**Neuroimmunoendocrine Interactions in Murine Cysticercosis: From the Lab Bench Work to Its Possible Applications in Controlling Porcine Cysticercosis and Human Neurocysticercosis**

Karen Nava-Castro, Romel Hernández-Bello, Saé Muñiz-Hernández, Lorena López-Griego, Jhonatan A. Hernández-Valdés, Valeria López-Salazar, Nelly Tiempos-Guzmán and Jorge Morales-Montor

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/50700

**1. Introduction** 

38 Novel Aspects on Cysticercosis and Neurocysticercosis

[160] Medina MT, Rosas E, Rubio-Donnadieu F, Sotelo J. Neurocysticercosis as the main cause of late-onset epilepsy in Mexico. Arch Intern Med. 1990 Feb;150(2):325-7.

> The immune and neuroendocrine systems are interconnected by a network in which hormones, antigens, receptors, cytokines, antibodies and neuropeptides modulate immune response in connection with neuroendocrine changes while maintaining homeostasis (Besedovsky & del Rey, 1996). Two of the main components of this network are the hypothalamic-pituitary-adrenocortical (HPA) and the hypothalamic-pituitary-gonadal axes (HPG) (Besedovsky & del Rey, 2000; Rivier & Rivest, 1993).

> Interactions between the immune system and both the HPA and HPG axes are characterized by their activation and starting of the stress response, which, in turn, has immunomodulating activities that are important in preventing excessive immune responses (Chikanza & Grossman, 2000; Morales-Montor *et al.*, 2004b). Furthermore, the important functions of both axes have been shown for adaptation and maintenance of homeostasis during critical illness and viral, bacterial, parasitic and autoimmune diseases (Besedovsky & del Rey, 1996). An important aspect of cell communication that has emerged as a result of studying neuro-endocrine-immune interactions is the redundancy of the use of some chemical messengers to communicate among them. As an example, neurotrophins are chemical messengers first identified and characterized in the nervous system. Members of this protein family are also expressed and secreted by immune and endocrine cells, and have immunological and endocrinological functions (Haddad *et al.*, 2002).

© 2013 Morales-Montor et al., 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 Morales-Montor et al., 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.

Thus, the lack ubiquitous use of some cellular messengers by different organic systems might be a rule, rather than an exception. Although strong evidence supports that neurons, endocrine and immune cells produce hormones, while neural, endocrine and immune cells synthesize and secrete neuroactive messengers (Ferone *et al.*, 2006), it remains somewhat controversial whether this network is involved in the final outcome of parasitic diseases, and, particularly in cysticercosis (natural and experimental) (Morales-Montor & Larralde, 2005).

Neuroimmunoendocrine Interactions in Murine Cysticercosis: From the Lab Bench Work to Its Possible Applications in Controlling Porcine Cysticercosis and Human Neurocysticercosis 41

infection. Its general representation of other forms of cysticercosis has later been strengthened by similar results in other mouse and parasite strains (Larralde *et al.*, 1986), by the parasite's extensive sharing of antigens with other taeniids and cestodes and by the DNA homology between *T. crassiceps and T. solium* (Larralde *et al.*, 1986; Larralde *et al.*, 1990). These characteristics have made murine cysticercosis a convenient instrument to test vaccine candidates (Sciutto *et al.*, 1990) and new drugs or treatments against CC. Several features of natural cysticercotic disease have been found by extrapolation from experimental murine

In order to figure out the effect of infection on the immune system, on the feminized male mice, thymic cell analysis performed by flow cytometry showed a diminution in the content of CD3+, CD4+, and CD8+ subpopulations in the infected mice. This suggest that the increase in estradiol levels of the host could change the expression pattern of several genes that participate in apoptosis regulation in the thymus of male mice during chronic infection with *T. crassiceps* cysticerci, by inhibiting the inhibit the specific cellular immune response to the parasite (Morales-Montor *et al.*, 1998). Previous immunological experiments had led to suspect that estradiol positively regulates parasite reproduction in hosts of both genders, presumably by interfering with the thymus-dependent cellular immune mechanisms that obstruct parasite growth (Th1) and favoring those that facilitate it (Th2) (Bojalil *et al.*, 1993; Terrazas *et al.*, 1994). A specific shift from Th1 to Th2 immune response in the course of infection was found that coincided with the initial low rate of reproduction that accelerates at later times of infection. The shift is characterized by a marked decrease of IL-2 and IFN-γ in both genders, while the secretion of cytokines involved in the specific humoral response (IL-6, IL-10 and IL-4) is enhanced (Terrazas *et al.*, 1998; Terrazas *et al.*, 1999). Thus, striking differences in susceptibility to cysticercosis between male and female mice may involve the joint action of the immune system and the gonads, both driven by a parasite, which is able to change the parasite´s restrictive male normal hormonal milieu during chronic infection to

To strengthen the above notions and in an effort to identify the sex steroids involved we studied the effects of testosterone (T4), dihydrotestosterone (DHT), and 17β-estradiol (E2) in castrated mice of both genders infected with *T. crassiceps* cysticerci (Morales-Montor *et al.*, 2002a). In this study, we found that castration and treatment with either T4 or DHT before infection markedly decreased parasite loads in both gender mice, while the treatment with E2 increased it in both genders (Morales-Montor *et al.*, 2002a). The specific splenocyte cell proliferation and IL-2 and IFN-γ production were depressed in infected-castrated mice of both genders, while treatment with T4 or DHT produced a significant cell proliferation recovery and enhanced production of IL-2 and IFN-γ (Morales-Montor *et al.*, 2002a). An opposite effect of the same sex steroids was found on the humoral response: it was unaffected with T4 or DHT restitution, while the treatment with E2 in both genders augmented the levels of anti-cysticerci IgG, as well as IL-6 and IL-10 production. These results suggest androgens mediate immune functions, which protect mice from

cysticercosis (Morales-Montor *et al.*, 2002a; Sciutto *et al.*, 2007).

**1.2. Immuno-endocrine interactions in the host** 

a more parasite´s permissive female environment.

Taeniids, particularly *Taenia solium,* the porcine cysticercosis (CC) and human neurocysticercosis (NCC) causal agent; and *Taenia crassiceps*, murine cysticercosis causal agent, are highly evolved parasites that have developed diverse mechanisms of survival that facilitate their establishment in the host. These mechanisms can be roughly grouped into two types: 1) evasion of the immune response by molecular mimicry or by inactivating effector immune processes (i.e, complement inhibition) (Baig *et al.*, 2005; Laclette *et al.*, 1989); and 2) by exploiting the host system to allow its establishment, growth or reproduction (Escobedo *et al.*, 2004). This exploitation mechanism provides parasites with a dual benefit: first, obtaining amino acids for metabolism, and second preventing the surface-bound antibody from interfering with cytotoxic cells interacting with the parasite (Damian, 1989; Locksley, 1997). A striking example of host's molecules exploitation is the ability of several taeniids to use host-synthesized cytokines as indirect growth factors for themselves and also exploit the hormonal microenvironment within the host in their favor (Escobedo *et al.*, 2005). Taeniids have evolved structures similar to the steroid and protein hormone receptors expressed in upper vertebrates, with binding properties and terminal effects similar to the hormonal metabolites synthesized by the host (Gomez *et al.*, 2000). Such cross regulation from host to parasite has been described in at least eight parasitic infections that are caused by parasitic cestodes, like schistosomiasis (LoVerde *et al.*, 1985), filariasis (Rajan *et al.*, 2005), hydatid disease (Brehm *et al.*, 2003) and murine cysticercosis (Escobedo *et al.*, 2004).

Understanding how the host's endocrine system can favor the establishment of taeniids under certain circumstances, led us to explore the parasite's hormone receptors that might be involved, designing hormonal analogs and drugs to specifically affect the parasite (Escobedo *et al.*, 2004). This review is focused on the literature concerning sex-steroids, adrenal steroids and other hormones and neurohormones that have been studied in regard to control parasite loads in experimental murine cysticercosis.

### **1.1. Experimental murine cysticercosis**

Due to the intrinsic difficulties in working with the natural hosts (pigs and humans) of *T. solium* and the high costs of enough pigs plus the slowness in data retrieval, we have used an experimental cysticercosis approach to gain knowledge of the complex host (H) parasite (P) relationship in CC. Murine intraperitoneal cysticercosis is caused by the taeniid *T. crassiceps* and it has been useful to explore the physiological host factors associated with porcine cysticercosis, and to some degree, with human NCC (Larralde *et al.*, 1990). Intraperitoneal *T. crassiceps* cysticercosis of mice (Huerta *et al.*, 1992; Larralde *et al.*, 1990; Smith *et al.*, 1972) lends itself well to controlled and reproducible experimentation, generating numerical data of parasite loads in individual mice in a matter of weeks after infection. Its general representation of other forms of cysticercosis has later been strengthened by similar results in other mouse and parasite strains (Larralde *et al.*, 1986), by the parasite's extensive sharing of antigens with other taeniids and cestodes and by the DNA homology between *T. crassiceps and T. solium* (Larralde *et al.*, 1986; Larralde *et al.*, 1990). These characteristics have made murine cysticercosis a convenient instrument to test vaccine candidates (Sciutto *et al.*, 1990) and new drugs or treatments against CC. Several features of natural cysticercotic disease have been found by extrapolation from experimental murine cysticercosis (Morales-Montor *et al.*, 2002a; Sciutto *et al.*, 2007).

#### **1.2. Immuno-endocrine interactions in the host**

40 Novel Aspects on Cysticercosis and Neurocysticercosis

Thus, the lack ubiquitous use of some cellular messengers by different organic systems might be a rule, rather than an exception. Although strong evidence supports that neurons, endocrine and immune cells produce hormones, while neural, endocrine and immune cells synthesize and secrete neuroactive messengers (Ferone *et al.*, 2006), it remains somewhat controversial whether this network is involved in the final outcome of parasitic diseases, and, particularly in cysticercosis (natural and experimental) (Morales-Montor & Larralde, 2005).

Taeniids, particularly *Taenia solium,* the porcine cysticercosis (CC) and human neurocysticercosis (NCC) causal agent; and *Taenia crassiceps*, murine cysticercosis causal agent, are highly evolved parasites that have developed diverse mechanisms of survival that facilitate their establishment in the host. These mechanisms can be roughly grouped into two types: 1) evasion of the immune response by molecular mimicry or by inactivating effector immune processes (i.e, complement inhibition) (Baig *et al.*, 2005; Laclette *et al.*, 1989); and 2) by exploiting the host system to allow its establishment, growth or reproduction (Escobedo *et al.*, 2004). This exploitation mechanism provides parasites with a dual benefit: first, obtaining amino acids for metabolism, and second preventing the surface-bound antibody from interfering with cytotoxic cells interacting with the parasite (Damian, 1989; Locksley, 1997). A striking example of host's molecules exploitation is the ability of several taeniids to use host-synthesized cytokines as indirect growth factors for themselves and also exploit the hormonal microenvironment within the host in their favor (Escobedo *et al.*, 2005). Taeniids have evolved structures similar to the steroid and protein hormone receptors expressed in upper vertebrates, with binding properties and terminal effects similar to the hormonal metabolites synthesized by the host (Gomez *et al.*, 2000). Such cross regulation from host to parasite has been described in at least eight parasitic infections that are caused by parasitic cestodes, like schistosomiasis (LoVerde *et al.*, 1985), filariasis (Rajan *et al.*, 2005),

hydatid disease (Brehm *et al.*, 2003) and murine cysticercosis (Escobedo *et al.*, 2004).

to control parasite loads in experimental murine cysticercosis.

**1.1. Experimental murine cysticercosis** 

Understanding how the host's endocrine system can favor the establishment of taeniids under certain circumstances, led us to explore the parasite's hormone receptors that might be involved, designing hormonal analogs and drugs to specifically affect the parasite (Escobedo *et al.*, 2004). This review is focused on the literature concerning sex-steroids, adrenal steroids and other hormones and neurohormones that have been studied in regard

Due to the intrinsic difficulties in working with the natural hosts (pigs and humans) of *T. solium* and the high costs of enough pigs plus the slowness in data retrieval, we have used an experimental cysticercosis approach to gain knowledge of the complex host (H) parasite (P) relationship in CC. Murine intraperitoneal cysticercosis is caused by the taeniid *T. crassiceps* and it has been useful to explore the physiological host factors associated with porcine cysticercosis, and to some degree, with human NCC (Larralde *et al.*, 1990). Intraperitoneal *T. crassiceps* cysticercosis of mice (Huerta *et al.*, 1992; Larralde *et al.*, 1990; Smith *et al.*, 1972) lends itself well to controlled and reproducible experimentation, generating numerical data of parasite loads in individual mice in a matter of weeks after In order to figure out the effect of infection on the immune system, on the feminized male mice, thymic cell analysis performed by flow cytometry showed a diminution in the content of CD3+, CD4+, and CD8+ subpopulations in the infected mice. This suggest that the increase in estradiol levels of the host could change the expression pattern of several genes that participate in apoptosis regulation in the thymus of male mice during chronic infection with *T. crassiceps* cysticerci, by inhibiting the inhibit the specific cellular immune response to the parasite (Morales-Montor *et al.*, 1998). Previous immunological experiments had led to suspect that estradiol positively regulates parasite reproduction in hosts of both genders, presumably by interfering with the thymus-dependent cellular immune mechanisms that obstruct parasite growth (Th1) and favoring those that facilitate it (Th2) (Bojalil *et al.*, 1993; Terrazas *et al.*, 1994). A specific shift from Th1 to Th2 immune response in the course of infection was found that coincided with the initial low rate of reproduction that accelerates at later times of infection. The shift is characterized by a marked decrease of IL-2 and IFN-γ in both genders, while the secretion of cytokines involved in the specific humoral response (IL-6, IL-10 and IL-4) is enhanced (Terrazas *et al.*, 1998; Terrazas *et al.*, 1999). Thus, striking differences in susceptibility to cysticercosis between male and female mice may involve the joint action of the immune system and the gonads, both driven by a parasite, which is able to change the parasite´s restrictive male normal hormonal milieu during chronic infection to a more parasite´s permissive female environment.

To strengthen the above notions and in an effort to identify the sex steroids involved we studied the effects of testosterone (T4), dihydrotestosterone (DHT), and 17β-estradiol (E2) in castrated mice of both genders infected with *T. crassiceps* cysticerci (Morales-Montor *et al.*, 2002a). In this study, we found that castration and treatment with either T4 or DHT before infection markedly decreased parasite loads in both gender mice, while the treatment with E2 increased it in both genders (Morales-Montor *et al.*, 2002a). The specific splenocyte cell proliferation and IL-2 and IFN-γ production were depressed in infected-castrated mice of both genders, while treatment with T4 or DHT produced a significant cell proliferation recovery and enhanced production of IL-2 and IFN-γ (Morales-Montor *et al.*, 2002a). An opposite effect of the same sex steroids was found on the humoral response: it was unaffected with T4 or DHT restitution, while the treatment with E2 in both genders augmented the levels of anti-cysticerci IgG, as well as IL-6 and IL-10 production. These results suggest androgens mediate immune functions, which protect mice from cysticercosis, possibly through the stimulation of the specific cellular immunity of the host (Morales-Montor *et al.*, 2002a).

Neuroimmunoendocrine Interactions in Murine Cysticercosis: From the Lab Bench Work to Its Possible Applications in Controlling Porcine Cysticercosis and Human Neurocysticercosis 43

(intact) of both genders, P4 treatment increased parasite loads, while gonadectomized mice, P4 completely decreases parasite loads, an impressive and unprecedented cysticidal effect. In the first case, the effect of P4 is possibly associated to the manipulation of the specific cellular immune response, besides the steroid's promotion of parasite reproduction (Vargas-Villavicencio *et al.*, 2006). In a second analysis, it was demonstrated that infected mice that received P4 treatment increased estrogen levels two-fold compared to infected control mice. (Vargas-Villavicencio *et al.*, 2005; Vargas-Villavicencio *et al.*, 2006). A flow chart of the main immunoendocrinological effects of *T. crassiceps* infection in male and female mice is depicted

**Figure 1. Early immune events during murine cysticercosis.** During murine cysticercosis, there is a marked sexual dimorfism in parasite loads, having females, higher parasite loads than males, because of the effect of E2 and T4. These hormones also regulate immune responses. During the second week post infection, there is a clear Th1 response characterized by the expression of STAT4, high levels of IFN-γ and reduced levels of IL-4. After 4 weeks post-infection, immune response polarizes to a Th2 profile, in which STAT6, high levels of IL-4 and reduced levels of IFN-γ are observed. All these changes correlate to an overproduction of E2. IL-6 levels are also increased as infection takes place. High levels of this cytokine are associated to a feminization process, as observed by the low levels of T4. Doted line: Female parasitic load. Solid line: Male parasitic load. Signs ( and ) denote increase or decrease

The major steroid produced by the adrenal gland is the androgen dehydroepiandrosterone (DHEA). So, another set of experiments showed DHEA effect on male and female infected mice. DHEA treatment reduced parasite loads by 70 and 80% respectively. In contrast with

in Figure 1.

phenomena.

Immunoendocrine interactions during cysticercosis are the cornerstone of the feminization of male mice. When the infected male mice have an intact immune system, there is an increase in serum estradiol levels and a decrease of those of T4 and DHT. However, when the immune system is knocked down by total irradiation or neonatal thymectomy, there is no change in the levels of serum steroids in chronically infected male mice, and the levels remain steady between infected and uninfected male mice (Morales-Montor *et al.*, 2001). Interleukin-6 (IL-6) was demonstrated a key factor in this puzzle: IL-6-/- (KO) infected mice do not develop the feminization process, while the restitution with IL-6 again allows the feminization. The expression of IL-6 gene in the testes of parasitized mice was enhanced, a fact that can explain the primordial role of the testes in the feminization process produced by cysticercosis (Morales-Montor *et al.*, 2002a; Morales-Montor *et al.*, 2001). Thus, IL-6 activates aromatase expression in the testes of the cysticercotic mice and produces active aromatization from androgens to estrogens. The increased serum levels of follicle stimulating hormone (FSH), the natural activator of aromatase expression, found in the chronically infected mice, supports the notion that FSH could be also a factor involved in the feminization process in the male mouse (Morales-Montor *et al.*, 2001). Actually, macrophage-migration inhibitory factor (MIF) is known to be involved in immunoendocrinological processes during sex-associated susceptibility in cysticercosis. Thus, to determine the role of IL-6 and MIF during infection, knockout (KO) mice were used, and the number of parasites and serum sex-steroid levels were measured. It was found that IL-6 and MIF KO mice of both genders infected with *T. crassiceps* cysticerci harbor similar numbers of parasites, with no change in sex-hormone levels. However, in wild-type strains, the sex-associated susceptibility to infection is observed, concomitantly with the feminization process in the chronically infected mice (Morales-Montor *et al.*, 2002b). These results suggest a role for both IL-6 and MIF genes in sex-associated susceptibility in murine *T. crassiceps* cysticercosis.

The importance of sex hormones driving the specific immune response during cysticercosis was assessed by administration of fadrozole (a P450-aromatase inhibitor) in male and female mice to suppress the production of E2 (Morales-Montor *et al.*, 2002c). A reduction was found in parasite loads (~ 70%) in infected mice treated with fadrozole. The protective effect of the P450-aromatase inhibitor was associated in male mice with a recovery of the specific cellular immune response. IL-6 serum levels, and its production by splenocytes were dramatically augmented, together with an increase in its expression in the testes of infected male mice. Fadrozole treatment returned these levels to baseline values. These results suggest that P450-ase and IL-6 are key molecules in feminization undergone by infected male mice and in regulating parasite loads. Fadrozole treatment appears as a possible new therapeutic approach to control murine cysticercosis (Morales-Montor *et al.*, 2002c) and perhaps other parasites with active asexual reproduction in intermediate hosts.

Progesterone (P4) was recently tested and implicated in the regulation of the parasite loads during murine cysticercosis. P4 treatment has a dichotomic effect: in non-gonadectomized (intact) of both genders, P4 treatment increased parasite loads, while gonadectomized mice, P4 completely decreases parasite loads, an impressive and unprecedented cysticidal effect. In the first case, the effect of P4 is possibly associated to the manipulation of the specific cellular immune response, besides the steroid's promotion of parasite reproduction (Vargas-Villavicencio *et al.*, 2006). In a second analysis, it was demonstrated that infected mice that received P4 treatment increased estrogen levels two-fold compared to infected control mice. (Vargas-Villavicencio *et al.*, 2005; Vargas-Villavicencio *et al.*, 2006). A flow chart of the main immunoendocrinological effects of *T. crassiceps* infection in male and female mice is depicted in Figure 1.

42 Novel Aspects on Cysticercosis and Neurocysticercosis

(Morales-Montor *et al.*, 2002a).

murine *T. crassiceps* cysticercosis.

cysticercosis, possibly through the stimulation of the specific cellular immunity of the host

Immunoendocrine interactions during cysticercosis are the cornerstone of the feminization of male mice. When the infected male mice have an intact immune system, there is an increase in serum estradiol levels and a decrease of those of T4 and DHT. However, when the immune system is knocked down by total irradiation or neonatal thymectomy, there is no change in the levels of serum steroids in chronically infected male mice, and the levels remain steady between infected and uninfected male mice (Morales-Montor *et al.*, 2001). Interleukin-6 (IL-6) was demonstrated a key factor in this puzzle: IL-6-/- (KO) infected mice do not develop the feminization process, while the restitution with IL-6 again allows the feminization. The expression of IL-6 gene in the testes of parasitized mice was enhanced, a fact that can explain the primordial role of the testes in the feminization process produced by cysticercosis (Morales-Montor *et al.*, 2002a; Morales-Montor *et al.*, 2001). Thus, IL-6 activates aromatase expression in the testes of the cysticercotic mice and produces active aromatization from androgens to estrogens. The increased serum levels of follicle stimulating hormone (FSH), the natural activator of aromatase expression, found in the chronically infected mice, supports the notion that FSH could be also a factor involved in the feminization process in the male mouse (Morales-Montor *et al.*, 2001). Actually, macrophage-migration inhibitory factor (MIF) is known to be involved in immunoendocrinological processes during sex-associated susceptibility in cysticercosis. Thus, to determine the role of IL-6 and MIF during infection, knockout (KO) mice were used, and the number of parasites and serum sex-steroid levels were measured. It was found that IL-6 and MIF KO mice of both genders infected with *T. crassiceps* cysticerci harbor similar numbers of parasites, with no change in sex-hormone levels. However, in wild-type strains, the sex-associated susceptibility to infection is observed, concomitantly with the feminization process in the chronically infected mice (Morales-Montor *et al.*, 2002b). These results suggest a role for both IL-6 and MIF genes in sex-associated susceptibility in

The importance of sex hormones driving the specific immune response during cysticercosis was assessed by administration of fadrozole (a P450-aromatase inhibitor) in male and female mice to suppress the production of E2 (Morales-Montor *et al.*, 2002c). A reduction was found in parasite loads (~ 70%) in infected mice treated with fadrozole. The protective effect of the P450-aromatase inhibitor was associated in male mice with a recovery of the specific cellular immune response. IL-6 serum levels, and its production by splenocytes were dramatically augmented, together with an increase in its expression in the testes of infected male mice. Fadrozole treatment returned these levels to baseline values. These results suggest that P450-ase and IL-6 are key molecules in feminization undergone by infected male mice and in regulating parasite loads. Fadrozole treatment appears as a possible new therapeutic approach to control murine cysticercosis (Morales-Montor *et al.*, 2002c) and

perhaps other parasites with active asexual reproduction in intermediate hosts.

Progesterone (P4) was recently tested and implicated in the regulation of the parasite loads during murine cysticercosis. P4 treatment has a dichotomic effect: in non-gonadectomized

**Figure 1. Early immune events during murine cysticercosis.** During murine cysticercosis, there is a marked sexual dimorfism in parasite loads, having females, higher parasite loads than males, because of the effect of E2 and T4. These hormones also regulate immune responses. During the second week post infection, there is a clear Th1 response characterized by the expression of STAT4, high levels of IFN-γ and reduced levels of IL-4. After 4 weeks post-infection, immune response polarizes to a Th2 profile, in which STAT6, high levels of IL-4 and reduced levels of IFN-γ are observed. All these changes correlate to an overproduction of E2. IL-6 levels are also increased as infection takes place. High levels of this cytokine are associated to a feminization process, as observed by the low levels of T4. Doted line: Female parasitic load. Solid line: Male parasitic load. Signs ( and ) denote increase or decrease phenomena.

The major steroid produced by the adrenal gland is the androgen dehydroepiandrosterone (DHEA). So, another set of experiments showed DHEA effect on male and female infected mice. DHEA treatment reduced parasite loads by 70 and 80% respectively. In contrast with

the common assumption of DHEA as an immune-stimulatory hormone, the immune responses of our mice, characterized by the expression of IL-2, IFN-γ, IL-4 or IL-10, was not affected by DHEA treatment (Vargas-Villavicencio *et al.*, 2008). *In vitro*, treatment of *T. crassiceps* cysticerci with DHEA induced 80% reduction in parasite reproduction, which may partially explain the reduction of parasite loads observed *in vivo* a partial effect suggesting the involvement of other unknown factors in the in vivo regulation of parasite loads (Vargas-Villavicencio *et al.*, 2008). In addition, the use of 16α-bromoepiandrosterone (EpiBr), a DHEA analog without significant androgenic activity, inhibited proliferation of cysticerci in vitro and decreased the *T. crassiceps* cysticerci load up to 50% in the peritoneal cavity of Balb/c mice (Carrero *et al.*, 2010).

Neuroimmunoendocrine Interactions in Murine Cysticercosis: From the Lab Bench Work to Its Possible Applications in Controlling Porcine Cysticercosis and Human Neurocysticercosis 45

hosts. Other similar mutually conflicting statements may be elaborated with the above premises, the true ones remain to be identified and could perhaps vary with each different

**Figure 2. Neuroimmunoendocrine changes in host during murine cysticercosis.** Infection with *Taenia sp*, leads to a Th2 response with high levels of IL-6 activating the P450-aromatase, which convert T4 into E2 increasing its level in the host. Estrogens are permissive for the infection while androgens (T4, DHT) inhibit parasite reproduction and reduce parasite load. E2 overproduction induces behavioral changes in male and female. Signs (+ and -) means induction and inhibition respectively; signs ( and )

However, not only male mice are behaviorally affected by CC, female mice also suffer perturbations in their sexual behavior. Infected females were less receptive to the male at 6 weeks post infection (p.i.) and until 12 weeks p.i.; and there was also an interruption in the estrous cycle that was clearly starting at 12 weeks of infection and remained until the 16th weeks. These changes were associated to the low levels of serum E2 that were comparable to those found during the diestrus stage of control mice (Arteaga-Silva *et al.*, 2009). That sex steroids, particularly E2 is very important to the host-parasite relationship in CC, was recently demonstrated by Guzman, *et al* (Guzman *et al.*, 2009). A single injection of E2 administered to 4-day-old male and female mice increased the cellular immune response and induced resistance to *T. crassiceps* cysticercosis. At the same time, there are changes in

host-parasite relationship.

denote increase or decrease phenomena.

### **1.3. Behavioral changes in the infected host**

The hormonal changes in cysticercotic mice, profoundly affect their behavior, such as sexual activity (Morales *et al.*, 1996), aggressiveness (Gourbal *et al.*, 2001), social status (Gourbal *et al.*, 2002) prey/predator defense responses, and also cognitive functions. Male mice infected with *T. crassiceps* show remarkable changes in sexual behavior, characterized by a complete loss of the ejaculation response early at the infection (six weeks), followed by a gradual decrease in the number of mounts and intromissions, and their latencies increased, until none of the parasitized mice showed any sexual response toward female mice (Morales *et al.*, 1996). Moreover, it was demonstrated that changes in sexual behavior were due to the change in the normal production of sex-steroids by the mouse, since there was a complete restoration of their sexual behavior after T4 or DHT restitution of the infected male mice (Gourbal *et al.*, 2001). Since *c-fos* and progesterone receptor gene (PGR), both are key E2-regulated genes involved in the regulation of sexual behavior, we studied possible changes of *c-fos* and PGR expression in the central nervous system (CNS) of infected male mice. Indeed, *c-fos* and PGR expression oscillated with time of infection and to different magnitudes in hypothalamus, brain cortex and preoptic area but neither in other areas of the brain nor in several other organs of the host (Morales-Montor *et al.*, 2004a; Rodriguez-Dorantes *et al.*, 2007).

