Pts.

incident epilepsy.

Author Country/year (reference)

Medina et al México/1990 (11)

Del Brutto et al Ecuador/1991 (43)

Murthy et al India/1999 (48)

Sawhney et al India/1996 (47)

Singh G, et al India/2006 (49)

based studies [3]

endemic for porcine cysticercosis [45], 2.4% were identified as definitive and 11% had lesions highly suggestive of NCC, using CT scan as part of the diagnoses. In another study from Africa, 37% of patients with epilepsy had NCC [46]. In studies from India, in which acute symptomatic seizures were excluded, only 11% (47) cases with epilepsy had NC; conversely, in a study of 572 patients with acute symptomatic seizures 67% had SECTL [48]. Another study was carried out in India [49] to determine the etiologic role of NCC in a hospital-based sample in 1026 patients with epilepsies divided according to the ILAE epidemiological criteria. NCC was diagnosed in imaging studies in 59% of those with acute symptomatic seizures, but only 2.0% with prevalent epilepsy, and none of the cases of

> Case Ascertainment

> > CT scan

CT scan

CT scan

CT scan

prevalent seizures CT scan

The above mentioned studies confirm the necessity to differentiate between acute seizure and recurrent unprovoked seizures (epilepsy). It is likely that most of the patients with NCC have acute symptomatic seizures which do not necessarily evolve into epilepsy. Similarly, it is crucial to determine NCC as etiology of epilepsy in incident cases instead of prevalent ones. These are probably some of the reasons of over diagnosis of epilepsy in some hospital-

Community-based studies in which CT scan was used to diagnose NCC are shown in Table 2. In a study carried out in Ecuador [43], the authors concluded that NCC is associated with one in three cases of epilepsy and was possibly the cause of the excessive proportion of epilepsy in that population. However, only three (8%) of 24 people with epilepsy had "definitive" NCC. Another community survey [44] carried out in Peru showed that seroprevalence (using the enzyme-linked immunoelectrotransfer blot (EITB) assay] was positive in 24.2% (200/825); 15 of 39 individuals with seizures (38.5%) had lesions compatible with NCC on CT scan. The authors concluded that brain CT abnormalities compatible with

100 All seizures,

225 All seizures,

572 Acute seizures

407 Single Sz. Excluded

1026 Single, incident and

**Table 1.** Neurocysticercosis as etiology of epilepsy: Hospital-based studies

Type of study NCC

Prevalent cases 50%

Prevalent cases 40%

Retrospect (SCTEL) 67 %

Prevalent and incident cases

Single Sz Prevalent cases Incident cases

(%)

11 %

59 % 2 % 0 %

There are several studies in the medical literature that have reported an association between epilepsy and NCC based on positive serum antibodies to Taenia solium/cysticercosis [17,50,51]. Unfortunately, the presence of antibodies may indicate only previous exposure to or infection with the parasite, but not necessarily brain infection. This information has created some distortion in the current perception of NCC epidemiology. A systematic review of the literature on the frequency of NCC, diagnosed with neuroimaging, has been published [15]. Overall, 565 articles were retrieved and only 26 had reliable information to estimate the frequency of NCC in various populations worldwide. The authors concluded that the prevalence of NCC worldwide remains unknown; however, the proportion of NCC among persons with epilepsy was very consistent and estimated at 29.6% (95%CI: 23.5%– 36.1%) from 12 studies conducted in Latin America, Sub-Saharan Africa, and Southeast Asia.

## **6. Inconsistencies in the relationship between neurocysticercosis and epilepsy**

There are clinical inconsistencies in the link between epilepsy and NCC. Parasite location may be remote from the apparent epileptogenic region [3]. There is also no correlation between the NCC burden of lesions and the severity of the epilepsy. Patients with severe refractory seizures may have only one calcified lesion; on the other hand, there are patients with multiple cysts or calcifications but no seizures.

EEG has been found to be abnormal in 30-50% of patients with seizures due to NC. It is assumed that EEG findings have poor correlation with symptoms and CT lesions in patients with NCC [52.53]. A positive correlation between CT lesions and localizing or lateralizing

EEG abnormalities has been reported for only 15-30% of patients. Similarly, the correlation between seizure type and EEG abnormalities ranges from around 7% to 20% [53]. Discrepancies between clinical localization based on seizure semiology and location of the lesion on neuroimaging is a not uncommon feature in patients with NC. A non-causal relationship between epilepsy and cysticercosis in some cases might explain these apparent discrepancies [54,55]. Further prospective cohort studies, properly designed to study ictal and interictal EEG abnormalities in patients with seizures, correlated with the different evolutionary stages of the parasite, may clarify the relationship between NCC and epilepsy.

Neurocysticercosis and Epilepsy 299

limited evidence of a modest effect of NCC treatment, since the effects of cysticidal treatment on neuroimaging end points were relatively small (OR <2.2) . A recent Cochrane review [65] of 21 randomized controlled clinical trials of cysticidal therapy concluded that with adults with viable cysts the use of albendazole is associated with a decrease in the

One of the main reasons for which there is a lot of confusion in the medical literature and a supposed controversy regarding the effectiveness of AHD, is that most of the publications report "reduction of the number of lesions" as a valid endpoint to measure effectiveness of the treatment, which is misleading. We should wonder, for example, in the hypothetical event that a person with 10 viable cysts has been administered AHD, whether, as a consequence of the treatment, 8 parasite die (80% reduction of lesion/successful treatment?), but two cysts remain which may provoke seizures or headache: Is this a successful

The appropriate end point to evaluate the effectiveness of AHD could be the disappearance of cysts. Strictly speaking, even in the case that treatment with AHD may kill all parasites in a patient, it is not possible to talk about "cure" because, as we know, most cysts once they die became calcifications, a permanent sequel, which could aggravate seizures long life If we compare those studies in which one of the end points to evaluate effectiveness of AHD is disappearance of cysts (table 3), including the results of the abovementioned meta-analysis, where about 30% to 40% of patients had disappearance of cysts [66-68]. Therefore, there is no controversy; we can affirm that, according to available evidence based medicine, AHD

**8. Risk of seizure recurrence in patients with neurocysticercosis** 

Some authors report that NCC patients with acute symptomatic seizures have a good prognosis in terms of remission of seizures [69-73]; others report that most patients have a high risk of seizure recurrence, and suggest that prognosis improves after antihelminthic treatment. [66]. Prospective cohort studies have determined the risk of seizure recurrence after a first seizure due to NCC is between 17% to 56%, depending on the viability of the parasite. The risk is greater in the transitional forms and it diminishes in the viable or calcified forms [73-76]. Overall, the risk of seizure recurrence involves around one third of

It has also been suggested that seizure control in patients with NCC is improved and that the chance of remaining seizure-free after the withdrawal of antiepileptic drugs is greater after a course of AHD, when compared with seizure control in those in whom the disease is left untreated [66]. However, current reliable information has shown that AHD treatment in patients with seizures due to NCC is not associated with the recurrence of seizures at all

Regarding the duration for which antiseizure medication should be continued following an acute NCC episode, some clinicians routinely continue antiseizure medication for 1 year, but

number of cysts but not in the recurrence of seizures lesions.

are effective in one third of patients, approximately.

treatment? Maybe not.

patients.

[67,68] (Table 3).

The coexistence of hippocampal atrophy and extrahippocampal pathological abnormalities, such as cortical dysgenesis and gliosis, referred to as "dual pathology", has been reported in 5 to 30% of patients with medically refractory partial seizures [56]. Dual pathology implies that both lesions somehow interact with each other and contribute to epileptogenesis through mechanisms still poorly understood. Some authors have also attributed hippocampal sclerosis to NCC [54.57,58]. Patients with calcifications due to NCC and mesial temporal lobe epilepsy (hippocampal sclerosis) became seizure free after anteromesial temporal lobectomy, without resection of the cysticercotic lesion [35], suggesting the two phenomena are independent. The presence of CNL does not influence the clinical and pathologic profile of patients with hippocampal atrophy. An irritative zone in the temporal lobe is more relevant in determining the severity, symptomatology and frequency of seizures than the number and location of calcifications [59]. The possibility of dual pathology related to NCC needs further clarification in prospective cohort studies.

NCC and epilepsy are common diseases in most developing countries. Because of their high prevalence, a causal as well as fortuitous relationship between the two conditions might exist [35,54,60] NCC is also an uncommon cause of intractable epilepsy, even in endemic regions and that it may only represent a coexistent pathology, according to a cross sectional study investigating the etiology of intractable epilepsy in 512 patients in Brazil [61].

## **7. Effect of antihelminthic drug treatment on recurrence of seizures**

Treatment for NCC with antihelminthic drugs (AHD) such as praziquantel and albendazole has been available for at least 25 years, and since then its use has been controversial. Praziquantel was used for the first time in México [62]. Albendazole was used for the first time in China [63] .

To date, there are no controlled clinical trials to establish definitive doses and duration of treatment. A meta-analysis was published in 2005 [64], in which only 11 studies, among 764, were selected, only 6 with viable cysts and 5 with degenerative or coloidal cysts. The authors reported disappearance of viable cysts in 44% of patients who were treated with albendazole vs. 19% of the placebo group (p <0.025). They also reported disappearance of degenerative cysts in 72% of patients of the albendazole group, and 63 % of the placebo group, but there was no statistical significance (p <0.38). The Editors of the journal where this meta-analysis was published affirmed that selected studies were small and heterogeneous, and only 5 of 11 were good quality. They concluded that studies provided limited evidence of a modest effect of NCC treatment, since the effects of cysticidal treatment on neuroimaging end points were relatively small (OR <2.2) . A recent Cochrane review [65] of 21 randomized controlled clinical trials of cysticidal therapy concluded that with adults with viable cysts the use of albendazole is associated with a decrease in the number of cysts but not in the recurrence of seizures lesions.

298 Novel Aspects on Cysticercosis and Neurocysticercosis

time in China [63] .

EEG abnormalities has been reported for only 15-30% of patients. Similarly, the correlation between seizure type and EEG abnormalities ranges from around 7% to 20% [53]. Discrepancies between clinical localization based on seizure semiology and location of the lesion on neuroimaging is a not uncommon feature in patients with NC. A non-causal relationship between epilepsy and cysticercosis in some cases might explain these apparent discrepancies [54,55]. Further prospective cohort studies, properly designed to study ictal and interictal EEG abnormalities in patients with seizures, correlated with the different evolutionary stages of the parasite, may clarify the relationship between NCC and epilepsy. The coexistence of hippocampal atrophy and extrahippocampal pathological abnormalities, such as cortical dysgenesis and gliosis, referred to as "dual pathology", has been reported in 5 to 30% of patients with medically refractory partial seizures [56]. Dual pathology implies that both lesions somehow interact with each other and contribute to epileptogenesis through mechanisms still poorly understood. Some authors have also attributed hippocampal sclerosis to NCC [54.57,58]. Patients with calcifications due to NCC and mesial temporal lobe epilepsy (hippocampal sclerosis) became seizure free after anteromesial temporal lobectomy, without resection of the cysticercotic lesion [35], suggesting the two phenomena are independent. The presence of CNL does not influence the clinical and pathologic profile of patients with hippocampal atrophy. An irritative zone in the temporal lobe is more relevant in determining the severity, symptomatology and frequency of seizures than the number and location of calcifications [59]. The possibility of dual

pathology related to NCC needs further clarification in prospective cohort studies.

study investigating the etiology of intractable epilepsy in 512 patients in Brazil [61].

**7. Effect of antihelminthic drug treatment on recurrence of seizures** 

NCC and epilepsy are common diseases in most developing countries. Because of their high prevalence, a causal as well as fortuitous relationship between the two conditions might exist [35,54,60] NCC is also an uncommon cause of intractable epilepsy, even in endemic regions and that it may only represent a coexistent pathology, according to a cross sectional

Treatment for NCC with antihelminthic drugs (AHD) such as praziquantel and albendazole has been available for at least 25 years, and since then its use has been controversial. Praziquantel was used for the first time in México [62]. Albendazole was used for the first

To date, there are no controlled clinical trials to establish definitive doses and duration of treatment. A meta-analysis was published in 2005 [64], in which only 11 studies, among 764, were selected, only 6 with viable cysts and 5 with degenerative or coloidal cysts. The authors reported disappearance of viable cysts in 44% of patients who were treated with albendazole vs. 19% of the placebo group (p <0.025). They also reported disappearance of degenerative cysts in 72% of patients of the albendazole group, and 63 % of the placebo group, but there was no statistical significance (p <0.38). The Editors of the journal where this meta-analysis was published affirmed that selected studies were small and heterogeneous, and only 5 of 11 were good quality. They concluded that studies provided One of the main reasons for which there is a lot of confusion in the medical literature and a supposed controversy regarding the effectiveness of AHD, is that most of the publications report "reduction of the number of lesions" as a valid endpoint to measure effectiveness of the treatment, which is misleading. We should wonder, for example, in the hypothetical event that a person with 10 viable cysts has been administered AHD, whether, as a consequence of the treatment, 8 parasite die (80% reduction of lesion/successful treatment?), but two cysts remain which may provoke seizures or headache: Is this a successful treatment? Maybe not.

The appropriate end point to evaluate the effectiveness of AHD could be the disappearance of cysts. Strictly speaking, even in the case that treatment with AHD may kill all parasites in a patient, it is not possible to talk about "cure" because, as we know, most cysts once they die became calcifications, a permanent sequel, which could aggravate seizures long life If we compare those studies in which one of the end points to evaluate effectiveness of AHD is disappearance of cysts (table 3), including the results of the abovementioned meta-analysis, where about 30% to 40% of patients had disappearance of cysts [66-68]. Therefore, there is no controversy; we can affirm that, according to available evidence based medicine, AHD are effective in one third of patients, approximately.

## **8. Risk of seizure recurrence in patients with neurocysticercosis**

Some authors report that NCC patients with acute symptomatic seizures have a good prognosis in terms of remission of seizures [69-73]; others report that most patients have a high risk of seizure recurrence, and suggest that prognosis improves after antihelminthic treatment. [66]. Prospective cohort studies have determined the risk of seizure recurrence after a first seizure due to NCC is between 17% to 56%, depending on the viability of the parasite. The risk is greater in the transitional forms and it diminishes in the viable or calcified forms [73-76]. Overall, the risk of seizure recurrence involves around one third of patients.

It has also been suggested that seizure control in patients with NCC is improved and that the chance of remaining seizure-free after the withdrawal of antiepileptic drugs is greater after a course of AHD, when compared with seizure control in those in whom the disease is left untreated [66]. However, current reliable information has shown that AHD treatment in patients with seizures due to NCC is not associated with the recurrence of seizures at all [67,68] (Table 3).

Regarding the duration for which antiseizure medication should be continued following an acute NCC episode, some clinicians routinely continue antiseizure medication for 1 year, but

shorter and longer intervals have been recommended [1]. One assumes that the risk of seizures is substantial as long as there is an active ongoing process as characterized by persistence of edema around the degenerating lesion. Because of this, CT scan is a useful tool for these treatment decisions. It is appropriate to monitor cyst activity with CT scanning and to continue antiseizure medication until resolution of the acute lesion. After this time antiseizure medication may be discontinued [1]. Seizures occurring in individuals after resolution of edema and resorption or calcification of the degenerating cyst should be considered unprovoked and, in this situation, long-term antiseizure medication is warranted.

Neurocysticercosis and Epilepsy 301

There are inconsistencies in the link between epilepsy and NC. Because of the high prevalence of each condition, a causal as well as fortuitous relationship between the two pathologies might exist. NCC is not necessarily the main cause of epilepsy in endemic countries, although it is one of the most frequent antecedents among adult patients with

Several studies have reported an association between epilepsy and NCC based on positive serum antibodies to Taenia solium/cysticercosis. This information has created distortion in

Seizures in the context of edema and a degenerative lesion should be considered acute symptomatic even if they occur many months after presentation. After resolution of the acute lesion antiseizure medication may be discontinued. Seizures occurring after resolution of edema or calcification of the degenerating cyst should be considered unprovoked and, in this situation, long term antiepileptic medication is warranted. There is no correlation

The prognosis of seizure in patients with NCC is good. In about two thirds of the patients with acute symptomatic seizures due to NCC the seizures do not recur [67] People with acute seizures NCC should be treated with antiseizure medication until cyst resolution on CT scan. The risk of seizure recurrence (epilepsy) occurs in the inactive or calcified form of

Recommendations: Further research should be undertaken in order to clarify: -the natural history of T.Solium/cysticercosis disease, -the variability of antihelminthic treatment efficacy, -the factors that contribute to clinical heterogeneity of NC, -immunological response of the host. It is also recommended to standardize a common methodology,

Health authorities should focus on prevention and eradication of taeniasis/cysticercosis in order to decrease the number of individuals with seizures/epilepsy and other consequences.

[1] Carpio A. Neurocysticercosis: an update. Lancet Infectious Diseases. 2002;2:751-762. [2] Pal DK, Carpio A, Sander JWAS. Neurocysticercosis and Epilepsy. J Neurol Neurosurg

[3] Carpio A, Escobar A, Hauser WA: Epilepsy and cysticercosis: a critical review.

between treatment with antihelminthic agents and seizure recurrence

including definitions, in order to propose new diagnoses criteria for NCC.

symptomatic epilepsy.

NC.

**Author details** 

**10. References** 

*School of Medicine, University of Cuenca, Ecuador* 

Psychiatry 2000;68:137-143

Epilepsia 1998;39:1025-1040.

*G.H. Sergievsky Center, Columbia University, New York, USA* 

Arturo Carpio

the perception of NCC epidemiology


\* CT scan at 6 months after finishing treatment

\*\* Seizures recurrence at one year follow-up

**Table 3.** Effects of cysticidal drugs on resolution of parenchymal viable cysts and seizures recurrence in patients with neurocysticercosis (randomized, placebo-controlled studies)

It seems that interpretation of risk of seizures after neurocysticercosis is difficult. These difficulties are increased in those patients who have mixed forms, including active, transitional, and calcified lesions. Further studies should be performed in order to estimate recurrence risk in those patients with seizures due to calcifications alone, in comparison with patients with acute seizures due to transitional cysts.

## **9. Conclusions**

Epilepsy and NCC are common diseases in poor countries, and NCC is increasingly diagnosed in developed countries due to migration from endemic regions. However, reliable data concerning prevalence and incidence of NCC is lacking worldwide.

Seizures are the most common symptom in patients with the parenchymal location of the parasite. Seizures may occur at any evolutionary stage of the parasite, but acute symptomatic seizures are more frequent in the transitional form, due to the inflammatory response of the brain. Most people with NCC have acute symptomatic seizures that do not necessarily evolve into epilepsy. This is one of the reasons that epilepsy is over diagnosed in some studies. The ILAE's Commission on Epidemiology includes NCC as a comorbid condition associated with epilepsy.

There are inconsistencies in the link between epilepsy and NC. Because of the high prevalence of each condition, a causal as well as fortuitous relationship between the two pathologies might exist. NCC is not necessarily the main cause of epilepsy in endemic countries, although it is one of the most frequent antecedents among adult patients with symptomatic epilepsy.

Several studies have reported an association between epilepsy and NCC based on positive serum antibodies to Taenia solium/cysticercosis. This information has created distortion in the perception of NCC epidemiology

Seizures in the context of edema and a degenerative lesion should be considered acute symptomatic even if they occur many months after presentation. After resolution of the acute lesion antiseizure medication may be discontinued. Seizures occurring after resolution of edema or calcification of the degenerating cyst should be considered unprovoked and, in this situation, long term antiepileptic medication is warranted. There is no correlation between treatment with antihelminthic agents and seizure recurrence

The prognosis of seizure in patients with NCC is good. In about two thirds of the patients with acute symptomatic seizures due to NCC the seizures do not recur [67] People with acute seizures NCC should be treated with antiseizure medication until cyst resolution on CT scan. The risk of seizure recurrence (epilepsy) occurs in the inactive or calcified form of NC.

Recommendations: Further research should be undertaken in order to clarify: -the natural history of T.Solium/cysticercosis disease, -the variability of antihelminthic treatment efficacy, -the factors that contribute to clinical heterogeneity of NC, -immunological response of the host. It is also recommended to standardize a common methodology, including definitions, in order to propose new diagnoses criteria for NCC.

Health authorities should focus on prevention and eradication of taeniasis/cysticercosis in order to decrease the number of individuals with seizures/epilepsy and other consequences.

## **Author details**

300 Novel Aspects on Cysticercosis and Neurocysticercosis

Author/year, reference

Garcia H, et al. 2004 (66)

> Carpio A, et al. 2008, (73)

> > Das K, et al. 2007 (68)

**9. Conclusions** 

\* CT scan at 6 months after finishing treatment \*\* Seizures recurrence at one year follow-up

condition associated with epilepsy.

shorter and longer intervals have been recommended [1]. One assumes that the risk of seizures is substantial as long as there is an active ongoing process as characterized by persistence of edema around the degenerating lesion. Because of this, CT scan is a useful tool for these treatment decisions. It is appropriate to monitor cyst activity with CT scanning and to continue antiseizure medication until resolution of the acute lesion. After this time antiseizure medication may be discontinued [1]. Seizures occurring in individuals after resolution of edema and resorption or calcification of the degenerating cyst should be considered

**Table 3.** Effects of cysticidal drugs on resolution of parenchymal viable cysts and seizures recurrence in

It seems that interpretation of risk of seizures after neurocysticercosis is difficult. These difficulties are increased in those patients who have mixed forms, including active, transitional, and calcified lesions. Further studies should be performed in order to estimate recurrence risk in those patients with seizures due to calcifications alone, in comparison

Epilepsy and NCC are common diseases in poor countries, and NCC is increasingly diagnosed in developed countries due to migration from endemic regions. However,

Seizures are the most common symptom in patients with the parenchymal location of the parasite. Seizures may occur at any evolutionary stage of the parasite, but acute symptomatic seizures are more frequent in the transitional form, due to the inflammatory response of the brain. Most people with NCC have acute symptomatic seizures that do not necessarily evolve into epilepsy. This is one of the reasons that epilepsy is over diagnosed in some studies. The ILAE's Commission on Epidemiology includes NCC as a comorbid

reliable data concerning prevalence and incidence of NCC is lacking worldwide.

Cysts disappearance\* No./%

> 21 (38%) 8 (15%)

> 18 (35%) 6 (12%)

10 (7%) 12 (8%) Seizures recurrence\*\* No./%

> 32 (56%) 32 (54%)

> 19 38%) 27 (48%)

> 40 (27%) 24 (16%)

unprovoked and, in this situation, long-term antiseizure medication is warranted.

Treatment groups (No. patients)

Albendazole (55) Placebo ( 54)

Albendazole ( 51) Placebo ( 50)

Albendazole (148) Placebo (150)

patients with neurocysticercosis (randomized, placebo-controlled studies)

with patients with acute seizures due to transitional cysts.

Arturo Carpio *School of Medicine, University of Cuenca, Ecuador G.H. Sergievsky Center, Columbia University, New York, USA* 

## **10. References**


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[53] Cukiert, A., Puglia, P., Scapola, H.B., et al. Congruence of the topography of intracraneal calcifications and epileptic foci. Arq Neuropsiquiatr 1993;52:289-294. [54] Sakamoto AC et al. Cysticercosis and Epilepsy. In, Kotagal P, Luders HO, eds. The Epilepsies: Etiologies and Prevention. San Diego: Academic Press, 1999. 275-282. [55] Singh, G., Sachdev, M.S., Tirath, A., Gupta, A.K., Avasthi, G. Focal cortical-subcortical calcifications (FCSCs) and epilepsy in the Indian subcontinent. Epilepsia. 2000;41:718-

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[57] Singla M, Singh P, Kaushal S, Bansal R, Singh G. Hippocampal sclerosis in association

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**Chapter 12** 

© 2013 Winkler, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 Winkler, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In sub-Saharan Africa neurocysticercosis (NCC), which represents the infection of a human brain with the larva (=cysticercus) of the pork tapeworm (=*Taenia solium*), and epilepsy due to various causes are among the most frequent neurological disorders/syndromes. To date, NCC in the context of sub-Saharan Africa has not attracted much attention despite the fact that the prevalence rates of human and porcine cysticercosis seem to increase and both diseases are treatable. Epilepsy represents the most common neurological disorder in many parts of sub-Saharan Africa and NCC seems to be a major cause of it in *Taenia solium* cysticercosis endemic areas. Diagnosing NCC among people with epilepsy is vital as this not only prevents further morbidity and mortality through potential aggravation of the disease, but also leads to a different treatment approach: from a mere symptomatic treatment with administration of antiepileptic medication only to a curative approach, assuming that once the parasite has been cleared epileptic seizures will cease. However, in the diagnosis and treatment of NCC neuroimaging plays a crucial role and this has to be considered when dealing with affected individuals form resource-poor settings, where neuroimaging is not available. Therefore special diagnostic and therapeutic guidelines for sub-Saharan Africa have to be developed, but so far national and international stakeholders have not taken this into consideration. This chapter aims at raising awareness of both NCC and epilepsy in sub-Saharan African, appealing to the international community to consider NCC in resourcepoor settings as a separate entity regarding its diagnostic and therapeutic approach with the

**Epilepsy and Neurocysticercosis** 

**in Sub-Saharan Africa** 

Additional information is available at the end of the chapter

need for clearly defined guidelines in the described context.

**1.1. Definition of epilepsy and acute symptomatic epileptic seizures** 

A condition characterized by recurrent (two or more) afebrile epileptic seizures that is unprovoked by any immediate identified cause and thus is not due to an acute intracranial or extracranial condition is termed epilepsy [1]. A person who has had a seizure within the

Andrea Sylvia Winkler

http://dx.doi.org/10.5772/53289

**1. Introduction** 


**Chapter 12** 

## **Epilepsy and Neurocysticercosis in Sub-Saharan Africa**

Andrea Sylvia Winkler

306 Novel Aspects on Cysticercosis and Neurocysticercosis

Acta Neurol Scand. 2010;121(3):204-208.

Neurosurg Psychiatry 2008;79:272–275.

neurocysticercosis. Neurology 2002;59:1730–1734.

normal neuroimaging. J Neurol Sci. 2011;15;301:21-26.

[70] Manreza ML. Epilepsia e neurocisticerose. In, Guerreiro CAM, Guerreiro MM, Cendes

[71] Ferreira LS, Zanardi VA, Scotoni AE, Li LM, Guerreiro MM. Childhood epilepsy due to

[72] Goel D, Mittal M, Bansal KK, Singhal A. Natural history of solitary cerebral cysticercosis cases after albendazole therapy: a longitudinal follow-up study from India.

[73] Carpio A, Hauser W: Prognosis for seizure recurrence in patients with newly diagnosed

[74] De Souza A, Thennarasu K, Yeshraj G, et al.: Randomized controlled trial of albendazole in new onset epilepsy and MRI confirmed solitary cerebral cysticercal

[75] Sharma P, Garg RK, Verma R, Singh MK, Shukla R. Risk of seizure recurrence in patients of new-onset partial seizure having a solitary cysticercus granuloma of brain or

[76] Thussu A, Chattopadhyay A, Sawhney IM, Khandelwal N: Albendazole therapy for single small enhancing CT lesions (SSECTL) in the brain in epilepsy. J Neurol

lesion: effect on long-term seizure outcome. J Neurol Sci 2009;276:108–114.

F, Lopes-Cendes I, eds. Epilepsia. Sao Paulo: Lemos Editorial. 2000. 255-264

neurocysticercosis: a comparative study. Epilepsia. 2001;42:1438-1444.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53289

## **1. Introduction**

In sub-Saharan Africa neurocysticercosis (NCC), which represents the infection of a human brain with the larva (=cysticercus) of the pork tapeworm (=*Taenia solium*), and epilepsy due to various causes are among the most frequent neurological disorders/syndromes. To date, NCC in the context of sub-Saharan Africa has not attracted much attention despite the fact that the prevalence rates of human and porcine cysticercosis seem to increase and both diseases are treatable. Epilepsy represents the most common neurological disorder in many parts of sub-Saharan Africa and NCC seems to be a major cause of it in *Taenia solium* cysticercosis endemic areas. Diagnosing NCC among people with epilepsy is vital as this not only prevents further morbidity and mortality through potential aggravation of the disease, but also leads to a different treatment approach: from a mere symptomatic treatment with administration of antiepileptic medication only to a curative approach, assuming that once the parasite has been cleared epileptic seizures will cease. However, in the diagnosis and treatment of NCC neuroimaging plays a crucial role and this has to be considered when dealing with affected individuals form resource-poor settings, where neuroimaging is not available. Therefore special diagnostic and therapeutic guidelines for sub-Saharan Africa have to be developed, but so far national and international stakeholders have not taken this into consideration. This chapter aims at raising awareness of both NCC and epilepsy in sub-Saharan African, appealing to the international community to consider NCC in resourcepoor settings as a separate entity regarding its diagnostic and therapeutic approach with the need for clearly defined guidelines in the described context.

