Taenia Solium Cysticercosis: From Basic to Clinical Science (Cabi Publishing)

Taenia solium Cysticercosis

From Basic to Clinical Science

Taenia solium Cysticercosis From Basic to Clinical Science

Edited by

Gagandeep Singh Dayanand Medical College & Hospital Ludhiana Punjab, India and

Sudesh Prabhakar Department of Neurology Postgraduate Institute of Medical Education and Research Chandigarh, India

CABI Publishing

CABI Publishing is a division of CAB International CABI Publishing CAB International Wallingford Oxon OX10 8DE UK Tel: +44 (0)1491 832111 Fax: +44 (0)1491 833508 E-mail: [email protected] Web site: www.cabi-publishing.org

CABI Publishing 10 E 40th Street Suite 3203 New York, NY 10016 USA Tel: +1 212 481 7018 Fax: +1 212 686 7993 E-mail: [email protected]

© CAB International 2002. All rights reserved. No part of this publication may be reproduced in any form or by any means, electronically, mechanically, by photocopying, recording or otherwise, without the prior permission of the copyright owners. A catalogue record for this book is available from the British Library, London, UK. Library of Congress Cataloging-in-Publication Data Singh, G. (Gagandeep) Taenia solium cysticercosis : from basic to clinical science / edited by G. Singh and S. Prabhakar. p. cm. Includes bibliographical references and index. ISBN 0-85199-628-0 1. Cysticercosis. 2. Taenia. I. Prabhakar, S. (Sudesh) II. Title. RC136.7 .S545 2002 616.9’64--dc21 2002001332 ISBN 0 85199 628 0

Typeset in Palatino by Columns Design Ltd, Reading, UK Printed and bound in the UK by Biddles Ltd, Guildford and Kings Lynn.

Contents

Contributors

ix

Preface

xiii

Abbreviations

xiv

SECTION I

TAENIA SOLIUM CYSTICERCOSIS: BASIC SCIENCE

1. Taenia solium: Basic Biology and Transmission Zbigniew S. Pawlowski

1

2. Taenia solium Cysticercosis: New and Revisited Immunological Aspects Ana Flisser, Dolores Correa and Carlton A.W. Evans

15

3. Molecular Determinants of Host–Parasite Interactions: Focus on Parasite José L. Molinari and Patricia Tato

25

4. Animal Models of Taenia solium Cysticercosis: Role in Understanding Host–Parasite Interactions Astrid E. Cardona and Judy M. Teale 5. Mitochondrial DNA of Taenia solium: From Basic to Applied Science Akira Ito, Minoru Nakao, Munehiro Okamoto, Yasuhito Sako and Hiroshi Yamasaki 6. Hereditary Factors in Neurocysticercosis with Emphasis on Single, Small, Enhancing CT Lesions Vasantha Padma, Satish Jain, Achal Srivastava, Manjari Tripathi and Mahesh C. Maheshwari SECTION II

35 47

57

EPIDEMIOLOGY

7. Taenia solium Cysticercosis: an Overview of Global Distribution and Transmission Peter M. Schantz 8. What Have We Learnt From Epidemiological Studies of Taenia solium Cysticercosis in Peru? Hector H. García, Robert H. Gilman, Armando E. Gonzalez, Manuela Verastegui, Victor C.W. Tsang and The Cysticercosis Working Group in Peru

63

75

v

vi

Contents

9. Epidemiology of Taenia solium Taeniasis and Cysticercosis in Mexico Elsa Sarti 10. Taenia solium Taeniasis and Cysticercosis in Central America José Garcia-Noval, Ana L. Sanchez and James C. Allan

83 91

11. Neurocysticercosis in Brazil: Epidemiological Aspects Svetlana Agapejev

101

12. Taenia solium Taeniasis and Cysticercosis in Asia Gagandeep Singh, Sudesh Prabhakar, Akira Ito, Seung Yull Cho and Dong-Chuan Qiu

111

13. Taenia solium Cysticercosis in Africa Michel Druet-Cabanac, Bienvenue Ramanankandrasana, Sylvie Bisser, Louis Dongmo, Gilbert Avodé, Léopold Nzisabira, Michel Dumas and Pierre-Marie Preux

129

14. Taenia solium Cysticercosis: the Special Case of the United States Wayne X. Shandera, Peter M. Schantz and A. Clinton White Jr

139

15. Porcine Cysticercosis Armando E. Gonzalez, Patricia P. Wilkins and Teresa Lopez

145

16. Taenia solium: A Historical Note Noshir H. Wadia and Gagandeep Singh

157

SECTION III

TAENIA SOLIUM CYSTICERCOSIS: CLINICAL ASPECTS

17. Neurocysticercosis: an Overview of Clinical Presentations Sudesh Prabhakar and Gagandeep Singh

169

18. Meningeal Cysticercosis Oscar H. Del Brutto

177

19. Heavy Multilesional Cysticercotic Syndromes Oscar H. Del Brutto, Hector H. García and Sudesh Prabhakar

189

20. Intraventricular Neurocysticercosis Albert C. Cuetter and Russell J. Andrews

199

21. Neurocysticercosis and Epilepsy Arturo Carpio and W. Allen Hauser

211

22. Cerebrovascular Manifestations of Neurocysticercosis Fernando Barinagarrementeria and Carlos Cantú

221

23. Taenia solium Cysticercosis: Uncommon Manifestations Gagandeep Singh and Indermohan S. Sawhney

229

24. The Story Behind Solitary Cysticercus Granuloma Vedantam Rajshekhar

241

25. Seizures Due to Solitary Cysticercus Granuloma J.M.K. Murthy

251

26. Paediatric Neurocysticercosis Sudesh Prabhakar and Gagandeep Singh

257

27. Psychiatric Manifestations of Neurocysticercosis Orestes V. Forlenza

263

28. Taenia solium Cysticercosis: Ophthalmic Aspects Atul Kumar and Namrata Sharma

269

Contents

29. Neurocysticercosis: Diagnosis and Treatment in Special Situations Ravindra K. Garg and Alok M. Kar SECTION IV

281

CYSTICERCOSIS: PATHOLOGY

30. The Pathology of Neurocysticercosis Alfonso Escobar and Karen M. Weidenheim 31. Single Small Enhancing Computed Tomography Lesions – Pathological Correlates Geeta Chacko SECTION V

vii

289

307

NEUROCYSTICERCOSIS: INVESTIGATIONAL ASPECTS

32. Imaging and Spectroscopy of Neurocysticercosis Deepshikha Sharda, Sanjeev Chawla and Rakesh K. Gupta 33. Taenia solium Cysticercosis: Immunodiagnosis of Neurocysticercosis and Taeniasis Patricia P. Wilkins, Marianna Wilson, James C. Allan and Victor C.W. Tsang

311

329

34. Antigen-based Immunoassays in the Diagnosis of Taenia solium Cysticercosis Dolores Correa, Raquel Tapia-Romero, Antonio Meza-Lucas and Olga Mata-Ruiz

343

35. Polymerase Chain Reaction in the Diagnosis of Taenia solium Cysticercosis Taru Meri and Seppo Meri

351

36. Immunodiagnosis in Solitary Cysticercus Granulomas Anna Oomen

359

SECTION VI

TAENIASIS–CYSTICERCOSIS: THERAPY AND PREVENTION

37. Pharmacology of Anticysticercal Therapy Helgi Jung and Dinora F. González-Esquivel

363

38. Controversies in the Drug Treatment of Neurocysticercosis Bhim S. Singhal and Rodrigo A. Salinas

375

39. Neurocysticercosis: Neurosurgical Perspective Bhawani S. Sharma and P. Sarat Chandra

387

40. Endoscopic Management of Intraventricular Cysticercosis Marvin Bergsneider and Jaime H. Nieto

399

41. Control of Taenia solium with Emphasis on Treatment of Taeniasis James C. Allan, Philip S. Craig and Zbigniew S. Pawlowski

411

42. Taenia solium Vaccination: Present Status and Future Prospects Carlton A.W. Evans

421

43. Control of Taenia solium with Porcine Chemotherapy Armando E. Gonzalez

431

44. Use of a Simulation Model to Evaluate Control Programmes against Taenia solium Cysticercosis Armando E. Gonzalez, Robert H. Gilman, Hector H. García and Teresa Lopez

437

Index

449

Contributors

Svetlana Agapejev, Department of Neurology and Psychiatry, PO Box 540, School of Medicine, UNESP, 18618-000 Botucatu, São Paulo, Brazil. James C. Allan, Pfizer Global Research and Development – Veterinary Medicine Clinical Development, Pfizer Ltd, Sandwich, CT13 9NJ, UK. Russell J. Andrews, Department of Neurology, Texas Tech University Health Sciences Center, El Paso, Texas 79905, USA. Gilbert Avodé, School of Medicine, Cotonou, Benin. Fernando Barinagarrementeria, Department of Neurology, Instituto Nacional de Ciencias Medicas y Nutricion, ‘Salvador Zubiran’, México City, México. Marvin Bergsneider, Division of Neurosurgery, University of California, Los Angeles, Harbor–UCLA Medical Center, Los Angeles, California, USA. Sylvie Bisser, Institut d’Epidémiologie Neurologique et de Neurologie Tropicale, EA 3174 (Neuroparasitologie et Neuroépidémiologie Tropicale) Faculté de Médecine, 2 rue du Dr Marcland, 87025 Limoges, France. Carlos Cantú, Department of Neurology, Instituto Nacional de Neurologia y Neurocirgia ‘Manuel Velasco Suarez’, México City, México. Astrid E. Cardona, Department of Microbiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. Arturo Carpio, Comprehensive Epilepsy Center, School of Medicine, University of Cuenca, Ecuador, PO Box 0101-719, Cuenca, Ecuador. Geeta Chacko, Division of Neuropathology, Department of Neurological Sciences, Christian Medical College and Hospital, Vellore 632 004, Tamil Nadu, India. P. Sarat Chandra, Department of Neurosurgery, CN Center, Room 720, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India. Sanjeev Chawla, Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226 014, Uttar Pradesh, India. Seung Yull Cho, Section of Molecular Parasitology, Department of Molecular Medicine, Sungkyunkwan University College of Medicine, Sungkyunkwan, Korea. Dolores Correa, Departmento de Biotecnologia, Instituto de Diagnostico y Referencia Epidemiologicos (INDRE), Secretaria de Salud, México DF, México. Philip S. Craig, Department of Biological Sciences, School of Environment and Life Sciences, University of Salford, Salford, M5 5W7, UK. Albert C. Cuetter, Department of Neurology, Texas Tech University Health Sciences Center, El Paso, Texas 79905, USA. © CAB International 2002. Taenia solium Cysticercosis (eds G. Singh and S. Prabhakar)

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Contributors

Oscar H. Del Brutto, Department of Neurology, Luis Vernaza Hospital, Guayaquil, Ecuador. Louis Dongmo, School of Medicine, Yaoude, Cameroon. Michel Druet-Cabanac, Institut d’Epidémiologie Neurologique et de Neurologie Tropicale, EA 3174 (Neuroparasitologie et Neuroépidémiologie Tropicale) Faculté de Médecine, 2 rue du Dr Marcland, 87025 Limoges, France. Michel Dumas, Institut d’Epidémiologie Neurologique et de Neurologie Tropicale, EA 3174 (Neuroparasitologie et Neuroépidémiologie Tropicale) Faculté de Médecine, 2 rue du Dr Marcland, 87025 Limoges, France. Alfonso Escobar, Instituto de Investigaciones, Biomedicas, National Autonomous University of México, Ciudad Universitaria 04510, México DF, México. Carlton A.W. Evans, Imperial College, Department of Infectious Diseases, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Ana Flisser, Departmento de Microbiologia y Parasitologia, Facultad de Medicina, National Autonomous University of México, Ciudad Universitaria, San Angel, México 04510 DF, México. Orestes V. Forlenza, Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil. Hector H. García, Departments of Transmissible Diseases, Microbiology, and Pathology, Universidad Peruana Cayetano Heredia, Lima, Peru. José Garcia-Noval, Centro de Investigaciones de las Ciencias de la Salud, Facultad de Ciencias Medicas, Universidad de San Carlos, Zona 12, Guatemala City, Guatemala. Ravindra K. Garg, Department of Neurology, King George’s Medical College, Lucknow, 226 003, Uttar Pradesh, India. Robert H. Gilman, Department of International Health, Johns Hopkins School of Public Health, Johns Hopkins University, 615 N Wolfe St, Room W 3501, Baltimore, Maryland 21205, USA. Armando E. Gonzalez, Facultad de Medicina Veterinaria, Universidad Nacional Mayor de San Marcos, Lima, Peru. Dinora F. González-Esquivel, Laboratorio de Neuropsicofarmacologia, Instituto Nacional de Neurologia y Neurocirugia, México City, México. Rakesh K. Gupta, Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226 014, Uttar Pradesh, India. W. Allen Hauser, Department of Neurology and Public Health, College of Physicians and Surgeons, Columbia University, GH Sergievsky Center, 630 West 168th Street, New York 10032, USA. Akira Ito, Department of Parasitology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Hokkaido, Japan. Satish Jain, Department of Neurology, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, 110 029, India. Helgi Jung, Laboratorio de Neuropsicofarmacologia, Instituto Nacional de Neurologia y Neurocirugia, México City, México. Alok M. Kar, Department of Neurology, King George’s Medical College, Lucknow, 226 003, Uttar Pradesh, India. Atul Kumar, Dr Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India. Teresa Lopez, Laboratorio de Micribiologia y Parasitologia, Facultad de Medicina Veterinaria, Universidad Nacional Mayor de San Macos, Cdra. 29 Av. Circunvalacion s/n San Borja, Lima, Peru. Mahesh C. Maheshwari, Department of Neurology, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, 110 029, India. Olga Mata-Ruiz, Departmento de Biotecnologia, Instituto de Diagnostico y Referencia Epidemiologicos, Secretaria de Salud, México DF, México.

Contributors

xi

Seppo Meri, Department of Bacteriology and Immunology, Haartman Insitute, PO Box 21 (Haartmaninkatu 3) 00014, University of Helsinki, Finland. Taru Meri, Department of Bacteriology and Immunology, Haartman Insitute, PO Box 21 (Haartmaninkatu 3) 00014, University of Helsinki, Finland. Antonio Meza-Lucas, Departmento de Biotecnologia, Instituto de Diagnostico y Referencia Epidemiologicos, Secretaria de Salud, México DF, México. José L. Molinari, Department of Molecular Genetics, Institute of Cellular Physiology, National Autonomous University of México, México DF 04510, Apartado Postal 70–242, México. J.M.K. Murthy, Department of Neurology, The Institute of Neurological Sciences, CARE Hospital, Nampally, Hyderabad, 500 001, India. Minoru Nakao, Department of Parasitology, Asahikawa Medical College, MidorigaokaHigashi 2-1-1-1, Asahikawa 078-8510, Hokkaido, Japan. Jaime H. Nieto, Division of Neurosurgery, University of California, Los Angeles, Harbor–UCLA Medical Center, Los Angeles, California, USA. Léopold Nzisabira, School of Medicine, Bujumbura, Burundi. Munehiro Okamoto, Department of Laboratory Animal Sciences, School of Veterinary Medicine, Faculty of Agriculture, Tottori University, Koyamacho-Minami 4-101, Tottori 680-8553, Tottori, Japan. Anna Oomen, Neurochemistry Laboratory, Department of Neurological Sciences, CMC Hospital, Vellore 632 004, India. Vasantha Padma, Department of Neurology, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, 110 029, India. Zbigniew S. Pawlowski, Clinic of Parasitic and Tropical Diseases, ul., Przybyszewskiego 49, 60-355 Poznan, Poland. Sudesh Prabhakar, Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, 161 001, India. Pierre-Marie Preux, Institut d’Epidémiologie Neurologique et de Neurologie Tropicale, EA 3174 (Neuroparasitologie et Neuroépidémiologie Tropicale) Faculté de Médecine, 2 rue du Dr Marcland, 87025 Limoges, France. Dong-Chuan Qiu, Sichuan Institute of Parasitic Diseases, 10 University Road, Chengdu 610041, Sichuan Province, People’s Republic of China. Vedantam Rajshekhar, Department of Neurological Sciences, Christian Medical College and Hospital, Vellore, 632 004, India. Bienvenue Ramanankandrasana, Institut d’Epidémiologie Neurologique et de Neurologie Tropicale, EA 3174 (Neuroparasitologie et Neuroépidémiologie Tropicale) Faculté de Médecine, 2 rue du Dr Marcland, 87025 Limoges, France. Yasuhito Sako, Department of Parasitology, Asahikawa Medical College, MidorigaokaHigashi 2-1-1-1, Asahikawa 078-8510, Hokkaido, Japan. Rodrigo A. Salinas, Healthcare Programmes Division, Ministry of Health, Chile. Ana L. Sanchez, Department of Microbiology, National Autonomous University of Honduras, Tegucigalpa, Honduras. Elsa Sarti, INDRE, Carpio no. 470, 3rd floor, Col. Sto. Tomás, CP 04230, Mexico City, Mexico. Indermohan S. Sawhney, Department of Neurology, Morriston Hospital, Morriston, Swansea SA6 6NL, UK. Peter M. Schantz, Division of Parasitic Diseases, National Center for Infectious Diseases Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA. Wayne X. Shandera, Department of Medicine, Sections of General Internal Medicine and Infectious Diseases, Baylor College of Medicine and Ben Taub General Hospital, Houston, Texas 77030, USA. Deepshikka Sharda, Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow, 226 014, Uttar Pradesh, India.

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Contributors

Bhawani S. Sharma, Department of Neurosurgery, CN Center, Room 720, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India. Namrata Sharma, Dr Rajendra Prasad Center of Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India. Gagandeep Singh, Department of Neurology, Dayanand Medical College and Hospital, Ludhiana, 141 001, Punjab, India. Bhim S. Singhal, Department of Neurology, Bombay Hospital Institute of Medical Sciences, 12 Marine Lines, Mumbai, 400 0020, India. Achal Srivastava, Department of Neurology, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, 110 029, India. Raquel Tapia-Romero, Departmento de Biotecnologia, Instituto de Diagnostico y Referencia Epidemiologicos, Secretaria de Salud, México DF, México. Patricia Tato, Department of Microbiology and Parasitology, Faculty of Medicine, National Autonomous University of México, México DF 04510, México. Judy M. Teale, Department of Microbiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. Manjari Tripathi, Department of Neurology, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, 110 029, India. Victor C.W. Tsang, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA. Manuela Verastegui, Laboratorio de Parasitologia, Facultad de Ciencias, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado s/n Urbanizacion Ingeniera, San Martin de Porres, Lima, Peru. Noshir H. Wadia, Director of Neurology, Jaslok Hospital and Research Center, Mumbai, India. Karen M. Weidenheim, Division of Neuropathology, Montefiore Medical Center, AECOM, YU111, East 210th Street, Bronx, New York 10467, USA. A. Clinton White Jr, Infectious Disease Section, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. Patricia P. Wilkins, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA. Marianna Wilson, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA. Hiroshi Yamasaki, Department of Parasitology, Asahikawa Medical College, MidorigaokaHigashi 2-1-1-1, Asahikawa, 078-8510, Hokkaido, Japan.

Preface

Neurocysticercosis and the macroparasite Taenia solium, which causes it, have been known about for time immemorial. Through history, one can follow the development of concepts regarding the aetiology, pathology, clinical science and treatment of the disorder. Recent times have however been complicated by accumulating knowledge regarding molecular biology, immunology and genetics of the disorder. The relationship between the molecular laboratory and bedside clinical practice is becoming increasingly powerful. In these times of molecular advances, a review of neurocysticercosis and T. solium that focuses on past accomplishments, current understanding and future hopes seems appropriate. A number of scientific antecedents mean that the goals of effective treatment and, more importantly, eradication are foreseeable. This alone prompted the genesis of this textbook, which symbolizes the spirit of unity between basic researchers, clinicians and field workers. Since the book involved a large number of subspeciality areas including parasitology, immunology, biology, genetics, epidemiology and public health, clinical neurology, radiology and veterinary medicine, it was impossible for two authors alone to write such a volume. Therefore, we solicited the contribution of a number of experts, each with great depth of knowledge and experience in their respective areas. The contributors to this book are its principal strength and we are indebted to them for their time and effort spent not only in writing their respective chapters but also for the years of painstaking work that led to the realization of knowledge through basic, clinical or field research. It is because of their involvement, that the book turns out what it was meant to be, a ‘one-stop shop for T. solium cysticercosis’. We express our appreciation of several associates among the contributors, who gave invaluable suggestions while planning the book project and were also involved in stimulating discussions: James Allan, Peter Schantz, Ana Flisser, Patricia Wilkins, Hector García, Akira Ito, Phillip Craig, Arturo Carpio, Carlton Evans and Svetlana Agapejev. Davinder Singh and Arun Gupta provided excellent editorial assistance with the text and illustrations, respectively. Finally, this book is a tribute to those millions afflicted by the disorder. They have contributed in their own way to the understanding of the disorder. It is our fervent hope that the recent accomplishments in scientific understanding brought out in this volume will ultimately lead to the goal of complete global eradication of the parasite, T. solium.

© CAB International 2002. Taenia solium Cysticercosis (eds G. Singh and S. Prabhakar)

xiii

Abbreviations

AED AFB AIDS ALBSO ATT AUC C1 CDC cDNA CECT CI Cmax CNS COI COII COIII Con A CSF CT CWG DTH EDTA EEG EITB ELISA ES FLAIR FMO Gd GIS GPL GST HIV HLA HPLC-ELISA hsps

antiepileptic drug acid-fast bacilli acquired immune-deficiency syndrome albendazole sulphoxide antitubercular treatment area under the plasma concentration–time curve first cervical vertebra Centers for Disease Control complementary deoxyribonucleic acid contrast enhanced CT confidence interval maximal concentration central nervous system cytochrome c oxidase subunit I cytochrome c oxidase subunit II cytochrome c oxidase subunit III concanavalin A cerebrospinal fluid computed tomography Cysticercosis Working Group delayed type hypersensitivity ethylenediamine tetra-acetic acid electroencephalography enzyme-linked immunoelectrotransfer blot enzyme-linked immunosorbent assay excretory–secretory fluid attenuation inversion recovery flavin-containing monoxygenase gadolinium global information system glycoproteins glutathione-S-transferase human immunodeficiency virus human leucocyte antigen high pressure liquid chromatography-ELISA heat shock proteins

© CAB International 2002. Taenia solium Cysticercosis xiv

Abbreviations

HU ICH ICP IDEMSC IEF IFN IgG IgM IHA IL ILAE IMOA IMSC IP IV IVNC LLGP LrRNA MAb MF MoAb MRI mtDNA NADH NADPH NC Nd:YAG NOD-SCID Pc PCR PD PoAb PRA Rnase RR rRNA SCG SDS-PAGE SrRNA SSECTL sTS TCD Th TNF tRNA VPS

Hounsfield units intracranial hypertension intracranial pressure intradural extramedullary spinal cysticercosis immunoelectrophoresis interferon immunoglobulin G immunoglobulin M indirect haemagglutination assay interleukin International League Against Epilepsy intramuscular oncosphere assay intramedullary spinal cysticercosis intraperitoneal intravascular intraventricular neurocysticercosis lentil lectin-bound glycoproteins large subunit rRNA monoclonal antibody metacestode factor monoclonal antibody magnetic resonance imaging mitochondrial deoxyribonucleic acid reduced nicotinamide-adenine dinucleotide nicotinamide-adenine dinucleotide phosphate (reduced form) neurocysticercosis neodymium:yttrium alminium-garnet non-obese diabetic-severe combined immunodeficiency corrected P value polymerase chain reaction proton density polyclonal antibody participatory rural appraisal ribonuclease relative risk ribosomal ribonucleic acid solitary cysticercus granuloma sodium dodecyl sulphate-polyacrylamide gel electrophoresis small subunit rRNA single small enhancing CT lesion synthetic Taenia solium transcranial doppler T helper cell tumour necrosis factor transfer ribonucleic acid ventriculoperitoneal shunt

xv

1

Taenia solium: Basic Biology and Transmission Zbigniew S. Pawlowski

No animal has been responsible for more hypotheses, discussions and errors than the tapeworm Casimir Joseph Davaine, 18601

Introduction Even today, the above statement by the author of a French textbook of parasitology deserves attention. While some of the earlier controversies regarding the taxonomic status, life cycle and pathogenicity of Taenia solium have been solved, several issues in relation to basic biology, modalities of transmission and control remain unsettled. A major reason for these persisting uncertainties has been that the study of Taeniidae is neither a research nor a control priority. Fifty years ago in UK, and in many countries today, taeniasis in humans was considered a trifle, and regarded as more suitable for an examination question than for consideration as a potential threat of cysticercosis2. Basic, experimental as well as field studies upon T. solium infection are still few. The control of human cysticercosis for a long time was left to veterinary services alone. The eradication of human cysticercosis in Europe made it clear that certain economic and social standards and community discipline and cooperation were necessary for successful control of infection. Since socioeconomic improvement is a gradual and slow process, long-term control programmes

would take time in several developing countries where cysticercosis is endemic. Recently, schemes for short-term control have been developed with an aim to bring about immediate control of T. solium infection in developing countries (reviewed in Chapters 41–44). These methods require multidisciplinary collaboration between clinical, veterinary and public health services, and immunology and parasitology disciplines as well as support at the community and national levels3. In order to understand the basis of the control strategies, it is necessary to have sound knowledge of the life cycle and mechanisms of transmission of infection. This chapter reviews basic biology of T. solium with emphasis on aspects related to its transmission.

