Neurocysticercosis and epilepsy in sub-Saharan Africa

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Review

Neurocysticercosis and epilepsy in sub-Saharan Africa ⁎

Athanase Millogoa,b, , Alfred Kongnyu Njamnshic,d, Mesu’a Kabwa-PierreLuabeyae a

Université Ouaga I Pr Joseph Ki-Zerbo, Burkina Faso Service de Neurologie, Département de Médecine, CHU Sourô Sanou, Bobo-Dioulasso, Burkina Faso Department of Neurology, Central Hospital Yaoundé/Faculty of Medicine and Biomedical Sciences, The University of Yaoundé I, Yaoundé, Cameroon d Brain Research Africa Initiative (BRAIN), Yaoundé, Cameroon e Kinshasa University School of Medicine, Democratic Republic of Congo b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Neurocysticercosis Epilepsy Sub-Saharan Africa Computed tomography Serology Treatment Prevention

Neurocysticercosis is a public health problem and the leading cause of epilepsy in developing countries especially in sub-Saharan Africa (SSA). In this paper, the authors review the epidemiology of cysticercosis and neurocysticercosis, as well as the non-specific clinical manifestations which render clinical diagnosis challenging especially in the sub-Saharan African context. Special attention is given to the association of epilepsy and neurocysticercosis, the former being the most common symptom of the later, and the role of the later in epileptogenesis is discussed. The state of the art guidelines regarding diagnostic tests and treatment options are discussed and proposals for prevention are made, given the specific socio-culturaland economic context of the endemic countries, mostly in SSA.

1. Introduction Neurocysticercosis is a public health problem and the leading cause of epilepsy in developing countries. Cysticercosis is a zoonosis caused by the larval form of Taenia solium. It is prevalent in countries with poor hygiene, where reared pigs have access to human faeces as result of defecation in the open air due to lack of latrines. Even though preventable, neurocysticercosis (NCC) is considered to be the leading cause of epilepsy in endemic countries (Carpio and Romo, 2014) including sub-Saharan Africa (SSA). However, epilepsy, which is one of the most frequent manifestations of NCC, is surrounded by mostly negative socio-cultural beliefs in sub-Saharan Africa (Atadzanov et al., 2010; Baskind and Birbeck, 2005; Birbeck and Kalichi, 2003; Njamnshi et al., 2009a, 2009b; Rafael et al., 2010). The management will most likely be affected more by its relationship with epilepsy than because of its link with environmental hygiene (Fig. 1). Epilepsy has often been associated with witchcraft or evil spirits in many African countries both in the rural and urban regions (Ndoye et al., 2005; Rwiza et al., 1993; Njamnshi et al., 2009b, 2010; Nyame and Biritwun, 1997; Mohammed and Babikir, 2013; Millogo and Siranyan, 2004; Millogo et al., 2004). General population knowledge on epilepsy remains limited (Kaddumukasa et al., 2016; Mohammed and Babikir, 2013), often giving it a contagious or hereditary character, or even relating it to mystical or unnatural forces (Baskind and Birbeck, 2005; Bruno et al., 2011). Neurocysticercosis which is one of the most ⁎

common causes of epilepsy in tropical countries will very likely suffer from prejudice. 2. Epidemiology of neurocysticercosis Cysticercosis, an infection caused by the larval form of Taenia solium, is the most common nervous system infection by helminths. It is very common in tropical and developing countries in sub-Saharan Africa, Asia and Latin America. Neurocysticercosis (NCC) is considered to be the most common parasitic disease of the central nervous system and the most common cause of active epilepsy in developing countries (Nsengiyumva et al., 2003; Prasad et al., 2008a,b). NCC is considered to be a marker of poverty in poor communities (Carpio, 2002; Winkler, 2012). It is a public health problem in developing countries where the level of hygiene, proximity to pigs and open defecation favour the persistence of the disease. 2.1. Prevalence of Taenia solium cysticercosis The seroprevalence of cysticercosis in the general population has been assessed in endemic areas around the world (Coral-Almeida et al., 2015; Rajshekhar et al., 2003). In sub-Saharan Africa, the seroprevalence of cysticercosis varies from one country to another (Rottbeck et al., 2013; Mwape et al., 2015; Kanobana et al., 2011; Nkouawa et al., 2015) and sometimes within the same country

Corresponding author at: 01 BP 854 Bobo-Dioulasso 01, Burkina Faso. E-mail address: [email protected] (A. Millogo).

https://doi.org/10.1016/j.brainresbull.2018.08.011 Received 9 March 2018; Received in revised form 20 June 2018; Accepted 16 August 2018 0361-9230/ © 2018 Published by Elsevier Inc.

