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Epidemiology of neurocysticercosis and epilepsy, is everything described?
YEBEH-05193; No of Pages 5 Epilepsy & Behavior xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
Epidemiology of neurocysticercosis and epilepsy, is everything described? Jose F. Tellez-Zenteno ⁎, Lizbeth Hernandez-Ronquillo Department of Medicine, Division of Neurology, University of Saskatchewan, Canada
a r t i c l e
i n f o
Article history: Received 16 December 2016 Revised 23 January 2017 Accepted 25 January 2017 Available online xxxx Keywords: Epidemiology Epilepsy Taeniasis Neurocysticercosis
a b s t r a c t In recent years clinical and epidemiological research on cysticercosis has gained significant interest in some countries, especially in Latin American countries and some countries in Asia and Africa. For many years it has been proposed that the higher prevalence of epilepsy seen in some regions such as Latin-America could be explained by parasitic infections, particularly neurocysticercosis (NCC). In this review we discussed selected epidemiological topics of the association of NCC and epilepsy, such as global distribution around the world, identification of NCC in developed countries, drug resistant epilepsy and NCC. Finally this review presents a critical review of biases of the published literature in NCC. This article is part of a Special Issue entitled “Neurocysticercosis and Epilepsy”. © 2017 Elsevier Inc. All rights reserved.
1. Background Approximately 85% of the global burden of epilepsy resides in the developing world, where most people with epilepsy receive no medical attention at all. Consequently, although diagnostic and therapeutic innovations remain important goals, the greatest challenge for world health lies in adequately identifying people with epilepsy and providing the best available treatment. Studies have showed that incidence and prevalence of epilepsy is high in developing countries but also there is a potential association with a high occurrence of neurocysticercosis (NCC). One of identified areas with high incidence and prevalence of epilepsy and potentially associated with NCC is Latin-America, a recent meta-analysis estimating the incidence and prevalence of epilepsy in Latin-America found that the median lifetime prevalence in all countries was 17.8 (range 6–43.2) per 1000 people, and the range for incidence was 77.7–190 per 100,000 people per year [1]. These rates contrast with the reported ones in developed countries where the incidence of epilepsy ranges from 24 to 53 per 100,000 person-years and the prevalence between 5 and 10 per 1000 population [2–4]. For many years, it has been proposed that the higher prevalence of epilepsy seen in some regions such as Latin-America could be explained by parasitic infections, particularly NCC. NCC is still an important public health issue worldwide and is widely prevalent in many low income countries such as the sub-Saharan Africa, Asia, and Latin America. Other factors that have been described are intracranial infections of bacterial or viral origin, perinatal brain damage, head trauma, toxic agents ⁎ Corresponding author at: Division of Neurology, Department of Medicine, Royal University Hospital, 103 Hospital Drive, Box 26, Room 1622, Saskatoon, SK S7N OW8, Canada. E-mail address: [email protected] (J.F. Tellez-Zenteno).
and hereditary factors. Unfortunately we do not have many studies in Latin-American and other regions to support that the main etiology of epilepsy in these countries is related to NCC. In this review we discuss some epidemiological controversies. The review describes selected studies and then in every section an analysis of information is done, describing potential biases in published information and future work to address the question.
2. High prevalence of cysticercosis In recent years clinical and epidemiological research on cysticercosis has gained significant interest in some countries, especially in Latin American countries and some countries in Asia and Africa. Cysticercosis is a highly prevalent disease in Latin-America. Flisser et al. [5] review the rates of cysticercosis in Latin-American countries. Studies performed in rural areas of Mexico (Table 1) and other regions in Latin America show a high prevalence of human cysticercosis ranging between 3.7 to 12.2% [5]. In Peru the prevalence of human cysticercosis ranges between 5 to 24% [5]. Finally other Latin-American countries have found high rates of cysticercosis such as Bolivia (22.6%), Ecuador (10.4%), and Guatemala (two studies 10 to 17%) [5]. The rates are similar to the ones reported in studies in India [6]. In Fig. 1 we can see the estimated geographical distribution of taeniasis/cysticercosis around the world (data from the world health organization). There is no doubt that cysticercosis is currently not only an endemic problem in many developing countries, but also is becoming a recognized disease in high income countries. This information is consistent over the years and despite that cysticercosis is a preventable disease related with population hygiene still it is not eradicated and still it is a significant burden for many countries.
