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Abstract

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Acute symptomatic versus unprovoked seizures
  5. Status epilepticus in developing versus developed countries
  6. Method
  7. Results
  8. Conclusion
  9. References

Central nervous system (CNS) infections are the main cause of seizures and acquired epilepsy in the developing world. Geographical variations determine the common causes in a particular region. Acute seizures are common in severe meningitis, viral encephalitis, malaria, and neurocysticercosis, and in most cases are associated with increased mortality and morbidity, including subsequent epilepsy. Neuronal excitability secondary to proinflammatory signals induced by CNS infections are an important common mechanism for the generation of seizures, in addition to various other specific mechanisms. Newer insights into the neurobiology of these infections and the associated epilepsy could help in developing neuroprotective interventions. Management issues include prompt treatment of acute seizures and the underlying CNS infection, correction of associated predisposing factors, and decisions regarding the appropriate choice and duration of antiepileptic therapy. Strategies for the prevention of epilepsy in CNS infections such as early anti-infective and anti-inflammatory therapy need scientific exploration. Prevention of CNS infections is the only definitive way forward to reduce the burden of epilepsy in developing countries.


Abbreviations
AED

Antiepileptic drug

HIV

Human immunodeficiency virus

NCC

Neurocysticercosis

TBM

Tubercular meningitis

What this paper adds

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Acute symptomatic versus unprovoked seizures
  5. Status epilepticus in developing versus developed countries
  6. Method
  7. Results
  8. Conclusion
  9. References
  •  It gives an overview of the common infections associated with seizures and epilepsy and their geographic distribution.
  •  The mechanism of the generation of seizures in CNS infections is examined.
  •  Specific issues in the management of seizures are addressed.

Of the estimated 50 million people with epilepsy worldwide, 40 million live in developing countries (World Health Organization [WHO])1 and about half of these are children. Reliable epidemiological data are scarce because of a lack of registration systems in developing countries. Moreover, methodological differences among studies make it difficult to compare accurately the differences in incidence, prevalence, aetiology, and prognosis of epilepsy between developing and developed countries. Nevertheless, several studies have shown that the incidence of epilepsy is much higher in developing countries (114–190 per 100 000)2 than in developed countries (24–53 per 100 000).3 On the other hand, the average age-adjusted prevalence of epilepsy (8.5 per 1000 people) in developing countries is similar to that in developed countries.4 This is probably related to the higher mortality associated with epilepsy in developing countries. Although the rates of idiopathic/cryptogenic epilepsy (60–70%) and symptomatic epilepsy (30–40%) are similar in developing and developed countries,2 the causes of symptomatic epilepsy are different. Infections of the central nervous system (CNS), whether acute or chronic–recurrent, are the most important cause of seizures and acquired epilepsy in the developing world, where the incidence of CNS infections is very high. Even among developing countries there is a significant geographic variation in the types of infections: malaria and human immunodeficiency virus (HIV) are much more common in Africa, whereas neurocysticercosis and Japanese encephalitis are widespread in most parts of Asia (Table I). Awareness of these variations is helpful for clinicians to determine causality in different regions. However, with increasing international travel and globalization, there are no fixed boundaries for any infectious disease. An infected individual travelling from an area where the disease is endemic may have clinical manifestations in another country. Moreover, infections are also being transmitted across countries through migration of carriers, transmission of vectors, and alterations in pathogenicity of organisms. An awareness of these disorders is, therefore, important not only for clinicians in endemic regions, but also for those living in other countries.

Table I.   Predominant geographic distribution of some common central nervous system infections
InfectionGeographical distributionComment
MalariaSub-Saharan Africa, South East Asia, Latin AmericaPlasmodium falciparum dominant in Africa, Plasmodium vivax outside Africa
NeurocysticercosisLatin America, India, China, South East Asia, some parts of AfricaExtraparenchymal forms much more common in Latin America than in India/Asia
Japanese encephalitisIndia, China, Japan, South East Asia, eastern Mediterranean region, Papua New Guinea, AustraliaVirus continually spreading across geographical regions
Human immunodeficiency virus (HIV)Sub-Saharan Africa, Central Asia, Latin America, Eastern EuropeVariations within countries also
TuberculosisIndia, China, South East Asia, sub-Saharan Africa, Latin AmericaCoinfection with HIV increasing

Acute symptomatic versus unprovoked seizures

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Acute symptomatic versus unprovoked seizures
  5. Status epilepticus in developing versus developed countries
  6. Method
  7. Results
  8. Conclusion
  9. References

Seizures associated with CNS infections can be either acute symptomatic or unprovoked. Acute symptomatic seizures occur in close temporal relationship with an acute infection generally within the first 7 days, sometimes even later. They subside once the acute insult is over and usually do not recur; however, there is often an increased risk of subsequent epilepsy. Acute symptomatic seizures occur in up to 31% of all CNS infections, and independently predict mortality with an odds ratio of 17.6.5 Unprovoked seizures occur beyond the estimated time for the occurrence of acute symptomatic seizures and have a propensity to recur. The reported risk of unprovoked seizures in population-based cohorts of survivors of CNS infections from developed countries is between 6.8% and 8.3%;6 it is much higher in developing countries: CNS infections were found to be the cause of epilepsy in 26% of affected individuals in sub-Saharan Africa.7