## **1.1. Definition of epilepsy and acute symptomatic epileptic seizures**

A condition characterized by recurrent (two or more) afebrile epileptic seizures that is unprovoked by any immediate identified cause and thus is not due to an acute intracranial or extracranial condition is termed epilepsy [1]. A person who has had a seizure within the

© 2013 Winkler, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Winkler, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

last five years and those on anticonvulsant medication are considered to have "active epilepsy" [1,2]. The definition of active epilepsy does not have implications on starting antiepileptic treatment. Some African researchers suggest starting treatment if the last seizure was within the previous year [3]. We advocate for a more flexible initiation of antiepileptic treatment. Treatment of epilepsy always has to be considered on a multifactorial basis and includes the risk of recurrence based on seizure pathology (e.g., generalized versus focal epilepsy), seizure frequency, associated disease and available antiepileptic treatment, among others.

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 309

infections, then epilepsy (65/272; 23.9%) as defined by the International League Against Epilepsy [1]. Assumed symptomatic seizures without an obvious cause that did not meet the criteria of epilepsy occurred in 15.4% (42/272) and pseudoseizures were witnessed in 4.0% (11/272). The mortality rate of the patients with epileptic seizures was high with 18.8% (51/272). Peak mortality rates were found in people with symptomatic disease and those with assumed symptomatic epileptic seizures, at 38.9% (28/72) and 31.0% (13/42), respectively. These results clearly show where the burden of neurological disorders in sub-Saharan Africa, in our case northern Tanzania, lies and have implications for the objective of

The high prevalence rates of epileptic seizures/epilepsy found in the above hospital-based study were also confirmed in a community-based setting. Of the 7399 people who were visited in a community-based study in the same area the above hospital-based study was conducted 83 people were diagnosed with epilepsy and of those 64 had active epilepsy (last seizure within the last 5 years; [12]). The point prevalence of epilepsy within the study population of 7399 people was 11.2/1000 (95% CI 8.9-13.9/1000) with an age-adjusted prevalence of 13.2/1000. The prevalence of active epilepsy was 8.7/1000 (95% CI 6.7- 11.0/1000) with an age-adjusted rate of 9.1/1000. The majority of patients suffered from generalized epilepsies. Not surprisingly, three quarters of the people with epilepsy had

Our findings confirm high prevalence rates of epileptic seizures/epilepsy in the hospital and the community, which agrees with the results of previous epidemiological studies of epilepsy in sub-Saharan Africa [5,6,9,13-19]. Most studies conducted in parts of Africa and Latin America indicate higher prevalence rates of epilepsy than have been found in high-income countries, but these prevalence rates can vary within a single country, as shown in Benin, the Ivory Coast, Senegal and Tanzania [6,9,19]. In a recent large-scale study from Kenya, it was shown that the active prevalence was only 4.5/1000, and therefore in the range of prevalence rates of high-income countries, with a high heterogeneity of prevalence rates across different areas ranging from below 1.0/1000 to 12.9/1000 [3]. Active epilepsy was defined as at least one seizure during the last year (the usual definition is one seizure during the last five years; see

**1.3. Classification of epileptic seizures/epilepsy in resource-poor settings** 

Classifying epileptic seizures/epilepsy in resource-poor countries can be challenging, bearing in mind that the availability of diagnostic tools such as appropriate serological investigations, electroencephalography and neuroimaging can be scare or, especially in rural Africa, absent altogether. Whether the seizures reported in rural Africa are primarily generalized or focal in nature is still a matter of debate and depends upon the setting and methodology used (e.g. hospital-based versus community-based), the country of investigation, the questionnaires used (different sensitivities and specificities) and the diagnostic tools available [6]. While members of the International League Against Epilepsy have developed consensus papers on the best classification of epileptic seizures [20] and

delivering appropriate care for patients suffering from epileptic seizures [10].

never accessed any health facilities [12].

1.1.) which may account for the lower prevalence rate found.

Epileptic seizures that are based on intracranial pathologies, such as parasitic disease, cerebrovascular accidents or trauma, and stop after the underlying cause, e.g. the associated oedema, has resolved, are called acute symptomatic epileptic seizures and have to be differentiated from epileptic seizures in the context of "chronic" epilepsy. In "chronic epilepsy" brain lesions may still be present, but they belong to the entity of neurological sequelae such as calcifications after parasitic diseases or chronic lesions in the context of cerebrovascular accidents or trauma, among others. These lesions most likely will not undergo further changes and therefore the "chronic" epilepsy type is treated symptomatically with antiepileptic drugs. In acute symptomatic epileptic seizures treatment of the primary cause is mandatory, if possible, but antiepileptic drugs are often added. After the acute phase withdrawal of antiepileptic treatment is desirable, but has to be decided on a case-to-case basis.

## **1.2. Prevalence of epilepsy in sub-Saharan Africa**

In sub-Saharan Africa, epilepsy is among the most common neurological disorders. Its devastating impact on individuals suffering from it as well as on affected African communities was described as early as 1960 in Mahenge, southern Tanzania [4]. These early anecdotal reports were corroborated by a large-scale hospital-based study in Nigeria in the 1970s [5]. Since then, prevalence data on epilepsy have been collected in community-based studies throughout Africa with varying results depending on the study population and the methodologies used (mainly on active epilepsy), ranging from 5.2-74.4/1000 with a median of 15/1000 inhabitants [6,7]. This is compared to high-income countries where the prevalence of active epilepsy is estimated to be about 4-8/1000 inhabitants [8]. Interestingly, hotspots of highly prevalent epilepsy have been reported in various African countries such as Benin, the Ivory Coast, Cameroon, Nigeria, Senegal and Tanzania [6,9]. Causes for these high prevalence rates have so far not been identified, but they are deemed to be partly genetic in nature, most likely with a consistent environmental factor that affects genetically predisposed individuals [6].

Our own data from a hospital-based study on neurological disorders in northern Tanzania show epileptic seizures to be the most prevalent neurological disorder [10,11]. Of the 740 patients with neurological symptoms/signs, 272 (36.8%) had at least one epileptic seizure during their stay at the hospital or immediately before admission to the hospital. Febrile seizures (82/272; 30.2%) accounted for the majority of epileptic seizures. This was followed by symptomatic epileptic seizures (72/272; 26.5%), which were mainly due to cerebral infections, then epilepsy (65/272; 23.9%) as defined by the International League Against Epilepsy [1]. Assumed symptomatic seizures without an obvious cause that did not meet the criteria of epilepsy occurred in 15.4% (42/272) and pseudoseizures were witnessed in 4.0% (11/272). The mortality rate of the patients with epileptic seizures was high with 18.8% (51/272). Peak mortality rates were found in people with symptomatic disease and those with assumed symptomatic epileptic seizures, at 38.9% (28/72) and 31.0% (13/42), respectively. These results clearly show where the burden of neurological disorders in sub-Saharan Africa, in our case northern Tanzania, lies and have implications for the objective of delivering appropriate care for patients suffering from epileptic seizures [10].

308 Novel Aspects on Cysticercosis and Neurocysticercosis

antiepileptic treatment, among others.

predisposed individuals [6].

last five years and those on anticonvulsant medication are considered to have "active epilepsy" [1,2]. The definition of active epilepsy does not have implications on starting antiepileptic treatment. Some African researchers suggest starting treatment if the last seizure was within the previous year [3]. We advocate for a more flexible initiation of antiepileptic treatment. Treatment of epilepsy always has to be considered on a multifactorial basis and includes the risk of recurrence based on seizure pathology (e.g., generalized versus focal epilepsy), seizure frequency, associated disease and available

Epileptic seizures that are based on intracranial pathologies, such as parasitic disease, cerebrovascular accidents or trauma, and stop after the underlying cause, e.g. the associated oedema, has resolved, are called acute symptomatic epileptic seizures and have to be differentiated from epileptic seizures in the context of "chronic" epilepsy. In "chronic epilepsy" brain lesions may still be present, but they belong to the entity of neurological sequelae such as calcifications after parasitic diseases or chronic lesions in the context of cerebrovascular accidents or trauma, among others. These lesions most likely will not undergo further changes and therefore the "chronic" epilepsy type is treated symptomatically with antiepileptic drugs. In acute symptomatic epileptic seizures treatment of the primary cause is mandatory, if possible, but antiepileptic drugs are often added. After the acute phase withdrawal of

In sub-Saharan Africa, epilepsy is among the most common neurological disorders. Its devastating impact on individuals suffering from it as well as on affected African communities was described as early as 1960 in Mahenge, southern Tanzania [4]. These early anecdotal reports were corroborated by a large-scale hospital-based study in Nigeria in the 1970s [5]. Since then, prevalence data on epilepsy have been collected in community-based studies throughout Africa with varying results depending on the study population and the methodologies used (mainly on active epilepsy), ranging from 5.2-74.4/1000 with a median of 15/1000 inhabitants [6,7]. This is compared to high-income countries where the prevalence of active epilepsy is estimated to be about 4-8/1000 inhabitants [8]. Interestingly, hotspots of highly prevalent epilepsy have been reported in various African countries such as Benin, the Ivory Coast, Cameroon, Nigeria, Senegal and Tanzania [6,9]. Causes for these high prevalence rates have so far not been identified, but they are deemed to be partly genetic in nature, most likely with a consistent environmental factor that affects genetically

Our own data from a hospital-based study on neurological disorders in northern Tanzania show epileptic seizures to be the most prevalent neurological disorder [10,11]. Of the 740 patients with neurological symptoms/signs, 272 (36.8%) had at least one epileptic seizure during their stay at the hospital or immediately before admission to the hospital. Febrile seizures (82/272; 30.2%) accounted for the majority of epileptic seizures. This was followed by symptomatic epileptic seizures (72/272; 26.5%), which were mainly due to cerebral

antiepileptic treatment is desirable, but has to be decided on a case-to-case basis.

**1.2. Prevalence of epilepsy in sub-Saharan Africa** 

The high prevalence rates of epileptic seizures/epilepsy found in the above hospital-based study were also confirmed in a community-based setting. Of the 7399 people who were visited in a community-based study in the same area the above hospital-based study was conducted 83 people were diagnosed with epilepsy and of those 64 had active epilepsy (last seizure within the last 5 years; [12]). The point prevalence of epilepsy within the study population of 7399 people was 11.2/1000 (95% CI 8.9-13.9/1000) with an age-adjusted prevalence of 13.2/1000. The prevalence of active epilepsy was 8.7/1000 (95% CI 6.7- 11.0/1000) with an age-adjusted rate of 9.1/1000. The majority of patients suffered from generalized epilepsies. Not surprisingly, three quarters of the people with epilepsy had never accessed any health facilities [12].

Our findings confirm high prevalence rates of epileptic seizures/epilepsy in the hospital and the community, which agrees with the results of previous epidemiological studies of epilepsy in sub-Saharan Africa [5,6,9,13-19]. Most studies conducted in parts of Africa and Latin America indicate higher prevalence rates of epilepsy than have been found in high-income countries, but these prevalence rates can vary within a single country, as shown in Benin, the Ivory Coast, Senegal and Tanzania [6,9,19]. In a recent large-scale study from Kenya, it was shown that the active prevalence was only 4.5/1000, and therefore in the range of prevalence rates of high-income countries, with a high heterogeneity of prevalence rates across different areas ranging from below 1.0/1000 to 12.9/1000 [3]. Active epilepsy was defined as at least one seizure during the last year (the usual definition is one seizure during the last five years; see 1.1.) which may account for the lower prevalence rate found.

## **1.3. Classification of epileptic seizures/epilepsy in resource-poor settings**

Classifying epileptic seizures/epilepsy in resource-poor countries can be challenging, bearing in mind that the availability of diagnostic tools such as appropriate serological investigations, electroencephalography and neuroimaging can be scare or, especially in rural Africa, absent altogether. Whether the seizures reported in rural Africa are primarily generalized or focal in nature is still a matter of debate and depends upon the setting and methodology used (e.g. hospital-based versus community-based), the country of investigation, the questionnaires used (different sensitivities and specificities) and the diagnostic tools available [6]. While members of the International League Against Epilepsy have developed consensus papers on the best classification of epileptic seizures [20] and

epilepsies [21,22] that are considered international standards, they mainly refer to highincome countries, which only include 20% of all people with epilepsy worldwide [23,24]. In contrast, appropriate classification systems for epileptic seizures/epilepsy in low-income countries seem to be virtually absent. Seizure semiology, the description of which can be incomplete due to language and sociocultural barriers, and important seizure related issues such as possible aetiologies and concomitant diseases (e.g. perinatal neurological sequelae) are relevant for the classification of epileptic seizures/epilepsy in these countries and should form parts of an adapted classification system. The growing relevance of global neurology together with the already substantial burden of epileptic seizures/epilepsy in sub-Saharan Africa calls for an expert-led committee to decide on an appropriate classification system for epileptic seizures/epilepsy for clinical use in low-resource countries.

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 311

4. *Generalized seizures with focal signs:* secondary generalized seizures with a focal start, clear unilateral seizures or focal neurological signs upon examination but without signs

Investigations: further investigations necessary (electroencephalography,

**Figure 1.** Algorithm on how to classify people with epilepsy in resource-poor countries regarding diagnostic and therapeutic implications. Primary generalised seizures are split according to the age of onset (see text); these two groups have a different diagnostic and therapeutic approach. Patients with primary generalised seizures that start outside 6-25 years are more likely to have cerebral lesions than patients whose epilepsies start within 6-25 years where idiopathic epilepsy prevails, and therefore need further investigation. In people with epilepsy and diffuse brain damage, diagnostic tests are rarely needed as the extent of the cerebral sequelae is known and the condition is not progressive. In contrast, in people with epilepsy who show focal signs without diffuse brain damage, further diagnostic steps are essential in order to identify the underlying, potentially treatable cause. In all four groups, treatment depends mainly on the age of the patient, seizure activity, seizure frequency, the presence of mental handicap and the presence of focal neurological signs, bearing in mind that the choice of antiepileptic

medication is limited. CBZ = carbamazepine, PHT = phenytoin, PHB = phenobarbitone.

We opted for a simply structured, easy-to-understand classification system that mainly consists of the four groups of epileptic seizures/epilepsy described above based on seizure description, clinical information and a physical examination (Figure 1). Our classification shares many similarities with the International League Against Epilepsy classifications [1, 20-22], especially the International Classification of Epileptic Seizures [20], but it has been

Cause: may become obvious upon further investigation

Prognosis: depends on the underlying cause

of diffuse brain damage.

neuroimaging)

We suggest a classification system that is based on clinical grounds alone, and mainly refers to the description of seizures provided by the patients and their relatives along with relevant information from past medical histories, birth and family histories and a thorough neurological examination. Electroencephalography and neuroimaging are not usually at hand in resource-poor settings and therefore are not included in the classification system. The classification system suggested is based on the classification of epileptic seizures and epilepsy as stipulated by the International League Against Epilepsy [1,20-22]. Based on our experience while working in northern Tanzania we identified four main categories of epileptic seizures/epilepsy that have different needs for further investigation, treatment and follow-up, showing variable prognoses ([25,26]; Figure 1).

#### *Generalized types of seizure:*

1. *Generalized seizures within a specific age range:* primary generalized seizures that start within a specific age group (mainly between 6 and 25 years). Seizures in this group can also be termed idiopathic generalized epilepsy.

Cause: none obvious

Prognosis: good Investigations: keep to a minimum

2. *Generalized seizures outside a specific age range:* primary generalized seizures that start outside the specific age range of most of the idiopathic generalized epilepsies where no symptoms/signs on clinical examination suggest a secondary cause. Cause: none obvious, seizures may be "cryptogenic".

Prognosis: variable

Investigations: further investigations necessary (electroencephalography, neuroimaging)

*Partial types of seizure that clinically appear as generalized seizures:* 

3. *Generalized seizures with diffuse brain damage:* secondary generalized seizures that start in a generalized way, but diffuse brain damage with mental retardation is obvious. The large majority of patients are children. Cause: mostly known (e.g. birth defect) Prognosis: variable Investigations: keep to a minimum

4. *Generalized seizures with focal signs:* secondary generalized seizures with a focal start, clear unilateral seizures or focal neurological signs upon examination but without signs of diffuse brain damage.

Cause: may become obvious upon further investigation

Prognosis: depends on the underlying cause

310 Novel Aspects on Cysticercosis and Neurocysticercosis

epilepsies [21,22] that are considered international standards, they mainly refer to highincome countries, which only include 20% of all people with epilepsy worldwide [23,24]. In contrast, appropriate classification systems for epileptic seizures/epilepsy in low-income countries seem to be virtually absent. Seizure semiology, the description of which can be incomplete due to language and sociocultural barriers, and important seizure related issues such as possible aetiologies and concomitant diseases (e.g. perinatal neurological sequelae) are relevant for the classification of epileptic seizures/epilepsy in these countries and should form parts of an adapted classification system. The growing relevance of global neurology together with the already substantial burden of epileptic seizures/epilepsy in sub-Saharan Africa calls for an expert-led committee to decide on an appropriate classification system for

We suggest a classification system that is based on clinical grounds alone, and mainly refers to the description of seizures provided by the patients and their relatives along with relevant information from past medical histories, birth and family histories and a thorough neurological examination. Electroencephalography and neuroimaging are not usually at hand in resource-poor settings and therefore are not included in the classification system. The classification system suggested is based on the classification of epileptic seizures and epilepsy as stipulated by the International League Against Epilepsy [1,20-22]. Based on our experience while working in northern Tanzania we identified four main categories of epileptic seizures/epilepsy that have different needs for further investigation, treatment and

1. *Generalized seizures within a specific age range:* primary generalized seizures that start within a specific age group (mainly between 6 and 25 years). Seizures in this group can

2. *Generalized seizures outside a specific age range:* primary generalized seizures that start outside the specific age range of most of the idiopathic generalized epilepsies where no

Investigations: further investigations necessary (electroencephalography, neuroimaging)

3. *Generalized seizures with diffuse brain damage:* secondary generalized seizures that start in a generalized way, but diffuse brain damage with mental retardation is obvious. The

symptoms/signs on clinical examination suggest a secondary cause.

epileptic seizures/epilepsy for clinical use in low-resource countries.

follow-up, showing variable prognoses ([25,26]; Figure 1).

also be termed idiopathic generalized epilepsy.

Cause: none obvious, seizures may be "cryptogenic".

*Partial types of seizure that clinically appear as generalized seizures:* 

Investigations: keep to a minimum

large majority of patients are children. Cause: mostly known (e.g. birth defect)

Investigations: keep to a minimum

*Generalized types of seizure:* 

Cause: none obvious Prognosis: good

Prognosis: variable

Prognosis: variable

Investigations: further investigations necessary (electroencephalography, neuroimaging)

**Figure 1.** Algorithm on how to classify people with epilepsy in resource-poor countries regarding diagnostic and therapeutic implications. Primary generalised seizures are split according to the age of onset (see text); these two groups have a different diagnostic and therapeutic approach. Patients with primary generalised seizures that start outside 6-25 years are more likely to have cerebral lesions than patients whose epilepsies start within 6-25 years where idiopathic epilepsy prevails, and therefore need further investigation. In people with epilepsy and diffuse brain damage, diagnostic tests are rarely needed as the extent of the cerebral sequelae is known and the condition is not progressive. In contrast, in people with epilepsy who show focal signs without diffuse brain damage, further diagnostic steps are essential in order to identify the underlying, potentially treatable cause. In all four groups, treatment depends mainly on the age of the patient, seizure activity, seizure frequency, the presence of mental handicap and the presence of focal neurological signs, bearing in mind that the choice of antiepileptic medication is limited. CBZ = carbamazepine, PHT = phenytoin, PHB = phenobarbitone.

We opted for a simply structured, easy-to-understand classification system that mainly consists of the four groups of epileptic seizures/epilepsy described above based on seizure description, clinical information and a physical examination (Figure 1). Our classification shares many similarities with the International League Against Epilepsy classifications [1, 20-22], especially the International Classification of Epileptic Seizures [20], but it has been

tailored to fit local circumstances. This was deemed important in order to gain information on possible causes, necessary investigations within a resource-poor setting, best antiepileptic treatments and prognoses of seizure disorders (Figure 1).

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 313

groups, and a classification of affected patients within the most appropriate group could help guide the clinician towards the appropriate management of people with epilepsy

In many African countries, epileptic seizures/epilepsy represent a tremendous socio-economic burden, partly due to the chronicity of the disease, and therefore not only have repercussions on individuals but also on their families and the community they live in. The figures released by the WHO are convincing: 50 million people worldwide suffer from epilepsy; 80% of them live in resource-poor countries [23] and of these up to 90% are untreated or treated insufficiently [34]. Newer figures indicate that 63 million people live with epilepsy in low- and middle-income countries [35]. This 90% treatment gap was corroborated by studies from northern and southern Tanzania showing that 76% and 95% of people with epilepsy, respectively, had not been treated [12,19]. Dramatic global disparities in this treatment gap were identified by a systematic review which showed that 75% and fewer than 10% of PWE from low-income and high-income countries, respectively, were untreated or insufficiently treated for their epilepsy [36]. A recent study from Kenya demonstrated an epilepsy treatment gap of 62% using serum antiepileptic drug levels as a measure of compliance and found that self-reporting of compliance to antiepileptic medication was very unreliable when compared

Although access to modern medicine is limited for people with epilepsy who live in sub-Saharan Africa, traditional medicines are widely used as they represent the only treatments that are accessible to most of the affected population. The lack of awareness of local and international policy makers, poor infrastructure, long travel distances, the insufficient or only intermittent availability of antiepileptic medications, the lack of education among people with epilepsy, their families and the communities, the predominance of traditional belief systems and the scarcity of trained medical personnel may be responsible for this large treatment gap [39,40]. Another important but often neglected cause of this treatment gap is social stigma. In many countries of sub-Saharan Africa, epilepsy has mystical connotations, which is another reason why the majority of people with epilepsy resort to traditional medicines before even considering modern medicine. In many societies, epilepsy is viewed as punishment for sins or breaking taboos, a curse, bewitchment or demoniac possession, as well as a contagious disease, resulting in the rejection and discrimination of affected individuals [41]. A recent study from Zambia showed that people with epilepsy are disadvantaged regarding social and economic matters compared to people with other chronic diseases without an attached stigma, such as asthma, diabetes mellitus, hypertension and rheumatic heart disease [42]. The aforementioned aspects all contribute to the fact that the majority of people with epilepsy go untreated. This treatment gap is the main cause of individual suffering and the socio-economic burden of the disease, necessitating improvements in therapeutic strategies [6,43,44]. A pre-requisite for successful treatment also includes a good knowledge of the possible aetiologies of seizure disorders as

within a rural African setting.

**1.4. Treatment gap of epilepsy in sub-Saharan Africa** 

to the serum antiepileptic drug levels [37,38].

treatment can largely depend on underlying pathologies.

The "generalized types of seizure" (groups 1 and 2; Figure 1) were divided according to age at onset. They presented as classic primary generalized seizures without any suggestion of focal neurological signs or focal seizure onset. The subdivision of primary generalized seizures into those that start within a specific age range (6-25 years;[27]) and those that start outside of this age range was deemed important as the approach used for each is different (Figure 1). Idiopathic epilepsy types include distinct seizure syndromes with distinct ages of onset, although mainly within the postulated age group of 6-25 years [27-29]. Primary generalized seizures outside of this age range, either below about 6 years or above about 25 years, can still be idiopathic in nature, although seizures caused by brain lesions, especially in a resource-poor setting, may prevail. Our hospital-based study showed that symptomatic seizures are frequent. When looking at the exact age distribution, 70.8 % (51/72) of the patients with symptomatic seizures were aged either below 6 years or above 25 years when presenting with symptomatic seizures [10]. Therefore, for people with epilepsy presenting with primary generalized seizures that fall into these age groups, further investigations with electroencephalography and neuroimaging seem to be important (Figure 1).

The "partial types of seizure with the clinical appearance of generalized seizures" (groups 3 and 4; Figure 1) were divided according to the extent of brain damage associated with the seizures. Mental retardation and intellectual decline due to serious brain disorders in children of resource-poor countries are much more frequent compared to resource-rich countries [30,31]. These are often associated with epileptic seizures that are difficult to treat and have an unfavourable prognosis [32]. Thus, this group of people with epilepsy deserves special attention, and therefore has been summarized as a separate group (group 3). In children with more widespread brain damage, antiepileptic drugs with sedative effects such as phenobarbitone could further hamper intellectual development. Often, additional diagnostic tests do not add to the management of these young patients as the cause of cerebral sequelae is known and the condition is not progressive (Figure 1). "Overdiagnosing" patients in this context can cause unnecessary financial burden to the families.

Epilepsy in resource-poor countries is often associated with brain lesions of various origins, with infection and trauma being the most important causes in this setting [2, 33]. These patients can show focal neurological signs and/or present with clinically obvious secondary generalized seizures, but, in contrast to group 3, they do not show signs of more widespread brain damage. Often, a patient is previously healthy before a special event precedes the onset of seizures, although this is not mandatory. Further diagnostic procedures in these patients are important in order to identify the underlying, potentially treatable cause of the epilepsy (Figure 1).

In summary, we have identified four major groups of epileptic seizures on clinical grounds that are relevant to the diagnosis of epilepsy in sub-Saharan Africa. The suggested investigations within a resource-poor setting, treatment and prognosis differ between the groups, and a classification of affected patients within the most appropriate group could help guide the clinician towards the appropriate management of people with epilepsy within a rural African setting.

### **1.4. Treatment gap of epilepsy in sub-Saharan Africa**

312 Novel Aspects on Cysticercosis and Neurocysticercosis

epilepsy (Figure 1).

treatments and prognoses of seizure disorders (Figure 1).

tailored to fit local circumstances. This was deemed important in order to gain information on possible causes, necessary investigations within a resource-poor setting, best antiepileptic

The "generalized types of seizure" (groups 1 and 2; Figure 1) were divided according to age at onset. They presented as classic primary generalized seizures without any suggestion of focal neurological signs or focal seizure onset. The subdivision of primary generalized seizures into those that start within a specific age range (6-25 years;[27]) and those that start outside of this age range was deemed important as the approach used for each is different (Figure 1). Idiopathic epilepsy types include distinct seizure syndromes with distinct ages of onset, although mainly within the postulated age group of 6-25 years [27-29]. Primary generalized seizures outside of this age range, either below about 6 years or above about 25 years, can still be idiopathic in nature, although seizures caused by brain lesions, especially in a resource-poor setting, may prevail. Our hospital-based study showed that symptomatic seizures are frequent. When looking at the exact age distribution, 70.8 % (51/72) of the patients with symptomatic seizures were aged either below 6 years or above 25 years when presenting with symptomatic seizures [10]. Therefore, for people with epilepsy presenting with primary generalized seizures that fall into these age groups, further investigations with

electroencephalography and neuroimaging seem to be important (Figure 1).

The "partial types of seizure with the clinical appearance of generalized seizures" (groups 3 and 4; Figure 1) were divided according to the extent of brain damage associated with the seizures. Mental retardation and intellectual decline due to serious brain disorders in children of resource-poor countries are much more frequent compared to resource-rich countries [30,31]. These are often associated with epileptic seizures that are difficult to treat and have an unfavourable prognosis [32]. Thus, this group of people with epilepsy deserves special attention, and therefore has been summarized as a separate group (group 3). In children with more widespread brain damage, antiepileptic drugs with sedative effects such as phenobarbitone could further hamper intellectual development. Often, additional diagnostic tests do not add to the management of these young patients as the cause of cerebral sequelae is known and the condition is not progressive (Figure 1). "Overdiagnosing" patients in this context can cause unnecessary financial burden to the families.

Epilepsy in resource-poor countries is often associated with brain lesions of various origins, with infection and trauma being the most important causes in this setting [2, 33]. These patients can show focal neurological signs and/or present with clinically obvious secondary generalized seizures, but, in contrast to group 3, they do not show signs of more widespread brain damage. Often, a patient is previously healthy before a special event precedes the onset of seizures, although this is not mandatory. Further diagnostic procedures in these patients are important in order to identify the underlying, potentially treatable cause of the

In summary, we have identified four major groups of epileptic seizures on clinical grounds that are relevant to the diagnosis of epilepsy in sub-Saharan Africa. The suggested investigations within a resource-poor setting, treatment and prognosis differ between the In many African countries, epileptic seizures/epilepsy represent a tremendous socio-economic burden, partly due to the chronicity of the disease, and therefore not only have repercussions on individuals but also on their families and the community they live in. The figures released by the WHO are convincing: 50 million people worldwide suffer from epilepsy; 80% of them live in resource-poor countries [23] and of these up to 90% are untreated or treated insufficiently [34]. Newer figures indicate that 63 million people live with epilepsy in low- and middle-income countries [35]. This 90% treatment gap was corroborated by studies from northern and southern Tanzania showing that 76% and 95% of people with epilepsy, respectively, had not been treated [12,19]. Dramatic global disparities in this treatment gap were identified by a systematic review which showed that 75% and fewer than 10% of PWE from low-income and high-income countries, respectively, were untreated or insufficiently treated for their epilepsy [36]. A recent study from Kenya demonstrated an epilepsy treatment gap of 62% using serum antiepileptic drug levels as a measure of compliance and found that self-reporting of compliance to antiepileptic medication was very unreliable when compared to the serum antiepileptic drug levels [37,38].

