Neurocysticercosis in Mexico

Parasitology Today, vol. 4, no. 5, 1988 57 Aggarwal, A. and Nash, T.E. (1987) Exp. Parasitol. 64, 336-341 58 Edson, C.M. et al. (1986) bzfection and Immunity 54, 621-625 59 Nash, T.E. and Aggarwal,A. (1986)J. lmmunol. 136, 2628-2632 60 Nash, T.E., Gillin, F.D. and Smith, P.D. (1983) J. lmmunol. 131,2004-2010

131 61 Upcroft, J.A. et al. (1987)Mol. Biochem. Parasitol. 26, 267-276 62 Rosoff, J. and Stibbs, H. (1986)J. Clin. Microbiol. 23, 905-910 63 Gillin, F.D. etal. (1987)Science235, 1040-1043 64 Aggarwal, A. and Nash, T.E. (1987) Am. J. Trop. Med. Hyg. 36,325-332 65 DeJonckheere, J.F. and Gordt8, B. (1987) Mol. Biochem. Parasiwl. 23, 85-89

Neurocysticercosis in Mexico A. Flisser* Cysticercosis is caused by the establishment ofTaenia solium larvae (cysticerci), mainly in the central nervous system ( C N S ) and skeletal muscle of humans and pigs, after ingestion of eggs shed in human faeces by the adult tapeworm (see centrepage diagram). Human neurocysticercosis - often a life-threatening disease - is increasingly recognized as a public health problem, especially in developing countries. Clinical incidence of neurocysticercosis can reach 7% in Mexico I and 18% in the Ekari population of New Guinea 2, while prevalence in autopsies ranges from 0.4% to 3.6% in several countries of Latin America, Asia and Africa z-s. Many cases have also been recently reported in the USA, usually in immigrants6. In this review, Ana Flisser focuses on the problems of cysticercosis in Mexico, where the disease is now recognized as a priority both in public health and economic terms. Recognition of the problem has been greatly aided in recent years by new developments in diagnosis especially computed tomography (CT) to diagnose early stages of neurocysticercosis- and by improved drug treatment. Neurocysticercosis, although a lifethreatening disease in severe cases, is generally an acute or long-lasting infection affecting the quality of the patient's life and social environment:. The disease has socioeconomic importance because 75% of patients with neurocysticercosis are at productive ages, and are frequently unable to work soon after the onset of symptoms 1. Calculations of costs for medical care, such as hospitalization, chemotherapy, neurosurgery and computed tomography, show that US$14.5 million were spent in Mexico during 1986 to treat only the 2700 new hospitalized cases of neurocysticercosis (I. Madrazo et al., unpublished). For these reasons, neurocysticercosis is recognized as being of major public health significance. Furthermore, swine cysticercosis is considered as a significant economic problem because of the condemnation of pig carcasses. In 1980 in Mexico, over US$43 million were lost, the equivalent of 68.5% of the total investment in pig stock production 7. T h e Disease

Clinical 6'8-10, computod tomography11-13,

and i m m u n o l o g i c a l 16-23 data indicate that neurocysticercosis is a complex disease (Table 1). Its major p a t h o l o g i c a l 14'15

~) 1988, Elsevier Publications, Cambridge 0169~758/88/$02 00

manifestations depend not only on the number, location and type of parasites lodged in the CNS and brain meninges, but also on the extent of the inflammatory response induced by the parasite, and on the condition of the host. Patients with convulsions, caused by parenchymal calcified parasites, are treated quite differently from those that have hydrocephalus as a consequence of meningeal arachnoiditis, which is frequently fatal 6'8'9'15. In the former, seizures - the only clinical manifestation of neurocysticercosis - are treated with anticonvulsive drugs such as Epamin (Dilantin, diphenylhydantoin). In the latter, intracranial hypertension and inflammation are therapeutic priorities and require surgery, steroids or cestocidal drugs such as praziquantel. However, patients may remain symptomatic, and a wide array of symptoms and forms of disease are found between these extremes. Cysticerci in the brain have a variable morphology ranging from small intact forms of the cellulose type causing slight inflammation in the surrounding tissue, to large racemose-type parasites causing considerable inflammation. The cysticerci may be viable, hyalinized, necrotic or calcified. Viable parasites are seen by CT as hypodense images, whereas calcified ones

Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico 04510 Mexico D.F.

