319 Neuroschistosomiasis 17 Fig.17.10 Spinal cord NSM. MRI scan of the thoracolumbar region after gadolinium injection. There is enlargement of the conus medullaris with spotty contrast-enhancement (courtesy of Dr. J.R. Lambertucci). 320 Tropical Neurology 17 Specific chemotherapy and corticosteroids have been administered to patients with cerebral NSJ associated with the Katayama syndrome. 9 According to the initial published reports, specific treatment has resulted in full recovery in a few patients, and to a partial to near-complete recovery in the majority. In a more recent study, a patient with cerebral NSJ associated with Katayama syndrome showed clearance of neurological and CT abnormalities following treatment with corticosteroids alone. The use of praziquantel in conjunction with corticosteroids, however, is recom- mended to eradicate adult worms living in sites close to the CNS and in other organs for preventing the further deposition of eggs. The use of antischistosomal drugs have been recommended for the treatment of spinal cord NS. 3,6 A dramatic improvement associated with the use of an antischistosomal drug alone was observed in several patients. Patients who did not receive antiparasitic chemotherapy and had spontaneous improvement or improve- ment following surgery or corticosteroid may have recurrence of signs and symp- toms later. It is possible that such recurrence was due to the additional egg laying in nervous tissue. Antischistosomal agents were part of the treatment schedule in most patients submitted to combined treatment who had a favorable outcome. In the early stage of spinal cord NS, administration of prednisolone or dexamethasone alone can result in marked improvement. Although results of corticosteroid therapy in spinal cord NS remain controversial, the available literature provides clear evi- dence for their beneficial effect. 3 It should be noted that in many of the reported cases, the use of corticosteroids was commenced several weeks or months after the appearance of neurological symptoms. A reduction of the inflammatory reaction to schistosomal eggs is only effective before formation of necrotic-exudative granu- Fig. 17.11. Spinal cord NSM. CT scan shows spinal cord atrophy at the T8 level in a patient a few months after the initial clinical presentation (Courtesy of Dr. T.C.A. Ferrari). 321 Neuroschistosomiasis 17 loma. Corticosteroids do not significantly alter the evolution of the disease if ad- ministered many weeks or months after the initial neurological symptoms. Table 17.3 summarizes the treatment of NS. Laminectomy should be reserved for patients who develop acute paraplegia with spinal block or who deteriorate despite conservative treatment. 3,6 Laminectomy is also used for diagnostic purposes. Apart from allowing the histologic confirmation, surgery in some cases may improve the clinical picture by decompression and mobi- lization of nerve roots. Analysis of the outcome of 191 cases of spinal cord NS, usually receiving at least two modalities of treatment shows: 1) about 38% of pa- tients had full or partial recovery without functional limitation; 2) 16% of patients had improvement in neurological status; 3) 36% of patients had sequelae which often prevented walking; and 4) 10% of patients died, as a result of pulmonary infection and less frequently, urinary complications. 3 Almost all patients who died did not receive any treatment. Therefore, without early diagnosis and prompt treatment, spinal cord NS patients have a poor prognosis. Summary Schistosomiasis is an infection caused by digenetic trematode platyhelminths of the genus Schistosoma. These blood flukes use man and other mammals as the de- finitive host and snails as the intermediate host. S. mansoni, S haematobium and S. japonicum are the most widely distributed species. This infection reaches about 200 million individuals in 74 countries in Latin America, Africa and Asia. Far less com- monly, schistosomes may reach the CNS. This may occur at any time from the moment the worms have matured and the eggs have been laid. The presence of eggs in the CNS induces a cell-mediated periovular granulomatous reaction. When eggs reach the CNS during the early stages of the infection or during evolution of the disease to its chronic forms, large necrotic-exudative granulomas