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Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, O'Connor S, Lemon SM, et al., editors. The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary. Washington (DC): National Academies Press (US); 2004.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary.

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INFECTIOUS AGENTS AND EPILEPSY

, M.D., Ph.D., M.R.C.P.

Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, and WHO Collaborative Centre for Research and Training in Neurosciences, London, United Kingdom

Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of the cortical physiology may lead to seizures and different conditions may express themselves solely by recurrent seizures and thus be labelled “epilepsy.” The semiology of seizures and the consequences for the sufferers are, however, similar and therefore epilepsy could be better described as a symptom complex or a condition rather than a disease on its own right (Sander, 2003).

Throughout the world, epilepsy is the most common serious neurological condition (Bergen, 1998). In high-income economies its incidence is around 50 per 100,000/year (range 40 to 70 per 100,000/year) and socioeconomically deprived people are at higher risk (Heaney et al., 2002). In low income countries incidence is generally quoted as between 100 and 190 cases per 100,000/year (Sander, 2003). Most large-scale studies have reported prevalence rates for active epilepsy between 4 and 10/1,000; many of these studies, particularly in low-income countries, have reported different rates for urban and rural areas, usually with higher rates in the latter (Sander and Shorvon, 1996). No clear explanation has been advanced for these differences. It is estimated that worldwide there are at least 50 million sufferers from epilepsy, the great majority of whom are in low-income countries (Scott et al., 2001). The overall prognosis for seizure control is quite good if epilepsy is treated. Epilepsy does, however, carry an increased mortality, particularly if untreated (Cockerell et al., 1994; Sander, 2003).

The range of risk factors for the development of epilepsy varies with age and geographic location (Sander, 2003). Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system and tumours may occur at any age and may lead to the development of epilepsy. Infections of the central nervous system have one of the highest risks for causing epilepsy (Hauser and Annegers, 1991; Annegers et al., 1996; Bittencourt et al., 1999). For instance, over three-quarters of the survivors of cerebral abscess develop severe epilepsy and survivors of viral encephalitis have an odds ratio of 16.2 for the development of epilepsy (Annegers et al., 1996). In the elderly, cerebrovascular disease is the commonest risk factor and accounts for over half the cases of epilepsy in this age group (Sander, 2003). The presence of a family history of epilepsy seems to enhance other risk factors and this suggests that the aetiology of epilepsy is multifactorial, with genetic predisposition playing a role (Johnson and Sander, 2001). It might be difficult, however, to say whether individuals share predisposition or are exposed to the same environmental sources. In epilepsy due to infections, it could also be argued that the interaction between infective agents and social, genetic, and environmental factors determines the extent of the risk (Bittencourt et al., 1999).

Endemic infections such as malaria, neurocysticercosis and paragonomiasis are associated with epilepsy in certain environments particularly in low-income countries (Sander, 2003). Neurocysticercosis, for instance, is the commonest cause of newly diagnosed epilepsy in large areas of the tropical belt, and malaria is the commonest cause of fever in febrile convulsions in endemic areas (Medina et al., 1990; Waruiru et al., 1996; Carpio, 2002). These infections are probably responsible for the higher incidence of epilepsy in low-income economies and this makes epilepsy one of the world's most preventable non-communicable conditions (Commission on Tropical Diseases of the International League Against Epilepsy, 1994; Bittencourt et al., 1999; Bergen and Silberberg, 2002). This paper briefly reviews central nervous infections and infestations that may lead to chronic epilepsy. The contribution of social and geographic factors and the putative pathophysiology are discussed in general terms and the natural history of the commonest infections is reviewed. Seizures that occur during the acute phase of an infection are termed acute symptomatic seizures and do not constitute epilepsy even if repeated, and are not covered here.

Social and Geographical Factors

The fact that the incidence of epilepsy seems to be higher in low-income countries is often attributed to social problems in these countries (Commission on Tropical Diseases of the International League Against Epilepsy, 1994; Sander and Shorvon, 1996; Bittencourt et al., 1999). Indeed, poor sanitation and malnutrition are risk factors for infections and these are common in low-income countries. In the past, malaria, schistosomiasis and neurocysticercosis were problems in parts of the high-income countries but improvements in social conditions and basic sanitation have resolved this. In most low-income countries there are inadequate health delivery systems, which results in late or no diagnosis and treatment for infective conditions that would carry a low risk if prompt action were instituted. As a result, neurological disabilities, including seizures, may be higher in survivors of CNS infection in low-income countries than in more developed economies (Bittencourt et al., 1999).

