**Epilepsy Secondary to Parasitic Zoonoses of the Brain**

### Humberto Foyaca-Sibat

*Walter Sisulu University, Nelson Mandela Academic Hospital, Division of Neurology Mthatha, South Africa* 

#### **1. Introduction**

304 Novel Aspects on Epilepsy

[36] James A. Talbot, Russell Sheldrick, Helen Caswell, Susan Duncan. Sexual function in men with epilepsy:How important is testosterone? *Neurology*. 2008;70:1346–1352. [37] Crawford PM. Managing epilepsy in women of childbearing age. *Drug Saf.*

[38] Crawford P. Best practice guidelines for the management of women with epilepsy.

[39] Gerhard Luef. Female issues in epilepsy: A critical review. *Epilepsy and Behavior*.

[40] Isojarvi JI, Laatkainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. *N Engl J Med*. 1993; 329:1383-8. [41] Sapna Cheravalloor Sukumaran, P. Sankara Sarma, Sanjeev V. Thomas. Polytherapy

[42] Wallace H, Shorvon S, Tallis R. Age-specific incidence and prevalence rates of treated

[43] Isojarvi J. Disorders of reproduction in patients with epilepsy: antiepileptic drug related

[44] Sabers A. Pharmacokinetic interaction s between contraceptives and antiepileptic drugs.

[45] Bergen D, Daugherty S, Eckenfels E. Reduction of sexual activities in females taking

[46] Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador KJ, Hopp J, Ting TY,

[48] Akinsulore A, Adewuya A. Psychosocial aspects of epilepsy in Nigeria: a review. *Afr J* 

[49] Kubota H. Social support for people with epilepsy. *Brain Nerv*e. 2011 Apr; 63(4):401-409. [50] Schachter SC. Quality of life for patients with epilepsy is determined by more than seizure control: the role of psychosocial factors. *Expert Rev Neurother.* 2006 Jan;6(1):111-8. [51] Fraser RT, Johnson EK, Miller JW, Temkin N, Barber J, Caylor L, Ciechanowski P,

Chaytor N. Managing epilepsy well: self-management needs assessment. *Epilepsy* 

et al. Practice parameter update: management issues for women with epilepsy- focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. *Neurology.* 2009 Jul 14;73(2):142-9. [47] Gerhard Luef. Female issues in epilepsy: A critical review. *Epilepsy and Behavior*.

of women with epilepsy. *Lancet.* 1998; 352:1970 –1973.

antiepileptic drugs. *Psychopathology*. 1992; 25:1-4,

*Psychiatry (Johannesburg)*. 2010 Nov; 13(5):351-6.

increases the risk of infertility in women with epilepsy. *Neurology*. 2010;75:1351–1355.

epilepsy in an unselected population of 2,052,922 and age-specific fertility rates

2009;32(4):293-307.

2009;15:78-82.

*Epilepsia.* 2005; 46 Suppl 9:117-24.

mechanisms. *Seizure*. 2008; 17:111-9.

*Seizure*. 2008; 17:141-50.

2009;15:78-82.

*Behav*. 2011 Feb;20(2):291-8.

In spite of natural disaster like the one we are seeing today in Japan (March 20, 2011) where thousand of peoples died due to earthquake and tsunami and some food are contaminated by radioactivity , and other disasters caused by human beings by different modalities of war like the one we are seeing today at the North of Africa plus different modalities of terrorism, destruction of their environment and so forth; world population continues to grow and there has been ever increasing need to develop and maintain food products with a high protein content (particularly livestock and fish) under intensive farming situations, which is inevitably leading to a greater spread of animal diseases and their transmission to humans (McCarthy & Moore 2000; Keiser & Utzinger 2005).