http://dx.doi.org/10.1016/j.yebeh.2017.01.030 1525-5050/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Tellez-Zenteno JF, Hernandez-Ronquillo L, Epidemiology of neurocysticercosis and epilepsy, is everything described?, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.01.030
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J.F. Tellez-Zenteno, L. Hernandez-Ronquillo / Epilepsy & Behavior xxx (2017) xxx–xxx
Table 1 Prevalence of cysticercosis in Latin-America. Community
Sample
Prevalence
El Salado (Mexico) Mexico City Tedzidz (Mexico) El Sotano (Mexico) Angangeo (Mexico) Xoxocotla (Mexico) Atotonilco (Mexico) Camino Real (Mexico) Chaupiojo (Mexico) Churusapa (Mexico) Haparquilla (Mexico) Maceda (Mexico) Monterredonda (Mexico) Rosaspeta (Mexico) Saylla (Mexico) Rural Bolivia Ecuador Guatemala Guatemala
432 1000 475 134 1552 1005 2911 109 184 279 371 421 1200 72 495 159 118 1161 1204
12 12.1 3.7 6.4 10.8 4.9 7.1 21 10 7 13 8 16 5 24 22.6 10.4 17 10
3. Information from studies using seroprevalence as a criterion for neurocysticercosis Some epidemiological studies have explored the association between neurocysticercosis and epilepsy using serology and CT. The study of Moyano [7] is an excellent example. In this study they included 17,450 individuals. The cases had an initial survey, then a neurological evaluation and the last step was a formal neurological examination plus blood sampling and brain CT scan. The lifetime prevalence of epilepsy was 17.25/1000 and the point prevalence was 10.8/1000 habitants. Forty percent of cases had positive antibodies for cysticercosis. Brain CT showed images compatible with neurocysticercosis in 39% of the cases. They concluded that neurocysticercosis is an important contributor to explain the high rate prevalence of epilepsy in this region. In a similar way Montano et al. [8], performed an epidemiological study assessing the prevalence of epilepsy and the seroprevalence of
cysticercosis. The study screened 903 residents from rural Peru. The overall prevalence of epilepsy was 32.1 per 1000, the active prevalence was 16.6 per 1000 and the seroprevalence of cysticercosis was 24.2%. Seroprevalence was associated with seizures (OR 2.1, p = 0.026). In a similar way as Moyano [9], Montano et al. concluded that an important proportion of seizure cases are associated with neurocysticercosis demonstrated by serology and CT scan. Similar studies have been reported in other endemic areas like India. Sekhar Pappala et al. [10] performed the serological diagnosis of NCC in 160 patients with recent onset seizures in a tertiary center in India. NCC was diagnosed in 44 of 160 (27.5%) seizure cases based on imaging characteristics, and a positive serum antibody ELISA. The authors suggest that NCC should be suspected as one of the major differential in every recent onset seizure with or without a radio imaging supportive diagnosis, especially in areas endemic for taeniasis/cysticercosis. Interestingly the study did not report other etiologies of seizures and not all the cases had MRI. These studies have to be analyzed carefully in order to avoid incorrect assumptions: a) the modern diagnosis of epilepsy is based in new technology such as MRI. Many lesions such as benign tumors, areas of cortical dysplasia and some vascular malformations can only be diagnosed with MRI therefore studies only using CT scan to determine etiology have a significant limitation. It is possible that a large proportion of cases can have dual pathology or maybe other lesions apart from the NCC as the cause of the epilepsy, b) it is probably controversial to attribute that patients with positive serology for cysticercosis can make a case for NCC, considering that seropositivity is very common in LatinAmerican countries, c) it is possible that the use of MRI with proper protocols in all cases and a more comprehensive diagnostic approach can identify other etiologies lowering the rates of NCC associated with epilepsy, d) finally in almost all the countries there is a significant benefit of epilepsy programs improving not only the diagnosis but also the management of patients with epilepsy. In many low-income countries, there are a limited number of epilepsy programs and the available ones, many times are not well equipped. It is possible that many of these patients where epilepsy has been associated to NCC, may have dual pathology of other etiology when they are look at carefully by an epilepsy program.
Fig. 1. Estimated geographical distribution of taeniasis/cysticercosis around the world (data from the world health organization).