* Currently a visiting CEC research fellow at the Department of Pure and Applied Biology, Imperial College of Science and Technology, London SW7 2BB

i

Table I.

Symptoms and

signsof human neurocysticercosis Headaches Endocranial hypertension

Seizures Mental alterations Vestibulocerebral alterations

Hemiparesis Intracranial calcifications

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appear as hyperdense areas 11-13. Enhancement of brain tissue surrounding cysticerci in CT images after injection of iodinated intravenous contrast medium is a common finding in human cases, and is considered to be due to hypervascularization and inflammation11-13. The only study regarding the onset of infection relates to British soldiers stationed in India 1° and reported that symptoms appeared up to 30 years after infection. Many asymptomatic cases are only detected at autopsy 15. Consequently, there is no information about the early development of the host-parasite relationship. In pigs, cysticercosis lasts less than one year because animals are usually slaughtered when 9-12 months old 7. Histopathological and CT studies of swine neurocysticercosis showed that parasites are usually small, similar in size and have visible scoleces, no contrast-enhanced images of cysticerci are seen in CT 24. Furthermore, even with large parasite burdens, no neurological signs of the disease are found in pigs 24. Thus the heterogeneity of clinical, CT and pathological findings in human neurocysticercosis6'8-1° suggests that it is a long-lasting disease. CT has made possible the detection of early cases of human neurocysticercosis25 which show tomographic characteristics similar to swine neurocysticercosis.

Fig. I. Surgical excision of cysts can reduce the parasite burden and intracranial hypertension due to neurocysticercosis.

Table 2.

Diagnosis of human neurocysticercosis

Immunological assays eg. ELISA, haemagglutination Antibodies in cerebrospinal fluid or serum confirm the diseasein symptomatic patients Computed t o m o g r a p h y Hypodense roundish areas Hyperdense dots (calcifications or scolices) Enhancement around these areasafter injection of contrast medium Hydrocephalus These imagesare highly suggestive in people from endemic areas Cysticerci in other locations Subcutaneous Ocular

Diagnosis Clinical diagnosis of human neurocysticercosis is often difficult owing to polymorphic symptomatology (Table 1). Immunodiagnostic tests can facilitate diagnosis of symptomatic patients (Table 2) but, despite recent improvements, difficulties of specificity still o c c u r 16'19. Circulating antibodies that react with T. solium antigens have been detected in most patients with neurocysticercosis 16-23. Antigen B (Mol. wt 95-105 kDa), an immunodominant antigen of T. $olium 17'19, is found in several platyhelminths 3°. Two low molecular weight antigens (26 kDa and 8 kDa) have been identified as specific for T. solium, since they react only with serum from patients with neurocysticercosis21. Detection of circulating parasite antigens or immune complexes in samples of CSF may improve immunodiagnosis of neurocysticercosis. Cysticercus components have been detected by ELISA in 77% of 17 CSF samples using hyperimmune rabbit serum 31, and in 86% of 29 CSF samples using monoclonal and polyclonal antibodies (D. Correa et al., unpublished). The advent of CT has further improved diagnostic accuracy and reduced the need for other more harmful Table3.

Treatmentofhumanneurocysticercosis

Cestocidal drugs

The immunology of human cysticercoPraziquantel- 50mg/kg day I, 15 days sis is poorly understood, although antiAlbendazole- 15mg/kg day i, 30 days cysficercus antibodies - mainly lgG - are Flubendazole-40mg/kg day- i, I 0 days found in patients' serum and cerebrospinal fluid (CSF) 16'17'19. The regulatory Surgery Excision of intraventricular cysticerci mechanisms involved in the immune Ventricular shuntinga response of patients with cysticercosis are to control symptoms not known, but immune evasion by the Drugs Anticonvulsants parasite has been proposed to occur by Steroids disguise mechanisms 26'27, increase of supHakimor P/Jdenzshuntis installedunderthe skinof the pressor T-cells 28 and polyclonal acti- ~A headandusedto drainthe CSFfrom the brainventriclesto vation 29. the peritonealcavityr4.

