**Clinical, Laboratory and Ultrasonographic Evaluation of Patients with Acute Schistosomiasis Mansoni**

Matheus Fernandes Costa-Silva\*\*, Denise da Silveira-Lemos\*\*, Amanda Cardoso de Oliveira Silveira, Pedro Henrique Gazzinelli-Guimarães, Helena Barbosa Ferraz, Cristiano Lara Massara, Martin Johannes Enk, Maria Carolina Barbosa Álvares, Olindo Assis Martins-Filho, Paulo Marcos Zech Coelho, Rodrigo Corrêa-Oliveira, Giovanni Gazzinelli and Andréa Teixeira-Carvalho

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53047

## **1. Introduction**

Schistosomiasis is a parasite chronic disease caused by the helminth of genus *Schistosoma*. The infection is common in parts of Africa, South America, Middle East, Caribbean and Asia where it is a leading cause of morbidity and mortality [1]. Recent estimates suggest there are 700 million people at risk worldwide with almost 200 million infected in Africa alone [2]. In Brazil, the schistosomiasis infection is caused by *Schistosoma mansoni,* where estimates suggest a range from 2.5 million [3, 4] to 12 million people infected [5]. In the state of Minas Gerais, schistoso‐ miasis mansoni is prevalent in 519 out of 853 municipalities, with an estimated number of one million infected people in an area of 300.000 km² [6].

One of the greatest public health problems in countries where the disease is highly endemic, including Brazil, is schistosomiasis control for the following reasons: (a) large intermediary hosts dissemination and their escape mechanisms from molluscicides and from biological

© 2013 Costa-Silva\*\* et al.; licensee InTech. This is an open access article 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 The Author(s). Licensee InTech. This chapter is 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 due to high costs and low efficacy; (b) high charges associated with implementation of sanitary conditions and water supply and the intense contact of rural population with polluted water, as well as engagement in agricultural and fishing activities; (c) the long time needed for sanitary education and for the community to adhere to controlling programs; (d) individual or massive treatment has been shown efficient for controlling the morbidity, but not for reducing prevalence due to reinfection; (e) individual protection is unlikely, except for specific groups of exposed people; (f) until the current days, there is no effective vaccine for preventing schistosomiasis [7, 8].

acute and chronic schistosomiasis. In addition, Caldas et al [21] showed that specific IgG, IgM and IgE titers against egg and worm antigens in acute patients do not differ from those presented by chronic patients. Regarding cellular immunological events, nitric ox‐ ide (NO) represents an important and versatile messenger in biological systems, and it has been identified as a cytotoxic factor in the immune system, presenting anti- or proinflammatory properties under different circumstances [22]. Oliveira et al. [23] demon‐ strated that human peripheral blood mononuclear cells (PBMC) are capable of *in vitro* NO production and the inhibition of its production through the addition of N omega-ni‐ tro-L-arginine methyl ester (L-NAME) is responsible for an exacerbated granulomatous

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99

In this report, we evaluated the clinical/laboratorial parameters and ultrasonographic fea‐ tures of patients who suffered acute schistosomiasis resulting from a simultaneous expo‐ sure in a country house in the metropolitan area of Belo Horizonte, Minas Gerais State,

The patients evaluated in this study acquired the acute phase of *S. mansoni* infection in a country house in the rural district of the municipality of Igarapé in the metropolitan area of Belo Horizonte, Brazil. The country house is frequently leased during the weekends and long holidays. It is a large house with a pool of water supplied by a stream. Beside the pool, the water from the stream was channeled into open channels to form a shower. During the inspection of the country house, researchers at the Research Center Rene Ra‐ chou (CPqRR) – Oswaldo Cruz Foundation, at the Brazilian Ministry of Health detected that the place did not have basic sanitation. All the water used was damped, discarded in a dam located near the house. Out of forty-two individuals who were in the country house, thirty-eight participated in the study and were previously evaluated. After a pre‐ liminary assessment, we found that nineteen infected patients had been treated previous to our evaluation and five patients did not fulfill the inclusion criteria described below. Therefore, these patients were excluded from the study apart from other four subjects who had negative stool examination for *S. mansoni*. Thus, the group of patients evaluat‐ ed was composed by ten individuals, five women and five men, aging 14 to 31 years,

To participate in the study, patients in the acute phase of schistosomiasis have fulfilled the following criteria for inclusion: age between 10 and 65 years; did not report having received any treatment with anti-helminthic drugs in the last 24 months; diagnosis of acute schistosomiasis mansoni based on epidemiological data (recent contact with *S. man‐ soni* cercariae-contaminated water), clinical symptoms (acute enterocolitis, nausea, vomit‐ ing, abdominal pain, fever, headache, weight loss, cough, cercarial dermatitis, hepatomegaly and splenomegaly) and laboratory data (eosinophilia and viable *S. mansoni*

with parasite load ranging from 8 to 768 eggs per gram of feces (epg).

reaction.

Brazil.

**2.1. Study population**

**2. Population, materials and methods**

According to previous data published by our group [9, 10], the proliferation of rural tourism in endemic areas may be an important contributing factor to the outbreak of schistosomiasis cases. The preservation of natural environment on the site, in order to at‐ tract visitors from urban centers, unintentionally contributes to create an ideal habitat for the intermediate host. Additionally, most areas chosen for leisure activities accommodate rural communities without any type of sanitation and, thus, represent a permanent risk of contamination of the flowing water.

In this context, visitors from urban areas, who never had previous contact with the parasite, contract the infection, and develop acute schistosomiasis [11]. Acute schistosomiasis is associated with a primary exposure and is more commonly seen in non-immune individuals traveling through endemic regions [12]. The clinical symptoms most commonly observed in such patients include fever, general weakness, headache, nausea, vomiting, diarrhea, anorexia, colic, weight loss, dry cough and hepatosplenomegaly accompanied by marked eosinophilia and leucocytosis [13-16]. However, these clinical symptoms may be confused with a number of infections such as visceral leishmaniasis, typhoid fever, malaria, tuberculosis, viral hepatitis, mononucleosis and bacterial infections [17]. Hence, the diagnosis of acute schistosomiasis becomes a challenge for the assistant doctor due to the wide diversity of non-specific symptoms presented by the patients; in addition, the presence of eggs in stool may not to be easily detected by parasitological examination in this phase of the infection.

Abdominal ultrasound is a complementary tool often used to assist the diagnoses of the *S. mansoni* infection, mainly on the study of the liver damage caused by the chronic in‐ fection. It is an inexpensive method, not radioactive or invasive, which provides immedi‐ ate results and can be used for epidemiological fieldwork in endemic areas. The hepatic ultrasound pattern in patients with severe hepatosplenic schistosomiasis is characterized by pronounced periportal thickening. However, reports of ultrasound studies in patients with acute schistosomiasis are still scarce [18], and additional trials are necessary to eval‐ uate the benefits and limitations of the ultrasound as a tool of clinical evaluation at the acute phase of the *S. mansoni* infection [19].

From the immunological point of view, the acute phase of the infection is characterized by a series of humoral and cellular immunological events. Hiatt et al. [20] showed eleva‐ tions of IgG, IgM, IgE, and high titers of total antibodies in serum of acute patients that indicated the illness is associated with intense immune activity, while the magnitude of the IgE responses was related to the intensity of the infection. De Jesus et al. [16] showed that there was no significant difference in total IgE level between patients with acute and chronic schistosomiasis. In addition, Caldas et al [21] showed that specific IgG, IgM and IgE titers against egg and worm antigens in acute patients do not differ from those presented by chronic patients. Regarding cellular immunological events, nitric ox‐ ide (NO) represents an important and versatile messenger in biological systems, and it has been identified as a cytotoxic factor in the immune system, presenting anti- or proinflammatory properties under different circumstances [22]. Oliveira et al. [23] demon‐ strated that human peripheral blood mononuclear cells (PBMC) are capable of *in vitro* NO production and the inhibition of its production through the addition of N omega-ni‐ tro-L-arginine methyl ester (L-NAME) is responsible for an exacerbated granulomatous reaction.

In this report, we evaluated the clinical/laboratorial parameters and ultrasonographic fea‐ tures of patients who suffered acute schistosomiasis resulting from a simultaneous expo‐ sure in a country house in the metropolitan area of Belo Horizonte, Minas Gerais State, Brazil.

## **2. Population, materials and methods**

#### **2.1. Study population**

control due to high costs and low efficacy; (b) high charges associated with implementation of sanitary conditions and water supply and the intense contact of rural population with polluted water, as well as engagement in agricultural and fishing activities; (c) the long time needed for sanitary education and for the community to adhere to controlling programs; (d) individual or massive treatment has been shown efficient for controlling the morbidity, but not for reducing prevalence due to reinfection; (e) individual protection is unlikely, except for specific groups of exposed people; (f) until the current days, there is no effective vaccine for preventing

According to previous data published by our group [9, 10], the proliferation of rural tourism in endemic areas may be an important contributing factor to the outbreak of schistosomiasis cases. The preservation of natural environment on the site, in order to at‐ tract visitors from urban centers, unintentionally contributes to create an ideal habitat for the intermediate host. Additionally, most areas chosen for leisure activities accommodate rural communities without any type of sanitation and, thus, represent a permanent risk

In this context, visitors from urban areas, who never had previous contact with the parasite, contract the infection, and develop acute schistosomiasis [11]. Acute schistosomiasis is associated with a primary exposure and is more commonly seen in non-immune individuals traveling through endemic regions [12]. The clinical symptoms most commonly observed in such patients include fever, general weakness, headache, nausea, vomiting, diarrhea, anorexia, colic, weight loss, dry cough and hepatosplenomegaly accompanied by marked eosinophilia and leucocytosis [13-16]. However, these clinical symptoms may be confused with a number of infections such as visceral leishmaniasis, typhoid fever, malaria, tuberculosis, viral hepatitis, mononucleosis and bacterial infections [17]. Hence, the diagnosis of acute schistosomiasis becomes a challenge for the assistant doctor due to the wide diversity of non-specific symptoms presented by the patients; in addition, the presence of eggs in stool may not to be easily detected

Abdominal ultrasound is a complementary tool often used to assist the diagnoses of the *S. mansoni* infection, mainly on the study of the liver damage caused by the chronic in‐ fection. It is an inexpensive method, not radioactive or invasive, which provides immedi‐ ate results and can be used for epidemiological fieldwork in endemic areas. The hepatic ultrasound pattern in patients with severe hepatosplenic schistosomiasis is characterized by pronounced periportal thickening. However, reports of ultrasound studies in patients with acute schistosomiasis are still scarce [18], and additional trials are necessary to eval‐ uate the benefits and limitations of the ultrasound as a tool of clinical evaluation at the

From the immunological point of view, the acute phase of the infection is characterized by a series of humoral and cellular immunological events. Hiatt et al. [20] showed eleva‐ tions of IgG, IgM, IgE, and high titers of total antibodies in serum of acute patients that indicated the illness is associated with intense immune activity, while the magnitude of the IgE responses was related to the intensity of the infection. De Jesus et al. [16] showed that there was no significant difference in total IgE level between patients with

schistosomiasis [7, 8].

98 Parasitic Diseases - Schistosomiasis

of contamination of the flowing water.

by parasitological examination in this phase of the infection.

acute phase of the *S. mansoni* infection [19].

The patients evaluated in this study acquired the acute phase of *S. mansoni* infection in a country house in the rural district of the municipality of Igarapé in the metropolitan area of Belo Horizonte, Brazil. The country house is frequently leased during the weekends and long holidays. It is a large house with a pool of water supplied by a stream. Beside the pool, the water from the stream was channeled into open channels to form a shower. During the inspection of the country house, researchers at the Research Center Rene Ra‐ chou (CPqRR) – Oswaldo Cruz Foundation, at the Brazilian Ministry of Health detected that the place did not have basic sanitation. All the water used was damped, discarded in a dam located near the house. Out of forty-two individuals who were in the country house, thirty-eight participated in the study and were previously evaluated. After a pre‐ liminary assessment, we found that nineteen infected patients had been treated previous to our evaluation and five patients did not fulfill the inclusion criteria described below. Therefore, these patients were excluded from the study apart from other four subjects who had negative stool examination for *S. mansoni*. Thus, the group of patients evaluat‐ ed was composed by ten individuals, five women and five men, aging 14 to 31 years, with parasite load ranging from 8 to 768 eggs per gram of feces (epg).

To participate in the study, patients in the acute phase of schistosomiasis have fulfilled the following criteria for inclusion: age between 10 and 65 years; did not report having received any treatment with anti-helminthic drugs in the last 24 months; diagnosis of acute schistosomiasis mansoni based on epidemiological data (recent contact with *S. man‐ soni* cercariae-contaminated water), clinical symptoms (acute enterocolitis, nausea, vomit‐ ing, abdominal pain, fever, headache, weight loss, cough, cercarial dermatitis, hepatomegaly and splenomegaly) and laboratory data (eosinophilia and viable *S. mansoni* eggs in stool). Each volunteer or their legal guardian signed their informed consent. In addition, we also excluded from this study all patients who had one of the following conditions: unable to hold examinations proposed; alcoholism, defined as above average weekly consumption of 420 grams of ethanol (daily average over 60 g of ethanol) [24]; pregnancy, defined by laboratory criteria; significant anemia defined as hemoglobin less than 10 g/dl [25] and any other significant systemic disease, acute or chronic, that could interfere with the results of the proposed methods.

praziquantel. The hemograms were performed in automated hematological electronic counter (Coulter MD18, E.U.A). The parameters measured were hemoglobin, number of erythrocytes and hematocrit values as well as total and differential counts of leukocytes including absolute

Clinical, Laboratory and Ultrasonographic Evaluation of Patients with Acute Schistosomiasis Mansoni

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101

The plasma levels of total IgE antibodies were quantified using *Colorimetric Immunoenzy‐ matic kit* (SYM Total IgE, Symbiosis Diagnostic, Brazil). Aliquots of 25 μL of plasma and six standards (Reagent kit SYM Total IgE Symbiosis Diagnostic, Brazil) at concentrations of 0, 5, 25, 50, 150 and 400UI/mL were dispensed in duplicates in wells of flat-bottomed plates, previously sensitized with streptavidin, together with 100 μL of monoclonal antihuman IgE conjugated to biotin (Reagent kit SYM Total IgE Symbiosis Diagnostic, Bra‐ zil). The plates were incubated for 30 minutes at room temperature in the dark and washed five times with 300 μL/well of wash solution (Reagent kit SYM Total IgE Sym‐ biosis Diagnostic, Brazil). Subsequently were added 100 μL of a second monoclonal antihuman IgE conjugated to peroxidase. The plates were incubated for 30 minutes at room temperature, in the dark, and washed five times with 300 μL/well of wash solution. Then, 100 μL of chromogen-substrate solution (tetramethylbenzidine-TMB) (Reagent kit SYM Total IgE Symbiosis Diagnostic, Brazil) were added by well, and the plate was in‐ cubated for 15 minutes in the dark. The reaction was stopped by adding 100 μL of 1N sulfuric acid (H2SO4) per well (Reagent kit SYM Total IgE Symbiosis Diagnostic, Brazil). The optical density of samples and standards was measured in an automatic reader (Mo‐

The plasma levels of nitric oxide were quantified using *Immunoenzymatic kit QuantiChromTM Nitric Oxide* (Quantitative Colorimetric Determination of Nitric Oxide, BioAssay Systems, USA). The assays were performed according to the manufacturer's recommendations. The deproteination of samples was made by adding 80 mL of zinc sulfate (ZnSO4) 75 mM final concentration and 120 mL of sodium hydroxide (NaOH) 55 mM final concentration. Samples were centrifuged at 400 g for 5 minutes at 4°C. Then 70 mL of glycine buffer was added in each sample. Afterwards, aliquots of 100 μL of plasma and eight standards at concentrations of 0, 5, 10, 15, 20, 30, 40 and 50 μM mL were dispensed in duplicates in 1.5 mL tubes. Then, samples were placed in the presence of cadmium activated with 200 mL of Buffer Activation and incubated for 15 minutes. The samples were transferred in duplicates to their respective wells in flat-bottomed plates and added to 50 mL of reagents A and B. The optical density of samples and standards was measured in an automatic reader (Molecular Devices Reader-Precision,

For the analysis of hepatic functions for the study group, plasma concentration of the en‐ zymes ALT (alaline amino transferase), AST (aspartate amino transferase) and γ-GT

counts of eosinophils, neutrophils, lymphocytes and monocytes.

lecular Devices Versa Max, California, USA) using a 450 nm filter.

**2.5. Total IgE measurement**

**2.6. Nitric oxide plasma levels**

USA) using a 540 nm filter.

**2.7. Evaluation of hepatic enzymes**

After blood collection, all patients who had positive stool examination for *S. mansoni*, regard‐ less of participation in the study, were submitted to treatment with the standard Brazilian dose of Praziquantel (50-60 mg/kg).

A group of healthy volunteers formed by nine individuals, one woman and eight men aged 25 to 42 years, blood donors of the blood bank of Hospital Felicio Rocho, Belo Horizonte, Minas Gerais, Brazil constituted a control group (CT). It is important to mention that these individuals were screened and selected after serological tests for negativity for Chagas disease, leishma‐ niasis, human immunodeficiency virus (HIV), hepatitis, and did not report previous infection with *S. mansoni*.

The study was carried out according to the National Health Council resolution 196/96, which regulates the research involving human beings, and was approved by the Ethics Committees of the Faculty of Medicine, Federal University of Minas Gerais, Oswaldo Cruz Foundation, and the Brazilian National Committee on Ethics in Research.

#### **2.2. Parasitological examination**

Parasitological examination was performed using the Kato-Katz method [26]. The presence and the number of *S. mansoni* eggs per gram of feces were determined through examination of six blades per one stool sample for each patient. The results are presented as the arithmetic mean of number of eggs. The Kato-Katz method is the method of choice to measure infection level and has been used extensively in epidemiological studies.

