Neurocysticercosis and Epilepsy in Developing Countries

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.137 on 1 February 2000. Downloaded from J Neurol Neurosurg Psychiatry 2000;68:137–143 137

NEUROLOGICAL ASPECTS OF TROPICAL DISEASE

Neurocysticercosis and epilepsy in developing countries

Deb K Pal, Arturo Carpio, JosemirWASSander

Abstract untreated.23Extending appropriate services to Neurocysticercosis is a disease of poverty these people will be one of the great challenges and underdevelopment. Little is known of the new millenium. Unfortunately little is about the natural history of the infection known about the causes of epilepsy in develop- in humans, but some of the mechanisms ing countries. However, many studies from whereby the parasite remains silent and Latin America have shown that infection of the evades the host immune response are brain by the larvae of the pork tapeworm understood. Symptomatic neurocysticer- Taenia solium is an important cause of epileptic cosis usually results from host inflamma- seizures in endemic communities.4–6 Many tory response after parasite death, and the recent reviews have covered in detail the clinical manifestations can be diverse. pathology,7 parasitology,8 clinical features,6 and There is no evidence that cysticidal treat- diagnostic criteria9 of neurocysticercosis. This ment does more good than harm in review concentrates on recent developments in addition to conventional antiepileptic the immunopathogenesis of neurocysticerco- treatment. Population control measures sis, the controversy over clinical classification, involving immunisation or mass treat- and the evidence base for diVerent treatment ment have not shown long term eVective- approaches. The challenges for the population ness. control of cysticercosis and epilepsy in the Epilepsy, similarly to neurocysticercosis, developing world are summarised. is a largely unrecognised but increasing burden on the welfare and economies of Neurocysticercosis developing countries. The technology of EPIDEMIOLOGY drug treatment and psychosocial rehabili- Taenia solium is endemic in Latin America, tation is well known but requires wide- India, and China, and may also be endemic in spread and eVective dissemination at low sub-Saharan Africa, although there are few cost. There is little epidemiological data studies.10 11 Poor hygiene and living conditions, http://jnnp.bmj.com/ Neurosciences Unit, on risk factors for epilepsy in developing allowing pigs access to human faeces, put peo- Institute of Child countries on which to base prevention ple at risk of developing cysticercosis.4 12–15 In Health, University strategies. The public health prioritisation endemic countries, the disease is also widely College London, UK of chronic disorders such as epilepsy 16 DKPal prevalent in urban, middle class areas. Migra- remains a challenge for policy and prac- tion from the countryside and the rise of urban Faculty of Medicine tice in developing countries. slums obviously influence the changing epide- and Research Institute, For both neurocysticercosis and epilepsy, miology of cysticercosis. T solium infections University of Cuenca, there is a dilemma about whether limited have also been imported by migrant workers on September 28, 2021 by guest. Protected copyright. Cuenca, Ecuador public resources would better be spent on into the United States.17 A Carpio general economic development, which Neurocysticercosis is of great economic would be expected to have a broad impact Epilepsy Research relevance, resulting from the cost of medical Group, Institute of on the health and welfare of communities, treatment, lost working days, and losses due to Neurology, 33 Queen or on specific programmes to help indi- livestock condemnation. A minimum estimate Square, University vidual aVected people with neurocysticer- of the cost of admissions to hospital and wage College London, UK cosis and epilepsy. Either approach loss for neurocysticercosis in the United States JWASSander requires detailed economic evaluation. (a non-endemic country) was $8.8 million (J Neurol Neurosurg Psychiatry 2000;68:137–143) Correspondence to: annually, wheres estimated treatment costs in Dr DK Pal, Neurosciences Keywords: neurocysticercosis; epilepsy; developing Mexico were $89 million, and Brazil $85 Unit, Institute of Child million.18 Health, University College countries; service delivery London, The Wolfson Centre, Mecklenburgh PATHOLOGY Square, London WC1N The immense burden of epilepsy is a growing 2AP, UK Life cycle biology email [email protected] problem in developing countries where the In the first stage, the human host ingests incidence of epilepsy may be higher than in diseased (measly) pork containing viable cyst- Received 6 August 1999 and western countries.1 Three quarters of the 50 icerci, from within which the scolex of the in revised form 6 October 1999 million people with epilepsy live in the poor metacestode evaginates in the gut and attaches Accepted 28 October 1999 countries of the world and up to 94% are to the intestinal mucosa.8 The tapeworm J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.137 on 1 February 2000. Downloaded from 138 Pal, Carpio, Sander