Although access to modern medicine is limited for people with epilepsy who live in sub-Saharan Africa, traditional medicines are widely used as they represent the only treatments that are accessible to most of the affected population. The lack of awareness of local and international policy makers, poor infrastructure, long travel distances, the insufficient or only intermittent availability of antiepileptic medications, the lack of education among people with epilepsy, their families and the communities, the predominance of traditional belief systems and the scarcity of trained medical personnel may be responsible for this large treatment gap [39,40]. Another important but often neglected cause of this treatment gap is social stigma. In many countries of sub-Saharan Africa, epilepsy has mystical connotations, which is another reason why the majority of people with epilepsy resort to traditional medicines before even considering modern medicine. In many societies, epilepsy is viewed as punishment for sins or breaking taboos, a curse, bewitchment or demoniac possession, as well as a contagious disease, resulting in the rejection and discrimination of affected individuals [41]. A recent study from Zambia showed that people with epilepsy are disadvantaged regarding social and economic matters compared to people with other chronic diseases without an attached stigma, such as asthma, diabetes mellitus, hypertension and rheumatic heart disease [42]. The aforementioned aspects all contribute to the fact that the majority of people with epilepsy go untreated. This treatment gap is the main cause of individual suffering and the socio-economic burden of the disease, necessitating improvements in therapeutic strategies [6,43,44]. A pre-requisite for successful treatment also includes a good knowledge of the possible aetiologies of seizure disorders as treatment can largely depend on underlying pathologies.

## **1.5. Causes of epileptic seizures/epilepsy in sub-Saharan Africa**

Causes of epileptic seizures/epilepsy are highly variable across different regions of sub-Saharan Africa and depend on geographical, climatic, political, social and hygienic conditions. However, the main and most important causes of epilepsy seem to be very similar throughout sub-Saharan Africa and have been studied in great detail, both in hospital and community settings, showing that a positive family history (genetic predisposition), a past history of febrile convulsions, perinatal neurological disorders, head injuries, cerebrovascular accidents and infections of the central nervous system account for most cases of epilepsy [6]. Also included are a variety of protozoon (the most important being cerebral malaria) and helminthic infections, of which *Taenia solium* (its larval stage causing cysticercosis) has attracted considerable attention in sub-Saharan Africa over the past few years. Therefore, epileptic seizures/epilepsy in the context of NCC will be described in more detail in the following paragraphs in order to provide adequate information on clinical characteristics, diagnosis and treatment in the context of sub-Saharan Africa.

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 315

2.4.). We also know that symptomatic NCC is only the tip of the iceberg and that the majority of people with NCC are asymptomatic. We assume conservatively 50% of all NCC cases to be asymptomatic [59]. Therefore the total of all people suffering from NCC in sub-Saharan Africa would be somewhere between 2.56-8.30 million. These figures would however come down if only areas confirmed with endemic *Taenia solium* cysticercosis would be considered. Currently a number of 631 776 908 people has been assumed to live in the *Taenia solium* cysticercosis endemic areas of sub-Saharan Africa (endemic countries: [60]; populations in these endemic countries: [61]) yielding an NCC-based epilepsy population of 0.76-2.46 million and a population suffering from symptomatic NCC of 0.95-3.08 million. The same amount of people would suffer from asymptomatic NCC, if assuming that 50% of

Latent NCC cases when harbouring *Taenia solium* cysticerci can become symptomatic at any time due to the natural course of disease or in the context of treatment received for intestinal parasites [62]. These people are also at risk of developing symptomatic disease through mass drug administration for soil-transmitted helminths and schistosomiasis, among others [63-66]. Praziquantel and albendazole, two antihelminthic drugs (see 2.6.1.), are at the heart of mass drug administration and may be able to convert latent NCC to symptomatic NCC by destroying the parasite and potentially provoking brain oedema [65,66]. Anecdotal reports of sudden onset of serious neurological signs and/or death after mass drug administration have been noted, but to date no large-scale studies on the topic of the side effects after mass drug administration in carriers of latent cysticerci have been performed. Such studies are desperately needed to evaluate the risk of symptomatic NCC with potentially ensuing death in many hundreds of thousands of people in sub-Saharan Africa. For more details on the calculation of how many people in sub-Saharan Africa would potentially be at risk of developing neurological side effects after mass drug administration

NCC not only imposes a huge socioeconomic burden onto the health systems of affected African nations (see 2.3.), but also indicates that people who potentially could be cured from their epilepsy by antihelminthic medication are practically left untreated. Data on sub-Saharan prevalence rates of NCC in people with epileptic seizures/epilepsy are mainly based on serological results and only exist from a few countries with results of over 40% (Cameroon) depending on the serological tests used [68-70]. A recent meta-analysis that only included African studies showed a significant association between epilepsy and cysticercosis with an odds ratio of 3.4 [71]. More details on the prevalence of NCC (serology and imaging) are available from South African studies [68], where one study found 50.6% of newly diagnosed people with epilepsy showing lesions of NCC on neuroimaging [72]. The only neuroimaging-based study in sub-Saharan Africa outside South Africa was performed from our own group. Definite NCC lesions on computed tomography (CT) were demonstrated in 2.4% (5/212) of people with epilepsy, lesions highly suggestive of NCC were present in 11.3% (24/212) and lesions compatible with NCC were found in 4.2% (9/212). The NCC lesions were significantly more frequent in people with epilepsy compared to the

all cases are asymptomatic.

controls [73].

of praziquantel and albendazole refer to Winkler [67].

## **2. Prevalence of neurocysticercosis in sub-Saharan Africa**

NCC represents the most common helminthic infection of the central nervous system [45] and is endemic in most countries of Latin America, Asia and sub-Saharan Africa. NCC is not only one of the major causes of acquired epileptic seizures/epilepsy in low-resource countries, but it is also of increasing concern in so far non-endemic countries, such as Europe and the United States, due to globalization and the migration of infected people [46-50].

Community-based estimation of the prevalence of NCC is difficult as neuroimaging would have to be applied to a large population putting seemingly healthy people at risk of radiation and therefore has been performed rarely so far [51]. In contrast, the prevalence of human *Taenia solium* cysticercosis in communities has been assessed as this requires blood analysis only. In cysticercosis endemic areas of the Democratic Republic of Congo, Burkina Faso and Zambia the prevalence of *Taenia solium* cysticercosis as measured with an antigen-ELISA was 22%, 10% and 5.8%, respectively [52-54]. Indirect approaches are used to get an impression about the prevalence of people with NCC in a certain population and often people suffering from epileptic seizures or epilepsy are included into these studies. The prevalence of epilepsy has shown to be high in a *Taenia solium* cysticercosis endemic area from Burkina Faso which found an epilepsy lifetime prevalence of 4.5% [55]. A recent metaanalysis on the prevalence of NCC in people with epilepsy, including 12 studies mainly from Latin America, India and sub-Saharan Africa, found that NCC was the cause of epilepsy in almost 30% of people with epilepsy [56].

If extrapolating the above results to the entire population of sub-Saharan Africa (850 million people; [57]) and assuming a prevalence of epilepsy of 4-13/1000 [3,12], approximately 3.4 to 11.05 million people would suffer from epilepsy. Thirty per cent of it is due to NCC yielding 1.02-3.32 million people with epilepsy due to NCC in sub-Saharan Africa. Epilepsy makes up for approximately 80% of the symptoms in NCC [58] and therefore 1.28-4.15 million people would suffer from symptomatic NCC including all neurological signs/symptoms (see 2.4.). We also know that symptomatic NCC is only the tip of the iceberg and that the majority of people with NCC are asymptomatic. We assume conservatively 50% of all NCC cases to be asymptomatic [59]. Therefore the total of all people suffering from NCC in sub-Saharan Africa would be somewhere between 2.56-8.30 million. These figures would however come down if only areas confirmed with endemic *Taenia solium* cysticercosis would be considered. Currently a number of 631 776 908 people has been assumed to live in the *Taenia solium* cysticercosis endemic areas of sub-Saharan Africa (endemic countries: [60]; populations in these endemic countries: [61]) yielding an NCC-based epilepsy population of 0.76-2.46 million and a population suffering from symptomatic NCC of 0.95-3.08 million. The same amount of people would suffer from asymptomatic NCC, if assuming that 50% of all cases are asymptomatic.

314 Novel Aspects on Cysticercosis and Neurocysticercosis

**1.5. Causes of epileptic seizures/epilepsy in sub-Saharan Africa** 

characteristics, diagnosis and treatment in the context of sub-Saharan Africa.

**2. Prevalence of neurocysticercosis in sub-Saharan Africa** 

United States, due to globalization and the migration of infected people [46-50].

epilepsy in almost 30% of people with epilepsy [56].

Causes of epileptic seizures/epilepsy are highly variable across different regions of sub-Saharan Africa and depend on geographical, climatic, political, social and hygienic conditions. However, the main and most important causes of epilepsy seem to be very similar throughout sub-Saharan Africa and have been studied in great detail, both in hospital and community settings, showing that a positive family history (genetic predisposition), a past history of febrile convulsions, perinatal neurological disorders, head injuries, cerebrovascular accidents and infections of the central nervous system account for most cases of epilepsy [6]. Also included are a variety of protozoon (the most important being cerebral malaria) and helminthic infections, of which *Taenia solium* (its larval stage causing cysticercosis) has attracted considerable attention in sub-Saharan Africa over the past few years. Therefore, epileptic seizures/epilepsy in the context of NCC will be described in more detail in the following paragraphs in order to provide adequate information on clinical

NCC represents the most common helminthic infection of the central nervous system [45] and is endemic in most countries of Latin America, Asia and sub-Saharan Africa. NCC is not only one of the major causes of acquired epileptic seizures/epilepsy in low-resource countries, but it is also of increasing concern in so far non-endemic countries, such as Europe and the

Community-based estimation of the prevalence of NCC is difficult as neuroimaging would have to be applied to a large population putting seemingly healthy people at risk of radiation and therefore has been performed rarely so far [51]. In contrast, the prevalence of human *Taenia solium* cysticercosis in communities has been assessed as this requires blood analysis only. In cysticercosis endemic areas of the Democratic Republic of Congo, Burkina Faso and Zambia the prevalence of *Taenia solium* cysticercosis as measured with an antigen-ELISA was 22%, 10% and 5.8%, respectively [52-54]. Indirect approaches are used to get an impression about the prevalence of people with NCC in a certain population and often people suffering from epileptic seizures or epilepsy are included into these studies. The prevalence of epilepsy has shown to be high in a *Taenia solium* cysticercosis endemic area from Burkina Faso which found an epilepsy lifetime prevalence of 4.5% [55]. A recent metaanalysis on the prevalence of NCC in people with epilepsy, including 12 studies mainly from Latin America, India and sub-Saharan Africa, found that NCC was the cause of

If extrapolating the above results to the entire population of sub-Saharan Africa (850 million people; [57]) and assuming a prevalence of epilepsy of 4-13/1000 [3,12], approximately 3.4 to 11.05 million people would suffer from epilepsy. Thirty per cent of it is due to NCC yielding 1.02-3.32 million people with epilepsy due to NCC in sub-Saharan Africa. Epilepsy makes up for approximately 80% of the symptoms in NCC [58] and therefore 1.28-4.15 million people would suffer from symptomatic NCC including all neurological signs/symptoms (see Latent NCC cases when harbouring *Taenia solium* cysticerci can become symptomatic at any time due to the natural course of disease or in the context of treatment received for intestinal parasites [62]. These people are also at risk of developing symptomatic disease through mass drug administration for soil-transmitted helminths and schistosomiasis, among others [63-66]. Praziquantel and albendazole, two antihelminthic drugs (see 2.6.1.), are at the heart of mass drug administration and may be able to convert latent NCC to symptomatic NCC by destroying the parasite and potentially provoking brain oedema [65,66]. Anecdotal reports of sudden onset of serious neurological signs and/or death after mass drug administration have been noted, but to date no large-scale studies on the topic of the side effects after mass drug administration in carriers of latent cysticerci have been performed. Such studies are desperately needed to evaluate the risk of symptomatic NCC with potentially ensuing death in many hundreds of thousands of people in sub-Saharan Africa. For more details on the calculation of how many people in sub-Saharan Africa would potentially be at risk of developing neurological side effects after mass drug administration of praziquantel and albendazole refer to Winkler [67].

NCC not only imposes a huge socioeconomic burden onto the health systems of affected African nations (see 2.3.), but also indicates that people who potentially could be cured from their epilepsy by antihelminthic medication are practically left untreated. Data on sub-Saharan prevalence rates of NCC in people with epileptic seizures/epilepsy are mainly based on serological results and only exist from a few countries with results of over 40% (Cameroon) depending on the serological tests used [68-70]. A recent meta-analysis that only included African studies showed a significant association between epilepsy and cysticercosis with an odds ratio of 3.4 [71]. More details on the prevalence of NCC (serology and imaging) are available from South African studies [68], where one study found 50.6% of newly diagnosed people with epilepsy showing lesions of NCC on neuroimaging [72]. The only neuroimaging-based study in sub-Saharan Africa outside South Africa was performed from our own group. Definite NCC lesions on computed tomography (CT) were demonstrated in 2.4% (5/212) of people with epilepsy, lesions highly suggestive of NCC were present in 11.3% (24/212) and lesions compatible with NCC were found in 4.2% (9/212). The NCC lesions were significantly more frequent in people with epilepsy compared to the controls [73].

Although it was clearly demonstrated that NCC in people with epilepsy from sub-Saharan Africa is prevalent, there is still some controversy regarding the manifestation of NCC in different age groups. In a recently conducted study, there was a trend of people with epilepsy and NCC being older and having their first seizure later compared to people with epilepsy without NCC [74]. Other studies also report that NCC is the cause of late-onset epilepsy [75-78]. A possible reason might be that older people with epilepsy are more susceptible to the infection. However, especially the calcified stage of NCC was found to be more common in younger people with epilepsy, whereas cysts were found to be more common in older people with epilepsy [73,74]. This may be explained by a different immunoresponse to the infection with age. The age of first manifestation of NCC seems however difficult to obtain, especially in sub-Saharan Africa, as children are often excluded from neuroimaging studies for obvious ethical reasons, although several reports have demonstrated the presence of NCC among children [79-83].

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 317

burden per capita to be between US\$ 2.6 and US\$ 4.8, which is substantial when compared to annual health expenditures of US\$ 41.3 per capita for people living in poor dwellings in that province. The overall monetary burden was calculated to vary from US\$ 18.6 million to US\$ 34.2 million depending on the method used to estimate productivity losses. The epilepsy prevalence of the Eastern Cape Province, the proportion of people with epilepsy seeking medical care and the proportion of epilepsy cases attributable to NCC as well as the proportion of work time lost due to NCC were found to have the most influence on the estimated monetary burden [88]. The total societal costs due to *Taenia solium* cysticercosis in the main pig breeding region of West Cameroon (West, Southwest and Northwest Provinces) was also recently estimated [89]. Based on an epilepsy prevalence of 3.6%, the number of people with NCC-associated epilepsy was estimated at 50 326, representing 1.0% of the local population, whereas the number of pigs diagnosed with cysticercosis was estimated at 15 961 (based on lingual examination results), which corresponds to 5.6% of the local pig population. The total annual costs due to *Taenia solium* cysticercosis in West Cameroon were estimated at € 10.3 million, of which 4.7% were due to losses in pig production and 95.3% to direct and indirect losses caused by human *Taenia solium* cysticercosis. The monetary burden per case of human NCC amounted to € 194 and the average number of Disability-Adjusted Life Years (DALYs) lost was 9.0 per thousand persons per year which was

higher than estimates for some other neglected tropical diseases [89].

resulting hydrocephalus.

**2.3. Staging, pathology and clinical characteristics of neurocysticercosis** 

In humans, after the ingestion of *Taenia solium* eggs, oncospheres hatch and penetrate the gut wall. They are transported via the bloodstream and cysticerci form within a few weeks/months, mainly in subcutaneous tissue (painless, palpable, cystic lesions), skeletal muscle (lesion may not be palpable), the eye and the central nervous system, particularly in the brain but also in the spinal cord ([90]; Figure 2). Differences in phenotype of cysticercosis between various regions of the world have been described, indicating that the subcutaneous form of cysticercosis is most frequent in Asia, least prevalent in Latin America and that reports of its occurrence are conflicting in sub-Saharan Africa [67]. Especially cysticercosis of the eye and central nervous system are of clinical importance, where cysticerci can cause inflammation and/or space-occupying lesions with a mass effect and/or obstruction with

In the brain, immature cysticerci appear within 1-4 weeks after the ingestion of eggs (stage 1). After approximately 1 month, this phase is followed by the maturation of cysticerci, which happens with surprisingly little or no inflammation (stage 2). This stage can last for more than 10 years and cysticerci survive by disarming host defences. Neurological symptoms and/or signs are not usually reported. Stage 3 (2-10 years or more after cysticerci maturation) is characterized by an intense host immunoresponse leading to the degeneration of cysticerci (granuloma), which may now cause neurological symptoms and/or signs [91]. The reasons for cysticerci to eventually be recognized by the host and thereby to go from stage 2 to stage 3 have not been understood so far. Antihelminthic treatment seems to accelerate this transition, as often the administration of antihelminthic

## **2.1. Neurocysticercosis in people with HIV/AIDS**

Most NCC endemic areas are also endemic for HIV/AIDS and interaction of the two diseases, as known for HIV/AIDS and malaria and HIV/AIDS and tuberculosis, would seem plausible. Indeed, acceleration of the clinical course of HIV/AIDS in patients co-infected with *Taenia solium* cysticerci has been suggested based on the manipulation of the immune system by the parasite [84,85]. In South Africa, NCC has been described as one of the most important focal brain lesion in people with HIV/AIDS with neurological signs depending on the location of the lesion. Interestingly intraventricular NCC seems to be especially common in patients with HIV/AIDS from South Africa presenting with epileptic seizures and signs of increased intracranial pressure, among others. Treatment with ventriculo-peritoneal shunts carries a bleak prognosis, whereas antihelminthic medication together with steroids shows a better outcome in these patients. These reports from South Africa are fairly worrying and repeated regular treatment with short courses of praziquantel together with steroids have been advocated for HIV/AIDS patients from highly endemic areas to reduce the rate of re-infection which may accelerate the course of disease, if left untreated [84]. However, to date no systematic studies on co-infection with *Taenia solium* cysticerci and HIV have been conducted in sub-Saharan Africa. Observations from South Africa indicate that co-infection is high [84,85]. Conversely, studies from India and Mexico have shown that seroprevalence of *Taenia solium* cysticercosis in patients with HIV/AIDS is lower than in the non-HIV/AIDS population, which may point to an impaired immunoreaction with unreliable detection of *Taenia solium* cysticercosis antibodies [86,87]. The fact of unreliable *Taenia solium* cysticercosis serodiagnosis could present a substantial problem in the HIV/AIDS population with focal neurological signs in whom tuberculous meningitis/tuberculoma and toxoplasmosis, two diseases with different therapeutic approaches, represent the most important differential diagnoses.

## **2.2. Monetary burden of neurocysticercosis in sub-Saharan Africa**

A comprehensive estimate of the monetary burden of cysticercosis in the *Taenia solium* cysticercosis hyperendemic Eastern Cape Province of South Africa indicated the monetary burden per capita to be between US\$ 2.6 and US\$ 4.8, which is substantial when compared to annual health expenditures of US\$ 41.3 per capita for people living in poor dwellings in that province. The overall monetary burden was calculated to vary from US\$ 18.6 million to US\$ 34.2 million depending on the method used to estimate productivity losses. The epilepsy prevalence of the Eastern Cape Province, the proportion of people with epilepsy seeking medical care and the proportion of epilepsy cases attributable to NCC as well as the proportion of work time lost due to NCC were found to have the most influence on the estimated monetary burden [88]. The total societal costs due to *Taenia solium* cysticercosis in the main pig breeding region of West Cameroon (West, Southwest and Northwest Provinces) was also recently estimated [89]. Based on an epilepsy prevalence of 3.6%, the number of people with NCC-associated epilepsy was estimated at 50 326, representing 1.0% of the local population, whereas the number of pigs diagnosed with cysticercosis was estimated at 15 961 (based on lingual examination results), which corresponds to 5.6% of the local pig population. The total annual costs due to *Taenia solium* cysticercosis in West Cameroon were estimated at € 10.3 million, of which 4.7% were due to losses in pig production and 95.3% to direct and indirect losses caused by human *Taenia solium* cysticercosis. The monetary burden per case of human NCC amounted to € 194 and the average number of Disability-Adjusted Life Years (DALYs) lost was 9.0 per thousand persons per year which was higher than estimates for some other neglected tropical diseases [89].

316 Novel Aspects on Cysticercosis and Neurocysticercosis

demonstrated the presence of NCC among children [79-83].

**2.1. Neurocysticercosis in people with HIV/AIDS** 

Although it was clearly demonstrated that NCC in people with epilepsy from sub-Saharan Africa is prevalent, there is still some controversy regarding the manifestation of NCC in different age groups. In a recently conducted study, there was a trend of people with epilepsy and NCC being older and having their first seizure later compared to people with epilepsy without NCC [74]. Other studies also report that NCC is the cause of late-onset epilepsy [75-78]. A possible reason might be that older people with epilepsy are more susceptible to the infection. However, especially the calcified stage of NCC was found to be more common in younger people with epilepsy, whereas cysts were found to be more common in older people with epilepsy [73,74]. This may be explained by a different immunoresponse to the infection with age. The age of first manifestation of NCC seems however difficult to obtain, especially in sub-Saharan Africa, as children are often excluded from neuroimaging studies for obvious ethical reasons, although several reports have

Most NCC endemic areas are also endemic for HIV/AIDS and interaction of the two diseases, as known for HIV/AIDS and malaria and HIV/AIDS and tuberculosis, would seem plausible. Indeed, acceleration of the clinical course of HIV/AIDS in patients co-infected with *Taenia solium* cysticerci has been suggested based on the manipulation of the immune system by the parasite [84,85]. In South Africa, NCC has been described as one of the most important focal brain lesion in people with HIV/AIDS with neurological signs depending on the location of the lesion. Interestingly intraventricular NCC seems to be especially common in patients with HIV/AIDS from South Africa presenting with epileptic seizures and signs of increased intracranial pressure, among others. Treatment with ventriculo-peritoneal shunts carries a bleak prognosis, whereas antihelminthic medication together with steroids shows a better outcome in these patients. These reports from South Africa are fairly worrying and repeated regular treatment with short courses of praziquantel together with steroids have been advocated for HIV/AIDS patients from highly endemic areas to reduce the rate of re-infection which may accelerate the course of disease, if left untreated [84]. However, to date no systematic studies on co-infection with *Taenia solium* cysticerci and HIV have been conducted in sub-Saharan Africa. Observations from South Africa indicate that co-infection is high [84,85]. Conversely, studies from India and Mexico have shown that seroprevalence of *Taenia solium* cysticercosis in patients with HIV/AIDS is lower than in the non-HIV/AIDS population, which may point to an impaired immunoreaction with unreliable detection of *Taenia solium* cysticercosis antibodies [86,87]. The fact of unreliable *Taenia solium* cysticercosis serodiagnosis could present a substantial problem in the HIV/AIDS population with focal neurological signs in whom tuberculous meningitis/tuberculoma and toxoplasmosis, two diseases with different

therapeutic approaches, represent the most important differential diagnoses.

**2.2. Monetary burden of neurocysticercosis in sub-Saharan Africa** 

A comprehensive estimate of the monetary burden of cysticercosis in the *Taenia solium* cysticercosis hyperendemic Eastern Cape Province of South Africa indicated the monetary

## **2.3. Staging, pathology and clinical characteristics of neurocysticercosis**

In humans, after the ingestion of *Taenia solium* eggs, oncospheres hatch and penetrate the gut wall. They are transported via the bloodstream and cysticerci form within a few weeks/months, mainly in subcutaneous tissue (painless, palpable, cystic lesions), skeletal muscle (lesion may not be palpable), the eye and the central nervous system, particularly in the brain but also in the spinal cord ([90]; Figure 2). Differences in phenotype of cysticercosis between various regions of the world have been described, indicating that the subcutaneous form of cysticercosis is most frequent in Asia, least prevalent in Latin America and that reports of its occurrence are conflicting in sub-Saharan Africa [67]. Especially cysticercosis of the eye and central nervous system are of clinical importance, where cysticerci can cause inflammation and/or space-occupying lesions with a mass effect and/or obstruction with resulting hydrocephalus.

In the brain, immature cysticerci appear within 1-4 weeks after the ingestion of eggs (stage 1). After approximately 1 month, this phase is followed by the maturation of cysticerci, which happens with surprisingly little or no inflammation (stage 2). This stage can last for more than 10 years and cysticerci survive by disarming host defences. Neurological symptoms and/or signs are not usually reported. Stage 3 (2-10 years or more after cysticerci maturation) is characterized by an intense host immunoresponse leading to the degeneration of cysticerci (granuloma), which may now cause neurological symptoms and/or signs [91]. The reasons for cysticerci to eventually be recognized by the host and thereby to go from stage 2 to stage 3 have not been understood so far. Antihelminthic treatment seems to accelerate this transition, as often the administration of antihelminthic

medication causes perifocal oedema surrounding the parasite [62]. In stage 4, the inflammatory response has resolved, either without scarring or leaving behind residual calcifications ([91]; Figure 2).

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 319

intraparenchymal NCC. Ventricular disease may cause ependymitis and/or increased intracranial pressure. Arachnoiditis, especially in the basal cisterns, which can lead to communicating hydrocephalus, vasculitis and/or compression of cerebral vessels, can result from subarachnoid disease. Intramedullary cysticerci can be found in the spinal cord, causing focal neurological symptoms/signs, and extramedullary cysticerci can cause

If cerebral cysticerci or calcifications are intraparenchymal, epileptic seizures and/or epilepsy may ensue [95,96]. During stage 3 of cyst degeneration new-onset acute symptomatic epileptic seizures can occur that usually resolve after the inflammation has died down, which is very characteristic of this phase. In the case of remaining calcifications, recurrent epileptic seizures, i.e. epilepsy, can develop, although fortunately most patients remain asymptomatic ([91,97]; see 1.1.). The majority of cysticerci calcify, but cysticerci may also become invisible on CT and magnetic resonance imaging (MRI). Although the parasite is assumed dead, intermittent flares of oedema around calcifications have been described and they seem to be associated with increased seizure activity. The mechanisms of oedema occurrence however is not fully understood, but increased antigen accessibility with subsequent enhanced immunoresponse have been suggested. Another cause for the development of epilepsy after cyst resolution is the development of perilesional gliosis

A systematic review on the clinical manifestations in people with NCC showed that the majority of symptomatic adult cases (78.9%) had epileptic seizures [58]. This may be the only presentation, especially in people with single enhancing granulomatous lesions that bears a good prognosis compared to infection with multiple cysticerci [92]. Epileptic seizures were followed by headaches in 27.7% of people [58]. Headache in people with NCC can be acute or chronic, and presents as tension-type or migraine-like episodes [98,99]. Headache can also indicate raised intracranial pressure [90]. Furthermore, adults with NCC also present with focal neurological signs (11.8%), signs of intracranial hypertension (16.3%), meningitic symptoms (5.6%), gait abnormalities (5.6%) and altered mental state/psychiatric symptoms (28.1%), among others [58]. Forlenza et al. [100] examined 38 cases with NCC and found cognitive decline in 87.5% and psychiatric illness in 65.8% of them, with depression and psychosis being the most frequent psychiatric disorders. These findings were corroborated by a study from Brazil which showed that cognitive impairment was ubiquitous in 40 patients with NCC and that dementia was obvious in 12.5% [101]. A recent interesting and well conducted study, although small in sample size, showed that people with new-onset epileptic seizures and NCC performed worse on cognitive tests including scores for attention, processing speed, learning and memory compared to controls with and without epilepsy (people with epilepsy unrelated to NCC and healthy neighbourhood controls). However, the difference was only significant for the attention score (people with epilepsy and NCC compared to epilepsy controls). Over time (6 month-follow up) people with NCC-based epilepsy, who were all treated with albendazole, had significant improvement in psychomotor speed and working memory, but there were no significant changes in any of the cognitive test scores above, although a general trend for better

radicular symptoms and/or signs [94].

around calcifications secondary to prior inflammation [97].

