Neuroschistosomiasis

Infectious Disorders

Updated 07.01.2024
Released 02.08.2015
Expires For CME 07.01.2027

Neuroschistosomiasis

Authors: Nancy E Bonthius PharmD, Daniel J Bonthius MD PhD

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Editor: Christina M Marra MD

Neuroschistosomiasis

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Introduction

Overview

Neuroschistosomiasis is an infection of the nervous system by a blood fluke of the genus Schistosoma. A common infection within tropical regions, neuroschistosomiasis can cause substantial neurologic disability. The brain and spinal cord can both be affected by this parasite. The infection can be effectively treated with a combination of antiparasite agents, corticosteroids, and surgery. Efforts are underway worldwide to eliminate, or at least substantially reduce, schistosomal infections.

Key points

	• Schistosomiasis is a common intravascular infection caused by parasitic Schistosoma trematode worms.
	• People are infected during routine agricultural, domestic, occupational, and recreational activities that expose them to infested water.
	• Neuroschistosomiasis results from migration of parasite eggs into the nervous tissue and resultant host immune response.
	• Neuroimaging, serology, molecular testing, and biopsy can all be important components of the diagnostic workup for neuroschistosomiasis.
	• Antischistosomal drugs, corticosteroids, and surgery are useful for treating neuroschistosomiasis.

Historical note and terminology

Humans have been afflicted with schistosomiasis for more than 2500 years (20). However, it was not until 1851 that Theodor Bilharz Maximilian, a German surgeon, discovered the trematode worm in an autopsy while working at the Kasr-el-Aini Hospital of Cairo in Egypt, initially naming it Distomum haematobium. He communicated his findings to his former teacher, Carl Theodor Ernst von Siebold, in a series of letters. In 1853, extracts from these letters together, with von Siebold’s comments, were published in the German Zoological Journal (05).

Due to the peculiar morphology of the worm, it could not be included in the genus Distomum, as was initially proposed; thus, the parasite was described in 1856 as Bilharzia haematobium by Meckel Von Hemsbach in a thesis entitled “The Geology of the Human Body” (44). A zoologist, David Weinland, apparently unaware of this thesis, re-described the worm as Schistosoma haematobium in 1858 (80). Subsequently, in 1948, the International Commission on Zoological Nomenclature established the name Schistosoma, which is the name of the parasite (30). Bilharz also described Schistosoma mansoni, but this species was re-described by Louis Westenra Sambon in 1907 at the London School of Tropical Medicine, who named it after his teacher Patrick Manson. The life cycle was described by da Silva in 1908 (07).

Molecular phylogenetic studies suggest that Schistosoma spp originated in Asia and that a mollusk-transmitted progenitor colonized Africa and gave rise to both the terminal-spined and lateral-spined egg species groups, the latter containing Schistosoma mansoni (66).

Schistosoma mansoni likely appeared only after the transatlantic dispersal of the snail species Biomphalaria from the neotropica to Africa, an event that occurred about 2 to 5 million years ago, based on the African fossil record. This parasite became abundant in tropical Africa and, much later, entered the New World with the slave trade (46). On arriving in South America, Schistosoma species found favorable climatic conditions that promoted its spread. Since then, factors that have continued to favor its spread include growth in international travel, refugee and population migration, and the development of new water resources (62).

Five species of Schistosoma infect humans. Schistosoma mansoni, Schistosoma hematobium, and Schistosoma japonicum are the most widely distributed and are present in multiple tropical and subtropical countries. In contrast, Schistosoma mekongi and Schistosoma intercalatum are much more restricted in their geographic distributions.

Most granulomas following schistosomal infection develop in the intestine and liver (Schistosoma mansoni and Schistosoma japonicum), or genitourinary tract (Schistosoma haematobium) (62). Cerebral schistosomiasis is usually caused by Schistosoma japonicum, whereas myelopathy is most often induced by Schistosoma mansoni and Schistosoma haematobium (56).

Clinical manifestations

Presentation and course

	• The first symptom of schistosomiasis is often a maculopapular rash, which erupts at the site on the skin where schistosome larvae have penetrated.
	• Symptoms of acute schistosomiasis appear several weeks after exposure to infected water and include fever, malaise, myalgia, fatigue, nonproductive cough, anorexia, diarrhea, hematuria, abdominal pain, and headaches.
	• Months after exposure, patients may develop chronic schistosomiasis, which typically manifests as disease of the urinary tract, intestines, or liver.
	• Neuroschistosomiasis occurs when schistosomal eggs gain access to the CNS.
	• Symptoms of neuroschistosomiasis in the brain most commonly include encephalopathy, seizures, and increased intracranial pressure.
	• Symptoms of neuroschistosomiasis in the spinal cord most commonly include back pain, radicular pain, leg weakness, and bladder incontinence.

Early symptoms. Schistosome larvae, referred to as “cercariae,” often produce a maculopapular rash at the site where they penetrate the skin of human hosts. Typical skin lesions are discrete erythematous raised eruptions that vary in size from 1 to 3 mm. The skin eruption may occur within a few hours of exposure or may be delayed up to 1 week.