are formed. In-situ egg deposition following the anomalous migration of adult worms appears to be the main, if not the only, mechanism by which Schistosoma may reach the CNS in these stages. Only clinical manifestations related to the CNS are evidenced by the medical history and clinical examination in the majority of symptomatic NS patients. The mass effect produced by the heavy concentration of eggs and the presence of large Table 17.1. Clinical manifestations of neuroschistosomiasis (NS) Cerebral NS Tumoral form Signs and symptoms of increased intracranial pressure Seizures Focal neurological signs NSJ associated with the Katayama syndrome Headache, speech disturbances, disorientation, visual abnormalities, motor deficit, urinary incontinence, ataxia and coma, usually lasting from several days to a few weeks Spinal cord NS Lumbar radicular pain Thoracolumbar rapidly progressing myelopathy—flaccid paraplegia, sensory loss and bladder dysfunction 322 Tropical Neurology 17 granulomas in circumscribed areas of the brain and spinal cord account for: 1) the signs and symptoms of increased intracranial pressure and focal neurological signs; and 2) the signs and symptoms of rapidly progressing myelopathy, usually affecting the thoracolumbar segments of the spinal cord, respectively. CT and MRI are essential for the demonstration and location of CNS lesions. Antischistosomal drugs, corticosteroids, and surgery are used for treatment of NS. Chemotherapy with oxamniquine, praziquantel or metrifonate, along with corti- costeroids, are indicated in NS patients. Treatment of the tumoral form of cerebral NS requires surgery. Acknowledgement This work was supported by Grant no. 302036/76 from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico). References 1. Jordan P, Webbe G, Sturrock RF, eds. Human Schistosomiasis. Wallingford: Cab International, 1993. 2. Pittella JEH. Neuroschistosomiasis. Brain Pathol 1997; 7:649-662. 3. Ferrari TCA. Spinal cord schistosomiasis. A report of 2 cases and review emphasiz- ing clinical aspects. Medicine (Baltimore) 1999; 78:176-190. 4. Pittella JEH. The relation between involvement of the central nervous system in schistosomiasis mansoni and the clinical forms of the parasitosis. A review. J Trop Med Hyg 1991; 94:15-21. Table 17.2. Diagnosis of neuroschistosomiasis (NS) Epidemiologic data: patient has resided in or migrated from an endemic area Clinical manifestations: increased intracranial pressure and focal neurological signs evolving acutely (NSJ associated with the Katayama syndrome) or chroni- cally (tumoral form of cerebral NSM and NSJ). Lumbar radicular pain soon followed by flaccid paraplegia, sensory loss and bladder dysfunction, in patients with spinal cord NS Hemogram: eosinophilia Cerebrospinal fluid: lymphocytic pleocytosis; eosinophils can be found; elevation of protein Stool examination: usually positive for eggs; should be repeated several times Rectal biopsy: has greater positivity in the identification of eggs than the stool examination Examination of urine: positive for eggs in about 25% of patients Neuroimaging: CT scan Cerebral NS—multifocal enhancing lesions with a surrounding edema in NSJ cases associated with the Katayama syndrome; hyperdense, enhancing area surrounded by a hypodense halo, with an associated mass effect in patients with the tumoral form Spinal cord NS—fusiform swelling of the conus medullaris MRI Cerebral NS—heterogeneous, fine punctate or homogeneous contrast-enhancing lesion with surrounding edema Spinal cord NS—focal enlargement of the spinal cord, usually of the conus medullaris, with spotty enhancement after gadolinium injection Biopsy: craniotomy or laminectomy 323 Neuroschistosomiasis 17 Table 17.3. Treatment of neuroschistosomiasis Species Drug Administration Dosage Duration of treatment Side effects S. mansoni oxamniquine oral 15mg/kg adults single dose dizziness, somnolence, headache, nausea, and rarely, fever, 20mg/kg children single dose ++ excitation and seizures* 60mg/kg + two daily doses of 15mg/kg on two days praziquantel oral 40mg/kg adults single dose +++ dizziness, nausea, vomiting, head- ache, vertigo, abdominal 60mg/kg children single dose +++ pain, anorexia, diarrhoea, somno lence, urticarial exanthem** S. haematobium metrifonate oral 22.5mg/kg three doses of 7.5mg/kg