesion (the cyst) from which a significant percentage of hosts may develop epilepsy through the common epileptogenesis. Such infection-triggered epileptogenesis may often occur over a long latent period prior to the first recurrent seizure with variable time course after an initial infection. Alterations in the blood-brain barrier and persistent proinflammatory response that surround the cysts or calcified granulomas may underlie the epileptogenesis in patients with NCC infection. MRI imaging supports the presence of such inciting lesions in patients with NCC-related recurrent seizures. Consistent with human cases, epilepsy is observed in some rodent models of experimental NCC infection after a latent period.
debilitated by recurrent seizures (Fig. 2). Currently, the most common concept about epileptogenesis suggests that it occurs over the course of three stages. The first stage requires an initial precipitating event. This is followed by the second stage, which is a latent period of variable time. The third stage is the chronic period, in which the subject exhibits spontaneous seizures. A few experimental models of NCC have been reported in mice and rats [50]. These rodents are infected intracranially with T. crassiceps or Mesocestoides corti [51,52]. Stringer and colleagues have found seizure activity in a rat model of NCC using granulomas associated with T. crassiceps infection [51]. In another study, epileptic seizures (generalized tonic-clonic seizures) were observed in a rat model of NCC using activated T. solium oncospheres [52]. The overall incidence of epilepsy was 9% in rats infected with NCC at 5 months postinfection. Histological reports show specific neurological abnormalities such as inflammation around cysts in the brain. There are recent news reports on the brain-infesting sickness on the U.S. Hawaii Island, which is attributed to rat lungworm Angiostrongylus cantonensis [53]. The parasite, which commonly resides in the pulmonary arteries of rats, enters into human from contaminated food via the intermediate host snails and slugs. This disease also affects the brain and spinal cord. The infection can cause a rare meningitis that can trigger seizures. It is unclear if meningitis is caused by A. cantonensis or secondary factors such as inflammation or autoimmune response. 4. Conclusion and clinical prospects Infections of the CNS are common risk factors for epilepsy. Viral and parasitic infections are widely considered as causes of postinfectious epilepsy [50]. Though there is strong association between NCC and the occurance of epilepsy (Table 1), the reports are variable in confirming NCC as a cause of infectious epilepsy worldwide. T. solium infection has a higher rate of occurrence in low income countries, as do subsequent rates of NCC; increasing the probability for coincidental occurance between an especially common neural disease in the developing world, such as epilepsy, and NCC. There is a real possibility that the prevalence rates of NCC in endemic countries are much higher than originally estimated,
due to a lack of resources needed to carry out the necessary research to assuredly identify the disease. The predominant method of solely investigating simultaneous occurrence of NCC and epilepsy is limiting this field of research from drawing substantiated conclusions as to the risk of epilepsy development in patients with NCC. Prospective studies that examine epilepsy occurrence in patient populations that have NCC are needed to further understand the true risk of epilepsy development associated with NCC lesions. It is also necessary that strict adherence be followed for the diagnosis of NCC, as many studies formulate their own criteria which could cause variability between studies that investigate NCC. A more universal inclusion and exlusion criteria should be utilized and adhered to for achieving consistency between various studies. In summary, many people with NCC may develop epilepsy but the rates are highly variable, and can be anywhere from 10% to 50% [49] (Table 1). NCC occurs in a homogeneous patient population with an inciting lesion (the cyst) from which a significant percentage, but not all patients, develop epilepsy. MRI imaging can show many changes including localization and number of cysts as well as the host response to treatment, prior to the development of chronic, recurrent seizures. Some evidence suggests that medically refractory epilepsy in a subset of these patients can also result from hippocampal sclerosis, suggesting that NCC may be a clinical opportunity to study hippocampal epileptogenesis [50,52]. Treatment and prevention aspects of NCC are covered elsewhere [54]. The ultimate method for controlling NCC in endemic regions is to prevent and eliminate parasite transmission by better hygiene and lifestyle changes. Based on the current pathogenic information, we propose a working model for NCCrelated epileptogenesis (see Fig. 2). A better understanding of the NCC infection began to emerge from animal models. Therefore, further studies during epileptogenic stages of these patients and animal models could lead to predictive biomarkers and specific treatments for neurological lesions that incite epilepsy. Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References [1] Fisher S, van Emde Boas W, Blume , Elger C, Genton P, Lee P, Engel Jr. J. Epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ILAE) and the international bureau for epilepsy (IBE). Epilepsia 2005;46(4):470–2. [2] Thurman L, Beghi E, Begley CE, Berg AT, Buchhalter JR, Ding D, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia 2011;52 (Suppl. 7):2–26. [3] Robert S, Fisher CA, Arzimanoglou Alexis, Bogacz Alicia, Helen Cross J, Elger Christian E, et al. A practical clinical definition of epilepsy. Epilepsia 2014;55 (4):475–82. [4] Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational classification of seizure types by the international league against epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58(4):522–30. [5] Reddy DS, Bhimani A, Kuruba R, Park MJ, Sohrabji F. Prospects of modeling poststroke epileptogenesis. J Neurosci Res 2017;95(4):1000–16. [6] Senanayake N, Román GC. Epidemiology of epilepsy in developing countries. Bull World Health Organ 1993;71(2):247–58. [7] Kvalsund MP, Birbeck GL. Epilepsy care challenges in developing countries. Curr Opin Neurol 2012;25(2):179–86. [8] Zack MM, Kobau R. National and state estimates of the numbers of adults and children with active epilepsy—United States, 2015. MMWR 2017;66:821–5. [9] Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in Europe—a systematic review. Eur J Neurol 2005;12:245–53. [10] Mac Luong, Tran DS, Quet Fabrice, Odermatt Peter, Preux Pierre-Marie, Tan Chong Tin. Epidemiology, aetiology, and clinical management of epilepsy in Asia: a systematic review. Lancet Neurol 2007;6:533–43.
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Review
Neurocysticercosis as an infectious acquired epilepsy worldwide Doodipala Samba Reddy* , Randy Volkmer II Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA
A R T I C L E I N F O
Article history: Received 7 August 2017 Received in revised form 5 October 2017 Accepted 7 October 2017 Available online xxx Keywords: Neurocysticercosis Epileptogenesis Infestation Parasite Taenia solium
A B S T R A C T
Aside from brain injury and genetic causes, there is emerging information on brain infection and inflammation as a common cause of epilepsy. Neurocysticercosis (NCC), the most common cause of epilepsy worldwide, is caused by brain cysts from the Taenia solium tapeworm. In this article, we provide a critical analysis of current and emerging information on the relationship between NCC infection and epilepsy occurrence. We searched PubMed and other databases for reports on the prevalence of NCC and incidence of epilepsy in certain regions worldwide. NCC is caused by brain cysts from the T. solium and related tapeworms. Many people with NCC infection may develop epilepsy but the rates are highly variable. MRI imaging shows many changes including localization of cysts as well as the host response to treatment. Epilepsy, in a subset of NCC patients, appears to be due to hippocampal sclerosis. Serologic and brain imaging profiles are likely diagnostic biomarkers of NCC infection and are also used to monitor the course of treatments. Limited access to these tools is a key limitation to identify and treat NCC-related epilepsy in places with high prevalence of this parasite infestation. Overall, NCC is a common infection in many patients with epilepsy worldwide. Additional clinical and animal studies could confirm common pathology of NCC as a postinfectious epilepsy that is curable. © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction Epilepsy is a chronic disorder of the brain that causes seizures [1–4]. Genetic and acquired conditions are common risk factors for the development of epilepsy. The most common acquired conditions or risk factors for epilepsy are brain injuries, neurotoxicity, prolonged seizures, stroke and infection [5–7], but they vary from country to country [8–11]. Infections of the central nervous system (CNS) are common risk factors for acquired epilepsy, also known as postinfectious epilepsy. Viral meningitis and parasitic infections are the most widely observed causes of postinfectious epilepsy worldwide. Many viruses, such as Theiler’s murine-encephalomyelitis virus, are widely reported to cause encephalitis and sometimes even epilepsy. Neurocysticercosis is one of the major parasitic infection that is known to cause seizures
Abbreviations: BBB, blood brain barrier; CDC, Center for Disease Control and Prevention; CSF, cerebrospinal fluid; CNS, central nervous system; CT, computerized tomography; ELISA, enzyme-linked immunosorbent assay; ILAE, International League Against Epilepsy; IL, interleukins; MMP, metalloproteinases; MRI, magnetic resonance imaging; NCC, neurocysticercosis. * Corresponding author at: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, 2008 Medical Research and Education Building, 8447 Riverside Parkway, Bryan, TX 77807-3260, USA. E-mail address: [email protected] (D.S. Reddy).