Acute schistosomiasis (Katayama syndrome). Katayama syndrome is an early clinical manifestation that occurs 2 to 6 weeks after contact with infected water (64). Symptoms may include fever, malaise, myalgia, fatigue, nonproductive cough, anorexia, diarrhea (with or without the presence of blood), hematuria (Schistosoma haematobium), abdominal pain, and headaches. Prolonged hypereosinophilia in Katayama syndrome due to Schistosoma mansoni can be associated with watershed cerebral infarctions (67).

Chronic phase. Chronic schistosomal infections begin insidiously and are usually associated with a chronic local inflammatory response to schistosomal eggs trapped in the host tissues, which may lead to inflammatory and obstructive disease in the urinary system (Schistosoma haematobium) or intestinal disease, hepatosplenic inflammation, and liver fibrosis (Schistosoma mansoni, Schistosoma intercalatum, Schistosoma japonicum, and Schistosoma mekongi) (27). Chronic schistosomal infections can also lead to cancer. In particular, Schistosoma haematobium is a proven carcinogenic agent; its chronic presence within the urinary tract can lead to bladder cancer, which is usually, but not exclusively, squamous cell carcinoma (84).

Neurologic manifestations. Neurologic manifestations of schistosomiasis occur after adult worms residing within the mesentery and pelvis lay eggs, which gain access to the brain or spinal cord via retrograde flow through venous systems (10). Neurologic complications are rare but are the most severe form of schistosomal infection. The neurologic complications can occur in both the acute and the chronic phases of schistosomiasis, but they occur more commonly in the chronic phase (63).

Cerebral complications of acute neuroschistosomiasis include delirium and acute confusional state, loss of consciousness, headache, dysphasia, visual field impairment, ataxia, and focal motor deficits (24; 63). Seizures are common in acute neuroschistosomiasis (85). Seizures occur most frequently with Schistosoma japonicum but have also been reported with Schistosoma mansoni (04).

Signs and symptoms of elevated intracranial pressure, such as headache, nausea, vomiting, and papilledema, are also common presentations of acute neuroschistosomiasis (03). A slowly expanding cerebral lesion mimicking a brain tumor has been reported with Schistosoma mansoni (55). Cerebellar schistosomiasis, with symptoms of ataxia, nystagmus, and vomiting, has been described due to severe necrotic-exudative granulomatous inflammation around numerous Schistosoma mansoni ova within the cerebellum (60). Cerebral hemorrhages due to a meningitic granulomatous reaction around Schistosoma mansoni eggs have also been reported (58).

Cognitive impairment is the principal manifestation of chronic neuroschistosomiasis. This problem has been described mostly in children with Schistosoma japonicum and Schistosoma mansoni infections (14). Memory impairment, delayed reaction times, and diminished academic performance have all been attributed to chronic neuroschistosomiasis in children (32). However, the specific cognitive dysfunctions associated with chronic schistosomal infections have not been clearly defined due to the many potential confounding factors that accompany the impoverished environments in which the infections most commonly occur. These confounding factors include poor educational systems, the presence of comorbidities, and compromised nutritional status. Evidence that the neurocognitive impairments in these children are actually due to the infection and not merely a byproduct of the confounding factors lies in the finding that schoolchildren infected with Schistosoma japonicum have shown improved performance on working memory after specific treatment for schistosomiasis (48).

Spinal schistosomal myeloradiculopathy, primarily caused by Schistosoma mansoni, usually occurs early after infection and is more likely to be symptomatic than cerebral schistosomiasis. Patients with spinal schistosomiasis usually present with lumbar pain, lower limb radicular pain, leg weakness, sensory loss, and bladder dysfunction due to egg deposition and granuloma formation in the spinal cord or cauda equina (51; 23; 19). The presentation often resembles the clinical picture of acute transverse myelitis (42). Spinal schistosomiasis can also present as a rapidly progressive paraparesis mimicking a spinal cord neoplasm or tuberculosis (10). Cervical intramedullary schistosomiasis has been reported as a rare cause of acute tetraparesis (33).

Prognosis and complications

For neuroschistosomiasis, prognosis and treatment outcome are more favorable in cerebral disease than in spinal myeloradiculopathy. Cerebral neuroschistosomiasis usually has an indolent course, responds well to therapy, and often has a good outcome if treatment is provided. In contrast, spinal cord disease often presents more acutely and is associated with severe and permanent neurologic deficits. The prognosis in spinal myeloradiculopathy depends in part on factors related to the disease itself (nature and location of the spinal cord involvement) and in part on the timing of treatment (early or late). Early treatment can substantially improve the outcome of patients with spinal cord involvement. For this reason, immediate empirical use of praziquantel in combination with a corticosteroid is recommended for presumptive treatment at the first clinical sign of spinal cord involvement. This is especially relevant for the management of patients presenting in rural areas of endemic countries where sophisticated diagnostic facilities are not available (26).

Clinical vignette

A 28-year-old, right-handed Northern European woman presented to the emergency department after a generalized tonic-clonic seizure. On initial assessment by a neurologist, she had intact cognition and language ability, and the remainder of her neurologic examination was unremarkable. Four years earlier, she had spent 4 months in Gambia and had gone swimming on several occasions in a local river.

During her workup for the seizure, an EEG revealed occasional left temporal theta-range slowing. A noncontrast MRI revealed T2 hyperintensities in both temporal lobes, and a subsequent MRI with gadolinium demonstrated mottled linear enhancement in the temporal lobes and right cerebellum. Cerebrospinal fluid and rheumatologic labs were normal. She was started on levetiracetam for seizure prophylaxis, though in the setting of self-tapering this medication, she experienced a breakthrough seizure.