Please cite this article as: Millogo, A., Brain Research Bulletin (2018), https://doi.org/10.1016/j.brainresbull.2018.08.011

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estimate the prevalence of NCC to vary widely among different countries (Millogo et al., 2012; Winkler, 2012; Rottbeck et al., 2013; Mwape et al., 2015; Winkler et al., 2009; Carabin et al., 2015). In rural areas in Tanzania, the mean age of people with epilepsy (PWE) with active NCC was higher than that of PWE having inactive NCC (Blocher et al., 2011) and more than 50% of PWE with abnormal brain computerized tomography (CT) scans were affected by NCC (Winkler et al., 2009). In areas where NCC is endemic, 30% of cases of epilepsy are due to neurocysticercosis (Ndimubanzi et al., 2009) and this could account for up to 80% of symptomatic forms of epilepsy in endemic countries (Carabin et al., 2011). In 2010, a meta-analysis found a significant association between cysticercosis and epilepsy (Quet et al., 2010). The estimated number of people suffering from NCC-epilepsy varies between 0.45–1.35 million in Latin America, 1 million in India, and between 0.3 and 0.7 million in China (Coyle et al., 2012; Winkler, 2012). Sub-Saharan Africa is the part of the world estimated by these authors to have the highest number of people suffering from NCC-induced epilepsy. This prevalence of NCC has been established on the basis of its association with epileptic seizures but does not always take into account other clinical manifestations of NCC. If we consider the underestimated frequency of severe chronic headaches and the various psychiatric manifestations as well as the asymptomatic forms of the disease (Winkler, 2012; Carabin et al., 2011), we can estimate that NCC represents a heavy burden in endemic countries. The natural evolution of this parasitosis and the mass distribution of antihelmintic medication could also precipitate latent forms of NCC into symptomatic forms. This

Fig. 1. Human-pig promiscuity in a village in Burkina Faso. “Close intimacy with animals”.

(Nguekam et al., 2003; Carabin et al., 2009). In all cases, the seroprevalence is by far much higher in Latin America or Asia (CoralAlmeida et al., 2015; Rajshekhar et al., 2003). Hence the importance of adapting preventive measures to each economic and socio-cultural context. 2.2. Prevalence of neurocysticercosis In sub-Saharan Africa, many studies have been conducted and they

Fig. 2. Life cycle of Taenia solium cysticerci. Reproduced from Center for Disease Control and Prevention. Cysticercosis. Atlanta, GA: Center for disease control and prevention. Available from: http://www.cdc. gov/parasites/cysticercosis/biology.html. 2

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3. Diagnosis of neurocysticercosis

could significantly increase the already very large number of NCC cases in sub-Saharan Africa where all the conditions favouring its high prevalence are present: low socio-economic level, poor hygiene with defecation in the open because of the scarcity of latrines in rural areas, promiscuity between humans and pigs and the absence of sanitary inspection of pork.