matures over 2–3 months to achieve a length phisms of tumour necrosis factor á and of the of 2–7 m. Gravid segments may contain membrane protein ICAM-1 are associated 50–60 000 eggs which are passively released in with increased risk of death from cerebral small groups in faeces, two or three times a malaria.28–30 It is hypothesised that HLA diVer- week, often unknown to the host. After ences might also determine the risk of intracra- ingestion, eggs hatch and activate in the pig nial infection or symptomatic parenchymal small intestine and develop in striated muscle disease in neurocysticercosis. and the CNS. When humans accidentally become intermediate hosts by ingesting eggs, CLINICAL PRESENTATION the life cycle is completed in a similar way in There are wide variations of clinical manifesta- muscle, skin, and CNS. tions of neurocysticercosis. These are a conse- quence of inflammation around a cyst(s), space Human pathology occupation and impedance to the flow of CSF, Our understanding of natural human infection less commonly meningeal or vascular inflam- depends on studies of expatriates from en- mation, and non-CNS disease. Seizures are the demic zones, and postmortem data. Initially, most common symptom in 70%-90% of there is an asymptomatic period after egg patients.6926These may occur both when a cyst ingestion lasting many years or even for life. is degenerating,31 or around a chronic, calcified The time between infection and symptoms in lesion.32 neurocysticercosis depends on number, size, Electroencephalography shows focal or gen- type, condition, and site of cysts in the brain. A eralised abnormalities, or no abnormality in study of British soldiers with neurocysticerco- neurocysticercosis epilepsy. Examination of sis returning from India showed that most CSF in neurocysticercosis usually yields mild developed seizures 2–8 years after infection.19 abnormalities such as increased protein or Postmortem studies in endemic zones show pleocytosis, not always eosinophils. Interest- that about 80% of infections are ingly, the proportion of seizures reported as asymptomatic.20 However, the risk of intracra- generalised tonic-clonic ranges from 28% to nial infection after T solium egg ingestion is 68%,53334despite the presence of a focal lesion. unknown. Some 10%-20% of patients present with ventricular cysts, sometimes also with seizures IMMUNOLOGY AND PATHOGENESIS or with meningeal inflammation. Symptoms Evidence from animal models and clinical include nausea, vomiting, headache, ataxia, studies shows that cysticerci remain clinically and confusion. Focal neurological deficits are silent as a result of active immune tolerance, uncommon. Patients with cysts in the basal and that symptomatic parenchymal disease cisterns can present with meningeal signs, occurs at the time of larval degeneration or hydrocephalus, vasculitis, and stroke.9 Rarer death by cysticidal therapy. Human neurocyst- neurological manifestations have also been icercosis treatment studies show rises in IgG, reported—namely, altered mental state; spinal interleukin-2, and neopterin in the CSF.21 A cysticercosis with radicular pain or paraesthe- study of patients with hepatic echinococcosis siae, or progressive cord compression; ophthal- (another human cestodiasis) suggests that a mic cysticercosis; migraine headaches; and switch in IgG subclass response from IgG1 to neurocognitive deficits.9 Cysticercal encephali- IgG4 might occur as the disease progresses tis, with multiple parenchymal cysts, an associ- http://jnnp.bmj.com/ from its asymptomatic to symptomatic stages.22 ated inflammatory response, and diVuse cer- Recently it has been reported that eotaxin and ebral oedema is a rare presentation, often in interleukin-5 concentrations are raised in the young girls; these patients are at risk of severe serum of patients with symptomatic neurocyst- neurological sequelae. Intracranial hyper- icercosis, and interleukin-5 and interleukin-6 tension and meningeal neurocysticercosis are concentrations are also raised in the CSF, pos- uncommon in India.35 Subcutaneous cysticer- sibly indicative of an acute phase response.23 cosis is much more common in China than in on September 28, 2021 by guest. Protected copyright. Epidemiological and clinical findings suggest Latin America or India. that individual immunological responses to cysticercosis might have a genetic basis. Firstly, Single enhancing CT lesions Guatemalan population studies have shown no Solitary enhancing CT lesions have commonly association between T solium seropositivity and been described in India.36 37 It is still unknown epileptic seizures in a highly endemic area.12 why single lesions are a more common presen- This could be explained by diVerences in tation in India than multiple lesions. These population genetics or parasite strains, al- single lesions are seen as areas of increased sig- though there is little evidence of the second.8 nal on MRI, and are mostly attributed to neu- Secondly, seizures are more common with rocysticercosis on the basis of resolution or cal- multiple lesions,24 and leucocyte chemotaxis is cification over months with conservative impaired in patients with multiple neurocyst- treatment (antiepileptic drugs). Tuberculosis is icercosis lesions.25 Multiple lesions are much the primary diVerential diagnosis, but pyogenic less common in India than in Latin American abscess, fungal infection, vasculitis, and neo- countries.26 Preliminary association of epilepsy plasms can account for similar appearances.7 in neurocysticercosis with HLA type I has been Criteria for diVerentiating cysticerci and soli- reported in India.27 HLA-DR polymorphisms tary tuberculosis lesions have been proposed by have been demonstrated in various infections Rajshekar et al.38 In their histologically estab- including leishmaniasis, onchocerciasis, filaria- lished series, intracranial hypertension and sis, hepatitis, and malaria, whereas polymor- progressive neurological deficit were not seen J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.137 on 1 February 2000. Downloaded from Neurocysticercosis and epilepsy in developing countries 139