fatigue, muscular weakness, tremor, at 14 day intervals sweating, vertigo, nausea, vomiting, abdominal pain, diarrhea, bronchospasm, *** praziquantel oral 40mg/kg adults single dose S. japonicum praziquantel oral 60mg/kg three doses of 20mg/kg at 4 hour intervals + dosage used for African strains of S. mansoni ++ may be divided into two equal doses at 4-8 hour intervals +++ may be divided into two equal doses at 24 hour intervals * observed in about 50% of patients ** observed transitorily in about 10 to 40% of patients ** * rare and well-tolerated, disappearing spontaneously within a few hours. Obs. Prednisone given 100mg/day orally during 30-90 days is indicated in the early stages of spinal cord NS. Thereafter, the dosage is gradually reduced until the drug is completely withheld. Dexamethasone given 16mg/day orally during 2 to 3 weeks is indicated i n the cases of cerebral NSJ associated with the Katayama syndrome. Thereafter, the dosage is gradually reduced over a period of 7 to 6 weeks until the drug is completely withheld. Treatment of the tumoral form of cerebral NS is surgical. Chemotherapy with oxamniquine or praziquantel, associated or not with corticosteroids, has been used following surgery. Anticonvulsants should be administered when seizures persist after surgery. 324 Tropical Neurology 17 5. Pittella JEH, Lana-Peixoto MA. Brain involvement in hepatosplenic schistosomsis mansoni. Brain 1981; 104:621-632. 6. Scrimgeour EM, Gajdusek DC. Involvement of the central nervous system in Schis- tosomiasis mansoni and S. haematobium infection. A review. Brain 1985; 108:1023-1038. 7. Lenzi HL, Kimmel E, Schechtman H et al. Histoarchitecture of schistosomal granu- loma development and involution: morphogenetic and biomechanical approaches. Mem Inst Oswaldo Cruz 1998; 93(Suppl 1):141-151. 8. Butterworth AE. Immunological aspects of human schistosomiasis. Br Med Bull 1998; 54:357-368. 9. Kane CA, Most H. Schistosomiasis of the central nervous system. Experiences in World War II and review of literature. Arch Neurol Psychiat 1948; 59:141-183. 10. Pollner JH, Schwartz A, Kobrine A, et al. Cerebral schistosomiasis caused by Schis- tosoma haematobium: Case report. Clin Infect Dis 1994; 18:354-357. 11. Torres Jr ML. Cerebral schistosomiasis: Clinical report of a proven cerebral granu- loma and review of 41 other proven cases in the literature. Philip J Surg Surg Special 1965; 20:289-307. 12. Pittella JEH. Partial hypotrophy of the posterior and lateral columns of the spinal cord, representing a sequela of schistosomiasis mansoni: Report of an autopsied case and a review of the literature. Clin Neuropathol 1989; 8:257-262. 13. Case Records of the Massachusetts General Hospital. Case 39. N Engl J Med 1996; 335:1906-1914. 14. Mackenzie IRA, Guha A. Manson’s schistosomiasis presenting as a brain tumor. J Neurosurg 1998; 89:1052-1054. 15. Pittella JEH, Gusmão SNS, Carvalho GTC, Silveira RL, Campos GF. Tumoral form of cerebral schistosomiasis mansoni. A report of four cases and a review of the literature. Clin Neurol Neurosurg 1996; 98:15-20. 16. Watt G, Long GW, Ranoa CP et al. Praziquantel in treatment of cerebral schisto- somiasis. Lancet 1986: 2:529-532. 17. Gonçalves EC, Fonseca APC, Pittella JEH. Frequency of schistosomiasis mansoni, of its clinicopathological forms and of the ectopic locations of the parasite in au- topsies in Belo Horizonte, Brazil. J Trop Med Hyg 1995; 98:289-295. CHAPTER 1 CHAPTER 18 Human African Trypanosomiasis, Sleeping Sickness Bernard Bouteille and Michel Dumas Human African trypanosomiasis (HAT) or sleeping sickness is an endemic vector borne parasitic disease in many sub-Saharan countries. It is caused by a unicellular hemoflagellate parasite Tr ypanosoma brucei (T.b. ), which is cyclically trans- mitted through the saliva of blood sucking tsetse flies. The vector is found only in Africa, between the fifteenth parallels north and south. Its habitat is the vegetation along watercourses and lakes, forest edges and gallery forests, extending to vast areas of scrub Savannah. The more chronic “Gambian” fatal form of sleeping sickness, which evolves over a period of several months or years predominates in West and Central Africa. It is caused by trypanosomes of the subspecies T. b. gambiense. The more fulminant “Rhodesian” form, T. b. rhodesiense, is found