Courtesy of Prof. Theodore Nash who has also given permission for reproduction, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

**Figure 2.** Cross-section of a human brain showing various stages of neurocysticercosis, including cysts showing the scolex (stage 2), granulomas with surrounding inflammation (stage 3) and calcifications (stage 4). For more details refer to section 2.4. in the main body of the text.

NCC can cause a variety of symptoms and signs depending on the number, size, stage and location of the pathological changes as well as the host's immunoresponse and the parasite's genotype, or it can also be clinically asymptomatic. Post-mortem studies have shown that in up to 50% of people with NCC the cerebral lesions were asymptomatic [59]. There may be single or multiple cysticerci in the brain (intraparenchymal NCC, approximately 80%; Figure 2) and, in extreme cases, encephalitis (Figure 2) may ensue. Single enhancing (intraparenchymal) lesions (SEL) represent a separate entity that has been described mainly in patients from the Indian subcontinent. Differential diagnosis is difficult and may encompass tuberculoma, toxoplasmosis, brain abscess and tumours, among others. A lesion < 2 cm in diameter without gross perifocal oedema and subsequent growth is likely to represent a degenerating *Taenia solium* cysticercus. Patients mainly present with partial onset seizure with or without generalisation and have a high risk of seizure recurrence. Contrary to India, multiple lesions mainly of the intraparenchymal type seem to prevail in people with NCC from Latin America, sub-Saharan Africa and other Asian countries although scientific publications on NCC-related neuroimaging from sub-Saharan Africa and Asian countries other than India are rare [67,92,93].

Cysticerci can also occur in the ventricular system and/or the subarachnoid space (extraparenchymal NCC, approximately 20%), which is often associated with intraparenchymal NCC. Ventricular disease may cause ependymitis and/or increased intracranial pressure. Arachnoiditis, especially in the basal cisterns, which can lead to communicating hydrocephalus, vasculitis and/or compression of cerebral vessels, can result from subarachnoid disease. Intramedullary cysticerci can be found in the spinal cord, causing focal neurological symptoms/signs, and extramedullary cysticerci can cause radicular symptoms and/or signs [94].

318 Novel Aspects on Cysticercosis and Neurocysticercosis

calcifications ([91]; Figure 2).

medication causes perifocal oedema surrounding the parasite [62]. In stage 4, the inflammatory response has resolved, either without scarring or leaving behind residual

Courtesy of Prof. Theodore Nash who has also given permission for reproduction, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. **Figure 2.** Cross-section of a human brain showing various stages of neurocysticercosis, including cysts showing the scolex (stage 2), granulomas with surrounding inflammation (stage 3) and calcifications

NCC can cause a variety of symptoms and signs depending on the number, size, stage and location of the pathological changes as well as the host's immunoresponse and the parasite's genotype, or it can also be clinically asymptomatic. Post-mortem studies have shown that in up to 50% of people with NCC the cerebral lesions were asymptomatic [59]. There may be single or multiple cysticerci in the brain (intraparenchymal NCC, approximately 80%; Figure 2) and, in extreme cases, encephalitis (Figure 2) may ensue. Single enhancing (intraparenchymal) lesions (SEL) represent a separate entity that has been described mainly in patients from the Indian subcontinent. Differential diagnosis is difficult and may encompass tuberculoma, toxoplasmosis, brain abscess and tumours, among others. A lesion < 2 cm in diameter without gross perifocal oedema and subsequent growth is likely to represent a degenerating *Taenia solium* cysticercus. Patients mainly present with partial onset seizure with or without generalisation and have a high risk of seizure recurrence. Contrary to India, multiple lesions mainly of the intraparenchymal type seem to prevail in people with NCC from Latin America, sub-Saharan Africa and other Asian countries although scientific publications on NCC-related neuroimaging from sub-Saharan Africa and

Cysticerci can also occur in the ventricular system and/or the subarachnoid space (extraparenchymal NCC, approximately 20%), which is often associated with

(stage 4). For more details refer to section 2.4. in the main body of the text.

Asian countries other than India are rare [67,92,93].

If cerebral cysticerci or calcifications are intraparenchymal, epileptic seizures and/or epilepsy may ensue [95,96]. During stage 3 of cyst degeneration new-onset acute symptomatic epileptic seizures can occur that usually resolve after the inflammation has died down, which is very characteristic of this phase. In the case of remaining calcifications, recurrent epileptic seizures, i.e. epilepsy, can develop, although fortunately most patients remain asymptomatic ([91,97]; see 1.1.). The majority of cysticerci calcify, but cysticerci may also become invisible on CT and magnetic resonance imaging (MRI). Although the parasite is assumed dead, intermittent flares of oedema around calcifications have been described and they seem to be associated with increased seizure activity. The mechanisms of oedema occurrence however is not fully understood, but increased antigen accessibility with subsequent enhanced immunoresponse have been suggested. Another cause for the development of epilepsy after cyst resolution is the development of perilesional gliosis around calcifications secondary to prior inflammation [97].

A systematic review on the clinical manifestations in people with NCC showed that the majority of symptomatic adult cases (78.9%) had epileptic seizures [58]. This may be the only presentation, especially in people with single enhancing granulomatous lesions that bears a good prognosis compared to infection with multiple cysticerci [92]. Epileptic seizures were followed by headaches in 27.7% of people [58]. Headache in people with NCC can be acute or chronic, and presents as tension-type or migraine-like episodes [98,99]. Headache can also indicate raised intracranial pressure [90]. Furthermore, adults with NCC also present with focal neurological signs (11.8%), signs of intracranial hypertension (16.3%), meningitic symptoms (5.6%), gait abnormalities (5.6%) and altered mental state/psychiatric symptoms (28.1%), among others [58]. Forlenza et al. [100] examined 38 cases with NCC and found cognitive decline in 87.5% and psychiatric illness in 65.8% of them, with depression and psychosis being the most frequent psychiatric disorders. These findings were corroborated by a study from Brazil which showed that cognitive impairment was ubiquitous in 40 patients with NCC and that dementia was obvious in 12.5% [101]. A recent interesting and well conducted study, although small in sample size, showed that people with new-onset epileptic seizures and NCC performed worse on cognitive tests including scores for attention, processing speed, learning and memory compared to controls with and without epilepsy (people with epilepsy unrelated to NCC and healthy neighbourhood controls). However, the difference was only significant for the attention score (people with epilepsy and NCC compared to epilepsy controls). Over time (6 month-follow up) people with NCC-based epilepsy, who were all treated with albendazole, had significant improvement in psychomotor speed and working memory, but there were no significant changes in any of the cognitive test scores above, although a general trend for better

performance after treatment was visible. Both epilepsy groups were controlled for seizure frequency and antiepileptic medication was kept constant during the study period [102].

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 321

*solium* cysticercosis immunodiagnostic tests available in countries of sub-Saharan Africa. The information I have got so far, even after communicating with various stakeholders, is not much different form the information published in Winkler et al. [110] and therefore would need updating by talking to reference people of the individual countries. In summary, in Mozambique and South Africa *Taenia solium* cysticercosis antibody-ELISA has been available for some years (personal communication with Dr Lee Willingham, WHO, Geneva, Switzerland). My own cysticercosis project in collaboration with the Department of Infectious Disease and Tropical Medicine of the University of Munich and funded by the German Research Foundation is currently transferring capacity for *Taenia solium* cysticercosis antibody-ELISA to the CWGESA Regional Reference Centre for Immunodiagnosis of *Taenia solium* Infections at the University of Zambia, to Gulu University of Uganda and to Muhimbili University of Health and Allied Sciences of Tanzania. There are also plans to transfer the new T24 recombinant-based antibody-ELISA test developed by the U.S. Centers for Disease Control and Prevention to Zambia, Mozambique and Madagascar (personal communication with Dr Lee Willingham, WHO, Geneva, Switzerland) and according to the latest information training of personnel has started (personal communication with Dr Patricia Wilkins, U.S. Centers for Disease Control and Prevention, Atlanta, USA). Diagnostic possibilities for *Taenia solium* cysticercosis in terms of immunoblot currently do not exist in countries of sub-Saharan Africa. A *Taenia solium* cysticercosis antigen-ELISA has been performed over the last years in Zambia at the CWGESA Regional Reference Centre for Immunodiagnosis of *Taenia solium* Infections at the University of Zambia. Member countries of the CWGESA send samples for antigen-ELISA testing to this reference laboratory. Recently, antigen-ELISA facilities have also been established in Mozambique, Madagascar, South Africa, Burkina Faso and Cameroon (personal communication with Dr Lee Willingham, WHO, Geneva, Switzerland). Confirmation whether these tests are still functional has not been obtained from the individual countries, but could be

included into the working schedule of the next CWGESA meeting.

calcifications are classified as inactive [95,97].

Although positive serological and/or DNA-based tests may give the first indication, the gold standard of NCC diagnosis is neuroimaging, including CT and/or MRI, both of which are generally not available in sub-Saharan Africa. In neuroimaging, only a lesion showing the scolex (= head of the parasite) is classified as a definite NCC lesion and considered pathognomonic [90,106,107,109]. Active NCC is defined as the presence of any cystic lesions (with or without scolex) or lesions with ring enhancement. In contrast, parenchymal

Cysts are best visualized on MRI, whereas CT is the imaging of choice for calcifications. Cyst fluid shows the same signal than cerebrospinal fluid and is hypointense (dark signal) on T1 weighted images as well as fluid attenuated inversion recovery (FLAIR) sequences and hyperintense (bright) on T2-weighted images. In the vesicular stage of NCC, there is no surrounding oedema. Cysts are usually 1-2 cm in diameter and the scoleces inside the cysts 1-2 mm. The latter is isointense relative to brain parenchyma (Figure 3a). During the degenerative process with thickening of the cyst wall, increased protein content of the cyst fluid and surrounding inflammatory signs, the signal intensity of the cyst fluid is higher

In children with NCC from a series of studies conducted in Latin America, mainly single colloidal parenchymal cysts were seen, but heavy infection was also described. Calcifications were seen less often and the development of hydrocephalus, and basal subarachnoid disease seemed to be rare [83,103,104]. The most frequent clinical presentation in children is epileptic seizures followed by headaches and signs of elevated intracranial pressures. The only major difference compared to adults was that children portrayed relatively little psychiatric symptoms [58].

## **2.4. Diagnosis of neurocysticercosis including information on sub-Saharan Africa**

A suspected diagnosis of NCC (e.g. epileptic seizures in a patient from an area endemic for *Taenia solium* cysticercosis) should be confirmed with a combination of neuroimaging and serology, if possible. On neuroimaging cysts, granulomas and/or calcifications will support the clinically based suspicion of NCC. However, these lesions may also be caused by other pathogens and pathological processes and therefore combination with *Taenia solium* cysticercosis serology is highly desirable. Both, neuroimaging and *Taenia solium* cysticercosis serology are often not available in resource-poor settings, but routine cerebrospinal fluid analysis may point the direction and can be obtained from patients without major impairment of consciousness. Cerebrospinal fluid analysis in NCC very often is unremarkable, but it may also show signs of parasitic disease, especially in multicystic disease and intraventricular/subarachnoid forms of NCC, including slightly elevated cell count (usually not exceeding 100 cells/µl, demonstrating mononuclear pleocytosis and eosinophilia) and increased protein levels in the range of 50 to 300 mg/dl. Glucose levels are usually normal [105].

Today a wide array of serological tests for *Taenia solium* cysticercosis exist such as the antigen/antibody enzyme-linked immunosorbent assay (ELISA) and immunoblots which can be performed in serum and/or cerebrospinal fluid of suspected cases [90,106-111]. However, a positive test only indicates cysticercosis but not necessarily NCC, and the sensitivity and specificity for current infection with *Taenia solium* cysticercus and prior exposure to the parasite can vary considerably according to the test used [106, 108, 112]. In addition, polymerase chain reaction (PCR) methods for the diagnosis of *Taenia solium*  cysticercosis are under development, but so far are not part of routine diagnosis due to varying levels of sensitivities and specificities [113,114]. Also, these techniques, with highcost equipment and need for regular maintenance may not be suitable for countries of sub-Saharan Africa.

When it comes to the availability of *Taenia solium* cysticercosis serological tests in sub-Saharan Africa the information is scarce and relies on personal communication. I therefore suggest that one of the tasks of the next Cysticercosis Working Group in Eastern and Southern Africa (CWGESA) meeting should be the establishment of an accurate list of *Taenia*  *solium* cysticercosis immunodiagnostic tests available in countries of sub-Saharan Africa. The information I have got so far, even after communicating with various stakeholders, is not much different form the information published in Winkler et al. [110] and therefore would need updating by talking to reference people of the individual countries. In summary, in Mozambique and South Africa *Taenia solium* cysticercosis antibody-ELISA has been available for some years (personal communication with Dr Lee Willingham, WHO, Geneva, Switzerland). My own cysticercosis project in collaboration with the Department of Infectious Disease and Tropical Medicine of the University of Munich and funded by the German Research Foundation is currently transferring capacity for *Taenia solium* cysticercosis antibody-ELISA to the CWGESA Regional Reference Centre for Immunodiagnosis of *Taenia solium* Infections at the University of Zambia, to Gulu University of Uganda and to Muhimbili University of Health and Allied Sciences of Tanzania. There are also plans to transfer the new T24 recombinant-based antibody-ELISA test developed by the U.S. Centers for Disease Control and Prevention to Zambia, Mozambique and Madagascar (personal communication with Dr Lee Willingham, WHO, Geneva, Switzerland) and according to the latest information training of personnel has started (personal communication with Dr Patricia Wilkins, U.S. Centers for Disease Control and Prevention, Atlanta, USA). Diagnostic possibilities for *Taenia solium* cysticercosis in terms of immunoblot currently do not exist in countries of sub-Saharan Africa. A *Taenia solium* cysticercosis antigen-ELISA has been performed over the last years in Zambia at the CWGESA Regional Reference Centre for Immunodiagnosis of *Taenia solium* Infections at the University of Zambia. Member countries of the CWGESA send samples for antigen-ELISA testing to this reference laboratory. Recently, antigen-ELISA facilities have also been established in Mozambique, Madagascar, South Africa, Burkina Faso and Cameroon (personal communication with Dr Lee Willingham, WHO, Geneva, Switzerland). Confirmation whether these tests are still functional has not been obtained from the individual countries, but could be included into the working schedule of the next CWGESA meeting.

320 Novel Aspects on Cysticercosis and Neurocysticercosis

relatively little psychiatric symptoms [58].

**Africa** 

usually normal [105].

Saharan Africa.

performance after treatment was visible. Both epilepsy groups were controlled for seizure frequency and antiepileptic medication was kept constant during the study period [102].

In children with NCC from a series of studies conducted in Latin America, mainly single colloidal parenchymal cysts were seen, but heavy infection was also described. Calcifications were seen less often and the development of hydrocephalus, and basal subarachnoid disease seemed to be rare [83,103,104]. The most frequent clinical presentation in children is epileptic seizures followed by headaches and signs of elevated intracranial pressures. The only major difference compared to adults was that children portrayed

**2.4. Diagnosis of neurocysticercosis including information on sub-Saharan** 

A suspected diagnosis of NCC (e.g. epileptic seizures in a patient from an area endemic for *Taenia solium* cysticercosis) should be confirmed with a combination of neuroimaging and serology, if possible. On neuroimaging cysts, granulomas and/or calcifications will support the clinically based suspicion of NCC. However, these lesions may also be caused by other pathogens and pathological processes and therefore combination with *Taenia solium* cysticercosis serology is highly desirable. Both, neuroimaging and *Taenia solium* cysticercosis serology are often not available in resource-poor settings, but routine cerebrospinal fluid analysis may point the direction and can be obtained from patients without major impairment of consciousness. Cerebrospinal fluid analysis in NCC very often is unremarkable, but it may also show signs of parasitic disease, especially in multicystic disease and intraventricular/subarachnoid forms of NCC, including slightly elevated cell count (usually not exceeding 100 cells/µl, demonstrating mononuclear pleocytosis and eosinophilia) and increased protein levels in the range of 50 to 300 mg/dl. Glucose levels are

Today a wide array of serological tests for *Taenia solium* cysticercosis exist such as the antigen/antibody enzyme-linked immunosorbent assay (ELISA) and immunoblots which can be performed in serum and/or cerebrospinal fluid of suspected cases [90,106-111]. However, a positive test only indicates cysticercosis but not necessarily NCC, and the sensitivity and specificity for current infection with *Taenia solium* cysticercus and prior exposure to the parasite can vary considerably according to the test used [106, 108, 112]. In addition, polymerase chain reaction (PCR) methods for the diagnosis of *Taenia solium*  cysticercosis are under development, but so far are not part of routine diagnosis due to varying levels of sensitivities and specificities [113,114]. Also, these techniques, with highcost equipment and need for regular maintenance may not be suitable for countries of sub-

When it comes to the availability of *Taenia solium* cysticercosis serological tests in sub-Saharan Africa the information is scarce and relies on personal communication. I therefore suggest that one of the tasks of the next Cysticercosis Working Group in Eastern and Southern Africa (CWGESA) meeting should be the establishment of an accurate list of *Taenia*  Although positive serological and/or DNA-based tests may give the first indication, the gold standard of NCC diagnosis is neuroimaging, including CT and/or MRI, both of which are generally not available in sub-Saharan Africa. In neuroimaging, only a lesion showing the scolex (= head of the parasite) is classified as a definite NCC lesion and considered pathognomonic [90,106,107,109]. Active NCC is defined as the presence of any cystic lesions (with or without scolex) or lesions with ring enhancement. In contrast, parenchymal calcifications are classified as inactive [95,97].

Cysts are best visualized on MRI, whereas CT is the imaging of choice for calcifications. Cyst fluid shows the same signal than cerebrospinal fluid and is hypointense (dark signal) on T1 weighted images as well as fluid attenuated inversion recovery (FLAIR) sequences and hyperintense (bright) on T2-weighted images. In the vesicular stage of NCC, there is no surrounding oedema. Cysts are usually 1-2 cm in diameter and the scoleces inside the cysts 1-2 mm. The latter is isointense relative to brain parenchyma (Figure 3a). During the degenerative process with thickening of the cyst wall, increased protein content of the cyst fluid and surrounding inflammatory signs, the signal intensity of the cyst fluid is higher

than that of cerebrospinal fluid on T1-weighted images, but still hypointense compared to parenchyma, and hyperintense on T2-weighted images (colloid vesicular stage), whereas the cyst wall is hyperintense on T1- and hypointense on T2-weighted sequences. As the degeneration goes on with proliferation and retraction of the cyst wall and reabsorption of the fluid (granular nodular stage) the granuloma becomes isointense and eventually hyperintense on T1- and hypointense on T2-weighted images. Ring-enhancement or total enhancement of the degenerative cysticerci after application of contrast indicates inflammation and subsequent disruption of the blood-brain barrier with leakage of plasma into cerebral tissue and is best visualized on T1-weighted images (Figure 3b). Perifocal oedema is best seen on FLAIR sequences (bright signal) and T2-weighted images (less bright signal). Calcifications (nodular calcified stage) often go unnoticed on MRI or may appear as small iso- or hypointense lesions on T1- and T2-weighted images [115]. Subarachnoid NCC shows multiple cystic masses in the basal cisterns or Sylvian fissure, among other locations. The masses may be lobulated and compress adjacent structures. Signal intensity usually compares with that of cerebrospinal fluid on all magnetic resonance sequences and is best seen as dark signal in T1-weighted and FLAIR images (Figure 3c). Ventricular NCC shows best on T1-weighted sequences, because on T2-weighted images the high signal intensity of the cyst fluid is indistinguishable from that of the cerebrospinal fluid (refer to chapter on extraparenchymal NCC) [115]. On CT scan cysts are hypodense (Figure 4a) and granuloma may be isodense to the parenchyma and only be seen after administration of contrast (Figure 4b). Calcifications are hyperdense (Figure 4c). Extraparenchymal NCC can easily be missed on CT, especially the ventricular form.

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 323

Permission for reproduction has been obtained from SpringerWienNewYork. The pictures were originally published in Winkler AS, Willingham L 3rd, Sikasunge CS, Schmutzhard E. Epilepsy and neurocysticercosis in sub-Saharan

**Figure 4.** a-c) axial computed tomography images of various stages of neurocysticercosis lesions; 4a) pathognomonic subcortical cyst left showing the scolex with a close-by calcification; calcified subcortical cyst right with perifocal/perilesional oedema; calcification in the left temporal muscle; 4b) "ring enhancing lesion" due to a degenerating subcortical cyst in the right occipital lobe; 4c) several

In a resource-rich setting the combination of MRI and CT makes a lot of sense to neither miss cystic lesions or granulomas nor calcifications. Combination of neuroimaging and immunodiagnostic test is strongly advised and their results together with clinical, pathological and epidemiological criteria as well as response to treatment with antihelminthic drugs are summarized in the diagnostic criteria for NCC suggested by Del Brutto et al. [107,109,116]. If neither immunodiagnostic tools nor neuroimaging are available, extirpation of subcutaneous nodules and a thorough ophthalmological examination may support the suspected diagnosis [107,109,116]. Due to an emphasis on neuroimaging and serological tests, the Del Brutto criteria seem to be rather impractical for

its use in resource-poor settings and may need adjustment to suit local circumstances.

In the treatment of NCC, symptomatic (steroids, antiepileptic medication, analgesics) and potentially curative treatment (antihelminthic medications) has to be differentiated. Indication and contraindication for antihelminthic treatment as outlined below must be observed. Neuroimaging is mandatory to start treatment with antihelminthic drugs and therefore antihelminthic treatment is not indicated in most patients from sub-Saharan Africa (except South Africa), where neuroimaging is absent. If there is any doubt as to the appropriateness of antihelminthic treatment, symptomatic treatment should be favoured. In addition, the treatment approach in acutely symptomatic and life-threatening disease is

**2.5. Treatment of neurocysticercosis with a focus on sub-Saharan Africa** 

different form the more chronically symptomatic condition (see 2.5.1.).

scattered intraparenchymal calcifications most likely in the context of neurocysticercosis.

Africa. Middle European Journal of Medicine 2009; 121 (suppl 3): 3-12.

All pictures are courtesy of Prof. Hector H. Garcia, Department of Microbiology, School of Sciences, and Director Center for Global Health - Tumbes, Universidad Peruana Cayetano Heredia, Lima, Peru.

**Figure 3.** a-c): magnetic resonance images of neurocysticercosis lesions; 3a) axial T1-weighted image showing a pathognomonic cyst with scolex (approximate diameter of 1 cm) in the right occipital lobe; 3b) coronal T1-weighted contrast enhanced image, showing a cystic lesion with an enhancing rim in the left parietal lobe; 3c) sagittal T1-weighted image showing extraparenchymal subarachnoid cysticercosis with multiple, lobulated cystic lesions predominantly in the subarachnoid space (prepontine, suprasellar cistern and cisterna ambiens) as well as probable intraventricular lesions with potential dilation of the 4th ventricle.

missed on CT, especially the ventricular form.

dilation of the 4th ventricle.

than that of cerebrospinal fluid on T1-weighted images, but still hypointense compared to parenchyma, and hyperintense on T2-weighted images (colloid vesicular stage), whereas the cyst wall is hyperintense on T1- and hypointense on T2-weighted sequences. As the degeneration goes on with proliferation and retraction of the cyst wall and reabsorption of the fluid (granular nodular stage) the granuloma becomes isointense and eventually hyperintense on T1- and hypointense on T2-weighted images. Ring-enhancement or total enhancement of the degenerative cysticerci after application of contrast indicates inflammation and subsequent disruption of the blood-brain barrier with leakage of plasma into cerebral tissue and is best visualized on T1-weighted images (Figure 3b). Perifocal oedema is best seen on FLAIR sequences (bright signal) and T2-weighted images (less bright signal). Calcifications (nodular calcified stage) often go unnoticed on MRI or may appear as small iso- or hypointense lesions on T1- and T2-weighted images [115]. Subarachnoid NCC shows multiple cystic masses in the basal cisterns or Sylvian fissure, among other locations. The masses may be lobulated and compress adjacent structures. Signal intensity usually compares with that of cerebrospinal fluid on all magnetic resonance sequences and is best seen as dark signal in T1-weighted and FLAIR images (Figure 3c). Ventricular NCC shows best on T1-weighted sequences, because on T2-weighted images the high signal intensity of the cyst fluid is indistinguishable from that of the cerebrospinal fluid (refer to chapter on extraparenchymal NCC) [115]. On CT scan cysts are hypodense (Figure 4a) and granuloma may be isodense to the parenchyma and only be seen after administration of contrast (Figure 4b). Calcifications are hyperdense (Figure 4c). Extraparenchymal NCC can easily be

All pictures are courtesy of Prof. Hector H. Garcia, Department of Microbiology, School of Sciences, and Director

**Figure 3.** a-c): magnetic resonance images of neurocysticercosis lesions; 3a) axial T1-weighted image showing a pathognomonic cyst with scolex (approximate diameter of 1 cm) in the right occipital lobe; 3b) coronal T1-weighted contrast enhanced image, showing a cystic lesion with an enhancing rim in the left parietal lobe; 3c) sagittal T1-weighted image showing extraparenchymal subarachnoid cysticercosis

with multiple, lobulated cystic lesions predominantly in the subarachnoid space (prepontine, suprasellar cistern and cisterna ambiens) as well as probable intraventricular lesions with potential

Center for Global Health - Tumbes, Universidad Peruana Cayetano Heredia, Lima, Peru.

Permission for reproduction has been obtained from SpringerWienNewYork. The pictures were originally published in Winkler AS, Willingham L 3rd, Sikasunge CS, Schmutzhard E. Epilepsy and neurocysticercosis in sub-Saharan Africa. Middle European Journal of Medicine 2009; 121 (suppl 3): 3-12.

**Figure 4.** a-c) axial computed tomography images of various stages of neurocysticercosis lesions; 4a) pathognomonic subcortical cyst left showing the scolex with a close-by calcification; calcified subcortical cyst right with perifocal/perilesional oedema; calcification in the left temporal muscle; 4b) "ring enhancing lesion" due to a degenerating subcortical cyst in the right occipital lobe; 4c) several scattered intraparenchymal calcifications most likely in the context of neurocysticercosis.

In a resource-rich setting the combination of MRI and CT makes a lot of sense to neither miss cystic lesions or granulomas nor calcifications. Combination of neuroimaging and immunodiagnostic test is strongly advised and their results together with clinical, pathological and epidemiological criteria as well as response to treatment with antihelminthic drugs are summarized in the diagnostic criteria for NCC suggested by Del Brutto et al. [107,109,116]. If neither immunodiagnostic tools nor neuroimaging are available, extirpation of subcutaneous nodules and a thorough ophthalmological examination may support the suspected diagnosis [107,109,116]. Due to an emphasis on neuroimaging and serological tests, the Del Brutto criteria seem to be rather impractical for its use in resource-poor settings and may need adjustment to suit local circumstances.

### **2.5. Treatment of neurocysticercosis with a focus on sub-Saharan Africa**

In the treatment of NCC, symptomatic (steroids, antiepileptic medication, analgesics) and potentially curative treatment (antihelminthic medications) has to be differentiated. Indication and contraindication for antihelminthic treatment as outlined below must be observed. Neuroimaging is mandatory to start treatment with antihelminthic drugs and therefore antihelminthic treatment is not indicated in most patients from sub-Saharan Africa (except South Africa), where neuroimaging is absent. If there is any doubt as to the appropriateness of antihelminthic treatment, symptomatic treatment should be favoured. In addition, the treatment approach in acutely symptomatic and life-threatening disease is different form the more chronically symptomatic condition (see 2.5.1.).