Taxonomic Status of T. solium The origin of tapeworms still remains a controversial issue4,5. According to actual systematics, there are two major subclasses of tapeworms: Cestodaria and Eucestoda. Taenia solium belongs to the subclass, Eucestoda, order, Cyclophyllidea and family, Taeniidae5. The family, Taeniidae

© CAB International 2002. Taenia solium Cysticercosis (eds G. Singh and S. Prabhakar)

1

2

Z.S. Pawlowski

comprises 11 genera of small to large sized tapeworms. They have a holdfast organ – the scolex – and an elongated-segmented tape-like body. Each segment has intricately developed sexual organs but does not have an alimentary canal. The genus Taenia has about 20 species; important among these are T. solium (pork tapeworm), T. saginata (beef tapeworm), T. crassiceps (rodent tapeworm), T. hydatigena (canine tapeworm), T. ovis (canine tapeworm) and T. pisiformis (canine tapeworm). Only a few species among Taeniidae present potential health hazards to humans: Taenia solium, T. saginata, Echinococcus granulosus and E. multilocularis. In addition, there are anecdotal reports of human infection with T. crassiceps, T. hydatigena and T. multiceps. Few other zoonotic species, e.g. T. taeniaeformis, T. ovis and T. hydatigena are good models for laboratory and field studies; the latter can hardly be performed with T. solium on account of its high pathogenic risk potential. Therefore, studies of related species constitute a useful source of information on biology and transmission of T. solium. Although the ‘Standardized Nomenclature of Animal Parasitic Diseases’ recommended the use of the term ‘taeniosis’ (T. solium taeniosis, T. saginata taeniosis), the term, ‘taeniasis’ continues to be widely used6. The term, ‘cysticercosis’ denotes infection with the metacestode stage (cysticercus) of Taenia. It was as late as 1853 that cysticerci were demonstrated to be a developmental stage of T. solium and not a separate parasite species as was previously held7. The terms, ‘cysticercus cellulosae’ and ‘cysticercus bovis’ were introduced in the 18th century; these are of historic value only and should never be used in a generic fashion. In medical literature, the expression ‘cysticercosis’ synonymously denotes T. solium metacestode infection unless otherwise specified, e.g. bovine cysticercosis.

Differences between T. solium, T. saginata and T. saginata asiatica Several morphological abnormalities of strobila or individual proglottides of T. sagi-

nata, and less frequently T. solium adult tapeworms have been noted, often giving rise to taxonomic confusion in the past. The taxonomic revision of genus Taenia, published by Verster, recognizes only two species of Taeniidae, namely, T. solium and T. saginata as capable of parasitizing the human gut8,9. The so called Asian Taenia, first described in 1980s in Taiwan, was initially proposed to be a new species but is now accepted to be a subspecies of T. saginata namely, T. saginata asiatica (see Chapter 5)10,11. The adult stage of T. solium needs to be differentiated from other Taeniidae, particularly the closely related T. saginata (Table 1.1, Fig. 1.1). Differences between scolices of T. solium and T. saginata were recognized as early as in the 17th century7. T. solium scolices are armed with hooks, while T. saginata scolices are not. This easily visible criterion is now of little routine diagnostic value as intact scolices can rarely be found after treatment with modern anthelminthics (that cause considerable damage to the worm). In general, the adult T. solium is smaller and more delicate than T. saginata. For nearly 150 years, gravid proglottides of T. solium and T. saginata were differentiated by counting the number of lateral uterine branches. In 1967, Verster questioned this criterion and proposed three morphological characteristics for distinguishing T. solium from T. saginata, namely the presence of an armed rostellum, three-lobed ovary and the absence of a vaginal sphincter (Table 1.1, Fig. 1.1)8. These differences are rarely observed in routine diagnostic parasitology practice as scolices and mature proglottides are not commonly available and counting ovarian lobes as well as finding the vaginal sphincter requires fixation and staining of mature proglottides, which is an arduous procedure. Enzyme electrophoresis for the differentiation of Taeniidae was elaborated in the early 1970s; it has been replaced by DNA fingerprinting in the 1990s12,13. Specific DNA probes for T. solium and T. saginata are now available13. Intraspecific DNA differences were demonstrated between T. solium tapeworms originating from various continents (reviewed in Chapter 5)14. These molecular studies also

Muscle, viscera 7–10  4–6 No rostellum Rugae

1.5–2.0 4 0.7–0.8 Absent Absent 4–12 12–14 c. 2000 800–1200 Two lobes Present No 18–32 (15) Dichotomous Single, spontaneously

0.6–1.0 4 0.4–0.5 Present 22–32 1.5–8 7–10 700–1000 375–575 Three lobes Absent Yes 7–12 (16) Dendritic Mainly in groups, passively

Cattle, reindeer

T. saginata

Brain, skin, muscle 5.6–8.5  3.1–6.5 Rostellum and hooks Wart-like formations

Pig, wild boar

Intermediate host

Metacestodes Site Size (mm) Scolex Bladder surface Adult tapeworm Scolex Diameter (m) Number of suckers Diameter of suckers (mm) Rostellum Number of hooks Proglottides Length (mm) Maximal breadth (mm) Number of proglottides Mature proglottides Number of testes Ovary Vaginal sphincter Cirrus pouch extending to excretory vessels Gravid proglottides Number of uterine branches Branching pattern Expulsion from host

T. solium

Characteristic

16–21 (32) Dichotomous Single, spontaneously

868–904 Two lobes Present No

c. 3.5 c. 9.5 260–1016

0.8 4 0.24–0.29 Present Absent

Liver (exclusively) 22 Rostellum, rudimentary hooklets (1–37) Wart-like formations

Pig, cattle, goat, some wild mammals

T. saginata asiatica

Table 1.1. Morphological differences between T. solium, T. saginata and T. saginata asiatica (compiled from references 10, 18, 37 and 46).

Basic Biology and Transmission 3

Z.S. Pawlowski

0.5 mm

4

(a)

(b)

(c)

2 mm (d)

(e)

(f)

(g)

5 mm

ut

(h)

(i)

(j)

Fig. 1.1. Diagrammatic representation of the comparative morphological features of adult T. solium (a, d, f, h), T. saginata (b, g, i) and T. saginata asiatica (c, e, j) (adapted from references 8, 10, 47). Note that tri-lobed ovary in the mature proglottid of T. solium (d), in comparison to two lobes in the mature proglottid of T. saginata and T. saginata asiatica (e), the presence of the vaginal sphincter in the atrium genitale of T. saginata (g). Note also the differences in the branching pattern of the uterus of T. solium (h), T. saginata (i) and T. saginata asiatica (j) proglottides.

Basic Biology and Transmission

support speciation of T. saginata asiatica as a subspecies of T. saginata15. Recently, a serologic assay, using T. solium excretory–secretory antigens that is 95% sensitive and 100% specific, has been developed to identify T. solium tapeworms carriers (reviewed in Chapter 33)16. A rapid, highly sensitive and specific dot blot assay has also been developed for detection of T. solium eggs, which otherwise cannot be differentiated from T. saginata and some other taeniid eggs by morphological criteria alone17. The differentiation of T. solium and T. saginata taeniasis is important for clinical reasons and epidemiological purposes. However, in regions, where both are endemic in animals, and when species-specific diagnosis in humans is not possible, any case of taeniasis should be considered and treated without delay as suspected T. solium infection.

5

Stages in Development of T. solium The life cycle of T. solium is divided into six characteristic developmental stages (Fig. 1.2): 1. Preadult tapeworm: a stage between the cysticercus, after it has successfully invaded the definite host, and the mature tapeworm. 2. Adult tapeworm: a reproductive stage capable of producing thousands of eggs. 3. Egg: a small embryo covered by an embryophore, a stage responsible for dissemination to the external environment. 4. Oncosphere: a hexacanth larva which migrates from the intestine to internal tissues or organs within the intermediate host. 5. Postoncospheral form: an intermediate stage between an oncosphere in the tissues and a fully developed cysticercus. 6. Cysticercus: a bladder metacestode form that parasitizes tissues of the intermediate host, mainly pigs as well as humans.

Taenia solium Infection: Host Characteristics Preadult and adult tapeworm Humans are the major natural final host of T. solium, implying that man, the only natural definite host, is the most important multiplier, reservoir and disseminator of the infection to pigs. However, experimental infections with adult T. solium after ingestion of cysticerci have been successfully established in lar gibbon (Hylobates lar), chacma baboon (Papio ursinus) and golden hamster (Mesocricetus auratus). T. solium metacestodes are less specific than adult cestodes18. The list of mammals in which cysticerci armed with hooks have been found includes monkeys (Ateles, Cercopithecus, Macacus sp.), wild boars, bush pigs, bush babies, camels, rabbits, hares, rock hyraxes, brown bears, dogs, foxes, cats, polecats, coatis, rats and mice18. In addition, experimental infection with T. solium oncospheres has been successfully established in immunosuppressed mice (see Chapter 4)19. However, many of the reported cysticerci differed in the size of hooks and immunoelectrophoretic pattern of T. solium cysticerci; not all armed cysticerci are those of T. solium18. Humans are unique in that they can harbour both adult and metacestode stages.

The ingestion of pork contaminated with cysticerci by man is a prerequisite for this stage. Upon reaching the human intestine the cysticercus evaginates and loses its bladder wall. The adult tapeworm grows up from behind the scolex of the cysticercus. It takes approximately 2 months to develop into a mature, reproductively competent, adult tapeworm that is capable of producing eggs. The adult tapeworm has a scolex, an elongated neck and a strobila4. The scolex is the holdfast organ armed with four suckers and a rostellum displaying 22–32 characteristic hooks4. The strobila consists of 700–1000 segments proglottids and can be extremely long (Fig. 1.3). It is made up of immature, mature and gravid proglottids, which differ in size, shape and stage of development with respect to their internal reproductive organs and egg content (Fig. 1.1). Proglottids located proximally are small, short and reproductively immature. Mature proglottids are almost rectangular and have fully developed sexual organs. The gravid segments, located towards the very distal end of the strobila, are

6

Z.S. Pawlowski

Stages

Habitat

Number

Time *Human taeniasis

HUMANS

**Human cysticercosis around a carrier **Human cysticercosis: external / internal autoinfection

1. Preadult tapeworm

Gut

One

2 months

2. Adult tapeworm

Gut

One

In years

(Gravid proglottids)

Several in a week

ENVIRONMENT

3. Eggs

Soil, water, dirt

300,000 per day

One year

Transmission of human cysticercosis PIGS 4. Oncosphere

Gut / tissue

One–several

2 days

5. Post-oncosphere

Muscle, brain, other organs

One–several

10–12 weeks

6. Cysticercus

Muscle, brain, other organs

One–several

<1 year

Transmission of human taeniasis: meatborne

Fig. 1.2. Diagrammatic representation of the life cycle of T. solium.

Basic Biology and Transmission

elongated (20  5 mm) and each is packed with a uterus full of eggs. The gravid proglottids detach from the strobila by ‘apolysis’ either individually or in groups of two to five, and are passed in the faeces a few times in a week20. Discharged proglottides remain active and may show some movements. The tapeworm is a protoandrous hermaphrodite4. Its reproductive system is intricately developed. Within each mature proglottid, a centrally located ovary, a vitelline gland and uterus, surrounded by numerous testes can be seen. The male reproductive organs include numerous

7

testes; each connected to the sperm duct (vas deferens) leading to the genital pore. The female reproductive system comprises of a vagina, also located within the genital pore, a receptaculum seminis, an oviduct, a trilobed ovary and a vitelline gland. Both self- and cross-fertilization may occur. Spermatozoa formed in the testes are conveyed through the sperm duct to the genital pore and thereafter to the vagina to finally reach the receptaculum seminis and the oviduct. The ovary discharges eggs in to the oviduct, where the latter are fertilized by spermatozoa. The fertilized eggs acquire

Fig. 1.3. Picture depicting the entire length of the adult T. solium tapeworm. (Source: Ana Flisser, National Autonomous University of México, México DF, México.)

8

Z.S. Pawlowski

yolk cells from a vitelline gland in the oviduct itself and are relocated into the uterus, where they are stored. As the uterus tube is closed without any opening to outside it develops several ramifications packed with eggs, thus occupying most of the gravid proglottid. Besides the reproductive system, the adult tapeworm has four major organ systems: tegument, nervous system, osmoregulatory system and muscular system. It has no digestive canal4. While the tapeworm lives in human small intestine, its scolex is temporarily fixed in the duodenum and the strobila is bent a few times21. However, it frequently moves up and down, in synchrony with the passage of incoming food. It adapts to the rather hostile intestinal environment, being mobile, anaerobic, and is able to withstand the varying pH and digestive enzymes within the intestine. The adult worm is believed to survive for a few years; new proglottides constantly replace those expelled. Studies performed by Yoshino in the 1930s are of interest22–26. He himself swallowed three T. solium cysticerci and noted passage of proglottides starting from 2 months after infection and lasting for 2 years and 3 months26. A tapeworm that dies naturally or after treatment is easily digested and disappears quickly without

(a) (b)

being noticed in the faeces. Usually, a single T. solium tapeworm parasitizes the human gut; however, multiple infections may occur. Superinfection probably exists; it has been documented in experimental T. saginata infection27.

Taenia solium eggs The eggs of T. solium are morphologically indistinguishable from those of other Taenia sp. (Fig. 1.4a). As with eggs of other Taeniidae, the outer shell of T. solium eggs is very delicate and is usually lost while leaving the uterus. What is found in the faeces is an oncosphere covered by an embryophore, characteristic for all Taenia. The embryophore is globular in shape and measures 31–43 m in diameter28. It has a thick striated cover and contains an oncosphere armed with six typical embryonic hooklets (giving it the name, ‘hexacanth embryo’), usually visible through the embryophore cover. The embryophore protects the oncosphere against various unfavourable environmental conditions but is easily broken in the gut of the intermediate host where the substance cementing the keratin-like prismatic elements of its cover is digested.

(b) (a)

Fig. 1.4. Taenia solium eggs (a) and oncospheres (b). The eggs are 40  30 m in size and surrounded by a shell; in the centre of figure (a) is a disintegrating egg, showing the process of hatching of an oncosphere. The oncospheres can be seen surrounding a single egg in (b); their size is smaller (30  20 m) and they contain characteristic embryonic hooklets. (Source: Akivo Ito, Asahikawa Medical College, Asahikawa, Japan.)

Basic Biology and Transmission

The T. solium tapeworm can shed up to 300,000 eggs daily29. Each apolysed proglottid has approximately 40,000 eggs. Most of the eggs are discharged from a pore at the anterior part of the proglottid, but some remain in the uterus. Eggs that are shed into faeces may serve as a source of external autoinfection to people in close contact with the carrier. However, most eggs are disseminated to the environment. The fate of T. solium eggs in the environment has not been adequately studied. In regions that lack sanitation, free-ranging pigs feed upon faecal matter that is indiscriminately deposited by people. This is a natural method to reduce contamination of the environment but it increases incidence of swine cysticercosis. The high reproductive potential of the adult T. solium tapeworm is counterbalanced by an enormous egg loss in the external environment29. Factors influencing egg survival and infectivity have been studied in other members of the genus Taenia and have been comprehensively reviewed elsewhere30–34. Egg survival is adversely affected by extremes of temperature and desiccation. Conversely, humidity and temperatures between 10°C and room temperature favour egg survival29. A number of agents such as wind and water, and some invertebrates and birds are believed to aid in taeniid egg dispersal30–35. However, egg dispersal may be of less importance in the life cycle of T. solium than in that of Echinococcus sp., where sheep presumably get infected while grazing heavily contaminated pasturage31.

Oncosphere The mature oncosphere is a globular larva, 30 m in diameter (Fig. 1.4b). Its body is composed of a few hundred cells differentiated into muscle, excretory and nervous system; it also has six characteristic embryonic hooklets and a pair of penetration glands that are helpful in migration5. Oncospheres, enclosed within embryophores while leaving the human gut, are in various stages of development. A few oncospheres are not fully developed and will mature in the environment (as in the case of

9

E. granulosus oncospheres). Others are mature and readily infective to humans and/or pigs. There are also few senile oncospheres that are incapable of developing further; nevertheless, they serve as immunizing factors while disintegrating in the intermediate host31. It is held that luminal factors such as bile salts are involved in the liberation and activation of mature oncospheres in the gut. Within 2 hours of liberation, oncospheres enter submucosal blood and/or lymphatic vessels and migrate to internal organs such as liver, lungs, muscles and brain. Why oncospheres have a predilection for certain sites such as muscle, brain and subcutaneous tissue is not clear.

Postoncospheral stage or cysticercus The postoncospheral development of the larva (also designated as ‘metacestode’) proceeds within the intermediate host. During this stage, the parasite does not attain sexual maturity. The metacestode of the genus Taenia is known as ‘cysticercus’. The parasite is located in a cavity lined by host epitheloid cells originating from small vessels. The oncosphere quickly change from a solid larva into a bladder form filled with fluid and having a group of cells that will differentiate further into an invaginated scolex. The experiments performed by Yoshino, referred to earlier, helped to clarify the sequence of development of the metacestode23–25. When the freed oncosphere enters the intestinal wall, it is less than 0.03 mm in size23. At about 6 days, the metacestode is still solid and measures 0.4  0.3 mm23. It has an outer membranous wall comprising of pleomorphic cells, while its inner contents are myxomatous. By 12 days, the metacestode is larger and becomes cystic. Between 20 and 30 days, a rudimentary scolex is discernable24. Hooks appear by 40 days and the rostellum and suckers are distinguishable by 40–50 days25. The metacestode reaches its fully grown size of 5.6–8.5 mm  3.1–6.5 mm by 60–70 days. The cysticercus is an ovoid bladder stage. It is filled with an opalescent fluid and contains an invaginated scolex. The bladder consists of outer and inner layers. The outer

10

Z.S. Pawlowski

layer has characteristic hair-like processes. This layer not only plays a protective role but also serves as a trophoblast that absorbs nutrients and excretes metabolites36. Between the outer and inner layers there are few muscle bundles, fine fibres, flame cells, calcareous corpuscles, neural and duct systems and a group of non-differentiated oval cells. Any change in osmotic pressure causes the scolex to become everted. The survival time of a cysticercus is limited to a few years. The naturally degenerating cysticercus becomes necrotic and eventually gets calcified, or forms a granuloma that finally transforms into a fibrotic scar. The cysticercus is typically found in the intermediate host, i.e. the pig. In humans, the cysticercus constitutes a dead-end stage, i.e. its life cycle cannot progress any further. However, its development in pigs, known as porcine cysticercosis, perpetuates the life cycle of the parasite when man ingests contaminated pork with viable cysticerci.

Biological and Economic Cycles of T. solium: Implications for Control Biological cycle The relatively simple natural biological cycle of T. solium zoonosis consists of two hosts and the environment. Man, the final host, harbours the adult tapeworm, which produces several thousands of eggs daily for years. The eggs are disseminated to the environment through faeces. The pig, which is the intermediate host, ingests some of these eggs; the latter develop into cysticerci. When man consumes contaminated pork containing cysticerci, the latter develop into an adult worm inhabiting the human intestine. This completes the life cycle of the parasite (Fig. 1.2). However, man may also be infected by T. solium eggs through internal and external autoinfection. External autoinfection implies faecal–oral infection with T. solium eggs in an individual with intestinal taeniasis. Neglect of hygienic standards such as washing hands after defecation and before consuming meals are principal reasons for external autoinfection. External autoinfection is an established

route of self-infection. Internal autoinfection, suggested by Leukart in 1856 and cited by others, implies infection with eggs through reverse peristalsis37. Internal autoinfection appears theoretically improbable since eggs are required to pass through a brief period of peptic digestion that is necessary for disintegration of the embryophores before being invasive to human tissue37. The possibility of internal autoinfection cannot be totally disregarded however, and merits further study. From 5 to 40% of adult T. solium carriers have been reported to develop cysticercosis38. In the case of infection with T. saginata, it has been demonstrated that the immediate environment of the infected individual is heavily contaminated39. This may not be the case, however, with pork tapeworm infection, because unlike T. saginata, the proglottides of T. solium do not pass out actively through the anus. Nevertheless, the high rates of cysticercosis in individuals with intestinal taeniasis and their family members and household contacts confirm that faecal–oral self- and cross-infection is common38. Similarly, there is the theoretical possibility of outbreak of cysticercosis around T. solium carriers in schools, closed institutions and public eating facilities, though this has never been adequately confirmed.

Economic cycle One can imagine that in addition to the biological cycle of T. solium described above, an economic cycle exists in several developing countries40,41. Several economic factors sustain the life cycle of T. solium in underdeveloped regions. Each rural household, in certain developing countries, rears pigs in small numbers; the latter constitute an important source not only of meat but also of immediate income. The production of freeranging animals needs minimal investment and running costs for the rural poor. In absence of sanitary infrastructure, people use houseyards, open areas and fields for defecation and ablution. This allows free-ranging pigs access to human faeces and perpetuates transmission of parasite from man to pig. Individual rural pork producers and unli-

Basic Biology and Transmission

censed pig dealers are not motivated to pass pork through meat inspection because of threat of condemnation. Furthermore, the lack of fuel as well as the local culinary habits facilitate the consumption of raw or semi-cooked meat. These factors lead to the transmission of the parasite from pig to man in endemic areas42. The socio-ecological and economic factors strongly influence the transmission of T. solium infection and are responsible for its concentration in certain areas, making short-term control with taeniasis therapy possible (discussed in Chapter 41)43,44.

Implications for control In 1993, the Task Force for Disease Eradication (Centers for Disease Control, Atlanta, USA) itemized four diseases that were potentially eradicable in the future; these included lymphatic filariasis, mumps, rubella and T. solium taeniasis/cysticercosis45. Several characteristics of T. solium infection make it suitable for eradication, namely, adult tapeworm infection in humans is the only source of infection for intermediate hosts (pigs); the animal intermediate host population can be managed;

11

there is no significant wildlife reservoir and finally a feasible intervention is available in the form of mass chemotherapy of human taeniasis with safe and effective drugs (reviewed in Chapter 41).

Conclusions Six major stages of development have been recognized in the life cycle of T. solium. Man is a major reservoir, multiplier of the parasite and disseminator of infection to both himself and to the pig. The pig does not play the most important role in spreading human cysticercosis, as was believed until not long ago. The role of the external environment in transmission of T. solium infection is incompletely understood. The control of taeniasis/cysticercosis depends much not only on the biological life cycle but also on the ‘economic’ cycle of T. solium. Several factors including inadequacies in pig husbandry, sanitary facilities, meat inspection, personal hygiene and local feeding habits are involved in the perpetuation of the life cycle of T. solium in the developing world. Control strategies should be able to deal with these deficiencies in order to be effective in eradicating taeniasis/cysticercosis.

References 1. Davaine, C.J. (1860) Traite des Entozoaires et des Maladies Vermineuses de l’Homme et des Animaux Domestiques. JB Bailière et fils, Paris, France. 2. Asher, R. (1953) Troublesome tapeworms. Lancet i, 1019–1021. 3. Schantz, P.M., Cruz, M., Sarti, E., et al. (1993) Potential eradicability of taeniasis and cysticercosis. Bulletin of the Pan American Health Organization 27, 397–403. 4. Wardle, R.A., McLeod, J.A., Radinovsky, S. (1974) Advances in the Zoology of Tapeworms 1950–1970. University of Minnesota Press, Minneapolis, pp. 10–22. 5. Smyth, J.D. (1994) Introduction to Animal Parasitology, 3rd edn. Cambridge University Press, Cambridge, pp. 277–387. 6. Kassai, T., Cordero del Campillo, M., Euzeby, J., et al. (1988) Standardized nomenclature of animal parasitic diseases (SNOAPAD). Veterinary Parasitology 29, 299–326. 7. Grove, D.I. (1990) Taenia solium taeniasis and cysticercosis. In: A History of Human Helminthology. CAB International, Wallingford, UK, pp. 355–383. 8. Verster, A. (1967) Redescription of Taenia solium Linnaeus, 1758 and Taenia saginata Goeze, 1782. Zeitschrift fuer Parasitenkunde 29, 313–328. 9. Verster, A. (1969) A taxonomic revision of the genus Taenia Linnaeus, 1758. Journal of Veterinary Research 36, 3–58. 10. Eom, K.S., Rim, H.J. (1993) Morphological descriptions of Taenia asiatica sp. Korean Journal of Parasitology 31, 1–6.