#### **2.3. Evaluation of clinical parameters**

All the individuals who came into contact with water contaminated by cercariae were subjected to a detailed history, performed by a physician of our team. The survey used during this study contained data referring to number of the protocol, name, gender, age, education and place of birth and questions about the clinical symptoms/signs such as fever, diarrhea, nausea, vomiting, abdominal pain, cough, weight loss, headache, asthenia, facial edema and cercarial dermatitis.

#### **2.4. Evaluation of hematological parameters**

Peripheral blood was collected in 5 mL vacuum tubes containing ethylenediamine tetraacetic acid (EDTA) as anticoagulant (Vacutainer, Beckton Dickinson, CA, USA), approximately 40 days after contact with contaminated water by cercariae and only once prior to treatment with praziquantel. The hemograms were performed in automated hematological electronic counter (Coulter MD18, E.U.A). The parameters measured were hemoglobin, number of erythrocytes and hematocrit values as well as total and differential counts of leukocytes including absolute counts of eosinophils, neutrophils, lymphocytes and monocytes.

## **2.5. Total IgE measurement**

eggs in stool). Each volunteer or their legal guardian signed their informed consent. In addition, we also excluded from this study all patients who had one of the following conditions: unable to hold examinations proposed; alcoholism, defined as above average weekly consumption of 420 grams of ethanol (daily average over 60 g of ethanol) [24]; pregnancy, defined by laboratory criteria; significant anemia defined as hemoglobin less than 10 g/dl [25] and any other significant systemic disease, acute or chronic, that could

After blood collection, all patients who had positive stool examination for *S. mansoni*, regard‐ less of participation in the study, were submitted to treatment with the standard Brazilian dose

A group of healthy volunteers formed by nine individuals, one woman and eight men aged 25 to 42 years, blood donors of the blood bank of Hospital Felicio Rocho, Belo Horizonte, Minas Gerais, Brazil constituted a control group (CT). It is important to mention that these individuals were screened and selected after serological tests for negativity for Chagas disease, leishma‐ niasis, human immunodeficiency virus (HIV), hepatitis, and did not report previous infection

The study was carried out according to the National Health Council resolution 196/96, which regulates the research involving human beings, and was approved by the Ethics Committees of the Faculty of Medicine, Federal University of Minas Gerais, Oswaldo Cruz Foundation,

Parasitological examination was performed using the Kato-Katz method [26]. The presence and the number of *S. mansoni* eggs per gram of feces were determined through examination of six blades per one stool sample for each patient. The results are presented as the arithmetic mean of number of eggs. The Kato-Katz method is the method of choice to measure infection

All the individuals who came into contact with water contaminated by cercariae were subjected to a detailed history, performed by a physician of our team. The survey used during this study contained data referring to number of the protocol, name, gender, age, education and place of birth and questions about the clinical symptoms/signs such as fever, diarrhea, nausea, vomiting, abdominal pain, cough, weight loss, headache, asthenia, facial edema and

Peripheral blood was collected in 5 mL vacuum tubes containing ethylenediamine tetraacetic acid (EDTA) as anticoagulant (Vacutainer, Beckton Dickinson, CA, USA), approximately 40 days after contact with contaminated water by cercariae and only once prior to treatment with

interfere with the results of the proposed methods.

and the Brazilian National Committee on Ethics in Research.

level and has been used extensively in epidemiological studies.

of Praziquantel (50-60 mg/kg).

100 Parasitic Diseases - Schistosomiasis

**2.2. Parasitological examination**

**2.3. Evaluation of clinical parameters**

**2.4. Evaluation of hematological parameters**

cercarial dermatitis.

with *S. mansoni*.

The plasma levels of total IgE antibodies were quantified using *Colorimetric Immunoenzy‐ matic kit* (SYM Total IgE, Symbiosis Diagnostic, Brazil). Aliquots of 25 μL of plasma and six standards (Reagent kit SYM Total IgE Symbiosis Diagnostic, Brazil) at concentrations of 0, 5, 25, 50, 150 and 400UI/mL were dispensed in duplicates in wells of flat-bottomed plates, previously sensitized with streptavidin, together with 100 μL of monoclonal antihuman IgE conjugated to biotin (Reagent kit SYM Total IgE Symbiosis Diagnostic, Bra‐ zil). The plates were incubated for 30 minutes at room temperature in the dark and washed five times with 300 μL/well of wash solution (Reagent kit SYM Total IgE Sym‐ biosis Diagnostic, Brazil). Subsequently were added 100 μL of a second monoclonal antihuman IgE conjugated to peroxidase. The plates were incubated for 30 minutes at room temperature, in the dark, and washed five times with 300 μL/well of wash solution. Then, 100 μL of chromogen-substrate solution (tetramethylbenzidine-TMB) (Reagent kit SYM Total IgE Symbiosis Diagnostic, Brazil) were added by well, and the plate was in‐ cubated for 15 minutes in the dark. The reaction was stopped by adding 100 μL of 1N sulfuric acid (H2SO4) per well (Reagent kit SYM Total IgE Symbiosis Diagnostic, Brazil). The optical density of samples and standards was measured in an automatic reader (Mo‐ lecular Devices Versa Max, California, USA) using a 450 nm filter.

## **2.6. Nitric oxide plasma levels**

The plasma levels of nitric oxide were quantified using *Immunoenzymatic kit QuantiChromTM Nitric Oxide* (Quantitative Colorimetric Determination of Nitric Oxide, BioAssay Systems, USA). The assays were performed according to the manufacturer's recommendations. The deproteination of samples was made by adding 80 mL of zinc sulfate (ZnSO4) 75 mM final concentration and 120 mL of sodium hydroxide (NaOH) 55 mM final concentration. Samples were centrifuged at 400 g for 5 minutes at 4°C. Then 70 mL of glycine buffer was added in each sample. Afterwards, aliquots of 100 μL of plasma and eight standards at concentrations of 0, 5, 10, 15, 20, 30, 40 and 50 μM mL were dispensed in duplicates in 1.5 mL tubes. Then, samples were placed in the presence of cadmium activated with 200 mL of Buffer Activation and incubated for 15 minutes. The samples were transferred in duplicates to their respective wells in flat-bottomed plates and added to 50 mL of reagents A and B. The optical density of samples and standards was measured in an automatic reader (Molecular Devices Reader-Precision, USA) using a 540 nm filter.

#### **2.7. Evaluation of hepatic enzymes**

For the analysis of hepatic functions for the study group, plasma concentration of the en‐ zymes ALT (alaline amino transferase), AST (aspartate amino transferase) and γ-GT (gamma-glutamyl transferase) were quantified by kinetic method using *ALT/GPT Liqui‐ form, AST/GOT Liquiform and GAMA GT Liquiform kits* (Labtest Diagnostic, Brazil) in the device Wiener Lab Metrolab 2300 plus (Model CM-200). The results were expressed in UI/mL.

**Parameter**

*Age*

*Gender*

*Parasitological Examination*

*Egg counts (eggs/g of feces)*

**Table 1.** Characterization of the study population

**3.2. Clinical manifestations**

dermatitis (both 10.0%).

**Subjects**

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103

Clinical, Laboratory and Ultrasonographic Evaluation of Patients with Acute Schistosomiasis Mansoni

**Total individuals Evaluated individuals Acute patients**

*Number of subjects (%)* 42 (100%) 38 (90.5%) 10 (23.8%)

Range 01 - 65 01 - 65 14 - 31

Mean ± SD 22.4 ± 15.2 22.5 ± 15.5 21.4 ± 6.2

Female 25 (59.5%) 22 (57.9%) 05 (50.0%)

Male 17 (40.5%) 16 (42.1%) 05 (50.0%)

Negative **----** 04 (10.5%) 0

Positive **----** 34 (89.5%) 10 (100%)

Range **----** 0 - 768 8 - 768

Median **----** 10.0 86.0

Mean ± SD **----** 50.8 ± 132.2 152.0 ± 224.7

The magnitude of clinical manifestations of schistosomiasis varies from light to severe intensity. Two patients showed serious clinical symptoms and required hospitalization due to the severity of the disease. The patients reported the onset of symptoms 20-30 days after water exposure. Headache and fever (60.0% and 50.0%, respectively) were the most common symptoms among patients, followed by diarrhea and weight loss (both 40.0%). Other clinical symptoms/signals were also recorded such as nausea/vomiting, abdominal pain, cough, asthenia, facial edema (each one with frequency of 30.0%) as well as urticaria and cercarial

Table 2 highlights the main features observed in different human studies evaluating acute phase of schistosomiasis mansoni performed in distinct brazilian states such as Pernambuco,

Median 21.5 20.5 22.5

### **2.8. Ultrasonographic analysis**

Ultrasonographic evaluation was performed using a Nemio SSA/550ª machine (Toshiba, Town, Japan) with a 3-MHz sector probe for patients ≥ 10 years old and a 5-MHz probe for patients under 10 years old. The group of healthy individuals non-infected with *S. mansoni* (CT group) consisted of twelve volunteers, paired by sex and age with the in‐ fected patients. Seven acute patients, three women and four men aged 14 to 31 years old have had ultrasonographic evaluation. All study population was examined by the same physician (MCBA). Liver size, portal-vein diameter, thickness of the central walls and pe‐ ripheral portal branches, spleen size and splenic vein diameters were assessed as descri‐ bed [27, 28]. The liver was also examined for surface smoothness. Portal vein diameter was measured at its entrance into the liver and its bifurcation inside the liver. The spleen was evaluated by using oblique and longitudinal scanning of the left upper quad‐ rant. The gallbladder was examined for wall thickness and stones. The periportal thick‐ ness was evaluated according to previous established criteria by [27-29].

#### **2.9. Statistical analysis**

The statistical analysis of the data was made through GraphPad PRISM® 5.00 software release for Windows (La Jolla, CA, USA). Student's t test was used for parametric data comparison between two groups, while for non-parametric data we used the Mann-Whitney test. In all cases, the data were considered significant at P < 0.05.

## **3. Results**

#### **3.1. Demographic data and intensity of S. mansoni infection**

Out of forty-two people who were present in the country house, thirty-eight (90.5%) partici‐ pated in this study and reported contact with water contaminated with cercariae. Out of these, thirty-four (89.5%) had eggs of *S*. *mansoni* in their feces and four (10.5%) were repeatedly negative. According to criteria previously mentioned, twenty-four patients were excluded from the study and ten patients were considered to be on an ongoing acute phase of schisto‐ somiasis. In the acute group (ACT), there were no significant differences in age between females and males (23.0 ± 7.8 and 19.8 ± 4.5 years old, respectively, p value = 0.45) and the intensity of infection did not differ regarding gender, (205.6 ± 318.5 and 98.4 ± 70.7 eggs/g of feces, respectively, P value = 0.50). The ACT group presented parasite load ranging from 8 to 768 eggs per gram of feces (152.0 ± 224.7).


**Table 1.** Characterization of the study population

#### **3.2. Clinical manifestations**

(gamma-glutamyl transferase) were quantified by kinetic method using *ALT/GPT Liqui‐ form, AST/GOT Liquiform and GAMA GT Liquiform kits* (Labtest Diagnostic, Brazil) in the device Wiener Lab Metrolab 2300 plus (Model CM-200). The results were expressed in

Ultrasonographic evaluation was performed using a Nemio SSA/550ª machine (Toshiba, Town, Japan) with a 3-MHz sector probe for patients ≥ 10 years old and a 5-MHz probe for patients under 10 years old. The group of healthy individuals non-infected with *S. mansoni* (CT group) consisted of twelve volunteers, paired by sex and age with the in‐ fected patients. Seven acute patients, three women and four men aged 14 to 31 years old have had ultrasonographic evaluation. All study population was examined by the same physician (MCBA). Liver size, portal-vein diameter, thickness of the central walls and pe‐ ripheral portal branches, spleen size and splenic vein diameters were assessed as descri‐ bed [27, 28]. The liver was also examined for surface smoothness. Portal vein diameter was measured at its entrance into the liver and its bifurcation inside the liver. The spleen was evaluated by using oblique and longitudinal scanning of the left upper quad‐ rant. The gallbladder was examined for wall thickness and stones. The periportal thick‐

The statistical analysis of the data was made through GraphPad PRISM® 5.00 software release for Windows (La Jolla, CA, USA). Student's t test was used for parametric data comparison between two groups, while for non-parametric data we used the Mann-Whitney test. In all

Out of forty-two people who were present in the country house, thirty-eight (90.5%) partici‐ pated in this study and reported contact with water contaminated with cercariae. Out of these, thirty-four (89.5%) had eggs of *S*. *mansoni* in their feces and four (10.5%) were repeatedly negative. According to criteria previously mentioned, twenty-four patients were excluded from the study and ten patients were considered to be on an ongoing acute phase of schisto‐ somiasis. In the acute group (ACT), there were no significant differences in age between females and males (23.0 ± 7.8 and 19.8 ± 4.5 years old, respectively, p value = 0.45) and the intensity of infection did not differ regarding gender, (205.6 ± 318.5 and 98.4 ± 70.7 eggs/g of feces, respectively, P value = 0.50). The ACT group presented parasite load ranging from 8 to

ness was evaluated according to previous established criteria by [27-29].

cases, the data were considered significant at P < 0.05.

768 eggs per gram of feces (152.0 ± 224.7).

**3.1. Demographic data and intensity of S. mansoni infection**

UI/mL.

**2.8. Ultrasonographic analysis**

102 Parasitic Diseases - Schistosomiasis

**2.9. Statistical analysis**

**3. Results**

The magnitude of clinical manifestations of schistosomiasis varies from light to severe intensity. Two patients showed serious clinical symptoms and required hospitalization due to the severity of the disease. The patients reported the onset of symptoms 20-30 days after water exposure. Headache and fever (60.0% and 50.0%, respectively) were the most common symptoms among patients, followed by diarrhea and weight loss (both 40.0%). Other clinical symptoms/signals were also recorded such as nausea/vomiting, abdominal pain, cough, asthenia, facial edema (each one with frequency of 30.0%) as well as urticaria and cercarial dermatitis (both 10.0%).

Table 2 highlights the main features observed in different human studies evaluating acute phase of schistosomiasis mansoni performed in distinct brazilian states such as Pernambuco, Sergipe and Minas Gerais. Although in these studies the frequency of exposed/infected individuals was similar ranging 90-100% and the incubation period has also occurred in comparable times such 20-30 days, we have observed strongly heterogeneous symptoms between them. Nonetheless, our study demonstrated some similar clinical symptoms in comparison to those found by Barbosa et al. 2001b [30] like the frequency of fever (50.0% and 54.0%, respectively), cough (30.0% and 33.0%, respectively) and urticaria (10.0% and 8.0%, respectively). However, other parameters presented distinct results like the frequency of headache (60.0% and 33.0%, respectively) and diarrhea (40.0% and 25.0%, respectively).

**3.3. Plasma levels of total IgE and nitric oxide**

**3.4. Hematological profile**

ces (connecting lines) were considered at *P* < 0.05.

monocytes.

increase of these parameters as compared with the CT group.

The plasma levels of total IgE and nitric oxide from the ACT group are illustrated in Figure 1. The analysis of the results showed that the ACT group presented a significant (*P* < 0.05)

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The main findings related to the hematological profile from the ACT group are illustrated in Figures 2 and 3. The analysis showed a significant reduction in the concentration of hemoglo‐ bin in the ACT group as well as an increase in the total leukocytes count as compared with the CT group. Increased total leukocytes were reflected in the absolute values of lymphocytes and eosinophils also increased in the ACT group as compared with the CT group. No significant difference was found between these two groups regarding other analyzed parameters such as number of erythrocytes, percentage of hematocrit, and absolute values of neutrophils and

**Figure 1.** Total plasma IgE and nitric oxide (NO) levels in acute schistosomiasis patients (ACT=10) and non-infected individuals (CT=09). The results are expressed in box-plot format. The box stretches from the lower hinge (defined as the 25th percentile) to the upper hinge (the 75th percentile) and therefore contains the middle half of the scores in the distribution. The median is shown as a line across the box. Therefore 1/4 of the distribution is between this line and the top of the box and 1/4 of the distribution is between this line and the bottom of the box. Significant differen‐


**Table 2.** Main features observed in different human studies evaluating the acute phase of schistosomiasis mansoni

## **3.3. Plasma levels of total IgE and nitric oxide**

The plasma levels of total IgE and nitric oxide from the ACT group are illustrated in Figure 1. The analysis of the results showed that the ACT group presented a significant (*P* < 0.05) increase of these parameters as compared with the CT group.

## **3.4. Hematological profile**

Sergipe and Minas Gerais. Although in these studies the frequency of exposed/infected individuals was similar ranging 90-100% and the incubation period has also occurred in comparable times such 20-30 days, we have observed strongly heterogeneous symptoms between them. Nonetheless, our study demonstrated some similar clinical symptoms in comparison to those found by Barbosa et al. 2001b [30] like the frequency of fever (50.0% and 54.0%, respectively), cough (30.0% and 33.0%, respectively) and urticaria (10.0% and 8.0%, respectively). However, other parameters presented distinct results like the frequency of headache (60.0% and 33.0%, respectively) and diarrhea (40.0% and 25.0%, respectively).

> **Barbosa Et Al. 2001b [30]**

Escada Pernambuco

15-30 20 20-30 20-30

36% N.E. 38% N.L.