The tropics provide the ideal environment for a number of organisms that may occasionally invade the CNS; most of them would not thrive in colder or temperate climates. Other factors may also play a role: malaria, highly prevalent in endemic coastal areas and lowlands, is non-existent at higher altitudes. Some fungi are restricted to small ecological niches. Other agents exhibit seasonal variation in their infectability. The interaction between infective organism and social, geographic and environmental factors determine the extent of infection (Bittencourt et al., 1999). There is, however, no objective information on the relative distribution of risk factors or attributable risk for the epilepsies in the community in most of the world and this is an area that requires urgent research (Sander and Shorvon, 1996).

Pathophysiology

Seizures in the aftermath of CNS infectious diseases are usually partial or focal in nature, i.e., they start in the epileptic focus, a localised area of (usually damaged) cortex (Bittencourt et al., 1999). The route of entry of infective agents to the CNS may be arterial—(through the blood-brain barrier or the choroid plexus), by passive venous transport through the spinal plexuses, by direct invasion through trauma or from cranial sinuses. Viruses may enter the CNS by the haematogenous route or via neuronal routes (Eeg-Olofsson, 2003). The infectious agent needs to reach and damage the cerebral cortex for seizures to develop, and this may be achieved through various mechanisms (Bittencourt et al., 1999). Fungal infections are often dependent on the immunological status of the person, and are therefore more prevalent in immunocompromised subjects. Cortical damage will not invariably lead to epilepsy but is a major risk factor affected by the location, severity and individual predisposition, which is likely to be genetically determined (Sander and Shorvon, 1996). There may be months, or even years, between the insult and the onset of epilepsy and the reasons for this are not well understood. The existence of critical modulators, which can turn damaged cortical tissue into an epileptic focus, has been postulated (Walker et al., 2002).

Arteritis, ischaemia and infarction are the main pathological outcome of severe viral or bacterial CNS disease and if this affects the cortical ribbon it may be the substrate for an epileptic focus (Bittencourt et al., 1999). Cerebral malaria may lead to capillary thrombosis, which is probably caused by intravascular aggregates of parasitised erythrocytes in cerebral tissues, particularly in white matter (Molyneux, 2000). Astroglial reaction results in the formation of granulomata and infarcts affecting the cortical ribbon and leading to seizures. Most other protozoan and helminthic infestations of the CNS lead to formation of granulomata, which, if located in cortical tissues, may lead to partial seizures (Bittencourt et al., 1999).

Viral Infections

Among the many viruses that have been associated with the development of encephalitis are arboviruses, coxsackie, rubella, measles, herpes simplex, flavivirus (Japanese encephalitis), and cytomegalovirus. Patients may present with seizures during the acute encephalitic process but more often develop neurological disability, including epilepsy, as a long-term complication (Eeg-Olofsson, 2003). Herpes simplex virus is the commonest and most severe viral encephalitis in immunocompetent subjects and epilepsy as its aftermath is particularly devastating (Marks et al., 1992).

HIV infections may be complicated by a subacute cortical and subcortical encephalopathy with progressive dementia, myoclunus and tonic-clonic seizures (Modi et al., 2000). Partial seizures in patients with HIV are usually the result of secondary infections with cytomegalovirus, cryptococcus or toxoplasmosis.

Bacterial Infections

Bacterial infections of the CNS usually involve the meninges or cerebral parenchyma and present as either meningitis or cerebral abscess. Acute bacterial meningitis is usually caused by H. influenzae, N. meningitidis, S. pneumoniae or streptococcus infections. Although it may occur in any age group, children are the group more likely to contract bacterial meningitis. Five to ten percent of survivors of acute bacterial meningitis will develop chronic epilepsy and this is usually associated with learning deficits and other neurological disabilities (Marks et al., 1992; Bittencourt et al., 1999; Oostenbrink et al., 2002).

Cerebral abscesses and intracranial empyemas are usually associated with a clear port of entry like sinusitis, otitis media, dental abscess or cardiac valvopathies (Bittencourt et al., 1999). In the majority of cases anaerobic organisms are involved. Epilepsy in the aftermath of a cortical abscess is the rule, and it is usually highly refractory to treatment and often associated with other neurological disabilities. Tuberculosis of the central nervous system may involve the meninges and cerebral parenchyma and is associated with neurological disabilities in a large number of survivors (Bittencourt et al., 1999). Many of these will have partial epilepsy that is often refractory to treatment.