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Fan, P.C., Chung, W.C. (1998) Taenia saginata asiatica: Epidemiology, infection, and immunological and molecular studies. Journal of Microbiology, Immunology and Infection 31, 84–89. La Riche, P.D., Sewell, M.M.H. (1978) Differentiation of taeniid cestodes by enzyme electrophoresis. International Journal of Parasitology 8, 479–483. McManus, D.P. (1990) Characterization of taeniid cestodes by DNA analysis. Revue Scientifique et Technique 9, 489–510. Rishi, A.K., McManus, D.P. (1988) Molecular cloning of Taenia solium genomic DNA and characterization of taeniid cestodes by DNA analysis. Parasitology 97, 161–176. Zarlenga, D.S., McManus, D.P., Fan, P.C., et al. (1991) Characterization and detection of a newly described Asian taeniid using cloned ribosomal DNA fragments and sequence amplification by the polymerase chain reaction. Experimental Parasitology 72, 174–183. Wilkins, P.P., Allan, J.C., Verastegui, M., et al. (1999) Development of a serologic assay to detect Taenia solium taeniasis. American Journal of Tropical Medicine and Hygiene 60, 199–204. Chapman, A., Vallejo, V., Mossie, K.G., et al. (1995) Isolation and characterization of species-specific DNA probes from Taenia solium and Taenia saginata and their use in an egg detection assay. Journal of Clinical Microbiology 33, 1283–1288. Pawlowski, Z.S. (1982) Taeniasis and cysticercosis. In: Steele, J.H. (ed.) Handbook Series. Zoonoses. Section C: Parasitic Zoonoses. CRC Press, Boca Raton, Florida Vol. 1, part 2, pp. 313–348. Wang, I.C., Ma, Y.X., Guo, J.X., et al. (1999) Oncospheres of Taenia solium and Taenia saginata asiatica develop into metacestodes in normal and immunosuppressed mice. Journal of Helminthology 73, 183–186. Pawlowski, Z.S. (1994) Taeniasis and cysticercosis. In: Hui, Y.H., Gorham, J.R., Murrel, K.D., et al. (eds) Foodborne Disease Handbook. Diseases Caused by Viruses, Parasites and Fungi. Marcel Dekker, New York, Vol. 2, pp. 199–254. Prevot, R., Hornbostel, H., Dorken, H. (1952) Lokalisations-studien bei Taenia saginata. Klinische Wochenschrift 30, 78–80. Yoshino, K. (1933) Studies on the postembryonal development of Taenia solium. Part I. On the hatching of eggs of Taenia solium. Journal of Medical Association of Formosa 32, 139–141 (English summary). Yoshino, K. (1933) Studies on the postembryonal development of Taenia solium. Part II. On the youngest form of cysticercus cellulosae and on the migratory course of the oncospheres of Taenia solium within the intermediate host. Journal of Medical Association of Formosa 32, 155–158 (English summary). Yoshino, K. (1933) Studies on the postembryonal development of Taenia solium. Part III. On the development of cysticercus cellulosae within the definite intermediate host. Journal of Medical Association of Formosa 32, 166–169 (English summary). Yoshino, K. (1933) Experimental studies on the formation of the scolex of Taenia solium. Journal of Medical Association of Formosa 32, 169–171 (English summary). Yoshino, K. (1934) On the subjective symptoms caused by parasitism of Taenia solium and its development in man. Journal of Medical Association of Formosa 33, 183–194 (English summary). Hornbostel, H. (1959) Bandwurmprobleme in neuer Sicht. Ferdinand Enke Verlag, Stuttgart, Germany, pp. 1–59. Laclette, J.P., Ornelas, Y., Merchant, M.T., et al. (1982) Ultrastructure of the surrounding envelopes of Taenia solium eggs. In: Flisser, A., Willms, K., Laclette, J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 375–387. Lawson, J.R., Gemmell, M.A. (1983) Hydatidosis and cysticercosis: the dynamics of transmission. In: Baker, J.R., Muller, R. (eds) Advances in Parasitology. Academic Press, London, Vol. 22, pp. 262–308. Gemmell, M.A., Johnstone, P.D. (1976) Factors regulating tapeworm populations: dispersion of eggs of Taenia hydatigena on pasture. Annals of Tropical Medicine and Parasitology 70, 431. Gemmell, M, Lawson, J.R., Roberts, M.G. (1987) Population dynamics in echinococcosis and cysticercosis: evaluation of the biological parameters of Taenia hydatigena and T. ovis and comparison with those of Echinococcus granulosus. Parasitology 94, 161–180. Gemmell, M.A., Lawson, J.R. (1989) The ovine cysticercosis as models for research into the epidemiology and control of the human and porcine cysticercosis Taenia solium. I. Epidemiological considerations. Acta Leidensia 57, 165–172. Gemmell, M.A., Johnstone, P.D., Boswell, C.C. (1978) Factors regulating tapeworm population dispersion patterns of Taenia hydatigena eggs on pasture. Research in Veterinary Science 24, 334–338.

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34. Gemmel, M.A., Lawson, J.R. (1982) Ovine cysticercosis: an epidemiological model for the cysticercosies II. Host immunity and regulation of the parasite population. In: Flisser, A., Willms, K., Laclette, J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 647–660. 35. Lonc, E. (1980) The possible role of the soil fauna in the epizootiology of cysticercosis in cattle. I. Earthworms, II. Dung beetles – the biotic factor in a transmission of Taenia saginata eggs. Angewandte Parasitologie 21, 133–138, and 139–144 36. Bon, E.R., Merchant, M.T., Gonzalez-del Pliego, M., et al. (1982) Ultrastructre of the bladder wall of the metacestode of Taenia solium. In: Flisser, A., Willms, K., Laclette, J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 261–280. 37. Goennert, R., Meister, G., Strufe, R., et al. (1967) Biologische Probleme bei Taenia solium. Journal of Tropical Medicine and Parasitology 18, 76–81. 38. Schantz, P.M., Wilkins, P.P., Tsang, V.C.W. (1998) Immigrants, imaging, and immunoblots: the emergence of neurocysticercosis as a significant public health problem. In: Scheld, W.M., Craig, W.A., Hughes, J.M. (eds) Emerging Infections. ASM Press, Washington, DC, pp. 213–242. 39. Pawlowski, Z., Schultz, M.G. (1972) Taeniasis and cysticercosis (Taenia saginata). Advances in Parasitology 10, 269–343. 40. Pawlowski, Z. (1991) Control of Taenia solium taeniasis and cysticercosis by focus oriented chemotherapy of taeniasis. Southeast Asian Journal of Tropical Medicine and Public Health 22, 284–286. 41. The Cysticercosis Working Group in Peru (1993) The marketing of cysticercotic pigs in the Sierra of Peru. Bulletin of the World Health Organization 71, 223–228. 42. Pawlowski, Z.S. (1990) Perspectives on the control of Taenia solium. Parasitology Today 6, 371–373. 43. Cruz, M., Davis, A., Dixon, H., et al. (1989) Operational studies on the control of Taenia solium taeniasis/cysticercosis in Ecuador. Bulletin of the World Health Organization 67, 401–407. 44. Craig, P.S., Rogan, M.T., Allan, J.C. (1996) Detection, screening and community epidemiology of taeniid cestode zoonoses: cystic echinococcosis, alveolar echinococcosis and neurocysticercosis. Advances in Parasitology 38, 169–250. 45. Centers for Disease Control and Prevention (1993) Recommendations of the International Task Force for Disease Eradication. Mortality and Morbidity Weekly Report 42, 1–27. 46. Fan, P.C. (1988) Taiwan Taenia and taeniasis. Parasitology Today 4, 86–88. 47. Faust, E.C., Russell, P.F., Jung, R.C. (1974) Clinical Parasitology. Lea and Fibiger, Philadelphia, USA.

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Taenia solium Cysticercosis: New and Revisited Immunological Aspects Ana Flisser, Dolores Correa and Carlton A.W. Evans

Introduction It has taken almost 25 years to unravel and understand some of the characteristics and mechanisms of the immune response elicited against Taenia solium cysticercus within the human host. Some of these are presently quite clear, for instance, the heterogeneity of the humoral immune response, the existence of immune evasive mechanisms and the fact that the immune response can both protect and harm the host, as demonstrated in several studies performed in animals. Others are still at the stage of requiring precise identification, such as the type and interactions of the components of the cellular immune response, with specific reference to cytokines that may play important roles in different stages of the host–parasite relationship. Four different aspects of the immunology of human T. solium cysticercosis are discussed in this chapter: (i) components and characteristics of the immune response; (ii) evasion of the host immune response by the parasites; (iii) neurocysticercosis (NC) and neoplasia; and (iv) protective immunity induced against T. solium.

Components and Characteristics of the Immune Response to T. solium Cysticercosis The immunology of NC is particularly important because of its paradoxical relationship

with disease pathogenesis. Living cysticerci may cause an asymptomatic infection through active evasion and suppression of immunity. Histological studies have shown that both in humans and pigs, live, viable cysticerci have little or no surrounding inflammation. Cysticerci may persist in the human host for long periods of time, often for years without eliciting surrounding host inflammatory reaction. In contrast, the immune mediated inflammation around one or more degenerating cysts may precipitate symptomatic disease. When the parasite begins to involute, either naturally or after treatment with anticysticercal drugs, a surrounding granulomatous inflammatory response develops both in human and porcine infections. Predominant components of this inflammatory response include plasma cells, lymphocytes, eosinophils and macrophages. The latter engulf parasite remnants, eventually leaving a gliotic scar with calcification. Several correlative clinical, neuroimaging, immunological and histopathological studies have amply demonstrated that symptomatic human cysticercosis corresponds to the presence of tissue inflammation around involuting cysticerci that are transiting between the live, viable stage and the calcified stage1–5. The host immunological response to cysticerci is becoming more and more complicated as more knowledge is accumulating. Broadly it can be divided into humoral and cellular components, outlined below.

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Humoral immune response The humoral immune response is better understood than the cellular one. The fact that humans respond immunologically to antigens of T. solium cysticerci is well evident from the number of immunodiagnostic assays that have been developed using different types of antigens6,7. Several immunoglobulin (Ig) classes are produced as specific antibodies against the parasite. The most frequent is IgG, which can be detected in serum, cerebrospinal fluid (CSF) and saliva and suggests that infection is of long duration8–15. An interesting aspect of the humoral immune response is its compartmentalization; there is evidence for local synthesis of specific IgG antibodies within the brain and the presence of a given antibody class in one compartment (i.e. CSF or serum) and its absence in the other compartments11,16–21. Those cases where both CSF and serum samples were obtained from the same patient and were positive only in one, suggest that the blood–brain barrier is not always damaged by the parasite. On the other hand, seemingly there is a correlation between the presence of antibodies and the intensity of infection1. Enzyme-linked immunoelectrotransfer blot (EITB) detected only 28% of cases with a single cysticercus compared with 94% of those with two or more cysts. Furthermore, antibodies were found in most cases that had live or involuting parasites, but only in few cases with calcified cysts, thereby suggesting that the presence of antibodies is influenced by the evolutionary stage of the parasite. Similarly, in pigs, antibody responses were found to

be proportional to the intensity and duration of infection. In human cysticercosis, differences were also found between benign and malignant cysticercosis, for instance, cysticercotic encephalitis is very immunogenic6,9,16. Thus, the humoral immune response in patients with NC is quite heterogeneous. Its heterogeneity is also evident from the number of antigens recognized: patients’ antibodies may react with one to eight antigens in immunoelectrophoresis and up to 30 antigens in EITB3,22,23.

Cellular immune response Some of the earlier studies that evaluated cellular immune responses in hospitalized patients with NC under corticosteroid treatment reported low proliferation of peripheral blood mononuclear cells after stimulation with mitogens and high proportions of CD8+ cells22,24. These initial studies generated the belief that cellular responses were impaired in NC. On the contrary, a recent study that compared immune responses in individuals with active, untreated NC with paired controls, showed that most patients responded adequately to concanavalin A and to cysticercus antigens; also, CD4+ and CD8+ counts were not significantly different from those of controls25. Precise patterns and pathways of the cellular responses in human NC are still under study and until recently, no clear hypothesis was available before demonstration of the Th1/Th2 duality of the T-helper-cell response (Fig. 2.1)26*. Precise molecular mechanisms underlying Th1 and Th2

*T cells are of the following two types: helper (Th, CD3+/CD4+) and cytotoxic (CTL, CD3+/CD8+). The former produce molecules that regulate the immune response, while the latter lyse histocompatible infected or transformed cells (Fig. 2.1). The type of response elicited by Th cells depends on the subtype they transform themselves to after antigen priming, i.e. Th1 or Th2. The two responses are becoming increasingly difficult to understand as knowledge about them accumulates. Nevertheless, it can generally be said that Th1 cells produce cytokines [including tumour necrosis factor- (TNF-) and interferon-gamma (IFN-)] that promote inflammation, macrophage activation, and intracellular destruction of infectious agents; they also stimulate proliferation of CD8+ cells. Thus, this response is primarily ‘cellular’. On the other hand, Th2 cells stimulate most of the antibody responses, as well as granulocyte proliferation, differentiation and chemotaxis. The major cytokines produced by the Th2 cells are interleukin-4 (IL-4), IL-5, IL-10 and IL-13. This type of response is primarily ‘humoral’. Each response reciprocally down-regulates the other, for instance, IFN- stimulates the Th1 response and inhibits Th2, while IL-4 promotes Th2 response and down-regulates Th1 response.

MHC class II

IL-4

Th0 CD4+

IL-12

MHC class I

Fig. 2.1. Diagrammatic overview of the Th1 and Th2 host immune responses.

Antigenpresenting cell (APC)

Antigens

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T helper cells

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IL-4 IL-5 IL-6 IL-13

TNF- IFN- IL-15

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Antibodies

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IgE

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immune responses to natural and experimental cysticercosis are yet to be clarified. Studies so far have addressed molecular components in the CSF, serum and the granuloma itself. Increased levels of interleukin (IL)-1 and IL-6 have been reported in CSF of patients with inflammatory NC27. High levels of IL-6 in CSF of patients with subarachnoid NC have also been reported; this possibly represents an acute phase response. In addition, high levels of tumour necrosis factor-alpha (TNF-alpha) have also been noted in CSF of children with active NC28. TNF-alpha was undetectable in controls and children with inactive NC. In asymptomatic humans, a single low dose of the taeniacidal drug praziquantel, given to treat intestinal parasites may cause sufficient damage to latent asymptomatic cysticerci that inflammation and seizures result29. Similarly, full dose anticysticercal therapy administered in heavy infections has precipitated fatal cerebral inflammation30,31. An immunological study of NC patients treated with praziquantel (without major adverse effects) reported elevated soluble IL-2 in the CSF suggesting a Th1-type immune response to therapy, in contrast with the Th2-type immune response found in animal models of viable cysticerci32. It was therefore hypothesized that living cysticerci facilitate immune evasion by inducing a Th2-type immune response until the death of the larval parasite allows a Th1mediated inflammatory response to develop. This model however, is not consistent with some of the other findings listed above and it seems likely that the regulation of immunity in T. solium cysticercosis is a complex phenomenon. Increased levels of eotaxin and IL-5, both eosinophil-selective mediators, have been found in the sera of patients with NC33. These cytokines are involved in recruiting eosinophils locally as well as systemically. Interestingly, in the mouse model of Angiostrongylus cantonensis infection, ablation of IL-5 activity with anti-IL-5 monoclonal antibody resulted in more severe intracranial disease34. Furthermore, the presence of eosinophils as the first attack cells was reported in porcine cysticercosis after

anticysticercal treatment and after vaccination35,36. This suggests that eosinophils may play an important role in the degenerative phase in this parasitic infection. Another study showed that IL-2 was synthesized by the peripheral blood cells of 58% of individuals with untreated, recently diagnosed NC, while interferon- (IFN-), IL-4 and IL-10, were only found in 11%, 10% and 14%, respectively25. Interestingly, only IFN- was increased in the group of patients as compared to controls. The macroscopic disappearance of killed cysticerci takes about 2 months, but the immunological processes that occur within the involuting granulomas are poorly understood. Very few immunohistochemical studies of the inflammatory response within cysticercus granulomas located in the human central nervous system have been performed, mainly due to limited specimen tissue37,38. Available reports suggest an intermixture of Th1 and Th2 responses in human brain cysticercus granulomas. Observations made in animals are of interest in understanding the complex phenomena that occur in granulomas within the central nervous system. Destruction of parasites in the natural intermediate host, the pig, is mediated by a granulomatous eosinophil-rich inflammation (driven by the Th2 response), followed by macrophage/lymphocyte-driven resolution (involving the Th1 response)35. In apparent discordance, a Th1 response prevails in ‘early’ granulomas, that is, when metacestodes are intact in a rodent model of cysticercosis (T. crassiceps in mice)39. In the same model, ‘late’ granulomas, wherein parasite destruction is complete, exhibit a mixture of Th1 and Th2 cytokines (IL-4). It would seem then that if the first antibody–complement phenomenon does not destroy the oncosphere, the latter develops into a metacestode, giving rise to a host–parasite relationship that, while in equilibrium, has a more ‘silent’ Th1-like pattern (i.e. IL-2), with concomitant presence of antibodies mostly of the IgG class. When this equilibrium is broken, a pro-inflammatory granulomatous Th2-like process provokes parasite destruction. This would be followed by resolution of the inflammatory reaction induced by Th1

New and Revisited Immunological Aspects

cytokines (i.e. macrophages/lymphocytes). The change from ‘equilibrium’ to ‘destruction’ has been demonstrated in cysticercal granulomas in naturally infected pigs35,36.

Evasion of Host Immune Responses by Parasites One of the most interesting phenomena in immunoparasitology is the evasion of host immune responses by the parasite. As alluded to earlier, cysticerci are capable of surviving in the human host for several years before their degeneration sets in. Live, viable cysticerci are associated with little surrounding inflammation. This allows for the maintenance of a host–parasite equilibrium as a result of which the parasite is able to survive in the host for long periods of time. The mechanisms underlying this process are complex and may involve the following40–42.

Survival of parasites lodged in ‘immunologically privileged sites’ After a brief period of migration, T. solium oncospheres lodge in host tissues and transform into cysticerci. The site where they settle and the nature of their relationship to the encapsulating host may contribute to sequestration of the parasites from immune attack. The unequal distribution of cysticerci throughout body tissues does not mirror regional blood flow but may result from selective invasion by the parasite or differential survival of larvae in ‘immunologically privileged sites’43. For example, an experimental model of intraocular T. crassiceps cysticercosis, where the parasite is maintained with ease in the anterior chamber of the eye, has demonstrated that there is little inflammatory response to the parasite in that location44. Similarly, experimental chemotherapy studies in pigs showed that parasites lodged within the brain remained alive longer after anticysticercal treatment than those located in the muscles35. These studies indicate that in naive hosts, cysticerci may develop or persist better in the eye and the brain, as compared to other tissues or organs.

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Masking of cysticercal antigens by host Igs Cysts obtained from brain, eye and muscle of patients with cysticercosis have demonstrable IgG, IgM, IgA and IgE on their surface, while specific antibodies of these classes, except for IgG, have not been detected in the surrounding fluids45. Morphologically intact cysticerci excised from pigs also present host Ig on their surface46. These results suggest that living parasites mask themselves with host Igs, probably through Fc receptors on the surface of the tegument, which could play a role in the process of Ig endocytosis4750.

Concomitant immunity Concomitant immunity refers to protection conferred by already established parasites against newly invading parasites of the same species in a given host. Concomitant immunity may result from ‘shifts’ in the expressed antigens as parasites develop through their life cycle. Hence, during initial infection, cysticerci may be able to counteract immune effector mechanisms that kill less developed forms. Experimental studies in the porcine model of cysticercosis have shown that reinfection following a challenge with T. solium eggs results in the partial destruction of established cysticerci rather than establishment of additional tissue cysts51. This implies that prior infection protects against new infection. It may be surmised that this protective effect results from ‘shifts’ in the antigens expressed by parasites through different stages of their development in the host. Hence, fully developed cysticerci may express different antigens that are able to withstand host immune responses more effectively than developing cysticerci. It is known that after 1 week of infection, the surface of parasites, previously covered by microvilli, changes to microtriches52 and that surface antigens change during development in Hymenolepis nana53. Concomitant immunity may explain the lack of overwhelming cysticercosis in hyperendemic regions, since animals may only be able to acquire cysticercosis for 1 or 2 weeks after primary exposure54.

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Parasites may evade immune recognition by synthesizing host-like antigenic determinants. Immunoglobulin G on the surface of T. solium cysticerci does not show specificity for antigens on the cysticercus55. The possibility that it is synthesized by the parasite was tested in vitro by translation of parasitederived messenger-RNA55. Though not adequately proven, molecular mimicry, i.e. synthesis of host-like antigens by the parasite, may be one the mechanisms involved in immune evasion.

and in healthy controls69,70. Also, 17% of 43 patients with glioma but only 3% of 172 controls had NC65. Whether these chromosomal alterations in lymphocytes or increased cytokine synthesis are responsible for the establishment of neoplasia is not clear. Even though, as mentioned in the earlier sections of this chapter, cysticerci do not seem to induce a generalized immune suppression, since patients produce antibodies, inflammatory reaction, and cytokines, have normal white cell counts and generally good state of health and their immune cells respond in vitro to parasite antigens and mitogens.

Suppression or deviation of the host responses

Protective Mechanisms against T. solium Cysticercosis

The presence of anti-complementary activity described long ago suggested that the classical and the alternative pathways of the complement cascade are inhibited by cysticerci56. Paramyosin (previously known as antigen B) was shown to bind and inhibit C1q, the first component of the complement cascade57. Since this antigen is being released by cysticerci and due to the fact that it is recognized by antibodies of most patients with NC, it could have a dual role in immune evasion: inhibition of C1q and deviation of antibodies to host tissues7,11,57,58. There are several reports of the presence of immunosuppressive factors in extracts prepared from metacestodes of various Taenia species, which inhibit proliferation of lymphocytes against mitogens, or the synthesis of IL259–64, that are reviewed by Molinari and Tato in Chapter 3.

Since there are many Taenia species that infect mammals, there are numerous studies in rodents, ovine and bovines which demonstrate that it is possible to acquire protection against cysticercosis by vaccination. In most studies, crude antigens have been obtained from oncospheres, cysticerci or tapeworms59,71. These studies have been relatively easy to perform since the different stages of the parasite (cysticerci and tapeworms) can develop in animals. Various degrees of protection have been reported, living oncospheres and oncospheral antigens being the most effective immunogens59,71. Recombinant proteins and DNA vaccines have yielded high degrees of immunity72–78. The reader is referred to a detailed discussion of this aspect in Chapter 42.

Molecular mimicry

Conclusions NC and Neoplasia A recent analysis of autopsy files suggested that NC might be a risk factor for human cancer, specifically of the lymphoid tissues65–68. Several data support this hypothesis. Chromosome aberrations in peripheral blood lymphocytes are more common in patients with NC and in cysticercotic pigs as compared to those observed in the same cases after anticysticercal treatment

It is known that antibodies and complement are protective against T. solium oncospheres (Fig. 2.2), but if the pace of the host immune response is slow, then the parasites develop mechanisms to evade the latter. As a result, metacestodes establish and antibodies and complement are no longer effective in destroying them. Thus, a race between development of protective immune mechanisms by the host and evasive mechanisms

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Phase II. Viable cysticerci and concomitant IR. Immune evasion?

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Phase III. Resolution. Immunotherapy?

Phase I: Oncosphere and developing immune response (IR). Vaccination?

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Infection time Fig. 2.2. Phases of cysticercosis in relation to immune response. The initial Phase I is characterized by the development of immune mediated protective mechanisms in the host and the differentiation of the oncosphere into a metacestode. Phase II is a period during which the parasite and the host coexist due to the development of immune evasive mechanisms by the parasite. Finally, in Phase III, the host–parasite equilibrium is broken and the parasite is destroyed by an immune reaction that sometimes even damages the host. This final phase leads to resolution of the infection.

by the parasite occurs during the initial period of infection. Subsequently, an equilibrated host–parasite relationship develops that may last for long periods of time and maintains concomitant immunity. The immune response against T. solium cysticerci appears to have both Th1 and Th2 components, although their precise roles remain controversial. Through not yet understood mechanisms, the parasite is killed primarily by eosinophils, which are

probably chemo-attracted to the site by lymphoid cells. It is surmised that this specific response is mediated by Th2 cytokines. Finally, an intense granulomatous type of inflammatory reaction occurs that leads to complete parasite destruction and resolution with fibrosis. This last mechanism is probably of the Th1-type. Thus, it seems that the Th1 and Th2 cytokines play different roles during various stages of the host–parasite relationship.