in Asian and African countries. This article provides a critical analysis of current and emerging information on neurocysticercosis as an infectious cause of acquired epilepsy. We reviewed clinical reports and articles on the prevalence of this parasitic infection and the incidence of epilepsy in endemic regions worldwide. 2. Neuropathology of neurocysticercosis 2.1. Introduction Neurocysticercosis (NCC) is one of the more thoroughly researched causes of CNS infection. It has a documented correlation to increased epilepsy prevalence in many countries, accounting for up to 30% of epileptic seizures in certain areas of Central and South America [12,13]. NCC is caused by Taenia solium, a parasitic helminth worm [13]. Specifically, T. solium belongs to the Platyhelminthes phylum which is the tapeworm subcategory of the helminth parasites [13]. The life cycle of T. solium is illustrated by the Center for Disease Control and Prevention (CDC) (Fig. 1). The initial infection of T. solium occurs from the ingestion of eggs, which are found in the feces of a human host that is inundated with T. solium infection, or by the consumption of undercooked pork that contains the larval cysts (cysticerci) [13,14]. While in the process of travelling through
https://doi.org/10.1016/j.seizure.2017.10.004 1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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Fig. 1. The CDC illustration of the lifecycle of Taenia solium and Taenia saginata, the suspected parasites for the infectious cause of epilepsy worldwide. According to U.S. Centers for Disease Control and Prevention (CDC), cysticercosis is a parasitic tissue infection caused by larval cysts of the tapeworm Taenia solium. These larval cysts infect brain, muscle, or other tissue, and are a major cause of adult onset seizures in some countries. A person gets cysticercosis by swallowing eggs found in the feces of a person who has an intestinal tapeworm. Eating undercooked pork can result in intestinal tapeworm infection if the pork contains larval cysts. Pigs become infected by eating tapeworm eggs in the feces of a human infected with a tapeworm. Pigs serve as intermediate reservoirs for larval and egg forms. Source: U.S. Centers for Disease Control and Prevention (CDC).