Fungal Infections

Fungal infections of the CNS are rare in immunocompetent subjects, particularly in high-income economies. The fungi are acquired by inhalation of spores that lodge initially in the lungs or paranasal sinuses and may seed to any organ, although with certain topographic preferences depending on the organism (Bittencourt et al., 1999). C. neoformans, C. immitis, H. capsulatum, C. albicans, A. fumigatus and A. flavus, and Mucoraceae sp. are the fungal species most likely to be involved and all of them may eventually provoke seizures.

Protozoal Infections

Plasmodium falciparum and Toxoplasma gondii are associated with epilepsy, although the former is by far the bigger culprit. Cerebral malaria may develop abruptly or subacutely, during systemic uncomplicated, as well as during severe, falciparum malaria and may have severe consequences. Survivors are at high risk of neurological disabilities including epilepsy (Waruiru et al., 1996; Molyneux, 2000; Versteeg et al., 2003). It is likely that this is responsible for the higher prevalence of epilepsy in endemic area. Intrauterine T. gondii infections are associated with a severe congenital encephalopathy with epilepsy as one of the symptoms. It may also cause seizures in immunocompromised patients. Recently, a suggestion has been made that it may be responsible for many cases of cryptogenic partial epilepsy but this has not been fully elucidated (Stommel et al., 2001).

Helminthic Infestations

A number of helminthic infestations can occasionally reach the CNS and lead to seizures. Taenia solium is probably the commonest of these helminthic infestations but Paragonomiasis westermani, Echinoccocus granulosis, Spargonomiasis mansonoides and Schistosoma japonicum and S. mansoni have also been implicated (Pal et al., 2000; Bittencourt et al., 1999). Recently, suggestions have been made that Toxocara canis could be a major culprit for the higher prevalence of epilepsy in low-income economies (Nicoletti et al., 2002).

Taeniasis and cysticercosis are caused by Taenia solium (Carpio, 2002). They are closely related to poor sanitation, and the coexistence of humans and pigs is a major factor. Humans are the final host for Taenia solium while hogs are the intermediate host. Eating uncooked pork contaminated with taenia cysts will lead to intestinal taeniasis. When humans, instead of pigs, ingest taenia eggs they may become the intermediate host and this may lead to neurocysticercosis. In pigs the cysts tend to lodge in subcutaneous and muscle tissues but in humans there is an attraction for the brain, particularly well irrigated areas like the cortex and the choroidal plexus, Here infestation may lead to epilepsy and other neurological symptoms. Indeed, neurological problems resulting from neurocysticercosis are very common in vast areas of South America, West Africa and Asia (Medina et al., 1990; Bergen, 1998; Sander, 2003). Neurocysticercosis is probably the most preventable form of epilepsy worldwide.

Cerebral hydatidosis is caused by Echinococcus granulosus and occurs in sheep-raising areas. It is acquired mainly by eating food contaminated with dog feces. Epilepsy is a rare complication of this condition (Bittencourt et al., 1999).

Paragonimiasis is a parasitic disease caused by Paragonimiasis westermanii and is common in some endemic areas in the Far East. Like neurocysticercosis, it may be associated with epilepsy when humans become the intermediate host (usually a fish). It is acquired by eating undercooked or raw crab or crayfish (Bittencourt et al., 1999).

A recent report has suggested the possibility of Toxocara canis being the culprit for partial epilepsy in low-income countries (Nicoletti et al., 2002). An odds ratio of 18.2 for the development of late onset epilepsy has been reported in association with positive serology for Toxocara canis. This same study in Bolivia found an odds ratio for positive serology for Taenia solium of 3.6. This is interesting as, over 30 years ago, Woodruff claimed that dog ownership was a major risk factor for epilepsy, but this was never taken forward (Woodruff et al., 1966). Further studies are urgently needed to clarify this issue.

Conclusion

Much of the existing evidence indicates that epilepsy resulting from infections is a major cause of neurological disability in low-income countries. Indeed, it is probably responsible for the higher incidence of epilepsy in these areas and is the commonest preventable cause of epilepsy worldwide. Improvement in basic sanitation is likely to be crucial to decrease the global burden of epilepsy. Much remains to be done in this area. Studies are urgently needed to elucidate the whole spectrum of attributable risk factors for epilepsy. More research is also needed to understand the molecular basis of all epilepsies particularly the ones caused by infectious agents.

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Copyright © 2004, National Academy of Sciences.
Bookshelf ID: NBK83677

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