Furthermore, infection disrupts the dominant-subordinate status (Gourbal *et al.*, 2002). In infected male mice strong perturbations in territorial behavior and aggressiveness were found. In addition, during confrontation between naive infected and healthy mice, infected animals more often assumed a subordinate status than healthy ones. The effects of the infection by *T. crassiceps* were more likely to prevent adult male mice from becoming behaviorally dominant than to reverse existing dominance relationships (Gourbal *et al.*, 2001).

Significant CNS changes in *c-fos,* and PR expression during infection signifies the brain senses the infection episode and may be involved in the ensuing behavioral changes of the infected mice, as well as, through its connectivity, extend the effects of infection to other physiological systems under its influence. That these changes in CNS are beneficial to the host or parasite remains speculative (Klein, 2000). One could argue that feminization of male hosts favors the parasite by allowing reproduction in otherwise restrictive male mice, but equally arguable would be to consider feminization of the male host as deleterious to the parasite's completion of its cycle by reducing male exposure to its predators, the definitive hosts. Other similar mutually conflicting statements may be elaborated with the above premises, the true ones remain to be identified and could perhaps vary with each different host-parasite relationship.

44 Novel Aspects on Cysticercosis and Neurocysticercosis

Balb/c mice (Carrero *et al.*, 2010).

**1.3. Behavioral changes in the infected host** 

the common assumption of DHEA as an immune-stimulatory hormone, the immune responses of our mice, characterized by the expression of IL-2, IFN-γ, IL-4 or IL-10, was not affected by DHEA treatment (Vargas-Villavicencio *et al.*, 2008). *In vitro*, treatment of *T. crassiceps* cysticerci with DHEA induced 80% reduction in parasite reproduction, which may partially explain the reduction of parasite loads observed *in vivo* a partial effect suggesting the involvement of other unknown factors in the in vivo regulation of parasite loads (Vargas-Villavicencio *et al.*, 2008). In addition, the use of 16α-bromoepiandrosterone (EpiBr), a DHEA analog without significant androgenic activity, inhibited proliferation of cysticerci in vitro and decreased the *T. crassiceps* cysticerci load up to 50% in the peritoneal cavity of

The hormonal changes in cysticercotic mice, profoundly affect their behavior, such as sexual activity (Morales *et al.*, 1996), aggressiveness (Gourbal *et al.*, 2001), social status (Gourbal *et al.*, 2002) prey/predator defense responses, and also cognitive functions. Male mice infected with *T. crassiceps* show remarkable changes in sexual behavior, characterized by a complete loss of the ejaculation response early at the infection (six weeks), followed by a gradual decrease in the number of mounts and intromissions, and their latencies increased, until none of the parasitized mice showed any sexual response toward female mice (Morales *et al.*, 1996). Moreover, it was demonstrated that changes in sexual behavior were due to the change in the normal production of sex-steroids by the mouse, since there was a complete restoration of their sexual behavior after T4 or DHT restitution of the infected male mice (Gourbal *et al.*, 2001). Since *c-fos* and progesterone receptor gene (PGR), both are key E2-regulated genes involved in the regulation of sexual behavior, we studied possible changes of *c-fos* and PGR expression in the central nervous system (CNS) of infected male mice. Indeed, *c-fos* and PGR expression oscillated with time of infection and to different magnitudes in hypothalamus, brain cortex and preoptic area but neither in other areas of the brain nor in several other

organs of the host (Morales-Montor *et al.*, 2004a; Rodriguez-Dorantes *et al.*, 2007).

than to reverse existing dominance relationships (Gourbal *et al.*, 2001).

Furthermore, infection disrupts the dominant-subordinate status (Gourbal *et al.*, 2002). In infected male mice strong perturbations in territorial behavior and aggressiveness were found. In addition, during confrontation between naive infected and healthy mice, infected animals more often assumed a subordinate status than healthy ones. The effects of the infection by *T. crassiceps* were more likely to prevent adult male mice from becoming behaviorally dominant

Significant CNS changes in *c-fos,* and PR expression during infection signifies the brain senses the infection episode and may be involved in the ensuing behavioral changes of the infected mice, as well as, through its connectivity, extend the effects of infection to other physiological systems under its influence. That these changes in CNS are beneficial to the host or parasite remains speculative (Klein, 2000). One could argue that feminization of male hosts favors the parasite by allowing reproduction in otherwise restrictive male mice, but equally arguable would be to consider feminization of the male host as deleterious to the parasite's completion of its cycle by reducing male exposure to its predators, the definitive

**Figure 2. Neuroimmunoendocrine changes in host during murine cysticercosis.** Infection with *Taenia sp*, leads to a Th2 response with high levels of IL-6 activating the P450-aromatase, which convert T4 into E2 increasing its level in the host. Estrogens are permissive for the infection while androgens (T4, DHT) inhibit parasite reproduction and reduce parasite load. E2 overproduction induces behavioral changes in male and female. Signs (+ and -) means induction and inhibition respectively; signs ( and ) denote increase or decrease phenomena.

However, not only male mice are behaviorally affected by CC, female mice also suffer perturbations in their sexual behavior. Infected females were less receptive to the male at 6 weeks post infection (p.i.) and until 12 weeks p.i.; and there was also an interruption in the estrous cycle that was clearly starting at 12 weeks of infection and remained until the 16th weeks. These changes were associated to the low levels of serum E2 that were comparable to those found during the diestrus stage of control mice (Arteaga-Silva *et al.*, 2009). That sex steroids, particularly E2 is very important to the host-parasite relationship in CC, was recently demonstrated by Guzman, *et al* (Guzman *et al.*, 2009). A single injection of E2 administered to 4-day-old male and female mice increased the cellular immune response and induced resistance to *T. crassiceps* cysticercosis. At the same time, there are changes in

the expression pattern of PR and estrogen receptor (ER) isoforms in the brain and splenocytes. Regardless of gender, when treated mice reached adulthood, they were highly resistant to infection. Female mice presented early vaginal opening and altered estrous cycles. In male and female mice, the expression of the PR and ER isoforms in the brain was differentially regulated after neonatal exposure to estradiol. Moreover, an increase in the expression of IL-4 and IFN-γ was found in the serum of experimentally infected neonatally estrogenized animals, which correlated with the observed protection against *T. crassiceps* infection. In conclusion, early exposure to E2 permanently modifies immune system activity and sex steroid hormone receptors in the brain, and causes profound changes in sex-associated susceptibility, leading to resistance to helminthic infection (Guzman *et al.*, 2009). A chart of all neuroimmunoendocrine changes during murine cysticercosis is depicted in Figure 2.

Neuroimmunoendocrine Interactions in Murine Cysticercosis: From the Lab Bench Work to Its Possible Applications in Controlling Porcine Cysticercosis and Human Neurocysticercosis 47

between disease heterogeneity, endocrine and immunological status. Since the proper diagnostic of the disease was fundamental in this study, a precise clinical and radiological description of the disease and a complete hormonal and immunological profile was performed to 50 patients and 22 healthy subjects. Patients had lower DHEA levels compared to healthy subjects. Concerning to gender, male patients showed a clear decrease in 17βestradiol serum levels and high levels of Luteinizing Hormone (LH), while female patients with clinically severe disease showed lower levels of progesterone and androstenedione. Higher concentrations of follicle stimulating hormone (FSH) and lower concentrations of testosterone (similar to those reported previously during murine cysticercosis) were found in male patients with severe disease, when compared with the less clinically severe patients. Significant correlations were found between E2 and IL-10 in male patients, and between DHEA and IL-1β, and androstenedione and IL-17 in female patients, suggesting a possible immunoendocrine interaction. The study by Cardenas, *et. al.* in neurocysticercotic patients constitutes the first demonstration that the presence of *T. solium* larvae in the central nervous system, can modify the host environment by the induction of endocrine and immunological changes. As the authors point out, these results provide a stimulating background to analyze the repercussions of the hormonal changes during the course of disease and on patient reproductive health (Cardenas *et al.*, 2012). Taken together, the above-presented evidence open up the possibility of the use analogues of hormones, as

**1.5. Direct effect of sex steroids on** *Taenia crassiceps* **and** *Taenia solium*

As described before, hormones play a significant role in murine *T. crassiceps* cysticercosis and participate in the susceptibility to *T. solium* cysticercosis. However, this effect is not only due to the regulation of the immune response by sex steroids, but also by acting directly upon cysticerci reproduction. For instance, it has been shown that *in vitro* treatment with E2 and P4 stimulates *T. crassiceps* reproduction. In contrast, T4 or DHT inhibit and even exert a toxic effect on the parasite (Escobedo *et al.*, 2004). The possible molecular mechanisms by which sex-steroids affect *T. crassiceps* reproduction imply the presence of sex hormone receptors, since the use of tamoxifen, an anti-estrogenic compound (Escobedo *et al.*, 2005), decreases parasite reproduction *in vitro* and parasite loads *in vivo*, as described before (Vargas-Villavicencio *et al.*, 2007), we look for a estrogen receptor expressed by parasitic cells. As described by Ibarra, *et. al.* there is a molecule similar to the estrogen receptor alpha (ERα) identified by diverse methods such as western blot and PCR. This receptor is expressed exclusively by parasitic cells, as identified by the expression of a parasite-specific protein, paramyosin (Ibarra-Coronado *et al.*, 2011). Parasite cells expressing the ER-like protein were located by confocal microscopy in the subtegumental tissue exclusively. Sequencing of the spot produced a small fragment of protein similar to the mammalian nuclear ER. In addition to, once host's E2 has bound to its parasite estrogen receptor, the dimeric complex would activate the transcription of several *T. crassiceps* proliferative genes, such as *c-fos*, *c-jun* and cyclin D1, directly or through the activation of the MAPK family of serine/threonine

novel anti-cysticercotic agents.

**cysticercy** 

## **1.4.** *Taenia solium* **cysticercosis, neurocysticercosis and taeniosis**

As described for the mouse model of CC, host's biological factors such as genetic background, the innate and acquired immunity and gender can lead to resistance and/or susceptibility to cysticercosis/taeniosis by *Taenia solium*. It has been shown that sexual hormones play an important role in porcine CC. For instance, castrated male pigs increased by 30% the prevalence of naturally acquired CC, while pregnant sows doubled the prevalence, compared to non castrated males and non-pregnant sows (Morales *et al.*, 2002). Another interesting finding, was found when in experiments designed to explore the hormonal profiles of sex steroids, as well as DHEA in serum of boars that had naturally acquired CC, it was observed a significant reduction in the T4 levels, change that was independent of the heterogeneous genetic background and large range of ages. These findings suggest that sex steroids can be associated to *T. solium* susceptibility and transmission dynamics of this parasite in natural conditions (Pena *et al.*, 2007).

Interestingly, sex steroids are not the unique hormones that can be useful to this parasite. It has been recently described that the *in vitro* culture of *T. crassiceps* with insulin stimulates parasite reproduction by two-fold and increased the average of the bud diameter. However, this hormone had no effect on *T. solium* cysticerci culture (Escobedo *et al.*, 2009). On the other hand, hamsters treated with P4 and experimentally infected with *T. solium* showed an 80% reduction of anchored-*T. solium* tapeworms, a reduced growth of these parasites and a down-regulation of the PR expression in 50% duodenum associated tapeworms. Immune response of P4 treated hamsters showed an increase in IL-4, IL-6 and TNF-α cytokines and an exacerbated inflammatory infiltrate located along the lamina propria, compared to infected non-progesterone treated controls (Escobedo *et al.*, 2011). These results clearly support the fact that P4 protects against the *T. solium* adult tapeworm establishment by improving the immune system.

The studies in mice and pigs have already been scaled to the natural human disease. A recent study on human NCC, caused by larvae of *T. solium* infiltration in the CNS demonstrated a strong correlation between the endocrine, immune systems, gender and age during the clinical manifestation and susceptibility to the disease. Cardenas, *et. al,* designed a clinical study to evaluate the hormonal changes associated with NCC and the relationships between disease heterogeneity, endocrine and immunological status. Since the proper diagnostic of the disease was fundamental in this study, a precise clinical and radiological description of the disease and a complete hormonal and immunological profile was performed to 50 patients and 22 healthy subjects. Patients had lower DHEA levels compared to healthy subjects. Concerning to gender, male patients showed a clear decrease in 17βestradiol serum levels and high levels of Luteinizing Hormone (LH), while female patients with clinically severe disease showed lower levels of progesterone and androstenedione. Higher concentrations of follicle stimulating hormone (FSH) and lower concentrations of testosterone (similar to those reported previously during murine cysticercosis) were found in male patients with severe disease, when compared with the less clinically severe patients. Significant correlations were found between E2 and IL-10 in male patients, and between DHEA and IL-1β, and androstenedione and IL-17 in female patients, suggesting a possible immunoendocrine interaction. The study by Cardenas, *et. al.* in neurocysticercotic patients constitutes the first demonstration that the presence of *T. solium* larvae in the central nervous system, can modify the host environment by the induction of endocrine and immunological changes. As the authors point out, these results provide a stimulating background to analyze the repercussions of the hormonal changes during the course of disease and on patient reproductive health (Cardenas *et al.*, 2012). Taken together, the above-presented evidence open up the possibility of the use analogues of hormones, as novel anti-cysticercotic agents.

46 Novel Aspects on Cysticercosis and Neurocysticercosis

improving the immune system.

changes during murine cysticercosis is depicted in Figure 2.

**1.4.** *Taenia solium* **cysticercosis, neurocysticercosis and taeniosis** 

transmission dynamics of this parasite in natural conditions (Pena *et al.*, 2007).

the expression pattern of PR and estrogen receptor (ER) isoforms in the brain and splenocytes. Regardless of gender, when treated mice reached adulthood, they were highly resistant to infection. Female mice presented early vaginal opening and altered estrous cycles. In male and female mice, the expression of the PR and ER isoforms in the brain was differentially regulated after neonatal exposure to estradiol. Moreover, an increase in the expression of IL-4 and IFN-γ was found in the serum of experimentally infected neonatally estrogenized animals, which correlated with the observed protection against *T. crassiceps* infection. In conclusion, early exposure to E2 permanently modifies immune system activity and sex steroid hormone receptors in the brain, and causes profound changes in sex-associated susceptibility, leading to resistance to helminthic infection (Guzman *et al.*, 2009). A chart of all neuroimmunoendocrine

As described for the mouse model of CC, host's biological factors such as genetic background, the innate and acquired immunity and gender can lead to resistance and/or susceptibility to cysticercosis/taeniosis by *Taenia solium*. It has been shown that sexual hormones play an important role in porcine CC. For instance, castrated male pigs increased by 30% the prevalence of naturally acquired CC, while pregnant sows doubled the prevalence, compared to non castrated males and non-pregnant sows (Morales *et al.*, 2002). Another interesting finding, was found when in experiments designed to explore the hormonal profiles of sex steroids, as well as DHEA in serum of boars that had naturally acquired CC, it was observed a significant reduction in the T4 levels, change that was independent of the heterogeneous genetic background and large range of ages. These findings suggest that sex steroids can be associated to *T. solium* susceptibility and

Interestingly, sex steroids are not the unique hormones that can be useful to this parasite. It has been recently described that the *in vitro* culture of *T. crassiceps* with insulin stimulates parasite reproduction by two-fold and increased the average of the bud diameter. However, this hormone had no effect on *T. solium* cysticerci culture (Escobedo *et al.*, 2009). On the other hand, hamsters treated with P4 and experimentally infected with *T. solium* showed an 80% reduction of anchored-*T. solium* tapeworms, a reduced growth of these parasites and a down-regulation of the PR expression in 50% duodenum associated tapeworms. Immune response of P4 treated hamsters showed an increase in IL-4, IL-6 and TNF-α cytokines and an exacerbated inflammatory infiltrate located along the lamina propria, compared to infected non-progesterone treated controls (Escobedo *et al.*, 2011). These results clearly support the fact that P4 protects against the *T. solium* adult tapeworm establishment by

The studies in mice and pigs have already been scaled to the natural human disease. A recent study on human NCC, caused by larvae of *T. solium* infiltration in the CNS demonstrated a strong correlation between the endocrine, immune systems, gender and age during the clinical manifestation and susceptibility to the disease. Cardenas, *et. al,* designed a clinical study to evaluate the hormonal changes associated with NCC and the relationships

## **1.5. Direct effect of sex steroids on** *Taenia crassiceps* **and** *Taenia solium* **cysticercy**

As described before, hormones play a significant role in murine *T. crassiceps* cysticercosis and participate in the susceptibility to *T. solium* cysticercosis. However, this effect is not only due to the regulation of the immune response by sex steroids, but also by acting directly upon cysticerci reproduction. For instance, it has been shown that *in vitro* treatment with E2 and P4 stimulates *T. crassiceps* reproduction. In contrast, T4 or DHT inhibit and even exert a toxic effect on the parasite (Escobedo *et al.*, 2004). The possible molecular mechanisms by which sex-steroids affect *T. crassiceps* reproduction imply the presence of sex hormone receptors, since the use of tamoxifen, an anti-estrogenic compound (Escobedo *et al.*, 2005), decreases parasite reproduction *in vitro* and parasite loads *in vivo*, as described before (Vargas-Villavicencio *et al.*, 2007), we look for a estrogen receptor expressed by parasitic cells. As described by Ibarra, *et. al.* there is a molecule similar to the estrogen receptor alpha (ERα) identified by diverse methods such as western blot and PCR. This receptor is expressed exclusively by parasitic cells, as identified by the expression of a parasite-specific protein, paramyosin (Ibarra-Coronado *et al.*, 2011). Parasite cells expressing the ER-like protein were located by confocal microscopy in the subtegumental tissue exclusively. Sequencing of the spot produced a small fragment of protein similar to the mammalian nuclear ER. In addition to, once host's E2 has bound to its parasite estrogen receptor, the dimeric complex would activate the transcription of several *T. crassiceps* proliferative genes, such as *c-fos*, *c-jun* and cyclin D1, directly or through the activation of the MAPK family of serine/threonine

kinase, such as ERK, which has been also recently described in this parasite (Escobedo *et al.*, 2010). Since this hypothetical molecular mechanism could be *in vitro* interrupted by using tamoxifen, we suggest a genomic action mechanism for E2 on the parasite.

Neuroimmunoendocrine Interactions in Murine Cysticercosis: From the Lab Bench Work to Its Possible Applications in Controlling Porcine Cysticercosis and Human Neurocysticercosis 49

> (Ramachandran *et al.*, 1996) (Spiliotis *et al.*, 2003)

(Khayath *et al.*, 2007) (You *et al.*, 2010) (Konrad *et al.*, 2003)

(Freebern *et al.*, 1999) (Tzertzinis *et al.*, 2010)

1997)

(Sani *et al.*, 1985)

2011)

(Tzertzinis *et al.*, 2010) (Shea *et al.*, 2010)

(Crossgrove *et al.*, 2002) (Crossgrove *et al.*, 2008) (Unnasch *et al.*, 1999) (Forster *et al.*, 2011)

*Brugia pahangi* (Gomez-Escobar *et al.*,

*Schistosoma mansonii* (Hu *et al.*, 2006)

*Trichinella spiralis* XP\_003375811

amphibian progesterone receptors, whereas it has a distant relation with birds and mammals. Conclusively, progesterone directly acts upon *T. solium* cysticerci, possibly by binding to a progesterone receptor synthesized by the parasite. The strong effects of sex steroids upon cysticercosis open new avenues for its control. In Table 1, there is a list of

**Hormone Receptor Parasite Ref/AC** 

*Echinococcus multilocularis*

*Schistosoma japonicum Echinococcus multilocularis*

*Brugia malayi*

*Onchocerca volvulus Onchocerca gibsoni, Dipetalonemaviteae Brugia pahangi Dirofilaria immitis*

Estrogen Receptor *Taenia crassiceps* (Ibarra-Coronado *et al.*,

*Dirofilaria immitis*

*Brugia malayi Dirofilaria immitis Onchocerca volvulus Echinococcus multilocularis*

*In vitro* effects of human chorionic gonadotropin (hCG) on the larval stages of *T. crassiceps* (WFU strain) and *T. solium* have also been reported*.* As a matter of fact, these effects were correlated to the presence of receptors for hCG in different developmental phases of both cultured parasites. Authors argued that direct effect of hCG can be recognized as a factor contributing to the growth and development of *T. crassiceps* and *T. solium* cysticerci (Castellanos-Sanchez *et al.*, 2009). *T. crassiceps* and *T. solium* cysticerci have the ability to

Estrogen-related receptor-β *Schistosoma japonicum* (Wu *et al.*, 2012)

some hormone receptors reported in helminth parasites to date.

Epidermal Growth Factor *Schistosoma mansonii*

Insulin Receptor *Schistosoma mansonii*

Retinoid X receptor *Schistosomamansonii*

Ecdysone receptor *Brugia malayi*

**Table 1.** Principal hormonal receptors in parasites reported to date.

Transforming growth factor-β

Retinoic acid-binding protein

Constitutive androstane Receptor

Putative Follicle-stimulating hormone receptor

> Nuclear Hormone Receptors

On the other hand, the androgen mechanism might be different from the found for estrogens and progesterone. T4 and DHT directly affect parasitic DNA integrity probably by activating apoptotic mechanism in the cysticercus cells. This experimental finding is not dependent of a nuclear receptor because flutamide (a well studied and used anti-androgen) did not have effects upon parasite reproduction *in vitro* (Escobedo *et al.*, 2005). These results demonstrate that sex steroids act directly upon parasite reproduction perhaps by binding to receptors closely resembling classic and specific sex-steroid vertebrate receptors (Escobedo *et al.*, 2005).

Furthermore, it has been shown that T. crassiceps cysticerci are able to metabolize sex steroids in vitro and, and that it possibly uses hosts hormones as positive or negative factors for its own reproduction (Gomez *et al.*, 2000). *T. solium* cysticercosis is a health problem in underdeveloped and developed countries. Sex hormones are involved in cysticercosis prevalence in female and male pigs. Interestingly, progesterone increased *T. solium* scolex evagination and worm growth, in a concentration-independent pattern. This effect could be mediated by the expression of a novel *T. solium* progesterone receptor (TsPR) since RU486 inhibits both scolex evagination and worm development induced by progesterone (Figure 3).

**Figure 3.** Effect of progesterone (P4) and RU486 (progesterone analogue) in cultured cysts of *T. solium*. Progesterone promotes scolex evagination and worm growth while RU486 inhibit scolex evagination.

Using RT-PCR and western blot, sequences related to progesterone receptor were detected in the parasite. A phylogenetic analysis reveals that TsPR is highly related to fish and amphibian progesterone receptors, whereas it has a distant relation with birds and mammals. Conclusively, progesterone directly acts upon *T. solium* cysticerci, possibly by binding to a progesterone receptor synthesized by the parasite. The strong effects of sex steroids upon cysticercosis open new avenues for its control. In Table 1, there is a list of some hormone receptors reported in helminth parasites to date.

48 Novel Aspects on Cysticercosis and Neurocysticercosis

kinase, such as ERK, which has been also recently described in this parasite (Escobedo *et al.*, 2010). Since this hypothetical molecular mechanism could be *in vitro* interrupted by using

On the other hand, the androgen mechanism might be different from the found for estrogens and progesterone. T4 and DHT directly affect parasitic DNA integrity probably by activating apoptotic mechanism in the cysticercus cells. This experimental finding is not dependent of a nuclear receptor because flutamide (a well studied and used anti-androgen) did not have effects upon parasite reproduction *in vitro* (Escobedo *et al.*, 2005). These results demonstrate that sex steroids act directly upon parasite reproduction perhaps by binding to receptors closely resembling classic and specific sex-steroid vertebrate receptors (Escobedo *et al.*, 2005).

Furthermore, it has been shown that T. crassiceps cysticerci are able to metabolize sex steroids in vitro and, and that it possibly uses hosts hormones as positive or negative factors for its own reproduction (Gomez *et al.*, 2000). *T. solium* cysticercosis is a health problem in underdeveloped and developed countries. Sex hormones are involved in cysticercosis prevalence in female and male pigs. Interestingly, progesterone increased *T. solium* scolex evagination and worm growth, in a concentration-independent pattern. This effect could be mediated by the expression of a novel *T. solium* progesterone receptor (TsPR) since RU486 inhibits both scolex evagination and worm development induced by progesterone (Figure 3).

**Figure 3.** Effect of progesterone (P4) and RU486 (progesterone analogue) in cultured cysts of *T. solium*. Progesterone promotes scolex evagination and worm growth while RU486 inhibit scolex evagination.

Using RT-PCR and western blot, sequences related to progesterone receptor were detected in the parasite. A phylogenetic analysis reveals that TsPR is highly related to fish and

tamoxifen, we suggest a genomic action mechanism for E2 on the parasite.



*In vitro* effects of human chorionic gonadotropin (hCG) on the larval stages of *T. crassiceps* (WFU strain) and *T. solium* have also been reported*.* As a matter of fact, these effects were correlated to the presence of receptors for hCG in different developmental phases of both cultured parasites. Authors argued that direct effect of hCG can be recognized as a factor contributing to the growth and development of *T. crassiceps* and *T. solium* cysticerci (Castellanos-Sanchez *et al.*, 2009). *T. crassiceps* and *T. solium* cysticerci have the ability to

metabolize exogenous androstenedione to T4, using different hormonal precursors (Jimenez *et al.*, 2006). A chart of all the immunoendocrine effects during *T. solium* cysticercosis is presented in Figure 2.

Neuroimmunoendocrine Interactions in Murine Cysticercosis: From the Lab Bench Work to Its Possible Applications in Controlling Porcine Cysticercosis and Human Neurocysticercosis 51

*Cryptosporidium parvum* (Rasmussen & Healey,

*Plasmodium falciparum* (Kurtis *et al.*, 2001) *Entamoeba histolytica* (Carrero *et al.*, 2006) *Schistosoma mansoni* (Fallon *et al.*, 1998) *Trypanosoma cruzi* (dos Santos *et al.*, 2005)

*Taenia crassiceps* (Carrero *et al.*, 2010) *Entamoeba histolytica* (Carrero *et al.*, 2010)

Feline immunodeficiency virus (Pedersen *et al.*, 2003)

AIDS (Reading *et al.*, 2006)

1992)

(Freilich *et al.*, 2000)

and survival (Vargas-Villavicencio *et al.*, 2007). Table 2 has a summary of the above-

**Compound Infection Reference** 

*Plasmodium falciparum Plasmodium berghei*

The evidence presented above illustrates the complexity and importance of neuroimmunoendocrine interactions during CC and provides clues to the many other possible mechanisms of parasite establishment, growth and reproduction in an immunocompetent host. Further, strong neuroimmunoendocrine interactions may have implications in the control of transmission and treatment of this parasitic disease in porcine and humans. In practical importance, the complexity of the cysticerci-host relationship suggests that all physiological factors (i.e., sex, age) should be taken into account in the

The differential response of cysticerci to sex steroids may also be involved in their ability to grow faster in the murine female or feminized male host. Host and parasite sex-associated biases may be combined to favor their evolution towards a mutually acceptable relationship. Moreover, the changes in behavior observed during CC, should not be regarded as simple biological curiosities but more as strong evidence of the plasticity of the host phenotype in response to infection by parasitic helminthes. Furthermore, by changing the reproductive, aggressive and dominant capacity of the host, parasites generate novel questions regarding to the evolution of host-parasite relationships in addition to only the prey/predator interaction.

Finally, we have documented here that a complex interactive network involving the immune, endocrine and nervous systems of the mouse, as well as the reproductive system of the cysticerci, is in control of the parasite load of each infected individual mouse. If such complex a management of the parasite loads, as that we shown here between mice and cysticerci, extends to other parasite diseases of mammals, as current research seems to indicate in a number of infections, their means of exploration, fuller understandings and

**Table 2.** Therapeutic use of DHEA or an analogue (EpiBr) during several parasitic infections.

mentioned therapeutic use of hormone analogue in *T. crassiceps* cysticercosis*.* 

DHEA / DHEAS

16α-bromoepiandrosterone (EpiBr or HE2000)

**2. Concluding remarks** 

design of vaccines and new drugs.