#### *2.5.1. Antihelminthic and/or anti-oedematous treatment*

Currently, there are no standard treatment guidelines for NCC; therefore treatment has to be tailored to the individual case. Only active disease needs treatment with antihelminthic drugs and/or steroids. Dosages and the duration of treatment can be highly variable and mainly depend on the number, size, location and developmental stage of the cysts, their surrounding inflammatory oedema, clinical symptoms/signs (their acuteness and severity) as well as potential risk factors of treatment. On the one hand, care needs to be taken not to "over-treat" as the administration of antihelminthic drugs can cause cerebral oedema and worsen symptoms and, on the other hand, one has to be prepared to extend treatment for some months as the penetration of drugs into cysts can be poor. The follow-up of patients has to be ensured, ideally with neuroimaging, but this may not be available in resource-poor settings [90,95,117]. Although treatment has to be flexible, there are some rules of thumb that should be followed. The administration of antihelminthic drugs may elicit or increase pre-existing cerebral oedema and therefore is contraindicated in cases with increased intracranial pressure, subarachnoidal NCC in close proximity to blood vessels and NCC encephalitis (Figure 2). In these conditions, steroids should be administered alone and may later be combined with antihelminthic drugs. In intraparenchymal active NCC without signs of increased intracranial pressure, steroids should be administered simultaneously with antihelminthic treatment, at least for the first week. The antihelminthic drug of choice is albendazole, which unfortunately is not often available in sub-Saharan Africa. The suggested dose is 15 mg/kg per day for 8-15 days. Praziquantel can also be used to treat NCC, although it is not as effective as albendazole [118], but it can be found in most sub-Saharan countries. Its recommended dose is 50 mg/kg per day for 15-30 days [90,94,117]. Metabolism of praziquantel and albendazole is increased with simultaneous usage of antiepileptic drugs, in particular phenytoin and carbamazepine, and the levels of praziquantel are reduced when the drug is administered together with steroids. Co-administration with cimetidine may increase the bioavailability of praziquantel [90,94]. Alternatively the dose of praziquantel may be increased or its course shortened and repeated. Also, in resource-poor settings, patients may not be particularly compliant with treatment. The best solution would be to keep the patient in hospital for the time of treatment, but due to financial expenses the patient may not agree. To minimise costs an elegant solution may be a high-dose short-term treatment with 100 mg/kg praziquantel in three divided doses every two hours followed by corticosteroids. This treatment regimen has been demonstrated to be successful in single cyst disease, but unfortunately efficacy could not be demonstrated in patients with multiple cysts, which is the phenotype that prevails in sub-Saharan Africa [67,119,120]. Even with normal dosage and course of treatment cure rates with antihelminthic drugs in general seem to be low. In untreated patients, 40% of cysts are cleared and in treated patients 60% of cysts disappear after one course of treatment. Furthermore, rebound inflammation may occur after abrupt withdrawal of antihelminthic medication and/or steroids and may be due to overcompensation of the immune system after removal of treatment with anti-inflammatory medication [117].

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 325

progressive headache, acute symptomatic epileptic seizures) but at least for the first days antihelminthic treatment is given. So far steroid doses in the treatment of NCC have not been standardized [121]. Prednisone is recommended at a dosage of 1 mg/kg per day either p.o. or i.v.. Alternatively, dexamethasone can be used at 12-24 mg/d, maximum of 30 mg/day, p.o. or i.v.. Metabolism of both drugs may be increased by antiepileptic medication [90,94]. Steroids are used in all condition where cerebral oedema is present or may develop. To date there are only four controlled trials of the use of steroids in NCC and all of them were conducted in single enhancing granulomatous lesions (see 2.4.). Treatment regimens consisted of prednisolone 1 mg/kg for 10 days with a 4-day taper with and without antiepileptic treatment, prednisolone 1 mg/kg for 7 days with a 3-day taper without antiepileptic treatment and methylprednisolone 1 g/1.72 m2 for 5 days without antiepileptic treatment. All studies showed a decrease in epileptic seizures and three showed a significant

In summary, only confirmed active intraparenchymal and symptomatic (e.g. epileptic seizures) disease requires treatment with triple therapy, i.e. antihelminthic medication, steroids and antiepileptic medication. For antiepileptic treatment see 2.6.2. Once the parasite has gone into the transitional stage, antihelminthic drugs may no longer be needed as the parasite is already attacked and destroyed by the host. Current advice is that the symptomatic patient of the transitional stage should be maintained on symptomatic treatment only, i.e. steroids and antiepileptic medication [126]. There is however some controversy over the topic of treatment of the transitional stage and new results are expected shortly (personal communication with Prof. Hector H. Garcia, Universidad Peruana Cayetano Heredia, Lima, Peru). In inactive symptomatic disease the patient should receive antiepileptic mediation only if seizures are present. If perilesional oedema is obvious, steroids may be beneficial, although there are only anecdotal reports [121]. Treatment of extraparenchymal disease is much more tedious than that of intraparenchymal disease, and in most cases requires lengthy treatment regimens with antihelminthic medication and steroids or operative procedure if cysts are located in the ventricles [117].

Furthermore, treatment of affected individuals only represents one facet in the multifaceted approach towards the eradication of NCC. Another important step is the prevention (reducing the number of free-roaming pigs, the vaccination of pigs) and treatment of porcine cysticercosis as well as the treatment of *Taenia solium* taeniosis (human tapeworm infection; [47,67,127,128]). In addition, increasing hygienic standards in affected communities, meat inspections, educating farmers and health education within communities should be top

Antiepileptic treatment should be initiated if seizure activity is recurrent, irrespective of whether epileptic seizures occur within the setting of stage-3 symptomatic cysts or stage-4 calcifications after clearance of the parasite (see 2.2.). According to the latest guidelines of the International League Against Epilepsy [129], treatment should be initiated after the

For more details refer to the chapter of extraparenchymal NCC…

priorities in the fight against NCC. For more details refer to the chapter of ...

clearance of cysts on CT [122-125].

*2.5.2. Antiepileptic treatment* 

Steroids should be initiated together with antihelminthic drugs in intraparenchymal disease and ideally should be administered for as long as the patient is symptomatic (e.g. chronic progressive headache, acute symptomatic epileptic seizures) but at least for the first days antihelminthic treatment is given. So far steroid doses in the treatment of NCC have not been standardized [121]. Prednisone is recommended at a dosage of 1 mg/kg per day either p.o. or i.v.. Alternatively, dexamethasone can be used at 12-24 mg/d, maximum of 30 mg/day, p.o. or i.v.. Metabolism of both drugs may be increased by antiepileptic medication [90,94]. Steroids are used in all condition where cerebral oedema is present or may develop. To date there are only four controlled trials of the use of steroids in NCC and all of them were conducted in single enhancing granulomatous lesions (see 2.4.). Treatment regimens consisted of prednisolone 1 mg/kg for 10 days with a 4-day taper with and without antiepileptic treatment, prednisolone 1 mg/kg for 7 days with a 3-day taper without antiepileptic treatment and methylprednisolone 1 g/1.72 m2 for 5 days without antiepileptic treatment. All studies showed a decrease in epileptic seizures and three showed a significant clearance of cysts on CT [122-125].

In summary, only confirmed active intraparenchymal and symptomatic (e.g. epileptic seizures) disease requires treatment with triple therapy, i.e. antihelminthic medication, steroids and antiepileptic medication. For antiepileptic treatment see 2.6.2. Once the parasite has gone into the transitional stage, antihelminthic drugs may no longer be needed as the parasite is already attacked and destroyed by the host. Current advice is that the symptomatic patient of the transitional stage should be maintained on symptomatic treatment only, i.e. steroids and antiepileptic medication [126]. There is however some controversy over the topic of treatment of the transitional stage and new results are expected shortly (personal communication with Prof. Hector H. Garcia, Universidad Peruana Cayetano Heredia, Lima, Peru). In inactive symptomatic disease the patient should receive antiepileptic mediation only if seizures are present. If perilesional oedema is obvious, steroids may be beneficial, although there are only anecdotal reports [121]. Treatment of extraparenchymal disease is much more tedious than that of intraparenchymal disease, and in most cases requires lengthy treatment regimens with antihelminthic medication and steroids or operative procedure if cysts are located in the ventricles [117]. For more details refer to the chapter of extraparenchymal NCC…

Furthermore, treatment of affected individuals only represents one facet in the multifaceted approach towards the eradication of NCC. Another important step is the prevention (reducing the number of free-roaming pigs, the vaccination of pigs) and treatment of porcine cysticercosis as well as the treatment of *Taenia solium* taeniosis (human tapeworm infection; [47,67,127,128]). In addition, increasing hygienic standards in affected communities, meat inspections, educating farmers and health education within communities should be top priorities in the fight against NCC. For more details refer to the chapter of ...

### *2.5.2. Antiepileptic treatment*

324 Novel Aspects on Cysticercosis and Neurocysticercosis

anti-inflammatory medication [117].

*2.5.1. Antihelminthic and/or anti-oedematous treatment* 

Currently, there are no standard treatment guidelines for NCC; therefore treatment has to be tailored to the individual case. Only active disease needs treatment with antihelminthic drugs and/or steroids. Dosages and the duration of treatment can be highly variable and mainly depend on the number, size, location and developmental stage of the cysts, their surrounding inflammatory oedema, clinical symptoms/signs (their acuteness and severity) as well as potential risk factors of treatment. On the one hand, care needs to be taken not to "over-treat" as the administration of antihelminthic drugs can cause cerebral oedema and worsen symptoms and, on the other hand, one has to be prepared to extend treatment for some months as the penetration of drugs into cysts can be poor. The follow-up of patients has to be ensured, ideally with neuroimaging, but this may not be available in resource-poor settings [90,95,117]. Although treatment has to be flexible, there are some rules of thumb that should be followed. The administration of antihelminthic drugs may elicit or increase pre-existing cerebral oedema and therefore is contraindicated in cases with increased intracranial pressure, subarachnoidal NCC in close proximity to blood vessels and NCC encephalitis (Figure 2). In these conditions, steroids should be administered alone and may later be combined with antihelminthic drugs. In intraparenchymal active NCC without signs of increased intracranial pressure, steroids should be administered simultaneously with antihelminthic treatment, at least for the first week. The antihelminthic drug of choice is albendazole, which unfortunately is not often available in sub-Saharan Africa. The suggested dose is 15 mg/kg per day for 8-15 days. Praziquantel can also be used to treat NCC, although it is not as effective as albendazole [118], but it can be found in most sub-Saharan countries. Its recommended dose is 50 mg/kg per day for 15-30 days [90,94,117]. Metabolism of praziquantel and albendazole is increased with simultaneous usage of antiepileptic drugs, in particular phenytoin and carbamazepine, and the levels of praziquantel are reduced when the drug is administered together with steroids. Co-administration with cimetidine may increase the bioavailability of praziquantel [90,94]. Alternatively the dose of praziquantel may be increased or its course shortened and repeated. Also, in resource-poor settings, patients may not be particularly compliant with treatment. The best solution would be to keep the patient in hospital for the time of treatment, but due to financial expenses the patient may not agree. To minimise costs an elegant solution may be a high-dose short-term treatment with 100 mg/kg praziquantel in three divided doses every two hours followed by corticosteroids. This treatment regimen has been demonstrated to be successful in single cyst disease, but unfortunately efficacy could not be demonstrated in patients with multiple cysts, which is the phenotype that prevails in sub-Saharan Africa [67,119,120]. Even with normal dosage and course of treatment cure rates with antihelminthic drugs in general seem to be low. In untreated patients, 40% of cysts are cleared and in treated patients 60% of cysts disappear after one course of treatment. Furthermore, rebound inflammation may occur after abrupt withdrawal of antihelminthic medication and/or steroids and may be due to overcompensation of the immune system after removal of treatment with

Steroids should be initiated together with antihelminthic drugs in intraparenchymal disease and ideally should be administered for as long as the patient is symptomatic (e.g. chronic Antiepileptic treatment should be initiated if seizure activity is recurrent, irrespective of whether epileptic seizures occur within the setting of stage-3 symptomatic cysts or stage-4 calcifications after clearance of the parasite (see 2.2.). According to the latest guidelines of the International League Against Epilepsy [129], treatment should be initiated after the

first epileptic seizure if seizures are caused by an underlying lesion. In resource-poor settings without access to neuroimaging, an underlying lesion in the context of NCC can only be assumed if certain factors such as neurological signs on examination or a contact history with a tapeworm carrier or pigs are present. In some hospitals, electroencephalography may be available and focal activities on electroencephalograms may help decide when to start treatment.

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 327

**Route of administration** 

oral, i.v. (beware of phlebitis)

**Side effects (list nonexhaustive)** 

failure, proteinuria, impotence;

neurological/psychiatric: dizziness, drowsiness, headache, ataxia, confusion, agitation, visual disturbances (double vision often associated with peak plasma levels), dyskinesia, paraesthesia, depression, activation of psychosis; other: alopecia, arthralgia, fever, lymph node enlargement, gynaecomastia, galactorrhoea, pulmonary hypersensitivity, hyponatraemia, oedema, osteomalacia; teratogenicity;

skin and gum: gingival hypertrophy and tenderness, coarse facies, hirsutism, acne, rash\*\*\*, lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis; blood: megaloblastic anaemia (may be treated with folic acid\*\*) leucopenia, thrombocytopenia, agranulocytosis, aplastic anaemia; gastro-intestinal: nausea, vomiting, hepatitis,

liver failure;

plasma calcium

hypotonia

concentration); teratogenicity; rapid titration in status: cardiac dysrhythmias,

neurological/psychiatric: vertigo, double vision, nystagmus, tremor, confusion, dizziness, headache, insomnia dyskinesia; ataxia, slurred speech, nystagmus and blurred vision (are signs of overdosage); peripheral neuropathy, irreversible cerebellar atrophy; other: fever, polyarthritis, lymphadenopathy, rickets and osteomalacia (lowered

anorexia; genito-urinary: renal

**Antiepileptic medication (indication)** 

Phenytoin (all forms of epilepsy except absence seizures and myoclonic seizures)

1. 300 mg p.o.

days

2. (rapid) 600 mg p.o. for 3

3. (status) 1.5 g i.v. diluted 1:10 with inj. water (first 250 mg as bolus over 10 minutes, next 500 mg in 0.5 to 6 hours, next 750 mg in 1- 24 hours according to clinic) (maximum rate: 20 mg/min)

**Starting dose Titration** 

**(~usual adult maintenance dose)** 

25-50 mg p.o. per day (~200-500 mg/day\*)

Antiepileptic medication is limited in sub-Saharan Africa. The mainstay of antiepileptic treatment is phenobarbitone, although phenytoin and carbamazepine can also be found in rural African hospitals, but their supply is often erratic. Valproate is stocked only occasionally, and most times is not delivered through the national pharmacies, but relies on private donations. Dosing and potential side effects of antiepileptic medication available in sub-Saharan Africa are given in Table 1.



may help decide when to start treatment.

sub-Saharan Africa are given in Table 1.

1. 30 mg p.o.

with inj. water 3. (status) 20 mg/kg i.v. diluted 1:10 with inj. water (start with 200-400 mg) (maximum rate: 100

mg/min)

2. (rapid) 50 mg i.v., s.c. or i.m. every 6 h diluted 1:10

**Starting dose Titration** 

200 mg p.o. 200 mg p.o.

**Antiepileptic medication (indication)** 

Phenobarbitone (all forms of epilepsy; may be tried in atypical absences, atonic and tonic seizures)

Carbamazepine (partial (simple and complex) and secondary generalised tonic-clonic seizures; some primary generalised seizures; not in absences and myoclonic seizures)

first epileptic seizure if seizures are caused by an underlying lesion. In resource-poor settings without access to neuroimaging, an underlying lesion in the context of NCC can only be assumed if certain factors such as neurological signs on examination or a contact history with a tapeworm carrier or pigs are present. In some hospitals, electroencephalography may be available and focal activities on electroencephalograms

Antiepileptic medication is limited in sub-Saharan Africa. The mainstay of antiepileptic treatment is phenobarbitone, although phenytoin and carbamazepine can also be found in rural African hospitals, but their supply is often erratic. Valproate is stocked only occasionally, and most times is not delivered through the national pharmacies, but relies on private donations. Dosing and potential side effects of antiepileptic medication available in

> **(~usual adult maintenance dose)**

30 mg p.o. every 3 days (long half-life) (~60-180 mg/day)

every 3-5 days (~800-2000 mg/day)

**Side effects (list nonexhaustive)** 

neurological/psychiatric: fatigue, drowsiness, lethargy, pronounced cognitive decline,

learning disabilities, headaches, ataxia, nystagmus, dysarthria, depression, agitation, aggression, hyperkinesia (children), confusion (elderly); other: megaloblastic anaemia (may be treated with folic acid\*\*), constipation, rickets and osteomalacia (vitamin D deficiency\*\*), impotence; vitamin K deficiency\*\* and withdrawal seizures in newborns; teratogenicity rapid titration in status: respiratory depression

skin: from transient erythematous rash\*\*\* (frequent) to Stevens-Johnson syndrome, photosensitivity lupus erythematosus; blood:

leucopenia, thrombocytopenia, agranulocytosis, aplastic anaemia; cardiovascular: conduction disturbances, thromboembolism; gastrointestinal: nausea, vomiting, cholestatic jaundice, hepatitis, constipation, diarrhoea,

**Route of administration** 

oral, i.v., s.c., i.m.

oral


Epilepsy and Neurocysticercosis in Sub-Saharan Africa 329

Epileptic seizures in the context of NCC are of the secondary generalized type, but very often clinical examination does not reveal neurological signs. Therefore, in practice, it is difficult to differentiate epileptic seizure due to NCC from other types of seizures. Given the limited supply of medication, the most appropriate antiepileptic medication for seizures caused by NCC would be carbamazepine which is effective for partial seizures and secondary generalised seizures. It has generally fewer side-effects than phenytoin or the barbiturates, but reversible blurring of vision, dizziness and unsteadiness are dose-related and may be dose-limiting (Table 1). If carbamazepine is absent or if it is not tolerated, phenobarbitone and phenytoin can also be administered. However side effects may limit their use (Table 1). Therefore, if in a patient with normal neurological examination additional tests such as a positive result on *Taenia solium* cysticercosis antigen serology and/or neuroimaging indicate a focal start of the seizure, the patient should be started on carbamazepine first. As most people with epilepsy in sub-Saharan Africa do not have access to these investigations, treatment has to be started according to the suspected origin of the seizures and based on the experience of the involved physician. Also, phenobarbitone, despite its unpleasant side effect profile, has been shown to be a highly effective drug when it comes to seizure control. Surprisingly, many adults tolerate it fairly well, but its use has to be very restrictive in children and women of child bearing age because of possible cognitive decline and withdrawal seizures in the new-born, respectively (Table 1). A recent study from a *Taenia solium* cysticercosis endemic area of northern Tanzania showed that compliant people with epilepsy and NCC were well controlled on antiepileptic monotherapy with a trend towards better seizure control under carbamazepine compared to phenobarbitone. However, sample size in the groups was small and a final conclusion as to which of the two drugs leads to better seizure control in people with epilepsy and NCC cannot be drawn with certainty [74]. In addition to choosing the right antiepileptic medication, communication with the patients and their families is vital. The treatment gap for people with epilepsy in sub-Saharan Africa is substantial and it is most important to take its causative factors into consideration when counselling people with epilepsy (see 1.4.). It is also mandatory that patients who are started on antiepileptic medication and their families are informed about potentially ensuing side effects as well as the temporary nature of some of them in order to enhance compliance with medication. Follow-up appointments in short interval are advisable in the early phase of antiepileptic treatment. When informing patients about their treatment it has to be emphasized that withdrawal seizures can occur when stopping antiepileptic medication abruptly and that once their seizures abate the medication still has to be continued until the physician decides to withdraw the medication. There are no guidelines as to withdrawal of antiepileptic mediation in the context of NCC and therefore this has to be decided on a caseto-case basis. Usually withdrawal is considered when the epilepsy is in remission, i.e. the patient has to be seizure free for two years, although one year may be considered enough in resource-poor settings. Predictors for remaining seizure-free after withdrawal of antiepileptic medication seem to be normal neurological examination and use of carbamazepine prior to withdrawal [130], indicating outcome after drug withdrawal may be favourable in people with epilepsy and NCC. However, longitudinal studies on withdrawal of antiepileptic medication in people with epilepsy and NCC in sub-Saharan Africa have not

\*has a narrow therapeutic index and the relationship between dose and plasma concentration is non-linear; small dosage increases in some patients may produce large rise in plasma concentration with acute toxic side-effects; a few missed doses or a small change in drug absorption may result in a marked change in plasma concentration. \*\*consider vitamin administration together with antiepileptic medication

\*\*\*discontinue; if mild re-introduce cautiously, but discontinue immediately if recurrence

\*\*\*\*withdraw treatment immediately if vomiting, anorexia, jaundice or/and loss of seizure control occurs \*\*\*\*\*measure plasma amylase in acute abdominal pain

\*\*\*\*\*\*withdraw treatment immediately if within the first week of starting medication impairment of consciousness, increased seizure frequency, dysarthria and/or, asterixis occurs

**Table 1.** Antiepileptic medication available in sub-Saharan Africa: indication, drug loading, titration and maintenance doses as well as side effects (in the order of their availability; adjusted from [67])

Epileptic seizures in the context of NCC are of the secondary generalized type, but very often clinical examination does not reveal neurological signs. Therefore, in practice, it is difficult to differentiate epileptic seizure due to NCC from other types of seizures. Given the limited supply of medication, the most appropriate antiepileptic medication for seizures caused by NCC would be carbamazepine which is effective for partial seizures and secondary generalised seizures. It has generally fewer side-effects than phenytoin or the barbiturates, but reversible blurring of vision, dizziness and unsteadiness are dose-related and may be dose-limiting (Table 1). If carbamazepine is absent or if it is not tolerated, phenobarbitone and phenytoin can also be administered. However side effects may limit their use (Table 1). Therefore, if in a patient with normal neurological examination additional tests such as a positive result on *Taenia solium* cysticercosis antigen serology and/or neuroimaging indicate a focal start of the seizure, the patient should be started on carbamazepine first. As most people with epilepsy in sub-Saharan Africa do not have access to these investigations, treatment has to be started according to the suspected origin of the seizures and based on the experience of the involved physician. Also, phenobarbitone, despite its unpleasant side effect profile, has been shown to be a highly effective drug when it comes to seizure control. Surprisingly, many adults tolerate it fairly well, but its use has to be very restrictive in children and women of child bearing age because of possible cognitive decline and withdrawal seizures in the new-born, respectively (Table 1). A recent study from a *Taenia solium* cysticercosis endemic area of northern Tanzania showed that compliant people with epilepsy and NCC were well controlled on antiepileptic monotherapy with a trend towards better seizure control under carbamazepine compared to phenobarbitone. However, sample size in the groups was small and a final conclusion as to which of the two drugs leads to better seizure control in people with epilepsy and NCC cannot be drawn with certainty [74].

328 Novel Aspects on Cysticercosis and Neurocysticercosis

1. 600 mg p.o.

mg/min)

2. (status) 3.6 g i.v. diluted approx. 1:10 with inj. water (first 1.2 g as bolus over 10 minutes, second 1.2 g as bolus over 10 minutes, next 1.2 g in 12-24 hours according to clinic) (maximum rate: 100-200

**Starting dose Titration** 

**(~usual adult maintenance dose)** 

150-300 mg p.o. every 3 days (~ 900-3000 mg/d)

**Side effects (list nonexhaustive)** 

skin: rash, toxic epidermal necrolysis, Stevens-Johnson syndrome, vasculitis, hirsutism, acne;

blood: thrombocytopenia, inhibition of platelet aggregation, leucopenia, pancytopenia, red cell hypoplasia, fibrinogen

gastro-intestinal: nausea, vomiting, increased appetite and weight gain, impaired hepatic function leading rarely to fatal hepatic failure\*\*\*\*, rarely pancreatitis\*\*\*\*\*, hyperammonaemia; neurological/psychiatric: ataxia, tremor, dizziness, sedation (rarely lethargy and confusion associated with too high an initial dose), increased alertness, occasionally aggression, hyperactivity and behavioural disturbances, extrapyramidal symptoms, dementia, acute valproate-

reduction;

induced

\*has a narrow therapeutic index and the relationship between dose and plasma concentration is non-linear; small dosage increases in some patients may produce large rise in plasma concentration with acute toxic side-effects; a few missed doses or a small change in drug absorption may result in a marked change in plasma concentration.

\*\*\*\*\*\*withdraw treatment immediately if within the first week of starting medication impairment of consciousness,

**Table 1.** Antiepileptic medication available in sub-Saharan Africa: indication, drug loading, titration and maintenance doses as well as side effects (in the order of their availability; adjusted from [67])

\*\*\*\*withdraw treatment immediately if vomiting, anorexia, jaundice or/and loss of seizure control occurs

\*\*consider vitamin administration together with antiepileptic medication

\*\*\*\*\*measure plasma amylase in acute abdominal pain

increased seizure frequency, dysarthria and/or, asterixis occurs

\*\*\*discontinue; if mild re-introduce cautiously, but discontinue immediately if recurrence

amenorrhoea,

hair loss, oedema

encephalopathy\*\*\*\*\*\*; other: irregular periods,

gynaecomastia, hearing loss, Fanconi's syndrome, fatigue, **Route of administration** 

oral, i.v.

**Antiepileptic medication (indication)** 

Valproate (all forms of epilepsy; drug of choice in primary generalised epilepsy, generalised absences and myoclonic seizures; may be tried in atypical absences, atonic and tonic seizures, Salaam attacks; has got similar efficacy to that of phenytoin and carbamazepine in partial epilepsy)

> In addition to choosing the right antiepileptic medication, communication with the patients and their families is vital. The treatment gap for people with epilepsy in sub-Saharan Africa is substantial and it is most important to take its causative factors into consideration when counselling people with epilepsy (see 1.4.). It is also mandatory that patients who are started on antiepileptic medication and their families are informed about potentially ensuing side effects as well as the temporary nature of some of them in order to enhance compliance with medication. Follow-up appointments in short interval are advisable in the early phase of antiepileptic treatment. When informing patients about their treatment it has to be emphasized that withdrawal seizures can occur when stopping antiepileptic medication abruptly and that once their seizures abate the medication still has to be continued until the physician decides to withdraw the medication. There are no guidelines as to withdrawal of antiepileptic mediation in the context of NCC and therefore this has to be decided on a caseto-case basis. Usually withdrawal is considered when the epilepsy is in remission, i.e. the patient has to be seizure free for two years, although one year may be considered enough in resource-poor settings. Predictors for remaining seizure-free after withdrawal of antiepileptic medication seem to be normal neurological examination and use of carbamazepine prior to withdrawal [130], indicating outcome after drug withdrawal may be favourable in people with epilepsy and NCC. However, longitudinal studies on withdrawal of antiepileptic medication in people with epilepsy and NCC in sub-Saharan Africa have not

been performed so far, but would definitely be needed to be able to develop guidelines on withdrawal of antiepileptic medication in this population.

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 331

not superior to therapy with antiepileptic drugs alone. The combination treatment led to increased hospital admission, increased seizure frequency, more cases of encephalopathy and deaths. A greater proportion of lesions calcified compared to the group that was treated

In summary, treatment of NCC in the absence of neuroimaging has to be decided on an individual basis and depends on clinical symptoms and/or signs, whether acute or chronic, and on the physician's experience as well as local practice. Most patients with NCC can be maintained on antiepileptic medication alone, but steroid application may be considered in the severely ill patient bearing in mind the implication of potential differential diagnoses.

This chapter demonstrates clearly the importance of epileptic seizures/epilepsy and NCC for sub-Saharan Africa in terms of prevalence and burden of each of the two disorders, but it also emphasizes NCC as an important cause of acute symptomatic seizures and secondary epilepsy in many African countries. *Taenia solium* cysticercosis is a potentially eradicable disease and successful implementation of treatment of human taeniosis and porcine cysticercosis (please refer to other chapters in the book) as well as enforcement of hygienic measure, such as building of latrines and hand washing after toilet use, among others, may prevent many cases of epileptic seizures/epilepsy and therefore reduce individual suffering as well as socioeconomic losses to African societies. Although eradication of the disease has to be the ultimate aim, treatment of affected individuals for now should be in the forefront of activities of African physicians who attend to people with epileptic seizures/epilepsy. I have suggested how people with epileptic seizures/epilepsy and/or NCC in resource-poor settings should be approached, but want to emphasize that this is my personal opinion/experience based on many years of work as a trained neurologist in sub-Saharan Africa. Conveying my own opinion in this chapter my aim was to stimulate discussion across disciplines and nations. Hopefully national and international stakeholders, such as the ministries of health of African countries and The World Health Organization, have by now become aware that NCC and the ensuing epilepsy in sub-Saharan African represent a "silent epidemic". Affected people deserve standardized treatment maximizing its benefits but at the same time minimizing its drawbacks. In that sense I am hopeful that in the near future guidelines on how to treat people with epilepsy and/or NCC will be decided by an expert-led commission and enforced as standard of care in sub-Saharan countries by the

with antiepileptic drugs alone, in which more lesions resolved completely [135].

**3. Conclusions and outlook** 

respective national and internal stakeholders.

FLAIR; fluid attenuated inversion recovery

MRI; magnetic resonance imaging

CWGESA; Cysticercosis Working Group in Eastern and Southern Africa

HIV/AIDS; human immunodeficiency virus/acquired immunodeficiency syndrome

**List of abbreviations** 

CT; computed tomography

## *2.5.3. Treatment in the absence of neuroimaging*

The majority of patients in resource-poor settings have neither got access to neuroimaging nor to *Taenia solium* cysticercosis immunodiagnostic tests. Although positive results on *Taenia solium* cysticercosis antigen-ELISA may indicate active disease [131], treatment with antihelminthic medication must not be initiated on the basis of serology alone as cyst stage and presence of oedema cannot be estimated. Oedema can potentially be aggravated by antihelminthic medication resulting in deterioration of the patient's condition and, in the worst case, death may ensue caused by cerebral herniation leading to compression of the brainstem with severe compromise of vital functions. Therefore, I strongly suggest that in the absence of neuroimaging patients should be treated symptomatically only, i.e. anti-pain medication and antiepileptic drugs (see 2.5.2.).