the gastrointestinal tract, the ingested larva eventually attach to the intestinal wall, and ultimately mature into egg-producing adult tapeworms [14,15]. Pigs are usually the intermediate host for the tapeworm infection, and humans are usually definitive hosts [14]. It is the ingestion of the eggs by exposure to egg-containing human or pig stools, and not consumption of the larval infected pork meat, that causes onset of NCC [14]. Once ingested and in the intestines, the eggs hatch into oncospheres (embryos) that cross the intestinal wall where they are transported by blood to various body tissues in which they form the larval cysts [14,15]. These larval cysts are usually destroyed by the host’s immune system, leading to what is typically an asymptomatic disease [14]. However, if the oncospheres form cysts in an immunologically privileged site (impervious to major immune response) such as the CNS, symptomatic features of NCC will appear [14]. These larvae usually infect the brain tissue via route of the blood [13]. Once there, they stimulate an immune response that will induce both granuloma formation as well as perilesional edema around the granuloma [13]. Later on, after the cyst degenerates, the lesion undergoes a further immunologic process in which there is a deposition of fibrotic
material and the cyst eventually hardens and turns into a calcific nodule [13]. 2.2. Immunopathology A large part of the pathology associated with NCC is due to the host’s immunologic response to the T. solium larval cysts [13]. The immunopathology of T. solium infection is largely due to the balanced response of the Helper T-cells: Th1 and Th2 [13,16]. IL-2, a cytokine that is produced by Th1, has been found in human cerebrospinal fluid (CSF) in individuals with symptomatic NCC, and was originally thought to be the major culprit of NCC symptomology [13]. Yet in more recent studies, symptomatic NCC immune response has also been found to be associated with high levels of Th2 cytokines such as IL-4 (increases IgE production) and IL-5 (chemokine for eosinophil recruitment) [15–17]. In one murine model where mice were infected with Taenia crassiceps cysts (a tapeworm closely related to T. solium), Th1 cells were found to release IL-2 and interferon-g and were associated with the dying of the T. crassiceps cysts [18]. Cytokines that are present in the
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beginning stages of cyst (active, non-calcific lesion) formation were once thought to cause the seizures classically seen with NCC, but murine models of mice with T. crassiceps induced brain lesions have proven this not to be the case [18,19]. Granuloma formation, which is a classic finding in chronic parasitic infection, was found in the same murine research experiment to be directly correlated with increased levels of interferon-g and could be related to the early pro-inflammatory response caused by Th1 [13,18]. Beyond cytokines, metalloproteinases (MMP) have been found in increased amounts in both mice and humans with symptomatic NCC [15,20,21]. MMPs are usually secreted by cells belonging to the monocyte lineage and have the capacity to degrade various extracellular matrix components and have been shown to degrade and increase the permeability of the blood-brain barrier in individuals with NCC [15,20–22]. 2.3. Diagnosis One of the most definitive ways in which NCC can be diagnosed is by neuroimaging. MRI and CT scanning can be used to identify the calcific, granulomatous “ring enhancing” lesions found in the brain [14]. However, each is not without its own limitations. CT scan has a strong sensitivity to picking up the classic NCC lesions, but has been found to be less than optimal at identifying lesions located in brain tissue that reside in the posterior fossa of the skull [14,23]. MRI is better in its ability to portray NCC lesions, but the sheer cost of this type of scan makes it a very limited and inaccessible resource in regions of the world where NCC is endemic [23]. Serologic testing can also be utilized in the diagnosis of NCC. Enzyme-linked immunoelectrotransfer blot assay can be used to detect antibodies that have been formed against T. solium cysts [24,25]. This form of serum testing has been shown to have a very high specificity for T. solium infection, but does not have a very strong sensitivity for only one brain lesion, which makes it problematic for diagnosing NCC [24]. Enzyme-linked immunosorbent assay (ELISA) testing is also used for detection of T. solium antibodies but has been shown to have both poor sensitivity and specificity [24]. Serum testing is useful in helping rule in or out parasitic infection of the host, but is limited in its ability to establish location of the parasitic infection. Antibody testing of the