Please cite this article as: Tellez-Zenteno JF, Hernandez-Ronquillo L, Epidemiology of neurocysticercosis and epilepsy, is everything described?, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.01.030
J.F. Tellez-Zenteno, L. Hernandez-Ronquillo / Epilepsy & Behavior xxx (2017) xxx–xxx
4. Information from meta-analysis and the potential overestimation of NCC as a cause of epilepsy There is a recent meta-analysis by Ndimubanzi [11] exploring the difference of epilepsy burden in Latin-America taking into account the infection by cysticercosis. The study included studies until 2012 and explored lifetime and active epilepsy prevalence, incidence, mortality, treatment gap and NCC proportion among people with epilepsy. This meta-analysis is very controversial because it tries to correlate studies instead of providing estimates. In the first analysis they included a group of studies where epidemiological rates of epilepsy were described (prevalence, incidence, mortality, etc.). On the other hand they had a second group of studies where the proportion of cases of cysticercosis and NCC among patients with epilepsy was explored. The median NCC proportion among patients with epilepsy was 32.3% and higher NCC estimates were associated with higher epilepsy prevalence. The last assumption was done with a geographical correlation of both groups of studies. The authors concluded that NCC prevalence is an important factor influencing epilepsy prevalence in Latin-America. Another metaanalysis explored the frequency of NCC with a focus on people with epilepsy around the world delivering similar conclusions to the study of Bruno [12]. This meta-analysis is very controversial and it not necessarily supports the idea that NCC could be the main reason explaining the high prevalence of epilepsy in Latin-America. Some observations could be drawn from this meta-analysis: a) the meta-analysis included two very different types of studies that may not be valid to overlap. The studies that explored epidemiological rates of epilepsy were studies done in open populations and some of the studies where serology of cysticercosis was explored were done in tertiary centers or in a different population than the epidemiological studies. It is probably hard to draw conclusions from one to the other group, b) a significant weakness of most of the studies is the use of CT and serology to determine etiology of epilepsy. As was mentioned before many specific etiologies such as benign tumors and areas of cortical dysplasia are diagnosed only with MRI, c) finally many studies included in the meta-analysis assume that the etiology of the epilepsy is NCC only using serology. 5. Exploration of etiologies of epilepsy in countries with a high prevalence of cysticercosis In 1993 Senanayake and Roman [13] published a key non-systematic review exploring some epidemiological aspects of epilepsy in developing countries. In this review they identify three studies that explored etiology/risk factors of epilepsy in Latin-American countries. The first two studies were from Brazil, one of them included patients from 1 month to 15 years and the second patients older than 13 years [13]. The last one was from Uruguay and included people from 1 month to 15 years. The three studies described specific etiological factors for epilepsy as follows: perinatal brain damage 14%, 11 and 8.5 respectively, head injuries 3, 13 and 8%, intracranial infections 5, 0 and 4, neurocysticercosis 13, 4 and 0%, intracranial tumors 0 in the three studies, cerebrovascular disease 0, 2.5 and 5%, toxic metabolic causes 0% in the three studies, other causes 4, 1.5, 6.5% febrile seizures 0 in the three studies and not identified causes in 63, 68 and 59% respectively [13]. Looking carefully these studies where the etiology of epilepsy is explored in a geographical region with a high prevalence of NCC we can draw some observations: a) neurocysticercosis is not the main cause of epilepsy in epidemiological studies where serology is not used as the main indicator to describe the etiology of epilepsy, b) there is a variety of etiologies and the rates look more similar to the ones reported in developed countries, c) the percentage of unknown etiologies is large and very similar to the reported in high income countries, d) unfortunately there are not many studies exploring specific etiologies not based in tertiary centers to draw more conclusion. It is possible that
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the etiology of epilepsy in developing countries can be related with a spectrum of causes as it has been showed in other regions of the world with some specific variations such as a predominance of NCC, but also other etiologies such as hypoxic brain injury, other infections and head trauma. A large proportion of studies exploring the association of epilepsy and NCC have been done in rural areas of Latin-America and India, where patients do not have access to epilepsy programs. This is a limitation because a more comprehensive assessment of patients in epilepsy centers can identify different etiologies. 6. Drug resistant epilepsy and NCC Epilepsy affects 50 million people worldwide [14]. It is estimated that between 6% and 69% of patients fail to respond to standard medical and surgical therapies and continue to experience debilitating refractory seizures. These patients are classified as having drug-resistant epilepsy (DRE), a diagnosis with poor prognostic implications that include premature death, physical injury, psychosocial dysfunction, and reduced quality of life [15]. The prevalence of DRE is not consistently defined and tends to vary among studies, owing to issues with population selection, sample size, classification, terminology, and characterization of seizure intractability [4]. There are very few studies analyzing the association between drug resistant epilepsy and NCC. Goyal et al. [16] conducted a study in a tertiary care center in India between July 2011 and July 2013. Two hundred patients with epilepsy and NCC were enrolled and followed for a minimum period of 1 year. This included patients with definite and probable NCC defined by the criteria of Del Bruto [17]. Thirteen patients (7%) with NCC were found to be refractory to drug therapy. The authors identified a low prevalence of DRE compared the majority of studies where other etiologies are mixed. There are some interesting studies showing that patients with epilepsy and NCC can develop DRE if calcifications are associated with mesial temporal sclerosis or gliosis [18]. There are also few reports showing some cases with DRE that actually have epilepsy surgery associated with NCC, but in general these represent selected cases [19]. The evidence is scanty although it shows that NCC associated with epilepsy has a low rate of intractability compared with classical studies where mixed etiologies are included, but also that does not require surgical work up and epilepsy surgery very frequently. More investigation is needed in this field in the next few years. 