The administration of steroids as symptomatic treatment in patients with signs and symptoms of increased intracranial pressure, such as chronic progressive headache in the context of suspected but not imaging-confirmed NCC, is debatable and has to be decided on an individual basis. A classical scenario where steroid administration may be advisable is in patients with acute symptomatic seizures who come from a *Taenia solium* cysticercosis endemic area. High doses of steroids may be started in these patients and tapered once symptoms abate. At the same time antiepileptic medication should be started on which the patient will be maintained until fit for withdrawal (see 2.5.2.). In this context, it is however crucial to exclude the most important differential diagnoses such as cerebral malaria, bacterial and tuberculous meningitis as well as encephalitis, among others, for which a spinal tap is necessary. The result of cerebrospinal fluid analysis is usually unequivocal for bacterial meningitis and in that case steroids are not to be started without antibacterial treatment. The result of cerebrospinal fluid analysis in tuberculous meningitis and viral encephalitis may be similar to that in NCC (although most patients with intraparenchymal NCC show normal results on cerebrospinal fluid; see 2.4.) with an unspecific medium increase in cell count and no major other obvious abnormalities, especially in a resourcepoor setting where protein and glucose often are not measured. The eosinophils may be elevated in NCC, but this is not mandatory. Therefore differential diagnosis may prove difficult, but a trial of steroids will not harm patients with tuberculous meningitis or viral encephalitis as brain oedema may be present and administration of steroids to these patients may actually improve their symptoms [132,133].

Even after satisfactory symptomatic treatment the question remains whether withholding antihelminthic treatment in patients with NCC will have disadvantages in terms of cyst clearance or seizure control. Results are controversial. Garcia et al. showed that treatment with albendazole in addition to antiepileptic medication significantly cleared the parasite and reduced seizure frequency, especially those with generalisation, when compared to the control group that received antiepileptic medication only [134]. In contrast, in another study the same combination of albendazole and antiepileptic treatment in people with NCC was not superior to therapy with antiepileptic drugs alone. The combination treatment led to increased hospital admission, increased seizure frequency, more cases of encephalopathy and deaths. A greater proportion of lesions calcified compared to the group that was treated with antiepileptic drugs alone, in which more lesions resolved completely [135].

In summary, treatment of NCC in the absence of neuroimaging has to be decided on an individual basis and depends on clinical symptoms and/or signs, whether acute or chronic, and on the physician's experience as well as local practice. Most patients with NCC can be maintained on antiepileptic medication alone, but steroid application may be considered in the severely ill patient bearing in mind the implication of potential differential diagnoses.

## **3. Conclusions and outlook**

330 Novel Aspects on Cysticercosis and Neurocysticercosis

withdrawal of antiepileptic medication in this population.

*2.5.3. Treatment in the absence of neuroimaging* 

medication and antiepileptic drugs (see 2.5.2.).

may actually improve their symptoms [132,133].

been performed so far, but would definitely be needed to be able to develop guidelines on

The majority of patients in resource-poor settings have neither got access to neuroimaging nor to *Taenia solium* cysticercosis immunodiagnostic tests. Although positive results on *Taenia solium* cysticercosis antigen-ELISA may indicate active disease [131], treatment with antihelminthic medication must not be initiated on the basis of serology alone as cyst stage and presence of oedema cannot be estimated. Oedema can potentially be aggravated by antihelminthic medication resulting in deterioration of the patient's condition and, in the worst case, death may ensue caused by cerebral herniation leading to compression of the brainstem with severe compromise of vital functions. Therefore, I strongly suggest that in the absence of neuroimaging patients should be treated symptomatically only, i.e. anti-pain

The administration of steroids as symptomatic treatment in patients with signs and symptoms of increased intracranial pressure, such as chronic progressive headache in the context of suspected but not imaging-confirmed NCC, is debatable and has to be decided on an individual basis. A classical scenario where steroid administration may be advisable is in patients with acute symptomatic seizures who come from a *Taenia solium* cysticercosis endemic area. High doses of steroids may be started in these patients and tapered once symptoms abate. At the same time antiepileptic medication should be started on which the patient will be maintained until fit for withdrawal (see 2.5.2.). In this context, it is however crucial to exclude the most important differential diagnoses such as cerebral malaria, bacterial and tuberculous meningitis as well as encephalitis, among others, for which a spinal tap is necessary. The result of cerebrospinal fluid analysis is usually unequivocal for bacterial meningitis and in that case steroids are not to be started without antibacterial treatment. The result of cerebrospinal fluid analysis in tuberculous meningitis and viral encephalitis may be similar to that in NCC (although most patients with intraparenchymal NCC show normal results on cerebrospinal fluid; see 2.4.) with an unspecific medium increase in cell count and no major other obvious abnormalities, especially in a resourcepoor setting where protein and glucose often are not measured. The eosinophils may be elevated in NCC, but this is not mandatory. Therefore differential diagnosis may prove difficult, but a trial of steroids will not harm patients with tuberculous meningitis or viral encephalitis as brain oedema may be present and administration of steroids to these patients

Even after satisfactory symptomatic treatment the question remains whether withholding antihelminthic treatment in patients with NCC will have disadvantages in terms of cyst clearance or seizure control. Results are controversial. Garcia et al. showed that treatment with albendazole in addition to antiepileptic medication significantly cleared the parasite and reduced seizure frequency, especially those with generalisation, when compared to the control group that received antiepileptic medication only [134]. In contrast, in another study the same combination of albendazole and antiepileptic treatment in people with NCC was This chapter demonstrates clearly the importance of epileptic seizures/epilepsy and NCC for sub-Saharan Africa in terms of prevalence and burden of each of the two disorders, but it also emphasizes NCC as an important cause of acute symptomatic seizures and secondary epilepsy in many African countries. *Taenia solium* cysticercosis is a potentially eradicable disease and successful implementation of treatment of human taeniosis and porcine cysticercosis (please refer to other chapters in the book) as well as enforcement of hygienic measure, such as building of latrines and hand washing after toilet use, among others, may prevent many cases of epileptic seizures/epilepsy and therefore reduce individual suffering as well as socioeconomic losses to African societies. Although eradication of the disease has to be the ultimate aim, treatment of affected individuals for now should be in the forefront of activities of African physicians who attend to people with epileptic seizures/epilepsy. I have suggested how people with epileptic seizures/epilepsy and/or NCC in resource-poor settings should be approached, but want to emphasize that this is my personal opinion/experience based on many years of work as a trained neurologist in sub-Saharan Africa. Conveying my own opinion in this chapter my aim was to stimulate discussion across disciplines and nations. Hopefully national and international stakeholders, such as the ministries of health of African countries and The World Health Organization, have by now become aware that NCC and the ensuing epilepsy in sub-Saharan African represent a "silent epidemic". Affected people deserve standardized treatment maximizing its benefits but at the same time minimizing its drawbacks. In that sense I am hopeful that in the near future guidelines on how to treat people with epilepsy and/or NCC will be decided by an expert-led commission and enforced as standard of care in sub-Saharan countries by the respective national and internal stakeholders.

## **List of abbreviations**

CT; computed tomography CWGESA; Cysticercosis Working Group in Eastern and Southern Africa FLAIR; fluid attenuated inversion recovery HIV/AIDS; human immunodeficiency virus/acquired immunodeficiency syndrome MRI; magnetic resonance imaging

NCC; neurocysticercosis

## **Author details**

Andrea Sylvia Winkler\*

*Department of Neurology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany* 

Epilepsy and Neurocysticercosis in Sub-Saharan Africa 333

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## **Acknowledgement**

I am extremely grateful to the patients of the Epilepsy Clinics of Haydom Lutheran Hospital (northern Tanzania) and Mahenge Hospital (southern Tanzania) for helping me gain all my experience which a good part of this book chapter is based on. I am further indebted to all my African, European and Canadian colleagues and friends who have always encouraged me to take up "neurology of sub-Saharan Africa" as my special field of research. I am also extremely thankful to the German Research Foundation (DFG) and the Bill and Melinda Gates foundation for supporting further work into the subject of epilepsy and NCC.

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**Chapter 13** 

© 2013 Escalaya and Burneo, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 Escalaya and Burneo, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Surgical Treatment of** 

Alejandro L. Escalaya and Jorge G. Burneo

Additional information is available at the end of the chapter

than the number and location of calcifications [8].

http://dx.doi.org/10.5772/54275

**1. Introduction** 

brain [11, 12].

**Neurocysticercosis-Related Epilepsy** 

Seizures are the most frequent clinical manifestation associated with neurocysticercosis (NCC) [1]. But, not all patients with NCC and seizures will develop epilepsy [2)]. Nearly 85% of patients with a single NCC in transitional or degenerative phase have a good seizure outcome following resolution of the lesion, and antiepileptic drugs (AEDs) withdrawal [3)]. Patients with residual calcifications and those with both recurrent seizures and multiple cysts before treatment with albendazole have the highest rate of relapse after complete disappearance of the cysts and withdrawal of AEDs [4]. Cerebral calcifications are a common finding in persons with seizures or epilepsy in endemic populations [5], and perilesional edema is associated with episodic seizure activity in patients with calcified NCC [6]. However, a high rate of negative correlations between the electroclinical localization and the topography of intracranial calcification has been reported [7], and an irritative zone in the temporal lobe is more relevant in determining the severity and frequency of seizures,

Drug-resistant epilepsy (DRE) is now defined as "failure of two adequate trials, appropriately chosen and tolerated AEDs schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom" [9]. NCC is an uncommon cause of DRE, even in endemic regions [10]. Perilesional gliosis (best visualized on magnetization transfer spin-echo magnetic resonance imaging), may cause seizures that could be difficult to control with antiepileptic drugs (AEDs) in patients with a solitary cysticercal cyst in the

Epilepsy surgery is highly effective in selected patients with DRE, has durable benefits, and improves quality of life [13]. The standard presurgical evaluation should encompass careful history and physical examination, interictal electroencephalography (EEG) including sleep, prolonged video EEG monitoring, magnetic resonance imaging (MRI) with specific


http://emedicine.medscape.com/article/1166190-overview Last accessed August 2012


## **Surgical Treatment of Neurocysticercosis-Related Epilepsy**

Alejandro L. Escalaya and Jorge G. Burneo

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54275

## **1. Introduction**

340 Novel Aspects on Cysticercosis and Neurocysticercosis

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225–229.

controlled trial. Journal of Infection 2006; 53: 65–69.

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randomized study. Journal of Clinical Neuroscience 2007; 14: 1172–1177.

American Journal of Tropical Medicine and Hygiene 2005; 72: 837–839.

Seizures are the most frequent clinical manifestation associated with neurocysticercosis (NCC) [1]. But, not all patients with NCC and seizures will develop epilepsy [2)]. Nearly 85% of patients with a single NCC in transitional or degenerative phase have a good seizure outcome following resolution of the lesion, and antiepileptic drugs (AEDs) withdrawal [3)]. Patients with residual calcifications and those with both recurrent seizures and multiple cysts before treatment with albendazole have the highest rate of relapse after complete disappearance of the cysts and withdrawal of AEDs [4]. Cerebral calcifications are a common finding in persons with seizures or epilepsy in endemic populations [5], and perilesional edema is associated with episodic seizure activity in patients with calcified NCC [6]. However, a high rate of negative correlations between the electroclinical localization and the topography of intracranial calcification has been reported [7], and an irritative zone in the temporal lobe is more relevant in determining the severity and frequency of seizures, than the number and location of calcifications [8].

Drug-resistant epilepsy (DRE) is now defined as "failure of two adequate trials, appropriately chosen and tolerated AEDs schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom" [9]. NCC is an uncommon cause of DRE, even in endemic regions [10]. Perilesional gliosis (best visualized on magnetization transfer spin-echo magnetic resonance imaging), may cause seizures that could be difficult to control with antiepileptic drugs (AEDs) in patients with a solitary cysticercal cyst in the brain [11, 12].

Epilepsy surgery is highly effective in selected patients with DRE, has durable benefits, and improves quality of life [13]. The standard presurgical evaluation should encompass careful history and physical examination, interictal electroencephalography (EEG) including sleep, prolonged video EEG monitoring, magnetic resonance imaging (MRI) with specific

© 2013 Escalaya and Burneo, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Escalaya and Burneo, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

sequences, and neuropsychological assessment. In some cases, invasive monitoring with intracranially-placed electrodes is needed for the purpose of seizure localization. Epilepsy surgery as a treatment of DRE due to NCC has been uncommonly reported.

Surgical Treatment of Neurocysticercosis-Related Epilepsy 343

**3. Epilepsy surgery in NCC and coexistence of other lesions** 

achieve good postsurgical seizure control in this set of patients.

in all six cases.

The association of NCC with hippocampal sclerosis (HS) has been reported in developing countries [17, 18]. In a cross-sectional study of 512 patients with DRE, 54.8% of them had HS, and 37% of them presented with HS plus NCC [19]. The mechanism of this association is not clarified. First, NCC might work as an initial precipitating injury leading to HS [20]. Second, the occurrence of NCC lesions in association with HS, or *vice versa*, may be merely coincidental [21]. Finally, both diseases might share common predisposing factors [10].

Leite et al. [21], in Brazil, determined the clinical and pathologic findings of 30 patients with HS and compared them with 32 patients with HS and calcified cysticercotic lesions (CCL) from an epilepsy surgery program. Preoperative data localized the focus to the anterior temporal region and patients were referred for a standardized en-bloc resection including 2 to 3 cm of the hippocampus. In three patients, a CCL ipsilateral to the atrophic hippocampus was located within the margins of resection and removed. The mean follow-up was 29.7 months. The percentage of patients with very good seizure control was similar in both groups. 81.2% patients in the HS + CCL group and 76.6% in the HS group had seizure-free outcome (*p* = 0.90]. No differences were found between the 2 groups in regards to age at seizure onset, hippocampal cell densities, or fascia dentata neo-Timm's staining patterns. Accordingly, their findings indicate that there is no need for removal of CCL in order to

Chandra et al. [22], in India, presented a series of 28 DRE cases resulting from postinfectious etiologies requiring surgery. All patients underwent a complete epilepsy presurgical evaluation. The criteria used to define infection-related DRE included absence of other potential etiologies preceding the infection as a cause of epilepsy. This was determined by reviewing the clinical history and MRI/CT scans performed at the time of onset of initial infection (the authors did not report if this initial MRI scan was with a special epilepsy protocol). The mean duration of epilepsy prior to surgery was 8.2 ± 2.1 years. Patients were followed after surgery for an average of 14.2 months. The pathologies included NCC in six cases. Four of the five cases with NCC in the temporal lobe, had HS. Histology of one of these cases showed evidence of early HS (not detected earlier on MRI, but with significant spike activity in electrocorticography). Free-seizure outcome was seen

In our center, one patient with DRE NCC-related epilepsy was assessed for possible epilepsy surgery. He was a 39 year-old man who had a previous history of a single, nonfebrile, generalized tonic–clonic seizure at age of 5. At age of 13, he began to experience recurrent seizures consisting of fear, followed by loss of awareness associated with unusual movement of the hands. He then would scream, run and have forceful eye deviation to the left. Postictal confusion and aggressiveness were reported. The episodes were lasting from two to five minutes and they would occur one to two times a month. Once a year, those events would be followed by a secondarily generalized tonic-clonic seizure. He had an unclear history of central nervous system infection at the age of two years and some developmental delay. He had been treated with three different AEDs before he was referred

## **2. Epilepsy surgery and NCC**

Rassi Neto et al. [14], in 1998, reported three cases of patients with DRE associated to calcified neurocysticercotic lesions in the temporal lobe. Two of them had MRI imaging, and one of the studies showed perilesional edema. In all cases, the epileptiform focus was demonstrated by EEG. The patients were submitted to removal of the lesion with use of perioperative electrocorticogram, also rendering possible removal of the irritative perilesional focus. In all the cases, the histologic examination showed NCC. However, the authors did not report complete histological description. Out-patient follow-up was approximately 30 months. Two patients were seizure-free and one patient presented an improvement of 95% in seizure frequency.

Chung et al. [15], in 1998, reported a 47-year-old man with intractable temporal lobe epilepsy. Computed tomography (CT) and MRI imaging showed a calcification in the region of the left medial temporal lobe, and atrophy of the hippocampal head portion. Interictal EEG and prolonged video-EEG monitoring were compatible with left temporal lobe epilepsy. The patient underwent standard left temporal lobectomy. Histologic examination revealed degenerated cysticercus and scolex, with the surrounded hippocampus showing a fascia dentada with neuronal loss and gliosis. He was seizure-free for two years after the first postoperative day.

Ooi et al. [16], in 2011, presented a 23-year-old male with recurrent focal seizures despite continued treatment with AED. CT and MRI imaging showed a calcified lesion with surrounding edema in the right frontal lobe that waxed and waned over time. After extensive presurgical evaluation, including mapping of the seizure focus to the right frontal lobe, the lesion was excised. The histological description was available. The capsule, around a degenerated cysticercus, contained marked mononuclear infiltrates that extended to adjacent brain, which showed marked astrocytosis, microgliosis, and inflammatory perivascular infiltrates. The patient was seizure-free for a period of 2 years while on AEDs until he presented again with seizures associated with perilesional edema around the one cyst in the left frontal lobe that had evolved into a calcified granuloma.

Based on these cases published in the literature, it appears important to presurgically identify the presence of perilesional gliosis (around the cysticercotic lesion), as this appeared to be an important predictor of seizure freedom following surgery. This would indicate the important role of gliosis in the generation of seizures, which are particularly difficult to treat in this group of patients. The technique of magnetization transfer spin-echo magnetic resonance imaging is useful for this purpose, as well as the use of electrocorticography when possible, which would allow delineating the epileptogenic tissue.

## **3. Epilepsy surgery in NCC and coexistence of other lesions**

342 Novel Aspects on Cysticercosis and Neurocysticercosis

**2. Epilepsy surgery and NCC** 

improvement of 95% in seizure frequency.

first postoperative day.

sequences, and neuropsychological assessment. In some cases, invasive monitoring with intracranially-placed electrodes is needed for the purpose of seizure localization. Epilepsy

Rassi Neto et al. [14], in 1998, reported three cases of patients with DRE associated to calcified neurocysticercotic lesions in the temporal lobe. Two of them had MRI imaging, and one of the studies showed perilesional edema. In all cases, the epileptiform focus was demonstrated by EEG. The patients were submitted to removal of the lesion with use of perioperative electrocorticogram, also rendering possible removal of the irritative perilesional focus. In all the cases, the histologic examination showed NCC. However, the authors did not report complete histological description. Out-patient follow-up was approximately 30 months. Two patients were seizure-free and one patient presented an

Chung et al. [15], in 1998, reported a 47-year-old man with intractable temporal lobe epilepsy. Computed tomography (CT) and MRI imaging showed a calcification in the region of the left medial temporal lobe, and atrophy of the hippocampal head portion. Interictal EEG and prolonged video-EEG monitoring were compatible with left temporal lobe epilepsy. The patient underwent standard left temporal lobectomy. Histologic examination revealed degenerated cysticercus and scolex, with the surrounded hippocampus showing a fascia dentada with neuronal loss and gliosis. He was seizure-free for two years after the

Ooi et al. [16], in 2011, presented a 23-year-old male with recurrent focal seizures despite continued treatment with AED. CT and MRI imaging showed a calcified lesion with surrounding edema in the right frontal lobe that waxed and waned over time. After extensive presurgical evaluation, including mapping of the seizure focus to the right frontal lobe, the lesion was excised. The histological description was available. The capsule, around a degenerated cysticercus, contained marked mononuclear infiltrates that extended to adjacent brain, which showed marked astrocytosis, microgliosis, and inflammatory perivascular infiltrates. The patient was seizure-free for a period of 2 years while on AEDs until he presented again with seizures associated with perilesional edema around the one

Based on these cases published in the literature, it appears important to presurgically identify the presence of perilesional gliosis (around the cysticercotic lesion), as this appeared to be an important predictor of seizure freedom following surgery. This would indicate the important role of gliosis in the generation of seizures, which are particularly difficult to treat in this group of patients. The technique of magnetization transfer spin-echo magnetic resonance imaging is useful for this purpose, as well as the use of electrocorticography

cyst in the left frontal lobe that had evolved into a calcified granuloma.

when possible, which would allow delineating the epileptogenic tissue.

surgery as a treatment of DRE due to NCC has been uncommonly reported.

The association of NCC with hippocampal sclerosis (HS) has been reported in developing countries [17, 18]. In a cross-sectional study of 512 patients with DRE, 54.8% of them had HS, and 37% of them presented with HS plus NCC [19]. The mechanism of this association is not clarified. First, NCC might work as an initial precipitating injury leading to HS [20]. Second, the occurrence of NCC lesions in association with HS, or *vice versa*, may be merely coincidental [21]. Finally, both diseases might share common predisposing factors [10].

Leite et al. [21], in Brazil, determined the clinical and pathologic findings of 30 patients with HS and compared them with 32 patients with HS and calcified cysticercotic lesions (CCL) from an epilepsy surgery program. Preoperative data localized the focus to the anterior temporal region and patients were referred for a standardized en-bloc resection including 2 to 3 cm of the hippocampus. In three patients, a CCL ipsilateral to the atrophic hippocampus was located within the margins of resection and removed. The mean follow-up was 29.7 months. The percentage of patients with very good seizure control was similar in both groups. 81.2% patients in the HS + CCL group and 76.6% in the HS group had seizure-free outcome (*p* = 0.90]. No differences were found between the 2 groups in regards to age at seizure onset, hippocampal cell densities, or fascia dentata neo-Timm's staining patterns. Accordingly, their findings indicate that there is no need for removal of CCL in order to achieve good postsurgical seizure control in this set of patients.

Chandra et al. [22], in India, presented a series of 28 DRE cases resulting from postinfectious etiologies requiring surgery. All patients underwent a complete epilepsy presurgical evaluation. The criteria used to define infection-related DRE included absence of other potential etiologies preceding the infection as a cause of epilepsy. This was determined by reviewing the clinical history and MRI/CT scans performed at the time of onset of initial infection (the authors did not report if this initial MRI scan was with a special epilepsy protocol). The mean duration of epilepsy prior to surgery was 8.2 ± 2.1 years. Patients were followed after surgery for an average of 14.2 months. The pathologies included NCC in six cases. Four of the five cases with NCC in the temporal lobe, had HS. Histology of one of these cases showed evidence of early HS (not detected earlier on MRI, but with significant spike activity in electrocorticography). Free-seizure outcome was seen in all six cases.

In our center, one patient with DRE NCC-related epilepsy was assessed for possible epilepsy surgery. He was a 39 year-old man who had a previous history of a single, nonfebrile, generalized tonic–clonic seizure at age of 5. At age of 13, he began to experience recurrent seizures consisting of fear, followed by loss of awareness associated with unusual movement of the hands. He then would scream, run and have forceful eye deviation to the left. Postictal confusion and aggressiveness were reported. The episodes were lasting from two to five minutes and they would occur one to two times a month. Once a year, those events would be followed by a secondarily generalized tonic-clonic seizure. He had an unclear history of central nervous system infection at the age of two years and some developmental delay. He had been treated with three different AEDs before he was referred

to our epilepsy program. He was a Mexican Mennonite, who immigrated to Canada at the age of 6 years, with frequent travels to his country of origin. The CT scan and the MRI study revealed right HS as well as 3 extratemporal calcified cysticerci (Figure 1). Initial presurgical evaluation indicated possible frontal epilepsy (Figure 2), but subsequent placement of intracranial electrodes identified that seizures arose from the right mesial temporal lobe (Figure 3). He underwent a right temporal lobectomy and has been seizure free for over 2 years.

Surgical Treatment of Neurocysticercosis-Related Epilepsy 345

**Figure 2.** Initial presurgical evaluation in one patient with drug resistant epilepsy with right hippocampal sclerosis and three extratemporal calcified cysticerci. Video electroencephalography monitoring was obscured by movement and muscle artifact (arrow), but the semiology of the seizures captured on video, were concerning for a possible extratemporal lobe focus, despite the initial symptom

of fear.

**Figure 1.** Preoperative imaging studies in one patient with drug resistant epilepsy. (A, B and C) Serial CT scan of the patient showing 3 extratemporal calcified cysticerci. (D) MRI fluid-attenuated inversion recovery (FLAIR) reveals a focal high signal intensity lesion in the right mesial temporal region and minimal atrophy of the hippocampus support hippocampal sclerosis.

**A B**

**C D**

years.

to our epilepsy program. He was a Mexican Mennonite, who immigrated to Canada at the age of 6 years, with frequent travels to his country of origin. The CT scan and the MRI study revealed right HS as well as 3 extratemporal calcified cysticerci (Figure 1). Initial presurgical evaluation indicated possible frontal epilepsy (Figure 2), but subsequent placement of intracranial electrodes identified that seizures arose from the right mesial temporal lobe (Figure 3). He underwent a right temporal lobectomy and has been seizure free for over 2

**Figure 1.** Preoperative imaging studies in one patient with drug resistant epilepsy. (A, B and C) Serial CT scan of the patient showing 3 extratemporal calcified cysticerci. (D) MRI fluid-attenuated inversion recovery (FLAIR) reveals a focal high signal intensity lesion in the right mesial temporal region and

minimal atrophy of the hippocampus support hippocampal sclerosis.

**Figure 2.** Initial presurgical evaluation in one patient with drug resistant epilepsy with right hippocampal sclerosis and three extratemporal calcified cysticerci. Video electroencephalography monitoring was obscured by movement and muscle artifact (arrow), but the semiology of the seizures captured on video, were concerning for a possible extratemporal lobe focus, despite the initial symptom of fear.

Surgical Treatment of Neurocysticercosis-Related Epilepsy 347

epileptogenic lesion in this set of patients. The association of NCC and HS is rather frequent,

[1] Carabin H, Ndimubanzi PC, Budke CM, Nguyen H, Qian Y, Cowan LD, et al. Clinical manifestations associated with neurocysticercosis: a systematic review. PLoS neglected

[2] Carpio A, Escobar A, Hauser WA. Cysticercosis and epilepsy: A critical review.

[3] Rajshekhar V, Jeyaseelan L. Seizure outcome in patients with a solitary cerebral

[4] Del Brutto OH. Prognostic factors for seizure recurrence after withdrawal of antiepileptic drugs in patients with neurocysticercosis. Neurology. 1994;44(9):1706-9. [5] Nash TE, Del Brutto OH, Butman JA, Corona T, Delgado-Escueta A, Duron RM, et al. Calcific neurocysticercosis and epileptogenesis. Neurology. 2004;62(11):1934-8. [6] Nash TE, Pretell EJ, Lescano AG, Bustos JA, Gilman RH, Gonzalez AE, et al. Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case-control study. The Lancet Neurology.

[7] Cukiert A, Puglia P, Scapolan HB, Vilela MM, Marino Junior R. Congruence of the topography of intracranial calcifications and epileptic foci. Arq Neuropsiquiatr.

[8] Kowacs PA, Rogacheski E, Muzzio J, Werneck LC. The role of the irritative zone and of the number and distribution of calcifications in the severity of epilepsy associated with intracranial calcifications.[Erratum appears in Arq Neuropsiquiatr. 2007 Mar;65(1):182].

[9] Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of

[11] Pradhan S, Kathuria MK, Gupta RK. Perilesional gliosis and seizure outcome: A study based on magnetization transfer magnetic resonance imaging in patients with

the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-77. [10] Velasco TR, Zanello PA, Dalmagro CL, Araujo D, Jr., Santos AC, Bianchin MM, et al. Calcified cysticercotic lesions and intractable epilepsy: a cross sectional study of 512

patients. J Neurol Neurosurg Psychiatry. 2006;77(4):485-8.

neurocysticercosis. Annals of Neurology. 2000;48(2):181-7.

further studies are necessary to clarify the mechanisms of this association.

*Epilepsy Program, Western University, London, Ontario, Canada* 

cysticercus granuloma. Neurology. 2004;62(12):2236-40.

**Author details** 

**5. References** 

Alejandro L Escalaya and Jorge G Burneo\*

tropical diseases. 2011;5(5):e1152.

Epilepsia. 1998;39(10):1025-40.

2008;7(12):1099-105.

1994;52(3):289-94.

 \*

Corresponding Author

Arq Neuropsiquiatr. 2006;64(4):905-11.

**Figure 3.** Presurgical evaluation in one patient with drug resistant epilepsy with right hippocampal sclerosis and three extratemporal calcified cysticerci. (A and B) Localization of the intracranial electrodes. (C) Invasive recordings show an ictal onset from the mesial right temporal lobe.

## **4. Conclusions**

Epilepsy surgery in NCC is rare but effective. Patient with DRE and NCC should be referred for consideration of epilepsy surgery. The presurgical evaluation is essential and extensive investigations at experienced centers may also be required. NCC itself is not necessarily the epileptogenic lesion in this set of patients. The association of NCC and HS is rather frequent, further studies are necessary to clarify the mechanisms of this association.