CSF gives a better indication of whether or not parasitic cysts are located in the CNS, but is not used as widely due to both the difficulty and painfulness of the procedure used to obtain a sample [26]. It has also been documented that serum and CSF antibody testing has very little capacity to identify inactive, calcific lesions of the brain which are prominent in later stages of NCC [26]. 3. Neurocysticercosis as infectious cause of epilepsy 3.1. Prevalence of NCC in developing countries NCC has been identified as what is mainly a problem in developing countries and communities that have low levels of sanitation and repeated exposure to pigs and pig feces [27] (Table 1). In one study that examined the CT scans and serology for NCC in people located in the Vellore district of southern India, it was found that there was a prevalence rate of 1.02 people with NCC per 1000 individuals for the rural areas of south India and a prevalence of 1.28 people with NCC per 1000 individuals for the urban areas [28,29]. Compared to the previous southern Indian study, the prevalence rate of NCC in rural northern India in the Dehradun district was found to be 3.48 people with NCC per 1000 individuals, although it is possible that the study underestimated the actual total of NCC cases since only subjects with some degree of a seizure disorder were examined by a neural CT scan [30]. In a study conducted in West Cameroon (sub-Saharan Africa) that utilized both serology as well as neural CT scans to identify the presence of NCC infection after receiving a positive test result for T. solium antibodies in the serum, the prevalence rate of NCC was found in 2.6 people per 1000 individuals [31]. Results of the NCC prevalence in the Cameroon study could be underestimated, due to both the death and dropping out of subjects found to be seropositive before they could be tested for neural lesions via CT scanning [31]. Subjects in each of the aforementioned studies (southern India, North India, Cameroon) had extensive exposure to pigs and pig feces, which consequently led to the high prevalence rates of NCC as compared to a country such as the United States, which has an estimated NCC prevalence of 0.2 to 0.6 per 100,000 people in the general population [32]. It is due to a higher prevalence of NCC that makes developing countries a more appropriate subject for analysis of NCC and its relation to epilepsy.
Table 1 An overview of clinical reports of neurocysticercosis (NCC) and epilepsy in various countries. Place
Number of subjects
Measurements Detection method: NCC (CT or Serology)
Prevalence general population: NCC
Prevalence general population: EP
Southern India (Vellore district)
50, 617 (38, 105 rural/12,512 urban)
NCC and Epilepsy
Both
Urban: 6.23 per 1000 55/162 Subjects with EP + NCC/ Rural: 3.04 per 1000 Total Subjects with EP
[29]
Northern India (Dehradun district) West Camaroon Zambia
14, 086
NCC and Epilepsy
Both
Urban: 1.28 per 1000 Rural: 1. 02 per 1000 3.48 per 1000
10 per 1000
[30]
4, 993 49
NCC NCC
Both Both
Mozambique
151
NCC
Both
Burkina Faso
32
NCC
Both
Ecuador
19
NCC and Epilepsy
Both
Peru
48
NCC and Neural Symptoms
Both
Prevalence
clinical subgroup
49/141 Subjects with EP + NCC/ Total Subjects with EP
2.6 per 1000
9.4 per 1000
188 per 1000
18/49 Subjects with EP + NCC/ Total Subjects with EP 85/151 Subjects with EP + NCC/ Total Subjects with EP 12/32 Subjects with EP + NCC/ Total Subjects with EP 5/19 Subjects with EP + NCC/Total Subjects with EP 8/48 Subjects with neural symptoms + NCC/Total Subjects with NCC
Reference
[31] [40] [41] [42] [27]
[47]
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Under-diagnosis of NCC is a potential issue given the limitations of the types of testing (serologic and neuroimaging) that are predominately used to diagnose it [14,23,24]. Depending on where the NCC lesion is located in the brain, such as within the parenchyma or within the ventricles, and even whether the cyst is active or inactive, either MRI or CT scanning should be used to more accurately to identify the lesion in question [33]. Whether it is within research studies or in the clinic, under-identification could occur due to the lack of utilizing both types of neural scanning (MRI/CT) because of either a lack of accessibility or a lack of financial means to carry out both diagnostic methods. It has also been documented that neuroimaging techniques are limited in their ability to illuminate neural NCC lesions under a certain size, which makes it increasingly difficult to diagnose the CNS infection altogether [34]. NCC lesions identified on neural scanning have the capacity to be misdiagnosed [35]. In