**Number of patients 11 12 31 10**

Exposed/infected 92% 100% 92% 90%

Headache 36% 33% 87% 60%

Fever 100% 54% 90% 50%

Diarrhea 64% 25% 81% 40%

Cough 91% 33% 91% 30%

Abdominal pain 64% N.E. 93% 30%

Urticaria 18% 08% N.E. 10%

Cercarial dermatitis 100% N.E. N.E. 10%

Hepatomegaly 75% N.E. 35% 86%

**Table 2.** Main features observed in different human studies evaluating the acute phase of schistosomiasis mansoni

**De Jesus Et Al.**

Aracaju Sergipe

**2002 [16] This Study**

Igarapé Minas Gerais

**Parameters**

104 Parasitic Diseases - Schistosomiasis

Site/State

(days)

Incubation period

Transaminases (increase)

N.E. - not evaluated N.L. - normal levels

**Barbosa Et Al. 2001a [15]**

Ilha de Itamaracá Pernambuco

The main findings related to the hematological profile from the ACT group are illustrated in Figures 2 and 3. The analysis showed a significant reduction in the concentration of hemoglo‐ bin in the ACT group as well as an increase in the total leukocytes count as compared with the CT group. Increased total leukocytes were reflected in the absolute values of lymphocytes and eosinophils also increased in the ACT group as compared with the CT group. No significant difference was found between these two groups regarding other analyzed parameters such as number of erythrocytes, percentage of hematocrit, and absolute values of neutrophils and monocytes.

**Figure 1.** Total plasma IgE and nitric oxide (NO) levels in acute schistosomiasis patients (ACT=10) and non-infected individuals (CT=09). The results are expressed in box-plot format. The box stretches from the lower hinge (defined as the 25th percentile) to the upper hinge (the 75th percentile) and therefore contains the middle half of the scores in the distribution. The median is shown as a line across the box. Therefore 1/4 of the distribution is between this line and the top of the box and 1/4 of the distribution is between this line and the bottom of the box. Significant differen‐ ces (connecting lines) were considered at *P* < 0.05.

**Figure 2.** Hematological profile (hemoglobin-g/dL, erythrocytes/mm3 and percentage of hematocrit) from acute schistosomiasis patients (ACT=10) and non-infected individuals (CT=09). The results are expressed in box-plot format. The box stretches from the lower hinge (defined as the 25th percentile) to the upper hinge (the 75th percentile) and therefore contains the middle half of the scores in the distribution. The median is shown as a line across the box. Therefore 1/4 of the distribution is between this line and the top of the box and 1/4 of the distribution is between this line and the bottom of the box. Significant differences (connecting lines) were considered at *P* < 0.05.

**Figure 3.** Total and differential leukocyte counts from acute schistosomiasis patients (ACT=10) and non-infected indi‐ viduals (CT=09). The results are expressed in box-plot format highlighting the gap of 50% of data set measurement for absolute values in mm3 of each leukocyte subset analyzed. Significant differences (connecting lines) were consid‐

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Acute patients presented levels of ALT, AST and γ-GT enzymes similar to reference values and there were no significant differences between these levels and those presented by CT

ered at *P* < 0.05.

group. (Table 3).

**3.5. Profile of hepatic enzymes**

**Figure 3.** Total and differential leukocyte counts from acute schistosomiasis patients (ACT=10) and non-infected indi‐ viduals (CT=09). The results are expressed in box-plot format highlighting the gap of 50% of data set measurement for absolute values in mm3 of each leukocyte subset analyzed. Significant differences (connecting lines) were consid‐ ered at *P* < 0.05.

#### **3.5. Profile of hepatic enzymes**

**Figure 2.** Hematological profile (hemoglobin-g/dL, erythrocytes/mm3 and percentage of hematocrit) from acute schistosomiasis patients (ACT=10) and non-infected individuals (CT=09). The results are expressed in box-plot format. The box stretches from the lower hinge (defined as the 25th percentile) to the upper hinge (the 75th percentile) and therefore contains the middle half of the scores in the distribution. The median is shown as a line across the box. Therefore 1/4 of the distribution is between this line and the top of the box and 1/4 of the distribution is between this

line and the bottom of the box. Significant differences (connecting lines) were considered at *P* < 0.05.

106 Parasitic Diseases - Schistosomiasis

Acute patients presented levels of ALT, AST and γ-GT enzymes similar to reference values and there were no significant differences between these levels and those presented by CT group. (Table 3).


Values are represented as mean ± standard deviation

\* Reference values

**Table 3.** Hepatic serological tests in the study group

#### **3.6. Ultrasonographic analysis**

The results demonstrated that the ACT group presented some significant differences as compared with the CT group: medium increase in the measurement (in mm) of longitudinal left/right lobe of liver (117.4 ± 19.7 and 99.0 ± 12.3 or 150.1 ± 18.2 and 102.2 ± 16.0, respectively), size of longitudinal spleen (110.6 ± 16.3 and 91.2 ± 12.7, respectively) as well as dimension of Hilar portal vein wall (3.4 ± 1.0 and 1.5 ± 0.3, respectively) (Table 4). Periportal lymph node enlargement was observed in six of seven patients (85.7%). The periportal lymph nodes were larger, round or ovoid in shape and sharply defined with thin halos surrounding hypoechoic areas (Figure 4). An additional ultrasonographic feature observed was an incipient periportal echogenic thickening named as grade I fibrosis (Figure 5).

**Figure 4.** Representative ultrasonographic images of periportal lymph nodes from acute schistosomiasis patients. The arrows indicate larger lymph nodes, ovoid in shape (a) and rounded (b) with thin halos surrounding hypoechoic areas.

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**Figure 5.** Representative ultrasonographic images of liver from acute schistosomiasis patient (a) and healthy volunteer (b). The arrows indicate incipient periportal echogenic thickening (a) and no periportal echogenic thickening (b). Ul‐

The transmission of *S. mansoni* may vary depending on the ecology of the disease and the social standing of the population in which it occurs. The prevalence and intensity of the infection is subject to cultural practices, specific for each locality or situation and usually associated to

During the last decades, the traditional epidemiological pattern showed a tendency to change. Accelerating migration from the countryside to cities threatened to overwhelm

Ultrasonographic analysis was performed with a Nemio SSA/550ª machine (Toshiba).

trasonographic analysis was performed with a Nemio SSA/550ª machine (Toshiba).

economic, domestic or leisure activities [15, 31].

**4. Discussion**


Values are represented in mm as mean ± standard deviation

\* Statistical difference (p < 0.05)

N.V. - not visualized (normal abdominal lymph nodes are usually not visualized by sonography)

**Table 4.** Ultrasonographic features of the study group

Clinical, Laboratory and Ultrasonographic Evaluation of Patients with Acute Schistosomiasis Mansoni http://dx.doi.org/10.5772/53047 109

**Figure 4.** Representative ultrasonographic images of periportal lymph nodes from acute schistosomiasis patients. The arrows indicate larger lymph nodes, ovoid in shape (a) and rounded (b) with thin halos surrounding hypoechoic areas. Ultrasonographic analysis was performed with a Nemio SSA/550ª machine (Toshiba).

**Figure 5.** Representative ultrasonographic images of liver from acute schistosomiasis patient (a) and healthy volunteer (b). The arrows indicate incipient periportal echogenic thickening (a) and no periportal echogenic thickening (b). Ul‐ trasonographic analysis was performed with a Nemio SSA/550ª machine (Toshiba).

## **4. Discussion**

**Hepatic Enzymes Control Group**

(3-50 U/mL)\* 12.5 ± 11.2 8.6 ± 5.5

(12-46 U/mL)\* 18.7 ± 5.9 23.0 ± 6.7

(9-61 U/L)\* 23.4 ± 9.9 33.9 ± 16.6

The results demonstrated that the ACT group presented some significant differences as compared with the CT group: medium increase in the measurement (in mm) of longitudinal left/right lobe of liver (117.4 ± 19.7 and 99.0 ± 12.3 or 150.1 ± 18.2 and 102.2 ± 16.0, respectively), size of longitudinal spleen (110.6 ± 16.3 and 91.2 ± 12.7, respectively) as well as dimension of Hilar portal vein wall (3.4 ± 1.0 and 1.5 ± 0.3, respectively) (Table 4). Periportal lymph node enlargement was observed in six of seven patients (85.7%). The periportal lymph nodes were larger, round or ovoid in shape and sharply defined with thin halos surrounding hypoechoic areas (Figure 4). An additional ultrasonographic feature observed was an incipient periportal

**(N = 12)**

ALT (alaline amino transferase)

108 Parasitic Diseases - Schistosomiasis

AST (aspartate amino transferase)

γ-GT (gamma-glutamyl transferase)

**3.6. Ultrasonographic analysis**

\*

Reference values

Values are represented as mean ± standard deviation

**Table 3.** Hepatic serological tests in the study group

echogenic thickening named as grade I fibrosis (Figure 5).

Values are represented in mm as mean ± standard deviation

**Table 4.** Ultrasonographic features of the study group

\* Statistical difference (p < 0.05)

**Site Of Measurement Control Group**

N.V. - not visualized (normal abdominal lymph nodes are usually not visualized by sonography)

Longitudinal left lobe of liver 99.0 ± 12.3 117.4 ± 19.7\* Anteroposterior left lobe of liver 46.7 ± 10.0 53.3 ± 10.9 Longitudinal right lobe of liver 102.2 ± 16.0 150.1 ± 18.2\* Anteroposterior right lobe of liver 68.6 ± 11.9 63.4 ± 9.6 Longitudinal spleen 91.2 ± 12.7 110.6 ± 16.3\* Anteroposterior spleen 35.1 ± 6.3 43.5 ± 11.1 Portal vein 10.0 ± 1.2 9.9 ± 1.9 Hilar portal vein wall 1.5 ± 0.3 3.4 ± 1.0\* Splenic vein 6.4 ± 1.3 7.1 ± 1.4 Superior mesenteric vein 6.7 ± 1.1 7.1 ± 1.3 Periportal lymph node N.V. 1.8 ± 1.0\*

**(N = 9)**

**Acute Patients (N = 8)**

**Acute Patients (N = 7)**

> The transmission of *S. mansoni* may vary depending on the ecology of the disease and the social standing of the population in which it occurs. The prevalence and intensity of the infection is subject to cultural practices, specific for each locality or situation and usually associated to economic, domestic or leisure activities [15, 31].

> During the last decades, the traditional epidemiological pattern showed a tendency to change. Accelerating migration from the countryside to cities threatened to overwhelm

existing water and sanitation systems, and to increase urban schistosomiasis [9, 32, 33]. In Brazil, especially in urban areas, acute schistosomiasis outbreaks were observed and documented with a certain frequency [9, 14, 15, 17, 34-36]. The increase of acute schisto‐ somiasis cases also indicates that a non-immune fraction of the population became ex‐ posed to the disease [9, 10, 36].

[50]. Experimental studies have shown that the eosinophilia would be induced by type 2 cytokines as interleukin (IL)-4, IL-9, IL-13 and mainly by IL-5 [51]. According to Rocha et al. [43], the eosinophilia may be considered a possible pathogenic factor in acute schisto‐ somiasis. The specific granules of the eosinophil contain lysosomal hydrolases as well as several cationic proteins like the major basic protein (MBP) [43, 52], the eosinophil cati‐ onic protein (ECP) and a neurotoxin, the eosinophil-derived neurotoxin (EDN), besides a peroxidase [43, 53]. The MBP in low concentrations is toxic to schistosomula but this ac‐ tion is non-selective since mammalian cells can also be damaged [43, 54, 55]. Both perox‐ idase and ECP are also toxic for helminths and mammal cells [43, 56, 57]. The cytolysis or eosinophil degranulation with the release of granule proteins can contribute to the genesis of local pathological alterations causing dysfunction or damage to the cells, espe‐

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111

According to this report, acute patients presented increased plasma levels of IgE and ni‐ tric oxide as compared with the CT group. Our result is similar to the data published by De Souza et al. [59], which evaluated the humoral immune response through quantifying of the total IgE levels from patients with acute clinical form of schistosomiasis. Thus, we suggest that total IgE may be related to disease morbidity, as established by Pereira et al. [60]. Nitric oxide (NO) has been identified as an important cytotoxic factor and versa‐ tile messenger in the immune system being responsible to induce both anti- and/or proinflammatory effects [61]. There are broad direct and indirect evidences that NO can act as an anti-schistosomal and antiparasitic molecule [62-64]. Moreover, NO produced by human leukocytes has been shown to kill larval schistosome parasites [64, 65]. Stud‐ ies in experimental models of acute schistosomiasis showed that the inhibition of iNOS resulted in cachexia and exacerbated hepatic pathology, suggesting that in schistosomia‐

From two to eight weeks after a first contact with natural water infested by *Schistosoma* cercariae, susceptible infected patients may present a syndrome comprising a period of 2 to 30 days of fever, diarrhea, toxemia and weakness, weight loss, abdominal pain, cough, mialgya, and arthralgia, edema, urticaria, nausea/vomiting and hepatosplenomegaly [7]. Until recently, acute schistosomiasis diagnosis was only based on epidemiological and clinical features, presence of *S. mansoni* eggs in stools and eosinophilia. However, the di‐ agnosis becomes a challenge to the physicians due to the non-specificity symptoms as well as the lack of positivity of the subjects for *S. mansoni* eggs in feces in earlier stage of the infection. In this context, abdominal ultrasound can be a complementary tool to as‐ sist the diagnoses of the *S. mansoni* infection. The ultrasonographic findings presented in this study were consistent with those described by Barata et al. [11]. According to this report, ultrasonographic evaluation showed non-specific increase in the size of liver, in‐ cipient periportal echogenic thickening, in addition to lymph nodes easily identified in the periportal region. The authors have also performed a histological liver analysis from hepatic biopsies of three patients, and the data demonstrated that the periportal thicken‐ ing seen on ultrasound was probably produced by inflammatory infiltration of the portal tracts caused by schistosomiasis, which disappeared after treatment with oxamniquine.

cially when a great number of eosinophils are involved [43, 53, 58].

sis, NO limits hepatocyte damage [66-68].

The incidence of the acute form of schistosomiasis mansoni is certainly underestimated. This illness has been mainly described as a disease of travelers. Many scientific publications concerning this acute disease refer to groups of tourists, fishermen or sailors originally from a non-endemic country who have visited a tropical zone [17, 37, 38]. However, as schistoso‐ miasis is a focally distributed infection [17, 39, 40], the acute form is also diagnosed in inhab‐ itants from endemic countries who do not live in endemic areas. Nevertheless, acute disease is seldom recognized in infected patients from endemic areas. According to Lambertucci [41], acute schistosomiasis is most evident in primary infection in non-immune individuals. Among people living in endemic areas, the acute phase may pass undiagnosed. Because in endemic areas exposure to infection occurs early in life, symptoms would be inconspicuous and diagnosis not even suspected.

The clinical features of the acute phase of schistosomiasis mansoni present a wide spec‐ trum [42, 43] and the relative contribution of host and parasite factors in the pathogene‐ sis of the disease is not completely elucidated [20, 43-45]. According to Neves [46], the clinical forms of the disease will depend on the interaction of at least three sequential events: (a) the evolution phase of the worms, whether before or after oviposition and the deposition of eggs in the tissues; (b) the organ predominantly involved by young or ma‐ ture worms and by their eggs; and (c) the type and the qualitative/quantitative deviation of the total and local host response to antigenic products derived from the disintegration of schistosomula, adult worms and their eggs.

The main clinical findings presented in our study such as headache, fever, diarrhea and weight loss were consistent with those found by other authors [9, 15-17]. Different intensities of clinical manifestation are observed in patients with acute schistosomiasis, some of them evolved with a relatively severe picture while others with mild symptoms. In our study, we have also observed a similar profile.

The development of non-apparent clinical form characterized by blood eosinophilia and a positive immediate cutaneous reaction in the initial phase of the *S. mansoni* infection was described by Rocha et al. [47]. According to previous data in the literature [13, 15, 16, 43], patients with acute phase of schistosomiasis in our study had an increased abso‐ lute number of eosinophils in comparison to reference data ranging between 400 to 600 cells/mm3 [48]. Eosinophils are thought to play a major role in a variety of human dis‐ eases, including allergic inflammation, malignancy, and host defense against helminth in‐ fections. However, the exact role(s) of eosinophils in schistosomiasis regarding immunopathology remains unclear. Eosinophils may participate in Ab-dependent protec‐ tive immune responses [49]. Human eosinophils express IgE receptors that participate in an IL-5-dependent Ab-dependent cell-mediated cytotoxicity reaction against schistosomu‐ la in vitro. Eosinophils also mediate the destruction of miracidia and schistosome eggs [50]. Experimental studies have shown that the eosinophilia would be induced by type 2 cytokines as interleukin (IL)-4, IL-9, IL-13 and mainly by IL-5 [51]. According to Rocha et al. [43], the eosinophilia may be considered a possible pathogenic factor in acute schisto‐ somiasis. The specific granules of the eosinophil contain lysosomal hydrolases as well as several cationic proteins like the major basic protein (MBP) [43, 52], the eosinophil cati‐ onic protein (ECP) and a neurotoxin, the eosinophil-derived neurotoxin (EDN), besides a peroxidase [43, 53]. The MBP in low concentrations is toxic to schistosomula but this ac‐ tion is non-selective since mammalian cells can also be damaged [43, 54, 55]. Both perox‐ idase and ECP are also toxic for helminths and mammal cells [43, 56, 57]. The cytolysis or eosinophil degranulation with the release of granule proteins can contribute to the genesis of local pathological alterations causing dysfunction or damage to the cells, espe‐ cially when a great number of eosinophils are involved [43, 53, 58].

existing water and sanitation systems, and to increase urban schistosomiasis [9, 32, 33]. In Brazil, especially in urban areas, acute schistosomiasis outbreaks were observed and documented with a certain frequency [9, 14, 15, 17, 34-36]. The increase of acute schisto‐ somiasis cases also indicates that a non-immune fraction of the population became ex‐

The incidence of the acute form of schistosomiasis mansoni is certainly underestimated. This illness has been mainly described as a disease of travelers. Many scientific publications concerning this acute disease refer to groups of tourists, fishermen or sailors originally from a non-endemic country who have visited a tropical zone [17, 37, 38]. However, as schistoso‐ miasis is a focally distributed infection [17, 39, 40], the acute form is also diagnosed in inhab‐ itants from endemic countries who do not live in endemic areas. Nevertheless, acute disease is seldom recognized in infected patients from endemic areas. According to Lambertucci [41], acute schistosomiasis is most evident in primary infection in non-immune individuals. Among people living in endemic areas, the acute phase may pass undiagnosed. Because in endemic areas exposure to infection occurs early in life, symptoms would be inconspicuous and

The clinical features of the acute phase of schistosomiasis mansoni present a wide spec‐ trum [42, 43] and the relative contribution of host and parasite factors in the pathogene‐ sis of the disease is not completely elucidated [20, 43-45]. According to Neves [46], the clinical forms of the disease will depend on the interaction of at least three sequential events: (a) the evolution phase of the worms, whether before or after oviposition and the deposition of eggs in the tissues; (b) the organ predominantly involved by young or ma‐ ture worms and by their eggs; and (c) the type and the qualitative/quantitative deviation of the total and local host response to antigenic products derived from the disintegration

The main clinical findings presented in our study such as headache, fever, diarrhea and weight loss were consistent with those found by other authors [9, 15-17]. Different intensities of clinical manifestation are observed in patients with acute schistosomiasis, some of them evolved with a relatively severe picture while others with mild symptoms. In our study, we have also

The development of non-apparent clinical form characterized by blood eosinophilia and a positive immediate cutaneous reaction in the initial phase of the *S. mansoni* infection was described by Rocha et al. [47]. According to previous data in the literature [13, 15, 16, 43], patients with acute phase of schistosomiasis in our study had an increased abso‐ lute number of eosinophils in comparison to reference data ranging between 400 to 600 cells/mm3 [48]. Eosinophils are thought to play a major role in a variety of human dis‐ eases, including allergic inflammation, malignancy, and host defense against helminth in‐ fections. However, the exact role(s) of eosinophils in schistosomiasis regarding immunopathology remains unclear. Eosinophils may participate in Ab-dependent protec‐ tive immune responses [49]. Human eosinophils express IgE receptors that participate in an IL-5-dependent Ab-dependent cell-mediated cytotoxicity reaction against schistosomu‐ la in vitro. Eosinophils also mediate the destruction of miracidia and schistosome eggs

posed to the disease [9, 10, 36].