in East Africa, where a large variety of game and domestic animals serve as reservoir hosts. At the beginning of the twentieth century, HAT surpassed all other health problems in sub-Saharan Africa. By the late 1950s, the incidence of HAT decreased in all endemic countries of West and Central Africa as a result of mass detection and treatment campaigns. Political unrest and civil war have disturbed the public health infrastructure result- ing in a resurgence of trypanosomiasis in tropical and subtropical Africa. Recent medical surveys have revealed a shockingly high prevalence in endemic areas of Africa. Tr ypanosome following tsetse fly bite produces a local lesion and then a systemic and often chronic illness with progressive meningoencephalitis. 1,2 At the site of in- oculation of the trypanosome an entry chancre develops, a lesion which constitutes a first cutaneous line of defence that is quickly overcome. Trypanosomes multiply in this lesion and spread via lymphatics and the blood stream to different organs (stage I). The heart and central nervous system (CNS) are particularly susceptible and the disease bears its name from original descriptions of sleep-wake disorders in menin- goencephalitic patients. The precise timing of crossing the blood-brain barrier (BBB) which is stage II of the disease is still not known but probably occurs early in the course of infection. The drugs which do not cross BBB are effective in stage I but not effective in stage II disease. Therapy of stage I sleeping sickness has not changed over the decades: suramin was introduced in 1922, pentamidine in 1941 and diminazene in the mid-1950s. Treatment of stage II disease still relies almost exclu- sively on melarsoprol. None of these drugs would easily pass current registration regulations, but fortunately for hundreds of thousands of patients who have been cured by these drugs, it established its market in the first half of the century. Tropical Neurology, edited by U. K. Misra, J. Kalita and R. A. Shakir. ©2003 Landes Bioscience. 326 Tropical Neurology 18 Epidemiology Geographical Distribution Sleeping sickness was first described in the 14th century by Ibn Khaldun and then in 1734 by John Atkins. Thereafter, the description of enlarged neck glands was made by Wintterbottom. The disease was described in the Caribbean Islands in black slaves from Africa by Dangaix and Guerin in the early 1900s. T. gambiense was first identified in the blood of a patient from Gambia. At the same time, Manson described the general symptoms, involvement of the CNS and the two main stages of this disease. In the first quarter of the 20th century, trypanosomiasis was preva- lent in African populations over a wide area until Jamot, a French army doctor, set up mobile teams for diagnosis and treatment of this disease. Following systematic search for patients in villages, trypanosomiasis was virtually eradicated from West Africa in 1950. By the 1960s, the relaxation of disease control due to political insta- bility and worsening economic condition of the endemic countries led to a resur- gence of trypanosomiasis. Since 1970 the situation has deteriorated and the disease has reappeared, with major outbreaks in the countries which have not maintained surveillance. Sixty million of the 400 million people living in 36 sub-Saharan Afri- can countries are at risk. 3 Four main levels of endemicity have been identified (Fig. 18.1): 1) epidemic: High prevalence and transmission level as Angola, Democratic Republic of Congo (DRC), Sudan and Uganda; 2) high endemic with increasing prevalence: Cameroon, Central African Republic, Chad, Congo, Ivory Coast, Guinea and Tanzania; 3) low endemic: Benin, Burkina-Faso, Equatorial Guinea, Gabon, Ghana, Guinea, Kenya, Mali, Mozambique, Nigeria, Togo and Zambia; and 4) un- known epidemiological status: Burundi, Botswana, Ethiopia, Liberia, Namibia, Rwanda, Senegal and Sierra Leone. It is estimated that more than 450,000 patients may be suffering from HAT. The epidemics are raging in the war-torn areas of southern Sudan, northern Uganda, DRC and Angola. About 2% of DRC’s population carries the disease, with the prevalence reaching up to 70% in certain communities. This picture is comparable to the one during 1925-1930. Life Cycle The distribution of trypanosomiasis in Africa is dependent