Improved diagnosis and/or recognition of neglected human infections can account for some diseases apparently emerging or re-emerging in recent times (e.g. Human fascioliasis). Climate change has also been suggested as a cause for disease spread and is a concern for the future (McCarthy & Moore 2000); thousand of wild or domestic animals are becoming sick and birds that usually migrate from one continent to another one they don't do it today. It will bring serious consequences to humans being by the increment of the number of infectious disease is transmitted from animals to humans (known by zoonotic diseases). Zoonotic infectious agents are among the most prevalent on earth and are thought to be responsible for more than 60 per cent of all human infections and 75 per cent of emerging human infectious diseases (Cunningham 2005). The success and widespread epidemiology of these infections can be attributed to a range of human factors including social and dietary changes as well as an increased mobility of the human population (McCarthy & Moore 2000; Vorou *et al*. 2007).

Some zoonotic diseases are grouped as neglected tropical diseases (NTD) which are uncommonly recognized or diagnosed in developed countries; are less well understood than more common infections due to a of lack of research interest and/or insufficient funding; and, lastly, remain mysterious or unknown to health care providers because of minimal or no instruction regarding the diseases during medical students training. However, certain food-borne trematode infections in particular remain "neglected" NTD, according to the World Health Organization. These include clonorchiasis (Chinese liver fluke disease), fascioliasis (sheep liver fluke disease), opisthorchiasis (fish liver fluke disease), and paragonimiasis (lung fluke disease). These diseases most often significantly

Epilepsy Secondary to Parasitic Zoonoses of the Brain 307

when it arises from an infection depend on the nature of the infectious illness, its duration, and the type and extent of damage to the brain but in general antisezures and antiepileptic treatment follow the same pattern describe for epilepsy secondary to neurocysticercosis(NC). We recommend to readers to consult our book about " Treatment

Human infections caused by parasitic helminths are of particular importance given the relatively recent acknowledgement of a number of species as important human pathogens (McCarthy & Moore 2000*;* Mas-Coma et al*.* 2005*;* Garcia et al*.* 2007*).* The main aim of this chapter is to review all information related to parasitic zoonoses of the brain causing epilepsy based on our personal experience and the medical literature and the way forward

Around the world the three major components of climate change already evident and escalating in magnitude and significance are; 1) warming; 2) altered patterns of precipitation; and 3) an increased incidence of extreme climatic events. For the structure and function of ecosystems, the impacts of climate change vary with place and with time, and among the key outcomes are shifting boundaries for many components and processes within the systems. Among these components are pathogens and infectious diseases, including those caused by helminth, arthropod and protozoan parasites in people, domestic

From viral zoonotic infections, rabies keeps the leadership in mortality rate. The word "rabies" is derived from a Latin word which means "madness" or "rage" – the very characteristic of people with this disease. A person with this illness usually dies of fatal encephalitis. This disease is caused by the bullet shaped rhabdovirus which is commonly called the rabies virus. The virus is transmitted to a human being when he or she is bitten by an infected animal, usually with dogs. There are reports which claim that even the saliva of those infected animals could cause rabies. Rabies virus from saliva could enter skin scratches and the eyelids. In fact, aerosols of bat secretions in caves have caused rabies to some researchers. Workers who have macerated infected tissues in the laboratory for analysis have acquired the virus and developed the disease; probably aerosols from the macerated tissue entered the workers' mouth, nose, or eye linings. (Sace, 2009) Rabies presents about 30 days after contact with a rabid animal. A nonspecific prodrome of fever, headache, sore throat, and abdominal pain progresses to an agitated, hallucinatory delirium followed by coma and death. Seizures occur in about 10% of cases (Goldstein & Harden, 2002) and rabies vaccine therapy has been

Avian influenza viruses do not typically replicate efficiently in humans, indicating direct transmission of avian influenza virus to humans is unlikely. However, since 1997, several cases of human infections with different subtypes (H5N1, H7N7, and H9N2) of avian influenza viruses have been identified and raised the pandemic potential of avian influenza virus in humans. A better understanding of the biological and genetic basis of host restriction of influenza viruses is a critical factor in determining whether the introduction of

excluded as antiseizures treatment many years ago (Inkeman et al., 1938)

approach to epilepsy"

**1.1 Zoonotic diseases** 

**1.1.1 Rabies** 

**1.1.2 Avian influenza** 

of toxocariasis (Robinson, 2009).