Status epilepticus in developing versus developed countries

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Acute symptomatic versus unprovoked seizures
  5. Status epilepticus in developing versus developed countries
  6. Method
  7. Results
  8. Conclusion
  9. References

Prolonged seizures and convulsive status epilepticus associated with infections are much more common in developing countries than in developed countries.8,9 In a study from Kenya, 75% of prolonged seizures were associated with a febrile illness.10 The rate of convulsive status epilepticus in Kenya was found to be two to five times that in a similar study in the UK.11 In another recent study from rural Kenya, 36% of people with active convulsive epilepsy had experienced status epilepticus. In 26% this was precipitated by fever. Additionally, a history of status epilepticus was significantly higher in children (55.9%) than in adults (18%; p<0.001).12

The aim of this review is to familiarize clinicians with the common infectious causes of seizures and epilepsy in various developing countries, the mechanisms of seizure generation in CNS infections, and specific issues in the management of such seizures. An idea of the burden of disease has been included to provide a perspective on the magnitude of the problem and associated challenges in order to foster new research on developing measures to control/prevent these infections. The focus is mainly on children, although much of what is discussed is also applicable to adults.

Method

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Acute symptomatic versus unprovoked seizures
  5. Status epilepticus in developing versus developed countries
  6. Method
  7. Results
  8. Conclusion
  9. References

Search strategy

An extensive literature search was conducted using the PubMed Entrez and MeSH databases with various combinations of the following terms: ‘infections’, ‘central nervous system infections’, ‘bacterial meningitis’, ‘CNS tuberculosis’, ‘tubercular meningitis’, ‘viral encephalitis’, ‘Japanese encephalitis’, ‘herpes simplex encephalitis’, ‘HIV’, ‘emerging viral infections’, ‘brain abscess’, ‘parasitic infections’, ‘malaria’, ‘helminthic infections’, ‘neurocysticercosis’, ‘toxocariasis’, ‘schiztosomiasis’, ‘sparganosis’, AND ‘seizures’, ‘epilepsy’, ‘acute symptomatic seizures’, ‘status epilepticus’, ‘provoked seizures’, ‘unprovoked seizures’, AND ‘aetiology’, ‘mechanisms’, ‘pathophysiology’, ‘neurobiology’, ‘prognosis’, ‘outcome’, ‘epidemiology’, ‘statistics’, ‘developing countries’, ‘resource poor countries’, etc. For some specific conditions an advanced search in PubMed was undertaken. Articles from links of the references obtained and cross-references from the bibliography of some of the articles were also reviewed. In addition, information was obtained from the WHO home page (health topic, data, and statistics) including the WHO report 2010, the WHO malaria report 2009, and the global HIV/acquired immunodeficiency syndrome online database. The Cochrane database was searched using the terms mentioned above. Other search engines were also used. From the several hundreds of abstracts, 200 articles were examined based on a detailed review of the abstracts. Abstracts that pertained exclusively to adults and/or were relevant only to developed countries were mostly excluded as they were outside the scope of this review. Those most relevant and representative studies of seizures and epilepsy associated with CNS infections in children and in developing countries were chosen.

Results

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Acute symptomatic versus unprovoked seizures
  5. Status epilepticus in developing versus developed countries
  6. Method
  7. Results
  8. Conclusion
  9. References

Bacterial meningitis

Bacterial meningitis is a common cause of seizures both in developed and in developing countries. However, the incidence of bacterial meningitis in developing countries is much higher than in developed countries.13 The three common aetiological agents worldwide are meningococcus, pneumococcus, and Haemophilus influenzae B (Hib). However, the proportion of meningitis caused by these organisms has changed in developed and developing countries. Universal immunization has led to a dramatic decrease in the rates of Hib and pneumococcal meningitis in developed countries, yet this has not happened in several developing countries and meningococcal epidemics are particularly common in Africa. Meningitis is essentially a disease of children, although it may occur in adults. Acute symptomatic seizures occur in about one-third of hospitalized individuals with bacterial meningitis usually within 24 to 48 hours of admission.14,15 Late seizures (after 72h) are often related to the development of complications (such as subdural collection, infarct, cerebritis) and are associated with an increased risk of death or major neurological deficits.16 In a study from India, 83% of children who had seizures after hospitalization had major neurological sequelae.16 Seizures are usually focal, with or without secondary generalization; generalized and myoclonic seizures may also be seen. Meningitis is a common cause of convulsive status epilepticus with fever in children in both developed17 and developing countries.18,19 It must, therefore, be considered in any child presenting with acute seizures with fever, lethargy, irritability, and meningeal signs (meningeal signs may be absent in one-third of affected individuals). A degree of coma, low glucose levels and high protein levels in the cerebrospinal fluid (CSF),20 abnormal neuroimaging, and pneumococcal meningitis21,22 are associated with an increased risk of acute seizures.