110 Parasitic Diseases - Schistosomiasis

diagnosis not even suspected.

observed a similar profile.

of schistosomula, adult worms and their eggs.

According to this report, acute patients presented increased plasma levels of IgE and ni‐ tric oxide as compared with the CT group. Our result is similar to the data published by De Souza et al. [59], which evaluated the humoral immune response through quantifying of the total IgE levels from patients with acute clinical form of schistosomiasis. Thus, we suggest that total IgE may be related to disease morbidity, as established by Pereira et al. [60]. Nitric oxide (NO) has been identified as an important cytotoxic factor and versa‐ tile messenger in the immune system being responsible to induce both anti- and/or proinflammatory effects [61]. There are broad direct and indirect evidences that NO can act as an anti-schistosomal and antiparasitic molecule [62-64]. Moreover, NO produced by human leukocytes has been shown to kill larval schistosome parasites [64, 65]. Stud‐ ies in experimental models of acute schistosomiasis showed that the inhibition of iNOS resulted in cachexia and exacerbated hepatic pathology, suggesting that in schistosomia‐ sis, NO limits hepatocyte damage [66-68].

From two to eight weeks after a first contact with natural water infested by *Schistosoma* cercariae, susceptible infected patients may present a syndrome comprising a period of 2 to 30 days of fever, diarrhea, toxemia and weakness, weight loss, abdominal pain, cough, mialgya, and arthralgia, edema, urticaria, nausea/vomiting and hepatosplenomegaly [7]. Until recently, acute schistosomiasis diagnosis was only based on epidemiological and clinical features, presence of *S. mansoni* eggs in stools and eosinophilia. However, the di‐ agnosis becomes a challenge to the physicians due to the non-specificity symptoms as well as the lack of positivity of the subjects for *S. mansoni* eggs in feces in earlier stage of the infection. In this context, abdominal ultrasound can be a complementary tool to as‐ sist the diagnoses of the *S. mansoni* infection. The ultrasonographic findings presented in this study were consistent with those described by Barata et al. [11]. According to this report, ultrasonographic evaluation showed non-specific increase in the size of liver, in‐ cipient periportal echogenic thickening, in addition to lymph nodes easily identified in the periportal region. The authors have also performed a histological liver analysis from hepatic biopsies of three patients, and the data demonstrated that the periportal thicken‐ ing seen on ultrasound was probably produced by inflammatory infiltration of the portal tracts caused by schistosomiasis, which disappeared after treatment with oxamniquine. However, liver biopsy is an invasive procedure that is seldom justified. It is important to mention that the ultrasonographic features of the lymph nodes, liver and spleen in acute schistosomiasis, although highly sensitive, are not pathognomonic of acute schistosomia‐ sis, and are also seen in other infectious diseases such as acute hepatitis and other viral diseases [19, 69, 70].

**Acknowledgements**

**Author details**

Helena Barbosa Ferraz1

are grateful for the CNPq fellowships.

Amanda Cardoso de Oliveira Silveira1

FIOCRUZ, Belo Horizonte, MG, Brazil

FIOCRUZ, Belo Horizonte, MG, Brazil

\*\*The authors contributed equally to this study

MG, Brazil

BA, Brasil

RUZ, Belo Horizonte, MG, Brazil

Rodrigo Corrêa-Oliveira1,7, Giovanni Gazzinelli2

\*Address all correspondence to: andreat@cpqrr.fiocruz.br

Maria Carolina Barbosa Álvares6

Matheus Fernandes Costa-Silva\*\*1,2, Denise da Silveira-Lemos\*\*1,2,3,

, Cristiano Lara Massara4

This work was supported by grants from Oswaldo Cruz Foundation (FIOCRUZ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), and UNDP World Bank/WHO Special Program for Research and Training in Tropical Diseases. The authors are grateful to the technical staff at the Laboratory of Cellular and Molecular Immunology and the Laboratory of Biomarkers of Diagnosis and Monitoring, Oswaldo Cruz Foundation, Brazil for their invaluable assistance during this study. The authors also thank the Program for Technological Development in Tools for Health - PDTIS - FIOCRUZ for the use of its facilities. OAMF, PMZC, RCO, GG, and ATC

Clinical, Laboratory and Ultrasonographic Evaluation of Patients with Acute Schistosomiasis Mansoni

, Olindo Assis Martins-Filho1

1 Laboratory of Biomarkers of Diagnosis and Monitoring, Research Center Rene Rachou,

2 Laboratory of Immunology Cellular and Molecular, Research Center Rene Rachou, FIOC‐

3 Laboratory of Immunoparasitology, Department of Biological Science, Institute of Exact

4 Laboratory of Helminthology and Medical Malacology, Research Center Rene Rachou,

5 Laboratory of Schistosomiasis, Research Center Rene Rachou, FIOCRUZ, Belo Horizonte,

7 National Institute of Science and Technology in Tropical Diseases - INCT-DT- Salvador,

Sciences and Biological/NUPEB, Federal University of Ouro Preto, MG, Brasil

6 Holy House of Mercy of Belo Horizonte, Belo Horizonte, MG, Brazil

, Pedro Henrique Gazzinelli-Guimarães2

, Martin Johannes Enk5

and Andréa Teixeira-Carvalho1,2,7\*

,

http://dx.doi.org/10.5772/53047

113

,

, Paulo Marcos Zech Coelho5

,

Normal abdominal lymph nodes are usually not visualized by sonography. Neoplastic lymph nodes are generally rounded and hypoechoic, sometimes with an irregular shape and borders [19, 71, 72]. Lymphomas can also affect periportal and peripancreatic lymph nodes, but there is generally an extensive involvement of other abdominal lymph nodes, mainly retroperitoneal, that is almost anechoic and usually rounded. In this circum‐ stance, the liver and spleen are enlarged and can show focal lesions [19, 72]. Patients with acquired immunodeficiency syndrome (AIDS) can also show hepatoesplenomegaly and abdominal lymphadenopathy, but the echogenicity of the liver is usually increased. Tumors related to AIDS, such as Kaposi's sarcoma, have also been reported as a cause of lymphadenopathy [73]. Mesenteric and periportal lymphadenomegaly is a common find‐ ing in blastomycosis and these are almost anechoic [19].

In the current study, we have also evaluated the liver function of acute schistosomiasis patients by the ALT, AST and γ-GT assessment. Comparing with other studies in litera‐ ture [15, 16], we did not observe changes in any of the enzymes evaluated, suggesting that the hepatocellular function is preserved or minimally compromised in the study population. In patients presenting intestinal or hepatointestinal clinical form of schistoso‐ miasis,it has been observed that the liver function is maintained. In those patients show‐ ing the hepatosplenic form, liver function related to protein metabolism was in general changed, but rarely this function is compromised in a broad spectrum. Only after repeat‐ ed blood spoliation, in the terminal stage of illness, there is strong involvement of the liver parenchymal. According to some authors, when liver cell damage occurs there is an increase of ALT and AST levels, but in the *S. mansoni* infection this type of injury is not commonly observed [74, 75]. On the other hand, the most important cause of increased

γ-GT levels is the chronic stimulation of the microsomal fraction of hepatocytes and the presence of cholestasis [76]. According to Martins & Borges [77], the chronic stimulation of the microsomal occurs only in patients with hepatosplenic form of schistosomiasis. Kardorff et al. [74] observed that the increase of γ-GT occurs only in patients with severe periportal fibrosis, irregular texture liver and collateral vessels.

## **5. Conclusion**

In conclusion, the data presented here suggest that alterations identified by analyses of clinical/ laboratorial parameters and ultrasonographic features, although not specific, are compatible with the acute phase of Schistosomiasis mansoni and provide a reliable complementary tool for the diagnosis of the infection.

## **Acknowledgements**

However, liver biopsy is an invasive procedure that is seldom justified. It is important to mention that the ultrasonographic features of the lymph nodes, liver and spleen in acute schistosomiasis, although highly sensitive, are not pathognomonic of acute schistosomia‐ sis, and are also seen in other infectious diseases such as acute hepatitis and other viral

Normal abdominal lymph nodes are usually not visualized by sonography. Neoplastic lymph nodes are generally rounded and hypoechoic, sometimes with an irregular shape and borders [19, 71, 72]. Lymphomas can also affect periportal and peripancreatic lymph nodes, but there is generally an extensive involvement of other abdominal lymph nodes, mainly retroperitoneal, that is almost anechoic and usually rounded. In this circum‐ stance, the liver and spleen are enlarged and can show focal lesions [19, 72]. Patients with acquired immunodeficiency syndrome (AIDS) can also show hepatoesplenomegaly and abdominal lymphadenopathy, but the echogenicity of the liver is usually increased. Tumors related to AIDS, such as Kaposi's sarcoma, have also been reported as a cause of lymphadenopathy [73]. Mesenteric and periportal lymphadenomegaly is a common find‐

In the current study, we have also evaluated the liver function of acute schistosomiasis patients by the ALT, AST and γ-GT assessment. Comparing with other studies in litera‐ ture [15, 16], we did not observe changes in any of the enzymes evaluated, suggesting that the hepatocellular function is preserved or minimally compromised in the study population. In patients presenting intestinal or hepatointestinal clinical form of schistoso‐ miasis,it has been observed that the liver function is maintained. In those patients show‐ ing the hepatosplenic form, liver function related to protein metabolism was in general changed, but rarely this function is compromised in a broad spectrum. Only after repeat‐ ed blood spoliation, in the terminal stage of illness, there is strong involvement of the liver parenchymal. According to some authors, when liver cell damage occurs there is an increase of ALT and AST levels, but in the *S. mansoni* infection this type of injury is not commonly observed [74, 75]. On the other hand, the most important cause of increased

γ-GT levels is the chronic stimulation of the microsomal fraction of hepatocytes and the presence of cholestasis [76]. According to Martins & Borges [77], the chronic stimulation of the microsomal occurs only in patients with hepatosplenic form of schistosomiasis. Kardorff et al. [74] observed that the increase of γ-GT occurs only in patients with severe periportal fibrosis,

In conclusion, the data presented here suggest that alterations identified by analyses of clinical/ laboratorial parameters and ultrasonographic features, although not specific, are compatible with the acute phase of Schistosomiasis mansoni and provide a reliable complementary tool

ing in blastomycosis and these are almost anechoic [19].

irregular texture liver and collateral vessels.

for the diagnosis of the infection.

**5. Conclusion**

diseases [19, 69, 70].

112 Parasitic Diseases - Schistosomiasis

This work was supported by grants from Oswaldo Cruz Foundation (FIOCRUZ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), and UNDP World Bank/WHO Special Program for Research and Training in Tropical Diseases. The authors are grateful to the technical staff at the Laboratory of Cellular and Molecular Immunology and the Laboratory of Biomarkers of Diagnosis and Monitoring, Oswaldo Cruz Foundation, Brazil for their invaluable assistance during this study. The authors also thank the Program for Technological Development in Tools for Health - PDTIS - FIOCRUZ for the use of its facilities. OAMF, PMZC, RCO, GG, and ATC are grateful for the CNPq fellowships.

## **Author details**

Matheus Fernandes Costa-Silva\*\*1,2, Denise da Silveira-Lemos\*\*1,2,3, Amanda Cardoso de Oliveira Silveira1 , Pedro Henrique Gazzinelli-Guimarães2 , Helena Barbosa Ferraz1 , Cristiano Lara Massara4 , Martin Johannes Enk5 , Maria Carolina Barbosa Álvares6 , Olindo Assis Martins-Filho1 , Paulo Marcos Zech Coelho5 , Rodrigo Corrêa-Oliveira1,7, Giovanni Gazzinelli2 and Andréa Teixeira-Carvalho1,2,7\*

\*Address all correspondence to: andreat@cpqrr.fiocruz.br

1 Laboratory of Biomarkers of Diagnosis and Monitoring, Research Center Rene Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil

2 Laboratory of Immunology Cellular and Molecular, Research Center Rene Rachou, FIOC‐ RUZ, Belo Horizonte, MG, Brazil

3 Laboratory of Immunoparasitology, Department of Biological Science, Institute of Exact Sciences and Biological/NUPEB, Federal University of Ouro Preto, MG, Brasil

4 Laboratory of Helminthology and Medical Malacology, Research Center Rene Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil

5 Laboratory of Schistosomiasis, Research Center Rene Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil

6 Holy House of Mercy of Belo Horizonte, Belo Horizonte, MG, Brazil

7 National Institute of Science and Technology in Tropical Diseases - INCT-DT- Salvador, BA, Brasil

\*\*The authors contributed equally to this study

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**Chapter 6**

**Spinal Cord Schistosomiasis**

Additional information is available at the end of the chapter

viously unrecognized public health problem.

The human central nervous system (CNS) may be affected by infections of several species in the *Schistosoma* genus that infect men. One of the CNS clinical presentation is the spinal cord schistosomiasis, a potentially severe disease, yet, for a long time, a poorly recognized clinical presentation of Schistosomiasis. However, recently, probably as a consequence significant improvements in diagnostic methods, more attention is being given to this clinical form of Schistosomiasis. This emerging medical and scientific interest about the spinal cord schisto‐ somiasis has allowed a better comprehension of its clinical impact and importance as a pre‐

Schistosomiasis is among the parasitic diseases with the highest epidemiological impor‐ tance in the world. According to the World Health Organization, schistosomiasis occurs in 76 countries and 230 million individuals require treatment annually [1,2]. Of these, about 100 million present some clinical manifestation and 20 million present severe forms of the disease [1-5]. Annually, over 200.000 people die as a consequence of schis‐ tosomiasis. In the year 2010, around 33.5 million people were treated. Despite advances in the control of the disease, with lowering of mortality and morbidity, schistosomiasis still represents a challenge to public health and has increased its area of transmission throughout the years [2]. Since it hits the poorer regions of the world, being associated with precarious sanitary and adverse social-economical conditions, this disease has been neglected. With the increase of migratory flow and adventure tourism travels, innumera‐ ble schistosomiasis cases have been occurring, even in non-endemic countries [6-13]. Schistosomiasis is a disease caused by trematode worms, belonging to the Schistosoma genus. There are many species which affect man in different clinical manifestations, elimination methods, intermediary hosts and geographical distribution. These species

> © 2013 Freitas and Angerami; licensee InTech. This is an open access article 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 The Author(s). Licensee InTech. This chapter is 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.

André Ricardo Ribas Freitas and Rodrigo Nogueira Angerami

http://dx.doi.org/10.5772/53771

**1. Introduction**


## **Chapter 6**

## **Spinal Cord Schistosomiasis**

André Ricardo Ribas Freitas and Rodrigo Nogueira Angerami

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53771

## **1. Introduction**

[73] Yee, J. M, Raghavendra, B. N, Horii, S. C, & Ambrosino, M. Abdominal sonography in AIDS. A review. American Institute of Ultrasound in Medicine (1993). , 12,

[74] Kardorff, R, Gabone, R. M, Mugashe, C, Obiga, D, Ramarokoto, C. E, Mahlert, C, Spannbrucker, N, Lang, A, Günzler, V, & Gryseels, B. Ehrich JHH, Doehring E. Schis‐ tosoma mansoni-related morbidity on Ukerewe Island, Tanzania: clinical, ultrasono‐ graphical and biochemical parameters. Tropical Medicine & International Health

[75] Aquino RTRChieffi PP, Catunda SM, Araújo MF, Ribeiro MCSA, Taddeo EF, Rolim EG. Hepatitis B and C virus markers among patients with hepatosplenic mansonic schistosomiasis. Revista do Instituto de Medicina Tropical de São Paulo (2000). , 42,

[76] Alves-júnior, A, Fontes, D. A, & Melo, V. A. Machado MCC, Cruz JF, Santos EAS. Hi‐ pertensão portal esquistossomótica: influência do fluxo sanguíneo portal nos níveis séricos das enzimas hepáticas. Arquivos de Gastroenterologia (2003). , 40, 203-208. [77] Martins, R. D, & Borges, D. R. Ethanol challenge in non-alcoholic patients with schis‐

tosomiasis. Journal of Clinical Pathology (1993). , 46, 250-253.

705-714.