Finally, both *T. crassiceps* and *T. solium* expressed the insulin receptor, although insulin had effects only on *T. crassiceps.* Thus, insulin may be recognized by *T. crassiceps* cysticercus cells as a mitogenic factor, and contribute to parasite proliferation inside the host. This phenomenon has not been reported for cysticercosis caused by *T. solium*, which could, in part, be related to the poor effect of insulin upon the human parasite (Escobedo *et al.*, 2009).

## **1.6. Therapeutic applications of hormones in cysticercosis/taeniosis**

The study and evaluation of new substances of hormonal nature and its analogues has emerged with great importance to develop a new generation of anti-parasitic drugs. In the case of *T. crassiceps*, the reconstitution and substitution (depending the host and hormone used) with sex steroids showed that T4 or DHT treatment before infection decreased parasite loads by 50 and 70% respectively, suggesting a protective role for androgens (Morales-Montor *et al.*, 2002a). In contrast the treatment with E2 increased it by three times in both genders as compared with controls. Even more, castrated mice of both genders treated with progesterone before infection, decreased parasite loads by 100% compared with intact uninfected mice. However the negative effects in the establishment, growth and reproduction of *T. crassiceps* was mediated by the metabolism of progesterone to DHEA in the adrenal gland of castrated animals (Vargas-Villavicencio *et al.*, 2006). To strength out the notion of DHEA as a protective agent, we designed experiments to test this hypothesis, by incubating *in vitro T. crassiceps* cysticerci with increasing concentrations of DHEA, and by *in vivo* treating male and female mice with DHEA and infecting them with *T. crassiceps* cysticerci. *In vitro*, DHEA has a strong cysticidal effect, being dose-dependent in physiological and pharmacological conditions. *In vivo* assays showed that DHEA reduce the viability of cysticerci in both male and female mice (Carrero *et al.*, 2006; Carrero *et al.*, 2010).

The use of EpiBr (analogue of DHEA) reduced the parasitic load in a major proportion in both male and female infected with *T. crassicepps* (Freilich *et al.*, 2000). Tamoxifen is an antiestrogen compound belonging to the group of Selective Estrogen Receptor Moduladors (SERM). Administration of tamoxifen in infected mice of both genders produced an 80% parasite load reduction in female mice, and a weaker effect of 50% in male mice. This protective effect was associated in both genders, with an increase in the mRNA levels of IL-2 (a cytokine associated with protection against cysticerci) and IL-4 (no effect on infection). Tamoxifen treatment modified E2 production on females, whereas serum testosterone was not affected. However, the expression of the 2 types of ER, i.e., ER-α and ER-β in the spleen of infected mice of both genders, was decreased by tamoxifen treatment. *In vitro*, treatment of *T. crassiceps* with tamoxifen reduced reproduction and loss of motility. These results indicate that tamoxifen treatment is a new therapeutic possibility to treat CC, because it can act at both ends of the host–parasite relationship, i.e., by increasing the cellular immune response protective against the parasite and by directly affecting the parasite's reproduction and survival (Vargas-Villavicencio *et al.*, 2007). Table 2 has a summary of the abovementioned therapeutic use of hormone analogue in *T. crassiceps* cysticercosis*.* 


**Table 2.** Therapeutic use of DHEA or an analogue (EpiBr) during several parasitic infections.

## **2. Concluding remarks**

50 Novel Aspects on Cysticercosis and Neurocysticercosis

presented in Figure 2.

metabolize exogenous androstenedione to T4, using different hormonal precursors (Jimenez *et al.*, 2006). A chart of all the immunoendocrine effects during *T. solium* cysticercosis is

Finally, both *T. crassiceps* and *T. solium* expressed the insulin receptor, although insulin had effects only on *T. crassiceps.* Thus, insulin may be recognized by *T. crassiceps* cysticercus cells as a mitogenic factor, and contribute to parasite proliferation inside the host. This phenomenon has not been reported for cysticercosis caused by *T. solium*, which could, in part, be related to the poor effect of insulin upon the human parasite (Escobedo *et al.*, 2009).

The study and evaluation of new substances of hormonal nature and its analogues has emerged with great importance to develop a new generation of anti-parasitic drugs. In the case of *T. crassiceps*, the reconstitution and substitution (depending the host and hormone used) with sex steroids showed that T4 or DHT treatment before infection decreased parasite loads by 50 and 70% respectively, suggesting a protective role for androgens (Morales-Montor *et al.*, 2002a). In contrast the treatment with E2 increased it by three times in both genders as compared with controls. Even more, castrated mice of both genders treated with progesterone before infection, decreased parasite loads by 100% compared with intact uninfected mice. However the negative effects in the establishment, growth and reproduction of *T. crassiceps* was mediated by the metabolism of progesterone to DHEA in the adrenal gland of castrated animals (Vargas-Villavicencio *et al.*, 2006). To strength out the notion of DHEA as a protective agent, we designed experiments to test this hypothesis, by incubating *in vitro T. crassiceps* cysticerci with increasing concentrations of DHEA, and by *in vivo* treating male and female mice with DHEA and infecting them with *T. crassiceps* cysticerci. *In vitro*, DHEA has a strong cysticidal effect, being dose-dependent in physiological and pharmacological conditions. *In vivo* assays showed that DHEA reduce the viability of cysticerci in both male and female mice (Carrero *et al.*, 2006; Carrero *et al.*, 2010).

The use of EpiBr (analogue of DHEA) reduced the parasitic load in a major proportion in both male and female infected with *T. crassicepps* (Freilich *et al.*, 2000). Tamoxifen is an antiestrogen compound belonging to the group of Selective Estrogen Receptor Moduladors (SERM). Administration of tamoxifen in infected mice of both genders produced an 80% parasite load reduction in female mice, and a weaker effect of 50% in male mice. This protective effect was associated in both genders, with an increase in the mRNA levels of IL-2 (a cytokine associated with protection against cysticerci) and IL-4 (no effect on infection). Tamoxifen treatment modified E2 production on females, whereas serum testosterone was not affected. However, the expression of the 2 types of ER, i.e., ER-α and ER-β in the spleen of infected mice of both genders, was decreased by tamoxifen treatment. *In vitro*, treatment of *T. crassiceps* with tamoxifen reduced reproduction and loss of motility. These results indicate that tamoxifen treatment is a new therapeutic possibility to treat CC, because it can act at both ends of the host–parasite relationship, i.e., by increasing the cellular immune response protective against the parasite and by directly affecting the parasite's reproduction

**1.6. Therapeutic applications of hormones in cysticercosis/taeniosis** 

The evidence presented above illustrates the complexity and importance of neuroimmunoendocrine interactions during CC and provides clues to the many other possible mechanisms of parasite establishment, growth and reproduction in an immunocompetent host. Further, strong neuroimmunoendocrine interactions may have implications in the control of transmission and treatment of this parasitic disease in porcine and humans. In practical importance, the complexity of the cysticerci-host relationship suggests that all physiological factors (i.e., sex, age) should be taken into account in the design of vaccines and new drugs.

The differential response of cysticerci to sex steroids may also be involved in their ability to grow faster in the murine female or feminized male host. Host and parasite sex-associated biases may be combined to favor their evolution towards a mutually acceptable relationship. Moreover, the changes in behavior observed during CC, should not be regarded as simple biological curiosities but more as strong evidence of the plasticity of the host phenotype in response to infection by parasitic helminthes. Furthermore, by changing the reproductive, aggressive and dominant capacity of the host, parasites generate novel questions regarding to the evolution of host-parasite relationships in addition to only the prey/predator interaction.

Finally, we have documented here that a complex interactive network involving the immune, endocrine and nervous systems of the mouse, as well as the reproductive system of the cysticerci, is in control of the parasite load of each infected individual mouse. If such complex a management of the parasite loads, as that we shown here between mice and cysticerci, extends to other parasite diseases of mammals, as current research seems to indicate in a number of infections, their means of exploration, fuller understandings and

forms of control must be reviewed and approached with designs matching in complexity and plasticity that of the infections.

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Escobedo, G., Camacho-Arroyo, I., Nava-Luna, P., Olivos, A., Perez-Torres, A., Leon-Cabrera, S., Carrero, J. C. and Morales-Montor, J. (2011). Progesterone induces mucosal immunity in a rodent model of human taeniosis by Taenia solium. *International journal* 

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26,4,Nov,pp (693-711),0889-857X (Print)

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culture. *J Parasitol,* 95,6,Dec,pp (1287-1294),1937-2345 (Electronic)

176),1879-0135 (Electronic)

4579 (Print)

(Print)

## **Author details**

Karen Nava-Castro *Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, México DF, México* 

Romel Hernández-Bello *Departamento de Microbiología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, México, México* 

Lorena López-Griego, Jhonatan A. Hernández-Valdés, Valeria López-Salazar, Nelly Tiempos-Guzmán and Jorge Morales-Montor *Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México DF, México* 

Saé Muñiz-Hernández *Subdirección de Investigación Médica, Instituto Nacional de Cancerología, Secretaria de Salud, México* 

## **Acknowledgement**

Financial support: Grant # 40072-Q from Consejo Nacional de Ciencia y Tecnología (CONACYT) de México, and Grant # IN-208103 from Programa de Apoyo a Proyectos de Investigación e Inovación Tecnológica (PAPIIT) from Dirección General de Asuntos del Personal Académico (DGAPA), U.N.A.M., both to J M-M. KNC received a postdoctoral fellowship from Dirección General de Asuntos del Personal Académico (DGAPA), U.N.A.M. and RHB received a postdoctoral fellowship from Instituto de Ciencia y Tecnología del Distrito Federal (ICyTDF).

## **3. References**


Besedovsky, H. O. and del Rey, A. (2000). The cytokine-HPA axis feed-back circuit. *Z Rheumatol,* 59 Suppl 2II/26-30),0340-1855 (Print)

52 Novel Aspects on Cysticercosis and Neurocysticercosis

and plasticity that of the infections.

**Author details** 

Karen Nava-Castro

*México DF, México* 

Romel Hernández-Bello

Saé Muñiz-Hernández

**Acknowledgement** 

Federal (ICyTDF).

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*Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional* 

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Morales-Montor, J., Arrieta, I., Del Castillo, L. I., Rodriguez-Dorantes, M., Cerbon, M. A. and Larralde, C. (2004a). Remote sensing of intraperitoneal parasitism by the host's brain: regional changes of c-fos gene expression in the brain of feminized cysticercotic male

Morales-Montor, J., Baig, S., Hallal-Calleros, C. and Damian, R. T. (2002a). Taenia crassiceps: androgen reconstitution of the host leads to protection during cysticercosis. *Exp* 

Morales-Montor, J., Baig, S., Kabbani, A. and Damian, R. T. (2002b). Do interleukin-6 and macrophage-migration inhibitory factor play a role during sex-associated susceptibility

in murine cysticercosis? *Parasitol Res,* 88,10,Oct,pp (901-904),0932-0113 (Print) Morales-Montor, J., Baig, S., Mitchell, R., Deway, K., Hallal-Calleros, C. and Damian, R. T. (2001). Immunoendocrine interactions during chronic cysticercosis determine male mouse

feminization: role of IL-6. *J Immunol,* 167,8,Oct 15,pp (4527-4533),0022-1767 (Print) Morales-Montor, J., Chavarria, A., De Leon, M. A., Del Castillo, L. I., Escobedo, E. G., Sanchez, E. N., Vargas, J. A., Hernandez-Flores, M., Romo-Gonzalez, T. and Larralde, C. (2004b). Host gender in parasitic infections of mammals: an evaluation of the female

host supremacy paradigm. *J Parasitol,* 90,3,Jun,pp (531-546),0022-3395 (Print)

Morales-Montor, J., Hallal-Calleros, C., Romano, M. C. and Damian, R. T. (2002c). Inhibition of p-450 aromatase prevents feminisation and induces protection during cysticercosis.

Morales-Montor, J. and Larralde, C. (2005). The role of sex steroids in the complex physiology of the host-parasite relationship: the case of the larval cestode of Taenia

Morales-Montor, J., Rodriguez-Dorantes, M., Mendoza-Rodriguez, C. A., Camacho-Arroyo, I. and Cerbon, M. A. (1998). Differential expression of the estrogen-regulated protooncogenes c-fos, c-jun, and bcl-2 and of the tumor-suppressor p53 gene in the male mouse chronically infected with Taenia crassiceps cysticerci. *Parasitol Res,* 84,8,Aug,pp

cysticercosis. *Vet Parasitol,* 108,1,Aug 30,pp (41-48),0304-4017 (Print)

mice. *Parasitology,* 128,Pt 3,Mar,pp (343-351),0031-1820 (Print)

an overview. *Parasitology,* 115 SupplS5-7),0031-1820 (Print)

*Parasitol,* 82,5,Oct,pp (689-693),0022-3395 (Print)

*Parasitol,* 100,4,Apr,pp (209-216),0014-4894 (Print)

*Int J Parasitol,* 32,11,Oct,pp (1379-1387),0020-7519 (Print)

(616-622),0932-0113 (Print)

crassiceps. *Parasitology,* 131,Pt 3,Sep,pp (287-294),0031-1820 (Print)


Smith, J. K., Esch, G. W. and Kuhn, R. E. (1972). Growth and development of larval Taenia crassiceps (cestoda). I. Aneuploidy in the anomalous ORF strain. *Int J Parasitol,* 2,2,Jun,pp (261-263),0020-7519 (Print)

**Chapter 3** 

© 2013 Carabin et al., 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 Carabin et al., 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 pigs, infection with the larval stages of the parasite results in the development of cysts primarily in the muscles, and less commonly in the tongue muscles, heart, diaphragm,

**The Burden of Cysticercosis** 

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51668

productivity might be further decreased.

**1. Introduction** 

Rachana Bhattarai, Hélène Carabin and Christine Budke

*Taenia solium* cysticercosis is a major public health and agricultural problem in many developing countries. It is predominantly found and considered endemic in Latin American, Asian, and African countries where pigs are raised using traditional methods, veterinary meat inspection is insufficient, and sanitation is poor [1-3]. However, it is now increasingly being diagnosed in other regions such as the United States, Western Europe, and Canada due to an increasing flow of immigrants from endemic areas who may have taeniasis or cysticercosis [4-7]. The parasite not only impacts human health, but also pig farmers and their communities. In humans, the larvae of the parasite (metacestodes) may migrate to the brain resulting in neurocysticercosis (NCC). The natural history of NCC infection remains poorly understood, and the proportion of cases with lesions in their brains that will manifest at some point during the course of the infection remains unknown. According to a recent systematic review of the literature, among diagnosed NCC patients who sought care in clinics where imaging was available, epileptic seizures were by far the most common presenting symptom, followed by headaches, focal deficits, and cranial hypertension/hydrocephalus [8]. Depression has been reported to be very common among NCC patients, but it has not been determined if this is due to the presence of epilepsy or NCC itself [9]. Other manifestations of NCC include stroke and dementia, but those aspects have been very poorly described [10, 11]. The social consequences of NCC possibly include stigmatization, incapacitation, and decreased work productivity. Epilepsy has been shown, in several countries, to lead to social discrimination, and NCC-associated epilepsy is no different. In many endemic countries, the stigma associated with epilepsy may have a greater impact on patients' lives and families than the disease itself [12]. In addition, due to the reduction in quality of life and the psychological effects of the condition, work


## **The Burden of Cysticercosis**

Rachana Bhattarai, Hélène Carabin and Christine Budke

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51668

## **1. Introduction**

58 Novel Aspects on Cysticercosis and Neurocysticercosis

2,2,Jun,pp (261-263),0020-7519 (Print)

80,4,Aug,pp (563-568),0022-3395 (Print)

(Electronic)

7519 (Print)

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Spiliotis, M., Kroner, A. and Brehm, K. (2003). Identification, molecular characterization and expression of the gene encoding the epidermal growth factor receptor orthologue from the fox-tapeworm Echinococcus multilocularis. *Gene,* 323Dec 24,pp (57-65),0378-1119 (Print) Terrazas, L. I., Bojalil, R., Govezensky, T. and Larralde, C. (1994). A role for 17-beta-estradiol in immunoendocrine regulation of murine cysticercosis (Taenia crassiceps). *J Parasitol,*

Terrazas, L. I., Bojalil, R., Govezensky, T. and Larralde, C. (1998). Shift from an early protective Th1-type immune response to a late permissive Th2-type response in murine

Tzertzinis, G., Egana, A. L., Palli, S. R., Robinson-Rechavi, M., Gissendanner, C. R., Liu, C., Unnasch, T. R. and Maina, C. V. (2010). Molecular evidence for a functional ecdysone signaling system in Brugia malayi. *PLoS neglected tropical diseases,* 4,3,e625),1935-2735

Unnasch, T. R., Bradley, J., Beauchamp, J., Tuan, R. and Kennedy, M. W. (1999). Characterization of a putative nuclear receptor from Onchocerca volvulus. *Mol Biochem* 

Vargas-Villavicencio, J. A., Larralde, C., De Leon-Nava, M. A., Escobedo, G. and Morales-Montor, J. (2007). Tamoxifen treatment induces protection in murine cysticercosis. *J* 

Vargas-Villavicencio, J. A., Larralde, C., De Leon-Nava, M. A. and Morales-Montor, J. (2005). Regulation of the immune response to cestode infection by progesterone is due to its

Vargas-Villavicencio, J. A., Larralde, C. and Morales-Montor, J. (2008). Treatment with dehydroepiandrosterone in vivo and in vitro inhibits reproduction, growth and viability of Taenia crassiceps metacestodes. *Int J Parasitol,* 38,7,Jun,pp (775-781),0020-

Wu, X., Zhao, B., Hong, Y., Li, X., Peng, J., Zhang, J., Wang, F., Shi, Y., Fu, Z. and Lin, J. (2012). Characterization of Schistosoma japonicum estrogen-related receptor beta like 1 and immunogenicity analysis of the recombinant protein. *Exp Parasitol,* 131,3,Jul,pp

You, H., Zhang, W., Jones, M. K., Gobert, G. N., Mulvenna, J., Rees, G., Spanevello, M., Blair, D., Duke, M., Brehm, K. and McManus, D. P. (2010). Cloning and characterisation of Schistosoma japonicum insulin receptors. *PLoS One,* 5,3,e9868),1932-6203 (Electronic)

metabolism to estradiol. *Microbes Infect,* 7,3,Mar,pp (485-493),1286-4579 (Print) Vargas-Villavicencio, J. A., Larralde, C. and Morales-Montor, J. (2006). Gonadectomy and progesterone treatment induce protection in murine cysticercosis. *Parasite Immunol,*

cysticercosis (Taenia crassiceps). *J Parasitol,* 84,1,Feb,pp (74-81),0022-3395 (Print) Terrazas, L. I., Cruz, M., Rodriguez-Sosa, M., Bojalil, R., Garcia-Tamayo, F. and Larralde, C. (1999). Th1-type cytokines improve resistance to murine cysticercosis caused by Taenia

crassiceps. *Parasitol Res,* 85,2,Feb,pp (135-141),0932-0113 (Print)

*Parasitol,* 104,2,Nov 30,pp (259-269),0166-6851 (Print)

*Parasitol,* 93,6,Dec,pp (1512-1517),0022-3395 (Print)

28,12,Dec,pp (667-674),0141-9838 (Print)

(383-392),1090-2449 (Electronic)

*Taenia solium* cysticercosis is a major public health and agricultural problem in many developing countries. It is predominantly found and considered endemic in Latin American, Asian, and African countries where pigs are raised using traditional methods, veterinary meat inspection is insufficient, and sanitation is poor [1-3]. However, it is now increasingly being diagnosed in other regions such as the United States, Western Europe, and Canada due to an increasing flow of immigrants from endemic areas who may have taeniasis or cysticercosis [4-7]. The parasite not only impacts human health, but also pig farmers and their communities. In humans, the larvae of the parasite (metacestodes) may migrate to the brain resulting in neurocysticercosis (NCC). The natural history of NCC infection remains poorly understood, and the proportion of cases with lesions in their brains that will manifest at some point during the course of the infection remains unknown. According to a recent systematic review of the literature, among diagnosed NCC patients who sought care in clinics where imaging was available, epileptic seizures were by far the most common presenting symptom, followed by headaches, focal deficits, and cranial hypertension/hydrocephalus [8]. Depression has been reported to be very common among NCC patients, but it has not been determined if this is due to the presence of epilepsy or NCC itself [9]. Other manifestations of NCC include stroke and dementia, but those aspects have been very poorly described [10, 11]. The social consequences of NCC possibly include stigmatization, incapacitation, and decreased work productivity. Epilepsy has been shown, in several countries, to lead to social discrimination, and NCC-associated epilepsy is no different. In many endemic countries, the stigma associated with epilepsy may have a greater impact on patients' lives and families than the disease itself [12]. In addition, due to the reduction in quality of life and the psychological effects of the condition, work productivity might be further decreased.

In pigs, infection with the larval stages of the parasite results in the development of cysts primarily in the muscles, and less commonly in the tongue muscles, heart, diaphragm,

© 2013 Carabin et al., 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 Carabin et al., 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.

brain, and other organ systems. The presence of these cysts can lead to partial or full condemnation of the carcass and economic losses in areas where meat is inspected. In some areas, pig traders look for the presence of cysts under the tongue before buying them, and will offer a lower price for animals affected. This parasite, therefore, can reduce the household income of farmers and whole communities that share the same environment. Porcine cysticercosis is most commonly associated with small holder farming practices and is often under-reported due to the absence of clinical signs in affected pigs and lack of meat inspection facilities and expertise in endemic countries.

The Burden of Cysticercosis 61

Serological tests are designed to measure the exposure to, or current infection with, cysticercosis [14], but can show low specificity and sensitivity in the diagnosis of NCC,

Specific measures have been designed to estimate the non-monetary burden of human diseases [16, 17]. We will not discuss here measures of mortality and morbidity that can also be used in animals. The most informative measure of non-monetary burden is believed to be "utility", an economical concept which has been adapted to health economics, and measures the preference that people have for certain health status along a continuum [18].The greater the preference for a particular health state, the greater the "utility" associated with it. Several Health Adjusted Life Years (HALYs) metrics have been developed as indicators of "utility". HALYs are summary measures of population health that enable measures of mortality to be combined with measures of disability associated with each sequela (manifestation) of the

There are two types of HALYs that have been commonly used in estimating human burden of disease: Quality Adjusted Life Years (QALYs) and Disability Adjusted Life Years (DALYs). Even though QALYs and DALYs may be used to estimate utilities, they were developed to serve different purposes. Where DALYs are meant as an objective, populationbased measure, QALYs are meant to be used as a subjective, individual-based measure of utility and health. In addition, these measures use opposite scales. The DALY is a negative concept, with one DALY being the equivalent of one year lived completely disabled (analogous to death) whereas the QALY is a positive concept, with one QALY being the equivalent of one year of healthy life [18]. Therefore, control strategies would aim to

The ideal way of measuring quality of life is to attribute a utility, or a weighted preference for a certain health status, to each disease and its associated manifestations. In theory, the utility of health status is best measured with choice-based methods which include uncertainty, such as the standard gamble method. Other choice-based methods, without uncertainty, include paired person-trade-off and time-trade-off techniques [19]. Utility measures are based on the fact that Paretian welfare economics requires that each individual be the judge of his or her own welfare. However, in practice, these methods are difficult to implement because different people have different reactions when faced with uncertainty and choices, especially when these are theoretical. For example, in the standard gamble method, the patients are asked to find the probability "*p*" at which they would be unable to choose between remaining in their current state of health or dying immediately with a probability of *p* (and living healthy with a probability of 1-*p*). Given the difficulty in implementing such measures, several groups of researchers have developed multi-attribute classification systems implemented in the form of scale-based

depending on the number and stages of lesions present in the brain [15].

**3. Measuring the non-monetary burden of cysticercosis** 

disease of interest into one metric.

minimize DALYs and maximize QALYs.

**3.1. Quality Adjusted Life Years (QALYs)** 

Because cysticercosis impacts human and pig heath and results in economic losses, there is a need to evaluate the socioeconomic impact, or burden, of this condition on endemic communities. Both non-monetary and monetary methods can be employed. These estimates may then be compared among diseases to better target which diseases to control. Disease burden estimates can subsequently be used to compare alternative control strategies for cysticercosis, as well as other diseases affecting the population, through cost-utility and costbenefit analyses. These analyses can guide stakeholders as to which diseases and control strategies should be prioritized to reduce the burden of diseases in the population.

## **2. Methods for evaluation of the burden of zoonotic infections**

*Taenia solium* cysticercosis results in mortality, morbidity, and economic losses in affected human and animal populations. To evaluate the burden of cysticercosis, the monetary and non-monetary impacts of the disease on human health, agriculture, and society must be considered comprehensively. Measuring burden is challenging because it requires various types of data from valid studies conducted in humans and pig populations. Because of those challenges, it is recommended to focus the evaluation on a certain period and to one geographical area where high quality epidemiological and clinical studies have been conducted, preferably in both pigs and humans. The disadvantage of such an approach is that the data cannot be generalized to other areas. Some data are required for the estimation of both the non-monetary and the monetary burden of cysticercosis. In humans, these data include: the death rate of NCC (the number of deaths, if available, can also be used); the proportion of patients with NCC who seek care in clinics (and hospitals); the number (or incidence rate) of cases of NCC diagnosed after care has been sought; and the frequency and duration of each NCC manifestation. In pigs, the data required include the proportion of pigs that are inspected pre or post-mortem and the proportion of infected pigs diagnosed pre or post-mortem. Such data may be found in the published/unpublished literature and national or regional databases. When some aspects of the data are unavailable, opinion of local experts may be sought and uncertainty analyses can be run. In estimating the burden of NCC, there is the additional challenge that the internationally recognized definition of NCC requires the use of diagnostic imaging (computed tomography (CT) scan or magnetic resonance imaging (MRI)), autopsy or biopsy of skin nodules [13]. The absence of advanced diagnostic imaging facilities limits the evaluation of the burden of NCC in many areas of the world, and especially in the poorest regions where the disease is likely to be most prevalent. Serological tests are designed to measure the exposure to, or current infection with, cysticercosis [14], but can show low specificity and sensitivity in the diagnosis of NCC, depending on the number and stages of lesions present in the brain [15].

## **3. Measuring the non-monetary burden of cysticercosis**

60 Novel Aspects on Cysticercosis and Neurocysticercosis

inspection facilities and expertise in endemic countries.

brain, and other organ systems. The presence of these cysts can lead to partial or full condemnation of the carcass and economic losses in areas where meat is inspected. In some areas, pig traders look for the presence of cysts under the tongue before buying them, and will offer a lower price for animals affected. This parasite, therefore, can reduce the household income of farmers and whole communities that share the same environment. Porcine cysticercosis is most commonly associated with small holder farming practices and is often under-reported due to the absence of clinical signs in affected pigs and lack of meat

Because cysticercosis impacts human and pig heath and results in economic losses, there is a need to evaluate the socioeconomic impact, or burden, of this condition on endemic communities. Both non-monetary and monetary methods can be employed. These estimates may then be compared among diseases to better target which diseases to control. Disease burden estimates can subsequently be used to compare alternative control strategies for cysticercosis, as well as other diseases affecting the population, through cost-utility and costbenefit analyses. These analyses can guide stakeholders as to which diseases and control

*Taenia solium* cysticercosis results in mortality, morbidity, and economic losses in affected human and animal populations. To evaluate the burden of cysticercosis, the monetary and non-monetary impacts of the disease on human health, agriculture, and society must be considered comprehensively. Measuring burden is challenging because it requires various types of data from valid studies conducted in humans and pig populations. Because of those challenges, it is recommended to focus the evaluation on a certain period and to one geographical area where high quality epidemiological and clinical studies have been conducted, preferably in both pigs and humans. The disadvantage of such an approach is that the data cannot be generalized to other areas. Some data are required for the estimation of both the non-monetary and the monetary burden of cysticercosis. In humans, these data include: the death rate of NCC (the number of deaths, if available, can also be used); the proportion of patients with NCC who seek care in clinics (and hospitals); the number (or incidence rate) of cases of NCC diagnosed after care has been sought; and the frequency and duration of each NCC manifestation. In pigs, the data required include the proportion of pigs that are inspected pre or post-mortem and the proportion of infected pigs diagnosed pre or post-mortem. Such data may be found in the published/unpublished literature and national or regional databases. When some aspects of the data are unavailable, opinion of local experts may be sought and uncertainty analyses can be run. In estimating the burden of NCC, there is the additional challenge that the internationally recognized definition of NCC requires the use of diagnostic imaging (computed tomography (CT) scan or magnetic resonance imaging (MRI)), autopsy or biopsy of skin nodules [13]. The absence of advanced diagnostic imaging facilities limits the evaluation of the burden of NCC in many areas of the world, and especially in the poorest regions where the disease is likely to be most prevalent.

strategies should be prioritized to reduce the burden of diseases in the population.