In a meta-analysis of 45 studies, the mean probability of unprovoked seizures after bacterial meningitis was 4.2%.21 A survey of children aged 5 years in the UK reported unprovoked seizures in 7.3% of those who developed meningitis in infancy compared with 2.7% of those who did not.23 Survivors of neonatal meningitis had a 5.4% risk of developing unprovoked seizures compared with 1.7% of those who did not develop neonatal meningitis.24 In a population-based study from the USA, the 20-year risk of developing unprovoked seizures was 13% in those with acute seizures and only 2% in those who did not experience acute seizures.6 There is a lack of well-conducted population-based studies from developing countries. Nevertheless, the risk of unprovoked seizures is higher in developing countries. In a systematic review of 132 studies involving 18 183 survivors, unprovoked seizures were reported in 12.6% of cases; the all-cause risk of a major sequela (including seizures) was found to be twice as high in African (pooled risk estimate 25.1% [95% confidence interval, CI 18.9–32.0%]) and South East Asian regions (21.6% [95% CI 13.1–31.5%]) as in European regions (9.4% [95% CI 7.0–12.3%]; overall I2=89.5; p<0.001).25 Risk factors for late unprovoked seizures include persistent neurological and electroencephalographic (EEG) abnormalities, low CSF glucose levels at presentation, and presence of acute seizures.16,20 Focal suppuration, such as brain abscesses or subdural or epidural empyemas that occur either as complications of meningitis or otherwise, is often associated with acute seizures and subsequent epilepsy. Seizures are generally focal; these conditions should be considered in the appropriate clinical setting.

Central nervous system tuberculosis

About one-third of the world’s population is infected with tuberculosis; 5 to 10% develop the clinical disease.26 In 2009 there were an estimated 9.4 million new cases and 1.7 million deaths (including 380 000 people with HIV), most of which occurred in developing countries; the highest number of deaths occurred in African countries.26 Individuals with HIV who are infected with tuberculosis are much more likely to develop the active disease than those who are HIV negative.26 Tubercular meningitis (TBM) is a very common chronic CNS infection in the developing world; although it can occur at any age, it affects mainly young children, often those who are less than 5 years of age. Seizures occur in over half the cases,27 generally during the late stages. Seizures are usually focal and are often associated with vasculitis and infarcts; a large proportion of survivors have subsequent neurodeficits and epilepsy.

In areas where TBM is endemic, it should be suspected in any child presenting with seizures associated with persistent low-grade fever, lethargy, and anorexia, particularly when associated with focal neurological deficits. Tuberculomas are often associated with focal seizures; they may occur with or without TBM, and on neuroimaging appear as ring-enhancing lesions, generally with thick irregular margins and surrounding oedema.

Viral encephalitis

Viral encephalitis is a common cause of seizures in both developed and developing countries, particularly in children. More than 100 viruses can produce encephalitis; however, because of the non-specific nature of the illness and lack of diagnostic facilities, aetiology remains undetected in most cases, even in developed countries.28 The situation is worse in developing countries. Diagnostic issues and aetiological case definitions for acute encephalitis by acute infectious agents have been detailed.29

Viral encephalitis can occur in epidemics or can be sporadic. Most epidemics are because of arboviruses (mosquito borne) and have a characteristic geographic distribution, both between and within countries. In the USA, the common viral encephalitides include eastern equine, western equine, St Crosse, St Louis, and West Nile. In the UK, Europe, and countries of the former Soviet Union, tick-borne encephalitis is common. In Asia the most common encephalitis is Japanese; others include West Nile, chikungunya, dengue, Murray Valley, and Nipah in South East Asia. The most common forms in Africa are West Nile, Rift Valley, dengue, and Crimean–Congo haemorrhagic fever, and in Australia Japanese, Murray Valley, dengue, and Kunjan dominate.

Japanese encephalitis is the single largest cause of acute epidemic encephalitis worldwide and is responsible for about 30 000 to 50 000 cases and 10 000 to 15 000 deaths each year.30 It is transmitted by the culex mosquito, with water birds serving as natural reservoirs and pigs as amplifying hosts. It affects mainly children and young adults, particularly in rural areas. Seizures are reported in 50% to 80 of cases31 and are much more frequent in children than in adults. The seizures are generalized or focal with secondary generalization, single or multiple, and may present as status epilepticus. Seizures are more frequent in cases with a low score on the Glasgow Coma Scale, raised intracranial pressure, and cortical and thalamic lesions on neuroimaging32 (Fig. 1). Almost one-third of children have extrapyramidal signs. Late-onset epilepsy is less common in Japanese encephalitis, possibly because of predominant involvement of deep grey matter with sparing of cortices.

image

Figure 1.  Japanese encephalitis – magnetic resonance image showing thalamic and cortical involvement.