particular, NCC lesions have the potential to be confused with tuberculoma, bacterial abscesses, fungal abscesses, brain tumors, or congenital arachnoid cysts [35]. All of these factors, both by themselves and/or coupled to one another, could directly contribute to a misrepresentation of the actual prevalence of NCC. 3.2. Incidence of epilepsy in NCC cohorts Based on the site of the neural lesion caused by NCC, infection can manifest itself through many different neurologic signs or syndromes such as headaches, confusion, ataxia, meningismus, and/or seizures [36,37]. In particular, the onset of seizures is the most commonly associated clinical feature of NCC [36,37]. It is thought that certain stages of cyst formation and degeneration are associated with varying risk of seizures, though this theory has not been proven experimentally [13,38]. Specifically, the inactive, calcific lesions that form after the cyst has degenerated have a higher propensity for inducing seizures than the earlier, activeedematous cystic stage [13]. Prevalence of epilepsy in patients with NCC is a heavily researched and contested area of study [39] (Table 1). In the rural and urban southern Indian population, 55 out of the 162 patients with epilepsy that underwent CT testing were found to have NCC [29]. The criteria for epilepsy diagnosis was based on whether or not the patient had two or more seizures in their life, one of which must have happened at least 5 years before the study was performed [29]. NCC in the rural northern Indian population was found in 49 of the 141 people with epilepsy that had further CT testing, and epilepsy was diagnosed by analysis via EEG and CT scan and was in accordance with ILAE criteria [30]. Upon examination of an epileptic population of people in Zambia, which was highly endemic for NCC, it was found that 28.6% of the subjects had neural lesions that were either highly suggestive or definite for NCC [40]. Epilepsy in this study was defined as having had seizures within the last two years or having been on antiepileptic medication at one point in their life [40]. Another study conducted in an epileptic, rural population in Mozambique that was highly endemic for T. solium infections showed that 56% of the subjects with epilepsy had NCC lesions seen on CT scan [41]. The diagnostic criteria for this study was in accordance with the ILAE definition of epilepsy [41]. In a study performed in an epileptic population in Burkina Faso, a country in sub-Saharan Africa, calcific lesions indicative of NCC were found in 12 of the 32 participants that were screened via CT [42]. In rural Ecuador, a study over the proportion of NCC in epileptic individuals was found in 5 of the 19 total individuals [43]. The criteria used to diagnose epilepsy was based on whether or not the individual had two or more seizures in their lifetime [43]. Over all of these studies, in the developing world, NCC was consistently found in around 37.6% of individuals with epilepsy or seizure disorders (Table 1). This rate is comparable to
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those that have previously been determined from other studies that have examined populations in the developing world as well [44,45] (Table 1). Caution should be used when examining the prevalence rates of research studies in this area, as not all of them utilize the same diagnostic criteria and techniques used to identify NCC and could thus misrepresent the actual proportion of individuals with NCC [44]. For example, certain studies utilized serum AG-ELISA to test for NCC antigen while others used serum antibody testing to determine T. solium infection [41,43]. These test results were then subjectively weighted and diagnoses were made, based on the preferences of the researchers and their respective diagnostic criteria. Furthermore, some studies have different definitions of epilepsy that could potentially lead to individuals being inappropriately included or excluded for NCC presence investigation, when in fact their neurological disorder is something else entirely, thus distorting the subsequent data. The ILAE definition of epilepsy states that the seizures must have been more than 24 h apart, and certain studies have been found to disregard that timeline in their subject recruitment [29,40,43]. Many studies that examine the relationship between rates of NCC in populations with epilepsy utilize prevalence as the quantitative value to analyze the correlation between the two [44]. Prevalence represents the simultaneous presence of both epilepsy and NCC present at a single point in time. This strategy diminishes the capacity to determine whether or not NCC occurred in the subjects before or after the