3.1. Clinical manifestations The clinical manifestations of NCC are variable, depending on the combination of several factors: number, size, stage of development and localization of lesions in the central nervous system, and also on the immune response of the host to the presence of parasite (Garcia et al., 2014; Gripper and Welburn, 2017). None of these clinical manifestations is pathognomonic to NCC and range from completely asymptomatic cases to severe clinical manifestations causing death (Garcia et al., 2014). This makes the clinical diagnosis of NCC really challenging. In many studies, up to 80% of neurocysticercosis cases remain asymptomatic (Garcia and Del Brutto, 2005; Takayanagi and Odashima, 2006; Fleury et al., 2006; Moyano et al., 2016; Singhi, 2011; Carabin et al., 2011; Winkler et al., 2009; Winkler, 2012). The condition may however become symptomatic at any time during its evolution. These asymptomatic forms further complicate the difficulty in diagnosing NCC, suggesting that most NCC prevalence data very likely underestimate the frequency of this parasitosis. While epileptic seizures are the clinical manifestations that most often lead to the diagnosis of NCC, many other signs or symptoms may be circumstances may lead to the diagnosis of NCC (Patel et al., 2006): severe chronic headaches, other manifestations including psychiatric, dementia (Carabin et al., 2011; Srivatava et al., 2013; RamirezBermudez et al., 2017). Epileptic seizures are the most frequent manifestation in intraparenchymal NCC at the time of diagnosis (Fleury et al., 2004; Serrano Ocana et al., 2009; Segamwenge et al., 2016). There is a whole range of seizure type associated with NCC described in the literature. Some authors observed generalized tonic-clonic seizures in Madagascar (Andriantsimahavandy et al., 1997), Burkina Faso (Millogo et al., 2012; Nitiéma et al., 2012), Zambia (Mwape et al., 2015), Tanzania (Winkler et al., 2009; Blocher et al., 2011) and in India (Goel et al., 2011; Varma and Gaur, 2000). On the other hand, other authors described partial seizures in Peru (Moyano et al., 2014), in Bolivia (Nicoletti et al., 2005), and in India (Prasad et al., 2009; Kelvin et al., 2011). In regions endemic for NCC, the occurrence of a partial epileptic seizure, with or without secondary generalization, of recent or late onset should suggest NCC (Blocher et al., 2011; Rajshekhar, 2016) and neuroimaging should be done in the patient. The spectacular nature of generalized tonic-clonic seizures makes their recognition easier and this may explain their predominance in studies in SSA. However, it is possible that partial seizures with secondary generalization are generally considered generalized tonic-clonic seizures, given that their mode of onset is not easily recognizable by the general population. NCC is one of the most common causes of late-onset epileptic seizures in people with epilepsy. This has been found in many studies (Blocher et al., 2011; Winkler et al., 2009; Millogo et al., 2012; Debacq et al., 2017). In extraparenchymal neurocysticercosis, the localization of the parasite in the subarachnoid space or in the ventricular system (Garcia et al., 2014; Marcin Sierra et al., 2017) may be responsible for symptoms related to intracranial hypertension that may be life threatening. The obstruction of the cerebrospinal fluid flow pathway is the main pathophysiological mechanism of this condition. Headache is the second most common manifestation of symptomatic NCC (Carabin et al., 2011; Cruz et al., 1995; Saito et al., 2017; Del Brutto and Del Brutto, 2011). Calcified lesions during NCC, usually considered inactive, may be responsible for headaches. Although the headaches are most often recurrent or chronic headaches similar to migraines or tension-type headaches (Del Brutto and Del Brutto, 2011; Chatterjee and Ghosh, 2013), they have no specific characteristics. Therefore, their occurrence in this context does not necessarily prompt the request for more specific examinations such as serology or brain imaging (Fogang et al., 2015). In extraparenchymal NCC, headaches are

2.3. Life cycle of Taenia solium Humans become infected with the adult worm by eating pork containing the cysticercus and develop taeniasis. The pregnant proglottides are excreted into the environment by an infected human individual and can be ingested by a wandering pig that will develop porcine cysticercosis with cysticerci located mainly in their muscles. The porcine cysticercosis / taeniasis cycle will be completed when infected and undercooked pork is ingested by a human host. The eggs of Taenia solium are infective for both pigs and humans. They can be ingested through direct or indirect contact with the worm carrier, which represents the usual cycle of infection, or through the consumption of water or food contaminated with the eggs from the worm carrier. When the human ingests Taenia solium eggs by the fecal-oral route, he/she becomes an accidental host of the larval stage of the parasite and develops human cysticercosis. In humans, the cysticercus can develop in many organs but it is its development in the central nervous system that gives rise to neurocysticercosis. The different stages of this evolutionary cycle have a major implication on both the curative and preventive measures to be implemented in the control and possible eradication of Taenia solium (Fig. 2).

2.4. Pathophysiology of NCC In the brain, immature cysticerci appear within a few weeks after ingestion of T. solium eggs (vesicular stage), with the parasite harbouring an invaginated scolex surrounded by a translucid vesicular fluid and covered by a transparent membrane. Cysticerci may remain in this state for years, or may degenerate after host immune response. The colloidal stage is the first stage of involution of cysticerci. Eventually, after some years, asymptomatic stage 2 cysticerci develop into symptomatic stage 3 degenerating cysticerci that no longer prevent the host’s immune response with resulting intense inflammation which may lead to clinical signs and symptoms. In the next stage, the cyst wall thickens and the scolex is mineralized. At this stage, which is called the granular stage, the cysticercus is no longer viable but with intense inflammation which may lead to clinical signs and symptoms. The final stage of this degenerative process is the calcification of parasite remnants. It is not uncommon to find cysticerci in different degenerative stages in the same person. Different mechanisms are involved in epileptogenesis during NCC. In the cerebral parenchyma, inflammation around the parasite is thought to be the main factor responsible for triggering epileptic seizures (Carpio et al., 2013). The inflammation which varies in intensity is necessary for the process of parasite death (Nash et al., 2015). During the early stages, epileptic seizures are related to the inflammatory reaction and especially the compression of the cerebral parenchyma. During the granular and calcification stages, astrocytic gliosis surrounding the lesion may be responsible for triggering seizures. The role of peri-lesional oedema as a cause or consequence of epileptic seizure remains unclear. Epileptic seizures during calcified NCC stages are thought to be related to residual peri-lesional gliosis causing a chronic epileptogenic focus (Nash et al., 2014; Nash, 2012; Nash et al., 2017).