**2. Methods for evaluation of the burden of zoonotic infections** 

Specific measures have been designed to estimate the non-monetary burden of human diseases [16, 17]. We will not discuss here measures of mortality and morbidity that can also be used in animals. The most informative measure of non-monetary burden is believed to be "utility", an economical concept which has been adapted to health economics, and measures the preference that people have for certain health status along a continuum [18].The greater the preference for a particular health state, the greater the "utility" associated with it. Several Health Adjusted Life Years (HALYs) metrics have been developed as indicators of "utility". HALYs are summary measures of population health that enable measures of mortality to be combined with measures of disability associated with each sequela (manifestation) of the disease of interest into one metric.

There are two types of HALYs that have been commonly used in estimating human burden of disease: Quality Adjusted Life Years (QALYs) and Disability Adjusted Life Years (DALYs). Even though QALYs and DALYs may be used to estimate utilities, they were developed to serve different purposes. Where DALYs are meant as an objective, populationbased measure, QALYs are meant to be used as a subjective, individual-based measure of utility and health. In addition, these measures use opposite scales. The DALY is a negative concept, with one DALY being the equivalent of one year lived completely disabled (analogous to death) whereas the QALY is a positive concept, with one QALY being the equivalent of one year of healthy life [18]. Therefore, control strategies would aim to minimize DALYs and maximize QALYs.

## **3.1. Quality Adjusted Life Years (QALYs)**

The ideal way of measuring quality of life is to attribute a utility, or a weighted preference for a certain health status, to each disease and its associated manifestations. In theory, the utility of health status is best measured with choice-based methods which include uncertainty, such as the standard gamble method. Other choice-based methods, without uncertainty, include paired person-trade-off and time-trade-off techniques [19]. Utility measures are based on the fact that Paretian welfare economics requires that each individual be the judge of his or her own welfare. However, in practice, these methods are difficult to implement because different people have different reactions when faced with uncertainty and choices, especially when these are theoretical. For example, in the standard gamble method, the patients are asked to find the probability "*p*" at which they would be unable to choose between remaining in their current state of health or dying immediately with a probability of *p* (and living healthy with a probability of 1-*p*). Given the difficulty in implementing such measures, several groups of researchers have developed multi-attribute classification systems implemented in the form of scale-based

questionnaires. Each answer to the scaled questions contributes a certain weight towards calculating utility. The utility weights are determined during studies where both the questionnaire and one of the choice-based methods are used, and then assumed to be generalizable to other contexts. Multi-attribute questionnaires are more commonly used than choice-based measures in QALYs studies. One advantage of multi-attribute questionnaires is that they may not only be used to estimate utility, but also to assess the perceptions of patients regarding different aspects of their health (i.e., mental, physical, social functioning, etc.).

The Burden of Cysticercosis 63

**score** 

0.760

0.5616

0.329

0.222

0.079


**Description Utility** 

No problems 1.000

No problems walking; no problems with self-care; some problems with

Some problems walking; some problems washing or dressing self; some problems with performing usual activities; moderate pain or discomfort;

No problems walking; some problems washing or dressing self; unable to perform usual activities; some pain or discomfort; not anxious or depressed

Some problems walking; no problems with self-care; no problems with

Confined to bed; unable to wash or dress self; unable to perform usual activities, extreme pain or discomfort; moderately anxious or depressed

moderately anxious or depressed

**Table 1.** Example of utility scores for the EQ-5D

**Domain Description**

Bodily pain Degree of pain to the body

Vitality Ratings of energy level

General health Ratings of current health in general

depressed

performing usual activities; some pain or discomfort; not anxious or depressed

performing usual activities; moderate pain or discomfort; extremely anxious or

Some problems walking; unable to wash or dress self; unable to perform usual activities; moderate pain or discomfort; moderately anxious or depressed

Physical functioning Degree to which health limits everyday physical activities Role physical Degree to which physical problems interfere with usual

Social functioning Degree to which health interferes with social activities Role emotional Degree to which emotional problems interfere with usual

Mental health Degree to which health limits emotional well- being,

Although QALYs are commonly used metrics in health economics, they also present some limitations. For example, adaptation of patients to certain symptoms may mask the impact of chronic disability. In addition, it is difficult to assign a single utility score to those diseases which cause a variety of clinical manifestations, such as NCC [24]. Another limitation is that scale-based measures can sometimes lead to "ceiling" or "flooring" effects where a majority of people consistently choose the "best" scenario or "worst" scenario. One important criticism of QALYs (which some view as an advantage), is that QALYs measures are subjective and not meant to be generalized to the society as a whole. QALYs associated with a disease in one country (or region) could not be used to estimate the burden in another

**Table 2.** Description of the health domains used in the SF-12 v2 quality of life survey

daily activities such as work or school

daily activities such as school or work

including depression, anxiety and well being

When used at a population level, QALYs combine quantitative estimates of death, frequency and duration of disease with a qualitative assessment of how well (or not) patients can live with the disease. In other words, rather than just counting the number of people with the disease, QALYs try to "adjust" for how well people can live with the disease. Therefore, QALYs are a product of life expectancy and a measure of the quality of remaining life years, with weights placed on time spent in different health states. Most preferable state receives more weight. A year of perfect health is worth 1 and a year of less than perfect health is worth less than 1. Death is considered to be equivalent to 0. However, some health states may be considered worse than death and have negative values [19].

The multi-attribute measurement scales most commonly used in developing countries, where NCC is endemic, are the Euro-Qol (EQ-5D) and the Short Form-12 (SF-12) [20, 21]. These tools provide patient-based determination of quality of life and can be used to compare perceptions of physical, mental, and social health among patients with different diseases (or lack of disease), different stages of the same disease, or before and after treatment of the disease. The latter approach is often used in clinical trials where a drug, while very effective in treating the disease, may be linked to numerous side effects which could lead to worse quality of life than the disease itself.

The EQ-5D is a standardized measure of health status developed by the EuroQol Group. The EQ-5D questionnaire has 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each domain, there are three levels of response: individuals are asked whether they have no problems, some problems, or severe problems. The answers to each domain are combined to generate a summary score, for a total of 125 possible combinations of answers, which indicates the overall utility. Table 1 provides an example of utility scores that can be allocated to different combinations of answers to the five EQ-5D questions [22].

The SF-12 is another tool developed by Quality Metric Inc. to assess the quality of life of an individual at a given time. It uses 12 questions to measure eight domains of functional health and well-being namely physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health (Table 2) [21]. Physical and mental component summary scores can be calculated by aggregating the eight domains [23].



**Table 1.** Example of utility scores for the EQ-5D

social functioning, etc.).

values [19].

[23].

questionnaires. Each answer to the scaled questions contributes a certain weight towards calculating utility. The utility weights are determined during studies where both the questionnaire and one of the choice-based methods are used, and then assumed to be generalizable to other contexts. Multi-attribute questionnaires are more commonly used than choice-based measures in QALYs studies. One advantage of multi-attribute questionnaires is that they may not only be used to estimate utility, but also to assess the perceptions of patients regarding different aspects of their health (i.e., mental, physical,

When used at a population level, QALYs combine quantitative estimates of death, frequency and duration of disease with a qualitative assessment of how well (or not) patients can live with the disease. In other words, rather than just counting the number of people with the disease, QALYs try to "adjust" for how well people can live with the disease. Therefore, QALYs are a product of life expectancy and a measure of the quality of remaining life years, with weights placed on time spent in different health states. Most preferable state receives more weight. A year of perfect health is worth 1 and a year of less than perfect health is worth less than 1. Death is considered to be equivalent to 0. However, some health states may be considered worse than death and have negative

The multi-attribute measurement scales most commonly used in developing countries, where NCC is endemic, are the Euro-Qol (EQ-5D) and the Short Form-12 (SF-12) [20, 21]. These tools provide patient-based determination of quality of life and can be used to compare perceptions of physical, mental, and social health among patients with different diseases (or lack of disease), different stages of the same disease, or before and after treatment of the disease. The latter approach is often used in clinical trials where a drug, while very effective in treating the disease, may be linked to numerous side effects which

The EQ-5D is a standardized measure of health status developed by the EuroQol Group. The EQ-5D questionnaire has 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each domain, there are three levels of response: individuals are asked whether they have no problems, some problems, or severe problems. The answers to each domain are combined to generate a summary score, for a total of 125 possible combinations of answers, which indicates the overall utility. Table 1 provides an example of utility scores that can be allocated to different combinations of

The SF-12 is another tool developed by Quality Metric Inc. to assess the quality of life of an individual at a given time. It uses 12 questions to measure eight domains of functional health and well-being namely physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health (Table 2) [21]. Physical and mental component summary scores can be calculated by aggregating the eight domains

could lead to worse quality of life than the disease itself.

answers to the five EQ-5D questions [22].

**Table 2.** Description of the health domains used in the SF-12 v2 quality of life survey

Although QALYs are commonly used metrics in health economics, they also present some limitations. For example, adaptation of patients to certain symptoms may mask the impact of chronic disability. In addition, it is difficult to assign a single utility score to those diseases which cause a variety of clinical manifestations, such as NCC [24]. Another limitation is that scale-based measures can sometimes lead to "ceiling" or "flooring" effects where a majority of people consistently choose the "best" scenario or "worst" scenario. One important criticism of QALYs (which some view as an advantage), is that QALYs measures are subjective and not meant to be generalized to the society as a whole. QALYs associated with a disease in one country (or region) could not be used to estimate the burden in another region (or country). For example, having epilepsy in the United States would have very different social and role functioning values than in Sub-Saharan Africa. This difficulty in using QALYs for international comparison led a group of researchers to develop a completely different type of metric for measuring burden: the DALY.

### **3.2. Disability Adjusted Life Years (DALYs)**

DALYs were first constructed for the Global Burden of Disease (GBD) Study in order to provide a comparable measure of output for interventions, program and sector evaluations, and planning [25]. The GBD Study was conducted to evaluate the non-monetary burden of a variety of infectious and non-infectious conditions, as well as risk factors, on pre-defined regions of the world. The latest comprehensive assessment of the burden of diseases is for the year 2004. However, DALY estimates from the 2010 GBD Study are expected to be released in late 2012 [26]. The DALY is a summary measure of population health that assesses the disability and early mortality associated with the condition of interest. DALYs measure the gap in years between age at death and gender-specific average life expectancy in Japan and combines it with time lived in states other than excellent health (disabled). They are obtained by summing years of life lost (YLL) from premature death and healthy years lost due to disability (YLD). The formulas used for the calculation of YLL and YLD are described below:

$$\text{YLL} = \text{N \* L} \tag{1}$$

The Burden of Cysticercosis 65

**weight** 

0.096

0.220

0.400

0.600

0.810

0.920

**Degree of morbidity Disability** 

Healthy 0

Limited ability to perform at least one activity in one of the following

Limited ability to perform most activities in one of the following areas:

Limited ability to perform most activities in two or more of the following

Limited ability to perform most activities in all of the following areas:

Requires assistance with instrumental activities of daily living such as

Requires assistance with activities of daily living such as eating, personal

Dead 1

Disability weights for NCC were not included in the original GBD study. However, in the 2010 GDB estimates, NCC will be included as causing an average of 29% of all epilepsy cases in endemic countries. This estimate is based on a meta-analysis of the percentage of NCC lesions present in the brain of people with epilepsy [29]. Disability weights of epilepsy will be used as there is no clinical difference between NCC-associated and other types of epilepsy. As better estimates of the distribution of manifestations among NCC patients become available, more sequelae will be added to DALYs estimates associated with NCC. The only two available estimates of DALYs associated with NCC used the disability weights

The original GBD Study calculations considered two additional parameters: 1) discounting future time and 2) age weighting [25]. Discounting future time is a common concept in economic and social policy. In burden of disease estimations, a discount rate is applied so that future healthy life has less value than the net value of life today [27]. In the context of DALYs, a disability occurring today is worth more than the same disability occurring in the future. The subject of discounting is complex and several papers have been published in favor and against its use in the context of DALYs and health outcomes [27, 32]. By including age weighting, the original GBD Study incorporated social preferences for the value of life lived during adulthood over life lived during childhood or later years. However, the newest version of the GBD Study (the GBD 2010 Study) will not include age weighting in the

DALYs calculations. Therefore, the influence of age weighting will be eliminated.

The use of DALYs remains controversial, especially in measuring utilities. According to Anand (1997), DALYs understate the burden of disease of females relative to males since the standard expectation of life at birth in Japan is very similar in men and women [32]. DALYs

areas: recreation, education, procreation or occupation

areas: recreation, education, procreation or occupation

**Table 3.** Examples of disability weights used to calculate DALYs [25]

associated with epilepsy (both studies) and migraine (1 study) [30, 31].

recreation, education, procreation or occupation

recreation, education, procreation or occupation

meal preparation, shopping or housework

hygiene or toilet use

where N = number of deaths per age-sex group, L = remaining life expectancy at age of death

$$\text{YLD} = \text{I}^\* \text{DW}^\* \text{D} \tag{2}$$

where I = age and sex specific estimates of incidence, DW = disability weight, D = average duration of disability.

Disability weights are allocated according to the opinion of experts on how disabling a certain health status is perceived to be. Disability is placed on a uni-dimensional scale between 0 (perfect health) and 1 (death). In theory, utility is equal to 1-disability weight. Disability weights of clinical manifestations (referred to as indicator states) were determined for the original GBD Study by the person trade-off (PTO) method [27]. The PTO method is a way of estimating social preferences for different health states by asking people how many people affected by the health state of interest they would be willing to trade for extending the lives of 100 healthy people. This question is asked using two different formats. For the 2010 GBD Study, community assessment of selected sequelae using discrete choice methods, assessment by health professionals of all sequelae using ranking and visual analog scale methods, and multi-method studies among highly educated respondents were utilized rather than the PTO method [28]. Results from the new disability weights have not yet been published. Examples of disability weights used to calculate DALYs for the original GBD Study are provided in table 3.


**Table 3.** Examples of disability weights used to calculate DALYs [25]

64 Novel Aspects on Cysticercosis and Neurocysticercosis

described below:

duration of disability.

Study are provided in table 3.

death

**3.2. Disability Adjusted Life Years (DALYs)** 

region (or country). For example, having epilepsy in the United States would have very different social and role functioning values than in Sub-Saharan Africa. This difficulty in using QALYs for international comparison led a group of researchers to develop a

DALYs were first constructed for the Global Burden of Disease (GBD) Study in order to provide a comparable measure of output for interventions, program and sector evaluations, and planning [25]. The GBD Study was conducted to evaluate the non-monetary burden of a variety of infectious and non-infectious conditions, as well as risk factors, on pre-defined regions of the world. The latest comprehensive assessment of the burden of diseases is for the year 2004. However, DALY estimates from the 2010 GBD Study are expected to be released in late 2012 [26]. The DALY is a summary measure of population health that assesses the disability and early mortality associated with the condition of interest. DALYs measure the gap in years between age at death and gender-specific average life expectancy in Japan and combines it with time lived in states other than excellent health (disabled). They are obtained by summing years of life lost (YLL) from premature death and healthy years lost due to disability (YLD). The formulas used for the calculation of YLL and YLD are

where N = number of deaths per age-sex group, L = remaining life expectancy at age of

where I = age and sex specific estimates of incidence, DW = disability weight, D = average

Disability weights are allocated according to the opinion of experts on how disabling a certain health status is perceived to be. Disability is placed on a uni-dimensional scale between 0 (perfect health) and 1 (death). In theory, utility is equal to 1-disability weight. Disability weights of clinical manifestations (referred to as indicator states) were determined for the original GBD Study by the person trade-off (PTO) method [27]. The PTO method is a way of estimating social preferences for different health states by asking people how many people affected by the health state of interest they would be willing to trade for extending the lives of 100 healthy people. This question is asked using two different formats. For the 2010 GBD Study, community assessment of selected sequelae using discrete choice methods, assessment by health professionals of all sequelae using ranking and visual analog scale methods, and multi-method studies among highly educated respondents were utilized rather than the PTO method [28]. Results from the new disability weights have not yet been published. Examples of disability weights used to calculate DALYs for the original GBD

YLL = N \* L (1)

YLD = I \* DW \* D (2)

completely different type of metric for measuring burden: the DALY.

Disability weights for NCC were not included in the original GBD study. However, in the 2010 GDB estimates, NCC will be included as causing an average of 29% of all epilepsy cases in endemic countries. This estimate is based on a meta-analysis of the percentage of NCC lesions present in the brain of people with epilepsy [29]. Disability weights of epilepsy will be used as there is no clinical difference between NCC-associated and other types of epilepsy. As better estimates of the distribution of manifestations among NCC patients become available, more sequelae will be added to DALYs estimates associated with NCC. The only two available estimates of DALYs associated with NCC used the disability weights associated with epilepsy (both studies) and migraine (1 study) [30, 31].

The original GBD Study calculations considered two additional parameters: 1) discounting future time and 2) age weighting [25]. Discounting future time is a common concept in economic and social policy. In burden of disease estimations, a discount rate is applied so that future healthy life has less value than the net value of life today [27]. In the context of DALYs, a disability occurring today is worth more than the same disability occurring in the future. The subject of discounting is complex and several papers have been published in favor and against its use in the context of DALYs and health outcomes [27, 32]. By including age weighting, the original GBD Study incorporated social preferences for the value of life lived during adulthood over life lived during childhood or later years. However, the newest version of the GBD Study (the GBD 2010 Study) will not include age weighting in the DALYs calculations. Therefore, the influence of age weighting will be eliminated.

The use of DALYs remains controversial, especially in measuring utilities. According to Anand (1997), DALYs understate the burden of disease of females relative to males since the standard expectation of life at birth in Japan is very similar in men and women [32]. DALYs also measure the burden of disease without considering cultural or socioeconomic differentiation of tested populations so that it underestimates the disease burden in developing countries [33]. DALYs also go against Paretian welfare economics where each individual is the best judge of his or her own welfare. By using utility weights measured by people that are unaffected by the disease of interest, this concept is not respected. Even with these controversies, the DALY remains a widely used summary measure of population health.

### **4. Measuring monetary burden**

Estimates of the monetary burden of zoonotic diseases that impact both human and livestock health should include assessment of both animal health costs and human health costs. The overall estimated cost can be calculated using the following equation: [34]

$$\sum\_{s=1}^{S} \sum\_{a=1}^{A} \left[ N\_{a,s} \beta\_{a,s} \left( \sum\_{s=1}^{X} \pi\_{x,a,s} C\_{x,a,s} \right) \right] \tag{3}$$

The Burden of Cysticercosis 67

reduced when, in the case of *T. solium* cysticercosis, reduction in the price of pigs due to the presences of cysts can lower a farmer's household income. In addition, presence of *T. solium*

Decision trees are very helpful in organizing the information gathered on the distribution of manifestations and treatment seeking pattern in the study population. They can also be used to incorporate the probability of receiving different types of diagnoses and treatments. The tree usually starts with a "trunk" which is the disease of interest (in the case of NCC, this can be epilepsy). From this trunk, a probability (chance node) corresponding to the frequency of the disease is used to create the first two "branches" of the tree: the presence or absence of the disease in the study population. Additional branches are added each time a new probability is added. Each probability (node) may lead to more than two branches. The end of each branch corresponds to the probability that a patient has of following a certain treatment/diagnosis path, including the path of not seeking any medical care. The probability of each branch of a path can be multiplied by the costs corresponding to the options in this branch. An example, the use of decision tree analysis to estimate losses due cysticercosis in South Africa is shown in Figure 1 [35]. In this example, for the branch of people with epilepsy who have NCC but do not seek medical attention, we would multiply 1.33% by 36.7% by 70% to obtain the frequency of having NCC but not being treated (0.34%, as shown in Figure 1) [15, 36-41]. This percentage would be multiplied by the salary lost due to a reduction in productivity among people with epilepsy. Such trees can be developed for

in a country's pig population results in restrictions on the export of pork products.

very complex treatment paths and for the impact of animal disease as well.

**Figure 1.** Decision tree analysis tree for estimating the monetary burden of NCC in Eastern Cape

Common sources of epidemiological and economic data used in the assessment of disease burden include government and agency reports and values reported in the scientific

Province, South Africa. Circle is a chance node and triangle is an end node [35].

**4.4. Uncertainty and sensitivity analysis** 

**4.3. Decision tree analysis** 

This equation corresponds to the additive societal costs for all affected species (*S*) across all age groups (*A*). For the age-species-specific population of size (*N*a,s), with the age-speciesspecific annual incidence (*ß*a,s), there is an age-species proportion (x,a,s,) of infected individuals with symptoms *X*. The treatment and consequences of each of these symptoms have a monetary burden of Cx,a,s. Ideally, the whole spectrum of symptoms and losses in humans and animals is included in the estimate [34].

#### **4.1. Human health costs**

Human health costs are classified into direct (health provider) and indirect (out-of-pocket) costs. Direct costs are costs associated with the diagnosis and treatment of patients. Commonly used diagnostic tests incorporated into direct costs include diagnostic imaging, sero-immunological and blood tests, and tests on cerebral spinal fluid (CSF). Diagnostic costs, for a neurological condition such as NCC, can be high since CT scans and MRI confirmatory tests are not readily available in developing countries and, if available, are often distantly located and expensive. Cost of treatment typically includes the cost of medicines, medical consultations, surgical charges, and hospital charges. In contrast to direct costs, indirect costs include costs of working days lost due to clinical manifestations or visits to hospitals, losses in productivity, buying over-the-counter drugs to relieve symptoms, costs of traditional treatment, and costs associated with transportation to and from medical treatment. Costs associated with the family members taking care of the patients would also need to be included.

#### **4.2. Animal health costs**

Animal health costs can be associated with partial or full condemnation of the carcass at slaughter or reduction in price of an infected carcass. The value of live animals can also be reduced when, in the case of *T. solium* cysticercosis, reduction in the price of pigs due to the presences of cysts can lower a farmer's household income. In addition, presence of *T. solium* in a country's pig population results in restrictions on the export of pork products.

## **4.3. Decision tree analysis**

66 Novel Aspects on Cysticercosis and Neurocysticercosis

**4. Measuring monetary burden** 

also measure the burden of disease without considering cultural or socioeconomic differentiation of tested populations so that it underestimates the disease burden in developing countries [33]. DALYs also go against Paretian welfare economics where each individual is the best judge of his or her own welfare. By using utility weights measured by people that are unaffected by the disease of interest, this concept is not respected. Even with these controversies, the DALY remains a widely used summary measure of population health.

Estimates of the monetary burden of zoonotic diseases that impact both human and livestock health should include assessment of both animal health costs and human health

, , ,, ,,

 

(3)

x,a,s,) of infected

*as as xas xas*

*N C* 

This equation corresponds to the additive societal costs for all affected species (*S*) across all age groups (*A*). For the age-species-specific population of size (*N*a,s), with the age-species-

individuals with symptoms *X*. The treatment and consequences of each of these symptoms have a monetary burden of Cx,a,s. Ideally, the whole spectrum of symptoms and losses in

Human health costs are classified into direct (health provider) and indirect (out-of-pocket) costs. Direct costs are costs associated with the diagnosis and treatment of patients. Commonly used diagnostic tests incorporated into direct costs include diagnostic imaging, sero-immunological and blood tests, and tests on cerebral spinal fluid (CSF). Diagnostic costs, for a neurological condition such as NCC, can be high since CT scans and MRI confirmatory tests are not readily available in developing countries and, if available, are often distantly located and expensive. Cost of treatment typically includes the cost of medicines, medical consultations, surgical charges, and hospital charges. In contrast to direct costs, indirect costs include costs of working days lost due to clinical manifestations or visits to hospitals, losses in productivity, buying over-the-counter drugs to relieve symptoms, costs of traditional treatment, and costs associated with transportation to and from medical treatment. Costs associated with the family members taking care of the

Animal health costs can be associated with partial or full condemnation of the carcass at slaughter or reduction in price of an infected carcass. The value of live animals can also be

costs. The overall estimated cost can be calculated using the following equation: [34]

1 1 1

*s a x*

specific annual incidence (*ß*a,s), there is an age-species proportion (

humans and animals is included in the estimate [34].

**4.1. Human health costs** 

patients would also need to be included.

**4.2. Animal health costs** 

*S A X*

Decision trees are very helpful in organizing the information gathered on the distribution of manifestations and treatment seeking pattern in the study population. They can also be used to incorporate the probability of receiving different types of diagnoses and treatments. The tree usually starts with a "trunk" which is the disease of interest (in the case of NCC, this can be epilepsy). From this trunk, a probability (chance node) corresponding to the frequency of the disease is used to create the first two "branches" of the tree: the presence or absence of the disease in the study population. Additional branches are added each time a new probability is added. Each probability (node) may lead to more than two branches. The end of each branch corresponds to the probability that a patient has of following a certain treatment/diagnosis path, including the path of not seeking any medical care. The probability of each branch of a path can be multiplied by the costs corresponding to the options in this branch. An example, the use of decision tree analysis to estimate losses due cysticercosis in South Africa is shown in Figure 1 [35]. In this example, for the branch of people with epilepsy who have NCC but do not seek medical attention, we would multiply 1.33% by 36.7% by 70% to obtain the frequency of having NCC but not being treated (0.34%, as shown in Figure 1) [15, 36-41]. This percentage would be multiplied by the salary lost due to a reduction in productivity among people with epilepsy. Such trees can be developed for very complex treatment paths and for the impact of animal disease as well.

**Figure 1.** Decision tree analysis tree for estimating the monetary burden of NCC in Eastern Cape Province, South Africa. Circle is a chance node and triangle is an end node [35].

### **4.4. Uncertainty and sensitivity analysis**

Common sources of epidemiological and economic data used in the assessment of disease burden include government and agency reports and values reported in the scientific

literature. Values for neglected zoonotic diseases, such as *T. solium* cysticercosis, are often underreported or else the method of collection might be biased. In short, exact estimates of these parameters are difficult to identify. Therefore, in order to account for uncertainties, the distribution of these parameters should be selected carefully. So, instead of using an exact value for each probability and cost value, a distribution of values is used to reflect uncertainty. To include these distributions into the final estimate, sampling methods such as the Monte Carlo or Latin Hypercube are often applied. The final estimate will itself be a distribution reflecting the uncertainty of all included parameters. Uniform distribution can be applied to parameters for which we have very limited knowledge. For example, instead of assuming that 1.33% of the population has epilepsy in the Eastern Cape Province of South Africa, we could assume that the prevalence lies anywhere between 0.5% and 2.8%, with an average at 1.33% [35]. The sampling method would start by sampling one value (for example, 1%) from this distribution, provide and save the estimate of the cost of NCC using this value. Next, another value would be sampled from the distribution and lead to another estimated cost, which will also be saved. This process is usually repeated up to 10,000 times until a distribution of the overall costs is obtained. The Latin Hypercube and Monte Carlo sampling methods are simply efficient tools of sampling several uncertain parameters iteratively.