References 1. Correa, D., Medina-Escutia, E. (1999) Host–parasite immune relationship in Taenia solium taeniosis and cysticercosis. In: García, H.H., Martínez, S.M. (eds) Taenia solium Taeniasis/Cisticercosis, 2nd edn. Editorial Universo, Lima, Perú, pp. 15–24. 2. de Aluja, A., Vargas, G. (1988) The histopathology of porcine cysticercosis. Veterinary Parasitology 28, 65–77. 3. Flisser, A. (1994) Taeniasis and cysticercosis due to Taenia solium. In: Sun, T. (ed) Progress in Clinical Parasitology. CRC Press, Boca Raton, Florida, pp. 77–116. 4. Sciutto, E., Fragoso, G., Fleury, A., et al. (2000) Taenia solium disease in humans and pigs: an ancient parasitosis disease rooted in developing countries and emerging as a major health problem of global dimensions. Microbes and Infection 2, 1875–1890.

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5. Willms, K., Sotelo, J. (2001) Cestodes. In: Gillespie, S., Pearson R.D. (eds) Principles and Practice of Clinical Parasitology. John Wiley & Sons, New York, pp. 613–633. 6. Flisser, A., Larralde, C. (1986) Cysticercosis. In: Walls, K.W., Schantz, P.M. (eds) Immunodiagnosis of Parasitic Diseases. Academic Press, New York, pp. 109–161. 7. Flisser, A., Woodhouse, E., Larralde, C. (1980) Human cysticercosis: antigens, antibodies and nonresponders. Clinical and Experimental Immunology 39, 27–37. 8. Grogl, M., Estrada, J.J., MacDonald, G., et al. (1985) Antigen–antibody analyses in neurocysticercosis. Journal of Parasitology 71, 433–442. 9. Cho, S.Y., Kim, S.I., Kang, S.Y., et al. (1986) Evaluation of enzyme-linked immunosorbent assay in serological diagnosis of human neurocysticercosis using paired samples of serum and cerebrospinal fluid. Korean Journal of Parasitology 24, 25–41. 10. Corona, T., Pascoe, D., Gonzalez-Barranco, D., et al. (1986) Anticysticercus antibodies in serum and cerebrospinal fluid in patients with cerebral cysticercosis. Journal of Neurology, Neurosurgery and Psychiatry 49, 1044–1049. 11. Espinoza, B., Ruiz-Palacios, G., Tovar, A., et al. (1986) Characterization by enzyme linked immunosorbent assay of the humoral immune response in patients with neurocysticercosis and its application in immunodiagnosis. Journal of Clinical Microbiology 24, 536–541. 12. Feldman, M., Plancarte, A., Sandoval, M., et al. (1990) Comparison of two assays (EIA and EITB) and two samples (saliva and serum) for the diagnosis of neurocysticercosis. Transactions of the Royal Society of Tropical Medicine and Hygiene 84, 559–562. 13. Zini, D., Farrell, V.J.R., Wadee, A.A. (1990) The relationship of antibody levels to the clinical spectrum of human neurocysticercosis. Journal of Neurology, Neurosurgery and Psychiatry 53, 656–661. 14. Short, J.A., Heiner, D.C., Hsiao, R.L., et al. (1991) Immunoglobulin E and G4 antibodies in cysticercosis. Journal of Clinical Microbiology 28, 1635–1639. 15. Spina-Franca, A., Livramento, J.A. (1982) Cerebrospinal fluid immunology in neurocysticercosis. European Review of Medicine and Pharmacological Science 4, 385–388. 16. Miller, B.L., Heiner, D., Golderg, M.A. (1983) The immunology of cerebral cysticercosis. Bulletin of Clinical Neurosciences 48, 18–23. 17. Pammenter, M.D., Rossouw, E.J., Epstein, S.R. (1987) Diagnosis of neurocysticercosis by enzymelinked immunosorbent assay. South African Medical Journal 71, 512–514. 18. Cho, S.Y., Kim, S.I., Kang, S.Y., et al. (1988) Intracranial synthesis of specific IgG antibody in cerebrospinal fluid of neurocysticercosis patients. Korean Journal of Parasitology 26, 15–26. 19. Correa, D., Plancarte, A., Sandoval, M.A., et al. (1989) Immunodiagnosis of human and porcine cysticercosis. Detection of antibodies and parasite products. Acta Leidensia 57, 93–100. 20. Estañol, B., Juarez, H., Irigoyen, M.C., et al. (1989) Humoral immune response in patients with cerebral parenchymal cysticercosis treated with praziquantel. Journal of Neurology, Neurosurgery and Psychiatry 52, 254–257. 21. Bueno, E.C., Vaz, A.J., Machado, L.R., et al. (2000) Total IgE detection in paired cerebrospinal fluid and serum samples from patients with neurocysticercosis. Revista do Instituto de Medicina Tropical de São Paulo (Sao Pãulo) 42, 67–70. 22. Flisser, A., Rivera, L., Trueba, J., et al. (1982) Immunology of human neurocysticercosis. In: Flisser, A., Willms, K., Laclette, J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 549–563. 23. Larralde, C., Montoya, R.M., Sciutto, E., et al. (1989) Deciphering western blots of tapeworm in antigens. Taenia solium, Echinococcus granulosus and Taenia crassiceps resolving with sera from neurocysticercosis and hydatid disease patients. American Journal of Tropical Medicine and Hygiene 40, 282–290. 24. Correa, D., Tovar, A., Espinoza, B., et al. (1989) Cisticercosis humana: relación inmunológica huésped-parásito. In: Flisser, A., Malagon, F. (eds) Cisticercosis Humana y Porcina. Su Conocimiento e Investigacion en Mexico. Limusa-Noriega, Mexico DF, Mexico, pp. 31–43. 25. Medina-Escutia, E., Morales-López, Z., Proaño, J.V., et al. (2001) Cellular immune response and Th1/Th2 cytokines in human neurocysticercosis: lack of immune suppression. Parasitology 87, 587–590. 26. Mosmann, T.R., Coffman, R.L. (1989) Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology 7, 145–173. 27. Ostrosky-Zeichner, L., García-Mendoza, E., Ríos, C., et al. (1996) Humoral and cellular immune response within the subarachnoid space of patients with neurocysticercosis. Archives of Medical Research 27, 513–517.

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28. Aguilar-Robolledo, F., Cedillo-Rivera, R., Llaguno-Violante, P., et al. (2001) Interleukin levels in cerebrospinal fluid from children with neurocysticercosis. American Journal of Tropical Medicine and Hygiene 64, 35–40. 29. Flisser, A., Madrazo, I., Plancarte, A., et al. (1993) Neurological symptoms in occult neurocysticercosis after a single taeniacidal dose of praziquantel. Lancet 342, 748. 30. Wadia, N., Desai, S., Bhatt, M. (1988) Disseminated cysticercosis: new observations, including CT scan findings and experience with treatment by praziquantel. Brain 111, 597–614. 31. Takayanagui, O.M., Chimelli, L.L. (1998) Disseminated muscular cysticercosis with myositis induced by praziquantel therapy. American Journal of Tropical Medicine and Hygiene 59, 1002–1003. 32. Cruz-Revilla, C., Rosas, G., Fragoso, G., et al. (2000) Taenia crassiceps cysticercosis: protective effect and immune response elicited by DNA immunization. Journal of Parasitology 86, 67–74. 33. Evans, C.A.W., García, H.H., Hartnell, A., et al. (1998) Elevated concentration of eotaxin and interleukin-5 in human neurocysticercosis. Infections and Immunity 66, 4522–4525. 34. Sasaki, O., Suguya, H., Ishida, K., et al. (1993) Ablation of eosinophils with anti IL-5 antibody enhances the survival of intracranial worms of Angiostrongylus cantonensis in the mouse. Parasite Immunology 15, 349–354. 35. Flisser, A., Gonzalez, D., Skhurovich, M., et al. (1990) Praziquantel treatment of porcine brain and muscle Taenia solium cysticercosis. 1. Radiological, physiological and histopathological studies. Parasitology Research 76, 263–269. 36. Molinari, J.L., Meza, R., Suarez, B., et al. (1983) Taenia solium: immunity in hogs to the cysticercus. Experimental Parasitology 55, 340–357. 37. Restrepo, B., Llaguno, P., Sandoval, M.A., et al. (1998) Analysis of immune lesions in neurocysticercosis patients: central nervous system response to helminth appears Th1-like instead of Th2. Journal of Neuroimmunology 89, 64–72. 38. Restrepo, B.I., Alvarez, J.I., Castano, L.F., et al. (2001) Brain granulomas in neurocysticercosis are associated with a Th1 and Th2 profile. Infections and Immunity 69, 4554–4560. 39. Robinson, P., Altamar, R., Lewis, D., et al. (1997) Granuloma cytokines in murine cysticercosis. Infections and Immunity 65, 2925–2931. 40. Mitchell, G.F. (1982) Genetic variation in resistance of mice to Taenia taeniaeformis: analysis of hostprotective immunity and immune evasion. In: Flisser, A., Willms, K., Laclette, J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 575–584. 41. Flisser, A. (1989) Taenia solium cysticercosis: some mechanisms of parasite survival in immunocompetent hosts. Acta Leidensia 57, 259–263. 42. White, A.C. Jr, Robinson, P., Kuhn, R. (1997) Taenia solium cysticercosis: host–parasite interaction and the immune response. Clinical Immunology 66, 209–230. 43. Barker, C.F., Billingham, R.E. (1977) Immunologically privileged sites. In: Kunkel, H.G., Dixon, F.J. (eds) Advances in Immunology, Vol. 25. Academic Press, New York, pp. 1–54. 44. Cárdenas, F., Plancarte, A., Quiroz, H., et al. (1989) Taenia crassiceps: experimental model of intraocular cysticercosis. Experimental Parasitology 69, 324–329. 45. Correa, D., Dalma, D., Espinoza, B., et al. (1985) Heterogeneity of humoral immune components in human cysticercosis. Journal of Parasitology 71, 535–541. 46. Willms, K., Arcos, L. (1977) Taenia solium: host serum proteins on the cysticercus surface identified by an ultrastructural immuno-enzyme technique. Experimental Parasitology 43, 396–401. 47. Mandujano, A., Vela, M., Alcántara, P., et al. (1990) Presence of a receptor for the Fc fraction of IgG in Taenia solium (Abstract). Bulletin de la Societie de la Socièté Française Parasitologie 8 (Suppl. 1), 578. 48. Kalinna, B., MacManus, D.P. (1993) An IgG (Fc gamma)-binding protein of Taenia crassiceps (Cestoda) exhibits sequence homology and antigenic similarity with schistosome paramyosin. Parasitology 106, 289–296. 49. Hayunga, E.G., Sumner, M.P., Letonja, T. (1989) Evidence of selective incorporation of host immunoglobulin by strobilocerci of Taenia taeniaeformis. Journal of Parasitology 75, 638–642. 50. Ambrosio, J., Landa, A., Merchant, M.T., et al. (1994) Protein uptake by cysticerci of Taenia crassiceps. Archives of Medical Research 25, 325–330. 51. Herbert, I.V., Oberg, C. (1974) Cysticercosis in pigs due to infection with Taenia solium Linnaeus, 1758. In: Soulsby, E.J.L. (ed.) Parasitic Zoonosis. Academic Press, New York, pp. 199–211. 52. Williams, J.F., Engelkirk, P.G., Lindsay, M.C. (1982) Mechanisms of immunity in rodent cysticercosis. In: Flisser, A., Willms, K., Laclette, J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 621–631. 53. Ito, A., Onitake, K. (1987) Changes in surface antigens of Hymenolepis nana during differentiation and maturation in mice. Journal of Helminthology 61, 129–136.

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54. Gemmell, M.A. (1972) Hydatidosis and cysticercosis 4. Acquired resistance to Taenia hydatigena under conditions of a strong infection pressure. Australian Veterinary Journal 48, 26–28. 55. Willms, K., Arcos, L. (1997) Taenia solium cysticercosis: host–parasite interactions and the immune response. Clinical Immunology 66, 209–230. 56. Hammemberg, B., Williams, J.F. (1978) Physico-chemical characterization of complement-interacting factors from Taenia taeniaeformis. Journal of Immunology 120, 1039–1045. 57. Laclette, J.P., Shoemaker, C., Richter, D., et al. (1992) Paramyosin inhibits complement C1. Journal of Immunology 148, 124–128. 58. Laclette, J.P., Merchant, M.T., Willms, K. (1987) Histological and ultrastructural localization of antigen B in the metacestode of Taenia solium. Journal of Parasitology 73, 121–125. 59. Flisser, A., Pérez-Montford, R., Larralde, C. (1979) The immunology of human and animal cysticercosis: a review. Bulletin of the World Health Organization 57, 839–856. 60. Burger, C.J., Rikihisa, Y., Lin, Y.C. (1986) Taenia taeniaeformis inhibition of mitogen induced proliferation and interleukin-2 production in rat splenocytes by larval in vitro products. Experimental Parasitology 62, 216–222. 61. Molinari, J.L., Tato, P., Reynoso, O.A., et al. (1990) Depressive effect of a Taenia solium cysticercus factor on cultured human lymphocytes stimulated with phytohemaglutinin. Annals of Tropical Medicine and Parasitology 84, 205–208. 62. Sciutto, E., Fragoso, G., Baca, M., et al. (1995) Depressed T cell proliferation associated with susceptibility to experimental infection with Taenia crassiceps infection. Infections and Immunology 63, 2277–2281. 63. Tato, P., Castro, A.M., Rodríguez, D., et al. (1995) Suppression of murine lymphocyte proliferation induced by a small RNA purified from the Taenia solium metacestode. Parasitology Research 81, 181–187. 64. Arechavaleta, F., Molinari, J.L., Tato, P. (1998) A Taenia solium metacestode factor non-specifically inhibits cytokine production. Parasitology Research 84, 117–122. 65. Del Brutto, O.H., Castillo, P.R., Mena, I.X., et al. (1997) Neurocysticercosis among patients with cerebral glioma. Archives of Neurology 54, 1125–1128. 66. Herrera, L.A., Benita-Bordes, A., Sotelo, J., et al. (1999) Possible relationship between neurocysticercosis and hematological malignancies. Archives of Medical Research 30, 154–158. 67. Herrera, L.A., Ostrosky-Wegman, P. (2001) Do helminths play a role in carcinogenesis? Trends in Parasitology 17, 172–175. 68. Herrera, L.A., Ramírez, T., Rodríguez, U., et al. (2000) Possible association between Taenia solium cysticercosis and cancer: increased frequency of DNA damage in peripheral lymphocytes from neurocysticercosis patients. Transactions of the Royal Society of Tropical Medicine and Hygiene 94, 1–5. 69. Montero, R., Flisser, A., Madrazo, I., et al. (1994) Mutation at the HPRT locus in patients with neurocysticercosis treated with praziquantel. Mutation Research 305, 181–188. 70. Flisser, A., González, D., Plancarte, A., et al. (1990) Praziquantel treatment of brain and muscle porcine Taenia solium cysticercosis. 2. Immunological and cytogenetic studies. Parasitology Research 76, 640–642. 71. Lightowlers, M.W. (1994) Vaccination against animal parasites. Veterinary Parasitology 54, 177–204. 72. Johnson, K.S., Harrison, G.B.L., Lightowlers, M.W., et al. (1989) Vaccination against ovine cysticercosis using a defined recombinant antigen. Nature 338, 585–587. 73. Mitchel, G.F. (1990) Vaccines and vaccination strategies against helminths. In: Agabian, N., Cerami, A. (eds) Parasites. Molecular Biology, Drug and Vaccine Design, Wiley-Liss Publications, New York, pp. 349–363. 74. Harrison, G.B.L., Heath, D.D., Dempster, R.P., et al. (1996) Identification and cDNA cloning of two novel low molecular weight host-protective antigens from Taenia ovis oncospheres. International Journal of Parasitology 26, 195–204. 75. Lightowlers, M.W., Rolfe, R., Gaucci, C.G. (1996) Taenia saginata: vaccination against cysticercosis in cattle with recombinant oncosphere antigens. Experimental Parasitology 84, 330–338. 76. Rosas, G., Cruz-Revilla, G., Fragoso, G., et al. (1998) Taenia crassiceps cysticercosis: humoral immune response and protection elicited by DNA immunization. Journal of Parasitology 84, 516–523. 77. Plancarte, A., Flisser, A., Gaucci, C.G., Lightowlers, M.W. (1999) Vaccination against Taenia solium cysticercosis in pigs using native and recombinant oncosphere antigens. International Journal for Parasitology 29, 643–647. 78. Flisser, A., Lightowlers, M.W. (2000) Vaccination against Taenia solium cysticercosis. Memorias do Instituto Oswaldo Cruz 96, 353–356.

3

Molecular Determinants of Host–Parasite Interactions: Focus on Parasite José L. Molinari and Patricia Tato

The relationship between helminths and their hosts is complex and interesting. It is well known that parasites elicit immunological responses in their hosts. What is less well known and appreciated, is that parasites have evolved numerous ways of evading the consequences of host immunological response. The net outcome is that parasites frequently survive for long periods in fully immunocompetent hosts. Host lymphocytes and their cytokines play a crucial role in determining the outcome of parasitic infection (reviewed in Chapter 2). In this chapter, we review certain aspects of the host–parasite interaction in Taenia solium cysticercosis with special emphasis on parasite related factors.

been studied. An idea of the process can be obtained from studies involving other helminths. For instance, Hymenolepis nana oncospheres make use of certain proteases in addition to three pairs of hooks in order to invade host tissues1. Similarly, serine protease activity and excretory–secretory peptidases have been isolated from penetration glands of oncospheres of H. diminuta and T. saginata, respectively2,3. It is held that these enzymes participate in tissue invasion in addition to performing nutritional functions. Finally, T. solium egg infection induces humoral immunological responses in human hosts. This assumption is based on evidence from in vitro studies, where serum from cysticercotic individuals destroys oncospheres in presence of complement4.

Host–oncosphere interactions

Host–metacestode interactions

Ingestion of food or water contaminated with T. solium eggs is the most preliminary step in the development of human cysticercosis. Hatched and activated oncospheres penetrate intestinal tissues, perforate small intestinal blood vessels, and reach the bloodstream. Here, they passively migrate and finally lodge in target tissues and develop into metacestodes. Specific mechanisms underlying T. solium oncosphere penetration have not

Host inflammatory response directed against T. solium metacestodes is a major determinant of clinical symptoms and signs of NC. There is great variability in its onset, duration and severity. The seminal study by Dixon and Lipscomb has established that metacestodes remain in host tissues in a viable, non-degenerate state for variable and prolonged periods of time5. Eventually, usually after 4–5 years, local and systemic immune responses against

Introduction

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metacestodes develop. As a result, metacestodes pass through a series of degenerativeevolutionary stages that are described in detail in Chapters 30 and 32. Clinical symptoms and signs owe their appearance and evolution to the host immune responses. Furthermore, histological studies corroborate the relationship between the evolutionary stages of metacestodes and host immune response. In both humans and pigs, live and viable metacestodes are surrounded by only discrete inflammatory reaction6,7. In comparison, studies on pigs pre-immunized with cysticercus antigens have revealed intense granulomatous inflammation surrounding the metacestodes8. These clinical, histological and experimental observations have led several workers including ourselves, to postulate that live T. solium metacestodes are able to down-modulate host immune responses by virtue of producing certain specific molecules. Several such molecules have been previously described9–11. Taenia metacestodes modulate complement function by sulphated polysaccharides that activate and consume complement9. Among other molecules, taeniaestatin inhibits both classic and alternative complement pathways and paramyosin inhibits C1q activation10,11.

Metacestode Factor (MF) Studies evaluating peripheral blood T cells in naturally and experimentally infected cysticercotic pigs, have consistently revealed diminution of CD4+ cell counts in proportion to parasite loads12,13. We postulated that Tcell suppression in cysticercotic pigs might be related to substances secreted by T. solium metacestodes. Similarly, low molecular weight isolates from Schistosoma mansoni and Onchocerca gibsoni have previously been reported to induce depression of (3H) thymidine uptake by lymphocytes stimulated with Concanavalin-A (Con-A)14,15.

Isolation and preliminary characterization A method to isolate substances of molecular weight less than 3500 Dalton from super-

natants of live T. solium metacestodes was designed. The isolate was tested at different doses in human lymphocyte cultures, stimulated with phytohaemagglutinin and was found to suppress (3H) thymidine uptake by lymphocytes. The suppression was forestalled by pre-digestion with ribonuclease (RNase), suggesting that the active molecule may be a RNA fraction16. A suppression of (3H) thymidine uptake has also been demonstrated in T lymphocytes from naturally infected-cysticercotic pigs17. The material that suppresses (3H) thymidine uptake was assigned the name, metacestode factor (MF). We proceeded to study its effects in vivo. Mice were inoculated with MF (four doses of 100 g per mouse) and challenged with one LD50 of Salmonella typhimurium virulent bacilli18. Mice were either treated with S. typhimurium antigen alone or MF alone, or with S. typhimurium antigens and MF in combination. A control group consisted of mice inoculated with saline solution. We observed that mice treated with MF alone, or with both S. typhimurium antigens and MF, died faster and in greater number than control mice. In contrast, all mice survived in the group that was given S. typhimurium antigens alone. When batches of MF were filtered through a Bio-gel P-6 column, two peaks (F1 and F2) were obtained. Further, F1 and F2 were tested in proliferation assays19. While, F1 induced a dose-dependent suppressive effect, F2 induced an increase of the (3H) thymidine uptake elicited by mitogen. Thereafter, an attempt was made to characterize F1 by treating it with several inactivating factors such as RNase, proteases and heat. After treatment, F1 was tested again in proliferation assays. RNase-treated F1 lost its suppressive effect. In contrast, trypsin and papain augmented (3H) thymidine uptake inhibition. Chymotrypsin or heat had no effect. Finally, the effect of F1 was studied in co-cultures of murine macrophages and lymphocytes. It was shown that macrophages pre-incubated with F1 and subsequently cocultured with fresh lymphocytes did not affect (3H) thymidine uptake. In contrast, incorporation of (3H) thymidine by fresh lymphocytes co-cultured with lymphocytes

Molecular Determinants of Host–Parasite Interactions

pre-incubated with F1 was inhibited. This study provided specific evidence for the probable existence of a RNA molecule, F1, whose principal site of action was shown to be the lymphocyte.

Effect on local inflammatory reactions In vivo studies further examined the effects of MF on the inflammatory reaction around implanted metacestodes in mice20. Female BALB/c syngeneic mice were divided into four groups based upon the following experimental protocol. One group of mice was treated with 100 g of MF (one dose every 96 h for 12 days). A second group consisted of mice inoculated with metacestode antigens (100 g as a single dose) alone, while a third group was constituted by mice that were first inoculated with metacestode antigens and then treated with MF. In the fourth (control) group, mice were inoculated with inert normal saline alone. Subsequently, mice in all four groups were implanted with live T. solium metacestodes (six metacestodes/mouse), obtained from cysticercotic pig meat under sterile conditions. Twelve days after the metacestode implantation, the mice were killed. Histopathological studies revealed that: 1. Metacestodes implanted in control mice were completely destroyed and their remnants were surrounded by an intense inflammatory reaction predominantly made up of neutrophils and eosinophils. 2. In metacestodes of mice that were treated with MF alone, there were clearly identifiable and intact suckers, rostellum, tegument and hooks. Few neutrophils, plasma cells, lymphocytes and histiocytes were noted in spiral canals; eosinophils were not observed. 3. Metacestodes implanted in mice immunized with metacestode antigens alone were completely destroyed; their caseous remnants were intensely surrounded and infiltrated by neutrophils and eosinophils. 4. Finally, in mice immunized with metacestode antigens and subsequently treated with MF, there were clearly identifiable (albeit necrotic) rostellum, suckers,

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parenchymal tissues and tegument; the hooks were dispersed in necrotic tissue. Moderate inflammatory reaction surrounded the metacestodes. Local inflammatory responses were also evaluated using scanning electron microscopy in the experimental protocol outlined above21. Samples from metacestodes removed at 6 and 12 days post-implantation were studied. At 6 days post-implantation, it was found that: 1. In control mice, metacestodes were disintegrated and covered by an intense inflammatory reaction (Fig. 3.1a). 2. Metacestodes removed from mice treated with MF alone were intact and exhibited a scarce inflammation on the bladder tegument (Fig. 3.1b). 3. An evaginated metacestode removed from a mouse inoculated with metacestode antigen alone displayed inflammatory reaction on its scolex. Inflammatory cells were disseminated on the double crown of hooks, suckers and the neck tegument; whereas the bladder wall tegument was covered by a dense net of fibrous material embedding numerous inflammatory cells. 4. Metacestodes removed from mice immunized with metacestode antigens and subsequently treated with MF exhibited few inflammatory cells on their bladder wall teguments. At 12 days post-implantation: 1. Metacestodes removed from control mice were completely enmeshed in an intense inflammatory reaction, with a dense collagen-like matrix embedding numerous inflammatory cells and covering the whole bladder wall tegument. 2. The inflammatory reaction surrounding metacestodes removed from mice treated with MF alone was more intense than that observed on day 6. In one partially evaginated metacestode, the scolex was apparently intact, with minimal amount of inflammatory infiltrate in the folds of its neck. At higher magnification ( 1500), the microtriches were visibly intact with scarce inflammatory cells and eosinophil like-granules.