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by far the most common symptom present in more than ¾ of cases (Bazan et al., 2016) but in half of these, the headaches were seemingly not associated with raised intracranial pressure. Headaches were reported as the suggestive finding of NCC in rural areas in Cameroon (Nguekam et al., 2003), Tanzania (Winkler et al., 2009) and Ecuador (Cruz et al., 1995). The association between epileptic seizures and headaches was found in a study in Mexico (Fleury et al., 2004). Some authors have reported neuro-psychiatric manifestations as circumstances that suggest the diagnosis of NCC (Carabin et al., 2011). These could include memory impairment (Varghese et al., 2016), dementia (Ramirez-Bermudez et al., 2005; Patel et al., 2006; RamirezBermudez et al., 2017), depression (Chatterjee and Ghosh, 2013; Forlenza et al., 1997; Srivatava et al., 2013). To the best of our knowledge, psychiatric manifestations have not been described in SSA probably because of limited human resources. It is therefore important to actively look for psychiatric manifestations in our context in patients with NCC. It would be equally interesting to consider the diagnosis of NCC in patients presenting primarily with psychiatric symptoms in our setting in order to assess their importance in NCC symptomatology. Other manifestations reflecting central nervous system involvement during NCC have been described, such as focal dystonia or parkinsonism (Patel et al., 2006), further conferring the nonspecific nature of all the signs found in the NCC. Spinal cord involvement of the cysticercus is possible and will be marked by focal signs. Fig. 3. Giant cyst associated with calcifications.

3.2. Neuroimaging Neuroimaging is essential not only for diagnosis but also for the management of the diagnosed cases. Through neuroimaging, it possible to evaluate the number and location of the lesions, to determine the evolutionary stage of the parasitic infection and the degree of the inflammatory reaction of the host against the parasite (Garcia and Del Brutto, 2003; Sarria Estrada et al., 2013; Verma and Lalla, 2012). However, the geographical accessibility (mainly in capitals of countries and / or major cities) and financial accessibility of imaging techniques (resource-limited countries, the cost of neuroimaging being generally higher than the Interprofessional Guaranteed Minimum Wage in endemic countries) limits its use. Brain imaging determines the type of treatment (medical or surgical) to be instituted and is useful for followup, to evaluate the effectiveness of the therapeutic approaches. It also helps in the differential diagnoses such as cerebral toxoplasmosis, brain abscesses and brain metastases (Mahanty and Garcia, 2010). Each of the brain imaging techniques, Computerised tomography (CT) and magnetic resonance imaging (MRI), has its advantages and disadvantages in the diagnosis of NCC. Nevertheless, the most important issue is to determine whether the parasite is still alive or not. Magnetic resonance imaging may however not detect the small calcifications (Garcia and Del Brutto, 2005). According to Verma and Lalla, NCC can be missed on CT of the brain and should be screening investigation for NCC whereas brain MRI is of great help in intraventricular NCC, brainstem cysts and subarachnoid NCC (Verma and Lalla, 2012). Acute symptomatic lesions are best visualized on contrastenhanced MRI (Lerner et al., 2012). Some pictures from CT scan of the brain are provided in Figs. 3–5.