The Burden of Cysticercosis 69

NCC. Similarly, people with cranial hypertension suffering from headaches may never seek medical attention. In contrast, people with hydrocephalus or stroke will most likely seek

In a systematic review of studies conducted in clinics or hospitals with imaging facilities, the distribution of presenting symptoms among diagnosed NCC patients was as follows: seizures/epilepsy were the most common (78.8%, 95% CI: 65.1% - 89.7%) followed by headaches (37.9%, 95% CI: 23.3% - 53.7%), focal deficits (16.0%, 95% CI: 9.7% - 23.6%), and signs of increased intracranial pressure (11.7%, 95%CI: 6.0% - 18.9%) [8]. These results, though consistent with what is usually believed for NCC, may be biased by what presenting symptoms the clinicians assessed at admission. This systematic review of the literature also revealed that NCC may contribute to an important percentage of stroke cases in endemic areas. Unfortunately, to our knowledge, there is only one case-control study which has been conducted on this topic [10]. If NCC is truly linked to strokes, this could lead to a very

The studies included in the systematic review described above were all clinical-based. There have also been several studies conducted in communities and small rural hospitals where, instead of sampling NCC cases, people with epilepsy received imaging for the diagnosis of NCC. When those studies were analyzed systematically, the percentage of people with epilepsy with lesions of NCC at imaging was 29% (95% CI: 23% - 36%) [29]. This finding is important as it suggests that nearly one third of all epilepsy cases living in endemic areas could possibly be prevented with appropriate control strategies. The measure of burden described above could help guide stakeholders as to which control strategy may lead to the

Compared to other helminthic infections, the socioeconomic burden of cysticercosis tends to be higher because the condition not only causes severe clinical manifestations, but can also result in mortality. Although limited data exist on NCC-related mortality, a study conducted in the United States and a study conducted in Brazil reported age-adjusted annual mortality rates of 0.06 (95% CI: 0.05 - 0.07) and 1.68 (95% CI: 1.58 - 1.78) deaths per million population, respectively [4, 43]. Additional studies from the U.S. states of California and Oregon reported crude mortality rates of 0.33 (95% CI: 0.27 - 0.38) and 0.29 (95% CI: 0.11

**6. The monetary and non-monetary burden of neurocysticercosis** 

Very few studies have been conducted to evaluate the burden of NCC. At present, two studies have been carried out in Africa evaluating the burden of cysticercosis/NCC. A study in West Cameroon revealed that 1.0% of the total population had NCC-associated epilepsy (based on serological results) and 5.6% of the pig population had cysticercosis [31]. Average number of DALYs lost due to NCC was 9.0 per 1,000 person-years and the monetary burden per case of NCC-associated epilepsy was 194 Euro in 2009. The total annual costs due to *T. solium* cysticercosis in West Cameroon were estimated at 10,255,202 Euro (95% CR

care.

important burden in endemic regions.

best cost-utility or cost-benefit for their area.


The sampling method described above will generate a database of 10,000 observations each associated with a different value for the uncertain parameters. We can then use linear regression using the estimated costs as the outcome and all of the uncertain parameters as "independent" variables to assess which parameters have the largest impacts on the estimated costs. The uncertain parameters with the largest impacts should be those that need to be better studied in the future because they have a strong influence on how much a disease costs a society. Sensitivity must be conducted with care to limit the values to those that are most likely and realistic. Including impossible values would lead to biased estimates and a false impression that they have an important impact on the overall cost estimate.

## **5. Review of morbidity and mortality associated with neurocysticercosis**

There are only a few studies in the literature which report the distribution of manifestations among definitive or probable cases of NCC as defined by the Garcia and Del Brutto criteria (2005) [42]. The challenge in studying the natural history of NCC is that it is impossible to diagnose the presence of brain cysts without the use of imaging, and using radiation among a population without symptoms is unethical. Hence, the only information available is the distribution of manifestations among NCC patients that are already under care in facilities where imaging is available. This introduces a major selection bias which leads to likely overestimation of the frequency of more severe (and less stigmatizing) manifestations, or manifestations which are more likely to lead to a medical visit (and a referral to a clinic with imaging). In countries where epilepsy is stigmatized, people may be afraid to seek care which would lead to an underestimate of the distribution of epilepsy among people with NCC. Similarly, people with cranial hypertension suffering from headaches may never seek medical attention. In contrast, people with hydrocephalus or stroke will most likely seek care.

68 Novel Aspects on Cysticercosis and Neurocysticercosis

iteratively.

estimate.

literature. Values for neglected zoonotic diseases, such as *T. solium* cysticercosis, are often underreported or else the method of collection might be biased. In short, exact estimates of these parameters are difficult to identify. Therefore, in order to account for uncertainties, the distribution of these parameters should be selected carefully. So, instead of using an exact value for each probability and cost value, a distribution of values is used to reflect uncertainty. To include these distributions into the final estimate, sampling methods such as the Monte Carlo or Latin Hypercube are often applied. The final estimate will itself be a distribution reflecting the uncertainty of all included parameters. Uniform distribution can be applied to parameters for which we have very limited knowledge. For example, instead of assuming that 1.33% of the population has epilepsy in the Eastern Cape Province of South Africa, we could assume that the prevalence lies anywhere between 0.5% and 2.8%, with an average at 1.33% [35]. The sampling method would start by sampling one value (for example, 1%) from this distribution, provide and save the estimate of the cost of NCC using this value. Next, another value would be sampled from the distribution and lead to another estimated cost, which will also be saved. This process is usually repeated up to 10,000 times until a distribution of the overall costs is obtained. The Latin Hypercube and Monte Carlo sampling methods are simply efficient tools of sampling several uncertain parameters

The sampling method described above will generate a database of 10,000 observations each associated with a different value for the uncertain parameters. We can then use linear regression using the estimated costs as the outcome and all of the uncertain parameters as "independent" variables to assess which parameters have the largest impacts on the estimated costs. The uncertain parameters with the largest impacts should be those that need to be better studied in the future because they have a strong influence on how much a disease costs a society. Sensitivity must be conducted with care to limit the values to those that are most likely and realistic. Including impossible values would lead to biased estimates and a false impression that they have an important impact on the overall cost

**5. Review of morbidity and mortality associated with neurocysticercosis** 

There are only a few studies in the literature which report the distribution of manifestations among definitive or probable cases of NCC as defined by the Garcia and Del Brutto criteria (2005) [42]. The challenge in studying the natural history of NCC is that it is impossible to diagnose the presence of brain cysts without the use of imaging, and using radiation among a population without symptoms is unethical. Hence, the only information available is the distribution of manifestations among NCC patients that are already under care in facilities where imaging is available. This introduces a major selection bias which leads to likely overestimation of the frequency of more severe (and less stigmatizing) manifestations, or manifestations which are more likely to lead to a medical visit (and a referral to a clinic with imaging). In countries where epilepsy is stigmatized, people may be afraid to seek care which would lead to an underestimate of the distribution of epilepsy among people with In a systematic review of studies conducted in clinics or hospitals with imaging facilities, the distribution of presenting symptoms among diagnosed NCC patients was as follows: seizures/epilepsy were the most common (78.8%, 95% CI: 65.1% - 89.7%) followed by headaches (37.9%, 95% CI: 23.3% - 53.7%), focal deficits (16.0%, 95% CI: 9.7% - 23.6%), and signs of increased intracranial pressure (11.7%, 95%CI: 6.0% - 18.9%) [8]. These results, though consistent with what is usually believed for NCC, may be biased by what presenting symptoms the clinicians assessed at admission. This systematic review of the literature also revealed that NCC may contribute to an important percentage of stroke cases in endemic areas. Unfortunately, to our knowledge, there is only one case-control study which has been conducted on this topic [10]. If NCC is truly linked to strokes, this could lead to a very important burden in endemic regions.

The studies included in the systematic review described above were all clinical-based. There have also been several studies conducted in communities and small rural hospitals where, instead of sampling NCC cases, people with epilepsy received imaging for the diagnosis of NCC. When those studies were analyzed systematically, the percentage of people with epilepsy with lesions of NCC at imaging was 29% (95% CI: 23% - 36%) [29]. This finding is important as it suggests that nearly one third of all epilepsy cases living in endemic areas could possibly be prevented with appropriate control strategies. The measure of burden described above could help guide stakeholders as to which control strategy may lead to the best cost-utility or cost-benefit for their area.

Compared to other helminthic infections, the socioeconomic burden of cysticercosis tends to be higher because the condition not only causes severe clinical manifestations, but can also result in mortality. Although limited data exist on NCC-related mortality, a study conducted in the United States and a study conducted in Brazil reported age-adjusted annual mortality rates of 0.06 (95% CI: 0.05 - 0.07) and 1.68 (95% CI: 1.58 - 1.78) deaths per million population, respectively [4, 43]. Additional studies from the U.S. states of California and Oregon reported crude mortality rates of 0.33 (95% CI: 0.27 - 0.38) and 0.29 (95% CI: 0.11 - 0.64) deaths per million population, respectively [44, 45].

## **6. The monetary and non-monetary burden of neurocysticercosis**

Very few studies have been conducted to evaluate the burden of NCC. At present, two studies have been carried out in Africa evaluating the burden of cysticercosis/NCC. A study in West Cameroon revealed that 1.0% of the total population had NCC-associated epilepsy (based on serological results) and 5.6% of the pig population had cysticercosis [31]. Average number of DALYs lost due to NCC was 9.0 per 1,000 person-years and the monetary burden per case of NCC-associated epilepsy was 194 Euro in 2009. The total annual costs due to *T. solium* cysticercosis in West Cameroon were estimated at 10,255,202 Euro (95% CR

6,889,048–14,754,044), of which 4.7% were due to losses in pig husbandry and 95.3% to direct and indirect losses caused by human cysticercosis. This estimate only accounted for the disease burden due to NCC-associated epilepsy and used serology for the diagnosis of NCC.

The Burden of Cysticercosis 71

Not applicable

Not applicable

*T. solium* cysticercosis. While non-monetary burden metrics, such as the DALY, are most often used by international agencies, these metrics are not capable of capturing the burden of disease associated with animal infection. Therefore, in order to fairly compare the burden of cysticercosis with that of non-zoonotic diseases, studies need to be conducted to evaluate how cysticercosis in pigs affects individuals in endemic regions in terms of income/livelihood losses and social impact. This information can then be used to develop questions to

between countries

Notifiable / registry disease

Quality / completeness

Knowledge of natural history of disease needed

highly variable

Special studies Place / time specific

between countries

highly variable

Notifiable / registry disease

Quality / completeness

Knowledge of natural history of disease needed

Knowledge of natural history of each sequelae

Special studies required

Special studies required

*Humans Animals* 

incorporate into a QALY scale or else be added to DALYs to capture this burden.

**Items Availability / quality of data**

data

data

needed

QALYs Cause specific death rates Quality highly variable

Disease-specific incidence

Time evolution of disease

Quality of life measure at various disease states

Disease-specific incidence

Distribution of sequelae associated with disease in

Duration of each sequelae

Distribution of sequelae associated with disease among people under

Duration of each sequelae

treatment free individuals

in treatment free individuals

treatment

under treatment

DALYs Cause specific death rates Quality highly variable

rates

states

rates

Life expectancy Largely available

**Measure of burden** 

Similarly, another study conducted in the Eastern Cape Province of South Africa estimated that the monetary burden of NCC-associated epilepsy in 2004 varied from US\$632 to US\$844 per case, indicating high financial losses associated with this condition [35]. The total number of estimated NCC-associated epilepsy cases was 34,662 (95% CI: 17,167 – 50,068) and among them, expert opinion and a review of the literature suggested that 70% of cases of epilepsy did not seek medical attention. Annual losses to the agricultural sector were estimated at US\$5.0 million (95% CI: 2.4 – 8.1), with the overall monetary burden estimated at US\$34.2 million (95% CI: 12.8 – 70.0) using the mean wage approach, US\$20.1 million (95% CI: 9.6 – 35.3) using generalist replacement costs, and US\$18.6 million (95% CI: 9.0 – 32.3) using the traditional opportunity costs approach.

A study conducted in Mexico showed that 0.25 DALY was lost per 1,000 person-years due to NCC-associated epilepsy and severe headaches, with NCC associated epilepsy responsible for 90% of this value [30]. According to 2004 GBD estimates, 1.7 DALYs per 1,000 personyears were estimated to be lost due to epilepsy in Mexico, with approximately the same number of DALYs lost due to migraine. This indicates that almost 15% of DALYs lost due to epilepsy were associated with NCC. This study used only epilepsy and severe chronic headaches as clinical manifestations due to lack of frequency data and disability weights for other known clinical manifestations associated with NCC. Therefore, like the African studies, the total estimated number of DALYs lost was most likely underestimated.

Three studies have been conducted to evaluate the quality of life of NCC patients. A study conducted at two tertiary neurology referral hospitals in Mexico City, Mexico indicated that NCC outpatients had significantly lower scores for each of the SF-12's eight domains of health compared to an age-sex-hospital-day matched control group [46]. Similarly, a study conducted in Peru showed that patients with parenchymal NCC had decreased quality of life compared with healthy neighborhood controls and controls with epilepsy as measured by the short-form 36 (SF-36) quality of life survey [47]. In addition, a study conducted in Brazil showed the presence of depression had a significant impact on the quality of life of patients with NCC as measured by a direct subjective quantification scale and the Functional Assessment of Cancer Therapy Quality of Life Measurement System (FACT-HN version IV) [48].

## **7. Suggested methods to improve the burden assessment of neurocysticercosis**

While there are currently numerous ways in which to evaluate disease burden, each method has its pros and cons. Table 4 provides an overview of the established measures of disease burden currently available with which to evaluate the non-monetary or monetary burden of *T. solium* cysticercosis. While non-monetary burden metrics, such as the DALY, are most often used by international agencies, these metrics are not capable of capturing the burden of disease associated with animal infection. Therefore, in order to fairly compare the burden of cysticercosis with that of non-zoonotic diseases, studies need to be conducted to evaluate how cysticercosis in pigs affects individuals in endemic regions in terms of income/livelihood losses and social impact. This information can then be used to develop questions to incorporate into a QALY scale or else be added to DALYs to capture this burden.

70 Novel Aspects on Cysticercosis and Neurocysticercosis

32.3) using the traditional opportunity costs approach.

NCC.

version IV) [48].

**neurocysticercosis** 

6,889,048–14,754,044), of which 4.7% were due to losses in pig husbandry and 95.3% to direct and indirect losses caused by human cysticercosis. This estimate only accounted for the disease burden due to NCC-associated epilepsy and used serology for the diagnosis of

Similarly, another study conducted in the Eastern Cape Province of South Africa estimated that the monetary burden of NCC-associated epilepsy in 2004 varied from US\$632 to US\$844 per case, indicating high financial losses associated with this condition [35]. The total number of estimated NCC-associated epilepsy cases was 34,662 (95% CI: 17,167 – 50,068) and among them, expert opinion and a review of the literature suggested that 70% of cases of epilepsy did not seek medical attention. Annual losses to the agricultural sector were estimated at US\$5.0 million (95% CI: 2.4 – 8.1), with the overall monetary burden estimated at US\$34.2 million (95% CI: 12.8 – 70.0) using the mean wage approach, US\$20.1 million (95% CI: 9.6 – 35.3) using generalist replacement costs, and US\$18.6 million (95% CI: 9.0 –

A study conducted in Mexico showed that 0.25 DALY was lost per 1,000 person-years due to NCC-associated epilepsy and severe headaches, with NCC associated epilepsy responsible for 90% of this value [30]. According to 2004 GBD estimates, 1.7 DALYs per 1,000 personyears were estimated to be lost due to epilepsy in Mexico, with approximately the same number of DALYs lost due to migraine. This indicates that almost 15% of DALYs lost due to epilepsy were associated with NCC. This study used only epilepsy and severe chronic headaches as clinical manifestations due to lack of frequency data and disability weights for other known clinical manifestations associated with NCC. Therefore, like the African

studies, the total estimated number of DALYs lost was most likely underestimated.

**7. Suggested methods to improve the burden assessment of** 

Three studies have been conducted to evaluate the quality of life of NCC patients. A study conducted at two tertiary neurology referral hospitals in Mexico City, Mexico indicated that NCC outpatients had significantly lower scores for each of the SF-12's eight domains of health compared to an age-sex-hospital-day matched control group [46]. Similarly, a study conducted in Peru showed that patients with parenchymal NCC had decreased quality of life compared with healthy neighborhood controls and controls with epilepsy as measured by the short-form 36 (SF-36) quality of life survey [47]. In addition, a study conducted in Brazil showed the presence of depression had a significant impact on the quality of life of patients with NCC as measured by a direct subjective quantification scale and the Functional Assessment of Cancer Therapy Quality of Life Measurement System (FACT-HN

While there are currently numerous ways in which to evaluate disease burden, each method has its pros and cons. Table 4 provides an overview of the established measures of disease burden currently available with which to evaluate the non-monetary or monetary burden of



The Burden of Cysticercosis 73

the biggest limitations, for most of the measures of disease burden currently used for NCC/cysticercosis, is the lack of available high quality epidemiologic and/or financial data. Adherence to recommended guidelines for the diagnosis of cysticercosis in humans and pigs and declaring NCC a reportable disease would contribute greatly towards better

**Cysticercosis:** Infection or disease of humans or animals caused by the larvae of *Taenia* spp.

**Decision tree analysis:** A method of organizing epidemiological data into infections and the

**Direct costs:** Costs associated with the diagnosis and treatment of a medical condition, in

**Disability Adjusted Life Year (DALY):** A measure of overall disease burden, expressed as

**Disability weight:** A score between 0 and 1 that is assigned to a condition depending on the

**Indirect costs:** Costs associated with lost wages or decreased productivity arising indirectly

**Neurocysticercosis (NCC):** A neurological disease caused by invasion of the CNS by larvae

**Quality Adjusted Life Year (QALY):** A measure of disease burden, including both the quality and the quantity of life lived. It is used in assessing the value for money of a medical intervention. A year of full health is equivalent to 1 QALY, whereas, death corresponds to 0

**Short-Form 12 (SF-12):** A generic dual (i.e., mental and physical health) scale measure of

*Texas A&M University, College of Veterinary Medicine and Biomedical Sciences, College Station,* 

*University of Oklahoma Health Sciences Center, Department of Epidemiology and Biostatistics,* 

**Euro-Qol (EQ-5D):** A standardized instrument for use as a measure of health outcome. **Health Adjusted Life Year (HALY):** An umbrella term for a family of measures of population health that includes, for example, Disability Adjusted Life Years (DALYs) and

In this chapter, the term refers to infection of humans or pigs with *Taenia solium*.

addition to, costs associated with condemnation of all or part of an infected carcass.

the number of years lost due to ill-health, disability, or early death.

burden estimates for this condition.

frequency of their consequences.

Quality Adjusted Life Year (QALYs).

Rachana Bhattarai and Christine M. Budke

**9. Nomenclature** 

degree of debilitation.

from infection.

of *Taenia solium*.

QALYs.

quality of life.

*Texas, USA* 

Hélène Carabin *Corresponding Author* 

*Oklahoma City, Oklahoma, USA* 

**Author details** 

**Table 4.** Comparison of using QALYs, DALYs and monetary estimates to evaluate the disease burden of cysticercosis/NCC and other neglected zoonotic diseases with a livestock component [17]

## **8. Conclusions**

*T. solium* cysticercosis is believed to contribute to high levels of human morbidity and some mortality, as well as pig production losses. This parasitic disease tends to disproportionately affect areas of low socio-economic status and should be prioritized for preventive measures because the disease is, in essence, 100% preventable. However, in order to make *T. solium*  cysticercosis/NCC a priority condition, efforts to obtain more accurate estimates of disease burden must be made. In particular, a better understanding of the distribution of manifestations among all NCC cases would be very helpful. In addition, studies on the impact of NCC on productivity are needed. Such estimates could be used to show policy makers the true socioeconomic impact of this disease in various regions of the world. One of the biggest limitations, for most of the measures of disease burden currently used for NCC/cysticercosis, is the lack of available high quality epidemiologic and/or financial data. Adherence to recommended guidelines for the diagnosis of cysticercosis in humans and pigs and declaring NCC a reportable disease would contribute greatly towards better burden estimates for this condition.

## **9. Nomenclature**

72 Novel Aspects on Cysticercosis and Neurocysticercosis

Disability weights for each sequela (treated /

non treated)

Disease-specific prevalence

Distribution of sequelae associated with disease

Frequency of care / treatments / diagnoses and productivity losses

Costs associated with care / treatments / productivity losses of

for each sequel

each sequel

**8. Conclusions** 

**Items Availability / quality of data**

Cause-specific death rates Quality highly variable

data

initiative

*Humans Animals* 

Rarely available except for notifiable diseases

Abattoir data where home slaughtering is

Special survey data often overestimate the

Knowledge of natural history of disease

Agricultural statistics Special surveys

rare

truth

needed

Special studies Expert opinion

Available from GBD

between countries

Not all sequelae have been attributed disability weights

National / special survey

Special survey data often overestimate the truth

Knowledge of natural history of disease needed

Country-level health / labor

Special studies Expert opinion

statistics Special surveys

**Table 4.** Comparison of using QALYs, DALYs and monetary estimates to evaluate the disease burden

*T. solium* cysticercosis is believed to contribute to high levels of human morbidity and some mortality, as well as pig production losses. This parasitic disease tends to disproportionately affect areas of low socio-economic status and should be prioritized for preventive measures because the disease is, in essence, 100% preventable. However, in order to make *T. solium*  cysticercosis/NCC a priority condition, efforts to obtain more accurate estimates of disease burden must be made. In particular, a better understanding of the distribution of manifestations among all NCC cases would be very helpful. In addition, studies on the impact of NCC on productivity are needed. Such estimates could be used to show policy makers the true socioeconomic impact of this disease in various regions of the world. One of

of cysticercosis/NCC and other neglected zoonotic diseases with a livestock component [17]

**Measure of burden** 

Monetary burden

**Cysticercosis:** Infection or disease of humans or animals caused by the larvae of *Taenia* spp. In this chapter, the term refers to infection of humans or pigs with *Taenia solium*.

**Decision tree analysis:** A method of organizing epidemiological data into infections and the frequency of their consequences.

**Direct costs:** Costs associated with the diagnosis and treatment of a medical condition, in addition to, costs associated with condemnation of all or part of an infected carcass.

**Disability Adjusted Life Year (DALY):** A measure of overall disease burden, expressed as the number of years lost due to ill-health, disability, or early death.

**Disability weight:** A score between 0 and 1 that is assigned to a condition depending on the degree of debilitation.

**Euro-Qol (EQ-5D):** A standardized instrument for use as a measure of health outcome.

**Health Adjusted Life Year (HALY):** An umbrella term for a family of measures of population health that includes, for example, Disability Adjusted Life Years (DALYs) and Quality Adjusted Life Year (QALYs).

**Indirect costs:** Costs associated with lost wages or decreased productivity arising indirectly from infection.

**Neurocysticercosis (NCC):** A neurological disease caused by invasion of the CNS by larvae of *Taenia solium*.

**Quality Adjusted Life Year (QALY):** A measure of disease burden, including both the quality and the quantity of life lived. It is used in assessing the value for money of a medical intervention. A year of full health is equivalent to 1 QALY, whereas, death corresponds to 0 QALYs.

**Short-Form 12 (SF-12):** A generic dual (i.e., mental and physical health) scale measure of quality of life.

## **Author details**

Rachana Bhattarai and Christine M. Budke *Texas A&M University, College of Veterinary Medicine and Biomedical Sciences, College Station, Texas, USA* 

Hélène Carabin *Corresponding Author University of Oklahoma Health Sciences Center, Department of Epidemiology and Biostatistics, Oklahoma City, Oklahoma, USA* 

### **10. References**

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[2] Zoli A, Shey-Njila O, Assana E, Nguekam JP, Dorny P, Brandt J, Geerts S. Regional status, epidemiology and impact of *Taenia solium* cysticercosis in Western and Central

[3] Flisser A, Sarti E, Lightowlers M, Schantz P. Neurocysticercosis: regional status, epidemiology, impact and control measures in the Americas. Acta Tropica 2003; 87(1)

[4] Sorvillo FJ, DeGiorgio C, Waterman SH. Deaths from cysticercosis, United States.

[5] del la Garza Y, Graviss EA, Daver NG, Gambarin KJ, Shandera WX, Schantz PM, White AC Jr. Epidemiology of neurocysticercosis in Houston, Texas. American Journal of

[6] Del Brutto OH. A review of cases of human cysticercosis in Canada. Canadian Journal

[7] Del Brutto OH. Neurocysticercosis in Western Europe: a re-emerging disease? Acta

[8] Carabin H, Ndimubanzi PC, Budke CM, Nguyen H, Qian Y, Cowan LD, Stoner JA, Rainwater E, Dickey M. Clinical manifestations associated with neurocysticercosis: a

[9] Almeida SM, Gurjao SA. Frequency of depression among patients with

[10] Alarcon F, Vanormelingen K, Moncayo J, Vinan I. Cerebral cysticercosis as a risk factor

[11] Ciampi de Andrade D, Rodrigues CL, Abraham R, Castro LHM, Livramento JA, Machado LR, Leite CC, Carameli P. Cognitive impairment and dementia in

[12] de Boer HM, Mula M, Sander JW. The global burden and stigma of epilepsy. Epilepsy &

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[15] Foyaca-Sibat H, Cowan LD, Carabin H, Targonska I, Anwary MA, Serrano-Ocana G, Krecek RC, Willingham AL. Accuracy of serological testing for the diagnosis of

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**Chapter 4** 

© 2013 Ngowi et al., 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 Ngowi et al., 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.

**Agricultural Impact of Porcine** 

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51196

**1. Introduction** 

**2. Background** 

**Cyisticercosis in Africa: A Review** 

Ramiandrasoa, Mary Louise Penrith and Arve Lee Willingham

Africa, southern Africa, western Africa, central Africa, and eastern Africa.

Helena A. Ngowi, Samson Mukaratirwa, Faustin P. Lekule, Ndichu Maingi, Charles Waiswa, Chummy Sikasunge, Sonia Afonso, Julienne Sumbu, Sylvia

This chapter reviews the status of pig production and porcine cysticercosis caused by *Taenia solium* in Africa. First, it provides background information regarding pig production and porcine cysticercosis in the region. The chapter then reviews in some more details the current status of porcine cysticercosis in each of the countries based on available scientific literature. Furthermore, this chapter analyses extensively the economic impact of porcine cysticercosis, especially to the agricultural sector in Africa. Finally, the chapter provides conclusions and recommendations to guide future work in relation to porcine cysticercosis in the African continent. To simplify the reporting, the African continent has been divided into five regions based on the United Nations classification system. The regions are northern

Porcine cysticercosis refers to as an infection of pigs with the larval form of *Taenia species. Taenia solium*, *T. saginata asiatica*, and *T. hydatigena* are the *Taenia species* that can infect pigs. While *T. saginata asiatica* is currently known to be limited to Asia, *T. solium* and *T. hydatigena*  have a worldwide distribution. On the African continent, however, *T. solium* ('pork tapeworm') is the most important species of *Taenia* economically and for public health. The larval form of this parasite is capable of infecting humans leading to life-threatening neurological disorders, including epilepsy. In addition, *T. solium* cysticercosis in humans and pigs causes serious economic losses in affected countries because of condemnation of infected pigs and disability in neurocysticercotic patients. The human is the only natural definitive host of *T. solium*. An adult tapeworm is harboured in the small intestine of


## **Agricultural Impact of Porcine Cyisticercosis in Africa: A Review**

Helena A. Ngowi, Samson Mukaratirwa, Faustin P. Lekule, Ndichu Maingi, Charles Waiswa, Chummy Sikasunge, Sonia Afonso, Julienne Sumbu, Sylvia Ramiandrasoa, Mary Louise Penrith and Arve Lee Willingham

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51196

## **1. Introduction**

76 Novel Aspects on Cysticercosis and Neurocysticercosis

99(4) 268-78.

378-83.

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Africa. Lancet Neurology 2005; 4(1) 21-31.

[32] Anand S and Hanson K, Disability-adjusted life years: a critical review. Journal of

[33] Reidpath DD, Allotey PA, Kouame A, Cummins RA. Measuring health in a vacuum: examining the disability weight of the DALY. Health Policy Plan 2003; 18(4) 351-6. [34] Majorowski MM, Carabin H, Kilani M, Bensalah A. Echinococcosis in Tunisia: a cost analysis. Transactions of the Royal Society of Tropical Medicine and Hygiene 2005;

[35] Carabin H, Krecek RC, Cowan LD, Michael L, Foyaca-Sibat H, Nash T, Willingham AL. Estimation of the cost of Taenia solium cysticercosis in Eastern Cape Province, South

[36] Preux PM, Druet-Cabanac M. Epidemiology and aetiology of epilepsy in sub-Saharan

[37] Del Rio-Romero AH, Foyaca-Sibat H, Ibanez-Valdes L de F, Vega-Novoa E. Prevalence of epilepsy and general knowledge about neurocysticercosis at Nkalukeni village,

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[40] Pal DK, Das T, Sengupta S, Chaudhury G. Help-seeking patterns for children with epilepsy in rural India: implications for service delivery. Epilepsia 2002; 43(8) 904-11. [41] Nsengiyumva G, Druet-Cabanac M, Ramanankandrasana B, Bouteille B, Nsizabira L, Preux PM. Cysticercosis as a major risk factor for epilepsy in Burundi, east Africa.