on the distribution of the tsetse fly which belongs to the genus Glossina and is divided into three species groups. The fusca group (subgenus Austenina) includes several vectors of livestock trypanosomiasis. The two other groups include species of medical importance; to date, these species have not been implicated in the transmission of sleeping sickness. The palpalis group (subgenus Nemorhina) mainly transmits T. gambiense in West and Central Africa and the morsitans group (subgenus Glossina) transmits T. rhodesiense in East Africa. The tsetse flies of the palpalis group are found on the shores of lakes and rivers in forested or formerly forested areas; some species have been shown to be highly adaptable to man-made environmental changes and are often well adapted to human settlements and agricultural areas. The riverine species of the palpalis group include G. palpalis, G. tachinoides and G. fuscipes. Man is the reservoir of infection, although both wild and domestic animals, mainly pigs and sheep, may play a role. Species of the morsitans group or “game” tsetse of the Savannah zones live in open woodland, bushland or acacia thicket. They include G. morsitans, G. pallidipes and G. swynnertoni. Human infection occurs sporadically in hunters, firewood collec- 327 Human African Trypanosomiasis 18 tors and tourists. A wide spectrum of animals, notably game animals and domestic cattle, provide a reservoir of infection. The tsetse flies are large, brown to grayish, narrow-bodied, 6-15 mm long, with a proboscis projecting forward well in front of the head. During feeding the mouth parts, but not the palps, are lowered 90 0 from the line of the body axis. Male and female tsetse feed exclusively on the blood of vertebrates. With the infective bite of a tsetse fly (Fig. 18.2), metacyclic trypanosomes present in the proboscis and the salivary gland of the insect are injected into the host, where these develop skin ulcer- ations called ‘chancres’. From the chancre, trypanosomes spread to lymph nodes and invade the bloodstream. In the bloodstream the trypanosomes divide as a long slender trypomastigote of one specific variable surface glycoprotein (VSG) or vari- able antigen type (VAT) until the majority of them are killed by the host’s antibodies directed against this VAT. However, a small percentage express a different VAT which survive and establish the next wave of infection and so on (antigenic variation). Each wave of infection leads to a new peak of parasitemia, which is associated with high fever and malaise. After some time, the trypanosomes invade the CNS. Some bloodstream forms do not divide and these metacyclic forms are infective for the tsetse flies. Fig. 18.1. Geographical distribution of HAT. 328 Tropical Neurology 18 Tr ypanosomes The trypanosomes belong to the large group of protozoa known as flagellates. All are characterized by a flagellum at some stage in their life-cycle. The protozoans that cause HAT belong to the genus Trypanozoon. They are classified in the order Kinetoplastida, the family Trypanosomatidae and the section Salivaria. Several sub- species of Tr ypanosoma (Trypanozoon) brucei are described; T. b. brucei is noninfec- tious to humans but coexists with the other trypanosomes in reservoir hosts and tsetse flies. T. b. gambiense and T.b. rhodesiense are infectious to humans. These sub- species, although morphologically identical, can be distinguished on the basis of biochemical and molecular criteria. The advent of molecular methods for taxonomy have raised the hope of development of biochemical markers for the 3 subspecies of Tr ypanosoma. However, the results of molecular characterization revealed a much more complex picture with several subdivisions within T. brucei, rather than the three expected groups. Fig. 18.2. Schematic diagram of T. brucei developmental cycle in mammal and tsetse fly (adapted from reference 21). [...]