Fig. 4. Colloidal cysts.

already treated patients or in patients with an extra-cerebral localization of cysticercosis (Garcia et al., 2014). Hence, there is a possibility of a large number of asymptomatic individuals who would have positive EITB serology without showing signs of NCC in endemic areas, as is the case in many countries in sub-Saharan Africa. The presence of T. solium antibodies in serum suggests parasite exposure or past/present asymptomatic infection (Garcia et al., 2012; Del Brutto et al., 2017). Numerous tests have been developed to confirm the diagnosis of NCC but the enzyme-linked immunoelectrotransfer blot (EITB) assay, detecting antibodies to Taenia solium in serum has a specificity close to 100% with a sensitivity of 98% in patients with at least 2 parasites living in the nervous system. This test is however expensive. Detection

3.3. Serological tests Serological tests for Taenia solium should be performed in suspected cases of NCC but they are not always available in the context of subSaharan Africa, and they can help to sort out those patients who need to be referred for neuroimaging. Furthermore, a positive serological test suggests cysticercosis but not necessarily neurocysticercosis. Moreover, the sensitivity and specificity vary considerably depending on the tests used, most of which are not always available in daily clinical practice. The enzyme-linked immunoelectrotransfer blot (EITB) test may be positive in people who have been exposed to the parasite antigen or in 4

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Fig. 5. A B: In the same patient: 5 A: Colloidal and granular lesions of NCC associated with significant oedema.5 B with contrast enhancement.

of Taenia solium antigens may have an added value in the diagnosis of NCC with epilepsy. The usefulness of serology in the absence of brain imaging remains controversial. In Latin America, high seroprevalence of cysticercosiswas found in Haiti, Venezuela and Peru (Raccurt et al., 2009; Ferrer et al., 2003; Gonzales et al., 2015), this seroprevalence being higher in rural areas. Two serological studies in highly endemic areas for epilepsy in Cameroon, have failed to show an association (Dongmo et al., 2004; Elliott et al., 2013). Although Gabriel et al. believe that the positivity of the Ag-ELISA could be an indication to do neuroimaging (Gabriel et al., 2012), this serology does not seem to be of practical interest for patients (Garcia et al., 2012). As such, the serology even contributive to the diagnosis of NCC cannot be considered as the main tool for the diagnosis. In addition, serology would be another expense increasing the burden of the diagnosis process of this disease and possibly delay the treatment. Among rural residents in three villages in rural Burkina Faso, Carabin et al. found a large variation in the prevalence of human seropositivity to the presence of the larval stages of T. solium cysticercosis among rural areas of the same country (Carabin et al., 2009). The differences could be explained by the use of toilets instead of open air defecation in some areas rather than others, and the tethered pigs have access to human feces which increases the risk to be infected and are more likely than penned pigs to have access to human feces as they are often moved to be able to feed.

have benefited from numerous revisions in order to make the diagnostic criteria of NCC more operational (Del Brutto et al., 2001; Del Brutto, 2012; Garcia et al., 2014; Del Brutto et al., 2017). In the revised version of the NCC diagnostic criteria, while the category of absolute diagnostic criteria remains essentially unchanged, the structure of the remaining categories was modified in accordance with two main principles: 1) neuroimaging studies are essential for the diagnosis of NCC; and 2) information from clinical manifestations, immunodiagnostic tests and epidemiologic settings only provides indirect evidence for the diagnosis of NCC. Therefore, instead of having categories of major, minor and epidemiologic criteria, where different types of criteria were grouped according to their individual diagnostic strength, we now use neuroimaging signatures of NCC on one side and clinical/exposure evidence for cysticercosis on the other. As a result, the requirements for a case being classified as “definitive” or “probable” NCC changed according to these principles (Table 1). One of the constraints for confirmation of imaging is to redo a scan that will confirm the disappearance of cystic images after anthelmintic treatment. The cost of this confirmation in the context of limited financial resources may be an obstacle to the completion of this posttherapeutic review.

4. Diagnosis criteria for neurocysticercosis

The management of NCC necessarily involves staging of the disease using neuroimaging to visualize lesions and differentiate them into active or inactive forms of NCC (Winkler, 2012) and treatment would include symptomatic treatment, antiparasitic medication (if the parasite is alive) or even surgical management. Only active intra-parenchymal and symptomatic forms with epileptic seizures will require the combination of anthelmintic, anti-inflammatory and antiepileptic drugs (Winkler, 2012). Corticosteroids are associated with anthelmintic drugs to control peri-lesional oedema for as long as the patient is symptomatic. In a parasitic disease in which the break in the T. solium life cycle proves to be important for the control and possibly the eradication of T. solium, preventive measures must be put in place to accompany the curative treatment. Each case should be analyzed individually. The principles underlying antiparasitic treatment are: not to treat asymptomatic or inactive lesions, or lesions in the degeneration stage nor to use anthelmintic drugs for cysticercal encephalitis, because of the risk of worsening the clinical condition. In resource-limited settings where neuroimaging and serologic testing are often unavailable, management can be limited to