[42] Garcia HH, Del Brutto OH, Nash TE, White AC Jr, Tsang VC, Gilman RH. New concepts in the diagnosis and management of neurocysticercosis (*Taenia solium*).

[43] Santo AH. Cysticercosis-related mortality in the State of Sao Paulo, Brazil, 1985-2004: a study using multiple causes of death. Cad Saude Publica 2007; 23(12) 2917-27. [44] Sorvillo FJ, Portigal L, DeGiorgio C, Smith L, Waterman SH, Berlin GW, Ash LR. Cysticercosis-related deaths, California. Emerging Infectious Diseases 2004; 10(3) 465-9. [45] Townes JM, Hoffmann CJ, Kohn MA. Neurocysticercosis in Oregon, 1995-2000.

[46] Bhattarai R, Budke CM, Carabin H, Proano JV, Flores-Rivera J, Corona T, Cowan LD, Ivanek R, Snowden KF, Flisser A. Quality of life in patients with neurocysticercosis in

[48] de Almeida SM, Gurjao SA. Quality of life assessment in patients with

Mexico. American Journal of Tropical Medicine and Hygeine 2011; 84(5) 782-6. [47] Wallin MT, Pretell EJ, Bustos JA, Caballero M, Alfaro M, Kane R, Wilken J, Sullivan C, Fratto T, Garcia HH. Cognitive changes and quality of life in neurocysticercosis: a

longitudinal study. PLoS Neglected Tropical Diseases 2012; 6(1) e1493.

neurocysticercosis. Journal of Community Health 2011; 36(4) 624-30.

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Emerging Infectious Diseases 2004; 10(3) 508-10.

Africa. Tropical Medicine & International Health 2006; 11(6) 906-16.

South Africa. The Internet Journal of Neurology 2005; 3(2).

South Africa. The Internet Journal of Neurology 2008; 9(1).

This chapter reviews the status of pig production and porcine cysticercosis caused by *Taenia solium* in Africa. First, it provides background information regarding pig production and porcine cysticercosis in the region. The chapter then reviews in some more details the current status of porcine cysticercosis in each of the countries based on available scientific literature. Furthermore, this chapter analyses extensively the economic impact of porcine cysticercosis, especially to the agricultural sector in Africa. Finally, the chapter provides conclusions and recommendations to guide future work in relation to porcine cysticercosis in the African continent. To simplify the reporting, the African continent has been divided into five regions based on the United Nations classification system. The regions are northern Africa, southern Africa, western Africa, central Africa, and eastern Africa.

## **2. Background**

Porcine cysticercosis refers to as an infection of pigs with the larval form of *Taenia species. Taenia solium*, *T. saginata asiatica*, and *T. hydatigena* are the *Taenia species* that can infect pigs. While *T. saginata asiatica* is currently known to be limited to Asia, *T. solium* and *T. hydatigena*  have a worldwide distribution. On the African continent, however, *T. solium* ('pork tapeworm') is the most important species of *Taenia* economically and for public health. The larval form of this parasite is capable of infecting humans leading to life-threatening neurological disorders, including epilepsy. In addition, *T. solium* cysticercosis in humans and pigs causes serious economic losses in affected countries because of condemnation of infected pigs and disability in neurocysticercotic patients. The human is the only natural definitive host of *T. solium*. An adult tapeworm is harboured in the small intestine of

© 2013 Ngowi et al., 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 Ngowi et al., 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.

humans, a condition referred to as taeniasis. *Taenia solium* taeniasis is acquired through ingestion of infective larvae of the parasite from infected meat. Raw or inadequately cooked pork provides the route for taeniasis transmission. On the other hand, the larval form of *T. solium*, cysticercosis, can infect both humans and pigs if the hosts ingest infective eggs of the parasite. The life cycle of *T. solium* is presented in Figure 1. Water and foodstuffs contaminated with faecal material from a human carrier of the adult tapeworm are the major sources of cysticercosis transmission. Several factors have been found to facilitate the occurrence of cysticercosis. These include open defaecation, poor personal hygiene, free ranging pigs, and lack of safe drinking water. These factors facilitate both human and animal host access to human faecal materials, which at times may contain *T. solium* eggs.

Agricultural Impact of Porcine Cyisticercosis in Africa: A Review 79

endemicity by inhibiting adequate sanitation and good pig husbandry, which are primary in the control of *T. solium* transmission. The currently emergence and re-emergence of cysticercosis in some industrialised countries of the USA and Europe resulting from international migration have been limited to human-human transmission leading to human cysticercosis (including neurocysticercosis). However, because of improved sanitation and intensive pig rearing, porcine cysticercosis can rarely be (re)introduced in these countries, and hence, a full cycle of the parasite is virtually impossible. In such countries, the major impact of the parasite is related to human morbidity and associated

In response to the WHO's effort to estimate the global burden of neurocysticercosis, four comprehensive studies have reported estimates of burdens of *T. solium* cysticercosis [4-7]. While three of the studies estimated the economic burden of cysticercosis, each focusing on a specific country [4,5,7], a global extensive systematic review of literature found that the frequency of neurocysticercosis in people with epilepsy was consistent across endemic countries. The pooled estimate was 29.0% (95%CI: 22.9%–35.5%) [6]. Knowledge on the proportion of epilepsy caused by neurocysticercosis is primary to enable estimation of the economic impact of neurocysticercosis in endemic countries. For the studies that have estimated the economic burden of cysticercosis in both human and pigs, the infected pigs have been found to contribute 4.7-26.9% of the overall costs of the infections [4,5]. The cost estimates in the pig industry have been entirely based on the prevalence of porcine cysticercosis and the economic loss of the pig's value due to the infection. Thus the observed variation between countries has been primarily due to the differences in porcine cysticercosis prevalence and reduced values of the infected pigs in the different country settings. A study in the Eastern Cape Province of South Africa also reported different values due to different data analytical methods [4]. Generally, the price of a finished pig was estimated to be reduced by 20-60% because of infection with

While *T. solium* is progressively being recognized as an important parasite at the global level, to date scientists in several developing countries endemic for the parasite are struggling to bring the disease to the national attention. Failure of *T. solium* endemic countries to recognize the importance of the parasite is attributed partly to lack of knowledge by stakeholders on the presence, magnitude and impacts of the parasite. While understanding both the human health and agricultural impacts of the parasite is necessary in order to establish the overall societal burden of the parasite to countries, for endemic diseases such as cysticercosis, political decisions in most developing countries are often based on economic impacts of the diseases. This is because most long-term, persisting endemic diseases are difficult to quickly appreciate their impact, especially to nonprofessional policy makers. This is different from epidemic diseases, which draw significant attention when they occur, and hence, favourable measures are usually taken urgently to control such diseases. Political will is important for countries to allocate necessary resources to solve community related problems such as diseases. Specific

economic losses.

cysticercosis [4,5].

Although a number of animal species including dogs [1] can be infected with *T. solium* cysticercosis, domesticated pigs play the major role in the transmission cycle of the parasite because of their close proximity to humans, especially in rural areas, and the increasing popularity of pig keeping and pork consumption in many developing countries [2]. Therefore, most of the literature on *T. solium* has focused on the human-pig transmission cycle. This is also the focus in this chapter.

Source [3]

**Figure 1.** The life cycle of *Taenia solium*.

*Taenia solium* is prevalent in several countries of Africa, Asia and Latin America, providing the full life cycle of the parasite. Poverty has facilitated the parasite's endemicity by inhibiting adequate sanitation and good pig husbandry, which are primary in the control of *T. solium* transmission. The currently emergence and re-emergence of cysticercosis in some industrialised countries of the USA and Europe resulting from international migration have been limited to human-human transmission leading to human cysticercosis (including neurocysticercosis). However, because of improved sanitation and intensive pig rearing, porcine cysticercosis can rarely be (re)introduced in these countries, and hence, a full cycle of the parasite is virtually impossible. In such countries, the major impact of the parasite is related to human morbidity and associated economic losses.

78 Novel Aspects on Cysticercosis and Neurocysticercosis

cycle. This is also the focus in this chapter.

Source [3]

**Figure 1.** The life cycle of *Taenia solium*.

humans, a condition referred to as taeniasis. *Taenia solium* taeniasis is acquired through ingestion of infective larvae of the parasite from infected meat. Raw or inadequately cooked pork provides the route for taeniasis transmission. On the other hand, the larval form of *T. solium*, cysticercosis, can infect both humans and pigs if the hosts ingest infective eggs of the parasite. The life cycle of *T. solium* is presented in Figure 1. Water and foodstuffs contaminated with faecal material from a human carrier of the adult tapeworm are the major sources of cysticercosis transmission. Several factors have been found to facilitate the occurrence of cysticercosis. These include open defaecation, poor personal hygiene, free ranging pigs, and lack of safe drinking water. These factors facilitate both human and animal host access to human faecal materials, which at times may contain *T. solium* eggs.

Although a number of animal species including dogs [1] can be infected with *T. solium* cysticercosis, domesticated pigs play the major role in the transmission cycle of the parasite because of their close proximity to humans, especially in rural areas, and the increasing popularity of pig keeping and pork consumption in many developing countries [2]. Therefore, most of the literature on *T. solium* has focused on the human-pig transmission

*Taenia solium* is prevalent in several countries of Africa, Asia and Latin America, providing the full life cycle of the parasite. Poverty has facilitated the parasite's In response to the WHO's effort to estimate the global burden of neurocysticercosis, four comprehensive studies have reported estimates of burdens of *T. solium* cysticercosis [4-7]. While three of the studies estimated the economic burden of cysticercosis, each focusing on a specific country [4,5,7], a global extensive systematic review of literature found that the frequency of neurocysticercosis in people with epilepsy was consistent across endemic countries. The pooled estimate was 29.0% (95%CI: 22.9%–35.5%) [6]. Knowledge on the proportion of epilepsy caused by neurocysticercosis is primary to enable estimation of the economic impact of neurocysticercosis in endemic countries. For the studies that have estimated the economic burden of cysticercosis in both human and pigs, the infected pigs have been found to contribute 4.7-26.9% of the overall costs of the infections [4,5]. The cost estimates in the pig industry have been entirely based on the prevalence of porcine cysticercosis and the economic loss of the pig's value due to the infection. Thus the observed variation between countries has been primarily due to the differences in porcine cysticercosis prevalence and reduced values of the infected pigs in the different country settings. A study in the Eastern Cape Province of South Africa also reported different values due to different data analytical methods [4]. Generally, the price of a finished pig was estimated to be reduced by 20-60% because of infection with cysticercosis [4,5].

While *T. solium* is progressively being recognized as an important parasite at the global level, to date scientists in several developing countries endemic for the parasite are struggling to bring the disease to the national attention. Failure of *T. solium* endemic countries to recognize the importance of the parasite is attributed partly to lack of knowledge by stakeholders on the presence, magnitude and impacts of the parasite. While understanding both the human health and agricultural impacts of the parasite is necessary in order to establish the overall societal burden of the parasite to countries, for endemic diseases such as cysticercosis, political decisions in most developing countries are often based on economic impacts of the diseases. This is because most long-term, persisting endemic diseases are difficult to quickly appreciate their impact, especially to nonprofessional policy makers. This is different from epidemic diseases, which draw significant attention when they occur, and hence, favourable measures are usually taken urgently to control such diseases. Political will is important for countries to allocate necessary resources to solve community related problems such as diseases. Specific

knowledge on the contribution of the various sectors in the overall societal burden of *T. solium* is of particular importance to promote inter-sectoral collaboration towards control of the parasite [8].

Agricultural Impact of Porcine Cyisticercosis in Africa: A Review 81

Northern Africa Western Africa Central Africa Eastern Africa Southern Africa

the productive performance of the pigs [12]. Similar findings have been reported in human infected with neurocysticercosis [13]. In both the pig and human studies, cysticercosis was found to significantly reduce serum level of testosterone while increasing significantly the level of follicle stimulating hormones in males [12,13]. On the other hand, cysticercosis significantly reduced the level of progesterone in females [13]. These endocrinological changes are thought to exert significant inhibitory action in the reproduction function of the infected individuals. However, it has been observed that the effect is more intense in male than female hosts. Although the study of pigs included males only, there is strong evidence from laboratory trials, which suggests that the effect of the parasite in female pigs will most

likely resemble that observed in female humans [12,13].

**Figure 2.** Regions of Africa based on the United Nations system of classification.

likely to contribute significantly to agricultural losses in the pig industry.

Disability in persons infected with neurocysticercosis is another potential factor that is likely to contribute to further economic losses in the agricultural sector through reduced manpower, some of which would be used in pig production in the countries. This can be supported by studies in Eastern Cape Province of South Africa and Cameroon, which show that the majority of people in Africa are not employed in salaried jobs [4,5]. This significant proportion of the population is likely to engage in small-scale businesses, including pig farming. Those suffering from neurocysticercosis in this category of the population are

Source: [11]

In Africa, pig keeping is popular in many countries. However, there has been no study that has clearly described the pattern of pig production and the overall status of porcine cysticercosis on the continent. This is important in order to understand the importance of the pig enterprise in the region as well as the potential for porcine cysticercosis to constrain the industry. Africa is one of the regions where the full cycle of *T. solium* is occurring because of the favourable environmental conditions and poverty, which inhibit application of effective control measures for the parasite. Thus Africa provides a suitable ecology for *T. solium* endemicity. While information on human taeniasis and cysticercosis status in Africa is still scant, inhibiting a full appraisal of the parasite's burden to the affected countries, a number of scientific publications are presumed to be available with regard to the magnitude and impact of porcine cysticercosis to the agricultural sector in the affected African countries. The emergence of *T. solium* cysticercosis in eastern and southern Africa as a serious agricultural problem and public health risk was described earlier by the Cysticercosis Working Group in Eastern and Southern Africa (CWGESA) [2]. Other authors have described the taeniasis-cysticercosis complex in West and Central Africa [9]. These provide some of the evidence on the importance of cysticercosis caused by *T. solium* in Africa. Synthesizing the information on the burden of porcine cysticercosis to the agricultural sector in Africa would inform on the regional status and guide future efforts towards control and ultimately elimination of the parasite

## **3. Scope**

In this chapter, we review the pig production and agricultural impact of porcine cysticercosis on the African continent based on available literature. Data on the pig population in Africa is based on the most current global pig population estimates [10]. For the prevalence of porcine cysticercosis, the most recent information is included, with a priority for prevalence estimated using antigen ELISA, where available, in order to reflect active infections. However, prevalence based on a less accurate diagnostic method is used if that is the only information available. Note that, the purpose of the review is to describe the current status of porcine cysticercosis in the African region rather than presenting all that has been done in the region with regard to porcine cysticercosis. For simplicity, the African continent is divided into five major regions as classified by the United Nations. That is northern Africa, southern Africa, western Africa, central Africa, and eastern Africa [Figure 2]. Only the 54 countries fully recognised by the United Nations are included. These consists of seven, five, 16, nine and 17 countries of the northern, southern, western, central and eastern Africa, respectively.

It is possible that porcine cysticercosis poses more economic losses than those only related to condemnation or reduced value of infected pigs. For example, studies have established possible reduced fertility of pigs naturally infected with cysticercosis, which would reduce the productive performance of the pigs [12]. Similar findings have been reported in human infected with neurocysticercosis [13]. In both the pig and human studies, cysticercosis was found to significantly reduce serum level of testosterone while increasing significantly the level of follicle stimulating hormones in males [12,13]. On the other hand, cysticercosis significantly reduced the level of progesterone in females [13]. These endocrinological changes are thought to exert significant inhibitory action in the reproduction function of the infected individuals. However, it has been observed that the effect is more intense in male than female hosts. Although the study of pigs included males only, there is strong evidence from laboratory trials, which suggests that the effect of the parasite in female pigs will most likely resemble that observed in female humans [12,13].

80 Novel Aspects on Cysticercosis and Neurocysticercosis

towards control and ultimately elimination of the parasite

the parasite [8].

**3. Scope** 

eastern Africa, respectively.

knowledge on the contribution of the various sectors in the overall societal burden of *T. solium* is of particular importance to promote inter-sectoral collaboration towards control of

In Africa, pig keeping is popular in many countries. However, there has been no study that has clearly described the pattern of pig production and the overall status of porcine cysticercosis on the continent. This is important in order to understand the importance of the pig enterprise in the region as well as the potential for porcine cysticercosis to constrain the industry. Africa is one of the regions where the full cycle of *T. solium* is occurring because of the favourable environmental conditions and poverty, which inhibit application of effective control measures for the parasite. Thus Africa provides a suitable ecology for *T. solium* endemicity. While information on human taeniasis and cysticercosis status in Africa is still scant, inhibiting a full appraisal of the parasite's burden to the affected countries, a number of scientific publications are presumed to be available with regard to the magnitude and impact of porcine cysticercosis to the agricultural sector in the affected African countries. The emergence of *T. solium* cysticercosis in eastern and southern Africa as a serious agricultural problem and public health risk was described earlier by the Cysticercosis Working Group in Eastern and Southern Africa (CWGESA) [2]. Other authors have described the taeniasis-cysticercosis complex in West and Central Africa [9]. These provide some of the evidence on the importance of cysticercosis caused by *T. solium* in Africa. Synthesizing the information on the burden of porcine cysticercosis to the agricultural sector in Africa would inform on the regional status and guide future efforts

In this chapter, we review the pig production and agricultural impact of porcine cysticercosis on the African continent based on available literature. Data on the pig population in Africa is based on the most current global pig population estimates [10]. For the prevalence of porcine cysticercosis, the most recent information is included, with a priority for prevalence estimated using antigen ELISA, where available, in order to reflect active infections. However, prevalence based on a less accurate diagnostic method is used if that is the only information available. Note that, the purpose of the review is to describe the current status of porcine cysticercosis in the African region rather than presenting all that has been done in the region with regard to porcine cysticercosis. For simplicity, the African continent is divided into five major regions as classified by the United Nations. That is northern Africa, southern Africa, western Africa, central Africa, and eastern Africa [Figure 2]. Only the 54 countries fully recognised by the United Nations are included. These consists of seven, five, 16, nine and 17 countries of the northern, southern, western, central and

It is possible that porcine cysticercosis poses more economic losses than those only related to condemnation or reduced value of infected pigs. For example, studies have established possible reduced fertility of pigs naturally infected with cysticercosis, which would reduce **Figure 2.** Regions of Africa based on the United Nations system of classification.

Disability in persons infected with neurocysticercosis is another potential factor that is likely to contribute to further economic losses in the agricultural sector through reduced manpower, some of which would be used in pig production in the countries. This can be supported by studies in Eastern Cape Province of South Africa and Cameroon, which show that the majority of people in Africa are not employed in salaried jobs [4,5]. This significant proportion of the population is likely to engage in small-scale businesses, including pig farming. Those suffering from neurocysticercosis in this category of the population are likely to contribute significantly to agricultural losses in the pig industry.

Because of the current lack of information on the actual reduction of pigs' reproductivity as a result of cysticercosis and specific contribution of unemployed populations to pig production in endemic countries, the analysis of the agricultural impact of *T. solium* in this study is mostly based on the costs related to the partial or total condemnation of infected pigs. However, we observe possible gross underestimation of the impact.

Agricultural Impact of Porcine Cyisticercosis in Africa: A Review 83

i. *Burden-of Taenia-solium cysticercosis* 

*ii. Impact-of Taenia-solium iii. Economic-impact Taenia-solium iv. Financial-impact Taenia-solium* 

The information collected was recorded as reported by the author(s) of the article. If there was different information regarding the cost of porcine cysticercosis in a country, a range of

**Figure 3.** The flow diagram of the literature sampling procedure to analyse the economic impact of

1

13

182

The study area consisted of 54 countries. The total population of pigs estimated in the study area in 2010 amounted 29,606,438. This was approximately 3.1% of the world pig population estimate (N = 965,855,414) of 2010. Out of the Africa regional pig population, approximately 0.2% was reared in the northern countries, while 6.1%, 43.3%, 16,4%, and 34.0% were reared in the southern, western, central, and eastern Africa, respectively. Overall, 19 (35.2%) of the 54 study countries reported prevalence of cysticercosis in pigs. While no data were available

values was given and data sources cited.

**200**  Google first articles retrieved after searching based on criteria i-iv

**18**  Articles relevant to *Taenia solium* burden

**5** 

**4** 

Studies conducted in Africa

Focus on economic burden

porcine cysticercosis in Africa.

**5.1. General results** 

**5. Results** 

## **4. Methodology**

## **4.1. Study area and duration**

This study was carried out between April and June, 2012 and included the 54 African countries that were fully recognised by the United Nations as of 2012 [14]

## *Collection of data on country pig populations and status of porcine cysticercosis*

Pig population data for each of the 54 countries were downloaded from the FAO statistical database [10]. The most recent pig population estimates (those of 2010) were used. Thereafter, several Google searches were performed for each country name and key English phrases and words such as "porcine cysticercosis", *"Taenia solium*", "*T. solium*", and "cysticercosis" to gather scientific publications related to porcine cysticercosis in each country. When a relevant article was encountered, necessary information such as disease magnitude, sample size and diagnostic method was recorded as available. If more than one article was found to be relevant, a range of values was given and authors for all the articles used were cited. The most current literature was preferred.

### *Estimation of agricultural impact of porcine cysticercosis*

This was the main focus of the study. Therefore, more attention was given to this aspect. A total of 200 articles were retrieved following several Google searches using the following four phrases in that order: (i) Burden-of Taenia-solium cysticercosis, (ii) Impactof Taenia-solium, (iii) Economic-impact Taenia-solium, and (iv) Financial-impact Taeniasolium. For each search phrase, 50 first articles we retrieved from which the relevant ones were downloaded from their publishers for further analysis. This first screening was based on a quick assessment of information given in the abstracts. Following the first screening, a total of 18 articles were considered relevant and different from each other, and hence, were included. Out of the 18 articles, 10 were obtained from the first search, seven new articles from the second search, one form the third, and none new from the fourth search phrase. In the second screening, only those articles that included information for Africa were sub-selected from the 18 articles. Five were obtained at this sub-sampling stage. Finally, only those articles that included information on the economic burden of porcine cysticercosis in Africa were selected. Four articles met this criterion and were included for further analysis. The four articles were all peer-reviewed journal papers [4,5,16,17]. A flow diagram to illustrate the sampling procedure described above is given in Figure 3.

The information collected was recorded as reported by the author(s) of the article. If there was different information regarding the cost of porcine cysticercosis in a country, a range of values was given and data sources cited.

**Figure 3.** The flow diagram of the literature sampling procedure to analyse the economic impact of porcine cysticercosis in Africa.

## **5. Results**

82 Novel Aspects on Cysticercosis and Neurocysticercosis

**4. Methodology** 

in Figure 3.

**4.1. Study area and duration** 

Because of the current lack of information on the actual reduction of pigs' reproductivity as a result of cysticercosis and specific contribution of unemployed populations to pig production in endemic countries, the analysis of the agricultural impact of *T. solium* in this study is mostly based on the costs related to the partial or total condemnation of

This study was carried out between April and June, 2012 and included the 54 African

Pig population data for each of the 54 countries were downloaded from the FAO statistical database [10]. The most recent pig population estimates (those of 2010) were used. Thereafter, several Google searches were performed for each country name and key English phrases and words such as "porcine cysticercosis", *"Taenia solium*", "*T. solium*", and "cysticercosis" to gather scientific publications related to porcine cysticercosis in each country. When a relevant article was encountered, necessary information such as disease magnitude, sample size and diagnostic method was recorded as available. If more than one article was found to be relevant, a range of values was given and authors for all the articles

This was the main focus of the study. Therefore, more attention was given to this aspect. A total of 200 articles were retrieved following several Google searches using the following four phrases in that order: (i) Burden-of Taenia-solium cysticercosis, (ii) Impactof Taenia-solium, (iii) Economic-impact Taenia-solium, and (iv) Financial-impact Taeniasolium. For each search phrase, 50 first articles we retrieved from which the relevant ones were downloaded from their publishers for further analysis. This first screening was based on a quick assessment of information given in the abstracts. Following the first screening, a total of 18 articles were considered relevant and different from each other, and hence, were included. Out of the 18 articles, 10 were obtained from the first search, seven new articles from the second search, one form the third, and none new from the fourth search phrase. In the second screening, only those articles that included information for Africa were sub-selected from the 18 articles. Five were obtained at this sub-sampling stage. Finally, only those articles that included information on the economic burden of porcine cysticercosis in Africa were selected. Four articles met this criterion and were included for further analysis. The four articles were all peer-reviewed journal papers [4,5,16,17]. A flow diagram to illustrate the sampling procedure described above is given

infected pigs. However, we observe possible gross underestimation of the impact.

countries that were fully recognised by the United Nations as of 2012 [14]

used were cited. The most current literature was preferred.

*Estimation of agricultural impact of porcine cysticercosis* 

*Collection of data on country pig populations and status of porcine cysticercosis* 

## **5.1. General results**

The study area consisted of 54 countries. The total population of pigs estimated in the study area in 2010 amounted 29,606,438. This was approximately 3.1% of the world pig population estimate (N = 965,855,414) of 2010. Out of the Africa regional pig population, approximately 0.2% was reared in the northern countries, while 6.1%, 43.3%, 16,4%, and 34.0% were reared in the southern, western, central, and eastern Africa, respectively. Overall, 19 (35.2%) of the 54 study countries reported prevalence of cysticercosis in pigs. While no data were available

in the northern region, the remaining regions provided prevalence data, with more reporting frequency observed in the eastern followed by central Africa.

Agricultural Impact of Porcine Cyisticercosis in Africa: A Review 85

**method** 

**Reference** 

**Reference** 

cysticercosis is yet to be scientifically proven. Such studies would be very valuable in guiding potential control measures for *T. solium* infections in South Africa by providing information on potential factors that may be encouraging the endemicity of the parasite in South Africa but

South Africa 1,594,490 54.8 – 57 Ag-ELISA [18]

**Table 2.** Pig population estimates of southern African countries in 2010 and the current status of

Western Africa has the largest pig population in the region (Table 3). Six of the 16 countries of the region have reported presence of porcine cysticercosis. Burkina Faso seems to have high prevalence of porcine cysticercosis in some region, probably because of variations in pig management practices. Apart from Burkina Faso, Gambia and Senegal, data from the other countries are rather old. This suggests that research on porcine cysticercosis in these

Burkina Faso 1,920,200 0-39.6 Ag-ELISA [16,19]

Gambia 28,500 4.8 (n = 371) Ag-ELISA [20] Ghana 536,000 11.7 [16]

Nigeria 7,471,730 15.3 [16] Senegal 346,681 6.4-13.2 (n=1334) Ag-ELISA [20]

Togo 643,630 17 [16]

**Table 3.** Pig population estimates of West African countries in 2010 and the current status of porcine

**Prevalence of PCC Diagnostic** 

**Prevalence of PCC Diagnostic** 

**method** 

not in the other countries if they prove to be free from the infections.

porcine cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

**2010** 

Botswana 12,950 ND Lesotho 83,976 ND Namibia 65,000 ND

Swaziland 50,000 ND

**Country Pig population** 

**Total 1,806,416**

*Porcine cysticercosis in western Africa* 

**Country Pig population** 

countries has been inactive for quite some time.

**2010** 

Benin 354,000 ND

Cape Verde 238,600 ND Cote d'Ivoire 350,000 ND

Guinea 95,180 ND Guinea Bissau 418,900 ND Liberia 265,300 ND Mali 75,015 ND Mauritania - ND Niger 40,000 ND

Sierra Leone 45,211 ND

cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

**Total 12,828,947**

### *Porcine cysticercosis in northern Africa*

Countries of northern Africa comprise Algeria, Egypt, Libya, Morocco, Sudan, Southern Sudan, and Tunisia. Pig rearing in this region is minimal (Table 1). While there were no pigs reported for Libya, Sudan, and Southern Sudan, indicating possibly absence of or insignificant pig rearing in the countries, pig populations in the remaining four countries ranged from 5,700-38,000 in 2010, making an overall regional pig population of 58,200 pigs. The small number of pigs reared in the northern Africa region is likely to be due to drought and the fact that most of the inhabitants in the region are Muslims. Generally, there was no report available with regard to porcine cysticercosis in the northern Africa. While there is an indication of Egypt providing the most ancient known case of *T. solium* infection in humans, there was currently no information regarding prevalence of cysticercosis in pigs in that country. Pigs in Egypt are known to be kept mainly by Coptic Christians. Before, the 2009 suspected swine flu pandemic, which nevertheless did not prove true, pigs in the country have been very valuable in cleaning the city garbage by being fed on garbage traditionally collected from cities and urban centres [15]. Although this practice might have been reduced after the 2009 suspect swine flu pandemic, generally pigs in Egypt are at a greater risk of acquiring *T. solium* cysticercosis because of feeding on the garbage. The lack of reports on porcine cysticercosis in the country can be due to lack of research, which could also be enhanced by religious conflicts towards pig keeping in that country.