The patient eventually underwent a craniotomy for biopsy of the left temporal lesion, which showed prominent granulomas with dense infiltrates composed of eosinophils, plasma cells, and lymphocytes surrounding light-refracting eggshells displaying the pathognomonic spine shape of Schistosoma mansoni. Stool and urine were negative for ova. However, serum ELISA and antibody immunoblots confirmed exposure to Schistosoma mansoni. She received treatment with praziquantel (50 mg/kg as a single oral dose) and steroids (methylprednisolone 1.0 gm IV/day for 5 consecutive days), followed by oral corticosteroid therapy (prednisone 1 mg/kg/day) for 6 months. At follow-up 6 months later, she was seizure-free and was experiencing no sequelae of her previous infection or its treatment. The levetiracetam was tapered and discontinued, and she remained seizure-free at the 12-month follow-up.

Biological basis

Etiology and pathogenesis

	• Schistosomiasis is caused by infection with a parasitic worm.
	• The larval form of the worm is released from snails into fresh water, then gains access to human hosts by penetrating the skin.
	• After entering humans, the larvae mature into adult worms that reside principally within the veins of the intestinal and hepatosplenic system.
	• Much of the pathology of schistosomiasis is due to the delayed hypersensitivity reaction triggered by the eggs of the parasite.
	• Within the CNS, the inflammatory response to the eggs results in tissue necrosis and granuloma formation.

Life cycle. Schistosomes are blood-dwelling trematodes. Mammals, including humans, are the definitive hosts, and freshwater snails are intermediate hosts of the parasites. Schistosoma mansoni infects the aquatic snail Biomphalaria glabrata. Cercarias (larval forms of parasites) are released by the snails about 1 month after infection. Human infection occurs after direct contact of human host skin with freshwater harboring cercariae within 12 to 24 hours after emerging from the snail (26). Skin penetration is achieved via mechanical activity and production of proteolytic enzymes. Following penetration of the skin, the larvae transform into the migrating stage, schistosomulum, invade the lymphatic system and are transported to the lungs through the blood circulation. After a short period of time in the lungs, the schistosomula re-emerge in the bloodstream and are carried to the portal circulation (liver sinusoids) to complete their life cycle. Parasites attain maturity in 6 to 8 weeks in the liver, after which they form mating pairs of males and females and begin to produce eggs. Many of these eggs become trapped in the inferior mesenteric veins or lodge in the liver (especially Schistosoma mansoni) where they cause intestinal and hepatosplenic disease. Different species of Schistosoma preferentially inhabit different venous tributaries, giving rise to the specific syndromes associated with each species. Most eggs release adult worms into the stool after invading the walls of the blood vessels and traveling through the intestinal wall. The life cycle is complete when the eggs hatch, releasing miracidia that subsequently infect freshwater snails (04).

Pathogenesis. Parasite eggs and the delayed hypersensitivity host reaction that the eggs induce are responsible for the clinical features of schistosomiasis (27). This complex interaction between parasite eggs and host immunity results in granuloma formation, which is a T-cell-dependent process. A predominantly T-helper 1 reaction occurs during the early stages of infection and later shifts to an egg-induced T-helper 2 (Th2) response, which is important in the immunologic mechanisms of defense against the parasite (52). Immunogenicity and pathogenicity depend on host genetic factors. In particular, specific HLA class I and II antigens are associated with more severe or less severe manifestations of disease. For example, HLA-B16 and HLA-Cw*02 increase the vulnerability to Schistosoma haematobium-related bladder cancer (81), whereas HLA-DR, DQ, and DP alleles protect against liver fibrosis (28).

CNS involvement during Schistosoma infection can occur as a result of embolization of eggs from the portal, mesenteric, and pelvic venous system or as a result of the anomalous migration of adult worms to sites close to the CNS followed by in situ egg deposition (54). Embolization of eggs from the porto-mesenteric or pelvic systems may occur in two ways: through the arterial system after crossing shunts or portopulmonary anastomosis (via the azygos vein in the setting of portal hypertension) or through retrograde venous flow into the valveless vertebral epidural Batson’s venous plexus, which connects the portal venous system and inferior venae cavae to the spinal cord and cerebral veins (61). Potential CNS infection sites include the forebrain, brainstem, cerebellum, leptomeninges, and the choroid plexus (68). The inflammatory response of the host to the antigens released by parasite eggs and ensuing severe immunogenic reactions may result in brain tissue necrosis with granuloma formation and eventually space-occupying lesions. Within the brain, microglia and macrophages constitute the principal cellular components of the granulomas in neuroschistosomiasis (72).

Immunogenicity of schistosomal egg components has been associated with specific antigens that are released after the egg’s death and disintegration. The immune response to the antigens released from the egg reaches a maximum intensity during the early stages of infection and results in the formation of necrotic-exudative granulomas. The immune response declines as infection evolves. At the peak of the granulomatous response (usually 8 to 10 weeks), the associated immunological responses include the production of cytokines, macrophage inhibitory factor, and eosinophil stimulation promoter. Cytokine production declines concurrently with the waning of the granulomatous inflammation (12 weeks and onwards), whereas the granulomatous response waxes and wanes. Eventually, fibrosis ensues and is usually irreversible (71).