120 Parasitic Diseases - Schistosomiasis

313-320.

(1997). , 2, 230-239.

The human central nervous system (CNS) may be affected by infections of several species in the *Schistosoma* genus that infect men. One of the CNS clinical presentation is the spinal cord schistosomiasis, a potentially severe disease, yet, for a long time, a poorly recognized clinical presentation of Schistosomiasis. However, recently, probably as a consequence significant improvements in diagnostic methods, more attention is being given to this clinical form of Schistosomiasis. This emerging medical and scientific interest about the spinal cord schisto‐ somiasis has allowed a better comprehension of its clinical impact and importance as a pre‐ viously unrecognized public health problem.

Schistosomiasis is among the parasitic diseases with the highest epidemiological impor‐ tance in the world. According to the World Health Organization, schistosomiasis occurs in 76 countries and 230 million individuals require treatment annually [1,2]. Of these, about 100 million present some clinical manifestation and 20 million present severe forms of the disease [1-5]. Annually, over 200.000 people die as a consequence of schis‐ tosomiasis. In the year 2010, around 33.5 million people were treated. Despite advances in the control of the disease, with lowering of mortality and morbidity, schistosomiasis still represents a challenge to public health and has increased its area of transmission throughout the years [2]. Since it hits the poorer regions of the world, being associated with precarious sanitary and adverse social-economical conditions, this disease has been neglected. With the increase of migratory flow and adventure tourism travels, innumera‐ ble schistosomiasis cases have been occurring, even in non-endemic countries [6-13]. Schistosomiasis is a disease caused by trematode worms, belonging to the Schistosoma genus. There are many species which affect man in different clinical manifestations, elimination methods, intermediary hosts and geographical distribution. These species

© 2013 Freitas and Angerami; licensee InTech. This is an open access article 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 The Author(s). Licensee InTech. This chapter is 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.

share the same pattern in reproductive cycle, the transmission occurring through eggs, a proportion of which are eliminated through urine (*S. haematobium*) or feces (*S. mansoni*, *S. japonicum* and others). These eggs release larvae (miracidium) that infect freshwater molluscs in which the parasites multiply through asexual reproduction. These molluscs release aquatic larvae (cercariae) that actively penetrate the skin of a new, vertebrate host. These larvae become adults that inhabit inside the veins in the digestive system (*S. mansoni* and *S*. *japonicum*) and of the urinary system (*S. haematobium*). The geographic distribution of each species is varied and depends on the presence of molluscs capable of serving as hosts (each *Schistosoma* species has different molluscs as hosts). Precarious sanitary conditions also contribute in the definition of locations where schistosomiasis occurs [14]. *Schistosoma mansoni* occurs in 74 countries located in Africa, the Middle East, South America and the Caribbean. Its eggs measure about 60 x 140 μm, with lateral spine and are eliminated in the feces, being a main cause of intestinal, hepatosplenic, cardiopulmonary and cerebral diseases, aside from being the main cause of spinal cord schistosomiasis. *S. haematobium* occurs in Africa and in the Middle East and its eggs measure about 60 x 150 μm, with terminal spine, are eliminated in the urine and on rare occasions in the feces, being the mains cause of urinary diseases and spinal cord schistosomiasis. *S. japonicum*, *S. mekongi* and *S. malayensis* occur in Asia (they are also called *S. japonicum*-like); eggs measure about 60 x 100 μm, lack spine and are eliminated in the feces, causing hepatic diseases, cerebral neuroschistosomiasis, although there have been rare reports of cases in which spinal cord schistosomiasis was caused by *S. japoni‐ cum*. S. intercalatum occurs in Africa. Eggs are eliminated in the feces. It causes mild in‐ testinal disease but not neuroschistosomiasis, being the least important species, clinically. The presence of spines in the eggs of *S. mansoni* and *S*. *haematobium* might explain why medullar and cerebral neuroschistosomiasis are more common in these species. Spine makes it more difficult for the eggs to travel through the vertebral veins, causing them to be stuck in the lumbar or thoracic spinal cord. *S. japonium*'s eggs, being smaller and lacking spine, migrate more easily to the brain through these veins, crossing the spinal cord without sticking to it. There are, still, species belonging to the *Schistosomatidae* fami‐ ly (ex: Trichobilharzia regenti) that can cause cercarial dermatitis (or *summer's itch*) with‐ out, however, reaching adult life in men and, therefore, not having any major clinical importance.

ies [15,16]. This form presents with fever, chills, cough, weakness, weight loss, diarrhea, vomiting, urticarial reactions, hepatosplenomegaly and eosinophilia. These manifestations last, in general, a few days but can last months and, in rare cases, be fatal. These patients present big periovular necrotic-exudative granulomas dispersed throughout the intestines, liver and other organs [17], and generally present spontaneous clinical improvement after a few weeks, but treatment associating schistosomicides and corticosteroids reduce the persis‐

**Species Regions where it occurs Main affected organs Most common neurological**

**forms**

(mainly) and cerebral schistosomiasis

Spinal Cord Schistosomiasis http://dx.doi.org/10.5772/53771 123

cerebral schistosomiasis

(mainly) and spinal cord schistosomiasis

Liver, spleen and intestines Spinal cord schistosomiasis

Bladder, urethra and ureter Spinal cord (mainly) and

Liver, spleen and intestines Cerebral schistosomiasis

tence time of symptoms and prevents evolution into the chronic phase.

Egypt, Middle-East, other regions in Africa and in the

Egypt, Middle-East, other regions in Africa

China, South-East Asia and

**Table 1.** Geographic distribution, usually affected organs, and most frequent neurological forms according

Schistosomiasis' chronic phase is frequently asymptomatic. Symptoms occur with more frequency in patients who are repeatedly exposed to transmissions focuses and end up developing high worm burden. Chronic forms depend on the involved species. Schisto‐ somiasis mansoni chronic forms are usually classified as: intestinal, hepatointestinal, hep‐ atosplenic and decompensated hepatosplenic. In the intestinal and hepatosplenic forms patients usually do not present significant symptoms, but when present they may in‐ clude abdominal discomfort, fecal urgency, episodes of diarrhea with eventual mucus or blood. Hepatic lesions are caused by egg embolism secondary to inflammatory reaction, but without significant clinical repercussions. With progression of infection and chronic inflammatory process, these patients may present significant periportal fibrosis, leading to portal hypertension. This phase is called hepatosplenic and the patient may suffer as‐ cites and severe esophageal varices [17]. Schistosomiasis japonica may cause the same kinds of manifestations, although liver function is usually more compromised. In schisto‐ somiasis haematobia, oviposition may cause bladder inflammation, alongside blood in the urine and urinary urgency. Lesions in the urinary tract may cause fibrosis and uri‐ nary obstruction, leading to obstructive uropathy and increasing the risk of bladder can‐ cer. These chronic forms depend fundamentally on high worm burdens, therefore they

*S. mansoni* Sub-Saharan Africa, Brazil,

*S. haematobium* Sub-Saharan Africa, Brazil,

*S. japonicum* and *S. japonicum*-like

*Schistosoma* species

**2.2. Chronic phase**

Americas

Pacific islands

## **2. Clinical forms of schistosomiasis**

#### **2.1. Acute phase**

Acute forms are basically cercarial dermatitis or summer's itch, cutaneous lesion secondary to the penetration of the skin by the cercaria, and Katayama's fever (or syndrome), which is also called acute or toxemic schistosomiasis and occurs, in genera, after three to nine weeks of cercariae penetration, when they have already become adult worms and start laying eggs. Toxemia is secondary to hypersensitivity reactions to the parasite, being characteristic to pa‐ tients who do not reside in endemic areas and that are exposed to contaminated water bod‐ ies [15,16]. This form presents with fever, chills, cough, weakness, weight loss, diarrhea, vomiting, urticarial reactions, hepatosplenomegaly and eosinophilia. These manifestations last, in general, a few days but can last months and, in rare cases, be fatal. These patients present big periovular necrotic-exudative granulomas dispersed throughout the intestines, liver and other organs [17], and generally present spontaneous clinical improvement after a few weeks, but treatment associating schistosomicides and corticosteroids reduce the persis‐ tence time of symptoms and prevents evolution into the chronic phase.


**Table 1.** Geographic distribution, usually affected organs, and most frequent neurological forms according *Schistosoma* species

#### **2.2. Chronic phase**

share the same pattern in reproductive cycle, the transmission occurring through eggs, a proportion of which are eliminated through urine (*S. haematobium*) or feces (*S. mansoni*, *S. japonicum* and others). These eggs release larvae (miracidium) that infect freshwater molluscs in which the parasites multiply through asexual reproduction. These molluscs release aquatic larvae (cercariae) that actively penetrate the skin of a new, vertebrate host. These larvae become adults that inhabit inside the veins in the digestive system (*S. mansoni* and *S*. *japonicum*) and of the urinary system (*S. haematobium*). The geographic distribution of each species is varied and depends on the presence of molluscs capable of serving as hosts (each *Schistosoma* species has different molluscs as hosts). Precarious sanitary conditions also contribute in the definition of locations where schistosomiasis occurs [14]. *Schistosoma mansoni* occurs in 74 countries located in Africa, the Middle East, South America and the Caribbean. Its eggs measure about 60 x 140 μm, with lateral spine and are eliminated in the feces, being a main cause of intestinal, hepatosplenic, cardiopulmonary and cerebral diseases, aside from being the main cause of spinal cord schistosomiasis. *S. haematobium* occurs in Africa and in the Middle East and its eggs measure about 60 x 150 μm, with terminal spine, are eliminated in the urine and on rare occasions in the feces, being the mains cause of urinary diseases and spinal cord schistosomiasis. *S. japonicum*, *S. mekongi* and *S. malayensis* occur in Asia (they are also called *S. japonicum*-like); eggs measure about 60 x 100 μm, lack spine and are eliminated in the feces, causing hepatic diseases, cerebral neuroschistosomiasis, although there have been rare reports of cases in which spinal cord schistosomiasis was caused by *S. japoni‐ cum*. S. intercalatum occurs in Africa. Eggs are eliminated in the feces. It causes mild in‐ testinal disease but not neuroschistosomiasis, being the least important species, clinically. The presence of spines in the eggs of *S. mansoni* and *S*. *haematobium* might explain why medullar and cerebral neuroschistosomiasis are more common in these species. Spine makes it more difficult for the eggs to travel through the vertebral veins, causing them to be stuck in the lumbar or thoracic spinal cord. *S. japonium*'s eggs, being smaller and lacking spine, migrate more easily to the brain through these veins, crossing the spinal cord without sticking to it. There are, still, species belonging to the *Schistosomatidae* fami‐ ly (ex: Trichobilharzia regenti) that can cause cercarial dermatitis (or *summer's itch*) with‐ out, however, reaching adult life in men and, therefore, not having any major clinical

Acute forms are basically cercarial dermatitis or summer's itch, cutaneous lesion secondary to the penetration of the skin by the cercaria, and Katayama's fever (or syndrome), which is also called acute or toxemic schistosomiasis and occurs, in genera, after three to nine weeks of cercariae penetration, when they have already become adult worms and start laying eggs. Toxemia is secondary to hypersensitivity reactions to the parasite, being characteristic to pa‐ tients who do not reside in endemic areas and that are exposed to contaminated water bod‐

importance.

122 Parasitic Diseases - Schistosomiasis

**2.1. Acute phase**

**2. Clinical forms of schistosomiasis**

Schistosomiasis' chronic phase is frequently asymptomatic. Symptoms occur with more frequency in patients who are repeatedly exposed to transmissions focuses and end up developing high worm burden. Chronic forms depend on the involved species. Schisto‐ somiasis mansoni chronic forms are usually classified as: intestinal, hepatointestinal, hep‐ atosplenic and decompensated hepatosplenic. In the intestinal and hepatosplenic forms patients usually do not present significant symptoms, but when present they may in‐ clude abdominal discomfort, fecal urgency, episodes of diarrhea with eventual mucus or blood. Hepatic lesions are caused by egg embolism secondary to inflammatory reaction, but without significant clinical repercussions. With progression of infection and chronic inflammatory process, these patients may present significant periportal fibrosis, leading to portal hypertension. This phase is called hepatosplenic and the patient may suffer as‐ cites and severe esophageal varices [17]. Schistosomiasis japonica may cause the same kinds of manifestations, although liver function is usually more compromised. In schisto‐ somiasis haematobia, oviposition may cause bladder inflammation, alongside blood in the urine and urinary urgency. Lesions in the urinary tract may cause fibrosis and uri‐ nary obstruction, leading to obstructive uropathy and increasing the risk of bladder can‐ cer. These chronic forms depend fundamentally on high worm burdens, therefore they are diseases that affect mainly inhabitants of endemic areas. For instance, hepatosplenic forms of schistosomiasis mansoni are more frequent in areas with high endemicity and very rare in areas of low endemicity. Differently, ectopic forms of schistosomiasis occur as consequence of egg or work accumulation in any organ of the patient and, therefore, is not related to high worm burdens. Thus, it can occur in patients of endemic areas or in patients of non-endemic areas with casual exposure to the focus of transmission.

symptoms". Despite the fact that the authors were referring to cerebral neuroschistosomiasis

Spinal Cord Schistosomiasis http://dx.doi.org/10.5772/53771 125

Up until the 1980's, medullar lesion caused by *Schistosoma* was, in most published cases, confirmed through fragments of nervous tissue obtained through biopsy or necropsy. In 1985, Scrimgeour and Gedjusek published a scientific literature review of the years between 1930 and 1984 in which they identified 52 cases of spinal cord schistosomiasis mansoni and 12 cases of spinal cord schistosomiasis haematobia, confirmed by pathological anatomy me‐ dullar examinations. On the occasion, the authors highlighted the importance of suspecting neuroschistosomiasis in any patient who had been exposed to the risk of infection and pre‐ sented neurological manifestations [25]. The authors reaffirmed that the patients in general had no previous manifestation of schistosomiasis and that only 22% of *S. mansoni* carriers had eggs found in their feces or rectum biopsy and only 25% of the *S. haematobium* carriers had eggs found in their urine or feces [25]. This difficulty in finding the eggs is not casual, nor an abnormal occurrence. It is part of the disease's laboratory findings pattern [26]. De‐ spite having already done some serological examinations that could have confirmed infec‐ tion by the parasites even without finding eggs, the diagnosis of spinal cord schistosomiasis was still very complicated and controversial at that time, specially because there were no de‐ tailed imaging examinations. Some studies already used presumptive diagnosis criteria, in which the presence of lower thoracic or high lumbar medullar symptoms, the demonstra‐ tion of exposure to *Schistosoma* through parasitological or immunological methods, and the exclusion of other causes for myelitis were enough for attributing the clinical manifestation to spinal cord schistosomiasis [27]. There were, still, some divergences in the literature re‐ garding the acceptance of the parasitological e/or immunological methods for case confirma‐ tion, but the risk of sequelae involved in biopsying the medulla led to the confirmation of the diagnosis through pathological anatomical methods being abandoned [28-31]. In the last decades, spinal cord schistosomiasis diagnosis has been reached through confirmation of *Schistosoma* infection using pararitological or serological methods associated with the exclu‐

With the technological improvement in the field of immunological methods and imag‐ ing examinations, including the introduction of Computerized Tomography (CT) and, mainly, Magnetic Resonance Imaging (MRI), differential diagnosis with other causes of myelopathy has become easier. This can explain, at least in part, the great amount of ar‐ ticles being published in this area [22,38-44]. With the increase in interest for adventure tourism, a growing number of spinal cord schistosomiasis cases, who live in non-endem‐ ic areas and are infected in their leisure time, have been described in the literature. Spi‐ nal cord schistosomiasis, which had been considered a rare disease from the beginning of the 20th century to the early 80's, now appeared to have been, in fact, under-recog‐ nized. In the last years, it has attracted more and more the interest of researchers and is considered one of the forms of schistosomiasis that must be reevaluated from the point

There are, in the literature, studies that allow an evaluation on the incidence or prevalence in the population with schistosomiasis or exposed to the risk of schistosomiasis. In biblio‐

japonica, the same advice is valid for spinal cord schistosomiasis today.

sion of other causes for myelopathy [32-37].

of view of disease burden by Public Health Organizations [45].

## **3. Spinal cord schistosomiasis**

The human central nervous system (CNS) may be affected by infections of several species in the *Schistosoma* genus that infect men, excluding S. intercalatum. Curiously, other species of Schistosomatidae, such as *Trichobilharzia regenti*, may cause brain or medullar lesions in wa‐ ter birds, but in man causes only swimmer's itch [18-20]. The first human case of neurologi‐ cal lesion cause by *Schistosoma* was described in 1889 by Yamagiwa in the necropsy of a patient with epilepsy that presented cerebral granulomas. It is curious that *S. japonicum* life cycle was described 15 years later, a fact that allowed the *a posteriori* identification of the eggs present in those granulomas [21,22]. In 1905, Shimamura and Tsunoda demonstrated for the first time the presence of *S. japonicum* in the spinal cord of a patient with transverse myelitis. Despite the fact that *S. japonicum* was the first species described as a cause of spinal cord medullar lesion, this species has been the less frequently associated with such lesions in the Schistosoma genera. The first case of medullar lesion caused by *S. mansoni* was described in 1930 by Muller and Stender and found in a 26 year old patient who had been to Brazil. In 1948, Faust published a review on the 82 cases of ectopic schistosomiasis described thus far [23]. Among these, there were 56 patients with brain compromising and 8 with medullar le‐ sions in the spinal cord. In that occasion, the author highlighted the importance of this form of disease, given that the number of cases was not inconsiderable and that the consequences were, in general, devastating. "In reports of the cases, it has been customary that most au‐ thors address ectopic schistosomiasis as rare or really rare. These designations are no more applicable, despite these syndromes being relatively infrequent" [23]. In the same year, Kane and Most wrote yet another review article on literature concerning neurological lesions caused by *Schistosoma*, including the medullary and brain forms, and called attention to the occurrence of 25 cases of cerebral neuroschistosomiasis japonica among north-American sol‐ diers in the Second World War, between the years of 1944 and 1946 [24]. In this study, 88% (22 cases) of the initial fecal exams of North-American military patients with cerebral neuro‐ schistosomiasis japonica were negative for eggs in the stool samples in the first examination and that 40% (10 cases) remained negative after several serial examinations. All patients had confirmation of *Schistosoma* eggs in pathological anatomy examinations, obtained through CNS biopsy or necropsy. The author, at the time, already said that "Cautious and repeated fecal examinations are important for clinical diagnosis, but specific treatment must not be postponed if there are adequate evidence for presumptive diagnosis, even because all fecal examinations may be negative for eggs even when the patient already shows neurological symptoms". Despite the fact that the authors were referring to cerebral neuroschistosomiasis japonica, the same advice is valid for spinal cord schistosomiasis today.

are diseases that affect mainly inhabitants of endemic areas. For instance, hepatosplenic forms of schistosomiasis mansoni are more frequent in areas with high endemicity and very rare in areas of low endemicity. Differently, ectopic forms of schistosomiasis occur as consequence of egg or work accumulation in any organ of the patient and, therefore, is not related to high worm burdens. Thus, it can occur in patients of endemic areas or in patients of non-endemic areas with casual exposure to the focus of transmission.