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Herpes simplex virus type 1 is the most common cause of sporadic encephalitis in developed and developing countries, and presents with seizures in more than 50% of individuals. The propensity of herpes simplex virus type 1 to involve the mesial temporal lobe including the hippocampus explains the high frequency of seizures (Fig. 2). Seizures are often focal, and periodic lateralized epileptiform discharges on EEGs are common in adults. Children can have atypical features, generalized convulsions, and absence of periodic lateralized epileptiform discharges.33 Behaviour disturbances are common in older children and adults. Herpes simplex virus type 1 also produces latent and persistent infection with late relapses and reactivation. Late unprovoked seizures and epilepsy occur in 42 to 60% of individuals and are often intractable.33

image

Figure 2.  Herpes encephalitis – magnetic resonance image showing mesial temporal involvement.

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Emerging viral central nervous system infections

Emerging viral diseases are those that have infected new hosts, spread into new geographical regions, altered characteristics of their pathogenesis, or are caused by agents not previously recognized as pathogens.34 Approximately 80% of these are zoonotic; of the zoonotic ones, 40% are vector borne. Severe neurological symptoms including encephalitis are associated with about 39%.34 These emerging infections can occur in developed and developing countries. It is predicted that they are most likely to occur in lower latitude developing countries, particularly in tropical Africa, Latin America, and Asia. This subject has been extensively reviewed.35

In the context of encephalitis and seizures, viruses that have spread across geographical regions and caused large epidemics include the West Nile virus, which spread from Uganda to the USA in 1999, the Japanese encephalitis virus, which spread from Japan to South East Asia, the enterovirus 71, which spread in South East Asia and Japan, and the Toscana virus, which spread from Italy to the rest of Europe. West Nile virus encephalitis occurs mainly in older people, whereas that caused by enterovirus 71 occurs predominantly in children; the neurovirulence of enterovirus is determined by its genotypes. The human herpes virus 6 is emerging as an important cause of acute limbic encephalitis in both immunocompromised and immunocompetent children and adults. Primary human herpes virus 6 infection has been commonly associated with febrile seizures and febrile status epilepticus. A potential pathophysiological role of human herpes virus 6B reactivation is being explored in temporal lobe epilepsy and mesial temporal sclerosis.36

Outbreaks of chikungunya virus have been reported from India, South East Asia, and sub-Saharan Africa. An epidemic on Réunion in the Indian Ocean occurred recently (2005–2006); neurological manifestations were a common cause (∼24%) of hospitalization. In a series of 30 children with neurological manifestations, 40% had encephalitis and 33% had febrile seizures.37

Nipah virus is an emergent paramyxovirus reported first from Malaysia and Singapore and then from Bangladesh and India. It causes severe febrile encephalitides with a high mortality rate of 40 to 70%.38 Seizures are reported in about one-quarter of affected individuals. Encephalitis can have a late onset in 3% of affected individuals and relapses in 8% of survivors. Individuals with relapsing encephalitis have more frequent seizures (50%) and focal neurological signs (42%) than those with acute encephalitis.39,40

Other viruses

Dengue virus causes large epidemics in many tropical countries including South East Asia, India, and the Caribbean islands. Neurological complications, although uncommon, include encephalitis, meningitis, and seizures.41,42 During an outbreak dengue virus should be suspected in a child presenting with features of viral encephalitis. Influenza B is also known to be associated with febrile seizures and encephalitis. Instances of encephalitis with seizures were reported during the epidemics of Chandipura virus in India, but the causality is being questioned.43

Varicella, and measles, mumps, and rubella are all known to be associated with encephalitis and may occur along with, or soon after, other clinical manifestations of the disease. Subacute sclerosing panencephalitis secondary to measles continues to be a problem in several developing countries and is suspected in individuals with progressive myoclonic, and at times generalized, seizures with neurodegeneration. Postinfectious immune-mediated encephalitis is also quite common in developing countries.29

The risk of postencephalitic epilepsy increases 22-fold in individuals with acute seizures compared with 10-fold in those without acute seizures.6 Most unprovoked seizures occur within the first 5 years following an episode of encephalitis, but the risk of unprovoked seizures continues for 20 years. Children with status epilepticus, slow background activity, and multifocal spike discharges on EEG, at presentation, and those with herpes simplex virus type 1 encephalitis have an increased risk of developing intractable epilepsy.44 The distribution and nature of pathological lesions in the brain in various encephalitides determines the risk of late epilepsy.

Human immunodeficiency virus

With an increasing burden of HIV infection, particularly in developing countries, this has become an important cause of acute seizures. According to WHO estimates, in 2008 the total number of people with HIV was 33.4 million, and 2.7 million were newly infected – of those, 71% were in sub-Saharan Africa.45 In South Africa, between 11% and 12% of the entire population is infected with HIV type 1, and up to 60% of all childhood hospital admissions are related to HIV infection;46 many have associated tuberculosis. About 20 to 60% of all children infected with HIV type 1 develop significant neurological manifestations,47 predominantly encephalopathy. Seizures are estimated to occur in 2 to 20% of individuals with seropositive HIV.48 They are less common in children than in adults.49 However, in a series of 40 children with neurological involvement, 39.6% had seizures.50 Seizures in HIV can result from primary cerebral HIV infection or secondary causes. The proportion of new-onset seizures due to primary cerebral HIV infection is higher in children. Although seizures generally occur in the late phase of disease, they may occur any time; generalized seizures are more common than focal seizures. In one study, status epilepticus was reported by 8 to 14% of individuals with HIV who developed new-onset seizures.51 In a series of 42 individuals with HIV presenting with status epilepticus, about half had previous seizures,52 suggesting that inadequate treatment might have led to status epilepticus. In adults, most seizures are secondary to opportunistic CNS infections such as toxoplasmosis, cryptococcal meningitis, and tuberculomas, and some are secondary to non-infective causes such as neoplastic lesions, particularly lymphoma and progressive multifocal leukoencephalopathy; these are less common in children.49 Drugs used for the treatment of HIV or for associated infections and metabolic derangements may also cause seizures.