To promote their survival in the host, schistosomal species suppress and evade host immune responses. They do this by driving strong regulatory responses that inhibit the development of normal immune responses to antigens. As a result, schistosomal infections can interfere with host responsiveness to vaccines. Indeed, several studies have shown that children in developing countries are less responsive to vaccines than children from developed nations. Although this lack of responsiveness to vaccines in developing countries is likely multifactorial in origin, schistosomal infections are believed to play an important role. Schistosomiasis has been associated with reduced antibody levels to measles, tetanus toxoid, and hepatitis B vaccines. Furthermore, clearance of the infection through administration of praziquantel restores normal vaccine responsiveness. Thus, schistosomiasis may render a host more vulnerable to other infections, including those for which people are usually protected by vaccines (49).

Some important aspects of schistosomal pathogenesis are mediated via an interaction between the parasite and host platelets. Schistosomes secrete serine proteases and express ectoenzymes that can bind to platelets and interfere with normal platelet function and survival. As a result, infected patients can develop thrombocytopenia and coagulopathy. Furthermore, because platelets are a component of the innate immune system, in which they recognize invading parasites and activate other immune cells, platelet dysfunction in schistosomiasis can weaken the immune response and reduce the host’s ability to recognize and eliminate parasites, potentially resulting in prolonged and chronic infection (01).

The interaction of schistosomes with platelets also activates platelets and induces them to release various immune mediators, including chemokines and cytokines, as well as anti-inflammatory factors, such as thromboxane and transforming growth factor-beta. As a result, platelet function disruption can contribute to excessive inflammation and inadequate immune response, both of which can impact disease progression (15).

Schistosomes not only affect platelet function but can also reduce platelet numbers. This occurs through decreased production and increased destruction. This reduction in platelet numbers interferes with hemostasis and can lead to increased bruising and gastrointestinal bleeding (06).

Several animal model systems of neuroschistosomiasis have been developed. Cerebral schistosomiasis has been effectively modeled by the injection of live S. japonicum eggs into the brains of rabbits or mice. This procedure leads to granuloma formation within the brain, accompanied by weight loss and behavioral deficits (21; 78; 72). Furthermore, schistosomal myeloradiculopathy can be modeled by injecting S mansoni eggs into the spinal subarachnoid space of rats. This leads to the deposition of eggs within the spinal cord parenchyma, accompanied by corresponding sensory and motor deficits, as well as histologic abnormalities (75). It is hoped that these animal model systems will elucidate the pathogenesis of neuroschistosomiasis and facilitate the development of more effective therapies.

Epidemiology

	• People are affected with schistosomiasis worldwide, but the great majority of infections occur in sub-Saharan Africa.
	• After malaria, schistosomiasis is the most impactful of human parasitic diseases.
	• Within endemic areas, children and young adults have the highest prevalence of schistosomiasis.
	• Following trauma and tumors, neuroschistosomiasis is the third most common cause of myelopathy worldwide.

Schistosomiasis is a disease caused by parasitic worms. Although the Schistosoma worms that cause this disease are not found in the United States, people are infected worldwide. Among parasitic diseases of humans, schistosomiasis is second only to malaria in its devastating clinical impact (13). The World Health Organization estimates that schistosomiasis currently infects more than 140 million people worldwide. Ninety percent of these infections occur in sub-Saharan Africa, where conditions are optimal for the parasite’s survival and its transmission among snails and impoverished humans (82).

Different species of the parasite have different geographical distributions. Most of the infections with Schistosoma haematobium, Schistosoma mansoni, and Schistosoma intercalatum occur in Sub-Saharan Africa, whereas Schistosoma mansoni infection is endemic in some parts of Brazil, Venezuela, and the Caribbean. Schistosoma japonicum infection occurs mostly in the People’s Republic of China and the Philippines, as well as some regions of Indonesia. Schistosoma mekongi is found along the Mekong River in Cambodia and Laos (62). Particularly important transmission sites include Lake Malawi, and Lake Victoria in Africa, the Poyang and Dongting Lakes in China, and the Mekong River in Laos.

In endemic areas, infection is usually acquired during childhood. Poor personal hygiene and playing in mud and water increase the risk of infection in children (22). Throughout childhood, in endemic areas, the intensity and prevalence of infection rise with age and peak between ages 15 and 20 years.

Schistosomiasis often affects women performing domestic chores, such as washing clothes in infested water. Those living in poor and rural communities, particularly those depending on agriculture and fishing, have the highest prevalence of infection. Contact of female genitalia with infested water can lead to female genital schistosomiasis, which occurs in half of infected women and affects approximately 40 million women and girls. This infection can cause genital itch, abnormal discharge, stress incontinence, dyspareunia, and infertility. Social stigma exacerbates this problem, as community health workers commonly confuse female genital schistosomiasis with sexually transmitted infections, and as the infection can damage the hymen, it can lead to accusations of sexual misconduct. In addition, female genital schistosomiasis may facilitate the spread and acquisition of HIV (29).

With the rise of tourism and travel, an increasing number of tourists are contracting schistosomiasis. Tourists may present with severe acute infection or unusual manifestations, such as paralysis.