133

Parasitology Today, vol. 4, no. 5, 1988

neuroradiological methods 11-13 (Table 2) (see also Parasitology Today 3, 30-31). However, hypodense or hyperdense images are not exclusive to cysticerci and can be confused with tuberculomas, mycosis and other granulomatous pro-

erated and only the hide and fat of the animal can be sold 7. In some places, pork meat with 'measles' (i.e. containing cysticerci) is even considered a delicacy44. Eggs enter the environment by outdoor

cesses 13.

Treatment Treatment of neurocysticercosis is based on drugs that control symptoms and inflammation6'8'9, and surgery that reduces intracranial hypertension or parasite burden (Fig. 1; Refs 6,32,33). Results are generally unsatisfactory in terms of curing the disease because the parasites or the damage they induce in the brain may remain. Of the cestocidal drugs introduced for the treatment of human neurocysticercosis (Table 3; Refs 6,25,3'I, "1,2) praziquantel has proved most efficient against living parasites, lodged in brain parenchyma and in subarachnoidal cysts z5'35~°. However, the drug is not used against cysticerci located in brain ventricles or in the eye, and has no effect on calcified (dead) parasites. Epidemiology and Control While neurocysticercosis can be diagnosed and treated with some success, its eradication depends on a number of complex factors. Cysticercosis is acquired after the ingestion of T. soliumeggs, so the main targets for control are cysticercotic pigs, human carriers of the adult tapeworm, and eggs in the e.nvironment. Pigs acquire cysticercosis mainly because they are allowed to roam and feed indiscriminately, and can ingest faecal matter from other animals and man 43. In remote areas of Mexico, it is still possible to find latrines built so that pigs haw.~ direct access to human excrement (Fig. 2). Humans acquire the infection by eating pig meat containing living cysticerci. Strict meat inspection is carried out by veterinary doctors in the large slaughterhouses of big Mexican cities, controlled by the Ministry of Health or the Ministry of Agriculture. In small villages and hamlets, slaughterhouses are under the supervision of the municipality, but meat is often sold without any inspection 43. During sanitary inspection, two incisions, one perpendicular to the other, are made in one shoulder of the carcass. If one or two cysticerci are found, the meat is deep fried and used for human consumption in a national dish called 'carnitas'. If more parasites are found, tile meat is incin-

Fig.2. Latrines in rural areas of Mexico (a) often allow faecal matter to remain accessible, in this case an the other side of the wall (b), where pigs can ingest the human excrement (c) - completing this part of the transmission cycle of Taenia solium. (Figures reprinted from Cysticercosis, Present State of Knowledge and Perspectives,courtesy of Academic Press.)

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When man ingests embryonated eggs or proglottids, the oncosphere hatches and penetrates the intestinal wall. Afterwards T. solium larvae (cysticerci) establish in the central nervous system, skeletal muscle, and subcutaneous tissue of the human host. The figures show cysticerci in the eye (a), tongue (b) and brain (c) of infected hosts. The heavily infected brain in (c) was that of a 9-year-old girl whose only symptom was mild chronic headache. A CSF puncture to determine the cause of symptoms led to ventricular collapse and death. a Courtesyof Academic Press b Courtesy of AcademicPress c Juan E. Olvera-Rabiela