Parasites

Malaria

Almost half the world’s population is at risk of malaria.53 In 2002 there were an estimated 515 million clinical attacks of Plasmodium falciparum malaria, with over 1 million deaths.54 Malaria occurs in many tropical countries, but is highly endemic in sub-Saharan Africa; in 2008, of an estimated 863 000 malaria deaths, 89% occurred in Africa.53 In Africa, P. falciparum malaria is the most common form, whereas in Asia, Plasmodium vivax is the most common type. Although P. vivax causes seizures in children, P. falciparum is responsible for almost all the neurological complications of malaria, including cerebral malaria.55 Severe malaria is associated with severe physiological derangements, including metabolic acidosis and hypoglycaemia, multiple seizures, and abnormal posturing. Cerebral malaria is the most serious manifestation of malaria and is defined by the WHO as an unarousable coma in an individual with P. falciparum malaria in whom other causes of encephalopathy have been excluded.56 Annually almost 600 000 children under 5 years of age suffer from cerebral malaria in sub-Saharan Africa.57

In endemic areas, nearly half the children hospitalized with P. falciparum malaria have neurological features58 and malaria is the most common cause of seizures. Seizures occur not only in cerebral malaria but also in uncomplicated malaria. The frequency of seizures varies from 22% in South East Asia to 80% in Africa.59 Seizures generally occur during the acute phase of malaria but may also occur in the later part of the acute febrile illness. In almost half the cases, seizures occur in the afebrile state. Seizures are often focal, with or without secondary generalization, but they may be generalized or even subtle or purely electrographic seizures. They are usually repetitive and prolonged. Status epilepticus is seen in almost one-third of children; often there is associated raised intracranial pressure, with evidence of brain swelling on neuroimaging in individuals with cerebral malaria.55 Deep coma, hypoglycaemia, severe metabolic acidosis, shock, repeated seizures,60 and an EEG that shows a slow and asymmetrical background or burst suppression are associated with a poor prognosis.61

The exact incidence of post-malaria epilepsy has not been systematically studied, but it is seen in about 10% of affected individuals.60 In a study of 487 children including 152 with cerebral malaria, the prevalence of epilepsy was significantly higher in children with prior cerebral malaria (odds ratio 4.4; 95% CI 1.4–13.7; p=0.01) compared with those presumably unexposed to cerebral malaria.62 In another study, the age-adjusted relative risk for developing epilepsy after exposure to cerebral malaria was 14.3 (95% CI 1.6–132.0; p=0.01), suggesting a strong association between cerebral malaria and epilepsy.63 The temporal association between cerebral malaria and epilepsy is a strong pointer towards causality. In a study that did not specifically address epilepsy, younger age, deep coma, multiple seizures during the acute phase, and possibly a genetic predisposition were associated with an increased risk of neurological sequelae.64

The diagnosis of P. falciparum malaria should be considered in any individual who has a febrile illness with neurological symptoms, including seizures, and has passed through a malaria-endemic area in the past 3 months.55

Helminths

About 2.2 billion people are infected with helminths, mostly in developing countries.65 CNS manifestations, including seizures, are seen in some.

Neurocysticercosis

Neurocysticercosis (NCC) caused by infection of the CNS by Taenia solium larvae is the most common cause of acquired epilepsy in many developing countries and accounts for over 20 million cases and 50 000 deaths each year.66 It is endemic in many parts of Asia, Latin America, and Mexico but is also seen in the developed world. NCC occurs when humans ingest food contaminated by T. solium eggs. The eggs hatch in the intestine and the larvae migrate to the CNS and other organs, where they form cysts. In the brain parenchyma the cysts pass through four phases. In the initial vesicular stage, viable larvae are contained within a clear fluid and affected individuals are asymptomatic; this stage can continue for prolonged periods of time, after which the larvae degenerate and cause an inflammatory reaction (colloidal stage). The cyst then contracts and the scolex is transformed into coarse mineralized granules forming the granular nodular stage. Finally, the granulation tissue is replaced by collagenous structures and calcification giving rise to the nodular calcified stage. Although seizures are most often associated with the degenerating stage, they can occur at any stage, including calcification. The most common presentation of NCC is with seizures, more so in children than adults. In a series of 500 children with NCC, 94.8% had seizures at presentation.67 The seizures occur in otherwise typical, afebrile individuals and are usually focal and brief (<5min); however, status epilepticus is seen in about one-third of affected individuals.67 Single small contrast-enhancing computed tomography lesions with an eccentric nodule representing the scolex with perilesional oedema are commonly seen on neuroimaging (Fig. 3). Some individuals have multiple lesions; numerous lesions in different stages constitute the ‘starry sky’ appearance characteristic of multiple NCCs. Extraparenchymal NCC involving the subarachnoid space, meninges, and ventricles is more often seen in Latin America than in Asia.

image

Figure 3.  Neurocysticercosis – computed tomography image showing single small enhancing lesion with scolex.