7. The case of high income countries There is a recent study performed by Fabiani and Brushi [20]. They search for PubMed articles of reported cases of NCC in European countries. One hundred seventy six cases of NCC were reported in seventeen European countries (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, The Netherlands, Sweden, United Kingdom, and Croatia, Norway, Switzerland). A particular epidemic situation is present in Spain and Portugal. Specifically Spain has an increasing incidence of NCC in immigrated patients and some people who were born in certain Spanish geographical areas. The case of Portugal is different because the prevalence is similar to that observed in endemic areas. For the case of Europe is clear that as a result of increased migration and travels from endemic regions, NCC is becoming an emerging public health problem in high-income European countries, particularly affecting communities with poor hygiene conditions where the parasite can spread from human to human through eggs even in absence of a travel to the tropics. A similar phenomenon has been seen in the US. A recent literature review of all case series in the United States with at least 20 patients during 1980–2004 identified 1494 patients with neurocysticercosis. The authors noted that 76 infections (5.1%) were likely acquired within the United States [21]. A more recent study assesses the effect of neurocysticercosis in the US using hospitalization discharge data in an Inpatient Sample for 2003–2012. The authors found an estimated of
Please cite this article as: Tellez-Zenteno JF, Hernandez-Ronquillo L, Epidemiology of neurocysticercosis and epilepsy, is everything described?, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.01.030
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J.F. Tellez-Zenteno, L. Hernandez-Ronquillo / Epilepsy & Behavior xxx (2017) xxx–xxx
Table 2 Key recommendations performed by the group of Peru to control Taenia solium, taeniosis and cysticercosis. Measure Providing continuing health education to the population and to the healthcare personnel, mainly improving hygiene and sanitary conditions, veterinary control or surveillance systems in general; first of all avoiding use of human infected feces as agricultural fertilizer; Searching and reporting the sources of transmission of taeniasis/cysticercosis both in animals, including meat inspection, and humans Limiting animal reservoir improving farm status and treating, and eventually vaccinating, pigs Developing easy to-use drugs, and safe and effective vaccine for pigs; Identifying community exposed to T. solium, carriers of adult tapeworms and closed contacts, considering tapeworm carriers as potential sources of contagion to both themselves and to those living in their close environment Targeting treatment against human taeniosis, selecting the drug of choice; Developing well defined protocols to clinically identify, and eventually manage, human cases.
18,584 hospitalizations for neurocysticercosis. The risk for hospitalizations was highest among Hispanics (2.5/100,000 population). Nearly three-quarters of all hospitalized patients with NCC were Hispanic [22]. The studies in the US show a similar phenomenon that is seen in high income European countries. In the past cysticercosis and NCC was exclusively a problem of some developing countries. Recently it is recognized as an emergent disease in high income countries and not only with imported cases. This is a significant epidemiological change and requires more awareness of the disease around the world. 8. Systematic exploration of other etiologies in studies with a high prevalence of NCC Bhalla et al. [23] performed a key comprehensive non-systematic review of etiologies in epilepsy. In this review the author suggests that some etiologies could be more prevalent in developing countries such as perinatal adverse events, bacterial/viral brain infections, parasitic infections, and traumatic epilepsy and brain tumors. Less frequent causes in developing countries could be genetic causes, malformation of cortical development, hippocampal sclerosis, cerebral immunological disorders, arterial–venous malformations, stroke and Alzheimer disease. This observation could be true unfortunately we do not have many epidemiological studies in open populations or in tertiary centers exploring etiologies in countries with a high prevalence of NCC. In countries with a high prevalence of NCC there is a significant lack of resources to properly diagnose patients with epilepsy; therefore some etiologies are clearly underreported such as genetic causes and etiologies where MRI is required such as mesial temporal sclerosis and cortical malformations. The systematic exploration of etiologies for epilepsy in countries with a high incidence is highly required. The real magnitude of NCC explaining the higher prevalence of epilepsy will remain controversial. Current studies have to be interpreted in the specific circumstances and avoid drawing general conclusions without more evidence. In the end NCC may have some overrepresentation of etiology of epilepsy in endemic countries, although in a similar way as other continents, etiology may show a spectrum of causes. 9. Prevention measures Several studies from developing countries show consistently that NCC is an endemic problem, but now with the significant migration patterns of people and travels, NCC is a constant growing public health problem in high-income countries. In the past only cases related with migration issues were identified in developed countries but now cases are identified in communities of high income countries where hygiene conditions are poor and consequently the parasite's eggs can spread. In Table 2 we list key recommendations performed by the group of Peru to control Taenia solium, taeniosis and cysticercosis [24,25]. Economic development has proven effective to achieve sustained eradication, although is difficult to implement in developing countries.
10. Future research Neurocysticercosis is an old disease, but unfortunately the burden of the disease has increased in the last few years. Originally NCC was a problem of developing countries nevertheless because migration patterns the disease is also recognized in developed countries. The belief that NCC is the main cause of epilepsy in some countries of LatinAmerica, Asia and Africa is controversial and it has to be better analyzed in the future. Better epidemiological studies characterizing different etiologies in patients with epilepsy have to be developed in the future. The development of epilepsy programs in countries where NCC has been associated with epilepsy will also help to understand the controversial high prevalence of NCC in patients with epilepsy. The more comprehensive assessment of patients with epilepsy in low income countries in the future using modern imaging may show that NCC is not the main etiology of epilepsy in many cases.