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136

defaecation and faecal contamination of vegetables from sewage water used for irrigation. There has been little effort either towards improving the diagnosis of people infected with the adult tapeworm, or the diagnosis of cysticercotic pigs. Diagnosis of human taeniasis is based on finding Taenia eggs or proglottids in stools, because infected carriers are usually asymptomatic. However, coproparasitoscopical methods are generally inefficient and the application of tests incorporating D N A probes may improve diagnosis 45'46. Swine cysticercosis is routinely diagnosed by meat inspection in slaughterhouses; no antemortem diagnostic methods are available although some efforts are being made to standardize immunodiagnostic techniques for swine cysticercosis 47. Recent epidemiological studies show an aggregated distribution of people infected with adult tapeworm together with people showing serological or clinical evidence of cysticercosis. This suggests that transmission tends to be focused around particular households 48'49. However, invertebrates can also participate in the transmission of taeniid eggs; in experimental trials, sheep acquired ovine cysticercosis from flies carrying T. hydatigena eggs 5°. Treatment of human taeniasis by chemotherapy is highly efficient (only one dose of niclosamide or praziquantel is needed 51) and safe. Meat from condemned cysticercotic pig carcasses is either prepared by deep frying, burned 7, or can be frozen 55. Alternatively, pigs can be treated with a cestocidal drug, because recent observations indicate the infected pigs can be cured with praziquantel (A. Flisser et al., unpublished). Control of Praziquantel for human use human taeniasis and pig cysticercosis by is called 'Cisticid' (Merck) optimal diagnosis and treatment, supporand a complete treatment ted by adequate sanitary improvement regime for a 60 kg adult costs £ 165 or U55297. The and health education will prevent new veterinary equivalent, cases of human neurocysticercosis. An 'Droncid" (Bayer) is not yet additional approach may involve vaccicommercially used for nation, because good results have been treatment of swine obtained with different immunizing cysticercosis. agents in experimental and veterinary cysticercosis 52. No vaccination strategy can yet be applied to humans living in highrisk areas. In 1984, the Mexican government established a priority health programme for the Control, Eradication and Surveillance of T. solium cysticercosis 53. The Technical Consultative Committee of this programme - composed of experts in cysticercosis 54- is initiating research projects