onset of epilepsy [44,46]. Inability to estimate time of NCC occurance as it relates to epilepsy onset greatly takes away from the conclusions that are made regarding the causative correlation of NCC to epilepsy. Another major limitation to most studies that investigate NCC as a major cause of epilepsy lies in the sole investigation of populations of people that have epilepsy or other seizure disorders. Emphasis should also be put on the prevalence of seizure symptoms in people with NCC, so as to better understand the likelihood that an individual with NCC will develop epilepsy or epilepsy like syndromes. A study that was conducted in a highly NCC endemic population in rural Peru found that out of 48 people with NCC lesions in their brain, 40 of them reportedly never had any neurologic history of seizure or recurring headaches [47]. Research in this area is very limited which is likely due to the cost inefficiency of performing neural scans on a general population. However, further studies must be conducted to better estimate the true prevalence of seizure disorders in patients with NCC. Beyond the variations of the studies themselves, there is disagreement in this field of research as to whether or not the seizure disorder induced by NCC should be classified as epilepsy [39,44]. The ILAE definition of epilepsy includes that the seizures in question must be “unprovoked” to be eligible for epilepsy diagnosis [2,44]. It was determined in one study that transient inflammation and subsequent edema surrounding a calcific NCC lesion was associated with recurrence of seizures [48,49]. This raises the question as to whether NCC is a direct cause of epilepsy development, or is a causative agent of symptommatic seizures that are provoked by the inflammation or damage to the brain tissue that is caused by the NCC lesions [44]. 3.3. Animal models of NCC infection Although NCC has been recognized as a common helminthic infection of the brain caused by the larval form of the tapeworm T. solium, there are few experimental studies to link the NCC as a major cause of seizures and epilepsy in animal models [50]. In experimental models, the term ‘epileptogenesis’ is used to describe the complex plastic changes in the brain that, following a precipitating insult or injury, convert a normal brain into a brain
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Fig. 2. A model for neurocystocercosis-induced epilepsy development. It is likely that NCC infection may act as an initial insult or inciting lesion (the cyst) from which a significant percentage of hosts may develop epilepsy through the common epileptogenesis. Such infection-triggered epileptogenesis may often occur over a long latent period prior to the first recurrent seizure with variable time course after an initial infection. Alterations in the blood-brain barrier and persistent proinflammatory response that surround the cysts or calcified granulomas may underlie the epileptogenesis in patients with NCC infection. MRI imaging supports the presence of such inciting lesions in patients with NCC-related recurrent seizures. Consistent with human cases, epilepsy is observed in some rodent models of experimental NCC infection after a latent period.
debilitated by recurrent seizures (Fig. 2). Currently, the most common concept about epileptogenesis suggests that it occurs over the course of three stages. The first stage requires an initial precipitating event. This is followed by the second stage, which is a latent period of variable time. The third stage is the chronic period, in which the subject exhibits spontaneous seizures. A few experimental models of NCC have been reported in mice and rats [50]. These rodents are infected intracranially with T. crassiceps or Mesocestoides corti [51,52]. Stringer and colleagues have found seizure activity in a rat model of NCC using granulomas associated with T. crassiceps infection [51]. In another study, epileptic seizures (generalized tonic-clonic seizures) were observed in a rat model of NCC using activated T. solium oncospheres [52]. The overall incidence of epilepsy was 9% in rats infected with NCC at 5 months postinfection. Histological reports show specific neurological abnormalities such as inflammation around cysts in the brain. There are recent news reports on the brain-infesting sickness on the U.S. Hawaii Island, which is attributed to rat lungworm Angiostrongylus cantonensis [53]. The parasite, which commonly resides in the pulmonary arteries of rats, enters into human from contaminated food via the intermediate host snails and slugs. This disease also affects the brain and spinal cord. The infection can cause a rare meningitis that can trigger seizures. It is unclear if meningitis is caused by A. cantonensis or secondary factors such as inflammation or autoimmune response. 