The human central nervous system (CNS) may be affected by infections of several species in the *Schistosoma* genus that infect men, excluding S. intercalatum. Curiously, other species of Schistosomatidae, such as *Trichobilharzia regenti*, may cause brain or medullar lesions in wa‐ ter birds, but in man causes only swimmer's itch [18-20]. The first human case of neurologi‐ cal lesion cause by *Schistosoma* was described in 1889 by Yamagiwa in the necropsy of a patient with epilepsy that presented cerebral granulomas. It is curious that *S. japonicum* life cycle was described 15 years later, a fact that allowed the *a posteriori* identification of the eggs present in those granulomas [21,22]. In 1905, Shimamura and Tsunoda demonstrated for the first time the presence of *S. japonicum* in the spinal cord of a patient with transverse myelitis. Despite the fact that *S. japonicum* was the first species described as a cause of spinal cord medullar lesion, this species has been the less frequently associated with such lesions in the Schistosoma genera. The first case of medullar lesion caused by *S. mansoni* was described in 1930 by Muller and Stender and found in a 26 year old patient who had been to Brazil. In 1948, Faust published a review on the 82 cases of ectopic schistosomiasis described thus far [23]. Among these, there were 56 patients with brain compromising and 8 with medullar le‐ sions in the spinal cord. In that occasion, the author highlighted the importance of this form of disease, given that the number of cases was not inconsiderable and that the consequences were, in general, devastating. "In reports of the cases, it has been customary that most au‐ thors address ectopic schistosomiasis as rare or really rare. These designations are no more applicable, despite these syndromes being relatively infrequent" [23]. In the same year, Kane and Most wrote yet another review article on literature concerning neurological lesions caused by *Schistosoma*, including the medullary and brain forms, and called attention to the occurrence of 25 cases of cerebral neuroschistosomiasis japonica among north-American sol‐ diers in the Second World War, between the years of 1944 and 1946 [24]. In this study, 88% (22 cases) of the initial fecal exams of North-American military patients with cerebral neuro‐ schistosomiasis japonica were negative for eggs in the stool samples in the first examination and that 40% (10 cases) remained negative after several serial examinations. All patients had confirmation of *Schistosoma* eggs in pathological anatomy examinations, obtained through CNS biopsy or necropsy. The author, at the time, already said that "Cautious and repeated fecal examinations are important for clinical diagnosis, but specific treatment must not be postponed if there are adequate evidence for presumptive diagnosis, even because all fecal examinations may be negative for eggs even when the patient already shows neurological

**3. Spinal cord schistosomiasis**

124 Parasitic Diseases - Schistosomiasis

Up until the 1980's, medullar lesion caused by *Schistosoma* was, in most published cases, confirmed through fragments of nervous tissue obtained through biopsy or necropsy. In 1985, Scrimgeour and Gedjusek published a scientific literature review of the years between 1930 and 1984 in which they identified 52 cases of spinal cord schistosomiasis mansoni and 12 cases of spinal cord schistosomiasis haematobia, confirmed by pathological anatomy me‐ dullar examinations. On the occasion, the authors highlighted the importance of suspecting neuroschistosomiasis in any patient who had been exposed to the risk of infection and pre‐ sented neurological manifestations [25]. The authors reaffirmed that the patients in general had no previous manifestation of schistosomiasis and that only 22% of *S. mansoni* carriers had eggs found in their feces or rectum biopsy and only 25% of the *S. haematobium* carriers had eggs found in their urine or feces [25]. This difficulty in finding the eggs is not casual, nor an abnormal occurrence. It is part of the disease's laboratory findings pattern [26]. De‐ spite having already done some serological examinations that could have confirmed infec‐ tion by the parasites even without finding eggs, the diagnosis of spinal cord schistosomiasis was still very complicated and controversial at that time, specially because there were no de‐ tailed imaging examinations. Some studies already used presumptive diagnosis criteria, in which the presence of lower thoracic or high lumbar medullar symptoms, the demonstra‐ tion of exposure to *Schistosoma* through parasitological or immunological methods, and the exclusion of other causes for myelitis were enough for attributing the clinical manifestation to spinal cord schistosomiasis [27]. There were, still, some divergences in the literature re‐ garding the acceptance of the parasitological e/or immunological methods for case confirma‐ tion, but the risk of sequelae involved in biopsying the medulla led to the confirmation of the diagnosis through pathological anatomical methods being abandoned [28-31]. In the last decades, spinal cord schistosomiasis diagnosis has been reached through confirmation of *Schistosoma* infection using pararitological or serological methods associated with the exclu‐ sion of other causes for myelopathy [32-37].

With the technological improvement in the field of immunological methods and imag‐ ing examinations, including the introduction of Computerized Tomography (CT) and, mainly, Magnetic Resonance Imaging (MRI), differential diagnosis with other causes of myelopathy has become easier. This can explain, at least in part, the great amount of ar‐ ticles being published in this area [22,38-44]. With the increase in interest for adventure tourism, a growing number of spinal cord schistosomiasis cases, who live in non-endem‐ ic areas and are infected in their leisure time, have been described in the literature. Spi‐ nal cord schistosomiasis, which had been considered a rare disease from the beginning of the 20th century to the early 80's, now appeared to have been, in fact, under-recog‐ nized. In the last years, it has attracted more and more the interest of researchers and is considered one of the forms of schistosomiasis that must be reevaluated from the point of view of disease burden by Public Health Organizations [45].

There are, in the literature, studies that allow an evaluation on the incidence or prevalence in the population with schistosomiasis or exposed to the risk of schistosomiasis. In biblio‐ graphical studies of international literature between 1930 and 1984, 64 patients were identi‐ fied (12 with *S. haematobium* and 52 with *S. mansoni*) and described in the literature [25]. Another bibliographical study published, which included 12 years worth of publications, identified 280 patients with described in the literature [21]. This sudden increase in the num‐ ber of publications regarding this disease reiterates the hypotheses that the improvement in diagnostic methods has allowed an increase in the recognition of this disease. Thus, neuro‐ schistosomiasis must now be recognized as a problem to be considered by the developers of public policies.

**4. Physiopathology**

Knowledge on spinal cord schistosomiasis physiopathology has greatly improved in the last years, although some blanks still remain. It is known that periovular granulomas play a cen‐ tral role in medullar lesion [54, 55]. Although signs of vasculitis with immune complexes de‐ posits close to the granulomas can be found [59], it is believed that these findings have a secondary role in the lesion. The mass effect produced by the granuloma and the edema that surrounds it may lead to the compression of internal structures to the spinal canal, causing secondary and definitive ischemic lesions. The eggs get to the medulla via the Batson venus plexus through embolization or through anomalous worm migration, in which case they would lay their eggs next to the medulla [54, 55]. This plexus was first described in 1940 by Batson, who intended to explain a mechanism for metastases being dispersed to the CNS [60]. It is a network of valveless veins that connects the inferior vena cava to the veins in the vertebrae. This plexus allows the embolization of eggs without the need for collateral circu‐ lation or arteriovenous shunts, seen only in the hepatosplenic and cardiopulmonary forms of schistosomiasis. The eggs of *S. mansoni* and of S. *haematobium* are larger, oval-shaped and have spine (terminal in *S. haematobium* and lateral in *S. mansoni*), which may explain why these species are associated with different neurological manifestations, most of them attrib‐ uted to lesions in the lower levels segments of spinal cord, and, less frequently, higher mani‐ festations in the spinal cord's medulla [54]. *S. japonicum* eggs are smaller, lack a spine, and are round, allowing them to reach the brain more easily through these anastomoses, causing a smaller proportion of medullar lesions. The probability of these eggs getting to the places where the lesion occurred through ectopic oviposition is reinforced in some situations, in which several eggs are found very close together, or even creating cordons. Aside from that, worm couples were found near these locations in medullar veins. The highest proportion of causes occurring in man can be explained by their greater exposure to focuses of transmis‐

Spinal Cord Schistosomiasis http://dx.doi.org/10.5772/53771 127

sion and by differences in pelvic anatomy between both sexes [54].

initial stages of the disease (Figures 1 and 2).

The greater proportion of spinal cord schistosomiasis cases in patients who present the initial form of schistosomiasis when compared to the ones who present the advanced form appears to have immunological and hemodynamic reasons. Pittella and Lana-Peixo‐ to studied extensively the occurrence of *Schistosoma* eggs in necropsy nervous tissue samples, and found eggs in 26% of the patients who presented hepatosplenic forms and 61,1% of the patients who presented cardiopulmonary forms [53, 61]. Periovular reac‐ tions in the CNS are intense in patients presenting medullary forms of neuroschistoso‐ miasis, with periovular necrotic-exudative granulomas that are typically found in the

Patients with hepatosplenic and cardiopulmonary forms usually present discreet periovular reaction, without granulomatous response or with smaller granulomas, in non-productive stages and located in several regions of the CNS [53-55, 61, 62]. Only 10% of the patients who had eggs in the CNS in the necropsy, and presented these advanced forms also present‐ ed neurological symptoms when alive. [53]. One of the suggested mechanisms to explain egg dispersion in cases of patients with hepatosplenic and cardiopulmonary schistosomiasis

The proportion of patients who go from schistosomiasis to spinal cord schistosomiasis is un‐ known. But a study done in Bahia with 212 patients with non-traumatic medullar lesion shows that 9.9% (21 cases) of patients had schistosomotic etiology [30]. In another, similar study performed at the Sarah Kubitschek Hospital, in Brazil, with 231 patients, this etiology corresponded to close to 6% of the patients (13 cases) of non-traumatic medullar lesion seen in 4.5 years [36]. There are several indications that this disease has been under-diagnosed [46-49] in endemic areas because of the difficulty of access to more sophisticated diagnostic methods and, in more developed areas, because of the lack of knowledge on the part of the doctors about this disease [26]. This situation has been changing in the last years, particular‐ ly in Brazil, due to the improvement in diagnostic tools and better access to medical atten‐ tion in the country. This may explain the increase of cases in patients of this country that are reported in the literature.

Knowledge of the epidemiological profile of the patient with spinal cord schistosomiasis can be obtained based on case reports or serial cases [26, 42, 50-52]. Spinal cord schistosomiasis occurs more frequently in male patients, with ages between 15 and 50, having low worm burden, up until then not presenting symptomatic neuroschistosomiasis, presenting intesti‐ nal and hepatointestinal forms, living in non-endemic areas (who had an eventual exposure to risk of infection) or in endemic areas.

There are several indications that a greater risk for spinal cord schistosomiasis cases in pa‐ tients is present for patients with low worm burdens [53-55]. This means that spinal cord schistosomiasis can occur in patients with low risk for severe hepatosplenic forms. They are patients who do not present symptoms relating to the digestive tract, which often may lead the assisting physician not to think of schistosomiasis diagnosis. Other patients, aside from not having digestive symptoms, are not frequently exposed to the risk of transmission, mak‐ ing the diagnosis even harder. Examples of said patient profile are tourists who have been only sporadically exposed in areas of schistosomiasis transmission [27, 56, 57], patients who live in urban areas who, usually, have sporadic contact with transmission focuses [58], resi‐ dents of areas that are recent focuses of transmission [56], and residents of areas with low prevalence for schistosomiasis [26].

Despite the severity of sequelae and disabilities caused by spinal cord schistosomiasis, this form of schistosomiasis is still not being considered in the development of public policies that aim to control the morbidity of schistosomiasis [1, 45, 58].

## **4. Physiopathology**

graphical studies of international literature between 1930 and 1984, 64 patients were identi‐ fied (12 with *S. haematobium* and 52 with *S. mansoni*) and described in the literature [25]. Another bibliographical study published, which included 12 years worth of publications, identified 280 patients with described in the literature [21]. This sudden increase in the num‐ ber of publications regarding this disease reiterates the hypotheses that the improvement in diagnostic methods has allowed an increase in the recognition of this disease. Thus, neuro‐ schistosomiasis must now be recognized as a problem to be considered by the developers of

The proportion of patients who go from schistosomiasis to spinal cord schistosomiasis is un‐ known. But a study done in Bahia with 212 patients with non-traumatic medullar lesion shows that 9.9% (21 cases) of patients had schistosomotic etiology [30]. In another, similar study performed at the Sarah Kubitschek Hospital, in Brazil, with 231 patients, this etiology corresponded to close to 6% of the patients (13 cases) of non-traumatic medullar lesion seen in 4.5 years [36]. There are several indications that this disease has been under-diagnosed [46-49] in endemic areas because of the difficulty of access to more sophisticated diagnostic methods and, in more developed areas, because of the lack of knowledge on the part of the doctors about this disease [26]. This situation has been changing in the last years, particular‐ ly in Brazil, due to the improvement in diagnostic tools and better access to medical atten‐ tion in the country. This may explain the increase of cases in patients of this country that are

Knowledge of the epidemiological profile of the patient with spinal cord schistosomiasis can be obtained based on case reports or serial cases [26, 42, 50-52]. Spinal cord schistosomiasis occurs more frequently in male patients, with ages between 15 and 50, having low worm burden, up until then not presenting symptomatic neuroschistosomiasis, presenting intesti‐ nal and hepatointestinal forms, living in non-endemic areas (who had an eventual exposure

There are several indications that a greater risk for spinal cord schistosomiasis cases in pa‐ tients is present for patients with low worm burdens [53-55]. This means that spinal cord schistosomiasis can occur in patients with low risk for severe hepatosplenic forms. They are patients who do not present symptoms relating to the digestive tract, which often may lead the assisting physician not to think of schistosomiasis diagnosis. Other patients, aside from not having digestive symptoms, are not frequently exposed to the risk of transmission, mak‐ ing the diagnosis even harder. Examples of said patient profile are tourists who have been only sporadically exposed in areas of schistosomiasis transmission [27, 56, 57], patients who live in urban areas who, usually, have sporadic contact with transmission focuses [58], resi‐ dents of areas that are recent focuses of transmission [56], and residents of areas with low

Despite the severity of sequelae and disabilities caused by spinal cord schistosomiasis, this form of schistosomiasis is still not being considered in the development of public policies

public policies.

126 Parasitic Diseases - Schistosomiasis

reported in the literature.

to risk of infection) or in endemic areas.

prevalence for schistosomiasis [26].

that aim to control the morbidity of schistosomiasis [1, 45, 58].

Knowledge on spinal cord schistosomiasis physiopathology has greatly improved in the last years, although some blanks still remain. It is known that periovular granulomas play a cen‐ tral role in medullar lesion [54, 55]. Although signs of vasculitis with immune complexes de‐ posits close to the granulomas can be found [59], it is believed that these findings have a secondary role in the lesion. The mass effect produced by the granuloma and the edema that surrounds it may lead to the compression of internal structures to the spinal canal, causing secondary and definitive ischemic lesions. The eggs get to the medulla via the Batson venus plexus through embolization or through anomalous worm migration, in which case they would lay their eggs next to the medulla [54, 55]. This plexus was first described in 1940 by Batson, who intended to explain a mechanism for metastases being dispersed to the CNS [60]. It is a network of valveless veins that connects the inferior vena cava to the veins in the vertebrae. This plexus allows the embolization of eggs without the need for collateral circu‐ lation or arteriovenous shunts, seen only in the hepatosplenic and cardiopulmonary forms of schistosomiasis. The eggs of *S. mansoni* and of S. *haematobium* are larger, oval-shaped and have spine (terminal in *S. haematobium* and lateral in *S. mansoni*), which may explain why these species are associated with different neurological manifestations, most of them attrib‐ uted to lesions in the lower levels segments of spinal cord, and, less frequently, higher mani‐ festations in the spinal cord's medulla [54]. *S. japonicum* eggs are smaller, lack a spine, and are round, allowing them to reach the brain more easily through these anastomoses, causing a smaller proportion of medullar lesions. The probability of these eggs getting to the places where the lesion occurred through ectopic oviposition is reinforced in some situations, in which several eggs are found very close together, or even creating cordons. Aside from that, worm couples were found near these locations in medullar veins. The highest proportion of causes occurring in man can be explained by their greater exposure to focuses of transmis‐ sion and by differences in pelvic anatomy between both sexes [54].

The greater proportion of spinal cord schistosomiasis cases in patients who present the initial form of schistosomiasis when compared to the ones who present the advanced form appears to have immunological and hemodynamic reasons. Pittella and Lana-Peixo‐ to studied extensively the occurrence of *Schistosoma* eggs in necropsy nervous tissue samples, and found eggs in 26% of the patients who presented hepatosplenic forms and 61,1% of the patients who presented cardiopulmonary forms [53, 61]. Periovular reac‐ tions in the CNS are intense in patients presenting medullary forms of neuroschistoso‐ miasis, with periovular necrotic-exudative granulomas that are typically found in the initial stages of the disease (Figures 1 and 2).