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It is estimated that in communities where NCC is endemic about one-third of seizures are associated with NCC.68 However, estimates based on seropositivity are not very reliable as a number of individuals who are seropositive for NCC do not have a brain parasite, and a number of individuals with brain parasites are seronegative.

Other helminthic causes

Other uncommon helminthic causes of seizures and epilepsy include toxocariasis, in which the brain becomes infected with T. canis and T. catis by eating food that is contaminated with eggs passed by infected dogs and cats. The clinical presentation includes meningo-encephalitis and seizures; neuroimaging shows multiple subcortical lesions.

Schistosomiasis is seen commonly in Egypt, Latin America, and South East Asia. CNS involvement is uncommon but is reported with Schistosoma japonicum; it presents with seizures and/or focal neurological deficits. Neuroimaging shows chronic granulomas, which may be haemorrhagic.

Sparganosis is caused by a migrating plerocercoid tapeworm larva or the genus Spirometra. It is seen mainly in South East Asia and is generally acquired by drinking water contaminated with infected cyclops. Cerebral sparganosis is rare; the common presentation is with headaches, seizures, and focal neurological deficits. Neuroimaging shows single or multiple enhancing granulomas that may change location owing to migration of larvae.

Systematic epidemiological studies to establish causality between most helminthic infections and epilepsy are lacking.69

Mechanism(s) of seizures and epilepsy in CNS infections

The mechanisms of the generation of acute symptomatic seizures vary with the type of infection and are often multifactorial. The triggering of the inflammatory cascade with release of inflammatory cytokines appears to be a common underlying factor in most CNS infections and has been well studied in meningitis and encephalitis. Both N-methyl-d-aspartic receptor and glutamate-mediated mechanisms are involved in cytokine-induced neuronal hyperexcitability. Cytokines also activate astrocytes and microglia; these activated astrocytes and microglia further increase the production of cytokines, thus creating a vicious circle. In viral infections, the host innate response involves CD4+ and CD8+ T-cells, which may affect the neurons through secretion of interferon-gamma. HIV causes neuronal injury not by direct infection, but by synaptodendritic alterations termed ‘beading’70 and through immune-related toxins via complex interactions among macrophages, microglia, monocytes, and astrocytes. Macrophage activation by the HIV type 1 envelope protein gp120 releases neurotoxins that affect the glutamate system, leading to activation of voltage-dependent calcium channels and modulation of N-methyl-d-aspartic signals. Elevated β2-microglobulin and neopterin levels in CSF have been found in individuals with HIV with seizures that do not have any identifiable cause.71 Some envelope glycoprotein variants (N283) are more frequently isolated from infected brains than from other organs.52 Secondary causes such as opportunistic infections, lymphomas, drugs, and metabolic disturbances may also cause seizures in individuals with HIV.

Helminths induce both humoral and cellular immune responses, causing increases in cytokines and activation of eosinophils and mast cells. In addition to the Th1 response, the Th2 response initiates formation of granulomas. In animal models, extracts from early granulomas but not the older granulomas have been found to be epileptogenic, indicating that the early inflammatory response secondary to degeneration of the parasite is responsible for epileptogenesis.72 Most parasites including NCC produce focal lesions with perilesional inflammatory reaction, both of which may trigger seizures. However, not all individuals with degenerating cysts have seizures, and seizures can occur with any stage of the cyst. The site of the lesion in the brain also determines the propensity of cysts to cause seizures.

In malaria, several factors have been implicated; blockage of cerebral microcirculation by sequestrated and aggregated parasitized erythrocytes possibly leads to a critical reduction in the supply of metabolic substrates to the brain, which is compounded by associated anaemia and hypoglycaemia.55 The parasites release glycophosphatidylinositol, which binds to pattern recognition receptors and triggers an inflammatory reaction with release of cytokines, including interleukins and tumour necrosis factor, that enhance the cytoadherence of infected erythrocytes to the endothelium through upregulation of the endothelial intercellular adhesion molecules.73 Transfer of P. falciparum antigens from infected erythrocytes that adhere to endothelial cells activates the immune system and causes opening of the intercellular junctions, leading to perivascular oedema.74 However, there is no transendothelial migration of leukocytes and no perivascular infiltrates. Hence, both the parasites and the inflammation remain intravascular.75 Release of nitric oxide, which causes changes in blood flow, decreased glutamate uptake, and increased excitotoxicity, as well as of quinolinic acid, which is an N-methyl-d-aspartic receptor agonist and an excitotoxin, has also been implicated. Also, activation of the blood coagulation cascade, platelet-induced clumping of infected erythrocytes, and haem may have additional pathogenic roles.55 Several other factors are being researched, and have been discussed in detail.60

The inflammatory cascade leads to breakdown of the blood–brain barrier with cerebral oedema, raised intracranial pressure, cerebral herniation, and infarction. All of these further contribute to the development of seizures.