4. Conclusion and clinical prospects Infections of the CNS are common risk factors for epilepsy. Viral and parasitic infections are widely considered as causes of postinfectious epilepsy [50]. Though there is strong association between NCC and the occurance of epilepsy (Table 1), the reports are variable in confirming NCC as a cause of infectious epilepsy worldwide. T. solium infection has a higher rate of occurrence in low income countries, as do subsequent rates of NCC; increasing the probability for coincidental occurance between an especially common neural disease in the developing world, such as epilepsy, and NCC. There is a real possibility that the prevalence rates of NCC in endemic countries are much higher than originally estimated,
due to a lack of resources needed to carry out the necessary research to assuredly identify the disease. The predominant method of solely investigating simultaneous occurrence of NCC and epilepsy is limiting this field of research from drawing substantiated conclusions as to the risk of epilepsy development in patients with NCC. Prospective studies that examine epilepsy occurrence in patient populations that have NCC are needed to further understand the true risk of epilepsy development associated with NCC lesions. It is also necessary that strict adherence be followed for the diagnosis of NCC, as many studies formulate their own criteria which could cause variability between studies that investigate NCC. A more universal inclusion and exlusion criteria should be utilized and adhered to for achieving consistency between various studies. In summary, many people with NCC may develop epilepsy but the rates are highly variable, and can be anywhere from 10% to 50% [49] (Table 1). NCC occurs in a homogeneous patient population with an inciting lesion (the cyst) from which a significant percentage, but not all patients, develop epilepsy. MRI imaging can show many changes including localization and number of cysts as well as the host response to treatment, prior to the development of chronic, recurrent seizures. Some evidence suggests that medically refractory epilepsy in a subset of these patients can also result from hippocampal sclerosis, suggesting that NCC may be a clinical opportunity to study hippocampal epileptogenesis [50,52]. Treatment and prevention aspects of NCC are covered elsewhere [54]. The ultimate method for controlling NCC in endemic regions is to prevent and eliminate parasite transmission by better hygiene and lifestyle changes. Based on the current pathogenic information, we propose a working model for NCCrelated epileptogenesis (see Fig. 2). A better understanding of the NCC infection began to emerge from animal models. Therefore, further studies during epileptogenic stages of these patients and animal models could lead to predictive biomarkers and specific treatments for neurological lesions that incite epilepsy. Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References [1] Fisher S, van Emde Boas W, Blume , Elger C, Genton P, Lee P, Engel Jr. J. Epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ILAE) and the international bureau for epilepsy (IBE). Epilepsia 2005;46(4):470–2. [2] Thurman L, Beghi E, Begley CE, Berg AT, Buchhalter JR, Ding D, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia 2011;52 (Suppl. 7):2–26. [3] Robert S, Fisher CA, Arzimanoglou Alexis, Bogacz Alicia, Helen Cross J, Elger Christian E, et al. A practical clinical definition of epilepsy. Epilepsia 2014;55 (4):475–82. [4] Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational classification of seizure types by the international league against epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58(4):522–30. [5] Reddy DS, Bhimani A, Kuruba R, Park MJ, Sohrabji F. Prospects of modeling poststroke epileptogenesis. J Neurosci Res 2017;95(4):1000–16. [6] Senanayake N, Román GC. Epidemiology of epilepsy in developing countries. Bull World Health Organ 1993;71(2):247–58. [7] Kvalsund MP, Birbeck GL. Epilepsy care challenges in developing countries. Curr Opin Neurol 2012;25(2):179–86. [8] Zack MM, Kobau R. National and state estimates of the numbers of adults and children with active epilepsy—United States, 2015. MMWR 2017;66:821–5. [9] Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in Europe—a systematic review. Eur J Neurol 2005;12:245–53. [10] Mac Luong, Tran DS, Quet Fabrice, Odermatt Peter, Preux Pierre-Marie, Tan Chong Tin. Epidemiology, aetiology, and clinical management of epilepsy in Asia: a systematic review. Lancet Neurol 2007;6:533–43.
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