In Brazil and Africa, refugee movements and migration into urban areas are introducing the disease into new locations. Increasing population size and corresponding needs for power and water have led to increased transmission. Infections are not uniformly distributed within communities. Within endemic communities, 5% to 10% of the people may be heavily infected, whereas the remainder have only mild to moderate infections. The risk of infection is highest among those who live near lakes or rivers. However, disease presence also depends on altitude and moisture conditions. For example, in Uganda, almost no transmission occurs at altitudes greater than 1400 meters or where the annual rainfall is less than 900 mm (34).

The World Health Organization estimates that schistosomiasis causes at least 12,000 deaths per year, and the number is probably much greater due to the unattributed pathologies that it causes, including liver and kidney failure, bladder cancer, and ectopic pregnancies due to female genital schistosomiasis (82). Most of these deaths occur in sub-Saharan Africa.

Outside of the primary infection sites within the intestines, liver, lungs, and genitourinary system, the CNS is the most common ectopic focus of infection. Postmortem studies have demonstrated that nearly one third of patients with schistosomiasis have some degree of nervous system involvement. However, only one third of these patients with histologic evidence of disease have neurologic symptoms. Within the nervous system, the spinal cord is the most common site of disease. Thus, because of the high prevalence of the parasitic worm and its proclivity to infect spinal cord tissues, neuroschistosomiasis is the third most common cause of myelopathy worldwide, following trauma and tumors. Why some patients develop nervous system involvement while others do not is unknown. However, at least one study suggests that a recent first-time exposure to the parasite makes patients more vulnerable to nervous system disease (77).

Prevention

	• Tourists to sub-Saharan Africa and other places where schistosomiasis is endemic can minimize their risk of acquiring the disease by avoiding swimming or wading in lakes, streams, and other bodies of fresh water.
	• Mass drug administration of antiparasite drugs, such as praziquantel, within endemic regions has successfully reduced the burden of disease within those regions.
	• People returning from endemic areas with a history of exposure to fresh water should be screened by serologic testing for schistosomiasis and, if positive, should be treated to prevent the onset of disease.
	• Because snails play a key role in the life cycle of schistosome worms, controlling snail populations or manipulating snail genetics may be effective methods of preventing schistosomiasis.

Because schistosomiasis is transmitted to humans through exposure to infested water, individuals can greatly reduce their risk of infection by remaining aware of their water sources and practicing good hygiene. On a population basis, however, water, sanitation, and hygiene programs have had little impact (09). Instead, an approach that has had greater public health success is mass drug administration. In this approach, an antischistosome medication is administered on a population basis with the goal of reducing the prevalence and intensity of infection. Because praziquantel is the only drug available to treat all forms of schistosomiasis, praziquantel has been the drug of choice for mass drug administration programs. In the mass drug administration strategy, praziquantel has been distributed primarily to school-aged children, 5 to 15 years of age, because they have the highest infection burden and can be accessed by their presence in schools. Praziquantel is distributed periodically at a rate determined by the local burden of disease (17).

Mass drug administration reduces the prevalence and severity of schistosomiasis within endemic regions. With mass drug administration as a cornerstone of its strategy, the World Health Organization has established the goal of eliminating schistosomiasis. In 2022, the World Health Organization issued guidelines geared toward the control and elimination of schistosomiasis. Among the most important of these guidelines is the expansion of mass drug administration from school-aged children alone to everyone over the age of 2 years. In addition, the guidelines call for a reduction in the prevalence threshold for triggering mass drug administration to a population and increasing the frequency of treatment (40).

Although widespread administration of praziquantel has had a positive public health impact in many countries and regions, praziquantel and the entire strategy of mass drug administration are limited in their ultimate ability to control the disease. Praziquantel kills only adult schistosomes and is ineffective against earlier developmental stages of the parasite. Furthermore, praziquantel does not prevent reinfection, and severe rebound disease can occur when mass drug administration is interrupted. Indeed, when wide-scale use of praziquantel has been discontinued in endemic areas, very high percentages of children (approximately 80%) have developed recurrent aggressive inflammation. This has sometimes required frequent praziquantel treatment to avoid severe morbidity that is worse than before the mass drug administration began (25). In addition, the parasite may become resistant to praziquantel following multiple rounds of mass drug administration. For these reasons, prevention strategies must go beyond mass drug administration alone and will likely need to include the provision of a safe water supply, health education that includes improvement of water sanitation, and snail control (43).

Ultimately, vaccination represents the greatest hope for eliminating schistosomiasis. No vaccine for schistosomiasis is yet available. However, clinical trials involving human volunteers are underway to develop an effective vaccine. One critically important factor bearing on the role of vaccination for schistosomiasis is the fact that schistosomes do not multiply within humans. Therefore, a vaccine would not need to completely eliminate schistosomiasis within an infected individual. Partial reduction in worm burden as a result of vaccination could be of substantial clinical benefit. Working groups of vaccination experts have established the metric that an effective prophylactic vaccine should reduce worm burden and egg excretion rates by 75% (45).

Travelers and those living in endemic areas should avoid contact with fresh water. Acute schistosomiasis should be suspected in a febrile patient with recent freshwater contact, and treatment with praziquantel should be initiated early if infection is confirmed through diagnostic testing results or clinical suspicion is high. Early treatment after high-risk exposures reduces morbidity.