## **Author details**

346 Novel Aspects on Cysticercosis and Neurocysticercosis

**4. Conclusions** 

**Figure 3.** Presurgical evaluation in one patient with drug resistant epilepsy with right hippocampal sclerosis and three extratemporal calcified cysticerci. (A and B) Localization of the intracranial electrodes. (C) Invasive recordings show an ictal onset from the mesial right temporal lobe.

Epilepsy surgery in NCC is rare but effective. Patient with DRE and NCC should be referred for consideration of epilepsy surgery. The presurgical evaluation is essential and extensive investigations at experienced centers may also be required. NCC itself is not necessarily the Alejandro L Escalaya and Jorge G Burneo\* *Epilepsy Program, Western University, London, Ontario, Canada* 

## **5. References**


<sup>\*</sup> Corresponding Author

[12] de Souza A, Nalini A, Kovoor JME, Yeshraj G, Siddalingaiah HS, Thennarasu K. Perilesional gliosis around solitary cerebral parenchymal cysticerci and long-term seizure outcome: a prospective study using serial magnetization transfer imaging. Epilepsia. 2011;52(10):1918-27.

**Chapter 14** 

© 2013 Theodoros, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 Theodoros, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Extraparenchymal Neurocysticercosis** 

Neurocysticercosis (NCC) is the most common disease causing cystic lesions in the central nervous system, especially in developing and tropical countries (1-5). Although neurocysticercosis is pleomorphic in its presentation, extraparenchymal neurocysticercosis may be challenging to diagnose and treat. With increasing globalization and international travel, NCC is now being reported from many developed countries such as the USA, UK and many European countries. Neurologists and neuroradiologists in these countries are often unaware of the pre-/post-treatment radiographic patterns of extraparenchymal NCC and the potentially poor prognosis if not correctly diagnosed and managed. Herein, we review the literature on extraparenchymal neurocysticercosis as a cause of meningitis and hydrochephalus and we discuss challenges in diagnosis and management of these cases.

Extraparenchymal neurocysticercosis (NCC) is defined as neurocysticercosis involving the subarachnoid, meningeal and intraventricular space (1;6;7). Thus, the clinical manifestations of extraparenchymal NCC range from asymptomatic lesions to meningitis and

Neurocysticercosis is the most common parasitic infestation of the central nervous system worldwide (1;4-7;11;12). Extraparenchymal NCC is frequently seen in Latin American countries whereas it is less common in the Indian subcontinent. Genetic differences in *T. solium* cysticerci have been reported from different countries (15) and may contribute towards the clinical variations across countries. These variations are perhaps due to complex interactions between the host, parasite and environmental factors (13;16-18). Cysticercal meningitis, although reported to constitute 42-48% of cases in Latin American case-series of

Additional information is available at the end of the chapter

Kelesidis Theodoros

http://dx.doi.org/10.5772/48801

**1. Introduction** 

**2. Definition** 

hydrocephalus (1;6;7).

**3. Epidemiology of extraparenchymal NCC** 


## **Chapter 14**

## **Extraparenchymal Neurocysticercosis**

## Kelesidis Theodoros

348 Novel Aspects on Cysticercosis and Neurocysticercosis

Epilepsia. 2011;52(10):1918-27.

Opinion in Neurology. 2012;25(2):187-93.

Medicine and Hygiene. 2011;85(3):460-3.

Lancet Neurology. 2006;5(1):20-1.

e2.

2010;51(6):1097-100.

neurocisticercose. J bras neurocir. 1998;9(3):99-102.

with neurocysticercosis. Epileptic Disorders. 2007;9(3):292-9.

with hippocampal sclerosis? Epilepsia. 2010;51(11):2359-60.

lobe epilepsy. Neurology. 2000;55(10):1485-91.

[12] de Souza A, Nalini A, Kovoor JME, Yeshraj G, Siddalingaiah HS, Thennarasu K. Perilesional gliosis around solitary cerebral parenchymal cysticerci and long-term seizure outcome: a prospective study using serial magnetization transfer imaging.

[13] Wiebe S, Jette N. Epilepsy surgery utilization: who, when, where, and why? Current

[14] Rassi Neto A, Centeno RS, Ferraz F. Tratamento cirúrgico da epilepsia associada à

[15] Chung CK, Lee SK, Chi JG. Temporal lobe epilepsy caused by intrahippocampal calcified cysticercus: a case report. Journal of Korean medical science. 1998;13(4):445-8. [16] Ooi WW, Wijemanne S, Thomas CB, Quezado M, Brown CR, Nash TE. Short report: A calcified Taenia solium granuloma associated with recurrent perilesional edema causing refractory seizures: Histopathological features. American Journal of Tropical

[17] Bianchin MM, Velasco TR, Takayanagui OM, Sakamoto AC. Neurocysticercosis, mesial temporal lobe epilepsy, and hippocampal sclerosis: An association largely ignored.

[18] Singla M, Singh P, Kaushal S, Bansal R, Singh G. Hippocampal sclerosis in association

[19] Bianchin MM, Velasco TR, Wichert-Ana L, Takayanagui OM, Leite JP, Sakamoto AC. How frequent is the association of neurocysticercosis and mesial temporal lobe epilepsy

[20] Rathore CT, B. ; Kesavadas, C. ; Radhakrishnan, K. Calcified neurocysticercosis lesions and hippocampal sclerosis: Potential dual pathology? Epilepsia. 2012;53(4):e60-

[21] Leite JP, Terra-Bustamante VC, Fernandes RMF, Santos AC, Chimelli L, Sakamoto AC, et al. Calcified neurocysticercotic lesions and postsurgery seizure control in temporal

[22] Chandra PS, Bal C, Garg A, Gaikwad S, Prasad K, Sharma BS, et al. Surgery for medically intractable epilepsy due to postinfectious etiologies. Epilepsia. Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/48801

## **1. Introduction**

Neurocysticercosis (NCC) is the most common disease causing cystic lesions in the central nervous system, especially in developing and tropical countries (1-5). Although neurocysticercosis is pleomorphic in its presentation, extraparenchymal neurocysticercosis may be challenging to diagnose and treat. With increasing globalization and international travel, NCC is now being reported from many developed countries such as the USA, UK and many European countries. Neurologists and neuroradiologists in these countries are often unaware of the pre-/post-treatment radiographic patterns of extraparenchymal NCC and the potentially poor prognosis if not correctly diagnosed and managed. Herein, we review the literature on extraparenchymal neurocysticercosis as a cause of meningitis and hydrochephalus and we discuss challenges in diagnosis and management of these cases.

## **2. Definition**

Extraparenchymal neurocysticercosis (NCC) is defined as neurocysticercosis involving the subarachnoid, meningeal and intraventricular space (1;6;7). Thus, the clinical manifestations of extraparenchymal NCC range from asymptomatic lesions to meningitis and hydrocephalus (1;6;7).

## **3. Epidemiology of extraparenchymal NCC**

Neurocysticercosis is the most common parasitic infestation of the central nervous system worldwide (1;4-7;11;12). Extraparenchymal NCC is frequently seen in Latin American countries whereas it is less common in the Indian subcontinent. Genetic differences in *T. solium* cysticerci have been reported from different countries (15) and may contribute towards the clinical variations across countries. These variations are perhaps due to complex interactions between the host, parasite and environmental factors (13;16-18). Cysticercal meningitis, although reported to constitute 42-48% of cases in Latin American case-series of

© 2013 Theodoros, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Theodoros, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

NC, is somewhat uncommon with <8% of cases having meningitis among adult patients (6- 9;19). Extraparenchymal NCC is also of emerging importance in developed countries (11;20). This increase likely includes extraparenchymal cases, and a recent study reported an overall frequency of subarachnoid cysts in 2%, ventricular cysts in 6%, and hydrocephalus in 16% of NCC cases (11). These cases represented almost one-third of NCC in a medical center in New Mexico (21). Intraventricular NCC, the presence of *Taenia solium* cysts in the cerebral ventricular system, occurs in 7–30% of patients with NCC (10;21-23).Thus, extraparenchymal NCC is probably more frequent than previously thought (14;18).

Extraparenchymal Neurocysticercosis 351

**4.3. Intraventricular NCC** 

**4.4. Extramedullary cysticercosis** 

Hydrocephalus can result either because of direct obstruction of cerebrospinal fluid (CSF) pathways by intraventricular cysts or secondary to inflammatory obstruction. Intraventricular neurocysticercal cysts occur singly or in multiples and frequently coexist with parenchymal and sub-arachnoid cysts (10;21-23). Intracranial hypertension is a common manifestation of extraparenhymal NCC and the increased intracranial pressure can be from the mass effect of a giant subarachnoid cyst (27), or from obstructive hydrocephalus produced by direct obstruction of the ventricular system by a cyst (28), distortion of ventricular CSF pathways (29), or blockage of CSF pathways within the subarachnoid space from the inflammatory reaction (28). However, a cyst in the fourth ventricle tends to be

Involvement of the spinal cord is rare, accounting for 1–5% of all cases of NCC (30;31). Spinal NCC may be intramedullary or extramedullary (intradural or extradural); however these forms are rare, and most disease involves the subarachnoid spaces, which may result from direct CSF dissemination (30;31). It has been suggested that small, or developing larvae present in the subarachnoid space settle to the basal cisterns by way of gravity and then further descend into the subarachnoid spaces of the lower parts of the spine including the lumbosacral space where they find adequate room to grow and develop (30;31). Many of the pathologic descriptions of cysticerci recovered from the spinal canal have a racemose morphology, which consists of membranous cells that proliferate, which may cause seeding of the spine from the base of the brain and subsequent growth (30;31). Cervical involvement consists mostly of unilocular or multilocular cystic forms, primarily due to direct extension of cysts located in the basal subarachnoid cisterns (30;31). Conversely, lumbosacral involvement has a more varied picture including multilocular cystic lesions causing spinal displacement or flattening, and clumping or displacement of the nerve roots most likely due to adhesive arachnoiditis (30;31). Clinical signs can be caused by direct compression of the spinal cord and/or roots by cysticerci or, indirectly, by the inflammatory reaction, including

Ocular cysticercosis is caused by the growth of the larvae of Taenia solium within the ocular tissues and the cysts may be located in descending order of frequency, subretinal space (35%), vitreous (22%), conjunctiva (22%), anterior segment (5%) and orbit (1%)(32). The extraocular muscle form is the most common type of orbital cysticercosis (33-35). In the ocular form, the most favored sites are the vitreous and the subretinal space whereas the inferior rectus and the medial rectus are the most common extraocular muscles involved (33-35). Intraocular cysticercosis is predominant in the Western countries, whereas extraocular is more common in the Indian population and several authors have attributed geographic and environmental factors to this difference (33-35). The continuation of the

solitary, without accompanying parenchymal cysts (10;21-23).

progressive paraparesis and sphincter disturbances.

**4.5. Orbital neurocysticercosis** 

## **4. Pathogenesis of extraparenchymal NCC**

## **4.1. Subarachnoid NCC**

The disease occurs when humans ingest eggs of *Taenia solium* from contaminated food (1). Brain parenchyma is most likely seeded through hematogenous dissemination and the ventricular system, subarachnoid space, and basal cisterns are then seeded via the choroid plexus (1). When cysts lodge outside the brain parenchyma (extraparenchymal NCC), they tend to grow irregularly depending on the space available and usually elicit a strong inflammatory response. Subarachnoid cysts can also grow abnormally as a membranous and/or cystic mass called racemose cysticercosis (7). Occasionally the cysts enlarge considerably, become racemose without scolices and cause mass effects. Cysticercus racemose is characterized by larger size (4–12 cm), absence of scolex and a variable appearance. Cysticercus racemosus is a form multilobular grape-like cluster without scolex thought to be a *forme fruste* of cysticercus cellulosae (24), most frequently located in the basal cisterns, Sylvian fissure, or ventricles (10;21-23).These cysts continually grow compared with intraparenchymal NCC and commonly result in basilar arachnoiditis (7) with inflammation and fibrosis in and around critical structures, causing meningeal inflammation, hydrocephalus due to CSF outflow obstruction, or cerebrovascular complications (10;21-23). The cyst often tends to migrate to the fourth ventricle because of gravity and CSF flow patterns (10;21-23). Although neurocysticerci undergo four stages of involution: vesicular, colloidal, granulovacuvolar and calcific, this evolution does not occur in the intraventricular or the subarachnoid forms (or racemose type) of NCC (25).

## **4.2. Cysticercal meningitis**

"Racemose" cysticercosis is associated with an intense inflammatory reaction and progressive thickening of the leptomeninges at the base of the brain. Signs of meningitis, cranial nerve palsy and cerebral infarcts secondary to vasculitis may also develop (26). In approximately 50–60% of the cases, there is an obstruction of the CSF circulation, resulting in progressive intracranial hypertension and hydrocephalus and mortality of over 20% of cases (26). When hydrocephalus secondary to cysticercotic meningitis is present, the mortality rate is high (50%) and most patients die within 2 years after CSF shunting(4). Therefore, basal cisternal locations are considered to be malignant forms of NCC (26).

## **4.3. Intraventricular NCC**

350 Novel Aspects on Cysticercosis and Neurocysticercosis

**4. Pathogenesis of extraparenchymal NCC** 

**4.1. Subarachnoid NCC** 

**4.2. Cysticercal meningitis** 

NC, is somewhat uncommon with <8% of cases having meningitis among adult patients (6- 9;19). Extraparenchymal NCC is also of emerging importance in developed countries (11;20). This increase likely includes extraparenchymal cases, and a recent study reported an overall frequency of subarachnoid cysts in 2%, ventricular cysts in 6%, and hydrocephalus in 16% of NCC cases (11). These cases represented almost one-third of NCC in a medical center in New Mexico (21). Intraventricular NCC, the presence of *Taenia solium* cysts in the cerebral ventricular system, occurs in 7–30% of patients with NCC (10;21-23).Thus,

The disease occurs when humans ingest eggs of *Taenia solium* from contaminated food (1). Brain parenchyma is most likely seeded through hematogenous dissemination and the ventricular system, subarachnoid space, and basal cisterns are then seeded via the choroid plexus (1). When cysts lodge outside the brain parenchyma (extraparenchymal NCC), they tend to grow irregularly depending on the space available and usually elicit a strong inflammatory response. Subarachnoid cysts can also grow abnormally as a membranous and/or cystic mass called racemose cysticercosis (7). Occasionally the cysts enlarge considerably, become racemose without scolices and cause mass effects. Cysticercus racemose is characterized by larger size (4–12 cm), absence of scolex and a variable appearance. Cysticercus racemosus is a form multilobular grape-like cluster without scolex thought to be a *forme fruste* of cysticercus cellulosae (24), most frequently located in the basal cisterns, Sylvian fissure, or ventricles (10;21-23).These cysts continually grow compared with intraparenchymal NCC and commonly result in basilar arachnoiditis (7) with inflammation and fibrosis in and around critical structures, causing meningeal inflammation, hydrocephalus due to CSF outflow obstruction, or cerebrovascular complications (10;21-23). The cyst often tends to migrate to the fourth ventricle because of gravity and CSF flow patterns (10;21-23). Although neurocysticerci undergo four stages of involution: vesicular, colloidal, granulovacuvolar and calcific, this evolution does not occur

extraparenchymal NCC is probably more frequent than previously thought (14;18).

in the intraventricular or the subarachnoid forms (or racemose type) of NCC (25).

"Racemose" cysticercosis is associated with an intense inflammatory reaction and progressive thickening of the leptomeninges at the base of the brain. Signs of meningitis, cranial nerve palsy and cerebral infarcts secondary to vasculitis may also develop (26). In approximately 50–60% of the cases, there is an obstruction of the CSF circulation, resulting in progressive intracranial hypertension and hydrocephalus and mortality of over 20% of cases (26). When hydrocephalus secondary to cysticercotic meningitis is present, the mortality rate is high (50%) and most patients die within 2 years after CSF shunting(4).

Therefore, basal cisternal locations are considered to be malignant forms of NCC (26).

Hydrocephalus can result either because of direct obstruction of cerebrospinal fluid (CSF) pathways by intraventricular cysts or secondary to inflammatory obstruction. Intraventricular neurocysticercal cysts occur singly or in multiples and frequently coexist with parenchymal and sub-arachnoid cysts (10;21-23). Intracranial hypertension is a common manifestation of extraparenhymal NCC and the increased intracranial pressure can be from the mass effect of a giant subarachnoid cyst (27), or from obstructive hydrocephalus produced by direct obstruction of the ventricular system by a cyst (28), distortion of ventricular CSF pathways (29), or blockage of CSF pathways within the subarachnoid space from the inflammatory reaction (28). However, a cyst in the fourth ventricle tends to be solitary, without accompanying parenchymal cysts (10;21-23).

## **4.4. Extramedullary cysticercosis**

Involvement of the spinal cord is rare, accounting for 1–5% of all cases of NCC (30;31). Spinal NCC may be intramedullary or extramedullary (intradural or extradural); however these forms are rare, and most disease involves the subarachnoid spaces, which may result from direct CSF dissemination (30;31). It has been suggested that small, or developing larvae present in the subarachnoid space settle to the basal cisterns by way of gravity and then further descend into the subarachnoid spaces of the lower parts of the spine including the lumbosacral space where they find adequate room to grow and develop (30;31). Many of the pathologic descriptions of cysticerci recovered from the spinal canal have a racemose morphology, which consists of membranous cells that proliferate, which may cause seeding of the spine from the base of the brain and subsequent growth (30;31). Cervical involvement consists mostly of unilocular or multilocular cystic forms, primarily due to direct extension of cysts located in the basal subarachnoid cisterns (30;31). Conversely, lumbosacral involvement has a more varied picture including multilocular cystic lesions causing spinal displacement or flattening, and clumping or displacement of the nerve roots most likely due to adhesive arachnoiditis (30;31). Clinical signs can be caused by direct compression of the spinal cord and/or roots by cysticerci or, indirectly, by the inflammatory reaction, including progressive paraparesis and sphincter disturbances.

## **4.5. Orbital neurocysticercosis**

Ocular cysticercosis is caused by the growth of the larvae of Taenia solium within the ocular tissues and the cysts may be located in descending order of frequency, subretinal space (35%), vitreous (22%), conjunctiva (22%), anterior segment (5%) and orbit (1%)(32). The extraocular muscle form is the most common type of orbital cysticercosis (33-35). In the ocular form, the most favored sites are the vitreous and the subretinal space whereas the inferior rectus and the medial rectus are the most common extraocular muscles involved (33-35). Intraocular cysticercosis is predominant in the Western countries, whereas extraocular is more common in the Indian population and several authors have attributed geographic and environmental factors to this difference (33-35). The continuation of the

retina with the optic nerve allows direct communication of the subarachnoid space with subretinal space but it remains unclear whether subretinal NCC can be considered another form of subarachnoid NCC (33-35).

Extraparenchymal Neurocysticercosis 353

cause chronic cysticercal meningitis. Cysticercal meningitis (CM) is characterized by inflammatory cerebrospinal fluid (CSF) and negative bacterial and fungal cultures (8). There have been no systematic studies of CM. In a recent study of patients with CM these patients often had intracranial hypertension, meningeal signs, CSF hypoglycorrachia, positive CSF results in an enzyme-linked immunosorbent assay (ELISA) for cysticercal antigens, negative CSF cultures for bacteria, fungi, and mycobacteria and longer clinical course of NCC (8). The management of the chronic inflammation and the complications caused by this meningitis are usually very difficult, and the mortality rate can be up to 33% (10;21-23). It is likely that CM is often not identified and its correct identification may reduce morbidity and risks of unnecessary surgery in patients with chronic

The diagnosis of NCC is often made based on presence of lesion highly suggestive of neurocysticercosis on neuroimaging study , positive serum immunoassay for the detection of anticysticercal antibodies , positive CSF immunoassay for detection of anticysticercal antibodies and epidemiologic criteria including individual coming from an area where cysticercosis is endemic (1).These diagnostic criteria have been stratified in four categories—absolute, major, minor, and epidemiological- on the basis of their individual diagnostic strength(1). Based on a previous consensus, the absolute criterion for the diagnosis of neurocysticercosis that is being considered as pathognomonic of this disease is the detection of a scolex inside a cyst by CT or MRI although, *C. racemosus* doesn't have a

Extraparenchymal NCC is associated with a local inflammatory response with high protein concentration and cell counts in the CSF (8). Clinical manifestations and CSF findings are similar to the more common tuberculous meningitis, (8;23) and other forms of chronic meningitis including chronic HIV- associated meningitis (42;43) since the CSF findings consist of pleocytosis (usually lymphocytic but frequently polymorphonuclear) , reduced glucose and elevated protein(8). In one series of cysticercal meningoencephalitis, confusion with tubercular meningitis was present in 61.5% cases (7;8). An important differentiating feature with these other forms of chronic meningitis is the presence of eosinophils in the CSF (7;8) which is usually seen only in the initial phases of the illness (8;21). However, this staining of the CSF is not routinely done in most places (8;23). Although the suspicion of NCC as the cause of chronic meningitis is increased when CSF eosinophils are found, CSF eosinophils (above 5%) occur in only 15% of patients (21). It is often a common practice to attribute chronic meningitis and hydrocephalus to tubercular meningitis in the presence of appropriate epidemiologic history and treat empirically by shunting and anti-tubercular therapy. Thus, an astute clinical acumen is required to make

neurocysticercosis and CSF shunts (10;21-23).

**6. Diagnosis of extraparenchymal NCC** 

scolex (1).

**6.1. Clinical presentation** 

the diagnosis of CM.

There is lack of understanding of the pathophysiology of extraparenchymal NCC. Circulating antigen detection assays could help establish if living parasites are still present after apparent radiographic cyst regression, providing an indication to continue or reuse antiparasitic treatment (36). It is unclear whether chronic inflammation in extraparenchymal NCC is due to continuous cyst degeneration, or continuous antigen release from dead parasitic tissues (37). Newer mechanisms are being explored to understand the complex neuropathology and heterogeneity of NCC.

## **5. Clinical manifestations of extraparenchymal NCC**

The clinical and radiologic manifestations of NCC are pleomorphic. Epilepsy, present in both intraparenchymal and extraparenchymal NCC, focal neurological signs, and headache are the most common clinical manifestations of the disease (1;38). Focal neurological signs that vary according to the size, number and location of the parasites have been described in up to 20% patients with neurocysticercosis (1;38). Pyramidal tract signs predominate, but sensory deficits, involuntary movements, and signs of brainstem dysfunction, may occur in some patients (1;38). These manifestations usually follow a subacute or chronic course resembling that of a brain tumor and are most often seen in patients with large subarachnoid cysts compressing the brain parenchyma (1;38). Thus, several varieties of NCC have been recognized depending upon the number, location, and evolutionary stage of the cysticerci in the human brain (39).

Extraparenchymal NCC occurs mainly in young adult males and is uncommon in children (38;40). The patients typically present with subacute or chronic intracranial hypertension from mass effect or hydrocephalus; chronic meningitis characterized by lack of meningeal signs of exam, often due to chronicity of symptoms , a mild-to-moderate CSF lymphocytic pleocytosis and moderate-high increase in protein; radiographic hydrocephalus with or without obvious cysts; radiographic presence of cysts in the ventricles or subarachnoid space and protracted clinical or radiographic course after antiparasitic treatment (8;21). Stroke can occur secondary to vasculitis caused by inflammatory occlusion of the arteries at the base of the brain secondary to arachnoiditis (4;5;12).

Hydrocephalus develops in approximately 30% of all patients with NCC because of obstruction by intraventricular or subarachnoid lesions (10;21-23). Intraventricular NCC can cause non-communicating hydrocephalus by obstructing the CSF pathway and communicating hydrocephalus by development of ependymitis (10;21-23). Abrupt permanent obstruction can cause sudden death due to brain herniation (10;21-23). Lifethreatening acute intermittent hydrocephalus (Brunn syndrome)(41) can occur due to cyst-inducing intermittent CSF obstruction from a ball-valve mechanism (10;22). Overall, extraparenchymal NCC has a more aggressive behavior and a higher morbidity and mortality rate than parenchymal form (10;21-23). Presence of sub-arachnoid cysts can cause chronic cysticercal meningitis. Cysticercal meningitis (CM) is characterized by inflammatory cerebrospinal fluid (CSF) and negative bacterial and fungal cultures (8). There have been no systematic studies of CM. In a recent study of patients with CM these patients often had intracranial hypertension, meningeal signs, CSF hypoglycorrachia, positive CSF results in an enzyme-linked immunosorbent assay (ELISA) for cysticercal antigens, negative CSF cultures for bacteria, fungi, and mycobacteria and longer clinical course of NCC (8). The management of the chronic inflammation and the complications caused by this meningitis are usually very difficult, and the mortality rate can be up to 33% (10;21-23). It is likely that CM is often not identified and its correct identification may reduce morbidity and risks of unnecessary surgery in patients with chronic neurocysticercosis and CSF shunts (10;21-23).

## **6. Diagnosis of extraparenchymal NCC**

The diagnosis of NCC is often made based on presence of lesion highly suggestive of neurocysticercosis on neuroimaging study , positive serum immunoassay for the detection of anticysticercal antibodies , positive CSF immunoassay for detection of anticysticercal antibodies and epidemiologic criteria including individual coming from an area where cysticercosis is endemic (1).These diagnostic criteria have been stratified in four categories—absolute, major, minor, and epidemiological- on the basis of their individual diagnostic strength(1). Based on a previous consensus, the absolute criterion for the diagnosis of neurocysticercosis that is being considered as pathognomonic of this disease is the detection of a scolex inside a cyst by CT or MRI although, *C. racemosus* doesn't have a scolex (1).

## **6.1. Clinical presentation**

352 Novel Aspects on Cysticercosis and Neurocysticercosis

form of subarachnoid NCC (33-35).

neuropathology and heterogeneity of NCC.

the cysticerci in the human brain (39).

the base of the brain secondary to arachnoiditis (4;5;12).

**5. Clinical manifestations of extraparenchymal NCC** 

retina with the optic nerve allows direct communication of the subarachnoid space with subretinal space but it remains unclear whether subretinal NCC can be considered another

There is lack of understanding of the pathophysiology of extraparenchymal NCC. Circulating antigen detection assays could help establish if living parasites are still present after apparent radiographic cyst regression, providing an indication to continue or reuse antiparasitic treatment (36). It is unclear whether chronic inflammation in extraparenchymal NCC is due to continuous cyst degeneration, or continuous antigen release from dead parasitic tissues (37). Newer mechanisms are being explored to understand the complex

The clinical and radiologic manifestations of NCC are pleomorphic. Epilepsy, present in both intraparenchymal and extraparenchymal NCC, focal neurological signs, and headache are the most common clinical manifestations of the disease (1;38). Focal neurological signs that vary according to the size, number and location of the parasites have been described in up to 20% patients with neurocysticercosis (1;38). Pyramidal tract signs predominate, but sensory deficits, involuntary movements, and signs of brainstem dysfunction, may occur in some patients (1;38). These manifestations usually follow a subacute or chronic course resembling that of a brain tumor and are most often seen in patients with large subarachnoid cysts compressing the brain parenchyma (1;38). Thus, several varieties of NCC have been recognized depending upon the number, location, and evolutionary stage of

Extraparenchymal NCC occurs mainly in young adult males and is uncommon in children (38;40). The patients typically present with subacute or chronic intracranial hypertension from mass effect or hydrocephalus; chronic meningitis characterized by lack of meningeal signs of exam, often due to chronicity of symptoms , a mild-to-moderate CSF lymphocytic pleocytosis and moderate-high increase in protein; radiographic hydrocephalus with or without obvious cysts; radiographic presence of cysts in the ventricles or subarachnoid space and protracted clinical or radiographic course after antiparasitic treatment (8;21). Stroke can occur secondary to vasculitis caused by inflammatory occlusion of the arteries at

Hydrocephalus develops in approximately 30% of all patients with NCC because of obstruction by intraventricular or subarachnoid lesions (10;21-23). Intraventricular NCC can cause non-communicating hydrocephalus by obstructing the CSF pathway and communicating hydrocephalus by development of ependymitis (10;21-23). Abrupt permanent obstruction can cause sudden death due to brain herniation (10;21-23). Lifethreatening acute intermittent hydrocephalus (Brunn syndrome)(41) can occur due to cyst-inducing intermittent CSF obstruction from a ball-valve mechanism (10;22). Overall, extraparenchymal NCC has a more aggressive behavior and a higher morbidity and mortality rate than parenchymal form (10;21-23). Presence of sub-arachnoid cysts can Extraparenchymal NCC is associated with a local inflammatory response with high protein concentration and cell counts in the CSF (8). Clinical manifestations and CSF findings are similar to the more common tuberculous meningitis, (8;23) and other forms of chronic meningitis including chronic HIV- associated meningitis (42;43) since the CSF findings consist of pleocytosis (usually lymphocytic but frequently polymorphonuclear) , reduced glucose and elevated protein(8). In one series of cysticercal meningoencephalitis, confusion with tubercular meningitis was present in 61.5% cases (7;8). An important differentiating feature with these other forms of chronic meningitis is the presence of eosinophils in the CSF (7;8) which is usually seen only in the initial phases of the illness (8;21). However, this staining of the CSF is not routinely done in most places (8;23). Although the suspicion of NCC as the cause of chronic meningitis is increased when CSF eosinophils are found, CSF eosinophils (above 5%) occur in only 15% of patients (21). It is often a common practice to attribute chronic meningitis and hydrocephalus to tubercular meningitis in the presence of appropriate epidemiologic history and treat empirically by shunting and anti-tubercular therapy. Thus, an astute clinical acumen is required to make the diagnosis of CM.

