Histoplasmosis of the nervous system
Histoplasmosis is an infection caused by the fungus Histoplasma capsulatum. Infection is endemic to certain areas of the United States, including the
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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. In this updated article, the author discusses the role of humans and snails in the fascinating life cycle of schistosomal worms, the presumed pathophysiology of neuroschistosomiasis, and advances in attempts to reduce this parasitic infection through vaccination and snail population controls.
• 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.
Humans have been afflicted with schistosomiasis for more than 2500 years (12). 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. Later in 1851, 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 (03).
Due to the peculiar morphology of the worm, it was clear that 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” (37). Weinland, apparently not knowing of this thesis, re-described the worm as Schistosoma haematobium in 1858 (71). However, in 1948, the International Commission on Zoological Nomenclature established the name Schistosoma and it is, thus, the current name of the parasite (24). 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 (04). The life cycle was described by da Silva in 1908 (04).
Molecular phylogenetic studies suggest that Schistosoma spp. originated in Asia and that a pulmonate-transmitted progenitor colonized Africa and gave rise to both the terminal-spined and lateral-spined egg species groups, the latter containing Schistosoma mansoni (57).
Schistosoma mansoni likely appeared only after the transatlantic dispersal of Biomphalaria from the neotropica to Africa, an event based on African fossil record, occurred about 2 to 5 million years ago. This parasite became abundant in tropical Africa and, much later, entered the New World with the slave trade (39).
Schistosomiasis was originally thought to have been exported from Africa to South America during the period of slave trade where it found favorable climatic conditions that promoted its spread. Factors that favor spread include growth in international travel, refugee and population migration, and the development of new water resources (Ross at el 2002).
Five species of Schistosoma to infect humans: Schistosoma mansoni, Schistosoma hematobium, and Schistosoma japonicum are the most widely distributed and are present in multiple tropical and subtropical countries whereas 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) (54). Cerebral schistosomiasis is usually caused by Schistosoma japonicum whereas myelopathy is most often induced by Schistosoma mansoni and Schistosoma haematobium (47).
Early symptoms. A maculopapular rash may arise at the site of skin penetration by schistosome larvae, referred to as “cercariae.” Typical skin lesions comprise discrete erythematous raised eruptions that vary in size from 1 to 3 mm. Migrants or tourists infected for the first time may develop a skin reaction within a few hours, although a rash may appear up to a week later.
Acute schistosomiasis (Katayama syndrome). Katayama syndrome is an early clinical manifestation that occurs 2 to 6 weeks after contact with infected water (55). 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 borderzone cerebral infarctions, and eosinophil-mediated toxicity leading to vasculitis and small-vessel thrombosis may be a pathogenic mechanism (58).
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) (20).
Neurologic manifestations. Neurologic manifestations of schistosomiasis occur after adult worms gain access to the brain or spinal cord. Neurologic complications are rare but are the most severe form of schistosomal infection and can occur both in acute and chronic phases of schistosomiasis--but more commonly in chronic phase.
Cerebral complications of acute neuroschistosomiasis include delirium and acute confusional state, loss of consciousness, headache, seizures, dysphasia, visual field impairment, and focal motor deficits (hemiparesis, paraparesis, cerebellar syndrome, and bladder and bowel incontinence) (18).
Seizures occur most frequently with Schistosoma japonicum but have also been reported with Schistosoma mansoni (02).
A slowly-expanding cerebral lesion mimicking a brain tumor syndrome has been reported with Schistosoma mansoni (46). Increased intracranial pressure and focal neurologic signs are common. Cerebellar schistosomiasis has been described due to severe necrotic-exudative granulomatous inflammation around numerous Schistosoma mansoni ova (51). Signs and symptoms of elevated intracranial pressure, such as headache, nausea, and vomiting, are common presentations (01). Cerebral hematoma due to a meningitic granulomatous reaction around Schistosoma mansoni eggs has also been reported (49).
Cognitive impairment is a manifestation of chronic neuroschistosomiasis that has also been described in children with Schistosoma japonicum and Schistosoma mansoni infections (41). The specific cognitive dysfunctions associated with schistosomal infections have not been clearly defined due to many potential confounding factors such as educational factors, presence of comorbidities, nutritional status, and type of cognitive test used. However, 1 study reported that school children infected with Schistosoma japonicum showed improved performance on working memory after treatment (41).