animals, and wildlife (Polley, 2010)

affect large numbers of poverty-stricken individuals, generally in resource-limited regions, and receive very little interest from funding or government agencies. As these diseases have complex life cycles and are rarely encountered in the developed world, they receive little attention in the education of physicians, which furthers their enigmatic status.(Tolan, 2011)

For human, domestic animal and wildlife health, key effects of directional climate change include the risk of the altered occurrence of infectious diseases. Many parasite zoonoses have high potential for vulnerability to the new climate, in part because their free-living lifecycle stages and ectothermic hosts are directly exposed to climatic conditions. For these zoonoses, climate change can shift boundaries for ecosystem components and processes integral to parasite transmission and persistence, and these shifts can impact host health. The vulnerable boundaries include those for spatial distributions, host-parasite assemblages, demographic rates, life-cycle phenologies, associations within ecosystems, virulence, and patterns of infection and disease (Polley & Thomson, 2009)

Zoonotic infections of humans are caused by a wide variety of agents including viruses (e.g. avian influenza and rabies), bacteria (e.g. brucellosis and salmonellosis), parasites (e.g. leishmaniasis, schistosomiasis, neurocysticercosis and toxocariasis) and others 'unconventional' agents such as prions (e.g. Bovine spongiform encephalopathy and its variant: Creutzfeldt–Jakob disease). As we previously reported (Foyaca-Sibat et al., 2010), the infectious agent may be transmitted in a variety of ways, as can be seen in Table 1


Table 1. Some zoonotic infections and its way of transmission

A seizure complication of zoonotic infections can consist of a single seizure or can go on to become chronic epilepsy. Seizures can arise as an acute, sub-acute, or long- term consequence of an infectious states. Seizures are temporary abnormal electro-physiologic phenomena of the brain, resulting in abnormal synchronization of electrical neuronal activity. They can manifest as an alteration in mental state, tonic, clonic or tonic-clonic movements, and various other psychic symptoms (such as déja vu, jamais vu, etc.).

A seizure can last from a few seconds to more than 20 minutes like: status epilepticus, a continuous seizure that will not stop without intervention and patients does not regain their normal level of consciousness between the attacks.

Sometimes, a seizure can also be as subtle as marching numbness of a part of the body, a brief loss of memory, sparkling of flashes, sensing an unpleasant odour, a strange epigastric sensation, a sensation of fear, levitation, laryngeal constriction, peribucal paresthesiae and dysphagia (last four seen in insular seizures).Therefore seizures are typically classified as motor, sensory, autonomic, emotional or cognitive. The type of epileptic complication and when it arises from an infection depend on the nature of the infectious illness, its duration, and the type and extent of damage to the brain but in general antisezures and antiepileptic treatment follow the same pattern describe for epilepsy secondary to neurocysticercosis(NC). We recommend to readers to consult our book about " Treatment approach to epilepsy"

Human infections caused by parasitic helminths are of particular importance given the relatively recent acknowledgement of a number of species as important human pathogens (McCarthy & Moore 2000*;* Mas-Coma et al*.* 2005*;* Garcia et al*.* 2007*).* The main aim of this chapter is to review all information related to parasitic zoonoses of the brain causing epilepsy based on our personal experience and the medical literature and the way forward of toxocariasis (Robinson, 2009).

#### **1.1 Zoonotic diseases**

306 Novel Aspects on Epilepsy

affect large numbers of poverty-stricken individuals, generally in resource-limited regions, and receive very little interest from funding or government agencies. As these diseases have complex life cycles and are rarely encountered in the developed world, they receive little attention in the education of physicians, which furthers their enigmatic status.(Tolan, 2011) For human, domestic animal and wildlife health, key effects of directional climate change include the risk of the altered occurrence of infectious diseases. Many parasite zoonoses have high potential for vulnerability to the new climate, in part because their free-living lifecycle stages and ectothermic hosts are directly exposed to climatic conditions. For these zoonoses, climate change can shift boundaries for ecosystem components and processes integral to parasite transmission and persistence, and these shifts can impact host health. The vulnerable boundaries include those for spatial distributions, host-parasite assemblages, demographic rates, life-cycle phenologies, associations within ecosystems, virulence, and