Patients with hepatosplenic and cardiopulmonary forms usually present discreet periovular reaction, without granulomatous response or with smaller granulomas, in non-productive stages and located in several regions of the CNS [53-55, 61, 62]. Only 10% of the patients who had eggs in the CNS in the necropsy, and presented these advanced forms also present‐ ed neurological symptoms when alive. [53]. One of the suggested mechanisms to explain egg dispersion in cases of patients with hepatosplenic and cardiopulmonary schistosomiasis is that the eggs would get to the CNS by bypassing through collateral portal-like circulation and intrapulmonary arteriovenous shunting, secondary to hemodynamic alterations com‐ mon to these advanced forms of schistosomiasis. In these cases there is major egg dispersion through the CNS through anastomoses, but few of these eggs cause symptoms given that the inflammatory response in these patients is usually discreet. In patients presenting schis‐ tosomiasis in the intestinal and hepatointestinal forms, the most viable way for the worm couples to reach the CNS is Batson's plexus and, therefore, the most common neurological forms are medullary.

**5. Schistosomiasis and immune response**

erally, smaller [63-65].

**6. Clinical manifestations**

During the disease's evolution, immune responses change over time, there being several cy‐ tokines that participate with different responses at each moment. Immediately after infec‐ tion by *Schistosoma*, there is a predominance of T-helper (Th) lymphocytes in action, producing interferon gamma (INF-γ), interleukin (IL)-2, and tumor necrosis factor (TNF)-α. This stage usually lasts an average of 5 to 6 weeks in murine models that corresponds to the acute phase of the disease (Katayama Fever) in humans [63-65]. With the evolution of the disease, this response is substituted by Th2 type and its associated cytokines are IL-4, IL-5, IL-10 and IL-13. At this stage, it is more common for spinal cord schistosomiasis to happen, as shown by the elevated concentration of these cytokines not only in the CSF, but also in the blood and serum from patients with spinal cord schistosomiasis [66]. Concentration of TH1 type cytokines found in patients with spinal cord schistosomiasis was also lower than in patients from the control group. In other words, spinal cord schistosomiasis seems to be more common in patients who present TH2 type of immunological responses, correspond‐ ing to the initial chronic phase of the patient with schistosomiasis, right after the acute phase of the disease, but that may last for years. CD4+ T-cells (T-helper) play a central role in the formation of the granuloma, so much so that in rats without a thymus there is no formation of granulomas and patients with CD4+ T-cell depletion granulomas that may form are, gen‐

Spinal Cord Schistosomiasis http://dx.doi.org/10.5772/53771 129

With the evolution of schistosomiasis, TH2 polarized response is attenuated by suppressor T-cells, which modulate immune response, diminishing the production of cytokines, inhibit‐ ing the formation of granulomas, and diminishing the size of the granulomas that do form [63-65], a situation which has been observed in patients with hepatosplenic and cardiopul‐ monary schistosomiasis. This may explain the reason why there are many patients with ad‐ vanced forms who present multiple eggs in the CNS, without inflammatory reaction around

The typical clinical manifestations of spinal cord spinal cord schistosomiasis is acute or subacute and presents with lumbar pain with or without radiation to lower limbs, evolving with diminishing of muscular strength in these limbs, with the possibility of presenting, in addition, sensory alterations such as hypoaesthesia, paresthesia and dyses‐ thesia [26]. Clinically, there may be myeloradicular or radicular compromising of the medulla, with lesions in several segments of the medulla. Lesions which are higher in the spinal cord and in a functional section of the medulla may present signs of pyrami‐ dal liberation, such as Babinski's or hyperreflexia in the lower limbs. Lower lesions may present themselves as cauda equina syndrome with hypo- or areflexia in the lower limbs and unresponsive plantar-cutaneous reflex. Patients with spinal cord schistosomia‐ sis usually present fecal and urinary retention, or other sphincter alterations, aside from

them and that, therefore, do not elicit any symptom [54, 55, 66].

**Figure 1.** Periovular reaction with granuloma in spinal cord biopsy fragment of a patient with neuroschistosomiasis caused by *Schistosoma mansoni* infection (Optical microscopy, hematoxiline eosine method).

**Figure 2.** Periovular reaction with granulomatous response in spinal cord biopsy fragment of a patient with neuro‐ schistosomiasis caused by *Schistosoma mansoni* infection (Optical microscopy, hematoxiline eosine method).

## **5. Schistosomiasis and immune response**

is that the eggs would get to the CNS by bypassing through collateral portal-like circulation and intrapulmonary arteriovenous shunting, secondary to hemodynamic alterations com‐ mon to these advanced forms of schistosomiasis. In these cases there is major egg dispersion through the CNS through anastomoses, but few of these eggs cause symptoms given that the inflammatory response in these patients is usually discreet. In patients presenting schis‐ tosomiasis in the intestinal and hepatointestinal forms, the most viable way for the worm couples to reach the CNS is Batson's plexus and, therefore, the most common neurological

**Figure 1.** Periovular reaction with granuloma in spinal cord biopsy fragment of a patient with neuroschistosomiasis

**Figure 2.** Periovular reaction with granulomatous response in spinal cord biopsy fragment of a patient with neuro‐ schistosomiasis caused by *Schistosoma mansoni* infection (Optical microscopy, hematoxiline eosine method).

caused by *Schistosoma mansoni* infection (Optical microscopy, hematoxiline eosine method).

forms are medullary.

128 Parasitic Diseases - Schistosomiasis

During the disease's evolution, immune responses change over time, there being several cy‐ tokines that participate with different responses at each moment. Immediately after infec‐ tion by *Schistosoma*, there is a predominance of T-helper (Th) lymphocytes in action, producing interferon gamma (INF-γ), interleukin (IL)-2, and tumor necrosis factor (TNF)-α. This stage usually lasts an average of 5 to 6 weeks in murine models that corresponds to the acute phase of the disease (Katayama Fever) in humans [63-65]. With the evolution of the disease, this response is substituted by Th2 type and its associated cytokines are IL-4, IL-5, IL-10 and IL-13. At this stage, it is more common for spinal cord schistosomiasis to happen, as shown by the elevated concentration of these cytokines not only in the CSF, but also in the blood and serum from patients with spinal cord schistosomiasis [66]. Concentration of TH1 type cytokines found in patients with spinal cord schistosomiasis was also lower than in patients from the control group. In other words, spinal cord schistosomiasis seems to be more common in patients who present TH2 type of immunological responses, correspond‐ ing to the initial chronic phase of the patient with schistosomiasis, right after the acute phase of the disease, but that may last for years. CD4+ T-cells (T-helper) play a central role in the formation of the granuloma, so much so that in rats without a thymus there is no formation of granulomas and patients with CD4+ T-cell depletion granulomas that may form are, gen‐ erally, smaller [63-65].

With the evolution of schistosomiasis, TH2 polarized response is attenuated by suppressor T-cells, which modulate immune response, diminishing the production of cytokines, inhibit‐ ing the formation of granulomas, and diminishing the size of the granulomas that do form [63-65], a situation which has been observed in patients with hepatosplenic and cardiopul‐ monary schistosomiasis. This may explain the reason why there are many patients with ad‐ vanced forms who present multiple eggs in the CNS, without inflammatory reaction around them and that, therefore, do not elicit any symptom [54, 55, 66].

## **6. Clinical manifestations**

The typical clinical manifestations of spinal cord spinal cord schistosomiasis is acute or subacute and presents with lumbar pain with or without radiation to lower limbs, evolving with diminishing of muscular strength in these limbs, with the possibility of presenting, in addition, sensory alterations such as hypoaesthesia, paresthesia and dyses‐ thesia [26]. Clinically, there may be myeloradicular or radicular compromising of the medulla, with lesions in several segments of the medulla. Lesions which are higher in the spinal cord and in a functional section of the medulla may present signs of pyrami‐ dal liberation, such as Babinski's or hyperreflexia in the lower limbs. Lower lesions may present themselves as cauda equina syndrome with hypo- or areflexia in the lower limbs and unresponsive plantar-cutaneous reflex. Patients with spinal cord schistosomia‐ sis usually present fecal and urinary retention, or other sphincter alterations, aside from erectile dysfunction [26]. The amount of time between the beginning of the symptoms and the establishment of the complete manifestation normally ranges from a few days to a couple of weeks [21, 26, 66-68]. In general, these patients do no present systemic symptoms. Some patients may present cephalalgia, vomiting and other signs of menin‐ geal irritation, such as Kernig's, Brudzinski's or nuchal rigidity [67]. When there is radi‐ culopathy, patient may present Lasègue's sign. Spinal cord schistosomiasis' typical triad is diminishing of muscular strength, with sensory alterations in the lower limbs associat‐ ed with bladder dysfunction, this triad is found in 92,6% of the cases [26].

ing inflammatory lesions and ruling out tumorous lesions. The affected area may present with increased volume or just an increase of paramagnetic contrast caption (Figures 3a, 3b, and 3c). The most frequently found aspect is a granulated pattern that may not be exclusive to, but is highly suggestive of, spinal cord schistosomiasis (Figures 4 and 5). A CT picture has a lower sensibility and, in some cases, may show evidence of increased volume or just

Spinal Cord Schistosomiasis http://dx.doi.org/10.5772/53771 131

**Figure 4.** Sagital magnetic ressonance imaging (T2 phase) in a spinal cord schistosomiasis patient. It is observed a

Nonspecific examinations may suggest the etiology in a clinically suggestive patient. Rou‐ tine CSF examination may show alterations in a high percentage of the cases, such as in‐ crease in proteins in 95% and of leukocytes in 98% of the cases, generally with predominance of lymphocytes and presence of eosinophil granulocytes in 40.8% of the cases

granular impregnation of gadolinium magnetic contrast in thoracic-lumbar spinal cord.

**9. Laboratory examinations**

high contrast caption [30, 38, 39, 41, 43, 44, 50, 68-71].

## **7. Diagnosis**

Spinal cord schistosomiasis' diagnosis it not always simple, but there is a consensus that an adequate diagnosis must include typical clinical manifestation (medullar and/or radicular symptoms), proof of exposure to *Schistosoma* through parasitological or immunological methods, and exclusion of other possible causes of myelopathy [26, 27, 32-37, 67-69].

**Figure 3.** a-c). Sagital magnetic ressonance imaging in T1 phase (Figure 3a), no contrast T2 phase (Figure 3b), and contrast T2 phase (Figure 3c) in a spinal cord schistosomiasis patient.

## **8. Imaging examinations**

MRIs are very important when investigating spinal cord schistosomiasis and may show im‐ portant data about the location and extension of the lesions. Although it's not a examination that can define completely the etiology, it may collaborate to differential diagnosis by show‐ ing inflammatory lesions and ruling out tumorous lesions. The affected area may present with increased volume or just an increase of paramagnetic contrast caption (Figures 3a, 3b, and 3c). The most frequently found aspect is a granulated pattern that may not be exclusive to, but is highly suggestive of, spinal cord schistosomiasis (Figures 4 and 5). A CT picture has a lower sensibility and, in some cases, may show evidence of increased volume or just high contrast caption [30, 38, 39, 41, 43, 44, 50, 68-71].

**Figure 4.** Sagital magnetic ressonance imaging (T2 phase) in a spinal cord schistosomiasis patient. It is observed a granular impregnation of gadolinium magnetic contrast in thoracic-lumbar spinal cord.

## **9. Laboratory examinations**

erectile dysfunction [26]. The amount of time between the beginning of the symptoms and the establishment of the complete manifestation normally ranges from a few days to a couple of weeks [21, 26, 66-68]. In general, these patients do no present systemic symptoms. Some patients may present cephalalgia, vomiting and other signs of menin‐ geal irritation, such as Kernig's, Brudzinski's or nuchal rigidity [67]. When there is radi‐ culopathy, patient may present Lasègue's sign. Spinal cord schistosomiasis' typical triad is diminishing of muscular strength, with sensory alterations in the lower limbs associat‐

Spinal cord schistosomiasis' diagnosis it not always simple, but there is a consensus that an adequate diagnosis must include typical clinical manifestation (medullar and/or radicular symptoms), proof of exposure to *Schistosoma* through parasitological or immunological

(a) (b) (c)

**Figure 3.** a-c). Sagital magnetic ressonance imaging in T1 phase (Figure 3a), no contrast T2 phase (Figure 3b), and

MRIs are very important when investigating spinal cord schistosomiasis and may show im‐ portant data about the location and extension of the lesions. Although it's not a examination that can define completely the etiology, it may collaborate to differential diagnosis by show‐

contrast T2 phase (Figure 3c) in a spinal cord schistosomiasis patient.

**8. Imaging examinations**

methods, and exclusion of other possible causes of myelopathy [26, 27, 32-37, 67-69].

ed with bladder dysfunction, this triad is found in 92,6% of the cases [26].

**7. Diagnosis**

130 Parasitic Diseases - Schistosomiasis

Nonspecific examinations may suggest the etiology in a clinically suggestive patient. Rou‐ tine CSF examination may show alterations in a high percentage of the cases, such as in‐ crease in proteins in 95% and of leukocytes in 98% of the cases, generally with predominance of lymphocytes and presence of eosinophil granulocytes in 40.8% of the cases [28]. Despite being highly suggestive of spinal cord schistosomiasis, pelocytoses, high pro‐ tein concentration and eosinophilia in CSF are not always present [28].

There are several immunological examination techniques to be used in the serum or CSF. The most used ones try to reveal the presence of antibodies which are specific for soluble egg antigens (SEAs), antigens from the digestive tube of adult worms, or antigens from cer‐ cariae. The most used serology techniques are ELISA (Enzyme-linked immunosorbent as‐ say) or indirect immunofluorescence assay. Immunological blood examinations have a sensitivity varying between 80% and 97% and when tested on CSF sensitivity may vary be‐ tween 56% to 97% (22, 26, 35, 68, 69, 72]. Immunological examinations must be considered as strong evidence of active *Schistosoma* infection, even though many patients who have been cured of the parasites still test positive for a long time and also that there is a chance of cross-reaction with other parasites. Biopsying the medulla is only done, nowadays, in cases when after extensive investigation, the need to rule out tumors is still present [26, 51, 68, 69, 72, 73]. It becomes apparent that no examination may be considered as gold standard for the diagnosis of *Schistosoma* infection and, therefore, analysis of specific examinations must oc‐ cur alongside analysis of clinical and epidemiological aspects. Also, results from imaging ex‐ aminations and presence of eosinophil granulocytes in CSF or eosinophilia in peripheral

Spinal Cord Schistosomiasis http://dx.doi.org/10.5772/53771 133

A proper investigation must be done to exclude other causes for the medullar and/or radicular lesion, such as bacterial infections (e.g. tuberculosis, syphilis, abscesses), viral infections (e.g. cytomegalovirus, poliovirus, enterovirus, HZV, HSV-1, HSV-2, HIV, HTLV-I) parasitic diseases (e.g. cysticercosis, toxoplasmosis), fungal infections or non-in‐ fectious, such as neoplasia, systemic lupus erythematosus, auto-immune vasculitis, dia‐ betic vasculitis, B12 vitamin deficiency, multiple sclerosis, Guillan-Barré Syndrome,

Treatment is done through the use of corticosteroids and schistosomicides. The corticoste‐ roids will diminish the inflammation and lead to regression of the granuloma, being even more important than the schistosomicide. The latter will eliminate the egg production by killing the adult worms and indirectly diminish the production of soluble egg antigens, which are important stimuli for the granulomas. In a few cases, surgical procedures may be necessary to decompress medullar structures. In other cases, treatment is clinical [26, 51, 73]. The schistosomicide may be oxamniquine (15 mg/kg dose for adults and 20 mg/kg for chil‐ dren with up to 5 years of age) or praziquantel (60 mg/kg for children with up to 15 years of age and 50 mg/kg for adults), both in a single dose [73]. The corticosteroid dose is the equiv‐ alent to prednisone 1 mg/kg/day, and must be administered for 6 months, with careful sus‐

In addition, complementary care involves adequate integral approach with psychosocial re‐ habilitation and motor physical therapy, intermittent bladder checking, prevention of pres‐ sure ulcers, among others. Special care must be taken regarding urodynamic aspects [26, 70,

73]. The use of laxatives or enema may be needed for patients with fecal retention.

pension, given that patients may present relapses during the process.

blood must be considered.

**10. Treatment**

among others [26, 51, 68, 69, 72, 73].

**Figure 5.** T2 phase axial magnetic ressonance imaging in a spinal cord schistosomiasis patient. It is observed a hyper‐ signal in the thoracic-lumbar spinal cord levels.

Identifying the *Schistosoma* infection through the presence of eggs in the feces (*S. mansoni* and *S. japonicum*) or urine (*S. haematobium*) presents less sensitivity than immunological ex‐ aminations. In the case of *S. mansoni*, sensitivity varies depending on the methodology and the number of samples being 15.4% [36], 40.0% [26], or 42.5% [42]. Among the several techni‐ ques for parasitological examinations, the one which presents the highest sensitivity for *S. mansoni* is Kato-Katz. A study in which 3 to 5 serial fecal samples were collected detected eggs in the feces of 59.4% of the patients [51]. Rectal biopsy, when identifying eggs, shows a positivity ranging from 57.5% [42] to 88,9% [51]. Given that parasitological examinations may be considered to have 100% specificity, any of these tests returning a positive must be considered proof of *Schistosoma* infection, but it may not exclude schistosomiasis when re‐ sults come back negative.