Parasitology Today, vol. 4, no. 5, 1988

and pilot control studies that may eventually lead to an official proposal for a nationwide control and surveillance programme. Similar initiatives will be required in other countries if this serious disease is to be controlled worldwide. The WHO has already published Guidelines for the Surveillance, Prevention and Control of Taeniasis and Cysticercosis 51. References 1 Velasco-Suarez, M., Bravo, M. A, and Quirasco, F. (1982) in Cysticercosis, Present State @Knowledge and Perspectives (Flisser, A. et al., eds), pp 47-52, Academic Press, New York 2 Gajdusek, D. C. (1978) Papua New Guinea Med. J, 21,329-342 3 Schenone, H. et al. (1982) in Cysticercosis, Present State @Knowledge and Perspectives (Flisser, A. et al., eds), pp 25-38, Academic Press, New York 4 Mahajan, R. C. (1982) in Cysticercosis, Present State of Knowledge and Perspectives (Flisser, A. et al., eds), pp 39--46, Academic Press, New York 5 Shasha, W., Dellen, J. and Cakata, E. (1986) S. Aft. J. Epidemiol. Infect. 1,94--97 6 Earnest, M. P. et al. (1987) Rev. Infect. Dis. 9, 961979 7 Acevedo-Hernandez, A. (1982) in Cysticercosis, Present State of Knowledge and Perspectives (Flisser, A. et al., eds), pp 63-68, Academic Press, New York 8 Estafiol, B., Corona, T. and Abad, P. (1986) J . Neural. Neurosurg. Psychiatry 49, 1131-1134 9 Sotelo, J., Guerrero, V. and Rubio-Donnadieu, F. (1985)Arch. Intern. Med. 145,442-445 10 Dixon, H. B. F. and Lipscomb, F. M. (1961) Pr/vy Couneil Med. Res., Spec. Rep. Ser. 299, 1-58 11 Madrazo, I. et al. (1981)J. N eurosurg. 55,947-951 12 Minguetti, G. and Ferreira, M. (1983)J. Neural. Neurosurg. Psychiatry 46,936-942 13 Rodriguez-Carbajal, J. and Boleaga-Duran, B. (1982) in Cysticercosis, Present State of Knowledge and Perspectives (Flisser, A. et al., eds), pp 139-162, Academic Press, New York 14 Escobar, A. (1983) in Cysticercosis of the Central Nervous System (Palacios, E., Rodriguez-Carbajal, J. and Taveras, J. M., eds), pp 27-54, Thomas, Springfield, Illinois 15 Rabiela-Cervantes, M. T. etal. (1982) inCysticercosis, Present State of Knowledge and Perspectives (Flisser, A. et al., eds), pp 179-200, Academic Press, New York 16 Flisser, A. and Larralde, C. (1986) in Immunodiagnosis of Parasitic Diseases. Helminthic Diseases (Walls, K. W. and Schantz, P. M., eds), pp 109-161, Academic Press, Florida 17 Flisser, A., Woodhouse, E. and Larralde, C2 (1980) Clin. Exp. Immunol. 39, 27-37 18 Cho, S. Y., Kim, S. I. and Kang, S. Y. (1986) Korean J. Parasitol. 24,159-170 19 Espinoza, B. et al. (1986)J. Clin. Microbial. 24, 536-541 20 Larralde, C. et al. (1986) Am. J. Trap. Med. Hyg. 35, 965-973 21 Gottstein, B., Zini, D. and Schantz, P. M. (1987) Trap. Med. Parasitol. 38,299-303 22 Nascimento, E., Nogueira, P. M. P. and Tavares, C. A. P. (1987) Parasitol. Res. 73,446-450 23 Pammenter, M. D., Rossouw, E. J. and Epstein, S. R. (1987)S. Aft. Med. y. 71,512-514 24 Gonzalez, D. etal. (1987) Vet. Parasitol. 26, 55-71 25 Joubert, J., Joubert, M. J. and Lombaard, C. M. (1985) S. Afr. Med.J. 68, 11-14 26 Correa, D. etal. (1985)J. Parasitol. 71,535-541 27 Willms, K. and Arcos, L. (1977) Exp. Parasitol. 43, 396--402 28 Flisser, A. et al. (1987) Gac. Med. Mex. 123,157-164 29 Sealey, M. et al. (1981) Parasite lmmunol. 3,299-303 30 Olivo, A., Plancarte, A. and Flisser, A. Int.J. Parasitol. (in press)

Parasitology Today, vol. 4, no. 5, 1988 31 Tellez-Giron, E. et al. (1987) Am. J. Trop. Med. Hyg. 37, 169-173 32 Escobedo, F. etal. (1982) in Cysticercosis, PresentState of Knowledge and Perspectives (Flisser, A. et al., eds), pp 201-206, Academic Press, New York 33 Madrazo, I. etal. (1983)Neurosurgery 12, 148--152 34 Groll, E. (1984) in Advances in Pharmacology and Chemotherapy, (Garattini, S., Goldin, A. and Hawking, F., eds), (Vol. 20), pp 219-238 Academic Press, New York 35 Sotelo, J. etal. (1984) N E J M 310, 1001-1007 36 Markwalder, K. et al. (1984)J. Trop. Med. Hyg. 33, 273-280 37 Leblanc, R. etal. (1986) Neurosurgery 18,419-427 38 Zhi-biao, X. etal. (1985) ChineseMed.J. 98,489-494 39 Overbosch, D. et al. (1987) Eur. J . Clin. Pharmacol. 33,287-292 40 Vasconcelos, D. et al. (198:7)J. Neurol. Neurosurg. Psychiatry 50,383-388 41 Tellez-Giron, E. et al. (1984) Am. J. Trop. Med. Hyg. 33,627-631 42 Escobedo, F. et al. (1987) Arch. Intern. Med. 147, 738-741 43 Aluja, A. (1982) in Cysticercosis, Present State of Knowledge and Perspectives (Flisser, A. etal., eds), pp 52-62, Academic Press, New York