5. Management of neurocysticercosis

The diagnosis of NCC requires the combination of imaging and immunological tests in patients with suggestive symptoms particularly epilepsy. Despite all these methods, the diagnosis of NCC remains difficult especially in the tropics where the numerous conditions could present with similar clinical features. The lack of specificity of clinical manifestations of NCC makes it impossible to diagnose NCC solely on the basis of clinical signs. The ideal would have been a cheap, sensitive and specific diagnostic method for all forms of NCC. So far, this method does not exist (Mewara et al., 2013). In addition, the NCC diagnostic tools are not always available in the endemic areas which are the places where they are most needed. This challenge for the clinician is due, on the one hand, to the nonspecific nature of the clinical symptomatology that can mimic any central nervous system disorder, none of the signs being pathognomonic of NCC, and on the other hand to the low availability (geographical and financial) of diagnostic tools, whether imaging or serological tests. Hence, the need for the combination of clinical, radiological, serological and epidemiological criteria, which 5

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manifestations of the patient's clinical picture. It is complex and each case should be considered specifically, based on clinical manifestations, localization and viability of the parasite: antiepileptic drugs in case of epileptic seizures, mannitol for intracranial hypertension, and analgesics for headaches. The majority of NCC patients in sub-Saharan Africa do not have access to brain imaging. The antiepileptic treatment will be undertaken empirically, first as monotherapy, and then evaluated according to the response on the recurrence of epileptic seizures, provided the correct dosage of the drug is prescribed. In case of failure, the addition of a second antiepileptic may be necessary. Treatment of NCC in the absence of neuroimaging has to be decided on an individual basis and depends on clinical symptoms and/or signs, whether acute or chronic, and on the physician’s experience as well as local practice. Most patients with NCC can be maintained on antiepileptic medication alone. In case of doubt about the necessity of antihelminthic treatment, symptomatic treatment should be favoured. As antihelmintic treatment may be not useful in case of calcified NCC or even armful when there are many active NCC lesions, when there is no possibility to have proof of the evolutive stage of the infection by brain imaging, symptomatic treatment should be the best choice especially in these settings. In Tanzania, it has been shown that most NCC patients with epileptic seizures are well controlled with monotherapy antiepileptic drug (Blocher et al., 2011). In order to promote patient’s adherence to antiepileptic treatment, it will be advisable to inform them of the different side effects of the prescribed drug. Discontinuing antiepileptic treatment should be considered in the patients that are seizure free for at least 2 years.

Table 1 Revised diagnostic criteria and degrees of diagnostic certainty for neurocysticercosis (Del Brutto et al., 2017). Diagnostic criteria Absolute criteria: • Histological demonstration of the parasite from biopsy of a brain or spinal cord lesion. • Visualization of subretinalcysticercus. • Conclusive demonstration of a scolex within a cystic lesion on neuroimaging studies. Neuroimaging criteria: Major neuroimaging criteria: • Cystic lesions without a discernible scolex. • Enhancing lesions. • Multilobulated cystic lesions in the subarachnoid space. • Typical parenchymal brain calcifications. Confirmative neuroimaging criteria: • Resolution of cystic lesions after cysticidal drug therapy. • Spontaneous resolution of single small enhancing lesions. • Migration of ventricular cysts documented on sequential neuroimaging studies. Minor neuroimaging criteria: • Obstructive hydrocephalus (symmetric or asymmetric) or abnormal enhancement of basal leptomeninges. Clinical/exposure criteria: Major clinical/exposure: • Detection of specific anticysticercal antibodies or cysticercal antigens by wellstandardized immunodiagnostic tests. • Cysticercosis outside the central nervous system. • Evidence of a household contact with T. solium infection. Minor clinical/exposure: • Clinical manifestations suggestive of neurocysticercosis. • Individuals coming from or living in an area where cysticercosis is endemic. Degrees of diagnostic certainty Definitive diagnosis: • One absolute criterion. • Two major neuroimaging criteria plus any clinical/exposure criteria. • One major and one confirmative neuroimaging criteria plus any clinical/ exposure criteria. • One major neuroimaging criteria plus two clinical/exposure criteria (including at least one major clinical/exposure criterion), together with the exclusion of other pathologies producing similar neuroimaging findings. Probable diagnosis: • One major neuroimaging criteria plus any two clinical/exposure criteria. • One minor neuroimaging criteria plus at least one major clinical/exposure criteria.