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[20] Fabiani S, Bruschi F. Neurocysticercosis in Europe: still a public health concern not only for imported cases. Acta Trop 2013;128(1):18–26. [21] Wallin MT, Kurtzke JF. Neurocysticercosis in the United States: review of an important emerging infection. Neurology 2004;63(9):1559–64. [22] O'Neal SE, Flecker RH. Hospitalization frequency and charges for neurocysticercosis, United States, 2003–2012. Emerg Infect Dis 2015;21(6):969–76. [23] Bhalla D, Godet B, Druet-Cabanac M, Preux PM. Etiologies of epilepsy: a comprehensive review. Expert Rev Neurother 2011;11(6):861–76. [24] Sarti E, Rajshekhar V. Measures for the prevention and control of Taenia solium taeniosis and cysticercosis. Acta Trop 2003;87(1):137–43. [25] Gonzalez AE, Garcia HH, Gilman RH, Tsang VC. Control of Taenia solium. Acta Trop 2003;87(1):103–9.
Please cite this article as: Tellez-Zenteno JF, Hernandez-Ronquillo L, Epidemiology of neurocysticercosis and epilepsy, is everything described?, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.01.030
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
Epidemiology of neurocysticercosis and epilepsy, is everything described? Jose F. Tellez-Zenteno ⁎, Lizbeth Hernandez-Ronquillo Department of Medicine, Division of Neurology, University of Saskatchewan, Canada
a r t i c l e
i n f o
Article history: Received 16 December 2016 Revised 23 January 2017 Accepted 25 January 2017 Available online xxxx Keywords: Epidemiology Epilepsy Taeniasis Neurocysticercosis
a b s t r a c t In recent years clinical and epidemiological research on cysticercosis has gained significant interest in some countries, especially in Latin American countries and some countries in Asia and Africa. For many years it has been proposed that the higher prevalence of epilepsy seen in some regions such as Latin-America could be explained by parasitic infections, particularly neurocysticercosis (NCC). In this review we discussed selected epidemiological topics of the association of NCC and epilepsy, such as global distribution around the world, identification of NCC in developed countries, drug resistant epilepsy and NCC. Finally this review presents a critical review of biases of the published literature in NCC. This article is part of a Special Issue entitled “Neurocysticercosis and Epilepsy”. © 2017 Elsevier Inc. All rights reserved.
1. Background Approximately 85% of the global burden of epilepsy resides in the developing world, where most people with epilepsy receive no medical attention at all. Consequently, although diagnostic and therapeutic innovations remain important goals, the greatest challenge for world health lies in adequately identifying people with epilepsy and providing the best available treatment. Studies have showed that incidence and prevalence of epilepsy is high in developing countries but also there is a potential association with a high occurrence of neurocysticercosis (NCC). One of identified areas with high incidence and prevalence of epilepsy and potentially associated with NCC is Latin-America, a recent meta-analysis estimating the incidence and prevalence of epilepsy in Latin-America found that the median lifetime prevalence in all countries was 17.8 (range 6–43.2) per 1000 people, and the range for incidence was 77.7–190 per 100,000 people per year [1]. These rates contrast with the reported ones in developed countries where the incidence of epilepsy ranges from 24 to 53 per 100,000 person-years and the prevalence between 5 and 10 per 1000 population [2–4]. For many years, it has been proposed that the higher prevalence of epilepsy seen in some regions such as Latin-America could be explained by parasitic infections, particularly NCC. NCC is still an important public health issue worldwide and is widely prevalent in many low income countries such as the sub-Saharan Africa, Asia, and Latin America. Other factors that have been described are intracranial infections of bacterial or viral origin, perinatal brain damage, head trauma, toxic agents ⁎ Corresponding author at: Division of Neurology, Department of Medicine, Royal University Hospital, 103 Hospital Drive, Box 26, Room 1622, Saskatoon, SK S7N OW8, Canada. E-mail address: [email protected] (J.F. Tellez-Zenteno).
and hereditary factors. Unfortunately we do not have many studies in Latin-American and other regions to support that the main etiology of epilepsy in these countries is related to NCC. In this review we discuss some epidemiological controversies. The review describes selected studies and then in every section an analysis of information is done, describing potential biases in published information and future work to address the question.
2. High prevalence of cysticercosis In recent years clinical and epidemiological research on cysticercosis has gained significant interest in some countries, especially in Latin American countries and some countries in Asia and Africa. Cysticercosis is a highly prevalent disease in Latin-America. Flisser et al. [5] review the rates of cysticercosis in Latin-American countries. Studies performed in rural areas of Mexico (Table 1) and other regions in Latin America show a high prevalence of human cysticercosis ranging between 3.7 to 12.2% [5]. In Peru the prevalence of human cysticercosis ranges between 5 to 24% [5]. Finally other Latin-American countries have found high rates of cysticercosis such as Bolivia (22.6%), Ecuador (10.4%), and Guatemala (two studies 10 to 17%) [5]. The rates are similar to the ones reported in studies in India [6]. In Fig. 1 we can see the estimated geographical distribution of taeniasis/cysticercosis around the world (data from the world health organization). There is no doubt that cysticercosis is currently not only an endemic problem in many developing countries, but also is becoming a recognized disease in high income countries. This information is consistent over the years and despite that cysticercosis is a preventable disease related with population hygiene still it is not eradicated and still it is a significant burden for many countries.