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Fig. 3.1a. Scanning electron micrograph of a Taenia solium metacestode removed from a control mouse at day 6. (Reproduced with permission from reference 21.) (ST, subtegument; T, tegument.)

Fig. 3.1b. Scanning electron micrograph of a metacestode removed from a MF-treated mouse at day 6. (Reproduced with permission from reference 21.)

3. Metacestodes from mice immunized with metacestode antigens exhibited much stronger inflammatory reactions on the scolex tegument in comparison to day-6. Copious inflammatory infiltrate was visible surrounding the tegument of an evaginated scolex (Fig. 3.2). Ruptures of different size and depth were evident in the tegument and sub-tegumental suckers. At higher magnification ( 1500), an intense accumulation of

different kinds of white cells, cell debris and fibrinoid material was apparent. 4. In mice immunized with metacestode antigen and treated subsequently with MF, the inflammatory reaction on the bladder wall tegument was less extensive in comparison to immunized (with metacestode antigens) or control groups. Very few inflammatory cells, cell debris and fibrous material were found adherent to intact microtriches.

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Fig. 3.2. Scanning electron micrograph of an evaginated scolex removed from an immunized mouse at day 12. An intense inflammatory reaction completely covers the scolex tegument. Note the large cell aggregates and several ruptures of the sucker and rostellum teguments. (Reproduced with permission from reference 21.)

Effects on humoral and cellular immune responses Humoral and cellular immune responses to inoculation with metacestode antigens, treatment with MF and metacestode implantation were also studied in the experimental model outlined above. Sera from mice immunized with metacestode antigens and treated with MF showed a significant decrease in antibody titres compared with those of mice treated with metacestode antigens alone. Metacestode implantation further suppressed antibody responses to metacestode antigens. Antibody titres were least in sera of implanted mice treated with MF alone (Fig. 3.3). A suppressive effect of MF was also noted on cellular immune functions. Splenic lymphocytes from mice immunized with metacestode antigens and treated with MF exhibited a significant decrease in (3H) thymidine uptake in comparison with lymphocytes from mice inoculated with metacestode antigens alone (Fig. 3.4)20.

were measured in culture supernatants in order to study the effects of MF on cytokine production22. When cultured with MF, cells showed significantly decreased production of interleukin 2 (IL-2), interferon- (IFN-), and interleukin 4 (IL-4) as compared to mitogen alone. Exogenous recombinant IL-2 and recombinant IL-4 largely restored proliferation responses (85% and 71% of control cells, respectively). MF also inhibited the production of tumour necrosis factor-alpha (TNFalpha) by macrophages stimulated with lipopolysaccharide and IFN-. The results of the above study provide additional evidence of an inhibitory effect of MF upon cytokine production, regardless of the cell type or cytokine (Fig. 3.5). It may be surmised that impairment, specifically of IL-2 and IFN- production may underlie modulatory influences of MF of the nature noted in experiments with metacestodes implanted in mice.

Metacestode Proteases Effects on cytokines Murine spleen cells were stimulated in vitro with Con-A and cytokine concentrations

There is sufficient evidence for the existence of several parasitic secretory proteases. The latter are believed to be involved in invasion, nutrition and immune evasion23–25. White et

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1.4 1.2 1.0 A (492)

0.8 0.6 0.4 0.2 0 0

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Fig. 3.3. Antibody titres determined by ELISA in sera from mice inoculated with Taenia solium metacestode antigens (I), inoculated with metacestode antigens plus MF (IF), inoculated with metacestode antigens and implanted with six metacestodes (IM), inoculated with metacestode antigens plus MF and implanted with six metacestodes (IFM), and inoculated with saline (C). Data are expressed as mean values  SE for each treatment (n = 4) (P0.05 for I versus IF, IM or IFM). (Reproduced with permission from reference 20.)

10,000

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9000 8000 7000 6000 5000 4000 3000 2000 1000 0 C

CM

I

IF

F

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Fig. 3.4. Effect of Taenia solium metacestode antigens on the proliferation of murine splenic lymphocytes from the following groups of mice: (C) control; (CM) implanted with six metacestodes; (I) inoculated with metacestode antigens; (IF) inoculated with metacestode antigens plus MF; (F) inoculated with MF; (IM) inoculated with metacestode antigens and implanted with six metacestodes; (IMF) inoculated with metacestode antigens plus MF and implanted with six metacestodes; and (MF) inoculated with MF and implanted with six metacestodes. Bars represent mean values  SE for thymidine uptake by cells stimulated with 1 g of metacestode antigens (P0.05 for I and IM versus IF, IMF, CM or C). (Reproduced with permission from reference 20.)

Molecular Determinants of Host–Parasite Interactions

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MF (g)

3

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MF (g)

Fig. 3.5. Effect of Taenia solium MF on the production of cytokines. IL-2, IFN- and IL-4 were measured in supernatants of mouse spleen cells treated with 10 and 20 g of MF (measured as ribose) and stimulated with Con-A. TNF-alpha was detected in supernatants of murine macrophage line (IC-21) treated with 10 and 20 g of MF and stimulated with lipopolysaccharide and recombinant IFN-. C are the cytokine concentrations from cells incubated in RPMI medium; C+ are the cytokine values from cells stimulated with Con-A or lipopolysaccharide/recombinant IFN-. (Reproduced with permission from reference 22.)

al., described cysteine, metallo- and serine protease activities in acid extracts from lyophilized T. solium metacestodes. The authors reported IgG digestion by the extracts in vitro26. We postulated that immunoglobulin molecules behaved as target substrates and molecular nutrients for T. solium proteases. Supernatants of live metacestode cultures were evaluated for protease activity on peptide substrates with T cell surface proteins27. Substantial cysteine protease activity in addition to metallo- and serine protease activities was found. Isolated human lymphocytes from volunteers were co-cultured with live

T. solium metacestodes (96% viability) at 37°C for 2 h. Cells were separated, washed and stained with monoclonal antibodies, antiCD4 FITC (fluoresceinated) and anti-CD8 PE (phycoerythrinated). Flow cytometric analysis revealed significant decrease in CD4+ expression (Fig. 3.6). The cause and effect relationship between protease activity and decrease in CD4 expression was demonstrated when human lymphocytes were cultured with metacestode excretory–secretory products in presence of L-cysteine, a reducing substance. Cells were washed and stained and analysed by flow cytometry. Metacestode excretory–

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102 103 FL1-H

104

103 102

FL2-H

100

100

100 101

c

101

102

FL2-H

103

b

101

102

FL2-H

103

a

101

CD8

100

R1 : 5685 104

R1 : 2210 104

104

R1 : 8467

100

101

102 103 FL1-H

104

100

101

102 103 FL1-H

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CD4 Fig. 3.6. Flow cytometry analysis of human T cells co-cultured with 100 Taenia solium metacestodes after cells were separated and stained with monoclonal antibody fluoresceinated anti-human CD4 and phycoerythrinated anti-human CD8. (a) Control cells in RPMI 1640 medium without metacestodes. (b) Cells co-cultured for 2 hours with 100 metacestodes. (c) Cells co-cultured for 2 hours with 100 metacestodes and 100 g of rabbit antiserum to metacestode excretory-secretory products. Values are expressed as gated percentages of CD8+and CD4+cells. (Reproduced with permission from reference 27.)

secretory products pre-incubated with E-64 (a specific inhibitor of cysteine protease) served as control material. A significant decrease in CD4 expression, attributable to cysteine protease activity was again demonstrated. Furthermore, treatment with E-64 resulted in the reversion of the inhibitory effect on CD4 expression.

Conclusions T. solium metacestodes exert a modulatory influence on host immunological responses through several molecular agents. MF, a 3500 Da RNA-like molecule is most significant in this regard. It inhibits humoral and cellular immune responses as well as inflammatory reaction around implanted metacestodes in mice. It has also been shown to

inhibit cytokine, particularly IFN- and IL-2, and to a lesser degree IL-4 production in vitro. Live metacestodes also secrete cysteine, metallo- and serine proteases. Cysteine protease activity significantly depletes CD4+ cells in vitro. The elucidation of these molecules and of their actions in experimental conditions have provided insights into the mechanisms by which T. solium metacestodes evade host immunological attack and are able to survive for long periods of time.

Acknowledgements This work was supported by grants from National Council of Science and Technology (Mexico) 23672-M, and National Autonomous University of Mexico. Authors thank Dr. Rodolfo Paredes for photographic material.

References 1. Miyasato, T., Furukawa, T., Inoue, M., et al. (1977) Electron microscopic observations on the penetration of oncospheres of Hymenolepis nana into the intestine of the mouse. Acta Medica Kinki University 2, 1–18. 2. Moczon, T. (1996) A serine proteinase in the penetration glands of the hexacants of Hymenolepis diminuta (Cestoda, Cyclophyllidea). Parasitology Research 82, 67–71. 3. White, A.C. Jr, Baig, S., Robinson, P. (1996) Taenia saginata oncosphere excretory/secretory peptidases. Journal of Parasitology 82, 7–10.

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4. Molinari, J.L., Tato, P., Lara, A.R., et al. (1993) Effects of serum from neurocysticercosis patients on the structure and viability of Taenia solium oncospheres. Journal of Parasitology 79, 124–127. 5. Dixon, H.B.F., Lipscomb, F.M. (1961) Cysticercosis. An analysis and follow-up of 450 cases. Medical Research Council Special Reports Series. Her Majesty’s Stationery Office, London, 299, 1–56. 6. Marquez, H. (1971) Cysticercosis. In: Marcial, R. (ed.) Pathology of Protozoal and Helminth Diseases. Williams and Wilkins, Baltimore, Maryland, pp. 592–617. 7. Hernandez, J.P.A., Marquez, M.H., Sastre, O.S. (1973) Cysticercosis of the central nervous system in hogs. American Journal of Veterinary Research 34, 451–453. 8. Molinari, J.L., Meza, R., Suarez, B., et al. (1983) Taenia solium: immunity in hogs to the cysticercus. Experimental Parasitology 55, 340–357. 9. Hammerberg, B., William, J.F. (1978) Interaction between Taenia taeniaeformis and the complement system. Journal of Immunology 120, 1033–1038. 10. Suquet, C., Green, E.C., Leid, R.W. (1984) Isolation and partial characterization of a Taenia taeniaeformis metacestode proteinase inhibitor. International Journal of Parasitology 14, 165–172. 11. Laclette, J.P., Shoemaker, C.B., Richter, D., et al. (1992) Paramyosin inhibits complement C1. Journal of Immunology 148, 124–128. 12. Tato, P., Valles, Y., Rolon, R., et al. (1987) Effect of the immunization on immunodepressed hogs, infected naturally by Cysticercus cellulosae. Revista LatinoAmericana de Microbiologia (México) 29, 67–71. 13. Molinari, J.L., Tato, P., Valles, Y. (1987) Immunodepression of T lymphocytes in hogs modulated by Cysticercus cellulosae. Revista LatinoAmericana de Microbiologia (México) 29, 293–300. 14. Dessaint, J.P., Camus, D., Fisher, E., et al. (1977) Inhibition of lymphocyte proliferation by factor(s) produced by Schistosoma mansoni. European Journal of Immunology 7, 624–629. 15. Yin, F.D., Nowak, M., Copeman, B., et al. (1983) A low molecular weight immunosuppressive factor produced by Onchocerca gibsoni. Veterinary Immunology and Parasitology 4, 445–451. 16. Molinari, J.L., Tato, P., Reynoso, O.A., et al. (1990) Depressive effect of a Taenia solium cysticercus factor on cultured human lymphocytes stimulated with phytohemagglutinin. Annals of Tropical Medicine and Parasitology 84, 205–208. 17. Molinari, J.L., Soto, R., Tato, P., et al. (1993) Immunization against porcine cysticercosis in an endemic area in Mexico: a field and laboratory study. American Journal of Tropical Medicine and Hygiene 49, 502–512. 18. Molinari, J.L., Tato, P., Reynoso, O.A., et al. (1989) Modulation effects on mice response to a Salmonella typhimurium infection by a Taenia solium cysticerci product of low molecular weight. Revista LatinoAmericana de Microbiologia (México) 31, 327–333. 19. Tato, P., Castro, A.M., Rodriguez, D., et al. (1995) Suppression of murine lymphocyte proliferation induced by a small RNA purified from Taenia solium metacestodes. Parasitology Research 81, 181–187. 20. Tato, P., White, A.C. Jr, Willms, K., et al. (1996) Immunosuppression and inhibition of inflammation in mice induced by a small Taenia solium RNA-peptide to implanted T. solium metacestodes. Parasitology Research 82, 590–597. 21. Molinari, J.L., Tato, P., Rodriguez, D., et al. (1998) Impairment of the inflammatory reaction on implanted Taenia solium metacestodes in mice by a T. solium RNA-peptide: a scanning electron microscopy study. Parasitology Research 84, 173–180. 22. Arechavaleta, F., Molinari, J.L., Tato, P. (1998) A Taenia solium metacestode factor nonspecifically inhibits cytokine production. Parasitology Research 84, 117–122. 23. McKerrow, J.H., Jones, P., Sage, H., et al. (1985) Proteinases from invasive larvae of the trematode parasite Schistosoma mansoni degrade connective tissue and basement membrane macromolecules. Biochemical Journal 231, 47–51. 24. Hotez, P.J., Trang, N.L., McKerrow, J.H., et al. (1985) Isolation and characterization of a proteolytic enzyme from the adult Ancylostoma caninum. Journal of Biological Chemistry 260, 7343–7348. 25. Chappel, C.L., Dresden, M.H. (1986) Schistosoma mansoni: proteinase activity of ‘hemoglobinase’ from the digestive tracts of adult worms. Experimental Parasitology 61, 160–167. 26. White, A.C. Jr, Molinari, J.L., Pillai, A.V., et al. (1992) Detection and preliminary characterization of Taenia solium metacestode proteases. Journal of Parasitology 78, 281–287. 27. Molinari, J.L., Mejia, H., Clinton, A.C. Jr, et al. (2000) Taenia solium: a cysteine protease secreted by metacestodes depletes human CD4 lymphocytes in vitro. Experimental Parasitology 94, 133–142.

4

Animal Models of Taenia solium Cysticercosis: Role in Understanding Host–Parasite Interactions Astrid E. Cardona and Judy M. Teale

Introduction An important outcome of initial clinical studies of neurocysticercosis (NC) was the realization that the brain is not only affected by the presence of metacestodes, but more significantly by the inflammatory response and its sequelae1–3. In the human central nervous system (CNS), host responses to Taenia solium cysticerci range from complete absence, to severe inflammatory reaction4. In most cases, viable parasites have little surrounding inflammation5, which correlates with an asymptomatic stage of NC. In contrast, virtually all cases of symptomatic disease are characterized by prominent immunological responses in host nervous tissue6–9. The reader is referred to Chapter 2 for an overview of host immune responses to cysticercosis. Besides the host immune response, the location, stage, number and the immunomodulatory effects of the metacestodes (reviewed in Chapter 3) also contribute to disease outcome. However, the extent of contribution of these factors and how such factors influence each other is still not clear. It is difficult to segregate and study each of the factors individually in humans. Given the large number of variables involved, the lack of predictability of their interactions in human hosts and complexity of the host immune system at cellular and subcellular

levels, animal models are critical to furthering our knowledge of the host–parasite relationship. Furthermore, animal models are useful in the study of other factors associated with disease acquisition, e.g. genetic factors both in relation to the host (see Chapter 6)10,11and parasite and in the development of novel therapeutic agents and schemes (see Chapter 15). The development of animal models to study T. solium infection has been an arduous task. The earliest experience with animal models was studies exploring immunological mechanisms of resistance to larval cestodes in mice and rats infected with Taenia taeniaeformis12,13. These studies elucidated components of the peripheral response to T. taeniaeformis and found that antibodies and complement were implicated in host defence mechanisms12,13.

Animal Models for Adult T. solium Several mammals have been evaluated as experimental models of adult T. solium. The oral route of infection with T. solium cysticerci obtained from infected pigs has been employed in these models14. In young dogs, tapeworms survived only for 8 days. Mice, albino rats and guinea pigs were not susceptible to T. solium infection. Rhesus monkeys, cats and rabbits did not prove to be useful models14. In contrast, in gerbils and golden

© CAB International 2002. Taenia solium Cysticercosis (eds G. Singh and S. Prabhakar)

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hamsters (Mesocricetus auratus), tapeworms developed and exhibited greater sexual development, though mature and infectious oncospheres were not produced14–16. Cysternal infection with scolex and membranes from T. solium cysticerci resulted in an intense granulomatous inflammatory response consisting of lymphocytes in rabbits17. Interestingly, the most successful hosts to date for adult T. solium tapeworms are chinchillas (Chinchillidae family of rodents), in which larvae develop into gravid proglottides, eventually producing infective oncospheres. Infectivity of eggs obtained from the chinchilla model was demonstrated in pigs. Metacestodes were found in pig skeletal muscle, 12 weeks after oral infection with gravid proglottides recovered from chinchillas14. Immunosuppressive treatment with steroids (prednisolone and methyl prednisolone) facilitates the establishment and development of adult T. solium and a related cestode, T. crassiceps in experimental host intestine14,18. The basis of the facilitatory effect of steroid treatment presumably relates to suppression of local mucosal inflammatory responses to worm attachment19. When T cells were depleted in vivo in Mongolian gerbils (Meriones unguiculatus) infected with T. crassiceps ova, only destrobilated adult worms were harvested in the faeces20. This indicated that T cells in some way prevented strobilar attachment to enteral mucosa. A similar effect was observed in prednisolonetreated gerbils, arguably due to an effect of prednisolone upon T cells20. The development of an experimental model that allows the recovery of T. solium eggs is likely to have a significant impact upon future research. Eggs will be available for antigen cloning, analysis and purification. Further application of the chinchilla model will be valuable in the areas of vaccine design and host–adult parasite interactions.

pigs are the natural intermediate host of the helminth. Most researchers employing this model so far have used naturally infected pigs21,22, although experimentally induced infections have also been studied (see also Chapter 15)23. The number of T. solium eggs required for inducing experimental infection varied between 1000 and 380,00023. The porcine model has provided information related to progression of the parasitosis in liver, muscles and lungs. In parallel to human CNS infections, histological studies in this model revealed the presence of immature, mature, degenerate and calcified cysts in pig liver and muscle22,24. As yet, a detailed analysis of the specific immunological elements has not been described in the porcine model. A major area of application of porcine models has been the development of treatment strategies to control porcine cysticercosis with the ultimate goal of preventing human infection. Two of the drugs that are currently used for treatment of human cysticercosis, albendazole and praziquantel, have been used in several different protocols to determine their efficacy for treatment of porcine cysticercosis21, 22, 25, 26. Another drug, oxfendazole has been found effective in controlling swine cysticercosis (reviewed in Chapter 43)27. These studies together with the epidemiological studies are important for the development of interventions to eradicate T. solium infection28,29. However, the scarcity of infected pigs in non-endemic areas, and the difficulty in obtaining T. solium eggs have limited the widespread use of the porcine model. Moreover, there are difficulties in handling pigs, and a high cost of support is involved. Therefore, other animal species have been used to develop experimental models for cysticercosis using related parasites.

Experimental intraocular cysticercosis

Animal Models for Cysticercosis T. solium cysticercosis in pigs Porcine cysticercosis is a successful experimental model for T. solium cysticercosis, as

The eye is an immunologically privileged site. T. crassiceps metacestodes have also been used in experimental models of intraocular/ intravitreous cysticercosis in rabbits30,31. Living T. crassiceps cysticerci in the vitreous cavity produced ocular lesions with an

Animal Models of T. solium Cysticercosis

intense inflammatory response in those rabbits that had been previously infected through the intraperitoneal route or had been inoculated with cysticercus antigen30,31. A granulomatous response comprising eosinophils and polymorphonuclear cells was noted. Naive rabbits and steroid treated rabbits did not exhibit inflammatory ocular lesions30,31. These models are significant in the understanding of immune reactions specifically involved in the intraocular compartment as well as the treatment of ocular cysticercosis.

T. crassiceps experimental cysticercosis Two related cestode parasites, T. crassiceps and Mesocestoides corti have been used extensively as animal models of cysticercosis. Their metacestodes are infectious to mice, and the larval stages of these parasites are easily maintained in the peritoneal cavity of infected mice32,33. Intraperitoneal injection of either organism results in invasion of liver and peritoneum. Intraperitoneal inoculation, however, does not produce CNS lesions, a major drawback of initial investigations with these models. Recently, however, infection with either organism was accomplished in the brain, thereby facilitating the study of infective mechanisms specific to the CNS34. T. crassiceps has a canine definitive host and a rodent intermediate host32,35. In natural infections, the larval form invades several tissues including the peritoneal cavity of the rodent. In BALB/c mice, chronic infection with T. crassiceps induced host immunosuppression. Analysis of the temporal course of the immune response in mice inoculated intraperitoneally with T. crassiceps, revealed a time dependent variation in the intensity of Th1 and Th2 type responses (see Chapter 2 for an overview of the Th1 and Th2 responses)36–38. In the early stages of infection when few or no parasites could be recovered from the peritoneal cavity, mice exhibited a strong Th1 type of immunological response characterized by high interferon- (IFN-) production, IgG2a dominated antibody response and delayed type hypersensitivity (DTH). Late in infection,

37

production of interleukin-2 (IL-2) and IFN- decreased and DTH was depressed, while IL-4, IL-10, IgG2b and IgG1 production was up-regulated. These results suggest that there is a shift from an initial parasite-restrictive, Th1-type based response to a later parasite-permissive, Th2 response. While the early response suppresses infection by metacestodes, the latter allows establishment and growth of T. crassiceps metacestodes in murine hosts36,38. Analyses of the immunological response around peritoneal granulomas formed 3–14 weeks after infection indicate that early granulomas are predominantly associated with a Th1-type response, whereas later granulomas, in which parasite destruction is complete, have a mixture of Th1- and Th2type responses39. These data suggest that dying parasites can no longer modulate host immunological responses. The Th1 granulomatous response is likely to be involved in the pathogenesis of symptomatic human infection in which active inflammation is a major cause of disease. As the parasite is destroyed, the response shifts to involve greater Th2-type cytokine expression, perhaps as a means of down-regulating inflammation39. Interestingly, it was demonstrated that subcutaneous inoculation with larvae induces protection against subsequent intraperitoneal challenge. Parasite destruction was associated with adherence of host cells to the tegument of larvae. The crucial effector population of host cells involved in parasite death is not known40. The T. crassiceps animal model has also been used to investigate mechanisms of immunological regulation that the parasite can exhibit in the host. T. crassiceps larvae release factors that are capable of down-regulating both proliferative responses of and cytokine production by T cells41. These parasite factors were found to down-regulate production of IFN- and IL-4 by mitogen stimulated spleen cells41. This inhibitory effect was caused by excretory–secretory products from the larvae in the early stages of infection. In contrast, excretory–secretory products from larvae harvested late in infection were not suppressive40. Future studies will be critical to elucidate immuno-

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logical mechanisms involved in larval destruction by the host and immunomodulatory mechanisms by which the parasite persists in the host. A major outcome of the development of the mouse–T. crassiceps, host–parasite model has been the recognition of several host factors that influence infection by metacestodes. The sex specific behaviour of the cestode is an outstanding example of one such host factor. In mouse models, T. crassiceps parasitize female mice in preference to male mice in large numbers following intraperitoneal inoculation42. Gonadectomy was found to increase parasite population in male mice but had an opposite effect in female mice42,43. Replacement with 17 -oestradiol favours parasite proliferation in host mice, an effect that is more prominent in male mice44. The sex specific behaviours are not observed in irradiated or neonatally thymectomized mice suggesting that sex hormones interact with the immune system in order to favour or suppress infection43,45. It has been surmised that oestrogens inhibit immune mechanisms and are thereby permissive to T. crassiceps proliferation in mice. The sex-related differences in rate and intensity of establishment described above are evident in the early stages of T. crassiceps infection in mice. In chronically parasitized mice, the parasite establishes itself in large numbers in male mice as well. The effect of chronic T. crassiceps infection on sexual behaviour and related morphological and biochemical parameters is of interest. Chronic infection results in inhibition of sexual responses in male mice, gonadal atrophy in male mice and hypertrophy in female mice and an overwhelming increase of plasma oestradiol levels and corresponding reduction in plasma testosterone levels in male mice46,47. Likewise, an increase in the expression of genes and enzymes associated with oestrogen synthesis has been noted in male mice48,49. Recently, it was demonstrated that the parasite could utilize sex hormone precursors from the host to synthesize sex hormones required for its own development and sustenance50. Another example of host factors involved in T. crassiceps infection is influence of the

human leukocyte antigen system10,11. Expression of the Qa-2, non-classic Class I major histocompatibility complex antigen was associated with resistance to T. crassiceps infection in BALB/cAnN mice10. An understanding of such protective genetic factors is likely to have an impact upon the development of genetically engineered animals, which are inherently resistant to cysticercosis, a novel strategy for its prevention and control.