People returning from endemic areas with a history of exposure to fresh water should be screened by serologic testing for schistosomiasis. Many infections are silent and may remain asymptomatic. Urine and stool screening should be obtained in patients with positive serologies to permit species identification. Rates of schistosomiasis seropositivity have been recorded as high as 23% in African refugees (57).

Topical lipid formulations of N, N-diethyl-m-toluamide (DEET), such as LipoDEET, are effective in killing schistosome cercariae. Minimal absorption, low cost, and a range of activity against schistosomes make this compound an excellent prophylactic agent against human and animal schistosomiasis, especially for travelers (59).

Because the snail plays a key role in the life cycle of Schistosoma and its transmission to humans, snail control could be a viable means of substantially reducing the incidence of schistosomiasis in humans. However, a major concern with issues of snail control is balancing the goal of snail curtailment with healthy environmental interests. Scientists have begun to explore effective and responsible methods of snail control, including spatiotemporal targeting, better molluscicides, as well as the use of natural enemies, traps, and repellants (70). One other unique strategy to reduce snail numbers is through the planting of trees. In 2006, China initiated a tree-planting program in endemic regions of schistosomiasis as part of an effort to eliminate the disease. Hundreds of thousands of fast-growing trees such as poplars were planted with the aim of reducing soil moisture, and consequently, reducing snail populations. Although the program’s impact is still being evaluated, preliminary results suggest that the program has successfully reduced snail densities and the incidence of acute schistosomiasis (83).

Because snails mount an immune response against schistosome infections, efforts have also focused on the possibility of exploiting the snail itself to control schistosomal populations and, thereby, reduce the human burden of schistosomiasis (53). One approach that has become scientifically possible is the use of gene drives to alter the resistance of snails to schistosome infection, thus, interrupting schistosome transmission at the intermediate host stage. Gene drives are genetic engineering technologies that alter the probability of specific alleles being transmitted from one generation to the next. The technological advances in genome editing make it possible to genetically modify natural snail populations to efficiently spread schistosome resistance traits among them. Through genetic alterations in snail populations, the ability of schistosomiasis to enter, infect, propagate, and exit from snails could all be reduced. Although the use of gene drives to reduce schistosomiasis in snails is technologically feasible, it carries substantial ecological and biological ramifications and risks that will require careful scientific and ethical review (41).

Diagnostic workup

	• The most definitive test for diagnosing schistosomiasis is the finding of viable eggs in urine, feces, or tissue biopsies. However, the search for viable eggs has a relatively low sensitivity, especially in urine and feces.
	• Serologic assays are useful for the detection of antibodies against schistosomal antigens but are unable to discriminate between active infection and past exposure and unable to distinguish among species.
	• Molecular techniques (PCR) to detect schistosome DNA in feces and bodily fluids is a valuable technique but suffers from sampling limitations because of the irregular distribution of eggs, especially in the feces.
	• Neuroimaging can be useful for detecting brain and spinal cord granuloma.

The gold standard for diagnosing active schistosomiasis is the detection of viable eggs in urine, feces, or tissue biopsies. Viability of the eggs is determined by the detection of fully differentiated larvae within them. However, attempts to detect eggs, especially in urine and feces, may be falsely negative, especially early in the course of infection or with light infections. Diagnosing neuroschistosomiasis can be difficult as neurologic symptoms are often nonspecific, and laboratory findings of eosinophilia or Schistosoma ova in stool or urine may be absent. In the absence of a brain or spinal cord biopsy, a presumptive diagnosis of neuroschistosomiasis should be made based on clinical, laboratory, and epidemiological evidence (14).

Definitive diagnosis of brain or spinal cord schistosomiasis can be confirmed through histopathological examination of biopsy material or at autopsy. Positive serological test results provide evidence of exposure only and may persist life-long despite successful pharmacological treatment. The most frequently used serologic test is an enzyme-linked immunosorbent assay (ELISA) IgG anti-SEA (surface egg antigen), which offers high sensitivity and intermediate specificity, because of cross-reaction with other helminths (38). Thus, the majority of patients with symptoms of neuroschistosomiasis in which the diagnosis is supported only by serologic evidence should be considered as having probable neuroschistosomiasis.

Cerebrospinal fluid from patients with schistosomal myeloradiculopathy shows lymphocytic pleocytosis, high protein concentrations, presence of eosinophils, and an increased IgG index (11). These findings in CSF, especially the presence of eosinophils, can point toward a parasitic infection as the cause of neurologic symptoms.

A PCR assay has been developed for schistosomiasis. This assay can quantitatively and with high sensitivity detect schistosomal DNA in human stool, serum, urine, saliva, and CSF. Much of the schistosomal DNA detected in bodily fluids by PCR is cell-free DNA. These are DNA fragments released into the blood and redistributed in other body fluids. The origin of the cell-free DNA fragments from parasites is not fully understood. They may be released inactively or actively secreted by the parasite directly or contained in their excretory-secretory products. The amount of cell-free schistosomal DNA depends on the pathogen burden within the host (73). The PCR method has become a valuable tool for both the diagnosis and surveillance of schistosomiasis (08; 79). It is especially valuable for low-intensity infections, where detection of infection would not be possible using other parasitological methods.