**Table 1.** Pig population estimates of North African countries in 2010 and the current status of porcine cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

#### *Porcine cysticercosis in southern Africa*

Table 2 presents the pig population estimates and status of porcine cysticercosis in southern Africa. South Africa is the only country in the region, which has reported prevalence of porcine cysticercosis. A number of studies have been conducted in several parts of the country for various periods of time. It is apparent that porcine cysticercosis is hyperendemic in some parts of the country. The possibility of the other countries in the region being free from porcine cysticercosis is yet to be scientifically proven. Such studies would be very valuable in guiding potential control measures for *T. solium* infections in South Africa by providing information on potential factors that may be encouraging the endemicity of the parasite in South Africa but not in the other countries if they prove to be free from the infections.


**Table 2.** Pig population estimates of southern African countries in 2010 and the current status of porcine cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

### *Porcine cysticercosis in western Africa*

84 Novel Aspects on Cysticercosis and Neurocysticercosis

*Porcine cysticercosis in northern Africa* 

Southern Sudan

*Porcine cysticercosis in southern Africa* 

**Total 58,200**

cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

Tunisia

in the northern region, the remaining regions provided prevalence data, with more

Countries of northern Africa comprise Algeria, Egypt, Libya, Morocco, Sudan, Southern Sudan, and Tunisia. Pig rearing in this region is minimal (Table 1). While there were no pigs reported for Libya, Sudan, and Southern Sudan, indicating possibly absence of or insignificant pig rearing in the countries, pig populations in the remaining four countries ranged from 5,700-38,000 in 2010, making an overall regional pig population of 58,200 pigs. The small number of pigs reared in the northern Africa region is likely to be due to drought and the fact that most of the inhabitants in the region are Muslims. Generally, there was no report available with regard to porcine cysticercosis in the northern Africa. While there is an indication of Egypt providing the most ancient known case of *T. solium* infection in humans, there was currently no information regarding prevalence of cysticercosis in pigs in that country. Pigs in Egypt are known to be kept mainly by Coptic Christians. Before, the 2009 suspected swine flu pandemic, which nevertheless did not prove true, pigs in the country have been very valuable in cleaning the city garbage by being fed on garbage traditionally collected from cities and urban centres [15]. Although this practice might have been reduced after the 2009 suspect swine flu pandemic, generally pigs in Egypt are at a greater risk of acquiring *T. solium* cysticercosis because of feeding on the garbage. The lack of reports on porcine cysticercosis in the country can be due to lack of research, which

reporting frequency observed in the eastern followed by central Africa.

could also be enhanced by religious conflicts towards pig keeping in that country.

**Country Pig population 2010 Prevalence of PCC** 


**Table 1.** Pig population estimates of North African countries in 2010 and the current status of porcine

Table 2 presents the pig population estimates and status of porcine cysticercosis in southern Africa. South Africa is the only country in the region, which has reported prevalence of porcine cysticercosis. A number of studies have been conducted in several parts of the country for various periods of time. It is apparent that porcine cysticercosis is hyperendemic in some parts of the country. The possibility of the other countries in the region being free from porcine

6,000 ND

Algeria 5,700 ND Egypt 38,000 ND Libya - ND Morocco 8,500 ND Sudan - ND Western Africa has the largest pig population in the region (Table 3). Six of the 16 countries of the region have reported presence of porcine cysticercosis. Burkina Faso seems to have high prevalence of porcine cysticercosis in some region, probably because of variations in pig management practices. Apart from Burkina Faso, Gambia and Senegal, data from the other countries are rather old. This suggests that research on porcine cysticercosis in these countries has been inactive for quite some time.


**Table 3.** Pig population estimates of West African countries in 2010 and the current status of porcine cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

## *Porcine cysticercosis in central Africa*

Four out of the ten countries of central Africa have reported prevalence of porcine cysticercosis. Extensive studies have been conducted in Cameroon, ranging from epidemiological, intervention trials and disease burden analysis. Porcine cysticercosis prevalence in Cameroon seems to resemble that in the Democratic Republic of Congo. Central Africa also indicates high infection rates of porcine cysticercosis.

Agricultural Impact of Porcine Cyisticercosis in Africa: A Review 87

**method** 

**Reference** 

**Prevalence of PCC Diagnostic** 

**Losses due to** 

**Annual DALYs lost due to NCC** 

€ 2,062,125 [16]

**Reference** 

**PCC** 

Ghana € 594,945 [16] Nigeria € 17,442, 000 [16] Senegal € 57,600 [16] Togo € 2,167,500 [16]

Angola € 408,000 [16] Chad € 56,063 [16] D R Congo € 2,141,700 [16]

Tanzania \* [17]

Tanzania 495,000 30.7-32 (n=600) Ag-ELISA [24] Kenya 347,400 4.0 Ag-ELISA [25] Uganda 2,300,000 8.6 (n=480) Ag-ELISA [26] Rwanda 602,324 20 [16] Burundi 244,791 2-39 Meat insp. [16]

Mozambique 1,350,000 34.9 (n=661) Ag-ELISA [27]

Zambia 500,000 8.2-23.3 (n=98-1691) Ag-ELISA [28, 29] Zimbabwe 635,000 2.7-28.6 Meat insp. [2]

**Table 5.** Pig population estimates of East African countries in 2010 and the current status of porcine

**monetary losses** 

Southern Africa S. Africa 04 US \$18.6 - 34.2 M US \$5.0 M ND [4]

Western Africa B/ Faso € 52,830 [16]

Central Africa Cameroon € 10,255,202 € 478,844 € 45,838.4 [5]

Eastern Africa Burundi € 218,325 [16]

**Table 6.** Monetary and non-monetary costs of *Taenia solium* cysticercosis in Africa

\* A community based health education intervention trial in Tanzania found out that over a period of 5 years, the health and pig management education intervention would have a significant financial benefit to a smallholder pig farmer

**Country Pig population** 

**2010** 

Djibouti - ND Eritrea - ND Ethiopia 29,000 ND Somalia 4,200 ND

Madagascar 1,380,250 ND Malawi 2,147,900 ND

Comoros - ND Mauritius 22,327 ND Seychelles 5,363 ND

cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

**Region Country Overall annual** 

receiving it [NPV: US \$3507 (95% CI: 3421 to 3591); IRR: 370%].

**Total 10,063,555**

Northern Africa -


**Table 4.** Pig population estimates of Central African countries in 2010 and the current status of porcine cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

## *Porcine cysticercosis in eastern Africa*

The eastern Africa region consists of 17 countries and approximately 10 million pigs were reared in the region in 2010 (Table 5). The region includes ten out of 13 countries that belong to the CWGESA, an international non-governmental scientific organisation that was founded in 2002 with the overall objective of combating taeniasis/cysticercosis on a regional effort, considering that the disease has no border. As shown in the table below, a number of countries have reported prevalence of porcine cysticercosis, also suggesting high infection pressure in some countries. In Tanzania, an incidence rate of 69 per 100 pig-yeas was estimated in sentinel pigs based on antigen ELISA [23].

### *Economic impact of porcine cysticercosis in Africa*

Quite a good amount of information regarding the monetary burden of porcine cysticercosis has been reported in the southern, western, central, and eastern Africa regions. Extensive and most recent studies are those conducted in South Africa and Cameroon [4,5]. These studies were also able to establish the disease burden in humans. Overall, the available information provides enough evidence of the agricultural impact of porcine cysticercosis in Africa, especially most of sub-Saharan Africa. Table 6 summarises the information on the monetary burden of porcine cysticercosis in Africa.



*Porcine cysticercosis in central Africa* 

**Country Pig population** 

**2010** 

Central Afr Rep 1,087,000 ND

Rep Congo 70,000 ND

Eq. Guinea 6,300 ND Gabon 215,000 ND Sao Tomé & Pr 2,620 ND

cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data

estimated in sentinel pigs based on antigen ELISA [23].

*Economic impact of porcine cysticercosis in Africa* 

monetary burden of porcine cysticercosis in Africa.

**Total 4,849,320**

*Porcine cysticercosis in eastern Africa* 

Four out of the ten countries of central Africa have reported prevalence of porcine cysticercosis. Extensive studies have been conducted in Cameroon, ranging from epidemiological, intervention trials and disease burden analysis. Porcine cysticercosis prevalence in Cameroon seems to resemble that in the Democratic Republic of Congo.

> **Prevalence of PCC**

Angola 791,000 0-6.8 Meat insp. [16] Cameroon 1,680,000 11-39.8 Ag-ELISA [21]

Chad 30,400 6.8-25.7 Tongue/Meat [16]

DR Congo 967,000 41.2 (n=153) Ag-ELISA [22]

**Table 4.** Pig population estimates of Central African countries in 2010 and the current status of porcine

The eastern Africa region consists of 17 countries and approximately 10 million pigs were reared in the region in 2010 (Table 5). The region includes ten out of 13 countries that belong to the CWGESA, an international non-governmental scientific organisation that was founded in 2002 with the overall objective of combating taeniasis/cysticercosis on a regional effort, considering that the disease has no border. As shown in the table below, a number of countries have reported prevalence of porcine cysticercosis, also suggesting high infection pressure in some countries. In Tanzania, an incidence rate of 69 per 100 pig-yeas was

Quite a good amount of information regarding the monetary burden of porcine cysticercosis has been reported in the southern, western, central, and eastern Africa regions. Extensive and most recent studies are those conducted in South Africa and Cameroon [4,5]. These studies were also able to establish the disease burden in humans. Overall, the available information provides enough evidence of the agricultural impact of porcine cysticercosis in Africa, especially most of sub-Saharan Africa. Table 6 summarises the information on the

**Diagnostic** 

**method Reference** 

Central Africa also indicates high infection rates of porcine cysticercosis.

**Table 5.** Pig population estimates of East African countries in 2010 and the current status of porcine cysticercosis (PCC) caused by *Taenia solium*. ND indicates no data


\* A community based health education intervention trial in Tanzania found out that over a period of 5 years, the health and pig management education intervention would have a significant financial benefit to a smallholder pig farmer receiving it [NPV: US \$3507 (95% CI: 3421 to 3591); IRR: 370%].

**Table 6.** Monetary and non-monetary costs of *Taenia solium* cysticercosis in Africa

### **6. Conclusion**

This extensive literature survey has established the agricultural impact of porcine cysticercosis in Africa. The results indicate a high disease burden and its economic impact to affected countries due to monetary losses in the agricultural sector, human health related costs and reduced manpower as a result of disabilities in neurocysticercotic patients. Most of the previous studies have focused on financial losses due to reduced value of infected pigs. This can grossly underestimate the burden of *T. solium* to the agricultural sector since disabilities in neurocysticercotic patients (including attached stigma) and possible reduced reproductive performance of infected pigs could add further to the impact of the parasite to the agricultural sector. Only two studies in the region have in addition analysed the cost of the parasite as a result of neurocysticercotic persons. These studies found that monetary losses due to pig condemnations account only approximately 5% of the overall cost of the disease [4,5]. In addition, the studies established significant Disability Adjusted Life Years (DALYs) lost by patients suffering from neurocysticercosis. Such opportunity costs are likely to exert additional burden of the parasite to the agricultural sector as a good number of rural communities are mostly engaged in agricultural activities, including pig farming. This study recommends urgent measures to control *T. solium* in endemic countries now that adequate epidemiological data are available in several countries. In addition, studies are needed to determine the impact of porcine cysticercosis to the fertility and eventually fecundity of infected pigs.

Agricultural Impact of Porcine Cyisticercosis in Africa: A Review 89

Chummy Sikasunge

*Maputo, Mozambique* 

*Department of Parasitology,* 

*Democratic Republic of Congo* 

Sylvia Ramiandrasoa *Division of Cysticercosis,* 

Mary Louise Penrith

Arve Lee Willingham

*The Faculty of Life Sciences,* 

**Acknowledgement** 

**7. References** 

*Zoonoses,* 

*Faculty of Veterinary Science,* 

*Central Veterinary Laboratory, Kinshasa,* 

*Ministry of Heath, Antananarivo, Madagascar* 

*Department of Veterinary Tropical Diseases,* 

*University of Pretoria, Pretoria, South Africa* 

*Danish Centre for Experimental Parasitology,* 

*University of Copenhagen, Frederiksberg, Denmark* 

presented in this chapter are highly acknowledged.

Journal of Helminthology 2002; 76(4):311-314.

*The Cysticercosis Working Group in Eastern and Southern Africa* 

*WHO/FAO Collaborating Center for Research and Training on Emerging and Other Parasitic* 

Authors for the various studies and data sources used in the compilation of the information

[1] Ito A, Putra M. I, Subahar R, Sato M. O, Okamoto M, Sako Y, Nakao M, Yamasaki H, Nakaya K, Craig P. S, Margono S. S Dogs as alternative intermediate hosts of *Taenia solium* in Papua (Irian Jaya), Indonesia confirmed by highly specific ELISA and immunoblot using native and recombinant antigens and mitochondrial DNA analysis.

Julienne Sumbu

Sonia Afonso

*Department of Para-Clinical Studies, University of Zambia, Lusaka, Zambia* 

*Faculty of Veterinary Medicine, Eduardo Mondlane University,* 

## **Author details**

Helena A. Ngowi *Department of Veterinary Medicine and Public Health, Sokoine University of Agriculture, Morogoro, Tanzania* 

Samson Mukaratirwa *School of Biological & Conservation Sciences, University of KwaZulu-Natal, Durban, South Africa* 

Faustin P. Lekule *Department of Animal Science and Production, Sokoine University of Agriculture, Morogoro, Tanzania* 

Ndichu Maingi *Department of Veterinary Pathology, Microbiology & Parasitology, University of Nairobi, Nairobi, Kenya* 

Charles Waiswa *Department of Veterinary Medicine, Makerere University, Kampala, Uganda*  Chummy Sikasunge *Department of Para-Clinical Studies, University of Zambia, Lusaka, Zambia* 

Sonia Afonso *Faculty of Veterinary Medicine, Eduardo Mondlane University, Maputo, Mozambique* 

88 Novel Aspects on Cysticercosis and Neurocysticercosis

This extensive literature survey has established the agricultural impact of porcine cysticercosis in Africa. The results indicate a high disease burden and its economic impact to affected countries due to monetary losses in the agricultural sector, human health related costs and reduced manpower as a result of disabilities in neurocysticercotic patients. Most of the previous studies have focused on financial losses due to reduced value of infected pigs. This can grossly underestimate the burden of *T. solium* to the agricultural sector since disabilities in neurocysticercotic patients (including attached stigma) and possible reduced reproductive performance of infected pigs could add further to the impact of the parasite to the agricultural sector. Only two studies in the region have in addition analysed the cost of the parasite as a result of neurocysticercotic persons. These studies found that monetary losses due to pig condemnations account only approximately 5% of the overall cost of the disease [4,5]. In addition, the studies established significant Disability Adjusted Life Years (DALYs) lost by patients suffering from neurocysticercosis. Such opportunity costs are likely to exert additional burden of the parasite to the agricultural sector as a good number of rural communities are mostly engaged in agricultural activities, including pig farming. This study recommends urgent measures to control *T. solium* in endemic countries now that adequate epidemiological data are available in several countries. In addition, studies are needed to determine the impact of porcine cysticercosis to the fertility and eventually fecundity of

**6. Conclusion** 

infected pigs.

**Author details** 

Helena A. Ngowi

Samson Mukaratirwa

Faustin P. Lekule

Ndichu Maingi

Charles Waiswa

*Department of Veterinary Medicine and Public Health, Sokoine University of Agriculture, Morogoro, Tanzania* 

*School of Biological & Conservation Sciences, University of KwaZulu-Natal, Durban, South Africa* 

*Department of Animal Science and Production,* 

*Department of Veterinary Pathology, Microbiology & Parasitology,* 

*University of Nairobi, Nairobi, Kenya* 

*Department of Veterinary Medicine, Makerere University, Kampala, Uganda* 

*Sokoine University of Agriculture, Morogoro, Tanzania* 

Julienne Sumbu *Department of Parasitology, Central Veterinary Laboratory, Kinshasa, Democratic Republic of Congo* 

Sylvia Ramiandrasoa *Division of Cysticercosis, Ministry of Heath, Antananarivo, Madagascar* 

Mary Louise Penrith *Department of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa* 

Arve Lee Willingham *WHO/FAO Collaborating Center for Research and Training on Emerging and Other Parasitic Zoonoses, Danish Centre for Experimental Parasitology, The Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark The Cysticercosis Working Group in Eastern and Southern Africa* 

## **Acknowledgement**

Authors for the various studies and data sources used in the compilation of the information presented in this chapter are highly acknowledged.

## **7. References**

[1] Ito A, Putra M. I, Subahar R, Sato M. O, Okamoto M, Sako Y, Nakao M, Yamasaki H, Nakaya K, Craig P. S, Margono S. S Dogs as alternative intermediate hosts of *Taenia solium* in Papua (Irian Jaya), Indonesia confirmed by highly specific ELISA and immunoblot using native and recombinant antigens and mitochondrial DNA analysis. Journal of Helminthology 2002; 76(4):311-314.

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Agricultural Impact of Porcine Cyisticercosis in Africa: A Review 91

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	- [29] Sikasunge C. S, Phiri I. K, Phiri A. M, Siziya S, Dorny P, Willingham A. L 3rd Prevalence of *Taenia solium* porcine cysticercosis in the Eastern, Southern and Western provinces of Zambia. Veterinary Journal 2008;176(2) 240-244.

**Chapter 5** 

© 2013 Fleury et al., 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 Fleury et al., 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.

**Control of** *Taenia Solium* **Transmission** 

Additional information is available at the end of the chapter

strategies that can improve the control of the T/C.

must surely go on and progress will be made.

**2. Actual tools for diagnosis and treatment** 

http://dx.doi.org/10.5772/51286

**1. Introduction** 

**of Taeniosis and Cysticercosis in Endemic** 

**Countries: The Roles of Continental Networks** 

**of Specialists and of Local Health Authorities** 

Agnès Fleury, Edda Sciutto, Aline S. de Aluja, Carlos Larralde, Sonia Agudelo, Gisela Maria Garcia, Jaime Fandiño, Randy Guerra, Cáris Nunes, Samuel Carvalho de Aragão, Marcello Sato, Ronaldo Abraham, Arturo Carpio, Franklin Santillan, Maria Milagros Cortez A., Glenda Rojas, Elizabeth Ferrer, Cruz Manuel Aguilar, Juan Carlos Durán and R. Michael E. Parkhouse

Neurocysticercosis (NCC) is still an endemic disease in most of the countries of Asia, Africa and Latin America, despite the important progress made in the development of effective tools for its prevention, diagnosis and treatment. Although the infection disappeared in many European countries during the nineteenth century, in some Eastern European countries control was not achieved until the beginning of the twentieth century, mainly due to the improvement of their political, social and economic status. Alarming recent reports show the persistence of the endemia in Africa [1-3] **(Table 1)**, as well as in the Americas [25] **(Table 2)**  and in Asia **(Table 3).** None of the endemic countries has been able to eradicate *Taenia solium´s* Taeniosis/Cysticercosis (T/C). Similarly, the frequency of human cases of NCC is increasing in some industrialized countries, such as the United States, Canada and Spain, due mostly to migrant workers, although some autochthonous cases have also occurred [92-97]. In this paper, we will try to understand the reasons behind such failures and propose

It is clear that there are efficient tools for diagnosis and treatment, although investigations

## **Control of** *Taenia Solium* **Transmission of Taeniosis and Cysticercosis in Endemic Countries: The Roles of Continental Networks of Specialists and of Local Health Authorities**

Agnès Fleury, Edda Sciutto, Aline S. de Aluja, Carlos Larralde, Sonia Agudelo, Gisela Maria Garcia, Jaime Fandiño, Randy Guerra, Cáris Nunes, Samuel Carvalho de Aragão, Marcello Sato, Ronaldo Abraham, Arturo Carpio, Franklin Santillan, Maria Milagros Cortez A., Glenda Rojas, Elizabeth Ferrer, Cruz Manuel Aguilar, Juan Carlos Durán and R. Michael E. Parkhouse

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51286

**1. Introduction** 

92 Novel Aspects on Cysticercosis and Neurocysticercosis

[29] Sikasunge C. S, Phiri I. K, Phiri A. M, Siziya S, Dorny P, Willingham A. L 3rd Prevalence of *Taenia solium* porcine cysticercosis in the Eastern, Southern and Western

provinces of Zambia. Veterinary Journal 2008;176(2) 240-244.

Neurocysticercosis (NCC) is still an endemic disease in most of the countries of Asia, Africa and Latin America, despite the important progress made in the development of effective tools for its prevention, diagnosis and treatment. Although the infection disappeared in many European countries during the nineteenth century, in some Eastern European countries control was not achieved until the beginning of the twentieth century, mainly due to the improvement of their political, social and economic status. Alarming recent reports show the persistence of the endemia in Africa [1-3] **(Table 1)**, as well as in the Americas [25] **(Table 2)**  and in Asia **(Table 3).** None of the endemic countries has been able to eradicate *Taenia solium´s* Taeniosis/Cysticercosis (T/C). Similarly, the frequency of human cases of NCC is increasing in some industrialized countries, such as the United States, Canada and Spain, due mostly to migrant workers, although some autochthonous cases have also occurred [92-97].

In this paper, we will try to understand the reasons behind such failures and propose strategies that can improve the control of the T/C.

## **2. Actual tools for diagnosis and treatment**

It is clear that there are efficient tools for diagnosis and treatment, although investigations must surely go on and progress will be made.

© 2013 Fleury et al., 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 Fleury et al., 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.


Control of *Taenia Solium* Transmission of Taeniosis and Cysticercosis in Endemic Countries:

Albendazole) have been used for at least 30 years. Although different studies evaluating their efficacy have shown that these drugs are not efficient in all patients, they also revealed that they eliminate the parasites and diminish the symptomatology significantly more than

included

PWE)

[29] Hospital-based 36379 CT-scan 0.20%

[31] Hospital-based 5 105 259 Admission 0.01%

[35] Hospital-based 1501 Autopsies 4.80\*\* [36] Hospital-based 1009 CT-scan 9.02 [37] Hospital- based 6500 Autopsies 0.80

[27] Blood donors 1133 Ab-ELISA 5.6 [28] Population-based 694 EITB 1.6

[33] Population-based 84 Ab-ELISA 5.9

Paulo state

Psychiatric patients with neurological signs (98) Primary psychiatric patients (153) Controls (246)

[39] Population-based 399 Ab- ELISA 52.9

[41] Population-based 157 Ab-ELISA 28.7 [42] Pig-breeders 46 EITB 8,7 [43] Population-based 665 Ab-ELISA 28.4 [44] PWE 111 Ab- ELISA 17,1 [45] PWE 223 Ab-ELISA 35,9 [46] Population-based 29360 Ab-ELISA 8.55

[47] Population-based 4306 Ag-ELISA 4.99

1890 sera 989 CSF 52 sera + CSF

placebo [99-101]. As a consequence, investigation in this area must continue.

[30] Population-based 110 PWE EITB,

[32] Population-based 354 Ab-ELISA,

[34] Population-based Deaths Sao

Country Reference Type of study Subject

Bolivia [26] Population-based 10124 (124

[38] Hospital based

Patients with neurological symptoms

[48] Population-based 2415 (24

Brazil

Colombia

Ecuador

[40]

The Roles of Continental Networks of Specialists and of Local Health Authorities 95

Diagnosis based on

EITB

Ag-ELISA

Death certificate

EITB

Ab-ELISA

EITB 11.3

Seroprevalence Cysticercosis (%)

CT-scan 27.4% PWE

8.2 (EITB) 3.6 (ELISA)

Group 1: 5.1 Group 2: 2.6 Group 3: 2

CTscan/MRI 14.9 82.2

PWE) CT scan 33% PWE

Prevalence NCC

0.55/1000,00 0\*\*

**Table 1.** Prevalence (sero prevalence) of human neurocysticercosis in Africa. Only 2002-2012 articles were considered.

Improvement of neuroimaging techniques permits a sensitive and accurate diagnosis of NCC in the great majority of cases, the problem being its limited accessibility to the principal rural population. Immunodiagnosis based on serum antibody detection is an efficient marker of contact with the parasite, permitting the identification of endemic areas in which control and preventive measures must be intensified. Detection of parasite antigens in serum and cerebrospinal fluid permits a confident diagnosis of severe neurocysticercosis forms, allowing opportune and adequate treatment and reducing the morbidity [98]. Regarding NCC treatment, two cestocidal drugs (Praziquantel and Albendazole) have been used for at least 30 years. Although different studies evaluating their efficacy have shown that these drugs are not efficient in all patients, they also revealed that they eliminate the parasites and diminish the symptomatology significantly more than placebo [99-101]. As a consequence, investigation in this area must continue.

94 Novel Aspects on Cysticercosis and Neurocysticercosis

Burkina Faso [4] Population-

Burundi

Cameroon

Democratic Republic of Congo

Country Reference Type of study Subject

[12] Population-

[13] Population-

[14] Population-

[15] Population-

Senegal [20] Population-based 403

Only 2002-2012 articles were considered.

[6] Case-control 324 PWE

[8] Case-control 303 PWE

based

based

Madagascar [17] Population-based 4375 Ab-ELISA

**Table 1.** Prevalence (sero prevalence) of human neurocysticercosis in Africa.

Mozambique [19] Urban children 269 Abs 20,8%

Zambia [24] Population-based 708 Ag-ELISA 5,8%

included

[5] Population-based 734 Ag-ELISA 4.5%

[7] PWE 250 Ab-ELISA 61%

606 Controls

137 Butchers

based 504 PWE Ab/Ag

based 4993 Ag-ELISA

93 PWE

[16] Population-based 943 Ag-ELISA 21.6%

[18] US Peace Corps 73 EITB 8,2%

South Africa [21] PWE (Hospital) 92 CT scan 37% Tanzania [22, 23] Hospital-based 212 PWE CT scan 16.5%

Improvement of neuroimaging techniques permits a sensitive and accurate diagnosis of NCC in the great majority of cases, the problem being its limited accessibility to the principal rural population. Immunodiagnosis based on serum antibody detection is an efficient marker of contact with the parasite, permitting the identification of endemic areas in which control and preventive measures must be intensified. Detection of parasite antigens in serum and cerebrospinal fluid permits a confident diagnosis of severe neurocysticercosis forms, allowing opportune and adequate treatment and reducing the morbidity [98]. Regarding NCC treatment, two cestocidal drugs (Praziquantel and

[9, 10] Population-based 168 Ab-ELISA 1,2% [11] Population-based 500 EITB 25,8%

Diagnosis based on

648 controls Ab-ELISA 59.6 % PWE

Ab/Ag - ELISA

198 Controls Ag-ELISA Butchers 3,6%

ELISA

CT scan

81Controls Ab-ELISA 18,3% PWE

Ag-ELISA EITB CT scan

EITB 7-21%

based 763 Ag-ELISA 10,3%; 1.4%; 0%

Seroprevalence Cysticercosis

31,5% controls

Ab 58,7% ; Ag 38,3 PWE Ab 31, 4% Ag 20 % controls

Controls: 4,5%

1,2% Ag 44,6% Ab

> 0,4% 1,0 % 3,0%

14,8% Controls

11,9% 23,3% of

sero+

Prevalence NCC

> 59.1% of sero+



Control of *Taenia Solium* Transmission of Taeniosis and Cysticercosis in Endemic Countries:

included

[73] Population-based 1063 EITB 15.9% [74] Population-based 450 Ab-ELISA 22.4%

[71] Population-based 72 CT-scan 26% [72] Hospital study 1026 PWE CT-scan 34.6%

[75] Population-based 595 CT-scan 15.1% [76] Population-based 141 PWE CT-scan 24.8%

patients 103 Ac-ELISA 33 (32%)

1442 controls 91 suspected cases of NCC 100 healthy students

1120 cases of burns, 293 PWE (Papua) / 74 PWE, 746 controls (Bali)

> 17 PWE 32 SCN 47 control

[83] Population-based 96 Ab-ELISA 45.8% [84] Population-based 311 Ab-ELISA 0.3%

Nepal [87] Hospital study 300 PWE MRI 47%

707 (303 mountain, 175 coast 229 urban)

Korea [85] Population-based 74,448 Ab-ELISA 8.3% (1993)

Malasya [86] Population-based 135 Ab-ELISA 2.2%.