Mesocestoides corti experimental cysticercosis Similar to T. crassiceps, intraperitoneal injection of the larval stage of the metacestode parasite, M. corti results in chronic infection in mice33,51,52. In nature, M. corti ova are believed to be ingested by terrestrial arthropods. An intermediate host such as the mouse or lizard then consumes the arthropod, where upon the oncosphere develops into the mature larva or metacestode53. Upon ingestion of the intermediate host by a carnivorous mammal such as dog, cat or skunk, a mature intestinal tapeworm develops releasing eggs and perpetuating the life cycle. M. corti infected mice develop splenomegaly and hepatomegaly, with encystment of the organism in the liver33,51,52.

Animal Models for Neurocysticercosis To study the immunological response in the brain during NC, we have developed a mouse model using M. corti and T. crassiceps metacestodes. Due to lack of CNS involvement in intraperitoneally infected mice, intracranial inoculation of the metacestodes was used to analyse immunological responses in CNS. This model has allowed us to follow the kinetics of immunological response in brain. With a view to parallel human disease, metacestodes were injected intracranially, avoiding penetration of brain parenchyma. Mice were sacrificed at different time points after

Animal Models of T. solium Cysticercosis

infection34. The associated pathological and immunological responses in the brain were analysed using haematoxylin and eosin staining (Fig. 4.1) and in situ immunohistochemistry of brain cryosections34.

39

M. corti metacestodes were found to be highly invasive. They infiltrated ventricles, subarachnoid spaces and brain parenchyma within days (Fig. 4.2). Pathological studies revealed presence of lesions with active

Fig. 4.1. Haematoxylin and eosin staining of a brain cryosection, 10 m in thickness. Mesocestoides corti metacestode is present in parenchyma associated with small inflammatory infiltrate shown by the long arrow. The short arrow demarcates a parasite in a lateral ventricle.

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80 P 60 EP 40

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0 2 days

1

3

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10

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Time p.i (weeks)

Fig. 4.2. Distribution of Mesocestoides corti larvae in the brain of BALB/c mice. Haematoxylin and eosin stained sections from infected mouse brains were analysed for the presence and location of larva. Parasites were counted and classified as P (parenchymal) or EP (extraparenchymal, i.e. located in ventricle, subarachnoid space or meninges). Each data point represents the average of three mice.

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necrosis in brain parenchyma (Fig. 4.3). An accumulation of inflammatory cells in the ventricles and meninges was noted (Fig. 4.4). Massive accumulation of gamma/delta T lymphocytes, macrophages, and to a lesser extent, dendritic cells, NK cells, mast cells and B cells was observed (Fig. 4.5). A Th1 pathway of cytokine expression was observed in the brain after M. corti infection with high levels of IL-2, IL-12, IL-15 and IFN- (Fig. 4.6). Importantly, Th2-related cytokines (IL-10 and IL-13) were either undetectable or found in very low levels (IL-4). Interestingly, gamma/delta T lymphocytes were found in the CNS by 2 days postinfection. These cells co-localized to areas where Th1 cytokines were detected34. The immunological response in the CNS in mice infected with T. crassiceps was similar with the exception that this organism was

larger and fewer organisms were able to penetrate brain parenchyma. In the mouse model, infection of CNS appears to induce initially an innate type of immunological response evidenced by the presence of neutrophils, macrophages and natural killer cells. By 3 days postinfection, an early-induced response develops with the added participation of large numbers of gamma/delta T cells. By 7 days postinfection, an adaptive immunological response is evident with parasite specific T and B cells. The immunological response that develops in mouse brain has been evaluated in both infected BALB/c and C57BL/6 mice. Little difference was found in the type of the cellular and cytokine response in the CNS in these two strains of mice. This is of interest since these two strains often differ dramatically in their response to infectious organisms such as Leishmania54,55.

(a)

(a)

(b)

(b)

Fig. 4.3. Haematoxylin and eosin staining reveal the presence of areas of active necrosis. (a) Hanks balanced salt solution inoculated mice do not reveal pathology showing normal parenchymal tissue. (b) The parasite (P) is associated with active areas of necrosis lacking cellularity (magnification: 150).

Fig. 4.4. Intense inflammatory response associated with parasite (P) in ventricle (a) and subarachnoid space (b) (magnification 150 in (a) and 100 in (b)).

Animal Models of T. solium Cysticercosis

41

4

Number of cells

3

2

1

0 2 days

5 days

1 Time p.i (weeks)

5

13

  CD19 Fig. 4.5. Immunological response in the brain after Mesocestoides corti infection. Two mouse brains obtained after intracranial inoculation with M. corti metacestodes were analysed by immunohistochemistry for the presence of various cell types. Cells in the extraparenchymal regions were counted, and the score given represents: 1–100 cells (1), 100–300 cells (2), 300–500 cells (3). The results represent the average of two mice.

4

Number of cells

3 2 1 0 2 days

5 days

1

5

13

Time p.i (weeks) IL-12 IL-4 Fig. 4.6. Predominance of a Th1 pathway of cytokine response in the brain after Mesocestoides corti infection. Results of immunohistochemical staining for IL-12 and IL-4 are shown. Cells were counted and scores given as described in Fig. 4.5. The results represent the average of two mice.

Data from the mouse model are consistent with previous reports of the cellular immunological responses in human brain.

Macrophages, NK cells and pro-inflammatory cytokines predominate with little or no detection of eosinophils, mast cells and IL-4

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production8. Within the brain, host responses to the parasite appears to be of Th1 inflammatory type in contrast to the Th2 response which is a characteristic response to helminths in peripheral extraneural tissue. However, as disease progresses with granuloma formation, a mixed Th1 and Th2 response is likely. The presence of gamma/delta T cells in large numbers predicts their important role in NC. In lymphoid tissues, gamma/delta T cells represent a minor proportion of T cells and their specific functions are uncertain56,57. We hypothesized that gamma/delta T cells play important immunoregulatory functions by producing cytokines that modulate the development of inflammatory response in CNS. Further studies in the animal model may improve our understanding of the role of this T cell subset in the human disease. The interactions between immunological cells and resident brain cells in the mouse model are of interest with specific reference to T cells. A question that needs to be answered is which antigens may be activating the gamma/delta T cell response? Previous studies have indicated that M. corti secretes a number of molecules when propagated in vitro58,59.

Two of these molecules are temperatureinduced heat shock proteins (hsps) of the hsp70 and hsp60 families58. Since gamma/delta T cells might be able to recognize whole proteins in an antibody-like manner60,61, M. corti hsps have a potential role in the development of an inflammatory response in the CNS. Furthermore, phospholipids have been found to induce specific expansion of human gamma/delta T cells62–64. Future studies with M. corti lipids may help define the mechanism by which the parasite induces an inflammatory response in the brain.

Conclusions Animal models contribute to the areas of parasite biology and immunology and are valuable for the recognition of new mechanisms involved in the host–parasite relationship during cestode infection. These models, and the data obtained from human studies will be critical for the understanding of the progression of the disease in the human host. The animal models hitherto described have been instrumental in the understanding of host–parasite interactions involved in NC.

References 1. Dixon, H., Lipscomb, F.M. (1991) Cysticercosis: an analysis and follow up of 450 cases. Medical Research Council Special Report Series. Her Majesty’s Stationery Office, London, 299, pp. 1–58. 2. Wiederholt, W.C., Grisiola, J.S. (1982) Cysticercosis: an old scourge revisited. Archives of Neurology 39, 533–535. 3. Shandera, W.X., White, A.C. Jr, Chen, J.C., et al. (1994) Neurocysticercosis in Houston, Texas: a report of 112 cases. Medicine 73, 37–52. 4. Ostrosky-Zeichner, P., Garcia-Mendoza, E., Rios, C., et al. (1996) Humoral and cellular immunological response within the subarachnoid space of patients with neurocysticercosis. Archives of Medical Research 27, 513–517. 5. White, A.C. Jr (2000) Neurocysticercosis: updates on epidemiology, pathogenesis, diagnosis, and management. Annual Review of Medicine 51, 187–206. 6. Cecilia, R. (1983) Clinical aspects, pathology and treatment of human cysticercosis. In: Flisser, A., Willms, K., Laclette, J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 179–199. 7. Correa, D., Dalma, D., Espinoca, B. (1985) Heterogeneity of humoral immunological components in human cysticercosis. Journal of Parasitology 71, 535–541. 8. Restrepo, B.I., Llaguno, P., Sandoval, M.A., et al. (1998) Analysis of immunological lesions in neurocysticercosis patients: central nervous system response to helminth appears Th1-like instead of Th2. Journal of Neuroimmunology 89, 64–72. 9. Grewal, J.S., Kaur, S., Bhatti, G., et al. (2000) Cellular immunological responses in human neurocysticercosis. Parasitology Research 86, 500–503.

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10. Frogoso, G., Lamoyi, E., Mellor, A., et al. (1996) Genetic control of susceptibility to Taenia crassiceps cysticercosis. Parasitology 112, 119–124. 11. Frogoso, G., Lamoyi, E., Mellor, A., et al. (1998) Increased resistance to Taenia crassiceps murine cysticercosis in Qa-2 transgenic mice. Infection and Immunity 66, 760–764. 12. Rickard, M., Williams, J. (1982) Hydatidosis/cysticercosis: immunological mechanisms and immunization against infection. Advances in Parasitology 21, 229–296. 13. Lloyd, S. (1987) Cysticercosis. In: Soulsby, E.J.L. (ed.) Immunological Responses to Parasite Infections, Vol. 2. CRC Press, Boca Raton, Florida, pp. 183–212. 14. Maravilla, P., Avila, G., Cabrera, V., et al. (1998) Comparative development of Taenia solium experimental models. Journal of Parasitology 84, 882–886. 15. Merchant, M.T., Aguilar, L., Avila, G., et al. (1998) Taenia solium: description of intestinal implantation sites in experimental hamster infections. Journal of Parasitology 84, 681–985. 16. Allan, J.C., Garcia-Dominguez, Craig, P.S., et al. (1991) Sexual development of Taenia solium in hamsters. Annals of Tropical Medicine and Parasitology 85, 473–477. 17. Garcia de Llano, C.A., Mateos, J.H., Rivas, A. (1989) Reacción inflamatoria en la neurocisticercosis estudio experimental en conejo. Archivos de Investigacion Medica (Mexico) 20, 61–68. 18. Sato, H., Oku, Y., Rausch, R.L., et al. (1993) Establishment and survival of the strobilar stage of Taenia crassiceps in hamsters, gerbils, and mice, with reference to different helminth isolates. Parasitology Research 79, 619–623. 19. Sato, H., Kamiya, H., Oku, Y., et al. (1994) Infection course of the strobilar stage of Taenia crassiceps in golden hamsters, with reference to host responses. Parasitology Research 80, 99–103. 20. Sato, H., Ihama, Y., Kamiya, H. (2000) Survival of destrobilated adults of Taenia crassiceps in T-celldepleted Mongolian gerbils. Parasitology Research 86, 284–289. 21. Flisser, A., Gonzalez, D., Shkurovich, M., et al. (1990) Praziquantel treatment of porcine brain and muscle Taenia solium cysticercosis. Parasitology Research 76, 263–269. 22. Flisser, A., Gonzalez, D., Plancarte, A., et al. (1990) Praziquantel treatment of brain and muscle porcine Taenia solium cysticercosis 2. Immunological and cytogenetics studies. Parasitology Research 76, 640–642. 23. Fan, P.C., Chung, W.C., Lin, C.Y., et al. (1990) The pig as an intermediate host for Taiwan Taenia infection. Journal of Helminthology 64, 223–231. 24. Kaur, M., Joshi, K., Ganguly, R., et al. (1995) Evaluation of the efficacy of albendazol against the larvae of Taenia solium in experimentally infected pigs, and kinetics of the immunological response. International Journal of Parasitology 25, 1443–1450. 25. Torres, A., Plancarte, A., Villalobos, A.N.M., et al. (1992) Praziquantel treatment of porcine brain and muscle Taenia solium cysticercosis 3. Effect of 1-day treatment. Parasitology Research 78, 161–164. 26. Gonzales, A.E., García, H.H., Gilman, R.H., et al. (1995) Treatment of porcine cysticercosis with albendazol. American Journal of Tropical Medicine and Hygiene 53, 571–574. 27. Gonzalez, A.E., Falcon, N., Gavidia, C., et al. (1998) Time–response curve of oxfendazole in the treatment of swine cysticercosis. American Journal of Tropical Medicine and Hygiene 59, 832–836. 28. Evans, C., Gonzales, A.E., Gilman, R.H., et al. (1997) Immunotherapy for porcine cysticercosis: implications for prevention of human disease. American Journal of Tropical Medicine and Hygiene 56, 33–37. 29. Gilman, R.H., García, H.H., Gonzales, A.E., et al. (1999) Short cuts to development: methods to control the transmission of cysticercosis in developing countries. In: García, H.H., Martinez, S.M. (eds) Taenia solium Taeniosis/Cysticercosis. Editorial Universo, Lima, Peru, pp. 313–326. 30. Cardenas, F., Plancarte, A., Quiroz, H., et al. (1989) Taenia crassiceps: experimental model of intraocular cysticercosis. Experimental Parasitology 69, 324. 31. Santos, A., Paczka, J.A., Jimenez-Sierra, J.M., et al. (1996) Experimental intravitreous cysticercosis. Graefe’s Archives of Clinical and Experimental Ophthalmology 234, 515–520. 32. Freeman, R.S. (1962) Studies on the biology of Taenia crassiceps. Canadian Journal of Zoology 40, 969–971. 33. Mitchell, G.F., Machalonis, J.J., Smith, P.M., et al. (1977) Studies on immunological responses to larval cestodes in mice. Immunoglobulins associated with the larvae of Mesocestoides corti. Australian Journal of Experimental Biology and Medical Science 55, 187–211. 34. Cardona, A.E., Restrepo, B.I., Jaramillo, J.M., et al. (1999) Development of an animal model for neurocysticercosis: immunological response in the central nervous system is characterized by a predominance of gamma/delta T cells. Journal of Immunology 162, 995–1002.

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35. Smyth, J.D. (1994) Introduction to Animal Parasitology. Cambridge University Press, New York, 1189 pp. 36. Terrazas, L.I., Bojalil, R., Govezensky, T., et al. (1998) Shift from an early protective Th1-type immunological response to a late permissive Th2-type response in murine cysticercosis (Taenia crassiceps). Journal of Parasitology 84, 74–81. 37. Villa, O.F., Kuhn, R.E. (1996) Mice infected with the larvae of Taenia crassiceps exhibit a Th2-like immunological response with concomitant anergy and downregulation of Th1-associated phenomena. Parasitology 112, 561–570. 38. Toenjes, S.A., Spolski, R.J., Mooney, K.A., et al. (1999) The systemic immunological response of BALB/c mice infected with larval Taenia crassiceps is a mixed Th1/Th2-type response. Parasitology 118, 623–633. 39. Robinson, P., Atmar, R.L., Lewis, D.E., et al. (1997) Granuloma cytokines in murine cysticercosis. Infection and Immunity 65, 2925–2931. 40. Mooney, K.A., Spolski, R.J., See, E.J., et al. (2000) Immunological destruction of larval Taenia crassiceps in mice. Infection and Immunity 68, 2393–2401. 41. Spolski, R.J., Corson, J., Thomas, P.G., et al. (2000) Parasite secreted products regulate the host response to larval Taenia crassiceps. Parasite Immunity 22, 297–305. 42. Garcia Tamayo, F., Terrazas Valdez, L.I. (1992) Immune response to parasitic infection in mice without seminal vesicles. Archives of Medical Research 23, 149–150. 43. Huerta, L., Terrazas, L.I., Sciutto, E., et al. (1992) Immunological mediation of gonadal effects on experimental murine cysticercosis caused by Taenia crassiceps metacestodes. Journal of Parasitology 78, 471–476. 44. Terrazas, L.I., Bojalil, R., Govezensky, T., et al. (1994) A role for 17-BETA-estradiol in immunoendocrine regulation of murine cysticercosis (Taenia crassiceps). Journal of Parasitology 80, 563–568. 45. Bojalil, R., Terrazas, L.I., Govezensky, T., et al. (1993) Thymus-related cellular immune mechanisms in sex-associated resistance to experimental murine cysticercosis (Taenia crassiceps). Journal of Parasitology 79, 384–489. 46. Larralde, C., Morales, J., Terrazas, L.I., et al. (1995) Sex hormone changes induced by the parasite lead to feminization of the male host in murine Taenia crassiceps cysticercosis. Journal of Steroid Biochemistry and Molecular Biology 52, 575–580. 47. Morales, J., Larralde, C., Arteaga, M., et al. (1996) Inhibition of sexual behaviour in male mice infected with Taenia crassiceps cysticerci. Journal of Parasitology 82, 689–693. 48. Morales-Montor, J., Rodriguez-Dorantes, M., Mendoza-Rodriguez, C.A., et al. (1998) Differential expression of the estrogen-regulated proto-oncogenes c-fos, c-jun, and bc1–2 and of the tumorsuppressor p53 gene in the male mouse chronically infected with Taenia crassiceps cysticerci. Parasitology Research 84, 616–622. 49. Morales-Montor, J., Rodriguez-Dorantes, M., Cerbon, M.A. (1999) Modified expression of steroid 5 alpha-reductase as well as aromatase, but not cholesterol side-chain cleavage enzyme, in the reproductive system of male mice during (Taenia crassiceps) cysticercosis. Parasitology Research 85, 393–398. 50. Gomez, Y., Valdez, R.A., Larralde, C., et al. (2000) Sex steroids and parasitism: Taenia crassiceps cysticercus metabolizes exogenous androstenedione to testosterone in vitro. Journal of Steroid Biochemistry and Molecular Biology 74, 143–147. 51. Johnson, G.W., Nicholas, D., Metcalf, D., et al. (1979) Peritoneal cell population of mice infected with Mesocestoides corti as a source of eosinophils. International Archives of Immunology 59, 315–317. 52. Chapman, C.P., Knopf, P., Hicks, J., et al. (1979) IgG1 hypergammaglobulinemia in chronic parasitic infections in mice: magnitude of the response in mice infected with various parasites. Australian Journal of Experimental Biology and Medical Science 57, 369–372. 53. Novak, M. (1972) Quantitative studies on the growth and multiplication of tetrathyridia of Mesocestoides corti (Hoeppli, 1925) (Cestoda: Cyclophyllidia) in rodents. Canadian Journal of Zoology 50, 1189–1199. 54. Heinzel, F., Sadick, M., Holaday, B., et al. (1989) Reciprocal expression of interferon-gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for the expansion of distinct helper T cell subsets. Journal of Experimental Medicine 169, 59–72. 55. Heinzel, F., Sadick, M., Mutha, S., et al. (1991) Production of interferon-gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proceedings of the National Academy of Sciences USA 88, 7011–7015. 56. Haas, W., Pereira, P., Tonegawa, S. (1993) Gamma/delta cells. Annual Review of Immunology 11, 637–685.

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57. Modlin, R.L., Pirmez, C., Horman, F.M., et al. (1989) Lymphocytes bearing antigen-specific gamma/delta T cell receptors accumulate in human infectious disease lesions. Nature 339, 8–12. 58. Estes, D.M., Teale, J.M. (1991) Biochemical and functional analysis of extracellular stress proteins of Mesocestoides corti. Journal of Immunology 147, 3926–3934. 59. Teale, J.M., Abraham, K.M. (1987) Regulation of antibody class expression. Immunology Today 138, 1699–1672. 60. Li, H., Lebedeva, M.I., Llera, A.S., et al. (1998) Structure of the Vdelta domain of the human gamma/delta T-cell receptor. Nature 391, 502–506. 61. Groh, V., Steinle, A., Bauer, S., et al. (1998) Recognition of stress-induced MHC molecules by intestinal epithelial gamma/delta T cells. Science 279, 1737–1739. 62. Morita, C., Beckman, E., Bukowski, J., et al. (1995) Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gamma/delta T cells. Immunity 3, 495–507. 63. Tanaka, Y., Morita, C., Nieves, E., et al. (1995) Natural and synthetic non-peptide antigens recognized by human gamma/delta T cells. Nature 375, 155–158. 64. Tanaka, Y., Sano, S., Nieves, E., et al. (1994) Nonpeptide ligands for human gamma/delta T cells. Proceedings of the National Academy of Sciences USA 91, 8175–8179.

5

Mitochondrial DNA of Taenia solium: From Basic to Applied Science

Akira Ito, Minoru Nakao, Munehiro Okamoto, Yasuhito Sako and Hiroshi Yamasaki

Introduction The mitochondrial genome has been sequenced and its variations have been established in humans and several other animal and plant species. Little is, however, known about mitochondrial DNA (mtDNA) of the parasitic flatworms, cestodes and trematodes1–4. While the study of human mitochondrial genome has led to the understanding of genetic basis of a wide range of diseases, a similar study in flatworms has important bearing upon three different areas of knowledge. First, variations in the mitochondrial genome of different species have been utilized for deducing phylogenic relationships and studying evolutionary sequences among different members of a phylum5–8. Secondly, the study of taeniid mtDNA has been useful in speciation as well as in elucidating similarities and differences between individual species. A good example has been the utilization of knowledge of mtDNA structure in establishing the status of a novel taeniid, Taenia saginata asiatica (see below). Finally, it could also provide insights into epidemiological aspects of pathogenicity and zoogeography of individual flatworms. Here, we review intra-species variations in relation to geographical location and molecular evolution of T. solium and their implications for the understanding of its pathogenicity and epidemiology.

Comparative Studies of mtDNA in T. solium, T. saginata and T. saginata asiatica Figure 5.1 depicts the molecular phylogeny of major cestodes. Taenia solium and T. saginata are well known cosmopolitan human tapeworms. In addition, a third taeniid, the Asian Taenia has been recognized lately. There is a high prevalence of this taeniid among aboriginal inhabitants of several East and Southeast Asian countries, including Korea, Taiwan, China, Malaysia, Thailand, Philippines and the Samosir Island of North Sumatra, Indonesia9–13. The Asian Taenia bears similarities to, and is different from both T. solium and T. saginata. It resembles the latter in morphology. However, a major distinguishing feature from T. saginata on one hand and a similarity to T. solium on the other hand is its utilization of swine and not cattle as intermediate hosts. However, it is not clear whether humans can also serve as intermediate hosts to Asian Taenia. Indeed, if human transmission were possible, cases of neurocysticercosis (NC) would abound in countries of East Asia. Fortunately, this is not the case. Two major factors account for the non-pathogenic nature of the Asian Taenia. Firstly, its metacestodes are far smaller in comparison to those of T. solium,

© CAB International 2002. Taenia solium Cysticercosis (eds G. Singh and S. Prabhakar)

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E. multilocularis

1000

E. granulosus LrRNA gene (377–387 bp)

T. hydatigena T. solium 956 1000

T. saginata T. asiatica

T. crassiceps T. pisiformis T. taeniaeformis

0.02

H. diminuta 669 986

H. nana H. microstoma M. corti M. expansa D. caninum 1000

D. latum D. ditremum

F. hepatica Fig. 5.1. A neighbour-joining phylogenic tree of 17 cestodes based on the sequences of partial LrRNA genes. Bootstrap values more than 500 are shown in the tree. The trematode, Fasciola hepatica served as an outgroup. The cestodes examined were Echinococcus multilocularis, E. granulosus, Taenia hydatigena, T. solium, T. saginata, T. asiatica, T. crassiceps, T. pisiformis, T. taeniaeformis, Hymenolepis diminuta, H. nana, H. microstoma, Mesocestoides corti, Moniezia expansa, Dipylidium caninum, Diphyllobothrium latum and D. ditremum.

a factor that may affect its potential to produce neurological symptoms. However, we have shown that larvae of the Asian Taenia can develop to 10 mm or larger in diameter in non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mice14. Secondly, while T. solium is neuro- and myotropic, the Asian Taenia is hepato- and viscero-tropic. In other words, in swine and possibly in humans, metacestodes of the latter are primarily found in the liver and viscera and not in the brain and muscles, as is the case with T. solium. Given the above background, controversy exists with regard to speciation of Asian Taenia

(T. asiatica vs. variant of T. saginata (T. saginata asiatica)),9–11 and also with reference to its potential to cause human cysticercosis12,13. Mitochondrial DNA analysis15–18 and comparative studies of morphology and development of metacestodes of each species in experimental animal models14,19–23 have provided preliminary insights into differences in the biological behaviour of the three human taeniids. Both suggest that the Asian Taenia is highly homologous to T. saginata, and although there are biological differences between the two9,14, T. asiatica should not be classified as a new species but rather a subspecies of T. saginata, i.e., T. saginata asiatica16–18,23.