Zoonotic infections of humans are caused by a wide variety of agents including viruses (e.g. avian influenza and rabies), bacteria (e.g. brucellosis and salmonellosis), parasites (e.g. leishmaniasis, schistosomiasis, neurocysticercosis and toxocariasis) and others 'unconventional' agents such as prions (e.g. Bovine spongiform encephalopathy and its variant: Creutzfeldt–Jakob disease). As we previously reported (Foyaca-Sibat et al., 2010), the infectious agent may be transmitted in a variety of ways, as can be seen in Table 1

patterns of infection and disease (Polley & Thomson, 2009)

or products (Q Fever & Anthrax)

Trichinosis, Taeniosis-*T solium)*

normal level of consciousness between the attacks.

Table 1. Some zoonotic infections and its way of transmission

Others ways

Direct contact with animal flesh (Tularemia)

Drinking of cows or goats milk ((TB and Brucellosis)

Eating of insufficiently cooked infected flesh (Anthrax,

Inhalation of dust particles contaminated by animal excreta

A bite by insect vectors (Plague, Scrub Typhus and Equine Encephalomyelitis) or a bite from a diseased animal (Rabies)

movements, and various other psychic symptoms (such as déja vu, jamais vu, etc.).

A seizure complication of zoonotic infections can consist of a single seizure or can go on to become chronic epilepsy. Seizures can arise as an acute, sub-acute, or long- term consequence of an infectious states. Seizures are temporary abnormal electro-physiologic phenomena of the brain, resulting in abnormal synchronization of electrical neuronal activity. They can manifest as an alteration in mental state, tonic, clonic or tonic-clonic

A seizure can last from a few seconds to more than 20 minutes like: status epilepticus, a continuous seizure that will not stop without intervention and patients does not regain their

Sometimes, a seizure can also be as subtle as marching numbness of a part of the body, a brief loss of memory, sparkling of flashes, sensing an unpleasant odour, a strange epigastric sensation, a sensation of fear, levitation, laryngeal constriction, peribucal paresthesiae and dysphagia (last four seen in insular seizures).Therefore seizures are typically classified as motor, sensory, autonomic, emotional or cognitive. The type of epileptic complication and Around the world the three major components of climate change already evident and escalating in magnitude and significance are; 1) warming; 2) altered patterns of precipitation; and 3) an increased incidence of extreme climatic events. For the structure and function of ecosystems, the impacts of climate change vary with place and with time, and among the key outcomes are shifting boundaries for many components and processes within the systems. Among these components are pathogens and infectious diseases, including those caused by helminth, arthropod and protozoan parasites in people, domestic animals, and wildlife (Polley, 2010)

#### **1.1.1 Rabies**

From viral zoonotic infections, rabies keeps the leadership in mortality rate. The word "rabies" is derived from a Latin word which means "madness" or "rage" – the very characteristic of people with this disease. A person with this illness usually dies of fatal encephalitis. This disease is caused by the bullet shaped rhabdovirus which is commonly called the rabies virus. The virus is transmitted to a human being when he or she is bitten by an infected animal, usually with dogs. There are reports which claim that even the saliva of those infected animals could cause rabies. Rabies virus from saliva could enter skin scratches and the eyelids. In fact, aerosols of bat secretions in caves have caused rabies to some researchers. Workers who have macerated infected tissues in the laboratory for analysis have acquired the virus and developed the disease; probably aerosols from the macerated tissue entered the workers' mouth, nose, or eye linings. (Sace, 2009) Rabies presents about 30 days after contact with a rabid animal. A nonspecific prodrome of fever, headache, sore throat, and abdominal pain progresses to an agitated, hallucinatory delirium followed by coma and death. Seizures occur in about 10% of cases (Goldstein & Harden, 2002) and rabies vaccine therapy has been excluded as antiseizures treatment many years ago (Inkeman et al., 1938)