5.2. Prevention 5.2.1. Break the evolutionary cycle of Taenia solium Neurocysticercosis is a leading cause of preventable epilepsy responsible for 30% of adult onset epilepsy in endemic regions (Ndimubanzi et al., 2009). Prevention is one of the most important aspects in the control and eradication of neurocysticercosis. Cysticercosis is considered a disease that can be controlled or even eradicated. This involves actions directed at all targets, including adult worm carriers, infected pigs and also T. solium eggs in the environment. These targets are the different stages of the T. solium life cycle and adequate control of these stages would break the life cycle. Although the World Health Assembly adopted resolution WHA66·12, making cysticercosis one of the neglected zoonosis targeted for control, elimination and eradication (WHO, 2015), no endemic country has reached elimination of T. solium nationally (Johansen et al., 2017). In developed countries, control of T. solium infection has been facilitated by industrialization and improvement of the level of hygiene. Improving health systems and educating the population requires economic progress and the political will to determine community priorities. These minimum conditions are expected to reduce the burden of cysticercosis in endemic countries. Chemotherapeutic interventions targeted at humans or pigs seem to be highly effective at reducing taeniasis and cysticercosis prevalence (Winskill et al., 2017). The World Health Organization considers that cysticercosis is a candidate disease for eradication (WHO, 2015) because of the simplicity of the T. solium life cycle and the low cost of control tools for this parasitosis (Gabriël et al., 2017) and the roadmap for elimination of T. Solium taeniosis/cysticercosis is under consideration by the World Health Organisation through the mass drug administration. Praziquantel is the antihelminthic drug used in this process because of its safety and ease of administration (WHO, 2010) but in intraventricular and racemose cysticercosis the medication of choice is Albendazole. Poor sanitation conditions, including the absence of latrines (Assane et al., 2017; Carabin et al., 2015) or the high proportion of people practicing open air defecation in many countries (Ngowi et al., 2017; Dahourou et al., 2018; Thys et al., 2015) and difficulties in accessing

symptomatic treatment (Winkler, 2012) including, depending on the case: antiepileptic drugs (AEDs), analgesics and / or anti-inflammatory drugs and possibly intracranial hypertension management (Nash et al., 2006). The available AEDs are started in case of recurrent epileptic seizures, or when an underlying cause is suspected. In sub-Saharan Africa, the choice is limited and will be based on the drug molecules usually available and whose cost / seizure control is favourable for patients. This is usually phenobarbital, carbamazepine and phenylhydantoin. Monotherapy is usually adequate to get good seizure control in patients with NCC. The follow-up of treated patients is a major challenge in resourcelimited settings as brain imaging may be unavailable at any time due to technical failure or lack of financial resources. In these cases, the practice of the ELISA antigen could be used to determine whether it is an active form of NCC, because of the important role of staging this parasitic infection in order to ensure that only active form of NCC will benefit from the antihelmintic drugs, especially when brain imaging is unavailable.

5.1. NCC treatment Neuroimaging is mandatory to start treatment with antihelminthic drugs and therefore antihelminthic treatment is not indicated in most patients from sub-Saharan Africa. The symptomatic treatment of parenchymal or extra-parenchymal forms of NCC is based on the dominant 6

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parasite life cycle, it could be argued that pig treatment and vaccination be part of the strategy to prevent transmission. Improved sanitation and pig management seem to be more effective and sustainable than pig vaccination, human or porcine mass treatment (Carabin and Traoré, 2014). Among the anthelmintic drugs evaluated, oxfendazole has proven to be safe and efficacious against porcine cysticercosis. It has been shown to be effective for the control of porcine cysticercosis; however, it needs to be integrated with other control approaches. Despite some limitations, the drug is safe, inexpensive, and easily administered as a solution, making it a good candidate for use in endemic areas (Mkupasi et al., 2013). Apart from the pig treatment, pig vaccination as a strategy to prevent transmission in combination with pig treatment, should be part of the control of Taenia solium cysticercosis process (Gabriël et al., 2017). Immunisation has to be performed at early age in order to prevent infection (Garcia and Del Brutto, 2003). In Cameroon, three doses of TSOL18 in combination with oxfendazole at 4 weeks, compared to a treatment with oxfendazole at 4 weeks, had shown effectiveness at eliminating any cysts in the vaccinated group (Assana et al., 2010). In many other countries facing NCC in SSA this example should be implemented, in combination with strong health education programme.