### **6.2. Imaging**

Both computed tomography (CT) and magnetic resonance imaging (MRI) are indispensable tools for diagnosis and characterization of NCC (38;44;45); CT is superior for diagnosis of racemose cysticercosis, brain granulomas and calcifications, which are the most frequent finding of NCC, and may be missed by MRI (38;44;45). However, neuroimaging findings of extraparenchymal cysticerci are subtle and are usually not seen by CT. Thus, MRI is more useful than CT for diagnosis of ocular, ventricular, and subarachnoid cysticercosis and for analysis of the inflammatory reaction that accompanies most cases of active NCC (38;44;45).

Extraparenchymal Neurocysticercosis 355

hypointensity (1) and show susceptibility at MR imaging, particularly on gradient-echo images (47). However MRI is not the imaging modality of choice for calcified NCC (47). Also, in the nodular calcified stage, when the cystic lesion is mineralized and shrunken and a nonenhanced CT scan is diagnostic, enhancement is unusual (51). The granular nodular phase is characterized by decreased ring enhancement and edema, along with the

Subarachnoid (racemose) neurocysticercosis usually infiltrates the basal cisterns and sylvian fissure and has different imaging findings compared to parenchymal NCC. Common neuroimaging findings to suspect the diagnosis include hydrocephalus (with or without obvious cysts), cysts obstructing CSF pathways or freely floating inside ventricles, cysts in the basal subarachnoid cisterns, migrating cysts across the cerebral aqueduct, and ependymitis or arachnoiditis (21). The most common CT finding in subarachnoid NCC is hydrocephalus (1;9). Because the cyst membrane is thin and the fluid is isodense with the cerebrospinal fluid, uninflamed extraparenchymal cysticerci are usually not visible on computed tomography scanning and may only reveal subtle, indirect findings on MRI (9).

Therefore, neuroimaging may reveal hydrocephalus without noticeable cysts (1;9).

*Taenia* antibodies detected by methods such as Western Blot is considered as a major criterion whereas the positive serologic test in the CSF is listed as a minor criterion (19).The development of numerous serodiagnostic tests using different parasitic antigens is indicative of the fact that none of them are 100% sensitive and specific. For multiple lesions, the enzyme-linked immunoelectrotransfer blot (EITB) assay using purified glycoprotein antigens from *T. solium* cysticerci was reported to be highly specific (100%) and nearly 98% sensitive (4;5;12). The sensitivity was less for single lesions (52)and for calcified lesions (2;2;53-56). A comparative study of enzyme-linked immunosorbent assay (ELISA) and dotblot assay in children found that both were more sensitive in cases with multiple brain lesions (100%) than in those with a single lesion (87%) (5). The sensitivity of antibody detecting EITB assays is not better with the use of CSF samples as compared with serum samples (55). Detection of circulating cysticercosis antigens using ELISA has a modest sensitivity especially for parenchymal lesions. The antigen detecting ELISA has a better sensitivity with the use of CSF samples as compared with serum samples. However, ELISA has less sensitivity as compared with EITB for serum as well as CSF samples, for both

It has been suggested that the use of excretory secretory (ES) antigens, rather than somatic antigens might improve the serodiagnosis of cases with vesicular stages of the parasite (60;61). The use of ES antigens for the detection of antibodies in serum was found to be more useful than that in urine in patients with enhancing lesions (62). Three ES peptides were reported to have high sensitivity and specificity in both serum and CSF reactivity; (60;61). It has been suggested that synthetic peptide selected by phage display may be useful in the

**6.3. Laboratory tests for diagnosis of NCC** 

intraparenchymal and extraparenchymal NCC (55;57-59).

immunodiagnosis of NCC (63;64).

calcification of cysts (46).

Neuroimaging findings are variable depending on the stage of the infection. The first stage, described as the larval tissue invasion phase, is not normally imaged owing to lack of symptoms at this very early stage (1;46). During the vesicular stage, cysts and scolex, the "mouth" of the tapeworm that is lined with suckers and hooks, are both imaged without enhancement. However, as observed in one study(47) in which imaging was performed regularly to follow anticysticercal therapy, this phase appears as a localized focus of edema on T2-weighted images and displays nodular tissue enhancement following the administration of gadopentetate dimeglumine (1;46).

The second stage (the vesicular stage) describes the formation of a cyst that encircles the scolex (1;46). These cysts are thin walled, contain clear fluid and are typically 1-2 cm. On imaging, the cyst fluid parallels cerebrospinal fluid intensity. The scolex is approximately 2– 4 mm and appears as a mural nodule that is isointense with brain parenchyma (48). The lesion is antigenically inert and therefore does not induce an inflammatory reaction or circumferential edema (49).

During the third stage (the colloidal stage) the parasite dies, and as a result the cysticercus becomes nonviable (1;46). As the scolex dies, the cyst fluid transforms into a colloidal suspension containing protein solutes (1;46) and on MRI imaging this results in T1 shortening while the scolex and cyst capsule are decreased in T2 signal intensity. The surrounding edema suggests that the parasite is in its colloidal state, and, therefore, enhancement of the capsule and scolex will occur avidly. In addition, the proteinaceous nature of the cyst fluid during involution of the cysticercus is appears as hypointense central T1 signal to white matter but hyperintense to cerebrospinal fluid and appears markedly hyperintense on T2-weighted images (1;46). At CT, cystic contents increase in attenuation (50). Thus, in the colloidal vesicular stage, ring enhancement and edema are appreciated by both CT and MRI imagings (1;46).

The fourth stage (the nodular granular stage) represents the degeneration of the cysticercus. The edema begins to subside gradually, the contents begin to mineralize and the cyst involutes. Thus, the lesion becomes isointense with brain parenchyma on T1-weighted MR images and hypointense on T2-weighted MR images. At CT, a thick nodular ring continues to enhance and the lesion becomes isoattenuating (51).

The final stage is the calcified stage, which describes complete involution of the lesion with continued mineralization. The calcifications are obvious at CT as small areas of hypointensity (1) and show susceptibility at MR imaging, particularly on gradient-echo images (47). However MRI is not the imaging modality of choice for calcified NCC (47). Also, in the nodular calcified stage, when the cystic lesion is mineralized and shrunken and a nonenhanced CT scan is diagnostic, enhancement is unusual (51). The granular nodular phase is characterized by decreased ring enhancement and edema, along with the calcification of cysts (46).

Subarachnoid (racemose) neurocysticercosis usually infiltrates the basal cisterns and sylvian fissure and has different imaging findings compared to parenchymal NCC. Common neuroimaging findings to suspect the diagnosis include hydrocephalus (with or without obvious cysts), cysts obstructing CSF pathways or freely floating inside ventricles, cysts in the basal subarachnoid cisterns, migrating cysts across the cerebral aqueduct, and ependymitis or arachnoiditis (21). The most common CT finding in subarachnoid NCC is hydrocephalus (1;9). Because the cyst membrane is thin and the fluid is isodense with the cerebrospinal fluid, uninflamed extraparenchymal cysticerci are usually not visible on computed tomography scanning and may only reveal subtle, indirect findings on MRI (9). Therefore, neuroimaging may reveal hydrocephalus without noticeable cysts (1;9).

## **6.3. Laboratory tests for diagnosis of NCC**

354 Novel Aspects on Cysticercosis and Neurocysticercosis

administration of gadopentetate dimeglumine (1;46).

appreciated by both CT and MRI imagings (1;46).

to enhance and the lesion becomes isoattenuating (51).

circumferential edema (49).

Both computed tomography (CT) and magnetic resonance imaging (MRI) are indispensable tools for diagnosis and characterization of NCC (38;44;45); CT is superior for diagnosis of racemose cysticercosis, brain granulomas and calcifications, which are the most frequent finding of NCC, and may be missed by MRI (38;44;45). However, neuroimaging findings of extraparenchymal cysticerci are subtle and are usually not seen by CT. Thus, MRI is more useful than CT for diagnosis of ocular, ventricular, and subarachnoid cysticercosis and for analysis of the inflammatory reaction that accompanies most cases of active NCC (38;44;45). Neuroimaging findings are variable depending on the stage of the infection. The first stage, described as the larval tissue invasion phase, is not normally imaged owing to lack of symptoms at this very early stage (1;46). During the vesicular stage, cysts and scolex, the "mouth" of the tapeworm that is lined with suckers and hooks, are both imaged without enhancement. However, as observed in one study(47) in which imaging was performed regularly to follow anticysticercal therapy, this phase appears as a localized focus of edema on T2-weighted images and displays nodular tissue enhancement following the

The second stage (the vesicular stage) describes the formation of a cyst that encircles the scolex (1;46). These cysts are thin walled, contain clear fluid and are typically 1-2 cm. On imaging, the cyst fluid parallels cerebrospinal fluid intensity. The scolex is approximately 2– 4 mm and appears as a mural nodule that is isointense with brain parenchyma (48). The lesion is antigenically inert and therefore does not induce an inflammatory reaction or

During the third stage (the colloidal stage) the parasite dies, and as a result the cysticercus becomes nonviable (1;46). As the scolex dies, the cyst fluid transforms into a colloidal suspension containing protein solutes (1;46) and on MRI imaging this results in T1 shortening while the scolex and cyst capsule are decreased in T2 signal intensity. The surrounding edema suggests that the parasite is in its colloidal state, and, therefore, enhancement of the capsule and scolex will occur avidly. In addition, the proteinaceous nature of the cyst fluid during involution of the cysticercus is appears as hypointense central T1 signal to white matter but hyperintense to cerebrospinal fluid and appears markedly hyperintense on T2-weighted images (1;46). At CT, cystic contents increase in attenuation (50). Thus, in the colloidal vesicular stage, ring enhancement and edema are

The fourth stage (the nodular granular stage) represents the degeneration of the cysticercus. The edema begins to subside gradually, the contents begin to mineralize and the cyst involutes. Thus, the lesion becomes isointense with brain parenchyma on T1-weighted MR images and hypointense on T2-weighted MR images. At CT, a thick nodular ring continues

The final stage is the calcified stage, which describes complete involution of the lesion with continued mineralization. The calcifications are obvious at CT as small areas of

**6.2. Imaging** 

*Taenia* antibodies detected by methods such as Western Blot is considered as a major criterion whereas the positive serologic test in the CSF is listed as a minor criterion (19).The development of numerous serodiagnostic tests using different parasitic antigens is indicative of the fact that none of them are 100% sensitive and specific. For multiple lesions, the enzyme-linked immunoelectrotransfer blot (EITB) assay using purified glycoprotein antigens from *T. solium* cysticerci was reported to be highly specific (100%) and nearly 98% sensitive (4;5;12). The sensitivity was less for single lesions (52)and for calcified lesions (2;2;53-56). A comparative study of enzyme-linked immunosorbent assay (ELISA) and dotblot assay in children found that both were more sensitive in cases with multiple brain lesions (100%) than in those with a single lesion (87%) (5). The sensitivity of antibody detecting EITB assays is not better with the use of CSF samples as compared with serum samples (55). Detection of circulating cysticercosis antigens using ELISA has a modest sensitivity especially for parenchymal lesions. The antigen detecting ELISA has a better sensitivity with the use of CSF samples as compared with serum samples. However, ELISA has less sensitivity as compared with EITB for serum as well as CSF samples, for both intraparenchymal and extraparenchymal NCC (55;57-59).

It has been suggested that the use of excretory secretory (ES) antigens, rather than somatic antigens might improve the serodiagnosis of cases with vesicular stages of the parasite (60;61). The use of ES antigens for the detection of antibodies in serum was found to be more useful than that in urine in patients with enhancing lesions (62). Three ES peptides were reported to have high sensitivity and specificity in both serum and CSF reactivity; (60;61). It has been suggested that synthetic peptide selected by phage display may be useful in the immunodiagnosis of NCC (63;64).

Polymerase chain reaction (PCR) in CSF has also been used for the diagnosis of neurocysticercosis but is not widely available (19). However, extensive and comprehensive revision of the diagnostic criteria of neurocysticercosis, especially of extraparenchymal neurocysticercosis is mandatory according to many recent publications (2;8-11).

Extraparenchymal Neurocysticercosis 357

hypertension is warranted and surgical evaluation is often needed prior to medical

In patients presenting with acute hydrocephalus, surgery is the only option (10;21-23). Neurosurgical procedures for NCC are still part of the armamentarium when treating this disease and good results for open craniotomy and rigid endoscopic surgery in patients with intraventricular and subarachnoid NCC have been reported (72;73). Infratentorial intraventricular cysts have been treated with open surgery for excision whereas it is generally suggested that supratentorial cysts, due to not only location but also the need to often treat hydrocephalus in these patients, be removed endoscopically (74). Ependymitis, confirmed by neuroimaging is a relative contraindication for surgical removal of the cysts

Ventriculoperitoneal CSF shunting is burdened by a high shunt dysfunction rate which leads to worsening obstruction of CSF flow and increased intracranial pressure, risk of infection and thus high mortality rates. Microneurosurgical approaches can be technically demanding and associated with various complications (10;21-23). For these reasons, endoscopic approaches for intraventricular neurocysticercosis have been described in recent years and often allow for cyst removal and hydrocephalus treatment, freeing the patient

Although the literature regarding the use of endoscopic management of intraventricular NCC is scarce, this modality has shown encouraging results in the treatment of intraventricular NCC (10;21-23). In a recent comparative study of 140 patients from Mexico with intraventricular NCC, traditional treatment with albendazole and steroid had similar outcome versus neuroendoscopic surgery in terms of survival, hospitalization (23). However, almost all patients with traditional treatment remained with at least one shunt whereas most of the patients from the neuroendoscopic surgery series did not have any shunts (23). Thus, the neuroendoscopic approach to intraventricular neurocysticercal cysts is safe and effective and offers the additional benefit of avoiding shunt placement (10;21-23). At centres having the required expertise, this should be the treatment of choice. Traditional treatment is a second option where the endoscopic procedure is not available. However, endoscopic cyst excision can be difficult and hazardous in patients with severe ependymitis and dense adhesions and intraventricular bleeding could also report (10;21-23). Thus, despite its many advantages, neuroendoscopy has some limitations even when performed

Regarding subarachnoid NCC, there are no controlled trials on the management of this form of extraparenchymal NCC (1;6;71). In a series of patients treated with only CSF diversion, 50% died at a median follow-up of 8 years and 11 months (2). More recently, case series using anti-parasitic drugs, corticosteroids, and shunting for hydrocephalus have been associated with an improved prognosis compared with older studies (1;2;6;71).Thus, most experts consider subarachnoid NCC a clear indication for anti-parasitic therapy (2).

treatment (8).

(10;21-23).

**7.2. Surgical therapy** 

from shunt procedures (75;76).

by experienced hands.

## **7. Treatment**

There is still no consensus regarding optimal treatment strategies in patients with extraparenchymal NCC (10;21-23). Various therapeutic modalities include antihelminthic medication, microneurosurgical removal, ventriculoperitoneal shunting, and endoscopic management (8).

## **7.1. Medical therapy**

Although parenchymal cysts have historically been treated quite effectively with antihelminthics such as praziquantel and albendazole, medical therapy alone is not favored for extraparenchymal NCC because of the limited efficacy in such cases, and a risk of developing acute hydrocephalus during the clinical treatment period (10;21-23). Good results for antiparasitic treatment with different albendazole and praziquantel regiments for extraparenchymal NCC including orbital, spinal , intraventricular and subarachnoid NCC, and even for giant cysts have been reported (57;65-69) although resistance has been reported by some (13;16;17). However, although treatment with antihelminthic medication such as albendazole has been shown to improve outcome in live, cystic parenchymal cysticercosis, the benefits of antihelminthic treatment in patients with solitary cystic lesion remain uncertain (70). While it is generally accepted that both praziquantel and albendazole are effective in destroying viable cysts, their use in cases with enhancing lesions has been debated as these lesions are considered to represent degenerating cysts, many of which resolve spontaneously (4;5;12). Thus, the decision whether antiparasitic treatment should be used in these cases is always a clinical decision and should be made on an individual basis.

Antihelminthic agents hasten the evolution of intraventricular viable cysts, which may trigger an inflammatory response similar to that seen with the natural history of the parasite (25). This may result in long-term sequelae (1;6;9;71). Extraparenchymal cysts may regress only after long term and multiple antiparasitic courses (1;6;9;71). The optimal treatment to prevent chronic inflammation is unknown due the lack of understanding of its pathophysiology and lack of controlled trials to help guide management. Likewise, controversy exists regarding the use of corticosteroids, alone or in combination with antihelminthic drugs (1;6;70;71). At a previous consensus meeting, experts agreed that no single treatment approach could be advocated and that management options varied according to the type of clinical presentation (9). However, intraventricular neurocysticercosis has a risk of ependymitis in those treated with anthelminthics such as albendazole and praziquantel regiments. Thus these agents should be used with caution in cases with extraparenchymal NCC as any increase in the inflammatory response may lead to the development of infarct; pretreatment with steroids and management of intracranial hypertension is warranted and surgical evaluation is often needed prior to medical treatment (8).

## **7.2. Surgical therapy**

356 Novel Aspects on Cysticercosis and Neurocysticercosis

**7. Treatment** 

management (8).

**7.1. Medical therapy** 

Polymerase chain reaction (PCR) in CSF has also been used for the diagnosis of neurocysticercosis but is not widely available (19). However, extensive and comprehensive revision of the diagnostic criteria of neurocysticercosis, especially of extraparenchymal

There is still no consensus regarding optimal treatment strategies in patients with extraparenchymal NCC (10;21-23). Various therapeutic modalities include antihelminthic medication, microneurosurgical removal, ventriculoperitoneal shunting, and endoscopic

Although parenchymal cysts have historically been treated quite effectively with antihelminthics such as praziquantel and albendazole, medical therapy alone is not favored for extraparenchymal NCC because of the limited efficacy in such cases, and a risk of developing acute hydrocephalus during the clinical treatment period (10;21-23). Good results for antiparasitic treatment with different albendazole and praziquantel regiments for extraparenchymal NCC including orbital, spinal , intraventricular and subarachnoid NCC, and even for giant cysts have been reported (57;65-69) although resistance has been reported by some (13;16;17). However, although treatment with antihelminthic medication such as albendazole has been shown to improve outcome in live, cystic parenchymal cysticercosis, the benefits of antihelminthic treatment in patients with solitary cystic lesion remain uncertain (70). While it is generally accepted that both praziquantel and albendazole are effective in destroying viable cysts, their use in cases with enhancing lesions has been debated as these lesions are considered to represent degenerating cysts, many of which resolve spontaneously (4;5;12). Thus, the decision whether antiparasitic treatment should be used in these cases is always a clinical decision and should be made on an individual basis. Antihelminthic agents hasten the evolution of intraventricular viable cysts, which may trigger an inflammatory response similar to that seen with the natural history of the parasite (25). This may result in long-term sequelae (1;6;9;71). Extraparenchymal cysts may regress only after long term and multiple antiparasitic courses (1;6;9;71). The optimal treatment to prevent chronic inflammation is unknown due the lack of understanding of its pathophysiology and lack of controlled trials to help guide management. Likewise, controversy exists regarding the use of corticosteroids, alone or in combination with antihelminthic drugs (1;6;70;71). At a previous consensus meeting, experts agreed that no single treatment approach could be advocated and that management options varied according to the type of clinical presentation (9). However, intraventricular neurocysticercosis has a risk of ependymitis in those treated with anthelminthics such as albendazole and praziquantel regiments. Thus these agents should be used with caution in cases with extraparenchymal NCC as any increase in the inflammatory response may lead to the development of infarct; pretreatment with steroids and management of intracranial

neurocysticercosis is mandatory according to many recent publications (2;8-11).

In patients presenting with acute hydrocephalus, surgery is the only option (10;21-23). Neurosurgical procedures for NCC are still part of the armamentarium when treating this disease and good results for open craniotomy and rigid endoscopic surgery in patients with intraventricular and subarachnoid NCC have been reported (72;73). Infratentorial intraventricular cysts have been treated with open surgery for excision whereas it is generally suggested that supratentorial cysts, due to not only location but also the need to often treat hydrocephalus in these patients, be removed endoscopically (74). Ependymitis, confirmed by neuroimaging is a relative contraindication for surgical removal of the cysts (10;21-23).

Ventriculoperitoneal CSF shunting is burdened by a high shunt dysfunction rate which leads to worsening obstruction of CSF flow and increased intracranial pressure, risk of infection and thus high mortality rates. Microneurosurgical approaches can be technically demanding and associated with various complications (10;21-23). For these reasons, endoscopic approaches for intraventricular neurocysticercosis have been described in recent years and often allow for cyst removal and hydrocephalus treatment, freeing the patient from shunt procedures (75;76).

Although the literature regarding the use of endoscopic management of intraventricular NCC is scarce, this modality has shown encouraging results in the treatment of intraventricular NCC (10;21-23). In a recent comparative study of 140 patients from Mexico with intraventricular NCC, traditional treatment with albendazole and steroid had similar outcome versus neuroendoscopic surgery in terms of survival, hospitalization (23). However, almost all patients with traditional treatment remained with at least one shunt whereas most of the patients from the neuroendoscopic surgery series did not have any shunts (23). Thus, the neuroendoscopic approach to intraventricular neurocysticercal cysts is safe and effective and offers the additional benefit of avoiding shunt placement (10;21-23). At centres having the required expertise, this should be the treatment of choice. Traditional treatment is a second option where the endoscopic procedure is not available. However, endoscopic cyst excision can be difficult and hazardous in patients with severe ependymitis and dense adhesions and intraventricular bleeding could also report (10;21-23). Thus, despite its many advantages, neuroendoscopy has some limitations even when performed by experienced hands.

Regarding subarachnoid NCC, there are no controlled trials on the management of this form of extraparenchymal NCC (1;6;71). In a series of patients treated with only CSF diversion, 50% died at a median follow-up of 8 years and 11 months (2). More recently, case series using anti-parasitic drugs, corticosteroids, and shunting for hydrocephalus have been associated with an improved prognosis compared with older studies (1;2;6;71).Thus, most experts consider subarachnoid NCC a clear indication for anti-parasitic therapy (2). However, the optimal dose and duration of anti-parasitic therapy for subarachnoid cysticercosis has not been established (2). In the largest cases series, Proaño and others treated 33 patients with giant cysticerci with albendazole (15 mg/kg/day) for 4 weeks and most patients required several courses of anti-parasitic therapy (23). However, with controversy in the literature in the optimal management of this condition and without further evidence-based guidelines to help management of extraparenchymal NCC, the decision of the total dose and duration of antiparasitic and steroid therapy must be made on a case by case basis.

Extraparenchymal Neurocysticercosis 359

[5] Mandal J, Singhi PD, Khandelwal N, Malla N. Evaluation of ELISA and dot blots for the serodiagnosis of neurocysticercosis, in children found to have single or multiple enhancing lesions in computerized tomographic scans of the brain. Ann Trop Med

[6] Cardenas G, Carrillo-Mezo R, Jung H, Sciutto E, Hernandez JL, Fleury A. Subarachnoidal Neurocysticercosis non-responsive to cysticidal drugs: a case series.

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[8] Cardenas G, Jung H, Rios C, Fleury A, Soto-Hernandez JL. Severe cysticercal meningitis: clinical and imaging characteristics. Am J Trop Med Hyg 2010; 82(1):121-

[9] Garcia HH, Evans CA, Nash TE, Takayanagui OM, White AC, Jr., Botero D et al. Current consensus guidelines for treatment of neurocysticercosis. Clin Microbiol Rev

[10] Kalra V, Mishra D, Suri A, Seth R, Garg A. Intraventricular neurocysticercosis. Indian J

[11] Wallin MT, Kurtzke JF. Neurocysticercosis in the United States: review of an important

[13] Cardenas G, Carrillo-Mezo R, Jung H, Sciutto E, Hernandez JL, Fleury A. Subarachnoidal Neurocysticercosis non-responsive to cysticidal drugs: a case series.

[14] Bluml S, Kirchberger S, Bochkov VN, Kronke G, Stuhlmeier K, Majdic O et al. Oxidized phospholipids negatively regulate dendritic cell maturation induced by TLRs and

[15] Maravilla P, Gonzalez-Guzman R, Zuniga G, Peniche A, Dominguez-Alpizar JL, Reyes-Montes R et al. Genetic polymorphism in Taenia solium cysticerci recovered from

[16] Cardenas G, Jung H, Rios C, Fleury A, Soto-Hernandez JL. Severe cysticercal meningitis: clinical and imaging characteristics. Am J Trop Med Hyg 2010; 82(1):121-

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## **8. Conclusion**

Extraparenchymal NCC may be a more common form of NCC than previously thought and is often difficult to diagnose, more complex to treat, and carries a graver prognosis. The clinical course is protracted and difficult to cure. Different medical (anthelmintics, steroids), surgical (cyst excision, CSF diversion), or medical-surgical approaches have been reported but not adequately studied. Because clinicians in developed countries often unfamiliar with NCC as a cause of chronic meningitis, chronic ventriculitis, or hydrocephalus without obvious cysts, the diagnosis of extraparenchymal NCC often depends on the correct interpretation of neuroimaging which may miss the diagnosis. Thus, extraparenchymal NCC should always be considered by clinicians and radiologists in the differential diagnosis of chronic meningitis and hydrocephalus.

## **Author details**

Kelesidis Theodoros

*Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, USA* 

## **9. References**


[5] Mandal J, Singhi PD, Khandelwal N, Malla N. Evaluation of ELISA and dot blots for the serodiagnosis of neurocysticercosis, in children found to have single or multiple enhancing lesions in computerized tomographic scans of the brain. Ann Trop Med Parasitol 2006; 100(1):39-48.

358 Novel Aspects on Cysticercosis and Neurocysticercosis

of chronic meningitis and hydrocephalus.

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a case by case basis.

**8. Conclusion** 

**Author details** 

**9. References** 

Kelesidis Theodoros

*Los Angeles, California, USA* 

2009; 110(1):22-27.

However, the optimal dose and duration of anti-parasitic therapy for subarachnoid cysticercosis has not been established (2). In the largest cases series, Proaño and others treated 33 patients with giant cysticerci with albendazole (15 mg/kg/day) for 4 weeks and most patients required several courses of anti-parasitic therapy (23). However, with controversy in the literature in the optimal management of this condition and without further evidence-based guidelines to help management of extraparenchymal NCC, the decision of the total dose and duration of antiparasitic and steroid therapy must be made on

Extraparenchymal NCC may be a more common form of NCC than previously thought and is often difficult to diagnose, more complex to treat, and carries a graver prognosis. The clinical course is protracted and difficult to cure. Different medical (anthelmintics, steroids), surgical (cyst excision, CSF diversion), or medical-surgical approaches have been reported but not adequately studied. Because clinicians in developed countries often unfamiliar with NCC as a cause of chronic meningitis, chronic ventriculitis, or hydrocephalus without obvious cysts, the diagnosis of extraparenchymal NCC often depends on the correct interpretation of neuroimaging which may miss the diagnosis. Thus, extraparenchymal NCC should always be considered by clinicians and radiologists in the differential diagnosis

*Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA,* 

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## *Edited by Humberto Foyaca Sibat*

This book includes selected peer-reviewed chapters which cover novel aspects of cysticercosis and neurocysticercosis written by well known international researchers, representing the most relevant Working Group for Cysticercosis of Mexico, Peru, Ecuador, most of the Eastern and Southern Africa countries and Europe plus other contributions from Canada and United States of America. Unfortunately, our colleagues from Asia could not participate in this project for several reasons but we hereby acknowledge their contribution to the scientific level reached by the international scientific community. Apart from the classic issue that cannot be missing in any book about cysticercosis/ neurocysticercosis, we introduced a new hypotheses and novel aspects on historical background, clinical descriptions, investigations, and treatment modalities related to this zoonotic parasitic disease as a leading cause of epilepsy in developing countries. We are looking forward with confidence and pride in the vital role that this book will play for a new vision and mission.

Novel Aspects on Cysticercosis and Neurocysticercosis

Novel Aspects on

Cysticercosis and

Neurocysticercosis

*Edited by Humberto Foyaca Sibat*

Photo by selvanegra / iStock