with neurocysticercosis; all neurocysticercosis tomatic, and on CT appears as a rounded, lesions were less than 20 mm in size, mostly hypodense area, or with CSF-like signal on regular in outline, and not associated with MRI. Both MRI and CT can show the midline shift. presence of an eccentric mural nodule (the invaginated scolex), an appearance, when mul- Diagnosis tiple, which is pathognomic of neurocysticerco- Neuroimaging is essential to the diagnosis of sis (starry night eVect). As the cyst degenerates, neurocysticercosis (see fig 1 and fig 2) Brain it goes through a transitional stage, with diVuse MRI is superior for showing intraventricular or hypodense appearance and irregular border on subarachnoid cysts, and for showing inflamma- CT, enhancing with contrast. On MRI T2 tion around a cyst,39 whereas CT is better for images, these show as low signal areas. Finally showing the calcification of inactive lesions. when the cyst dies, it may disappear or end up There may be single or multiple cysts in diVer- as an inactive calcified nodule of homogenous ent pathological stages. Carpio has proposed a high density on CT, or low intensity on proton classification system that corresponds to the weighted MRI. viability of the parasite: active, transitional, and Standard enzyme linked immunosorbent inactive.7 In the active stage, the cyst is asymp- assay (ELISA) techniques have disappointing

Figure 1 Postcontrast CT of a patient with seizures and intracranial hypertension syndrome, who received albendazole treatment. Left: multiple active cysts with the scolex in their interior (vesicular phase) and calciﬁcations. Right: 16 months after treatment more cysts appeared, and some of them increased in size. http://jnnp.bmj.com/ on September 28, 2021 by guest. Protected copyright.

Figure 2 Brain MRI of the same patient of ﬁg 1 (7 months after last CT), who received additional treatment using praziquantel. Left: T2 weighted MRI shows multiple cysts. Right: gadolinium enhanced T1 weighted MRI shows cortical active cysts on parietal lobes and multiple transitional cysts disseminated in both hemispheres. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.137 on 1 February 2000. Downloaded from 140 Pal, Carpio, Sander