drinking water (Rottbeck et al., 2013) are very often associated with high prevalence of cysticercosis in sub-Saharan Africa. In this region, the exclusive use of latrines to prevent pigs from accessing human faeces remains a serious challenge and for socio-cultural reasons because the community do not consider the construction of a latrine for themselves as a priority, their use is not an habit, the promotion of latrines failed, or the maintenance of latrines is perceived as difficult (Thys et al., 2015), not only for economic reasons. In a recent study in Burkina Faso, among people who have heard of porcine cysticercosis, less than 1% knew that a pig acquires porcine cysticercosis by eating human faeces (Ngowi et al., 2017). In a context where financial resources are limited and socio-cultural beliefs and attitudes promote open air defecation (Thys et al., 2015; Segamwenge et al., 2016), the systematic use of latrines is proving to be one of the indispensable conditions for achieving NCC control. Even if the construction and use of latrines could prevent pigs from having access to human fecal material, access to potable water remains a major challenge in trying to break the life cycle of T. solium. Besides, socio-cultural barriers prevent the use of latrines for various reasons (Thys et al., 2015). However, the cost limits the use of this strategy. On another hand, community awareness about the host-parasite transmission cycle should be promoted in order to break the host-parasite life cycle. This could be done by community health education, improvement of sanitation as it was done in Europe in the 19th century to eliminate cysticercosis in their environment. The success of such a programme depends on combining a strategy focusing on both human and animal hosts, involving medical, veterinary and environmental sectors with a strong commitment of policy makers in order to control and hopefully eliminate Taenia solium infection in sub-Saharan Africa. The routine use of latrines/toilets thus avoiding open defecation, improved breeding conditions for pigs, improved socio-economic conditions, have led to the elimination of cysticercosis in developed countries, although imported cases are still reported in some studies (Fabiani and Bruschi, 2013; Giordani et al., 2014). The elimination of cysticercosis has been made possible by the level of development of these high-income countries (Fig. 6). Consequently in SSA, emphasis should be laid living in hygienic conditions and rearing pigs in hygienic conditions with the veterinary physicians playing a leading role alongside physicians within the framework of the “One Health” concept. Some studies as shown that poor hand hygiene, such as not using soap to wash hands after defecation, can be associated with greater risk of exposure to porcine cysticercosis (Vora et al., 2008). As such, proper hand washing could be included in health education in communities with high prevalence of T. solium infection, especially in SSA.

6. Conclusion Neurocysticercosis, which is an important cause of epilepsy in endemic countries, remains a public health challenge in developing countries and even more so in sub-Saharan Africa, where people are already challenged with poverty and weak health systems. Its diagnosis is all the more difficult as its manifestations are very diverse and any manifestation of involvement of the central nervous system could be suggestive of NCC. As a result, the diagnosis of neurocysticercosis is rendered even more difficult by the lack of diagnostic technology (imaging and serology) in endemic areas. In this context, its management remains mainly symptomatic with treatment epileptic seizures and severe chronic headaches. The absence of brain imaging could make the treatment dangerous as long as the number, the location and the evolutionary stage of the parasite have not been specified. Neurocysticercosis is potentially preventable provided that control programmes and eradication through better environmental conditions, pig breeding, pork control, breaking the evolutionary cycle of this parasitic disease are implemented to alleviate the burden of this important cause of epilepsy. Another important strategy would be to develop inexpensive, safe, effective and easy-to-administer pig vaccines. One simple step would be to provide communities with latrines and promote good hand washing after every visit to the toilet to effectively prevent many cases of epilepsy.

5.2.2. Treatment of T. solium larval carriers Adult intestinal tapeworms are the immediate source of both human and pig cysticercosis, thus treatment of intestinal tapeworm carriers is a key to control, as they disseminate the eggs in their environment leading to the contamination of soil, water. The carrier of the lone tapeworm is the only source of infection for both humans and pigs. Besides, the life span of Tania solium eggs in the environment can reach several years and contribute to maintaining the infection in a large population. The strategy to control this parasitic disease must include treating all carriers and mass treatment with Praziquantel has been done for some years in some countries (WHO, 2010, 2015).

Conflict of interest None. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References

5.2.3. Treatment / vaccination of pigs As pigs constitute an important part of the life cycle of T. solium, their proper rearing avoiding them getting infected, should be an important component of a control programme of cysticercocis. In many endemic areas, however, the seroprevalence in pigs exceeds 30% of the population (Gilman et al., 2012) and in sub-Saharan Africa, usually pigs are reared under a free-roaming condition, without veterinary inspection and treatment. In such a setting, with associated poor level of hygiene, open air defecation and low level of knowledge about the

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