... interferon (IFN )- , tumor necrosis factor (TNF )- and numerous interleukins (IL), which play a major role in trypanosomiasis TNF-α, IL-1β, IL-2, IL -7 , IL-12 and IL-15 can activate NK cell functions IL-10 and transforming growth factor (TGF )- inhibit NK cell functions NK cells also participate in the initiation of the inflammatory response through the synthesis of chemokines such as IL-8, granulocyte... serotonergic hypothesis Chronobiol Internat 1999; 16: 47 7- 4 89 Sabbah P, Brosset C, Imbert P et al Human African Trypanosomiasis: MRI Neuroradiology 19 97; 39: 70 8 -7 10 Magnus E, Vervoort T, Van Meirvenne N A card-agglutination test with stained trypanosomes (C.A.T.T.) for the serological diagnosis of T.b gambiense trypanosomiasis Ann Soc Belge Med Trop 1 978 ; 58:16 9-1 76 Enanga B, Keita M, Chauviere G et al Megazol... opisthotonus and leg weakness in chicks Two free aminoacids, β N-oxalylamino-L alanine (BOAA) and β diaminopropionic acids have been found to be toxic to various animal models such as rats, mice and monkeys Two nonprotein aminoacids of L sativus, -( isoxazoline5-one-2-yl) alanine (BIA) and its higher homologue alpha-aminogamma (isoxazoline5-one-2-yl) alanine (ACI), were recently tested for their toxic properties... Wallingford: CAB International, 19 97: 14 9-1 61 Van Bogaert L, Janssen P Contribution å l’etude de la neurologie et de la neuropathologie de la trypanosomiase humaine Ann Soc Belge Med Trop 19 57; 37: 37 9-4 26 Vincendeau P, Daulouede S, Veyret B et al Nitric oxide mediated cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei Exp Parasitol 1992; 75 :35 3-3 60 Olsson T, Bakhiet M, Edlund... A trypanosome released factor triggers interferon-γ production that stimulates parasite growth Eur J Immunol 1991; 21:244 7- 2 454 Bakhiet M, Olsson T, Ljungdahl A et al Induction of interferon-g transforming growth factor-β and interleukin-4 in mouse strains with different susceptibilities to Trypanosoma brucei brucei J Interfer Cytok Res 1996; 16:42 7- 4 33 Poltera AA, Cox JN, Owor R Pancarditis affecting... sleep-inducing activity of muramyl peptides both under normal and pathological conditions In HAT, high levels of plasma IL-10 are found which are very potent inhibitors of IFN-γ-stimulated monocyte-macrophage effector functions, including their oxidative burst, NO synthesis and microbicidal activity IL-10 is also a potent inhibitor of IFN−γ secretion by NK cells TNF-α is potent stimulus for IL-10 secretion,... stimulus for IL-10 secretion, and IL-10 specifically inhibits TNF-α, as well as its own production, via an autoregulatory feedback loop These events suggest a homeostatic mechanism whereby chronic exposure to trypanosome-derived LPS in the late-stages of HAT triggers excessive TNF-α secretion, which in turn stimulates IL-10 release from activated monocyte-macrophages TGF-β is a peptide that regulates cell... clustering is noted with nearly one-third of patients having a first or second-degree affected relative The majority of cases of Konzo occur in epidemics About 10% of patients with Environmental Neurotoxins in the Tropics 3 47 Fig 19.1 Photograph of patients with lathyrism having spastic paraparesis (with permission from Misra UK, Sharma VP J Neurol Neurosurg Psychiat 1994; 57: 57 2-5 77 © BMJ) Konzo may suffer... astrocytes and microglial cells in the CNS IFN-γ and TGF-β can be produced by CD8 T cells activated by a factor released by T.b brucei called TLTF (trypanosome-released lymphocyte-triggering factor); TGF-β has immunosuppressive effects and IFN-γ stimulates parasite growth.9 TNF-α and other cytokines contribute to the generation of somnogenic molecules such as IL-1 Nitric oxide (NO) is involved in the inflammatory... reported following cassava meal and were attributed to 19 348 Tropical Neurology Fig 19.2 Central motor conduction study in a patient with lathyrism Central motor conduction time to tibialis anterior in lathyrism patient is 25.6 ms and that in control 12.4 ms (with permission from Misra UK, Sharma VP J Neurol Neurosurg Psychiat 1994; 57: 57 2-5 77 © BMJ) 19 cyanide poisoning Moderate cyanide exposure over . interferon (IFN )- , tumor necrosis factor (TNF )- and numerous interleukins (IL), which play a major role in trypanosomiasis. TNF-α, IL-1β, IL-2, IL -7 , IL-12 and IL-15 can activate NK cell functions. IL-10. Neuroschistosomiasis. Brain Pathol 19 97; 7: 64 9-6 62. 3. Ferrari TCA. Spinal cord schistosomiasis. A report of 2 cases and review emphasiz- ing clinical aspects. Medicine (Baltimore) 1999; 78 : 17 6-1 90. 4. Pittella. in immunosuppressive cytokines (INF-γ and TGF-β) has also been detected during infection. However, TGF-β is known to inhibit the pro- duction of IL-4, IL-5, IL-6, the major cytokines implied in