#### **1.1.2 Avian influenza**

Avian influenza viruses do not typically replicate efficiently in humans, indicating direct transmission of avian influenza virus to humans is unlikely. However, since 1997, several cases of human infections with different subtypes (H5N1, H7N7, and H9N2) of avian influenza viruses have been identified and raised the pandemic potential of avian influenza virus in humans. A better understanding of the biological and genetic basis of host restriction of influenza viruses is a critical factor in determining whether the introduction of

Epilepsy Secondary to Parasitic Zoonoses of the Brain 309

psychiatric disorders and should suspected in individuals with pyrexia of unknown origin so that early detection and treatment could prevent long-term sequelae such as focal neurologic deficits, hydrocephalus, transient ischemic attack, intracerebral vasculopathy granulomas, seizures, paralysis of sixth and seventh cranial nerves and psychiatric illness and seizures responding well to first AED, doxycycline, rifampin, and ceftriaxone (Obiako et

Early detection and treatment is the only predictor of a favourable outcome of neurobrucellosis, but there is no standardized treatment protocol. Neurobrucellosis may be difficult to diagnose especially in patients with atypical syndromes. Therefore, it should be suspected in patients who experience inexplicable neurological and psychiatric problems and the CSF must be adequately analysed. It should be kept in mind and to be included in differential diagnosis for any patient presenting central or peripheral neurological manifestations especially in the endemic zones. (Guenifi et al., 2010 Tekin-Koruk et al., 2010)

*Salmonella* serotypes *typhi, typhimurium*, and *enteritidis* occurred most frequently. The precipitating factors of these infections included meningitis, trauma, and intracranial hematoma. Focal intracranial infections are unusual manifestations of salmonellosis. In one hundred years only 43 such infections have been reported in the world literature. Brain abscess occurred more often in adults; in contrast, subdural empyema presented more often in children and fever, signs and symptoms of increased intracranial pressure, change in mental status, seizures, and focal neurologic deficits were the commonest clinical

Zoonotic parasites are separated into four categories, such as direct-zoonotic, meta-zoonotic, cyclo-zoonotic , and sapro-zoonotic parasites. Direct-zoonotic parasites, such as, *C. parvum*, *T. gondii,* and *P. carinii* have been prevalent in endemic areas and places where the prevalence of HIV/AIDS is increasing. Meta-zoonotic parasites can infect humans from invertebrate intermediate hosts, such as, *Babesia bovis, Babesia divergens, Plasmodium schwetzi, Clonorchis sinensis, Fasciola hepatica, Paragonimus westermani, Diphyllobothrium latum, Dipylidium caninum, Dirofilaria immitis, Brugia malayi, Onchocerca gibsoni,*and *Polymorphus boschadis* and some of them like *C. sinensis, H. nocens,M. yokogawai, P. westermanii,* and sparganum (*Spirometra* spp.), remain prevalent among people who consume raw freshwater fish or crabs in endemic areas. Cyclo-zoonotic parasites have vertebrate intermediate hosts, such as, *Taenia multiceps, Echinococcus granulosus, Taenia saginata, Taenia solium,* sparganum (*Spirometra* spp.), *Porrocaecum crassum, Contracaecum osculatum, Capillaria hepatica,* and *Gnathostoma spinigerum.* Cyclo-zoonotic parasites, such as, *T. saginata, T. solium,* and *T. asiatica,* are still prevalent in peoples who consumed raw cattle or pig meat and there is a tendency to increase and spread all over the world due to globalization. Sapro-zoonotic parasites mean that parasites can infect humans from soil or water, such as, *Ancylostoma caninum, Ascaris suum, Capillaria hepatica, Strongyloides stercoralis, Trichuris vulpis,* and

Many of carnivorous parasites are zoonotic parasites because dogs and cats have lived with humans for a long period of time. On the other hand, anthroponotic parasites mean that the

al., 2010; Asuman et al., 2010; Türel et al., 2010 ).

**1.1.5 Neurosalmonellosis** 

features.(Rodriguez et al,. 1986)

**2. Zoonotic parasites** 

*Hypoderma bovis.* 

a novel influenza virus into the human population will result in a pandemic. (Lee & Saif, 2009) Epilepsy is not a known complication in this group and its presence suggests reviewing the clinical diagnosis.