Mitochondrial DNA of T. solium

Taenia solium mtDNA The structure of the mtDNA in T. solium and a related cestode, Echinococcus multilocularis has been recently established using polymerase chain reaction-amplification and nucleotide sequencing. Between the two species, there are minor variations in the size of the mitochondrial genome (13,709 bp in the case of T. solium and 13,738 bp for E. multilocularis) (M. Nakao et al., Asahikawa, unpublished observations). The heavy chains of the mtDNA of each have 12 genes encoding proteins, two ribosomal RNA (rRNA) genes and 22 transfer RNA (tRNA) genes (Fig. 5.2).

Gene order within mtDNA Gene sequences constituting mitochondrial genomes of various animal phyla are diagrammatically depicted in Fig. 5.3. From the

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illustration, it is clear that the gene arrangement in the T. solium mitochondrion is highly unique and differs from nematodes as well as other animal phyla. In studies performed on cestodes and trematodes, this unique arrangement has been found to be highly conserved24,35.

Initiating and stop codons The earliest breakthrough in the study of mtDNA of the phylum Platyhelminthes was the determination of the sequence and codon assignments of a 3.5 kb mtDNA segment of the trematode, Fasciola hepatica25–27,35. Bessho et al.27 partially sequenced the cytochrome c oxidase subunit I (COI) gene of mtDNA of the planaria, Dugesia japonica and proposed a unique genetic code for planarian mtDNA. The codon assignments of trematode and planarian are nearly similar except that the

Fig. 5.2. The mitochondrial genome of Taenia solium. Arrows indicate the direction of transcription (COI–III: cytochrome c oxidase subunits I–III; ND1–6 and 4L: NADH dehydrogenase subunits 1–6 and 4L; ATP6: ATPase subunit 6; LrRNA and SrRNA: large and small subunit rRNAs). Genes for tRNAs are indicated as abbreviated capital letters for amino acids. The gene arrangement of T. solium mtDNA is the same as those of Echinococcus multilocularis and T. crassiceps mtDNAs.

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Vertebrata Mus musculus (16,295 bp) Echinodermata S. purpuratus (15,650 bp) Arthropoda D. yakuba (16,019 bp) Nematoda Caenorhabditis elegans (13,794 bp) Platyhelminthes Taenia solium (13,709 bp) Fig. 5.3. The arrangements of protein and rRNA genes among representative metazoan mitochondrial genomes. The sites of tRNA genes are omitted from this figure. Arrows indicate the direction of transcription.

UAA codon specifies tyrosine in the latter. The codon sequences are unified into the mitochondrial code of the entire phylum Platyhelminthes, and its range is conceived to cover all three classes: Turbellaria, Trematoda and Cestoda. The genetic code is similar to that of echinoderm mitochondria5; however it differs from the universal code27. Our group28 recently found that GUG is an initiating methionine codon and UAA is a terminating codon (Table 5.1).

tRNA and rRNA genes Individual sizes of 22 tRNA genes identified in the cestode mtDNA range from 58 to 73 nucleotides (nt). The variations in length are mostly due to differences in stem and loop sizes of the D and T arms (M. Nakao et al., Asahikawa, unpublished observations). The nucleotide compositions of cestode and nematode mtDNAs are similar. However, the secondary structures of their tRNAs differ from each other. A majority of cestode tRNAs (18 out of 22) can be folded into conventional four-arm cloverleaf structures, whereas the remaining four [tRNASer(AGN), tRNASer(UCN), tRNAArg and tRNACys] have unorthodox structures wherein their D-arms

are unpaired and replaced by loops of 6–9 nt. This unorthodox structure, particularly in tRNAArg and tRNACys, has not been found in any other metazoan mitochondrion so far28. The cestode mtDNA contains genes for large and small subunit rRNAs (LrRNA and SrRNA) of mitochondrial ribosomes. The putative LrRNA and SrRNA genes are 983 and 704 nt long, respectively (M. Nakao et al., Asahikawa, unpublished observations). The length of these genes are similar to those of their nematode counterparts29 but are shorter than those of other metazoan mitochondrial rRNAs, so far reported. It is speculated that the compactness of the cestode rRNAs results from the pressure to minimize the size of the mitochodrial genome. Predicted secondary structures of cestode LrRNA and SrRNA are more similar to those of nematodes30 and trematodes2.

Polymorphism of T. solium: global variations A comparison of sequences of complete COI genes in different isolates of T. solium from Asia (China, India, Indonesia, Thailand), Africa (Mozambique, Tanzania) and Latin

Mitochondrial DNA of T. solium

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Table 5.1. The flatworm mitochondrial genetic code modified for cestodes. TTT TTC TTA TTG

Phe (F) Phe (F) Leu (L) Leu (L)

TCT TCC TCA TCG

Ser (S) Ser (S) Ser (S) Ser (S)

TAT TAC TAA TAG

Tyr (Y) Tyr (Y) Stop Stop

TGT TGC TGA TGG

Cys ( C ) Cys ( C ) Trp (W) Trp (W)

CCT CTC CTA CTG

Leu (L) Leu (L) Leu (L) Leu (L)

CCT CCC CCA CCG

Pro (P) Pro (P) Pro (P) Pro (P)

CAT CAC CAA CAG

His (H) His (H) Gln (Q) Gln (Q)

CGT CGC CGA CGG

Arg ( R ) Arg ( R ) Arg ( R ) Arg ( R)

ATT ATC ATA ATG*

Ile (I) Ile (I) Ile (I) Met (M)

ACT ACC ACA ACG

Thr (T) Thr (T) Thr (T) Thr (T)

AAT AAC AAA AAG

Asn (N) Asn (N) Asn (N) Lys (K)

AGT AGC AGA AGG

Ser (S) Ser (S) Ser (S) Ser (S)

GTT GTC GTA GTG*

Val (V) Val (V) Val (V) Val (V)

GCT GCC GCA GCG

Ala (A) Ala (A) Ala (A) Ala (A)

GAT GAC GAA GAG

Asp (D) Asp (D) Glu (E) Glu (E)

GGT GGC GGA GGG

Gly (G) Gly (G) Gly (G) Gly (G)

*Initiation codon.

America (Mexico, Ecuador and Peru) was undertaken18,24. Based upon the sequencing data, it was apparent that the Asian isolates differed from the African and American isolates (Fig. 5.4)24. We surmised that the similarities between African and American isolates could be related to a common ancestor or origin. Indeed, pigs were exported from Europe (perhaps, Spain or Portugal) to Africa and America from the 15th century onwards. Therefore, it is conceivable that African and American isolates of T. solium were introduced by European colonization. The hypothesized export phenomenon draws a parallel to the recent export of T. solium from Bali to Irian Jaya after the latter came under Indonesian control in 196911,31,32. The confirmation of the above hypothesis requires an analysis of the mtDNA of T. solium isolated from Europe and the demonstration of its similarity to American and African strains24. The demonstrated differences in the COI gene sequences between Asian and American–African isolates may be surmised to translate into different clinical implications. Indeed, there are differences in the clinical spectrum of NC between Asia and South America. For instance, parenchymal NC and subcutaneous cysticercosis are common while racemose cysticercosis is

rare in Asia. On the other hand, racemose cysticercosis is comparatively more common in Central and South America. Similarly, muscular cysticercosis leading to pseudohypertrophy has almost exclusively been reported from China and India and is uncommon in Central and South America. Furthermore, serological analysis of purified glycoproteins33 and the antigenic components of cyst fluid of T. solium cysticerci34 have revealed differences in the immunoblot profile of isolates from Ecuador and Mozambique on one hand and Irian Jaya, Indonesia and China on the other hand (Fig. 5.5; A. Ito et al., Asahikawa, unpublished data). An increasing amount of travel, immigration and refugeeism in the world is likely to dilute strict geographical predilections of any supposed strains and their different clinical and serological expressions. This is likely to interfere with the determination of a logical inference of phylogenic relationships between substrains as well as the study of epidemiology based on mitochondrial genomics. This however does not prevent us from forming a preliminary opinion that there are indeed at least two different substrains of T. solium based on differences in their mitochondrial genomes, biological and clinical behaviour.

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Mexico Peru

COI gene (1620 bp)

Tanzania 981

0.01 Da

A

Mozambique

Ecuador

Thailand 1000 Taenia solium

India

China 2

B

China 1 1000 Irian Jaya

1000

Taenia saginata

Taenia asiatica

Echinococcus multilocularis Fig. 5.4. A neighbour-joining phylogenetic tree of various isolates of Taenia solium. The tree was constructed from complete nucleotide sequences of COI genes. Bootstrap values are shown in the tree (group A: the African and Latin American isolates; group B: the Asian isolates).

Suggested Protocol for Collection of Material for mtDNA Studies While setting up a mitochondrial genomics laboratory is an elaborate affair, the collection of biological material is relatively simple. Viable segments or eggs from taeniasic individuals may be frozen or stored in 80–100% ethanol in a capped tube at 4°C for mtDNA studies. Viable T. solium eggs may also be prepared immediately from fresh segments. At our laboratory, oncospheres are hatched in vitro and inoculated into the peritoneal cavity of NOD-SCID mice to obtain well-developed cysticerci within a

few months14. Morphological, microscopic and mtDNA studies are then performed upon the larval stage with the intent of obtaining epidemiological, species and other biological data. Cysticerci resected either from the brain or subcutaneous tissue of humans may also be used as a source for mtDNA32.

Conclusions Most recently, the Asahikawa group in Japan has analysed the complete sequence of mtDNA of T. solium. The mtDNA of T.

Mitochondrial DNA of T. solium

Fig. 5.5. Immunoblot figures of cysticercosis patients from Latin America (Ecuador) reacting with various cyst fluid of Taenia solium from different continents. Lanes 1–4: Cyst fluid of T. solium from pigs in Ecuador (lane 1), in Irian Jaya, Indonesia (lane 2), in China (lane 3) and in Mozambique (lane 4).

solium consists of 13,709 bp and 12 protein genes, two rRNA genes and 22 tRNA genes located exclusively on the heavy chain. It uniquely uses GUG as an initiating methionine codon and UAA as a terminating codon. The unique codon usages are shared by

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other cestodes including E. multilocularis, E. granulosus and T. crassiceps. These cestodes have a unique gene order that is different from other animals except trematodes. MtDNA studies have established similarities between the Asian Taenia and T. saginata. Furthermore, sequencing of the complete COI gene has revealed differences between isolates of T. solium from Asia and those from Africa and America18,24. The genetic diversity may have important biological, serological and clinical implications and it is likely that the two geographical isolates have different ancestral origins. More such studies, from different geographical locations, particularly Europe, are required. The African and American isolates are believed to have arisen out of European colonization. Mitochondrial DNA studies may be the key to demonstrate a link between European and American–African substrains.

Acknowledgements This study was supported in part by grants from the Nissan Science Foundation and the Uehara Memorial Foundation, by a Grant-inAid for International Scientific Research (Joint Research, 06044089, 07044243, 09044279) and by a Grant-in-Aid for Scientific Research (A) 11694259, (B) 10557029, 12557024 to A. Ito and by a Grant-in-Aid for Scientific Research (C) 70155670 to M. Nakao.

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8. Boore, J.L. (1999) Animal mitochondrial genomes. Nucleic Acids Research 27, 1767–1780. 9. Fan, P.C. (1988) Taiwan Taenia and taeniasis. Parasitology Today 4, 86–88. 10. Eom, K.S., Rim, H.J. (1993) Morphologic descriptions of Taenia asiatica sp. North Korean Journal of Parasitology 31, 1–6. 11. Simanjuntak, G.M., Margono, S.S., Okamoto, M., et al. (1997) Taeniasis/cysticercosis in Indonesia as an emerging disease. Parasitology Today 13, 321–323. 12. Ito, A. (1992) Cysticercosis in Asia-Pacific regions. Parasitology Today 8, 182–183. 13. Galan-Puchardes, M.T., Fuentes, M.V. (1999) Human cysticercosis and larval tropism of Taenia asiatica. Parasitology Today 16, 174. 14. Ito, A., Nakaya, K., Sako, Y., et al. (2001) NOD-SCID mouse as an experimental animal model for cysticercosis. Southeast Asian Journal of Tropical Medicine and Public Health 32 (Suppl.), 85–89. 15. McManus, D.P. (1990) Characterization of taeniid cestodes by DNA analysis. Revue Scientifique et Technique 9, 489–510. 16. Bowles, J., McManus, D.P. (1994) Genetic characterization of the Asian Taenia, a newly described taeniid cestode of humans. American Journal of Tropical Medicine and Hygiene 50, 33–44. 17. Zarlenga, D.S., George, M. (1995) Taenia crassiceps: cloning and mapping of mitochondrial DNA and its application to the phenetic analysis of a new species of Taenia from Southeast Asia. Experimental Parasitology 81, 604–607. 18. Okamoto, M., Nakao, M., Sako, Y., et al. (2001) Molecular variation of Taenia solium in the world. Southeast Asian Journal of Tropical Medicine and Public Health 32 (Suppl.), 90–93. 19. Ito, A., Cheng, W.C., Chen, C.C., et al. (1997) Human Taenia eggs develop into cysticerci in SCID mice. Parasitology 114, 85–88. 20. Ito, A., Ito, M., Eom, K.S., et al. (1997) In vitro hatched oncospheres of Asian Taenia from Korea and Taiwan develop into cysticerci in the peritoneal cavity of female scid (severe combined immunodeficiency) mice. International Journal for Parasitology 27, 631–633. 21. Ito, A., Ma, L., Sato, Y. (1997) Cystic metacestodes of a rat-adapted Taenia taeniaeformis established in the peritoneal cavity of scid and nude mice. International Journal for Parasitology 27, 903–905. 22. Ito, A., Ito, M. (1999) Human Taenia in severe combined immunodeficiency (SCID) mice. Parasitology Today 15, 64–67. 23. Fan, P.C., et al. (1995) Morphological description of Taenia saginata asiatica (Cyclophyllidea: Taeniidae) from man in Asia. Journal of Helminthology 69, 299–303. 24. Nakao, M., Okamoto, M., Sako, Y., et al. (2002) A hypothesis for the distribution of two genotypes of the pork tapeworm Taenia solium worldwide. Parasitology 126 (in press). 25. Garey, J.R., Wolstenholme, D.R. (1989) Platyhelminth mitochondrial DNA: evidence for early evolutionary origin of a tRNASerAGN that contains a dihydrouridine arm replacement loop, and of serine-specifying AGA and AGG codons. Journal of Molecular Evolution 28, 374–387. 26. Ohma, T., Osawa, S., Watanabe, K., et al. (1990) Evolution of the mitochondrial genetic code IV. AAA as an asparagine codon in some animal mitochondria. Journal of Molecular Evolution 30, 329–332. 27. Bessho, Y., Ohama, T., Osawa, S. (1992) Planarian mitochondria II. The unique genetic code as deduced from cytochrome c oxidase subunit I gene sequences. Journal of Molecular Evolution 34, 331–335. 28. Nakao, M., Sako, Y., Yokoyama, N., et al. (2000) Mitochondrial genetic code of cestodes. Molecular Biochemistry and Parasitology 111, 415–424. 29. Okimoto, R., Macfarlane, J.L., Clary, D.O., et al. (1992) The mitochondrial genomes of two nematodes, Caenorhabditis elegans and Ascaris suum. Genetics 130, 471–498. 30. Okimoto, R., Macfarlane, J.L., Wolstenholme, D.R. (1994) The mitochondrial ribosomal RNA genes of the nematodes Caenorhabditis elegans and Ascaris suum: consensus secondary-structure models and conserved nucleotide sets for phylogenetic analysis. Journal of Molecular Evolution 39, 598–613. 31. Schantz, P.M., Wilkins, P.P., Tsang, V.C.W. (1998) Immigrants, imaging and immunoblots: the emergence of neurocysticercosis as a significant public health problem. In: Scheld, W.M., Craig, W.A., Hughes, J.M. (eds) Emerging Infections 2. ASM Press, Washington, DC, pp. 213–242. 32. Wandra, T., Subahar, R., Simanjuntak, G.M., et al. (2000) Resurgence of cases of epileptic seizures and burns associated with cysticercosis in Assologaima, Jayawijaya, Irian Jaya, Indonesia, 1991–95. Transactions of the Royal Society of Tropical Medicine and Hygiene 94, 46–50.

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Ito, A., Sako, Y., Nakao, M., et al. (1999) ELISA and immunoblot using purified glycoproteins for serodiagnosis of cycsticercosis in pigs naturally injected with Taenia solium. Journal of Helminthology 73, 363–365. 34. Ito, A., Plancarte, A., Ma, L., et al. (1998) Novel antigens for neurocysticercosis: simple method for preparation and evaluation for serodiagnosis. American Journal of Tropical Medicine and Hygiene 59, 291–294. 35. Ito, A., Plancarte, A., Nakao, M., et al. (2002) Neurocysticercosis in Asia: serology/seroepidemiology in humans and pigs. In: Craig, P., Pawlowski, Z. (eds) Cestode Zoonoses: Echinococcosis and Cysticercosis – an Emergent and Global Problem. IOS Press, Amsterdam, pp. 25–31. 36. Le, T.H., Blair, D., Agatsuma, T., et al. (2002) Phylogenies inferred from mitochondrial gene orders – a cautionary tale from parasitic flatworms. Molecular Biology and Evolution 17, 1123–1125.

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Hereditary Factors in Neurocysticercosis with Emphasis on Single, Small, Enhancing CT Lesions Vasantha Padma, Satish Jain, Achal Srivastava, Manjari Tripathi and Mahesh C. Maheshwari

Introduction Most human disorders are a result of an interaction between environmental and genetic factors. In certain diseases, there is a dominant genetic influence and environmental agencies exert a modulating influence. In others, the primary cause is an environmental agent, most often a microbial, toxic or an immune element, but in addition, there is a small but definite genetic predisposition. A number of infectious and inflammatory disorders fall into the latter category. Significant in this context is the predisposition conferred by the major histocompatibility complex, also known as the ‘human leucocyte antigen (HLA)’ on chromosome 61. Different alleles of the HLA genes either predispose or protect against specific disorders. Multiple sclerosis, systemic lupus erythematosus and diabetes are examples of such disorders2–4. Neurocysticercosis (NC) is a somatic form of taeniasis that is acquired by ingestion of Taenia solium eggs. Environmental factors including poor personal hygiene, improper sanitation and inadequate pig husbandry are primary reasons for its occurrence. The role of genetic factors in NC has not been sufficiently recognized. It might be interesting to postulate the existence of genetic influence, that predisposes certain populations to acquire T. solium cysticercosis, and among

these, subpopulations to exhibit differences in disease manifestations and behaviour. On a different note, the study of genetic factors may also unravel novel control strategies of developing genetically engineered pigs that are resistant to cysticercosis and can effectively check the human–environment–pig– human cycle. The study of genetic influences in human T. solium cysticercosis is at a preliminary stage. In this review, we present some of our data on HLA studies in single, small, enhancing CT lesions (SSECTLs)5,6 and review some of the published human7 and experimental evidence8,9 of the influence of the major histocompatibility complex in disease acquisition.

HLA Studies in SSECTL Aetiology of SSECTL Computed tomography (CT) often demonstrates SSECTLs or the so-called ‘disappearing CT lesions’ in individuals with recent seizures in several developing countries, including India. These lesions are seen to be associated with a benign form of seizure disorder. Rajshekhar has reviewed the events that led to the recognition of the aetiological agent for SSECTL. The reader is referred to

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Chapter 24 for a review of aetiological considerations. Current opinion links an overwhelming majority of the SSECTLs to T. solium cysticercosis. This has been based upon histological findings, which have been summarized in this book by Chacko (see Chapter 31). However, other aetiological agents such as tuberculosis, brain abscesses and miscellaneous inflammatory conditions cannot be completely disregarded10.

HLA studies We performed HLA studies in 63 Indian probands with seizures and SSECTL, and also studied the occurrence of seizure types among their family members5. All probands included in the study were clinically evaluated by one of the three authors (SJ, MCM, and VP). Family pedigrees were drawn to include all the first- and second-degree relatives of the probands. Information on affected relatives was collected and, wherever possible, the affected relatives were examined in the outpatient clinic. All probands and affected relatives underwent electroencephalographic evaluations. CT scan was done when possible and indicated. All 63 patients and 340 healthy controls were serologically tested using complement mediated standard micro-lymphotoxicity test for HLA-A, HLA-B and HLA-C antigens. We found a positive family history of seizures among 16 out of 63 (25%) probands with SSECTL. Among affected relatives, 13% had symptomatic generalized epilepsy. A SSECTL was noted in four relatives (17%). The occurrence of different epileptic syndromes among the relatives prompted us to consider either a genetic contribution in the aetiopathogenesis of this syndrome or a hereditary susceptibility to an environmental agent5. Further, preliminary results of HLA class I studies revealed that the frequencies of HLAA11 were decreased, whereas those of HLAB63 and HLA-B58 were increased in probands, when compared with healthy controls (the values were not significant after application of correction factor for P value). Among HLA class II antigens (tested subse-

quently in 41 randomly selected probands), HLA-DR B1*13 occurred in 29.3% of probands in comparison to 9.7% in healthy controls (2 = 10.35; Pc = 0.036; relative risk (RR) = 3.83). In addition, HLA-DR B1*09 was observed with an increased frequency in probands (7.3 vs. 1.3%; 2 = 4.69; RR = 6). No other class II antigens deviated significantly from control5. The HLA Class II genomic typing results in our patients are statistically significant. These associations may be surmised to be an indicator of susceptibility to an infection or infestation in Indian patients with seizures. From a different viewpoint, our report adds to the list of results associating different class I and class II alleles with epileptic syndromes such as juvenile myoclonic epilepsy, Lennox–Gastaut syndrome and severe myoclonic epilepsy in infants11–17. We hypothesized that the condition to which we have been assigning different names is actually an ‘imaging phenotype’. This CT lesion represents a benign epileptic syndrome that occurs predominantly in Asian Indians. The results of our preliminary study prompted us to investigate further, hereditary factors in this syndrome. We reported clinical features in 235 Indian probands with seizures in association with SSECTL along with those in their family members6. HLA class II antigen frequencies were further studied in 41 randomly selected probands. A total of 235 individuals with SSECTL were followed at the outpatient clinic of the Neurology Department, Neurosciences Center, All India Institute of Medical Sciences, New Delhi. These patients represented the ethnic groups of North Indian Hindus. Follow-up CT scan revealed complete or nearly complete (only a residual calcified dot) spontaneous resolution of the lesion in all cases with no specific therapy. Individuals in whom the CT lesion resolved while they were taking antitubercular or anticysticercal drugs, antibiotics and steroids were excluded6. Family history of seizures was considered positive when one or more first- or second-degree relative had seizures. Family pedigrees were similarly drawn for probands having other neurological disease, for instance, muscular dystrophy, to determine the occurrence of seizures in their fam-

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ily members. The affected relatives with seizures in these families also were examined in the same way as the affected relatives of probands. The 41 patients (from a total 235) included for HLA-DR typing were unrelated and randomly selected. HLA-DR typing also was performed on 154 healthy controls (from the same ethnic groups living in the same geographic region)18. A history of seizures was documented among first- and second-degree relatives of 50 (21%) probands. A first-degree relative was affected in 35 and a second-degree relative in 15 probands. Thirty-eight (3%) of 1212 first-degree relatives and 28 (0.8%) of 3379 second-degree relatives were affected. Therefore, the ratio of affected firstdegree : second-degree relatives was 4.3 : 1. Localization-related epilepsies were more common among first-degree relatives (P0.05), whereas generalized epilepsies were more often noted among second-degree relatives (P0.01). Interestingly, seven of 35 first-degree relatives had seizures in association with SSECTL compared with only one of 15 second-degree relatives. Other syndromes were almost equally distributed among the relatives. Among affected firstdegree relatives, seven had localizationrelated epilepsy, while five had SSECTL. Among 1587 first- and 3797 second-degree relatives of 212 controls with neurological diseases other than epilepsy, 20 first- and four second-degree relatives had epilepsy. Affected probands had a significantly higher frequency or a positive family history in comparison to controls6. HLA-DR B1*13 was expressed in 29.3% of probands in comparison to 97% in healthy controls (2 = 10.35; RR = 3.83). On the other hand, HLA-DR B1*09 was observed with an increased frequency in probands (7.3 vs. 1.3%; 2 = 4.69; RR = 6). None of the other class II antigens tested revealed any significant deviation in patients as compared to controls6. Several previously published reports suggest a role of the HLA system in different epileptic syndromes11,13,14,19,20. Juvenile myoclonic epilepsy was shown to be linked to the BF and HLA loci on human chromosome 6 in two population groups from the United States and Germany, and HLA-DRW

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13 in Arab patients14,19,20. Some ‘genes’ predisposing to the susceptibility to seizures may be located near the HLA locus. From this viewpoint, seizures in association with SSECTL in Asian Indians may represent a genetically determined predisposition to a unique benign epileptic syndrome with particular imaging characteristics.