Hyperthermia associated with various CNS infections can itself lead to neuronal hyperexcitability. Other predisposing factors include fluid and electrolyte imbalance and hypoglycaemia; vasculitis, thrombosis, and infarction are predominant mechanisms in individuals with tubercular meningitis and fungal CNS infections, and may also be seen in NCCs. Abscess formation in pyogenic, tubercular, and fungal infections increases the propensity to seizures. Neurotoxins such as quinolinic acid, production of autoantibodies against glutamate and N-methyl-d-aspartate receptors, voltage-gated calcium, and potassium channels, antiphospholipid, anticardiolipin, and antinuclear antibodies are postulated to be other mechanisms responsible for seizures.

The mechanisms of epilepsy following CNS infections are not well established. Structural damage such as cortical necrosis with herpes simplex virus, infarction in meningitis, hypoxic–ischaemic injury in cerebral malaria, and gliosis around calcified NCC may all constitute epileptogenic foci. It is also thought that prolonged stimulation of proinflammatory signals either by chronic inflammation or by seizures themselves may lead to a residual pathological state such as damaged blood–brain barrier, neuronal death, and persistent neuronal hyperexcitability – all of which may contribute to epileptogenesis.76 Perilesional oedema seen in some cases of NCC with seizures and calcified lesions possibly represents a persistent inflammatory response secondary to antigens released from the lesions.77 However, it remains to be established whether these proinflammatory signals are just an epiphenomenon or actually contribute to epileptogenesis.

Management aspects

Acute symptomatic seizures and status epilepticus associated with CNS infections are treated like any other acute seizures. A search for the infectious cause of seizures needs to be performed simultaneously. It is imperative that physicians are aware of endemic as well as epidemic (Table I) and emerging infections in their region so that they can prioritize the investigative approach accordingly. In a febrile child with acute seizures, acute bacterial meningitis should be seriously considered, particularly in the presence of meningeal signs, and a CSF examination should be carried out as soon as possible. In children with marked alteration in sensorium, viral encephalitis is an important consideration and neuroimaging is often helpful in arriving at an aetiological diagnosis, particularly when herpes simplex and Japanese encephalitis are suspected. In sub-Saharan Africa, and other regions where malaria is endemic, malaria must be considered in any febrile child with seizures, and blood films should be obtained to look for malarial parasites. It must, however, be remembered that in endemic areas a child with acute bacterial meningitis may also have malarial parasites in the blood film. In countries where there is high-burden tuberculosis, TBM should be strongly considered in a child with seizures, a history of prolonged low-grade fever, and systemic symptoms, particularly if there are associated neurological deficits. Neuroimaging and CSF examinations should be carried out to confirm the diagnosis. In India and other South Asian countries, NCC needs to be considered in an afebrile, otherwise healthy child with new-onset partial seizures, and neuroimaging is warranted in all such individuals.

Appropriate treatment of the CNS infection and correction of predisposing factors such as fluid and electrolyte imbalance are warranted when present. So too are hypoglycaemia, and management of raised intracranial pressure.

The treatment of post CNS infection epilepsy is similar to other symptomatic epilepsies and the antiepileptic drug (AED) is chosen according to the seizure semiology. Some specific issues that need to be addressed are: (1) What are the interactions between AEDs and anti-infective therapy? (2) Can early treatment of the underlying CNS infection prevent or modify the course of seizures and epilepsy? (3) Are there any other treatment modalities to reduce the incidence of seizures and epilepsy in CNS infections? and (4) What is the optimal duration of AED therapy?

Interaction between AEDs and anti-infective therapy can significantly alter the level of each drug, leading to either decreased efficacy or toxicity. It is, therefore, important for physicians to be aware of such interactions, some of which are listed in Table II. This is of particular importance in individuals with HIV, in whom antiretroviral agents have considerable interactions with AEDs. Some of the newer AEDs, such as levetiracetam and topiramate, which have very few interactions, may be preferred in some instances.

Table II.   Interaction between anti-infective agents and antiepileptic drugs
Meropenem[DOWNWARDS ARROW] Valproate
Choloramphenicol[UPWARDS ARROW] Phenytoin, phenobarbital
Phenobarbital[DOWNWARDS ARROW] Choloramphenicol
Phenytoin[UPWARDS ARROW] Choloramphenicol
Erythromycin[UPWARDS ARROW] Carbamazepine, valproate
Phenytoin, carbamazepine[DOWNWARDS ARROW] Praziquantal, albendazole
Isoniazid[UPWARDS ARROW] Phenytoin, carbamazepine, valproate, ethosuximide
Rifampicin[DOWNWARDS ARROW] Phenytoin, carbamazepine, valproate, ethosuximide, lamotrigine
Phenytoin, carbamazepine, phenobarbital[DOWNWARDS ARROW] Antiretroviral agents
Valproate[UPWARDS ARROW] Zidovudine
Ritonabir, indinavir[UPWARDS ARROW] Carbamazepine