Spinal schistosomiasis is primarily caused by Schistosoma mansoni. Schistosomal myeloradiculopathy usually occurs early after infection and is more likely to be symptomatic than cerebral schistosomiasis. Pathological changes seen in acute transverse myelitis include tissue necrosis, vacuolization, and atrophy (07). The cellular immune reaction around the egg leads to the formation of a granulomatous lesion, and in most cases, these masses tend to be localized in the conus medullaris and at a spinal T12-L1 levels. If multiple granulomas are deposited on the spinal roots with congestion and edema, radicular and cauda equina symptoms usually result (42). Progressive paraparesis and radicular pain can be features of spinal neuroschistosomiasis (31). Cervical intramedullary schistosomiasis has been reported as a rare cause of acute tetraparesis (27). Chronic voiding dysfunction can be associated with schistosomal myelopathy (17). Other urinary symptoms include urinary retention and incontinence, urinary tract infection, hydronephrosis and bladder calculi. Schistosomal meningomyeloradiculitis in children is probably underdiagnosed and should be included in the differential diagnosis of acute childhood paraplegia in areas of the world where Schistosoma mansoni infection is endemic (32).
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 (13). 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 (26; 21). This is especially relevant for the management of patients presenting in rural areas of endemic countries where sophisticated diagnostic facilities are not available.
A 28-year-old, right-handed Polish 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 1 occasion 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 refractory egg shells 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 and steroids. The levetiracetam was tapered and discontinued and she did not experience significant sequelae over 6 months of follow-up (76).
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 fresh water harboring cercariae within 12 to 24 hours after emerging from the snail. Skin penetration is achieved by mechanical activity as well as by the 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 blood stream 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 maturing into mating pairs of males and females) at which time they 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 (02).
Pathogenesis. Parasite eggs and delayed hypersensitivity host reaction are responsible for the clinical features of schistosomiasis (20). This complex interaction between parasite eggs and the host immunity results in granuloma formation, which is essentially a T-cell-dependent process. A predominantly T-helper 1 reaction occurs mostly 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 (43). Immunogenicity and pathogenicity depend on host genetic factors. HLA class I and II antigens are associated with more severe manifestations of disease. For example, HLA-B16 and HLA-Cw*02 have been associated with Schistosoma haematobium-related bladder cancer among patients in Egypt (72). HLA-DR and DQ alleles provide some protection against mild liver fibrosis whereas HLA-DP alleles are associated with protection against severe hepatic fibrosis (22). On the other hand, advanced hepatic fibrosis has been closely linked to the interferon-g-receptor gene on chromosome 6q22-q23.54 (22). Another locus (SM1) is associated with resistance to reinfection with S. mansoni and is located on chromosome 5q31-q33.55; a gene product of this locus may play a role in regulating the development of type 2 helper T cells (53).
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 (45). Embolization of eggs from the porto-mesenteric or pelvic systems may occur in 2 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 (52). Potential CNS infection sites include the forebrain, brainstem, cerebellum, leptomeninges, and the choroid plexus (59). 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 (64).
Immunogenicity of schistosomal egg components has been associated with specific antigens, Sm-p40, Sm-PEPCK, Sm-TPx-1 that are released after the egg’s death and disintegration (63). The most abundant antigen is Sm-p40, which together with Sm-PEPCK has demonstrated greater immunogenicity in humans (63). The immune response to the antigens released from the ova 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 a delayed dermal reaction and the production of cytokines, macrophage inhibitory factor, and eosinophil stimulation promoter (63). Cytokine production declines concurrently with the waning of the granulomatous inflammation (12 weeks and onwards), whereas the granulomatous response waxes and wanes, and then finally fibrosis ensues and is usually irreversible (63).
Chemokines, especially CCL3/MIP-1alpha, play an important role in hepatosplenic human schistosomiasis (62). Schistosomal myeloradiculopathy has also been associated with enhanced production of both interleukin-13 and CCR3-acting chemokines, both of which may facilitate the expression of a Th2 response leading to Th2-dependent damage to the spinal cord (07; 52).
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 brains, accompanied by weight loss and behavioral deficits (14; 69; 64). 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 (66). It is hoped that the use of these animal model systems will be useful for better understanding the pathogenesis of neuroschistosomiasis and for development of more effective therapies.
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 (08). 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 (74).
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 mostly occurs 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 (54). 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 risk of infection in children (16). 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 (23).
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 or have recently lived near lakes or rivers (28). 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 (28).
Schistosomiasis causes about 200,000 deaths per year. Most of these deaths occur in sub-Saharan Africa and are due to liver failure, intestinal dysfunction, renal failure, or CNS inflammation (73).
Outside of the primary infection sites within the intestines, liver, lungs, and genitourinary system, the central nervous system 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 1 study suggests that a recent first-time exposure to the parasite makes patients more vulnerable to nervous system disease (68).
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, these water, sanitation, and hygiene programs have had little impact (06). 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 is 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 (10).
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 goals of controlling schistosomiasis by 2020 and eliminating it by 2025. However, 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. In addition, the parasite may become less vulnerable 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 provision of a safe water supply, health education that includes improvement of water sanitation and avoidance of schistosome-contaminated urine or stool, and snail control (36).
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% (38).
Clinical studies show that artemether may be used as a prophylactic agent if given once every 2 to 4 weeks (40). Travelers and those living in endemic areas should avoid contact with fresh water. Acute schistosomiasis should be suspected in a febrile patient with recent fresh water 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 (48).