sensitivity and specificity in routine clinical or Community treatment and prevention epidemiological use.40 41 False negative serology Eradication of cysticercosis should be possible can result because of immune tolerance, by removing it from either pig or human hosts, inactive disease, or localised antibody produc- or both. Reform of animal husbandry tech- tion in the CSF. False positive serology can niques, meat inspection procedures, and ad- result from past infection with T solium or cross equate cooking of pork are diYcult approaches reactivity with other helminth species. Newer and of limited relevance in developing coun- enzyme linked immunoelectrotransfer blot tries, where pigs are free roaming, or raised by (EITB) assays on serum or CSF have much subsistence farmers who cannot aVord en- higher claimed sensitivity (95%) and specificity closed pens or proper animal feed, and meat is (100%)42 in Latin American samples. sold oV outside the abattoir system. Vaccina- However, EITB test properties are less good tion of pigs and immunotherapy have been for solitary enhancing CT lesions in India.43 In proposed as measures to break the parasite life Ecuador, more than 50% of patients with neu- cycle. Partial protection against porcine cyst- rocysticercosis diagnosed by CT were negative icercosis has been demonstrated.51–53 Taenicidal by EITB test; conversely, 18% with positive eradication in humans may have adverse eVects EITB had neurocysticercosis parenchymal in people with occult neurocysticercosis, who lesions on CT16 indicating that EITB and neu- may become ill when cysticerci die.54 Studies of roimaging should be used in conjunction mass treatment with praziquantel may produce to increase diagnostic sensitivity. Recently, an early benefit, but longer term evaluation shows antigen detection assay specific for viable no lasting impact. metacestodes in CSF has been created.44 Immunodiagnostic kits are unfortunately diY- Management of epilepsy in the cult to obtain in endemic countries, so the use developing world of the EITB and other special assays may only EPIDEMIOLOGY be restricted to research studies. Epilepsy aVects 5–10/1000 population Del Brutto have proposed international throughout the world, with 75% of cases et al 1 diagnostic criteria for neurocysticercosis using arising in childhood. Neurocysticercosis is a 4512 a combination of clinical, radiological, serologi- major cause in developing countries, but cal, and epidemiological factors.45 These have the relative contribution to all incident cases is been criticised for complexity and diYculties in unknown. Malaria and other parasites are 55–57 clinical and epidemiological application, and a associated with epilepsy. Studies in Ecua- satisfactory consensus is yet to be reached.46 dor, Tanzania, Nigeria, and Pakistan have con- sistently found higher prevalence of epilepsy in rural than in urban areas using identical meth- MANAGEMENT: CASE AND COMMUNITY odologies, further suggesting that infectious Clinical case management diseases may be an important aetiological fac- The presence of viable parenchymal cysts is not tor for epilepsy in the developing world.58–61 usually associated with symptoms. Most pa- New epidemiological associations have been tients with neurocysticercosis present with sei- suggested between low body mass index, previ- zures and in most cases (75%), these are easily ous adverse reproductive experience, recent controlled with antiepileptic monotherapy with infective illness, and risk of epilepsy in eventual remission. The natural history of children.62–64 These interesting associations http://jnnp.bmj.com/ these lesions is for resolution within 2 years.24 47 merit further study in developing countries, as Clinical controversy has centred around the they may disclose new mechanisms of risk and role of cysticidal agents and steroids for risk interaction for focal brain damage in child- epilepsy associated with symptomatic neuro- hood. cysticercosis. Cysticidal agents in current use for neurocysticercosis include praziquantel and IMPACT albendazole. Praziquantel has the disadvantage Everyday conditions for most of the world’s on September 28, 2021 by guest. Protected copyright. that its hepatic metabolism is inducable by poor are radically diVerent from the experience phenobarbital and phenytoin. Cysticidal of the western hospital outpatient. This context therapy seems to hasten radiological resolution must be appreciated when considering the of cysts but can be associated with an impact of epilepsy. The primary concern of exacerbation of neurological symptoms and families is often subsistence, and this shapes there is also the possibility of massive cerebral their attitudes to health and their contact with oedema and death in some patients who have health services. Poor female literacy, often multiple cysts.48 Some authors have advocated associated with underdevelopment, is an im- simultaneous administration of steroids to portant influence on child health, whereas cul- reduce the inflammatory response and exacer- tural and religious beliefs may also impinge on bation of symptoms, but the safety of this has health related attitudes and practices. not been evaluated. There have been claims Few studies have measured the impact of that more patients remain seizure free after epilepsy on family life in developing countries. cysticidal treatment.32 Randomised clinical One population study of childhood epilepsy in trials of cysticidal therapy versus placebo for rural India has shown that epilepsy has perva- neurocysticercosis have not shown any clinical sive eVects on social adjustment, which prob- benefit of cysticidal therapy.49 50 A possible ably do not spontaneously resolve.65 One third increase in risk of hydrocephalus, and in- of children had motor or cognitive impairment creased seizures during treatment, was also and one third had intractable seizures. Only identified in the treated group. 50% went to school compared with over 95% J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.137 on 1 February 2000. Downloaded from Neurocysticercosis and epilepsy in developing countries 141