http://dx.doi.org/10.1016/j.yebeh.2017.01.030 1525-5050/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Tellez-Zenteno JF, Hernandez-Ronquillo L, Epidemiology of neurocysticercosis and epilepsy, is everything described?, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.01.030
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J.F. Tellez-Zenteno, L. Hernandez-Ronquillo / Epilepsy & Behavior xxx (2017) xxx–xxx
Table 1 Prevalence of cysticercosis in Latin-America. Community
Sample
Prevalence
El Salado (Mexico) Mexico City Tedzidz (Mexico) El Sotano (Mexico) Angangeo (Mexico) Xoxocotla (Mexico) Atotonilco (Mexico) Camino Real (Mexico) Chaupiojo (Mexico) Churusapa (Mexico) Haparquilla (Mexico) Maceda (Mexico) Monterredonda (Mexico) Rosaspeta (Mexico) Saylla (Mexico) Rural Bolivia Ecuador Guatemala Guatemala
432 1000 475 134 1552 1005 2911 109 184 279 371 421 1200 72 495 159 118 1161 1204
12 12.1 3.7 6.4 10.8 4.9 7.1 21 10 7 13 8 16 5 24 22.6 10.4 17 10
3. Information from studies using seroprevalence as a criterion for neurocysticercosis Some epidemiological studies have explored the association between neurocysticercosis and epilepsy using serology and CT. The study of Moyano [7] is an excellent example. In this study they included 17,450 individuals. The cases had an initial survey, then a neurological evaluation and the last step was a formal neurological examination plus blood sampling and brain CT scan. The lifetime prevalence of epilepsy was 17.25/1000 and the point prevalence was 10.8/1000 habitants. Forty percent of cases had positive antibodies for cysticercosis. Brain CT showed images compatible with neurocysticercosis in 39% of the cases. They concluded that neurocysticercosis is an important contributor to explain the high rate prevalence of epilepsy in this region. In a similar way Montano et al. [8], performed an epidemiological study assessing the prevalence of epilepsy and the seroprevalence of
cysticercosis. The study screened 903 residents from rural Peru. The overall prevalence of epilepsy was 32.1 per 1000, the active prevalence was 16.6 per 1000 and the seroprevalence of cysticercosis was 24.2%. Seroprevalence was associated with seizures (OR 2.1, p = 0.026). In a similar way as Moyano [9], Montano et al. concluded that an important proportion of seizure cases are associated with neurocysticercosis demonstrated by serology and CT scan. Similar studies have been reported in other endemic areas like India. Sekhar Pappala et al. [10] performed the serological diagnosis of NCC in 160 patients with recent onset seizures in a tertiary center in India. NCC was diagnosed in 44 of 160 (27.5%) seizure cases based on imaging characteristics, and a positive serum antibody ELISA. The authors suggest that NCC should be suspected as one of the major differential in every recent onset seizure with or without a radio imaging supportive diagnosis, especially in areas endemic for taeniasis/cysticercosis. Interestingly the study did not report other etiologies of seizures and not all the cases had MRI. These studies have to be analyzed carefully in order to avoid incorrect assumptions: a) the modern diagnosis of epilepsy is based in new technology such as MRI. Many lesions such as benign tumors, areas of cortical dysplasia and some vascular malformations can only be diagnosed with MRI therefore studies only using CT scan to determine etiology have a significant limitation. It is possible that a large proportion of cases can have dual pathology or maybe other lesions apart from the NCC as the cause of the epilepsy, b) it is probably controversial to attribute that patients with positive serology for cysticercosis can make a case for NCC, considering that seropositivity is very common in LatinAmerican countries, c) it is possible that the use of MRI with proper protocols in all cases and a more comprehensive diagnostic approach can identify other etiologies lowering the rates of NCC associated with epilepsy, d) finally in almost all the countries there is a significant benefit of epilepsy programs improving not only the diagnosis but also the management of patients with epilepsy. In many low-income countries, there are a limited number of epilepsy programs and the available ones, many times are not well equipped. It is possible that many of these patients where epilepsy has been associated to NCC, may have dual pathology of other etiology when they are look at carefully by an epilepsy program.
Fig. 1. Estimated geographical distribution of taeniasis/cysticercosis around the world (data from the world health organization).