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 (50).
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 (61). 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 (75).
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 (44). 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 1 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 (35).
Cerebral schistosomiasis has a wide differential diagnosis, including other causes of eosinophilic meningoencephalitis, such as helminthic infections (fasciolasis, filariasis, toxocariasis, trichinellosis, cysticercosis, paragonimiasis) and protozoal infections (trypanosomiasis, toxoplasmosis). Thus, serological tests for these organisms should be tailored to the appropriate epidemiological setting. Other conditions that produce a solitary intracranial lesion and present with seizures, motor deficits, or an altered mental status should be considered in the differential diagnoses of myeloradiculopathy and solitary intracranial masses due to schistosomiasis (Table 1).
Cerebral schistosomiasis with solitary intracranial mass
Hernia of the lumbosacral disc
Adapted from (33)
Diagnosing neuroschistosomiasis can be difficult as neurologic symptoms are often nonspecific and laboratory findings of eosinophilia for 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.
Definitive diagnosis of brain or spinal cord schistosomiasis can be confirmed through histopathological 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 helminthes (33). Thus, the majority of patients 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 (07).
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. This new method will likely be a valuable tool for both the diagnosis and surveillance of schistosomiasis (05; 70).
Neuroimaging with CT or MRI are 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 (34). 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, medullary atrophy can be seen, with diffuse hyperintensity on T2-weighted imaging (09).
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 inhibit egg-laying by adult worms. Therefore, declining numbers of eggs is associated with successful treatment. 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, patients’ stool and urine should be tested for the presence of viable 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. However, serology may remain positive for years.
Praziquantel and oxamniquine (no longer available in the United States) are used commonly, but praziquantel is the treatment of choice for all species of schistosomiasis. By destroying the adult worms, these schistosomicidal drugs interrupt egg production and, consequently, eliminate inflammatory reactions in the CNS. Praziquantel is a broad-spectrum schistosomicidal drug that kills female adult worms, resulting in a parasitological cure in 70% to 90% of patients (56). 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 (11). Calcium ions accumulate in the parasite cytosol, leading to muscle contractions and ultimate paralysis of adult worms. 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 (11). In persons who are not cured by initial treatment, the egg burden is usually markedly decreased. The dose of praziquantel ranges between 40 and 60 mg/kg/day. A 5-day course of praziquantel (50 mg/kg/day in 2 daily doses) is recommended for neuroschistosomiasis (07). Feces and urine should be re-examined 1 month after completion of treatment to ascertain the efficacy of pharmacological treatment. When measured 5 to 10 days after treatment, newer tests that measure antigens may help to assess therapeutic response. Persistent circulating antigen and the excretion of eggs indicate residual infection. These patients should be retreated with praziquantel. Resistance to praziquantel treatment is developing but uncommon (67).
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 schistosomula during the first 3 weeks of infection and is synergistic in killing adult worms (65). Clinical studies show that artemether is also active against all 3 major schistosome parasites (mainly schistosomula) (40).
Another antimalarial drug under investigation is the combination mefloquine-artesunate. Individuals co-infected with Plasmodium and Schistosoma who are treated with a mefloquine-artesunate against Schistosoma haematobium may experience a dual benefit of clearance of malaria parasitemia and reduction of schistosomiasis-related morbidity (29). However, for the treatment of schistosomiasis, the addition of mefloquine-artesunate to praziquantel showed no benefit over praziquantel alone (30).
Oxamniquine is another anti-schistosomal 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.
Patients with prominent neurologic symptoms or space-occupying lesions should receive adjunctive therapy with corticosteroids (15). 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 (60). Treatment of acute schistosomiasis with corticosteroids prior to treatment with praziquantel may avoid potential neurologic complications triggered by massive release of antigenic materials by anti-schistosomal agents (25). 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 (59; 13). Decompressive laminectomy, mass extirpation, and liberation of roots may be necessary when myelitis progresses despite clinical improvement.
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 (20; 19).
Christina M Marra MD
Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.See Profile
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Histoplasmosis is an infection caused by the fungus Histoplasma capsulatum. Infection is endemic to certain areas of the United States, including the
Jun. 09, 2021
May. 19, 2021
Apr. 24, 2021
Creutzfeldt-Jakob disease (CJD) is a member of the group of diseases known as prion diseases or the subacute spongiform encephalopathies. CJD is a subacute fatal disease with a clinical triad of dementia, myoclonus, and EEG abnormalities that is usually associated with other neurologic signs, along with neuropathological evidence of neuronal loss, spongiform changes, and astrocytosis.
Apr. 23, 2021
Apr. 10, 2021
Epstein-Barr virus is a ubiquitous herpes virus associated with infectious mononucleosis. Neurologic complications due to acute Epstein-Barr virus infection
Apr. 06, 2021
Apr. 03, 2021
Apr. 03, 2021