Since seizures and epilepsy are often associated with severity and complications of the underlying infection, it seems logical that early aggressive therapy could prevent late seizures and epilepsy. However, systematic studies to document this are not available. Early treatment of bacterial meningitis with appropriate antibiotics could reduce complications such as infarction, subdural empyema, or cerebral abscess, and perhaps reduce the incidence of late seizures and epilepsy. Cysticidal therapy for NCC has been shown to enhance the resolution of lesions;78,79 however, improvement in seizure control is less certain. A reduction in secondarily generalized seizures was reported with antiparasitic treatment.80 A recent meta-analysis confirmed the beneficial effect of cysticidal therapy in resolution of lesions and also found that 14% of treated versus 32% of untreated instances had seizures on follow-up (p<0.001).81 Hence, cysticidal therapy seems to improve long-term seizure outcome. Early antimalarial treatment reduces mortality, but its impact on epilepsy and other sequelae has not been studied. The prophylactic administration of phenobarbital in cerebral malaria reduces the incidence of seizures but is possibly associated with increased mortality.82

Since seizure generation in most CNS infections is associated with an inflammatory response, the possibility of reducing seizures with the use of anti-inflammatory agents can be hypothesized. Early administration of adjunctive corticosteroids has been shown to reduce mortality, severe hearing loss, and neurological sequelae in cases of Hib and pneumococcal meningitis in developed countries. However, this is not so in developing countries.83 Use of corticosteroids is advocated in TBM as they reduce death and disability.84 However, whether corticosteroids have any role in the reduction of seizures and epilepsy in bacterial or tubercular meningitis has not been specifically studied. In malaria, the adjunctive use of dexamethasone was not found to be of any benefit, and in one trial was associated with increased complications.85 Corticosteroids are used in NCC to reduce perilesional oedema; their role in decreasing seizures in NCC is as yet uncertain.86,87 Other anti-inflammatory agents such as pentoxyfyline and immunomodulatory agents such as intravenous immunoglobulins are being explored.

The duration of antiepileptic therapy has been debated: there are no evidence-based recommendations. In acute bacterial meningitis, early seizures do not require long-term AEDs; however, those occurring late (after 4d) are often associated with an underlying complication and have a propensity for recurrence. AEDs are often continued for a few months in such cases. In HIV, acute seizures have a high propensity for recurrence, hence AEDs are continued for a long period of time. Unprovoked seizures and epilepsy require long-term AEDs. In NCC the conventional practice was to use AEDs for a 2-year seizure-free period. A randomized study did not find any difference in seizure recurrence between those who received AEDs for 1 year versus those who received AEDs for a 2-year seizure-free interval. Seizure recurrence was associated with persistence or calcification of lesion and an abnormal EEG.88 Hence, 1-year AED therapy seems adequate for children in whom the lesions disappear; those with persistent lesions require longer duration of AEDs. The duration of AED therapy depends on several factors and needs to be individualized.

Prognosis

The prognosis of epilepsy is determined by the aetiology, severity, site of infection, and certain host factors. Epilepsy following meningitis and encephalitis is generally well controlled with AEDs; however, there are no prospective studies to determine what proportion of children with post-meningitic or post-encephalitic epilepsy will eventually develop medically intractable epilepsy. Intractable seizures and catastrophic epilepsy following meningoencephalitis have been described.89 Among those with intractable epilepsy, a subset with mesial temporal sclerosis is reported in children who had meningitis before 4 years of age: the vulnerability of the hippocampus in younger children may account for this; surgical outcome is reportedly excellent.89 The response to AEDs and the outcome of malaria-associated epilepsy is largely undetermined.55,59 The outcome of unprovoked seizures in childhood HIV has not been systematically studied. In cases with single-lesion NCC, seizures are often well controlled with a single AED; late seizure recurrences and epilepsy occur in a small percentage (∼11%) of cases and are associated with persistent/calcified lesions and an abnormal EEG,90 those with multiple lesions have multiple seizure recurrences.

Conclusion

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Acute symptomatic versus unprovoked seizures
  5. Status epilepticus in developing versus developed countries
  6. Method
  7. Results
  8. Conclusion
  9. References

Several infections, mostly preventable, cause seizures and epilepsy in developing countries. Awareness of these causes, their geographical distribution, and burden could be helpful to clinicians in formulating differential diagnosis and to health providers in prioritizing resources towards appropriate preventative/control measures. Insight into the mechanisms of seizures and epilepsy in CNS infections could help in evolving innovative neuroprotective interventions. Prevention of CNS infections such as meningitis and encephalitis through immunization and eradication of parasitic infections by increasing public awareness and improving sanitation are the definitive steps towards reducing the burden of epilepsy.

References

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Acute symptomatic versus unprovoked seizures
  5. Status epilepticus in developing versus developed countries
  6. Method
  7. Results
  8. Conclusion
  9. References