Please cite this article as: Tellez-Zenteno JF, Hernandez-Ronquillo L, Epidemiology of neurocysticercosis and epilepsy, is everything described?, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.01.030
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4. Information from meta-analysis and the potential overestimation of NCC as a cause of epilepsy There is a recent meta-analysis by Ndimubanzi [11] exploring the difference of epilepsy burden in Latin-America taking into account the infection by cysticercosis. The study included studies until 2012 and explored lifetime and active epilepsy prevalence, incidence, mortality, treatment gap and NCC proportion among people with epilepsy. This meta-analysis is very controversial because it tries to correlate studies instead of providing estimates. In the first analysis they included a group of studies where epidemiological rates of epilepsy were described (prevalence, incidence, mortality, etc.). On the other hand they had a second group of studies where the proportion of cases of cysticercosis and NCC among patients with epilepsy was explored. The median NCC proportion among patients with epilepsy was 32.3% and higher NCC estimates were associated with higher epilepsy prevalence. The last assumption was done with a geographical correlation of both groups of studies. The authors concluded that NCC prevalence is an important factor influencing epilepsy prevalence in Latin-America. Another metaanalysis explored the frequency of NCC with a focus on people with epilepsy around the world delivering similar conclusions to the study of Bruno [12]. This meta-analysis is very controversial and it not necessarily supports the idea that NCC could be the main reason explaining the high prevalence of epilepsy in Latin-America. Some observations could be drawn from this meta-analysis: a) the meta-analysis included two very different types of studies that may not be valid to overlap. The studies that explored epidemiological rates of epilepsy were studies done in open populations and some of the studies where serology of cysticercosis was explored were done in tertiary centers or in a different population than the epidemiological studies. It is probably hard to draw conclusions from one to the other group, b) a significant weakness of most of the studies is the use of CT and serology to determine etiology of epilepsy. As was mentioned before many specific etiologies such as benign tumors and areas of cortical dysplasia are diagnosed only with MRI, c) finally many studies included in the meta-analysis assume that the etiology of the epilepsy is NCC only using serology. 5. Exploration of etiologies of epilepsy in countries with a high prevalence of cysticercosis In 1993 Senanayake and Roman [13] published a key non-systematic review exploring some epidemiological aspects of epilepsy in developing countries. In this review they identify three studies that explored etiology/risk factors of epilepsy in Latin-American countries. The first two studies were from Brazil, one of them included patients from 1 month to 15 years and the second patients older than 13 years [13]. The last one was from Uruguay and included people from 1 month to 15 years. The three studies described specific etiological factors for epilepsy as follows: perinatal brain damage 14%, 11 and 8.5 respectively, head injuries 3, 13 and 8%, intracranial infections 5, 0 and 4, neurocysticercosis 13, 4 and 0%, intracranial tumors 0 in the three studies, cerebrovascular disease 0, 2.5 and 5%, toxic metabolic causes 0% in the three studies, other causes 4, 1.5, 6.5% febrile seizures 0 in the three studies and not identified causes in 63, 68 and 59% respectively [13]. Looking carefully these studies where the etiology of epilepsy is explored in a geographical region with a high prevalence of NCC we can draw some observations: a) neurocysticercosis is not the main cause of epilepsy in epidemiological studies where serology is not used as the main indicator to describe the etiology of epilepsy, b) there is a variety of etiologies and the rates look more similar to the ones reported in developed countries, c) the percentage of unknown etiologies is large and very similar to the reported in high income countries, d) unfortunately there are not many studies exploring specific etiologies not based in tertiary centers to draw more conclusion. It is possible that
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the etiology of epilepsy in developing countries can be related with a spectrum of causes as it has been showed in other regions of the world with some specific variations such as a predominance of NCC, but also other etiologies such as hypoxic brain injury, other infections and head trauma. A large proportion of studies exploring the association of epilepsy and NCC have been done in rural areas of Latin-America and India, where patients do not have access to epilepsy programs. This is a limitation because a more comprehensive assessment of patients in epilepsy centers can identify different etiologies. 6. Drug resistant epilepsy and NCC Epilepsy affects 50 million people worldwide [14]. It is estimated that between 6% and 69% of patients fail to respond to standard medical and surgical therapies and continue to experience debilitating refractory seizures. These patients are classified as having drug-resistant epilepsy (DRE), a diagnosis with poor prognostic implications that include premature death, physical injury, psychosocial dysfunction, and reduced quality of life [15]. The prevalence of DRE is not consistently defined and tends to vary among studies, owing to issues with population selection, sample size, classification, terminology, and characterization of seizure intractability [4]. There are very few studies analyzing the association between drug resistant epilepsy and NCC. Goyal et al. [16] conducted a study in a tertiary care center in India between July 2011 and July 2013. Two hundred patients with epilepsy and NCC were enrolled and followed for a minimum period of 1 year. This included patients with definite and probable NCC defined by the criteria of Del Bruto [17]. Thirteen patients (7%) with NCC were found to be refractory to drug therapy. The authors identified a low prevalence of DRE compared the majority of studies where other etiologies are mixed. There are some interesting studies showing that patients with epilepsy and NCC can develop DRE if calcifications are associated with mesial temporal sclerosis or gliosis [18]. There are also few reports showing some cases with DRE that actually have epilepsy surgery associated with NCC, but in general these represent selected cases [19]. The evidence is scanty although it shows that NCC associated with epilepsy has a low rate of intractability compared with classical studies where mixed etiologies are included, but also that does not require surgical work up and epilepsy surgery very frequently. More investigation is needed in this field in the next few years. 