137 44 Salazar-Schettino, P. M. (1983) Am. J. Trop. Med. Hyg. 32, 1179-1180 45 Rishi, A. K. and McManus, D. P. (1987) Lancet i, 1275-1276 46 Rishi, A. K. and McManus, D. P. Parasitology (in press) 47 Varma, T. K., Malviya, H. C. and Ahluwalia, S. S. (1986) Indian J. Anita. Sci. 56,621-627 48 Sarti-Gutierrez, E. J. et al. (1987) in 36th Annu. Meeting Am. Soc. Trop. Med. Hyg. Los Angeles, CA., p. 147 49 Diaz-Camacho, S. et al. in Cisticercosis Humana y Porcina, su Conocimiento e Investigation en Mexico (Flisser, A. and Malagon, F., eds), CONACyT, Mexico (in press) 50 Lawson, J. R. and Gemmell, M. A. (1985) Parasitology91,129-143 51 Gemmell, M. A. et al. (eds), (1983) F A O / U N E P / WHO VPH/83.49 World Health Organization, Geneva 52 Rickard, M. D. and Williams, J. F. (1982) Adv. Parasitol. 21,230-296 53 Secretaria de Salud (1984) Diario Oficial 24, 11-13 Mexico 54 Aluja, A. et al. (1987) Biblioteca de la Salud Fondo de Cultura Economica S. A. de C. V., Mexico. 55 Flisser A. etal. (1986)SaludPubl. Mex. 28,551-555

Acknowledgements I am deeply grateful to Don McManus and Ignacio Madrazo for correcting my manuscript.

Trypanosoma evansi in Asia A. G. Luckins Trypanosoma evansi has the widest geographical range of all the pathogenic trypanosome species and infects domesticated livestock in many countries of South America, Africa and Asia. In spite of this wide distribution, T. evansi has been less intensively investigated than the African tsetse-transmitted trypanosomes and there is correspondingly less information available on the incidence and economic importance of the disease that it causes. Many of the new techniques in immunology and molecular biology, which have provided much fundamental information on the tsetse-transmitted trypanosomes, have yet to be applied to T. evansi. Interest in T. evansi is increasing and a Working Group has now been established to coordinate and promote future research (Box I). T. evansi is an important aetiological agent of disease in the livestock of Asia; this article evaluates both the historical perspective and our current knowledge of the epidemiology and pathology ofT. evansi in this region.

Trypanosoma evansi was the first pathogenic trypanosome shown to cause disease in domesticated live.stock. It infects equids, camels, cattle, buffalo, goats, sheep and pigs. T. evansi belongs to the brucei group of trypanosomes and is morphologically identical to the long slender forms of the pleomorphic tsetsetransmitted T. brucei. Hoare ~ has postulated that T. evansi evolved from T. brucei by adaptation to a non-cyclical mode of transmission involving loss of pleomorphism (see Box 2). He suggested that camels coming into contact with tsetse flies at the northernmost limit of tsetse distribution became :infected with T. b.rucei, and when the camels returned to tsetse-free areas, infection was spread by other haematophagous insects. Thereafter, camels further disseminated the disease when camel caravans travelled throughout North Afi:ica and into the ~) 1988,ElsevierPublications,Cambridge01694758/88/$02.00

Middle East and Asia. Subsequently, T. evansi was probably introduced into the N e w World along with livestock brought to the Americas by Europeans in the 16th century. The epidemiology of trypanosomiasis caused by T. evansi in Asia is of particular interest because although the disease has long been known to affect horses and camels in India, its spread to neighbouring territories appears to have been comparatively recent. Consequently, much more information is available on its initial introduction and prevalence. T. evansi was first isolated from infected camels and equids in the Dera Ismail Khan district of the Punjab in 18802. A variety of local names, descriptive of the clinical signs of the disease, were used by livestock owners (eg. 'purana' - chronic or old; 'tibarsa' - 3-year disease; 'dubla' emaciated) but the Hindi term 'surra'

Centre for Tropical Veterinary Medicine, Easter Bush, Roslin Midlothian EH25 9RG, UK