of their peers. DiYculties of parental adjust- most important and neglected aspect of ment, reported in north American studies,66 intervention. were even more prominent in rural India, with An intractability rate of one third should be marked maternal depression.65 A strong social expected. Ideally, primary facilities need to support network helped with parental have links with specialists for advice and refer- adjustment.65 ral. In some areas epilepsy surgery programmes The economic impact of epilepsy has not maybeoVered, but opportunities for postop- been prospectively studied, but estimates from erative rehabilitation and reintegration should rural India suggest that the social and financial be major considerations before planning sur- cost of hospital attendance is a major disincen- gery. tive to continued treatment.65 India (until The treatment and rehabilitation of people recently) and other countries also have laws with epilepsy is a long term matter, and so it is that discriminate against people with essential that services, once started, continue in epilepsy—for example, with regard to mar- a predictable way. Sustainability of health pro- 67 riage, employment, and insurance. For practi- grammes is associated with strong community cal purposes epilepsy must therefore be consid- ownership, political will, and stable financing. ered a disability and interventions should Services should be cheap to set up and run, and consider all aspects. this can be achieved at marginal cost by integrating epilepsy services alongside existing INTERVENTION medical or welfare programmes, rather than The type of intervention required, as suggested starting a new vertical programme. by studies of impact, and the necessary It is well known that those most in need of resources for service delivery are not widely health provision are often least able to gain available in the developing world. The “treat- access to it. A central tenet of primary health ment gap” refers to the proportion of people services is equity. Our studies of dropout with epilepsy untreated with antiepileptic showed that a significant proportion could not drugs on any given day. The estimates in devel- aVord time away from home or work to attend oping countries range from 80%-94%.3 The clinics, despite wanting to continue follow causes of the treatment gap have not yet been up.65a Hospital based services (in India) have systematically studied but they must be multiple, overlapping, and varying between coun- very high attrition rates and so are ill equipped to provide necessary long term monitoring and tries. They may be considered at infrastruc- 65 tural, health sector, and community levels. For treatment. Flexibility in delivering services is example, some countries may have established therefore important to prevent attrition, ideally health systems but lack finances or reliable to the door if necessary. Services can be drug supplies. In some communities, there may extended through community mental health and community based rehabilitation agencies, be preferred alternatives to antiepileptic drug 70 treatment. Generalisation is diYcult. There are in both state and non-governmental sectors. several themes that should be considered in the A community based approach can fulfil the design of services in developing countries: essential aim of rehabilitation through eVective ascertainment, disability, intractability, sustain- case holding, thus minimising dropout. Low ability, equity, community involvement, and cost is also a major motive for reattendance, financing.68 and therefore precludes expensive investiga- http://jnnp.bmj.com/ The first issue is that of ascertainment. In tions or new generation drugs at first contact. many communities, epilepsy is a stigmatising Community based services still need to be disorder. House to house surveys are thought aVordable by their users. to be an epidemiologically sensitive method of Expertise in dealing with epilepsy has to be finding cases. However, in our experience, they devolved to local health personnel to attain may cause unnecessary distress to families and wide coverage. In many countries, epilepsy is the community. They are an expensive method, not covered in the medical undergraduate cur- on September 28, 2021 by guest. Protected copyright. and sensitivity can be as low as 60% because of riculum, and most general practitioners are not concealment.69 The use of key informants, or familiar with routine management. Training is leading members of the community, to identify required at all levels, and systems of monitoring people with epilepsy, has several distinct and evaluation designed for local use. advantages. These include the opportunity to The use of phenobarbital as first line agent explain the aims of the service, finding out local remains very controversial among clinicians. priorities, and working with the community to Although the most widely available antiepilep- overcome social barriers to integration. Strong tic drug in the world, and eVective against community involvement is also a key element many seizure types, its use has been discour- to ensuring sustainability. aged in some quarters because of concern A third of people with epilepsy have physical about excessive side eVects in children. How- or cognitive diYculties. Whether or not sei- ever, a recent clinical trial has established that zures can be controlled, people with epilepsy phenobarbital is indeed acceptable as a first need to resume as normal a life as possible. line antiepileptic drug for children in India,71 This requires a holistic assessment and formu- and this is supported by a population study lation of an action plan with the community. which refutes the notion that it is often used as This is especially important for children’s a drug of misuse or for suicides among adults.72 development. This kind of intervention can In many parts of the world, the supply of anti- only be planned and executed at a local level. epileptic drug is unreliable, and the choice may The disability aspect of epilepsy is perhaps the be between phenobarbital or nothing.73 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.2.137 on 1 February 2000. Downloaded from 142 Pal, Carpio, Sander

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