Philippines [88] Population-based 497 Ab-ELISA 24.6% Thailand [89] Population-based 159 Ab-ELISA 5.70% Viet Nam [90] Population-based 210 Ag-ELISA 5.7%

China [70] Population-based 202 Ab-ELISA 2.97%.

[77] Population-based 1064 (sera)

Country Reference Type of Study Subject

[78] Neurological

[79] Population-based

[81] Population-based (1539 people)

[82] Population-based

[91] Population-based

**Table 3.** Prevalence (seroprevalence) of human neurocysticercosis in Asia

PWE: people with epilepsy / SCN: subcutaneous nodules

only 2002-2012 articles were considered.

[80] Blood donors 216

India

Indonésia

The Roles of Continental Networks of Specialists and of Local Health Authorities 97

Diagnosis

Ab / Ag-ELISA CT-scan

Indirect haemaggluti nation (IHA)

Ab-ELISA / Ag-Coagglutination

Ab-ELISA

Ab-ELISA

Ag-ELISA, CT scan

Based on seroprevalence Prevalence

15.9% (Ac) / 4.5% (Ag)

6.1% controls 21.97% suspected cases 0% healthy students

14 (6.48 %)

67% PWE, 65% SCN (Papua) 13.5% PWE 12.5% controls (Bali)

70.6% PWE 62.5% SCN 25.5% control

2.2% (2006)

5.3% (mountain) 0.6% (coast) 0% (urban)

NCC

EITB: Electro immune transfer blot; PWE: people with epilepsy. Ag: Circulating antigens of *T. solium* metacestodes, Ab: Antibodies anti-cysticercal. \* Only patients diagnosed between 2000 and 2009 were included. \*\* Cases of cysticercosis in general were reported

**Table 2.** Prevalence (sero prevalence) of human neurocysticercosis in Latin America. Only 2002-2012 articles were considered.

Control of *Taenia Solium* Transmission of Taeniosis and Cysticercosis in Endemic Countries: The Roles of Continental Networks of Specialists and of Local Health Authorities 97

96 Novel Aspects on Cysticercosis and Neurocysticercosis

Honduras

Mexico

Peru

Venezuela

Country Reference Type of study Subject

[56] Psychiatric

[58]

[68]

Only 2002-2012 articles were considered.

included

PWE)

PWE)

patients 105 Ab-ELISA

[60] Population-based 2583 EITB 13.9 [61] Population-based 316 EITB 21

[62] Population-based 903 EITB (825)

[63] Housemaids 1178 EITB

[64] Population-based 803 EITB

[65] Population-based 817 (8 PWE) EITB

[66] Population-based 368 Ab-ELISA,

[67] Population-based 68 Ag/Ab

**Table 2.** Prevalence (sero prevalence) of human neurocysticercosis in Latin America.

(3) 1254 Ag/Ab

158 psychiatric patients 127 controls

EITB: Electro immune transfer blot; PWE: people with epilepsy. Ag: Circulating antigens of *T. solium* metacestodes, Ab: Antibodies anti-cysticercal. \* Only patients diagnosed between 2000 and 2009 were

Population-based

[69] Hospital-based

included. \*\* Cases of cysticercosis in general were reported

[54] Population-based 154 CT scan 9.1 [55] Population-based 649 CT scan 9.1

[57] PWE (late-onset) 455 CT scan 21.1

<sup>4706</sup>CT scan/

[49] Population-based 800 Ag-ELISA,

Haiti [51] Medical visits 216 EITB 2.8

[50] Hospital-based 194 PWE

[52] Population-based 6473 (151

[53] Population-based 5609 (33

All NC patients diagnosed at INNN in 2004

Nicaragua [59] PWE 88 Ab-ELISA

Diagnosis based on

EITB

EITB

EITB

EITB

EITB 2.25

(late-onset) CT scan/MRI 19.6\*

Seroprevalence Cysticercosis (%)

CT scan 37 (PWE)

CT scan 13.9 (PWE)

7.6 (ELISA) 0.9 (EITB)

MRI 2.5

8.0 (ELISA) 14.8 (EITB)

CTscan (150) 24.2 27.3

CT-scan 14.6 50 (of

CT-scan 24.4 3

EITB 3.3

ELISA

ELISA Ag: 64.7, Ab: 79

EITB Patients:18.3

CT-scan 50 (PWE)

Ag: 9.1; 6.1; 5.7 Ab: 36.5;36.5; 4

Controls:1.6

sero+)

Prevalence NCC


**Table 3.** Prevalence (seroprevalence) of human neurocysticercosis in Asia only 2002-2012 articles were considered.

Regarding porcine cysticercosis, diagnosis based on tongue inspection has been conventionally used, but does not detect all affected pigs. Serology permits, although not with ideal sensibility and specificity, identification of the areas where the life-cycle of the parasite persists. Echography (ultrasound) has recently been introduced as a sensitive (95%) and specific (97%) method of diagnosis (Kappa coefficient of 90%) [102]. Treatment of cysticercotic pigs with oxfendazole has shown a good efficiency [103].

Control of *Taenia Solium* Transmission of Taeniosis and Cysticercosis in Endemic Countries:

of pig housing have not been tested (probably due to economic and logistic costs) although it seems to be a very efficient strategy for many parasitic and infectious disease transmitted

This is a truly kafkian situation: we are in the presence of a parasite that causes a potentially severe human disease, as well as important economic losses; paradoxically, it is clear that the disease is potentially eradicable and, in fact, scientists and health authorities know how to eradicate it and have strategies to reach this goal. Despite all these resources, and their demonstrated effectiveness, the signs of a decrease of the transmission rate in the endemic countries are inconclusive or doubtful and, worse yet, in some non-endemic countries, an

Faced with this perspective, it becomes evident that we will not attain the eradication of *T.* 

International initiatives have been concerned with the problem of cysticercosis for many years and several meetings were organised, the most important being: WHO Technical Consultation (Geneva, 1983), Pan American Health Organization (PAHO) Informal Consultation on Taeniasis/Cysticercosis (Porto Allegre, 1990), International Task Force for Disease Eradication (ITFDE, Atlanta, 1993), PAHO/WHO Informal Consultation on the Taeniasis/Cysticercosis Complex (Brasilia, 1995), North Atlantic Treaty Organization (NATO) Seminar on Emergent Helminth Zoonoses, (Pozna, 2000), Fifty-Fifth World Health Assembly, (Geneva, 2002), ITFDE II (Atlanta, 2003), WHO Expert Consultation on Foodborne Trematode Infections (Ventiane, 2009). In most of them, strategies for prevention and control of T/C were analyzed and recommendations were made. Since 2008, the WHO

**4.1. The intervention of the national and international health authorities in** 

has included T/C in its Global Plan to combat Neglected Tropical diseases [124].

Regarding national health authorities, not much has been done. In very few countries, specific norms have been recommended. Such is the case of Latin America where only Mexico has an official norm for the vigilance, the prevention and the control of T/C in the first level of attention which was published in 1994 (modified in 2004) [125]. The Mexican norm includes the implementation of education and information programs, the identification and treatment of tapeworm carriers, the referral of subjects with suspected of NCC to a second level of attention, the confiscation of infected pigs, and the obligation to notify the diagnosed cases of NCC, taeniosis and swine cysticercosis to the corresponding authorities. The effort must be applauded, and has surely contributed to the awareness of the general population and of the medical personnel about the problem. Unfortunately, still, 15 years after its promulgation, cases of swine and human cysticercosis are still being diagnosed and not notified in Mexico. Probably, this is due to the fact that this norm did not

increase in the number of neurocysticercosis cases is occurring.

by faeces.

*solium* without:

**control programs** 

**4. What must be done?** 

The Roles of Continental Networks of Specialists and of Local Health Authorities 99

Diagnosis of the adult form of *T. solium* is perhaps the topic where more efforts must be made. Although a species-specific coproantigen ELISA was developed, reaching very good performance [104], further studies are required to evaluate it in field conditions. And this is not so easy, as prevalence of taeniosis seems to be much lower than that of cysticercosis, a fact understandable as one tapeworm carrier can infect hundreds of people and thousands of pigs. Treatment of taeniosis with niclosamide or praziquantel has shown to be very efficient [105].

In conclusion, although efforts must continue in some areas, today we have tools that allow the detection of endemic areas and the effective diagnosis and treatment of patients in most circumstances. This situation, adding to the existence of specific tools for prevention (vaccine), allows the design of extensive and effective preventive and control programs.

## **3. Strategies to eradicate the disease**

Cysticercosis is considered a neglected "tools-ready disease" according to WHO [106] and as a potentially eradicable disease since 1993 [107].This is feasible because there are no animal reservoirs besides humans and pigs, the only source of *T. solium* infection for pigs being humans (the definitive host), interrupting the parasite´s life cycle seems an easy task by intervention strategies acting upon different stages of the parasite´s development.

Different strategies have been proposed and tested, generally experimental and at small scale, to eradicate the (T/C) complex, the most notable being:


Almost all these strategies have shown some degree of efficacy, this fact contrasting with the persistence of the parasite in all the endemic countries in the 1950's. It should be noted that, to our knowledge, programs promoting letrinization of rural communities and construction of pig housing have not been tested (probably due to economic and logistic costs) although it seems to be a very efficient strategy for many parasitic and infectious disease transmitted by faeces.

## **4. What must be done?**

98 Novel Aspects on Cysticercosis and Neurocysticercosis

**3. Strategies to eradicate the disease** 

3. Treatment of infected pigs [103, 114-116].

carriers [108-110].

efficient [105].

Regarding porcine cysticercosis, diagnosis based on tongue inspection has been conventionally used, but does not detect all affected pigs. Serology permits, although not with ideal sensibility and specificity, identification of the areas where the life-cycle of the parasite persists. Echography (ultrasound) has recently been introduced as a sensitive (95%) and specific (97%) method of diagnosis (Kappa coefficient of 90%) [102]. Treatment of

Diagnosis of the adult form of *T. solium* is perhaps the topic where more efforts must be made. Although a species-specific coproantigen ELISA was developed, reaching very good performance [104], further studies are required to evaluate it in field conditions. And this is not so easy, as prevalence of taeniosis seems to be much lower than that of cysticercosis, a fact understandable as one tapeworm carrier can infect hundreds of people and thousands of pigs. Treatment of taeniosis with niclosamide or praziquantel has shown to be very

In conclusion, although efforts must continue in some areas, today we have tools that allow the detection of endemic areas and the effective diagnosis and treatment of patients in most circumstances. This situation, adding to the existence of specific tools for prevention (vaccine), allows the design of extensive and effective preventive and control programs.

Cysticercosis is considered a neglected "tools-ready disease" according to WHO [106] and as a potentially eradicable disease since 1993 [107].This is feasible because there are no animal reservoirs besides humans and pigs, the only source of *T. solium* infection for pigs being humans (the definitive host), interrupting the parasite´s life cycle seems an easy task by

Different strategies have been proposed and tested, generally experimental and at small

1. Massive cestocidal treatment to humans in order to reduce the number of tapeworm

2. Health education programs aiming to promote the understanding of the mechanisms of transmission of the parasite and to improve hygienic behavior, pig-management and

4. Vaccination of rural pigs: different vaccines have been tested in field conditions and have demonstrated their efficacy in preventing swine cysticercosis [117-120]. 5. Combinations of different strategies: pig vaccination and treatment [121], massive human cestocidal treatment associated with pig vaccination and treatment [122,123]. Almost all these strategies have shown some degree of efficacy, this fact contrasting with the persistence of the parasite in all the endemic countries in the 1950's. It should be noted that, to our knowledge, programs promoting letrinization of rural communities and construction

intervention strategies acting upon different stages of the parasite´s development.

scale, to eradicate the (T/C) complex, the most notable being:

sanitary conditions which fosters transmission [111-113].

cysticercotic pigs with oxfendazole has shown a good efficiency [103].

This is a truly kafkian situation: we are in the presence of a parasite that causes a potentially severe human disease, as well as important economic losses; paradoxically, it is clear that the disease is potentially eradicable and, in fact, scientists and health authorities know how to eradicate it and have strategies to reach this goal. Despite all these resources, and their demonstrated effectiveness, the signs of a decrease of the transmission rate in the endemic countries are inconclusive or doubtful and, worse yet, in some non-endemic countries, an increase in the number of neurocysticercosis cases is occurring.

Faced with this perspective, it becomes evident that we will not attain the eradication of *T. solium* without:

## **4.1. The intervention of the national and international health authorities in control programs**

International initiatives have been concerned with the problem of cysticercosis for many years and several meetings were organised, the most important being: WHO Technical Consultation (Geneva, 1983), Pan American Health Organization (PAHO) Informal Consultation on Taeniasis/Cysticercosis (Porto Allegre, 1990), International Task Force for Disease Eradication (ITFDE, Atlanta, 1993), PAHO/WHO Informal Consultation on the Taeniasis/Cysticercosis Complex (Brasilia, 1995), North Atlantic Treaty Organization (NATO) Seminar on Emergent Helminth Zoonoses, (Pozna, 2000), Fifty-Fifth World Health Assembly, (Geneva, 2002), ITFDE II (Atlanta, 2003), WHO Expert Consultation on Foodborne Trematode Infections (Ventiane, 2009). In most of them, strategies for prevention and control of T/C were analyzed and recommendations were made. Since 2008, the WHO has included T/C in its Global Plan to combat Neglected Tropical diseases [124].

Regarding national health authorities, not much has been done. In very few countries, specific norms have been recommended. Such is the case of Latin America where only Mexico has an official norm for the vigilance, the prevention and the control of T/C in the first level of attention which was published in 1994 (modified in 2004) [125]. The Mexican norm includes the implementation of education and information programs, the identification and treatment of tapeworm carriers, the referral of subjects with suspected of NCC to a second level of attention, the confiscation of infected pigs, and the obligation to notify the diagnosed cases of NCC, taeniosis and swine cysticercosis to the corresponding authorities. The effort must be applauded, and has surely contributed to the awareness of the general population and of the medical personnel about the problem. Unfortunately, still, 15 years after its promulgation, cases of swine and human cysticercosis are still being diagnosed and not notified in Mexico. Probably, this is due to the fact that this norm did not

reach the rural zones where the life-cycle of *T. solium* is still active and notification is not equally honored by all professionals (or because there are no health facilities in these areas).

Control of *Taenia Solium* Transmission of Taeniosis and Cysticercosis in Endemic Countries:

As *T. solium* does not respect frontiers, it is necessary to organize multidisciplinary regional networks of specialists that must be the interlocutors of the local government and international organizations, and that must participate in the decision of where the preventive measures must be applied, and what type of measures are the most adequate regarding the individual





At the moment, although some objectives have been reached, their scope is still limited. To improve the situation, it is necessary: 1) to expand exchanges between the different networks; 2) to open ways of communication between these networks and the national and

In conclusion, to reach the control of *T.solium* infections it is very important to open new ways of communication between the scientists, grouped in networks, and with the international and the national health authorities. Agreements must be made in which the role and responsibilities of each of them are clearly defined. If one of these conditions fails,

and the implementation of preventive measures in the entire continent.

we are afraid that in 50 years, today's T/C epidemiological situation will persist.

*Peripheral Unit of the Institute of Biomedical Research in the National Neurology Institute,* 

characteristics of the country affected. Such efforts are currently established:

integrated research and control activities to combat cysticercosis.

**4.2. Implementation of regional networks** 

to be applied to effectively combat zoonoses.

America [128].

international authorities.

**Author details** 

Corresponding Author

*For the Ibero Latinamerican Cysticercosis Network* 

*National Autonomous University of Mexico, Mexico DF* 

Agnès Fleury\*

 \*

The Roles of Continental Networks of Specialists and of Local Health Authorities 101

It is important to promote the confiscation of infected pigs, but who is going to pay the owners, and who will go to the endemic communities (for example >2500 municipalities in Mexico) and make the diagnosis in more than six million rural pigs that get renewed every year? Clearly, pig owners must be included in a control program, for the obvious reason that they are the most interested in not having infected pigs.

It is highly relevant to promote the notification of infected individuals, but who will make this notification? Hospitals with an efficient epidemiologic department are scarce and medical doctors in public institutions are generally over loaded by the clinical workload. The comparison of the official statistics and the statistics published from only one hospital center can demonstrate the problem: in 2004, in the Instituto Nacional de Neurología y Neurocirugía, located in Mexico City, an institution that treats only patients lacking social security, 120 new cases of NCC were diagnosed [58], while in the official statistics, in this same year, approximately 400 new NCC cases were reported throughout Mexico [126]. It is very improbable that a sole institution accounts for a quarter of all the Mexican NCC cases, and probably this is due to a significant under-reporting of cases. Faced with this undesirable practice, what actions can the governments take? It is probably necessary: 1) to maintain a continuing health education program available to the population and the medical personnel, insisting on their obligation to notify the cases and promoting the establishment of epidemiological departments and surveillance system in all the hospitals, 2) to actively lobby for the implementation of a National Control Program that could be started as a priority in the areas from where most cases are referred. In relation to this point, the critical question is, who can organize a preventive program? The scientists probably not, as the logistics of such programs require an established structure supported by a recognized local authority. Since 2009, in Mexico, an extensive pilot control program is under way, in certain areas of the poorest states, based on health and sanitary education and associated with vaccination of pigs. Local authorities are part of the efforts, helping with the identification of the endemic areas, by furnishing sera collected from the pigs, and by funding the program. The results so far are encouraging. People in the remote areas accept suggestions for improvement in their pig raising methods and for their personal hygiene, including the indispensable installation of latrines [127]. What has become clear is that programs must be of long duration, at least 5 years. It is of little use to visit communities, give talks, vaccinate pigs and leave. People in theses "forgotten" areas need long-lasting help, advice and supervision. Therefore, without the active participation of the governments, failure of any control program is predictable because scientists cannot apply it at large enough scales and sufficient time. Finally, the presence of cysticercosis is an objective indicator of unacceptable conditions in a rural community, and their improvement will not only contribute to the eradication of cysticercosis, but will also bring collateral benefits, such as the control of other soil transmitted diseases and increased public awareness of respect for adequate simple public health measures.

## **4.2. Implementation of regional networks**

100 Novel Aspects on Cysticercosis and Neurocysticercosis

that they are the most interested in not having infected pigs.

awareness of respect for adequate simple public health measures.

reach the rural zones where the life-cycle of *T. solium* is still active and notification is not equally honored by all professionals (or because there are no health facilities in these areas). It is important to promote the confiscation of infected pigs, but who is going to pay the owners, and who will go to the endemic communities (for example >2500 municipalities in Mexico) and make the diagnosis in more than six million rural pigs that get renewed every year? Clearly, pig owners must be included in a control program, for the obvious reason

It is highly relevant to promote the notification of infected individuals, but who will make this notification? Hospitals with an efficient epidemiologic department are scarce and medical doctors in public institutions are generally over loaded by the clinical workload. The comparison of the official statistics and the statistics published from only one hospital center can demonstrate the problem: in 2004, in the Instituto Nacional de Neurología y Neurocirugía, located in Mexico City, an institution that treats only patients lacking social security, 120 new cases of NCC were diagnosed [58], while in the official statistics, in this same year, approximately 400 new NCC cases were reported throughout Mexico [126]. It is very improbable that a sole institution accounts for a quarter of all the Mexican NCC cases, and probably this is due to a significant under-reporting of cases. Faced with this undesirable practice, what actions can the governments take? It is probably necessary: 1) to maintain a continuing health education program available to the population and the medical personnel, insisting on their obligation to notify the cases and promoting the establishment of epidemiological departments and surveillance system in all the hospitals, 2) to actively lobby for the implementation of a National Control Program that could be started as a priority in the areas from where most cases are referred. In relation to this point, the critical question is, who can organize a preventive program? The scientists probably not, as the logistics of such programs require an established structure supported by a recognized local authority. Since 2009, in Mexico, an extensive pilot control program is under way, in certain areas of the poorest states, based on health and sanitary education and associated with vaccination of pigs. Local authorities are part of the efforts, helping with the identification of the endemic areas, by furnishing sera collected from the pigs, and by funding the program. The results so far are encouraging. People in the remote areas accept suggestions for improvement in their pig raising methods and for their personal hygiene, including the indispensable installation of latrines [127]. What has become clear is that programs must be of long duration, at least 5 years. It is of little use to visit communities, give talks, vaccinate pigs and leave. People in theses "forgotten" areas need long-lasting help, advice and supervision. Therefore, without the active participation of the governments, failure of any control program is predictable because scientists cannot apply it at large enough scales and sufficient time. Finally, the presence of cysticercosis is an objective indicator of unacceptable conditions in a rural community, and their improvement will not only contribute to the eradication of cysticercosis, but will also bring collateral benefits, such as the control of other soil transmitted diseases and increased public As *T. solium* does not respect frontiers, it is necessary to organize multidisciplinary regional networks of specialists that must be the interlocutors of the local government and international organizations, and that must participate in the decision of where the preventive measures must be applied, and what type of measures are the most adequate regarding the individual characteristics of the country affected. Such efforts are currently established:


At the moment, although some objectives have been reached, their scope is still limited. To improve the situation, it is necessary: 1) to expand exchanges between the different networks; 2) to open ways of communication between these networks and the national and international authorities.

In conclusion, to reach the control of *T.solium* infections it is very important to open new ways of communication between the scientists, grouped in networks, and with the international and the national health authorities. Agreements must be made in which the role and responsibilities of each of them are clearly defined. If one of these conditions fails, we are afraid that in 50 years, today's T/C epidemiological situation will persist.

## **Author details**

Agnès Fleury\* *For the Ibero Latinamerican Cysticercosis Network Peripheral Unit of the Institute of Biomedical Research in the National Neurology Institute, National Autonomous University of Mexico, Mexico DF* 

<sup>\*</sup> Corresponding Author

Edda Sciutto and Carlos Larralde *Immunology Department, Institute of Biomedical Research, National Autonomous University of Mexico, Mexico DF* 

Aline S. de Aluja *Department of Pathology, School of Veterinary Medicine and Zootecnies, National Autonomous University of Mexico, Mexico DF* 

Sonia Agudelo and Maria Garcia Gisela *Department of Parasitology, Academic Corporation for the Study of Tropical Pathologies, School of Medicine, Antioquia University, Medellin, Colombia* 

Control of *Taenia Solium* Transmission of Taeniosis and Cysticercosis in Endemic Countries:

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Jaime Fandiño and Randy Guerra *Latin America Research Center in Epilepsy, Cartagena, Colombia* 

Cáris Nunes and Samuel Carvalho de Aragão *School of Veterinary Medicine, University Estadual Paulista Julio de Mesquita Filho, Brazil* 

Marcello Sato *University Federal Do Tocantins, Brazil* 

Ronaldo Abraham *Medicine Department, Taubaté University, Brazil* 

Arturo Carpio *University of Cuenca, Ecuador* 

Franklin Santillan *Santa Ana Clinic, Cuenca, Ecuador* 

Maria Milagros Cortez A., Glenda Rojas and Elizabeth Ferrer *Biomedical Research Institute "Dr. Francisco J. Triana Alonso", Faculty of Health Sciences, University of Carabobo, Maracay, Venezuela* 

Cruz Manuel Aguilar *Tropical Diseases Research Center, University of Carabobo, San Carlos, Cjedes state, Venezuela* 

Juan Carlos Durán *Higher University of San Andrés, La Paz, Bolivia* 

Teresa Garate *Carlos III Institute of Health, National Center of Microbiology, Majadahonda, Madrid, Spain* 

R. Michael E. Parkhouse *Instituto Gulbenkian de Ciencias, Oeiras, Portugal* 

## **Acknowledgement**

The authors acknowledge the CYTED program (Ibero-American Programme for Science, Technology and Development) that has founded partially the network.

## **5. References**

102 Novel Aspects on Cysticercosis and Neurocysticercosis

Sonia Agudelo and Maria Garcia Gisela

Cáris Nunes and Samuel Carvalho de Aragão

*Medicine Department, Taubaté University, Brazil* 

Jaime Fandiño and Randy Guerra

*University Federal Do Tocantins, Brazil* 

*Immunology Department, Institute of Biomedical Research, National Autonomous University of Mexico, Mexico DF* 

*National Autonomous University of Mexico, Mexico DF* 

*School of Medicine, Antioquia University, Medellin, Colombia* 

*Latin America Research Center in Epilepsy, Cartagena, Colombia* 

Maria Milagros Cortez A., Glenda Rojas and Elizabeth Ferrer

*Department of Pathology, School of Veterinary Medicine and Zootecnies,* 

*Department of Parasitology, Academic Corporation for the Study of Tropical Pathologies,* 

*School of Veterinary Medicine, University Estadual Paulista Julio de Mesquita Filho, Brazil* 

*Biomedical Research Institute "Dr. Francisco J. Triana Alonso", Faculty of Health Sciences,* 

*Tropical Diseases Research Center, University of Carabobo, San Carlos, Cjedes state, Venezuela* 

*Carlos III Institute of Health, National Center of Microbiology, Majadahonda, Madrid, Spain* 

The authors acknowledge the CYTED program (Ibero-American Programme for Science,

Technology and Development) that has founded partially the network.

Edda Sciutto and Carlos Larralde

Aline S. de Aluja

Marcello Sato

Arturo Carpio

Franklin Santillan

Cruz Manuel Aguilar

Juan Carlos Durán

R. Michael E. Parkhouse

**Acknowledgement** 

Teresa Garate

Ronaldo Abraham

*University of Cuenca, Ecuador* 

*Santa Ana Clinic, Cuenca, Ecuador* 

*University of Carabobo, Maracay, Venezuela* 

*Higher University of San Andrés, La Paz, Bolivia* 

*Instituto Gulbenkian de Ciencias, Oeiras, Portugal* 


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**Chapter 6** 

© 2013 Foyaca Sibat et al., 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 Foyaca Sibat et al., 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.

**Orbital Cisticercosis. A Challenger** 

Humberto Foyaca Sibat, María Carolina Salazar Campos

and Lourdes de Fátima Ibañez Valdés

http://dx.doi.org/10.5772/52515

**1. Introduction** 

NCC (ESNCC).

cysticerci).

Additional information is available at the end of the chapter

**for Neurologists, Ophthalmologists, Neuro-**

**Opthalmologists, and General Practitioners** 

Cysticercosis is a disease closely related to poverty in general and in particular with a poor personal hygiene and food, socio-cultural factors, environmental, education for health in the community, and also very closely related to the hygienic and sanitary conditions of each region. This is a preventable and an eradicable disease [1] that currently affects more than 50 million people in the entire world, of which 400 thousand live in Latin America [2] is internationally accepted that the onset of epilepsy, intracranial hypertension or headache of unknown cause in a person originating, visitor or in contact with another person from an area where *T solium* is endemic suggests considering the diagnosis of NCC. The patient affected by the NCC can remain asymptomatic for several months or years, and its diagnosis can be confirmed by accident when a CT scan is carried out in search of another diagnosis. [3,4] According to WHO figures confirmed by Roman and collaborators [5] around 50 thousand people die each year as a result of the NCC and the epilepsy secondary to the

*Taenia solium* produces two different diseases: taeniasis (Te) and/or cysticercosis (CC). When the parasite is an adult expels its mature proglotides and eggs with the stool to the environment; the subsequent ingestion of these eggs of pork cause porcine cysticercosis (PCC). When a person swallows raw pork meat or not well cooked and infected with cysticerci (CT) then develops a new adult parasite. The human then becomes an accidental intermediate host. These oncosphere (primary larvae) penetrate the intestinal mucosa and enter the circulatory system. The Hematogenous spread of neural, muscular, and ocular tissues occurs. Within these tissues, the oncosphere develop into secondary larvae (i.e., the