Neuroimaging with CT or MRI is useful for detecting brain and spinal cord granuloma. With cerebral involvement, CT demonstrates a hyperdense lesion surrounded by hypodense edema, with an associated mass effect. A linear enhancement surrounded by multiple tree-like punctuate nodules may be pathognomonic of cerebral schistosomiasis (39). MRI of the spinal cord typically reveals enlargement of the middle or lower thoracic cord in the acute phase and hyperintensity on T2-weighted sequences, with solitary or multiple irregularly enhancing patches following intravenous gadolinium injection on T1-weighted sequences. When infection is chronic, spinal cord atrophy can be seen, with diffuse hyperintensity on T2-weighted imaging (16).

Management

	• Praziquantel is the cornerstone of treatment for schistosomiasis.
	• Because praziquantel kills adult worms but not eggs or larvae, a second dose of praziquantel may be necessary weeks or months after the first dose.
	• Corticosteroids are useful for treatment of the hypersensitivity reaction against schistosomal worms and for treatment of the edema surrounding granulomas within the CNS.
	• Surgical interventions may be necessary for lesions causing mass effect within the brain or spinal cord.

The goals of chemotherapy are 2-fold. The first goal is to cure the disease. The second goal is to control transmission of the parasite in endemic areas. Response to treatment is evaluated by resolution of symptoms and by the number of eggs excreted. Antischistosomal drugs prevent egg-laying by killing adult worms. Therefore, a declining number of eggs is associated with successful treatment. However, the antischistosomal drugs do not kill the eggs or developing worms. For this reason, in the initial 2 weeks after treatment, the egg count may not decrease because eggs laid before the treatment require 2 weeks to be shed. Viable eggs can be excreted for 6 to 8 weeks after treatment. Therefore, 6 to 8 weeks after treatment, the treatment should be repeated to improve parasitologic cure. Patients’ stool and urine should again be tested for the presence of eggs 6 months after treatment. Treatment is repeated for patients who persistently excrete eggs. If symptoms recur, hematuria occurs, or eosinophilia is noted, then repeat parasite investigation should be performed. It must be remembered that, even following complete eradication of the parasite, serology may remain positive for years (02).

Among the antischistosomal drugs, praziquantel and oxamniquine (no longer available in the United States) are commonly used, but praziquantel is the treatment of choice for all species of schistosomiasis. Praziquantel is a broad-spectrum schistosomicidal drug that kills adult worms, resulting in a parasitological cure in 70% to 90% of patients (65). It is used for the treatment of individual patients and for mass community treatment programs and is usually well-tolerated. Praziquantel induces ultrastructural changes in the parasite, resulting in increased permeability to calcium ions (18). Calcium ions accumulate in the parasite cytosol, leading to muscle contractions and ultimate paralysis of adult worms. In addition, the worm's tegument membrane (the natural covering of the worm body) is damaged, exposing the worm to the patient's immune response, which leads to worm death (18). The dose of praziquantel ranges between 40 and 60 mg/kg/day (02). A 5-day course of praziquantel (50 mg/kg/day in two daily doses) is recommended for neuroschistosomiasis (11). Resistance to praziquantel treatment is developing but uncommon (76).

There are several issues with the pharmacodynamics of praziquantel that limit its effectiveness. The drug is orally administered and has a substantial first-pass effect in the liver, which reduces its bioavailability. Due to this first-pass effect, high doses of praziquantel are required, which necessitates large tablet sizes, thus making its administration challenging for children. When tablets are split to treat children, the bitter taste is unacceptable to them. Furthermore, high oral doses often induce abdominal pain, nausea, and allergic reactions (50). To circumvent these problems, nanotechnology solutions are being devised. In particular, investigations are underway to utilize nanoparticles to encapsulate praziquantel and serve as drug delivery systems. Both polymers and inorganic nanoparticles have been developed for this purpose. Preliminary results are promising, as the nanoformulations are showing improved pharmacokinetics (increased efficiency, longer sustained plasma concentrations, and enhanced bioavailability) and increased efficacy (reduction in parasite burden, egg counts, and granuloma diameters) (37).

In addition to their use as delivery systems for praziquantel, nanoparticles are also being developed that have their own intrinsic antischistosomal actions. Most of the experimental work is being done with compounds derived from plants. For example, an imidazole alkaloid extracted from the leaves of the jaborandi plant has strong activity against adult, young, and egg forms of Schistosoma mansoni. However, because it is an apolar molecule with poor solubility, its usefulness as a therapeutic in the conventional sense is poor. However, when incorporated into a nanosystem, its practical usefulness is greatly increased. Nanotechnology for treating schistosomiasis is still in preclinical phases but may eventually improve options and outcomes (12).

Because of a need to expand the armamentarium of therapeutic agents against schistosomiasis and because development and testing of new drugs is time- and resource-intensive, existing antimalarial drugs are being evaluated for use against schistosomiasis. One such antimalarial drug being evaluated is artemether. Combination treatment with artemether and praziquantel can kill schistosomes during the first 3 weeks of infection and is synergistic in killing adult worms (74). Clinical studies show that artemether is also active against all three major schistosome parasites (mainly schistosomula) (47).