There are several immunological examination techniques to be used in the serum or CSF. The most used ones try to reveal the presence of antibodies which are specific for soluble egg antigens (SEAs), antigens from the digestive tube of adult worms, or antigens from cer‐ cariae. The most used serology techniques are ELISA (Enzyme-linked immunosorbent as‐ say) or indirect immunofluorescence assay. Immunological blood examinations have a sensitivity varying between 80% and 97% and when tested on CSF sensitivity may vary be‐ tween 56% to 97% (22, 26, 35, 68, 69, 72]. Immunological examinations must be considered as strong evidence of active *Schistosoma* infection, even though many patients who have been cured of the parasites still test positive for a long time and also that there is a chance of cross-reaction with other parasites. Biopsying the medulla is only done, nowadays, in cases when after extensive investigation, the need to rule out tumors is still present [26, 51, 68, 69, 72, 73]. It becomes apparent that no examination may be considered as gold standard for the diagnosis of *Schistosoma* infection and, therefore, analysis of specific examinations must oc‐ cur alongside analysis of clinical and epidemiological aspects. Also, results from imaging ex‐ aminations and presence of eosinophil granulocytes in CSF or eosinophilia in peripheral blood must be considered.

A proper investigation must be done to exclude other causes for the medullar and/or radicular lesion, such as bacterial infections (e.g. tuberculosis, syphilis, abscesses), viral infections (e.g. cytomegalovirus, poliovirus, enterovirus, HZV, HSV-1, HSV-2, HIV, HTLV-I) parasitic diseases (e.g. cysticercosis, toxoplasmosis), fungal infections or non-in‐ fectious, such as neoplasia, systemic lupus erythematosus, auto-immune vasculitis, dia‐ betic vasculitis, B12 vitamin deficiency, multiple sclerosis, Guillan-Barré Syndrome, among others [26, 51, 68, 69, 72, 73].

## **10. Treatment**

[28]. Despite being highly suggestive of spinal cord schistosomiasis, pelocytoses, high pro‐

**Figure 5.** T2 phase axial magnetic ressonance imaging in a spinal cord schistosomiasis patient. It is observed a hyper‐

Identifying the *Schistosoma* infection through the presence of eggs in the feces (*S. mansoni* and *S. japonicum*) or urine (*S. haematobium*) presents less sensitivity than immunological ex‐ aminations. In the case of *S. mansoni*, sensitivity varies depending on the methodology and the number of samples being 15.4% [36], 40.0% [26], or 42.5% [42]. Among the several techni‐ ques for parasitological examinations, the one which presents the highest sensitivity for *S. mansoni* is Kato-Katz. A study in which 3 to 5 serial fecal samples were collected detected eggs in the feces of 59.4% of the patients [51]. Rectal biopsy, when identifying eggs, shows a positivity ranging from 57.5% [42] to 88,9% [51]. Given that parasitological examinations may be considered to have 100% specificity, any of these tests returning a positive must be considered proof of *Schistosoma* infection, but it may not exclude schistosomiasis when re‐

signal in the thoracic-lumbar spinal cord levels.

sults come back negative.

tein concentration and eosinophilia in CSF are not always present [28].

132 Parasitic Diseases - Schistosomiasis

Treatment is done through the use of corticosteroids and schistosomicides. The corticoste‐ roids will diminish the inflammation and lead to regression of the granuloma, being even more important than the schistosomicide. The latter will eliminate the egg production by killing the adult worms and indirectly diminish the production of soluble egg antigens, which are important stimuli for the granulomas. In a few cases, surgical procedures may be necessary to decompress medullar structures. In other cases, treatment is clinical [26, 51, 73]. The schistosomicide may be oxamniquine (15 mg/kg dose for adults and 20 mg/kg for chil‐ dren with up to 5 years of age) or praziquantel (60 mg/kg for children with up to 15 years of age and 50 mg/kg for adults), both in a single dose [73]. The corticosteroid dose is the equiv‐ alent to prednisone 1 mg/kg/day, and must be administered for 6 months, with careful sus‐ pension, given that patients may present relapses during the process.

In addition, complementary care involves adequate integral approach with psychosocial re‐ habilitation and motor physical therapy, intermittent bladder checking, prevention of pres‐ sure ulcers, among others. Special care must be taken regarding urodynamic aspects [26, 70, 73]. The use of laxatives or enema may be needed for patients with fecal retention.

## **11. Prognosis**

Evolution depends, fundamentally, on early diagnosis and care, better prognosis being asso‐ ciated with an early introduction of the treatment, and particularly the introduction of glu‐ cocorticoids [26]. Although symptoms and urological functional alterations do not always respond well to adequate treatment, despite its being started precociously [26, 70, 74, 75]. Patients may recover motor function, sensitivity, sphincter and erectile function control, or they may end up with any combination of absence or recovery of some of the aforemen‐ tioned functions. Urodynamic alterations have not shown significant improvement in pa‐ tients who underwent protocol treatment. Ferrari and colleagues (2004) found complete recovery in 31.7% (20) of the patients, 28.3% (18) of the patients presented partial recovery with no functional limitation, 25.4% (16) patients presented partial recovery with functional limitation, and 14.3% (9) of the patients did not improve at all [51]. There were no deaths in this case series. Among the sequelae are paraplegia, paraparesis, dysfunction in the bladder or anal sphincter, sexual dysfunction, definitive sensitivity loss in the affected areas or even paraesthesia and dysesthesia [26, 30, 51]. Detailed studies on the urological aspects, done by Lima (2004) in the Hospital da Restauração in Recife, PE, show that after 9 months of treat‐ ment 52 (80%) of 65 patients, showed alterations in urodynamic examinations and 45 (69.2%) showed alterations in voiding cystourethrogram [74].

treatment of mild forms of schistosomiasis with low worm burdens will be needed in the basic health systems. For an initial diagnosis, the possibility of immediate introduction of se‐ rology as a diagnostic instrument in the Basic Health Units. This examination can be used as diagnostic in those patients who are still untreated. But more studies will be necessary for the development of more effective medicines and of more sensitive methods for parasitolog‐ ical removal. It is also important to disclose the occurrence of this form of schistosomiasis, as well as capacitating professionals for attending these patients, particularly in endemic areas and recently formed focus points. A secondary gain of disclosing information on the exis‐ tence of severe forms may be the population increase in attendance to control measures for

Spinal Cord Schistosomiasis http://dx.doi.org/10.5772/53771 135

this disease.

**Differential diagnosis:**

**Typical clinical manifestation:**

• Paraparesis or paraplegia

**Presumptive diagnosis:**

• Ages between 15 and 50 • Predominantly male • Low worm burden

**Acknowledgements**

HIS)

• Anal and bladder sphincter dysfunction

• Exclusion of other causes for myelitis

• Bacterial infections: tuberculosis, syphilis, abscesses, Lyme's disease.

• Lumbar pain with or without radiation to lower limbs • Paraesthesia or diminishing of lower limb sensitivity

• Low thoracic or high lumbar medullar symptoms,

• Evolution is generally acute or subacute (between 2 to 60 days)

• Other infections: cysticercosis, toxoplasmosis, Chagas disease, fungal infections

• Viral infections: cytomegalovirus, poliovirus, enterovirus, HZV, HSV-1, HSV-2, HIV, HTLV, EBV, HBV.

multiple sclerosis, polyradiculopathy, Guillan-Barré Syndrome, spinal disc herniation, syringomyelia

• Proof of exposure to *Schistosoma ssp* through parasitological or immunological methods and

**Typical epidemiological profile of patients with spinal cord schistosomiasis:**

• Non-infectious: neoplasia, systemic lupus erythematosus, auto-immune vasculitis, diabetic vasculitis, B12 deficiency,

• Patients thus far do not present symptomatic schistosomiasis or present intestinal and hepatointestinal forms (IS or

A special acknowledgment is dedicated to Luana Hughes Freitas for the discussion of the central ideas, inspiration and encouragement for the production of this document. The au‐ thors also acknowledge Nicole Montenegro, Marcela Montenegro Coelho e Bruno Montene‐

• Patients may reside in endemic areas or non-endemic areas, with eventual exposure to risk of infection

#### **12. Perspectives**

Several factors can actively contribute to the increase in the identification of spinal cord schistosomiasis cases, such as: improvement in diagnostic resources, increase in ecotourism activities with greater exposure of the population to risk of infection, growth of the trans‐ mission area, even in urban areas, and lowering of high parasitical loads, without diminish‐ ing of the global prevalence of schistosomiasis. There is need of investing in the study of spinal cord schistosomiasis, focusing epidemiological aspects such as: prevalence and inci‐ dence, relations between general schistosomiasis incidence and spinal cord schistosomiasis, prevalence and incidence in areas of high and low endemicity, and predisposing factors. De‐ spite how successful controlling the hepatosplenic and cardiopulmonary forms has been throughout the years, control instruments used currently have not shown themselves as suf‐ ficient to control the spinal cord schistosomiasis problem. More studies are needed for im‐ proving the understanding on the real prevalence of the medullary forms of schistosomiasis. Changes in the Health Surveillance Systems are needed to improve control of schistosomia‐ sis, aiming at a better understanding of the schistosomotic morbidity, particularly that of spinal cord schistosomiasis. It is not surprising that schistosomiasis control politics, based on parasitical diagnostic and treatment of the infected, have not been able to reduce the morbidity of the disease due to medullar lesions, since most patients who present this form of schistosomiasis have low worm burdens and present with negative fecal examinations. To reach effective control of spinal cord schistosomiasis, the introduction of more sensitive diagnostic methods and the development of more effective medicines for diagnosis and treatment of mild forms of schistosomiasis with low worm burdens will be needed in the basic health systems. For an initial diagnosis, the possibility of immediate introduction of se‐ rology as a diagnostic instrument in the Basic Health Units. This examination can be used as diagnostic in those patients who are still untreated. But more studies will be necessary for the development of more effective medicines and of more sensitive methods for parasitolog‐ ical removal. It is also important to disclose the occurrence of this form of schistosomiasis, as well as capacitating professionals for attending these patients, particularly in endemic areas and recently formed focus points. A secondary gain of disclosing information on the exis‐ tence of severe forms may be the population increase in attendance to control measures for this disease.

#### **Differential diagnosis:**

**11. Prognosis**

134 Parasitic Diseases - Schistosomiasis

**12. Perspectives**

Evolution depends, fundamentally, on early diagnosis and care, better prognosis being asso‐ ciated with an early introduction of the treatment, and particularly the introduction of glu‐ cocorticoids [26]. Although symptoms and urological functional alterations do not always respond well to adequate treatment, despite its being started precociously [26, 70, 74, 75]. Patients may recover motor function, sensitivity, sphincter and erectile function control, or they may end up with any combination of absence or recovery of some of the aforemen‐ tioned functions. Urodynamic alterations have not shown significant improvement in pa‐ tients who underwent protocol treatment. Ferrari and colleagues (2004) found complete recovery in 31.7% (20) of the patients, 28.3% (18) of the patients presented partial recovery with no functional limitation, 25.4% (16) patients presented partial recovery with functional limitation, and 14.3% (9) of the patients did not improve at all [51]. There were no deaths in this case series. Among the sequelae are paraplegia, paraparesis, dysfunction in the bladder or anal sphincter, sexual dysfunction, definitive sensitivity loss in the affected areas or even paraesthesia and dysesthesia [26, 30, 51]. Detailed studies on the urological aspects, done by Lima (2004) in the Hospital da Restauração in Recife, PE, show that after 9 months of treat‐ ment 52 (80%) of 65 patients, showed alterations in urodynamic examinations and 45

Several factors can actively contribute to the increase in the identification of spinal cord schistosomiasis cases, such as: improvement in diagnostic resources, increase in ecotourism activities with greater exposure of the population to risk of infection, growth of the trans‐ mission area, even in urban areas, and lowering of high parasitical loads, without diminish‐ ing of the global prevalence of schistosomiasis. There is need of investing in the study of spinal cord schistosomiasis, focusing epidemiological aspects such as: prevalence and inci‐ dence, relations between general schistosomiasis incidence and spinal cord schistosomiasis, prevalence and incidence in areas of high and low endemicity, and predisposing factors. De‐ spite how successful controlling the hepatosplenic and cardiopulmonary forms has been throughout the years, control instruments used currently have not shown themselves as suf‐ ficient to control the spinal cord schistosomiasis problem. More studies are needed for im‐ proving the understanding on the real prevalence of the medullary forms of schistosomiasis. Changes in the Health Surveillance Systems are needed to improve control of schistosomia‐ sis, aiming at a better understanding of the schistosomotic morbidity, particularly that of spinal cord schistosomiasis. It is not surprising that schistosomiasis control politics, based on parasitical diagnostic and treatment of the infected, have not been able to reduce the morbidity of the disease due to medullar lesions, since most patients who present this form of schistosomiasis have low worm burdens and present with negative fecal examinations. To reach effective control of spinal cord schistosomiasis, the introduction of more sensitive diagnostic methods and the development of more effective medicines for diagnosis and

(69.2%) showed alterations in voiding cystourethrogram [74].


• Non-infectious: neoplasia, systemic lupus erythematosus, auto-immune vasculitis, diabetic vasculitis, B12 deficiency, multiple sclerosis, polyradiculopathy, Guillan-Barré Syndrome, spinal disc herniation, syringomyelia

#### **Typical clinical manifestation:**


#### **Presumptive diagnosis:**


#### **Typical epidemiological profile of patients with spinal cord schistosomiasis:**


## **Acknowledgements**

A special acknowledgment is dedicated to Luana Hughes Freitas for the discussion of the central ideas, inspiration and encouragement for the production of this document. The au‐ thors also acknowledge Nicole Montenegro, Marcela Montenegro Coelho e Bruno Montene‐ gro Coelho for their dedication and support for studies in medullary neuroschistosomiasis. Acknowledgment is also due to Professor Luciano de Souza Queiroz, Department of Pathol‐ ogy, FCM-UNICAMP who produced the images of optical microscopy.

[10] Greenwald B. Schistosomiasis: implications for world travelers and healthcare pro‐

Spinal Cord Schistosomiasis http://dx.doi.org/10.5772/53771 137

[11] Cantiniaux S, Serratrice J, De Roux-Serratrice C, Disdier P, Perez L, Bricaire F, Caumes E, Mary C, Weiller PJ. A group fever: safari's fever. Rev Med Interne 2004;

[12] Ranque S, Gazin P, Delmont J. Schistosomiasis and tourism in the Dogon country,

[13] Grobusch MP, Muhlberger N, Jelinek T, Bisoffi Z, Corachan M, Harms G, Matteelli A, Fry G, Hatz C, Gjorup I, Schmid ML, Knobloch J, Puente S, Bronner U, Kapaun A, Clerinx J, Nielsen LN, Fleischer K, Beran J, da CS, Schulze M, Myrvang B, Hellgren U. Imported schistosomiasis in Europe: sentinel surveillance data from TropNetEur‐

[14] Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. Lancet 2006;

[15] Lambertucci JR, Sousa-Pereira SR, Silva LC. Myeloradiculopathy in acute schistoso‐

[16] Jesus AR, Silva A, Santana LB, Magalhaes A, de Jesus AA, de Almeida RP, Rego MA, Burattini MN, Pearce EJ, Carvalho EM. Clinical and immunologic evaluation of 31

[17] Lambertucci JR, Serufo JC, Gerspacher-Lara R, Rayes AA, Teixeira R, Nobre V, An‐ tunes CM. Schistosoma mansoni: assessment of morbidity before and after control.

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## **Author details**

André Ricardo Ribas Freitas1 and Rodrigo Nogueira Angerami2

1 Municipal Secretary of Health of Campinas and Department of Public Health State, Facul‐ ty of Medical Sciences, University of Campinas – UNICAMP, Campinas-SP, Brazil

2 Municipal Secretary of Health of Campinas and Department of Clinical Medicine, Faculty of Medical Sciences, State University of Campinas – UNICAMP, Campinas-SP, Brazil

## **References**


[10] Greenwald B. Schistosomiasis: implications for world travelers and healthcare pro‐ viders. Gastroenterol Nurs 2005; 28(3):203-205.

gro Coelho for their dedication and support for studies in medullary neuroschistosomiasis. Acknowledgment is also due to Professor Luciano de Souza Queiroz, Department of Pathol‐

and Rodrigo Nogueira Angerami2

1 Municipal Secretary of Health of Campinas and Department of Public Health State, Facul‐

2 Municipal Secretary of Health of Campinas and Department of Clinical Medicine, Faculty

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140 Parasitic Diseases - Schistosomiasis


**Chapter 7**

**Study on** *Schistosomiasis mansoni* **and Comorbidity with**

In Brazil, despite decreases in the prevalence rates of schistosomiasis and in the frequency of severe forms, the targets for transmission control have not been reached. This should be taken to be a warning sign indicating that schistosomiasis must not be neglected in this country (Conceição & Coura 2012). It is also important to emphasize that co-infections such as the

One of the few studies involving comorbidity with hepatitis B was conducted by Serufo et al. (1998). Two areas with schistosomiasis infection in Minas Gerais were correlated: one endemic and the other, a controlled non-endemic area, where it was shown that schistosomiasis did not change the course of hepatitis B. This had previously been emphasized by Andrade (1965) and

Lyra et al. (1976) compared cases of hepatosplenic schistosomiasis (HSS) and control cases of the hepatointestinal form of the disease, including cases with a variety of illnesses. They found that the patients with HSS were carriers for HBsAg more frequently than the other groups were. Bassily et al. (1979, 1983) detected hepatitis B surface antigen in cases of hepatosplenic schistosomiasis. Pereira et al. (1994) did not find any significant difference in the frequency of these markers for hepatitis B between patients with the hepatointestinal form of schistoso‐ miasis, the hepatosplenic form and controls. Conceição et al. (1998) evaluated the prognosis for individuals infected with *S. mansoni* and carriers of hepatitis B virus, among patients attended at the Teaching Hospital of the Federal University of Rio de Janeiro, Brazil. Non‐ significant predominance of HBsAg, anti-HBsAg and anti-HBc was detected among patients with the hepatosplenic form of schistosomiasis, who presented greater severity of clinical

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© 2013 Conceição and Coura; licensee InTech. This is an open access article 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 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Hepatitis B and C Virus Infection**

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55510

hepatitis B and C viruses play a role.

**1. Introduction**

Maria José Conceição and José Rodrigues Coura

**1.1. Comorbidity of** *S. mansoni* **infection and hepatitis B**

Prince (1970), in studies on patients in different geographical regions.