#### **1.1.3 Slow virus infections**

Slow virus infections are also known as prion diseases. Prions are proteinaceous infectious particles (PrPs). The brain pathology of prion diseases consists of a vacuolar (spongiform) degeneration of the neuropil, cortical neurons, and subcortical gray matter with neuronal loss and gliosis. Early diagnosis is difficult, in part because prions do not have nucleic acids, making conventional nucleic acid–based viral detection systems ineffective. PrPs also elude detection by not producing a humoral immune response (Johnson & Gibbs, 1998) As part of this group is: bovine spongiform encephalopathy (BSE) which is thought to have originated in Great Britain where it was first observed (April 1985) and was officially diagnosed. Control measures have since reduced incidence of the disease, and currently fewer than 100 new cases are reported per week. It occurs in cattle between two and eight years old and is always fatal.

A transmissible spongiform encephalopathy of adult cattle, transmitted by feed containing protein in the form of meat and bone meal derived from infected animals. Affected adults may have seizures as part of the serious neurological illness. Renkawek et al (1992), hypothesized that a defect of Na+/K+ -ATPase of the astrocytes could be the most common pathogenetic factor for the congenital convulsive status and for the spongy state.

Cellular prion protein (PrPc) plays an essential role in maintaining neurotransmitter homeostasis in the central nervous system. This discovery has been made possible by the observation that both a deficiency and an excess of the protein have a considerable effect on this homeostasis. Surprisingly, in both cases, the central nervous excitability threshold is altered to such an extent that an epileptic seizure may result. Thanks to this discovery, we now have more tools at our disposal that can help us to deepen our basic understanding of epilepsy. (IBEC, 2009)

As under normal conditions the protein is found in adequate concentrations, it was expected that greater amounts of PrPc would provide greater protection against seizures. Surprisingly, however, the study showed that this is not the case. With an excessive amount of the protein, the level of excitability of the central nervous system is increased even more than in the absence of PrPc, due to the fact that both the excitatory and inhibitory mechanisms are altered. Such alterations further increase the possibility of suffering severe epileptic seizures. The protein, when present at adequate concentrations, is essential for maintaining neurotransmitter homeostasis or equilibrium in the central nervous system. The researchers of IBEC who participated in the study are currently involved in developing a description of the possible differences in the expression and modification of the cellular prion protein in epileptic patients. (IBEC, 2009)

#### **1.1.4 Neurobrucellosis**

Brucellosis is a major ubiquitous zoonosis transmitted from livestock to humans. It is a public health problem in developing countries. The estimated mean incidence of neurobrucellosis is 4% with clinical manifestations that are variable and often multi-focal in the same patient. (Guenifi et al., 2010)

Neurobrucellosis is a rare form of systemic brucellosis, a disease acquired through ingestion of unpasteurized dairy products, it can affect any part of the nervous system and can mimic any neurological disease which may manifest as stroke, encephalitis, meningitis, or psychiatric disorders and should suspected in individuals with pyrexia of unknown origin so that early detection and treatment could prevent long-term sequelae such as focal neurologic deficits, hydrocephalus, transient ischemic attack, intracerebral vasculopathy granulomas, seizures, paralysis of sixth and seventh cranial nerves and psychiatric illness and seizures responding well to first AED, doxycycline, rifampin, and ceftriaxone (Obiako et al., 2010; Asuman et al., 2010; Türel et al., 2010 ).

Early detection and treatment is the only predictor of a favourable outcome of neurobrucellosis, but there is no standardized treatment protocol. Neurobrucellosis may be difficult to diagnose especially in patients with atypical syndromes. Therefore, it should be suspected in patients who experience inexplicable neurological and psychiatric problems and the CSF must be adequately analysed. It should be kept in mind and to be included in differential diagnosis for any patient presenting central or peripheral neurological manifestations especially in the endemic zones. (Guenifi et al., 2010 Tekin-Koruk et al., 2010)