7. The case of high income countries There is a recent study performed by Fabiani and Brushi [20]. They search for PubMed articles of reported cases of NCC in European countries. One hundred seventy six cases of NCC were reported in seventeen European countries (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, The Netherlands, Sweden, United Kingdom, and Croatia, Norway, Switzerland). A particular epidemic situation is present in Spain and Portugal. Specifically Spain has an increasing incidence of NCC in immigrated patients and some people who were born in certain Spanish geographical areas. The case of Portugal is different because the prevalence is similar to that observed in endemic areas. For the case of Europe is clear that as a result of increased migration and travels from endemic regions, NCC is becoming an emerging public health problem in high-income European countries, particularly affecting communities with poor hygiene conditions where the parasite can spread from human to human through eggs even in absence of a travel to the tropics. A similar phenomenon has been seen in the US. A recent literature review of all case series in the United States with at least 20 patients during 1980–2004 identified 1494 patients with neurocysticercosis. The authors noted that 76 infections (5.1%) were likely acquired within the United States [21]. A more recent study assesses the effect of neurocysticercosis in the US using hospitalization discharge data in an Inpatient Sample for 2003–2012. The authors found an estimated of
Please cite this article as: Tellez-Zenteno JF, Hernandez-Ronquillo L, Epidemiology of neurocysticercosis and epilepsy, is everything described?, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.01.030
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Table 2 Key recommendations performed by the group of Peru to control Taenia solium, taeniosis and cysticercosis. Measure Providing continuing health education to the population and to the healthcare personnel, mainly improving hygiene and sanitary conditions, veterinary control or surveillance systems in general; first of all avoiding use of human infected feces as agricultural fertilizer; Searching and reporting the sources of transmission of taeniasis/cysticercosis both in animals, including meat inspection, and humans Limiting animal reservoir improving farm status and treating, and eventually vaccinating, pigs Developing easy to-use drugs, and safe and effective vaccine for pigs; Identifying community exposed to T. solium, carriers of adult tapeworms and closed contacts, considering tapeworm carriers as potential sources of contagion to both themselves and to those living in their close environment Targeting treatment against human taeniosis, selecting the drug of choice; Developing well defined protocols to clinically identify, and eventually manage, human cases.
18,584 hospitalizations for neurocysticercosis. The risk for hospitalizations was highest among Hispanics (2.5/100,000 population). Nearly three-quarters of all hospitalized patients with NCC were Hispanic [22]. The studies in the US show a similar phenomenon that is seen in high income European countries. In the past cysticercosis and NCC was exclusively a problem of some developing countries. Recently it is recognized as an emergent disease in high income countries and not only with imported cases. This is a significant epidemiological change and requires more awareness of the disease around the world. 8. Systematic exploration of other etiologies in studies with a high prevalence of NCC Bhalla et al. [23] performed a key comprehensive non-systematic review of etiologies in epilepsy. In this review the author suggests that some etiologies could be more prevalent in developing countries such as perinatal adverse events, bacterial/viral brain infections, parasitic infections, and traumatic epilepsy and brain tumors. Less frequent causes in developing countries could be genetic causes, malformation of cortical development, hippocampal sclerosis, cerebral immunological disorders, arterial–venous malformations, stroke and Alzheimer disease. This observation could be true unfortunately we do not have many epidemiological studies in open populations or in tertiary centers exploring etiologies in countries with a high prevalence of NCC. In countries with a high prevalence of NCC there is a significant lack of resources to properly diagnose patients with epilepsy; therefore some etiologies are clearly underreported such as genetic causes and etiologies where MRI is required such as mesial temporal sclerosis and cortical malformations. The systematic exploration of etiologies for epilepsy in countries with a high incidence is highly required. The real magnitude of NCC explaining the higher prevalence of epilepsy will remain controversial. Current studies have to be interpreted in the specific circumstances and avoid drawing general conclusions without more evidence. In the end NCC may have some overrepresentation of etiology of epilepsy in endemic countries, although in a similar way as other continents, etiology may show a spectrum of causes. 9. Prevention measures Several studies from developing countries show consistently that NCC is an endemic problem, but now with the significant migration patterns of people and travels, NCC is a constant growing public health problem in high-income countries. In the past only cases related with migration issues were identified in developed countries but now cases are identified in communities of high income countries where hygiene conditions are poor and consequently the parasite's eggs can spread. In Table 2 we list key recommendations performed by the group of Peru to control Taenia solium, taeniosis and cysticercosis [24,25]. Economic development has proven effective to achieve sustained eradication, although is difficult to implement in developing countries.
10. Future research Neurocysticercosis is an old disease, but unfortunately the burden of the disease has increased in the last few years. Originally NCC was a problem of developing countries nevertheless because migration patterns the disease is also recognized in developed countries. The belief that NCC is the main cause of epilepsy in some countries of LatinAmerica, Asia and Africa is controversial and it has to be better analyzed in the future. Better epidemiological studies characterizing different etiologies in patients with epilepsy have to be developed in the future. The development of epilepsy programs in countries where NCC has been associated with epilepsy will also help to understand the controversial high prevalence of NCC in patients with epilepsy. The more comprehensive assessment of patients with epilepsy in low income countries in the future using modern imaging may show that NCC is not the main etiology of epilepsy in many cases.
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Please cite this article as: Tellez-Zenteno JF, Hernandez-Ronquillo L, Epidemiology of neurocysticercosis and epilepsy, is everything described?, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.01.030