Another antimalarial drug under investigation is the combination mefloquine-artesunate. Individuals co-infected with Plasmodium and Schistosoma who are treated with a mefloquine-artesunate for Schistosoma haematobium may experience a dual benefit of clearance of malaria parasitemia and reduction of schistosomiasis-related morbidity (35). However, for the treatment of schistosomiasis, the addition of mefloquine-artesunate to praziquantel showed no benefit over praziquantel alone (36).

Oxamniquine is another antischistosomal agent. However, it appears to be effective only against Schistosoma mansoni, with a cure rate of 60% to 90%. It is metabolized into an ester by schistosomes, and this metabolite damages the tegument of male schistosome worms while interrupting egg production in their female counterparts.

Prednisolone, 40 mg daily for 5 days, can be used for the hypersensitivity reaction known as Katayama syndrome, but no consensus exists regarding proper antihelminthic treatment for this syndrome.

Patients with prominent neurologic symptoms or space-occupying lesions should receive adjunctive therapy with corticosteroids (02). Corticosteroids suppress inflammatory response and granuloma formation, thereby preventing further tissue damage. Prednisolone or dexamethasone can be used in combination with schistosomicidal agents in schistosomal encephalopathy. Rapid improvement of acute schistosomal myelitis has been observed after use of corticosteroids (69). Treatment of acute schistosomiasis with corticosteroids prior to treatment with praziquantel may avoid potential neurologic complications triggered by massive release of antigenic materials by antischistosomal agents (31). Corticosteroids can be started with intravenous methylprednisolone (15 to 20 mg/kg) over 5 to 7 days followed by oral prednisolone (1 to 1.5 mg/kg/day for 3 weeks followed by a progressive and gradual dose reduction). Surgical intervention may be necessary in lesions causing mass effect but is more often performed as a diagnostic procedure.

Surgical treatment should be reserved for specific cases, such as those with evidence of spinal cord compression, when there is clinical deterioration despite medical treatment, and when there is considerable diagnostic uncertainty. Decompressive laminectomy, mass extirpation, and liberation of roots may be necessary when myelitis progresses (26).

Future challenges. The fight against schistosomiasis will require a multifaceted approach. Part of this approach will be medical. New drugs need to be developed that act effectively on both adult and larval schistosomes. Effective vaccines need to be developed. There is also a need to develop new diagnostic procedures that are simple, rapid, and specific to CNS infections. Other important aspects of the effort to curtail schistosomiasis are nonmedical. These will include measures to contain transmission by snail control, health education and promotion, and improved sanitary conditions. Ultimately, substantial containment of the schistosomiasis problem will likely occur only with elimination of its principal underlying cause, which is poverty (27; 25).

References

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Ernest Nwazor FMCP MBBS
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Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: Female = male
Heredity: None
Population groups selectively affected: None
Occupation groups selectively affected: None

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Neuroschistosomiasis

Differential Diagnosis

Hernia of the lumbosacral disc
Trauma
Intrathecal injection of contrast or chemotherapy
Radiotherapy
Tumor
- Vitamin B12-deficiency
- Antiphospholipid syndrome
- Diabetic vasculitis
- Autoimmune vasculitis
- HIV
- HTLV-1
- HSV
- Syphilis
- Bacterial abscess
- Tuberculosis
- Hepatitis B and C
- Multiple sclerosis
- Neuromyelitis optica
- Syringomyelia
- Polyradiculopathy
- Cavernous malformation
- Aneurysm
- Stroke
- HSV and other viral encephalitis
- Mycobacteria abscess
- Syphilitic gumma
- Cryptococcosis
- Histoplasmosis
- Coccidioidomycosis
- Blastomycosis
- Toxoplasmosis
- Other parasitic diseases of the nervous system
- Neoplastic disorders
- Systemic lupus erythematosus
- Behçet disease
- Sarcoidosis
- Hematoma
- Tuberous sclerosis
- MOG antibody disease (MOGAD)
- Neurofibromatosis

Schistosomal myeloradiculopathy	Cerebral schistosomiasis with solitary intracranial mass
Hernia of the lumbosacral disc Trauma Intrathecal injection of contrast or chemotherapy Radiotherapy Tumor Vitamin E or B12 deficiency Copper deficiency Antiphospholipid syndrome Diabetic vasculitis Autoimmune vasculitis HIV HTLV-1 HSV Syphilis Bacterial abscess Tuberculosis Hepatitis B and C Multiple sclerosis Neuromyelitis optica Syringomyelia Polyradiculopathy	Cavernous malformation Aneurysm Stroke HSV and other viral encephalitis Mycobacterial abscess Syphilitic gumma Cryptococcosis Histoplasmosis Coccidioidomycosis Blastomycosis Toxoplasmosis Other parasitic diseases of the nervous system Neoplastic disorders Systemic lupus erythematosus Behçet disease Sarcoidosis Hematoma Tuberous sclerosis MOG antibody disease (MOGAD) Neurofibromatosis
Adapted from (38)

Neuroschistosomiasis

Neuroschistosomiasis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Table1. Differential Diagnoses of Neuroschistosomiasis

Diagnostic workup

Management

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Neuroschistosomiasis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Table1. Differential Diagnoses of Neuroschistosomiasis

Diagnostic workup

Management

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Prion diseases

Rabies

Malaria

Neuropathies associated with cytomegalovirus infection

Genital herpes: neurologic complications

Neurocysticercosis

Trichinosis

Zika virus: neurologic complications

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