HLA Studies in Human Neurocysticercosis From a contrasting point of view to that presented above, HLA associations have been reported with other infective diseases such as leprosy, tuberculosis and cysticercosis7,21,22. Del Brutto et al. reported significantly increased frequency of HLA-A28 and decreased frequency of HLA-DQW2 in a Mexican cohort with parenchymal NC7. The authors surmised that HLA-A28 confers susceptibility to NC, while HLA-DQW2 accords resistance. With a similar view, our results of HLA studies in the Indian probands with SSECTLs point to an increased susceptibility to an infective agent such as cysticercosis. It is also possible that affected relatives of individuals with SSECTLs were exposed to the common causative agent (through food and water for cysticercosis). The high prevalence of seizures among first-degree relatives could also be reflection of an exposure to a common environmental agent.

Experimental Evidence for a Genetic Contribution Fragoso et al. investigated the influence of nonclassic Class I MHC Qa-2 antigen expression and acquisition of T. crassiceps cysticercosis in mice8. The authors found that the BALB/cAnN substrain of mice, which did not express Qa-2 antigen was highly susceptible to infection, while another substrain BALB/cJ, which expressed Qa-2 was resistant to T. crassiceps cysticercosis. In further experiments, Qa-2 transgenic mice (C57BL/67/BALBcAnN) were backcrossed to BALB/cAnN mice and then infected with T. crassiceps9. A significantly lower yield of cysticercus larvae was noted in

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the Qa-2 transgenic mice than in non-transgenic mice. These studies have established a definite relationship between Qa-2 antigen expression and resistance to infection with T. crassiceps cysticercosis in mice. Furthermore, human Class I MHC, HLA-G has been suggested to be functionally similar to murine Qa-2. The experimental data outlined above are significant for the understanding of factors that lead to resistance or susceptibility to cysticercosis.

Conclusions Several HLA molecules have been demonstrated to confer susceptibility or resistance to cysticercosis in humans with SSECTLs, NC and in experimental models of a related cysticercus. The identification of these genetic factors offers the promise of developing strategies for inducing resistance to cysticercosis through genetic manipulation.

References 1. Robinson, J., Waller, M.J., Parham, P., et al. (2001) IMGT/HLA database – a sequence database for the human major histocompatibility complex. Nucleic Acids Research 29, 210–213. 2. Ruiz, N., Giudecelli, V., Ginestoux, C., et al. (2000) IMGT, the international immunogenetics database. Nucleic Acids Research 28, 219–221. 3. Nepom, G.T., Nepom, B.S. (1992) Prediction of susceptibility to rheumatoid arthritis by human leukocyte antigen genotyping. Rheumatic Diseases Clinics of North America 18, 785–794. 4. Subbah, I., Savola, K., Ebeling, T., et al. (2000) Genetic, autoimmune and clinical characteristics of childhood- and adult-onset type 1 diabetes. Diabetes Care 23, 1326–1332. 5. Jain, S., Padma, M.V., Kanga, U., et al. (1997) Human leukocyte antigen studies in Indian probands with seizures associated with single small enhancing computed tomography lesions and seizure types in their family members. Journal of Epilepsy 10, 55–61. 6. Jain, S., Padma, M.V., Kanga, U., et al. (1999) Family studies and human leukocyte antigen class II typing in Indian probands with seizures in association with single small enhancing computed tomography lesions. Epilepsia 40, 232–238. 7. Del Brutto, O.H., Granados, G., Talamas, O., et al. (1991) Genetic pattern of the HLA system: HLA A, B, C, DR, DQ antigens in Mexican patients with parenchymal brain cysticercosis. Human Biology 63, 85–93. 8. Frogoso, G., Lamoyi, E., Mellor, A., et al. (1996) Genetic control of susceptibility to Taenia crassiceps cysticercosis. Parasitology 112, 119–124. 9. Frogoso, G., Lamoyi, E., Mellor, A., et al. (1998) Increased resistance to Taenia crassiceps murine cysticercosis in Qa-2 transgenic mice. Infection and Immunity 66, 760–764. 10. Padma, M.V., Behari, M., Misra, N.K., et al. (1994) Albendazole in single CT ring lesions in epilepsy. Neurology 44, 1344–1346. 11. Durner, M., Janz, D., Zingsem, J., et al. (1992) Possible association of juvenile myoclonic epilepsy with HLA-DRw6. Epilepsia 33, 814–816. 12. Arali, J.A. (1993) Immunological aspects of epilepsy. Brain Development 15, 41–49. 13. van Engelen, B.G., de Waal, L.P., Weemeas, C.M., et al. (1994) Serologic HLA typing in cryptogenic Lennox Gastaut syndrome. Epilepsy Research 17, 43–47. 14. Obeid, T., el Rab, M.O., Daif, A.K., et al. (1994) Is HLA-DRw13 (W6) associated with juvenile myoclonic epilepsy in Arab patients? Epilepsia 35, 319–321. 15. Moen, T., Brodtkorb, E., Michler, R.P., et al. (1995) Juvenile myoclonic epilepsy and human leukocyte antigens. Seizure 4, 119–122. 16. Oguni, H., Uehara, T., Fzumi, T., et al. (1995) Immunogenetic study of patients with severe myoclonic epilepsy in infants and its variant. Epilepsia 36 (Suppl. 3), S9–10. 17. Suastegui, R.A., De la Rosa, G., Fonzalez-Austiazaran, A., et al. (1995) HLA – class II genetic markers are involved in resistance/susceptibility for the expression of massive spasm. Epilepsia 36 (Suppl. 3), S10. 18. Mehra, N.K., Verduijn, W., Taneja, V., et al. (1991) Analysis of HLA-DR2 associated polymorphism by oligonucleotide hybridization in an Asian Indian population. Human Immunology 32, 246–253. 19. Greenberg, D.A., Delgado-Escueta, A.V., Widlitz, H., et al. (1988) Juvenile myoclonic epilepsy may be linked to the BF and HLA loci on human chromosome 6. American Journal of Medical Genetics 31, 185–192.

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20. Liu, A.W., Delgado-Escueta, A.V., Serratose, J.M., et al. (1995) Juvenile myoclonic epilepsy locus in chromosome 6p21.2–p11: linkage to convulsions and electroencephalographic trait. American Journal of Human Genetics 57, 368–381. 21. Zerva, L., Ciznam, B., Mehra, N.K., et al. (1996) Arginine at positions 13 or 70–71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy. Journal of Experimental Medicine 183, 829–836. 22. Rajalingam, R., Mehra, N.K., Jain, R.C., et al. (1996) Polymerase chain reaction-based sequence specific oligonucleotide hybridization analysis of HLA class II antigens in pulmonary tuberculosis: relevance to chemotherapy and disease severity. Journal of Infectious Diseases 173, 669–676.

7

Taenia solium Cysticercosis: an Overview of Global Distribution and Transmission Peter M. Schantz

Introduction

History

Taeniasis/cysticercosis caused by Taenia solium, often referred to as the pork tapeworm, is a classical zoonosis, recognized since antiquity, which, as a result of a variety of demographical, technological and political factors, has emerged as an increasingly important disease in regions where it has long been endemic, as well as in regions into which it has been imported or introduced. The two-host life cycle of the tapeworm involves humans as definitive hosts and swine as intermediate hosts. Infected pigs are the source of human taeniasis, an intestinal tapeworm infection acquired by eating undercooked pork contaminated with cysticerci, the larval stage of the cestode. Cysticercosis, however, is acquired by ingesting Taenia eggs shed in the faeces of a human tapeworm carrier and thus may occur in humans who neither eat pork nor share environments with pigs. Although cysticerci may localize throughout the body, most clinical manifestations result from their presence in the central nervous system (neurocysticercosis (NC)), where they can cause seizures, hydrocephalus and other neurological disorders1.

Prominently visible in both its intestinal and tissue stages, the macroparasite T. solium has been known since the earliest times. Spontaneous elimination of individual tapeworm segments was alluded to by writers at the beginnings of recorded history2. The ancient Greeks made reference to ‘measles’ in pork, which were in fact larval cysticerci; however, their significance was not understood. Aristotle compared their appearance to hailstones; he and others regarded them as worm-like animals. In the 16th century, European pathologists associated the condition with disease in humans and described cysticerci in the brains of epileptic persons. By the mid-19th century a number of investigators had demonstrated the link between cystic and strobilar (intestinal) forms of several species of Taenia by showing that cystic forms metamorphosed into adult worms when ingested by suitable hosts. This relationship for T. solium was confirmed in 1855 by Küchenmeister who administered cystinfected pork to a condemned criminal and observed developing adult forms in the man’s intestine after his execution2. About the same time, van Beneden in Belgium

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demonstrated that he could produce cysticerci in the muscles of pigs by feeding them T. solium eggs obtained from tapeworm segments passed by infected humans. Further studies confirmed that humans alone were the definitive host of the worm and pigs were the only significant intermediate host; thus, the reasons for the well-recognized paucity of infection in Moslems and Jews, for whom Mosaic laws forbade the ingestion of pork, could then be understood. Scattered reports suggest that the infection was prevalent in pigs and in humans in various parts of the world; however, highest rates of transmission most likely occurred in populations with the poorest recorded medical documentation. During the first half of the 19th century, approximately 2% of postmortem examinations of humans conducted in Berlin, Germany, revealed cysticercosis and details of the clinical and pathologic characteristics of NC were extensively described in German medical literature by the turn of the 20th century3. Although the infection has been virtually eliminated from Germany and

most of the rest of Western Europe, similar or higher prevalence rates have been documented recently in parts of Africa, Asia, and Central and South America4. Improvements in diagnosis (neuroimaging methods and specific antibody detection) have revolutionized the antemortem recognition of this disease, thus improving our understanding of the nature of the disease and its true prevalence while large-scale migration of populations in modern times have continued to expand its distribution.

Geographic Distribution Taenia solium infection is widely endemic in rural areas of developing countries in Central and South America, Asia and Africa (Fig. 7.1). Published reports document the occurrence of clinical NC in most of the countries of the Americas (most notably Mexico, Guatemala, El Salvador, Honduras, Colombia, Ecuador, Peru, Bolivia and Brazil). The infection was reported to be present in

Fig. 7.1. Approximate global geographic distribution of Taenia solium.

Global Distribution and Transmission

18 countries of South and Central America whose combined populations represented 94% of the total 1980 population of the Latin American countries5. Of the American countries, only Canada, the United States, Argentina and Uruguay appear to be free of transmission in the pig–human cycle; however, these latter countries are observing an increase in imported and introduced infections related to immigration of persons from neighbouring countries where T. solium infection is endemic4. No information is available concerning the occurrence, or absence, of infection in Guyana, Suriname and French Guiana. In Asia, most available data are from clinic-based populations and, consequently, are biased in terms of the true geographic origin and epidemiologic factors associated with transmission. Transmission in much of Asia is strongly influenced by prevailing cultural practices and socio-economic conditions. In India, for example, intestinal-stage T. solium infections occur mainly in pork-eating populations, particularly in rural populations and lower socio-economic classes; 78% of children of pig farmers were reported to be passing taeniid eggs6,7. Vegetarian populations are presumably exposed to cysticercosis through direct and indirect contact with Taenia carriers. The vast majority of clinical cases reported in India are of the single-lesion variety with relatively mild symptoms and benign outcome; these are believed to be associated with exposure to eggs in contaminated foodstuffs or other indirect exposure to tapeworm carriers8. Curiously, the greatest number of cases of the rare, massive, disseminated form of the disease have also been reported from India; the explanations for these extremes are unknown9. As might be expected, there are no reports from the strictly Moslem countries of Iran, Pakistan, Afghanistan and Bangladesh. Human NC is reported widely from China and parts of Korea. It is known to occur also, although few published data are available, in the Southeastern Asian countries of Myanmar, Cambodia, Laos, Vietnam and parts of the Philippines. In Indonesia, T. solium infection is endemic in parts of numerous islands including Sumatra, Bali,

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West Kalimantan, Sulawesi, Flores, East Timor and Irian Jaya10,11. The cestode was apparently introduced into Irian Jaya in recent times when swine from Bali were translocated to (former) West New Guinea12. Improvements in socio-economic conditions were associated with reduction or disappearance of the infection in Japan, Taiwan, Hong Kong, Singapore, and Thailand, where, in recent years, most cases diagnosed were apparently imported. In Africa, T. solium is transmitted throughout most of the continent with the exception of the strictly Muslim areas of North and sub-Saharan Africa. NC is an important cause of neurological disability in regions of Africa in which it has been studied; epilepsy in several countries has been documented to be caused by T. solium infection in 30–51% of cases13. In Africa, as in Asia, subcutaneous localization of cysticerci, concomitant with intracerebral infection, is common (30%); this is in contrast to the infection in American countries where subcutaneous localization in patients with NC is relatively rare4. Because of the limited development of medical and sanitary infrastructure, the impact of the disease may be underestimated to a greater degree than in other regions. The widespread absence of sanitary services, especially adequate disposal of human excrement, and the frequent practice of allowing pigs to roam free, permits transmission of T. solium in most of the regions. Controlled slaughter of swine is rarely practised and consequently cysticerci-infected pork is generally consumed by humans who either ignore or are ignorant of its significance14,15. In South Africa, Zimbabwe and Madagascar where medical services are relatively sophisticated, NC has long been a subject of scientific reports16–19; from other regions, however, there are very limited data because of the lack of diagnostic facilities. NC is reportedly a common clinical entity in many countries of West Africa (Senegal, Benin, Ivory Coast, Togo, Ghana) and Central Africa (Zaire, Cameroon, Burundi and Rwanda)20. Few reports of NC in humans in East Africa have been documented; however, a recent report of T. solium cysticercosis in 13% of pigs slaughtered in

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three abattoirs in Tanzania suggests that the cestode occurs in at least some regions21. There is increasing recognition that the medical and economic costs of T. solium cysticercosis are greatly underestimated in countries like Tanzania, Zambia, Zimbabwe and South Africa and efforts are underway to document these costs and to organize effective methods of prevention and control (A.L. Willingham, Frederiksberg, Denmark and R.C. Krecek, Onderstepoort, South Africa, personal communication, 2000). Historically, T. solium occurred widely in European countries; indeed, many of the earliest recorded observations about the parasite and its life cycle were reported by European authors2. In the mid-19th century, it was reported that cysticerci were observed in 2% of autopsied human cadavers in Germany and infections were commonly observed in swine at slaughter2. The same was apparently true in many countries of the continent. Today, as a result of improvements in swine husbandry, sanitation and hygiene, the infection has largely disappeared; however, locally acquired infections are still occasionally reported from Spain (Castilla, Extremadura and Andalucia)22,23, northern Portugal24, southern Italy25 and Poland (Z. Pawlowski and A. Ramisz, Poznan, Poland, personal communication, 1997), indicating persisting foci of transmission in some regions.

Prevalence Data Until recently, the only available quantitative data on cysticercosis from any country were clinic-based statistics on the frequency of NC among hospital patients or autopsied cadavers. In Mexico, for example, NC has long been considered to have an important impact on health services expenditures. Through the 1980s, this diagnosis accounted for nearly 9% of admissions in neurology and neurosurgical services and was the final diagnosis in 11–25% of patients operated on for removal of brain tumours1. NC was found in 2.8–3.6% of all autopsies in Mexico City hospitals and was reported as the cause of death in 0.6–1.5% of hospitalized patients. Similar statistics documenting the frequency of clinical

diagnoses of NC have been reported from many other countries; however, such statistics are misleading because differences in availability of medical services and lack of comprehensive and consistent reporting in most countries confound attempts to compare incidence and prevalence between countries and, within a country, between rural and urban areas. For example, extensive documentation in the medical literature on the occurrence of NC in Mexico over many years might have suggested that the disease was more prevalent there than in neighbouring countries; however, recent surveys using modern diagnostic techniques reveal that the prevalences of T. solium infection in some countries of the region exceed rates in Mexico by considerable margins (Table 7.1). In all countries, improved diagnostic technology, new options for treatment, and greater awareness of cysticercosis by the medical and public health communities have resulted in documentation of increased numbers of cases diagnosed in traditional disease-endemic areas as well as new disclosures of active transmission from regions where the disease was previously unrecognized or not reported. Recent surveys and epidemiological studies, using state-of-the-art diagnostic methods26, have begun to document the occurrence of the infection and its impact on affected populations. Table 7.1 compares recent prevalence estimates for T. solium cysticercosis and taeniasis in humans and cysticercosis in pigs in surveys of community-based population samples in Latin America in which comparable diagnostic methods were used27–40. Prevalence varied among communities; however, a consistent relative pattern of prevalence ratios of the different forms of infection has been observed. Prevalences of intestinal stage infection (taeniasis) are relatively low; however, rates of cysticercosis in humans and pigs are usually related quantitatively to the rates of taeniasis. People in affected communities are not usually aware that the parasitic cysts they see in the meat of pigs is the cause of seizures and other neurological disorders; however, use of modern serological and imaging diagnostic technology has identified NC as the most important contributor to the

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Table 7.1. Prevalence estimates of Taenia solium cysticercosis and taeniasis in humans and pigs in Latin American communities.

Country

Community

Mexico

Angahuan

SeroPrevalence prevalence of Prevalence Sample (EITB1) taeniasis in pigs size (%) (%) (%) Reference 10.8

0.3e

4.0t

Sarti et al., 1992, 199428,27

1005

4.9

0.2e

6.5t

Sarti et al., 199229

1552

Mexico

Xoxocotla

Guatemala

Quesada

862

11.0

1.0c,e

4.0t

Allan et al.,199630, Garcia Noval et al., 200131

Guatemala

El Jocote

955

20.0

2.8c,e

14.0t

Allan et al.,199630, Garcia-Noval et al., 200131

0

n.d.

Military recruits

Ï urban (363) Ì rural Ó (41)

15.0

Honduras

22.0

0.6e

n.d.

Sanchez et al., 199832

Honduras

Agua Caliente

68 536

34.0

1.5e

n.d.

Sanchez et al., 199733

Honduras

Salama County

480

17.0

2.5e

27.1t

Sanchez et al., 199934 , Sakai et al., 199835

Bolivia

‘rural community’

159

22.6

n.d.

38.9i

Tsang and Wilson, 199536

Ecuador

San Pablo del Lago

118

10.4

n.d.

7.5t

Cruz et al., 199837

Peru

Lima (urban)

250

0

n.d.

0

Tsang and Wilson, 199536

Peru

Maceda

371

8.0

0.3e

43.0i

Diaz et al., 199238 García et al., 199639

Peru

Churusapa

134

7.0

n.d.

49.0i

Peru

Haparquilla

108

13.0

n.d.

46.0i

García et al., 199639

Peru

Monterredonda

489

16.0

n.d.

13.0i

García et al., 199639

18.0

n.d.

60–70i

García et al., 199639

24.0

8.6i

36.0i

García et al., 199639, 199940

Peru Peru

Quilcas Saylla

99

Notes: 1. EITB: enzyme-linked immunoelectrotransfer blot. 2. Prevalence of antibodies to cysticercosis measured in humans by EITB assay (Reference 26). 3. Prevalence of taeniasis measured by examination of faecal specimens for eggs e or coproantigensc or both. 4. Prevalence of cysticercosis in pigs measured by visual examination and palpation of tongue t or detection of antibodies by EITB assay i. 5. n.d.: not done.

high rates of epilepsy and migraine headaches in many regions where T. solium infection is endemic. For example, in community-based studies from Mexico, Guatemala, Honduras, Ecuador and Peru, large proportions of persons with histories of seizures had

serological (21–34%) or neurological imaging (54–70%) evidence of NC31,37,41. It is important to note that the seizure episodes in these rural people had not previously been linked to NC and it required this type of active diagnostic intervention to be able to demonstrate

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P.M. Schantz

the impact of the disease on the health of these communities. Using data on seroprevalence and seizure disorder rates from multiple populationbased community studies in Peru, Bern et al. estimated that there were from 23,512 to 39,186 symptomatic cases of NC in Peru alone42. Extrapolating from limited serological surveys in other countries of Latin America, these authors calculated that 30–50 million persons may have been exposed to T. solium in Latin America alone and that there were an estimated 400,000 infected persons with symptomatic disease. In most countries where T. solium infection is endemic, community-based prevalence data are not yet available and there exist no realistic, databased estimates of the worldwide prevalence of T. solium infection in humans, however, the diagnostic technology now exists to begin to amass such data. There is a need for provision of diagnostic and therapeutic resources at the community level to determine the prevalence of infection and rates of associated morbidity.

Patterns of Transmission Endemic transmission Throughout its worldwide distribution, T. solium is maintained by cyclic transmission in swine and human hosts. More than 40 years ago, T. solium infection was called a ‘testimony to under-development’43; that characterization remains true today. Transmission of T. solium requires that pigs have access to human faeces and that humans ingest inadequately cooked meat of pigs. Such conditions are common in rural areas of many under-developed or unevenly developed countries characterized by poor hygiene, deficient sanitary facilities and primitive swine husbandry practices that allow pigs to run loose all or part of the time; such communities have not yet directly benefited from the achievements in sanitation and hygiene often referred to as the ‘first public health revolution’. In certain situations where pigs are kept in enclosures or are restrained, they may be fed human faeces

purposefully, e.g. ‘pig-sty privies’, thus also leading to transmission of T. solium. Such conditions may appear to be the endpoint of social neglect but usually represent an effective adaptation to poverty and circumstance whereby the pig is nourished adequately at virtually no cost to the owner and, simultaneously, serves as a community scavenger or ‘sanitary police’. Through coprophagy, pigs readily become infected, often at high rates and very intense levels. Recent surveys in disease-endemic communities of Latin America have revealed that infection rates in pigs approach 5–50%27–31,35,36,39,44–46. In T. solium-endemic areas, local populations, including pig owners, are often unaware of the threat to public health that this infection in pigs represents and do not relate the lesions in their animals to disease in humans. Nevertheless, pig owners may routinely check their live pigs for cysticercosis by direct examination of the tongue. This concern is motivated by the knowledge that cysticerci-infected meat may be rejected at slaughter (where visual meat inspection is practised) or will bring a significantly reduced price. Consequently, infected pigs may be slaughtered and sold clandestinely or consumed by the pig-owner’s family. In villages of Central Peru, where infection rates in pigs varied from 14% to 25%, virtually none of the infected pigs were processed at the local slaughterhouse. Rather, pig owners and vendors purposefully bypassed formal slaughterhouses. The investigators estimated that 23% of the total pork consumed in the community was derived from pigs infected with cysticerci46. Studies in Mexico, Guatemala and Peru have shown that the principal factors associated with the likelihood of infection in pigs include increasing age and access to human faeces. Confined pigs tend to be protected from infection but only if confinement is habitual and they are not deliberately fed faeces28,29,47. Improved understanding of the epidemiology of T. solium transmission requires a better understanding of the risk factors for intestinal-stage infection and the modes of dispersal of infective eggs by human tapeworm carriers because taeniid eggs in faeces or contamination of the

Global Distribution and Transmission

hands of infected humans are the direct source of cysticercosis in both pigs and humans. Surveys in disease-endemic communities in Mexico, Guatemala, Peru and Honduras have shown rates of T. solium taeniasis varying from 0.3% to 6%27,29,30,35,38. Factors associated with taeniasis include age (rates of intestinal taeniid infections tend to peak in middle adulthood; however, infections occur in all age groups) and frequency of pork consumption11,29,30,38. In some populations, taeniid infections are observed significantly more frequently in women than in men29,30. The presence of a tapeworm-infected individual within a household is an important risk factor for exposure to T. solium cysticercosis and this risk may be increased if the tapeworm carrier is an individual engaged in food preparation and child care activities. In Peruvian mountain villages, food handlers engaged in preparing and selling a traditional pork dish (‘chicharrones’) were shown to harbour intestinal taeniid infections at a significantly higher rate than other persons in the community39,40. Serological screening of humans from these villages documented levels of apparent exposure to T. solium cysticercosis varying from 5% to 24% (Table 7.1). Significantly higher levels of seropositivity in humans were associated with low levels of sanitary infrastructure and personal hygiene, age more than 20 years and personal histories of taeniasis. Highest seropositivity rates were found in persons with multiple factors39, suggesting that these apparent risk factors and behaviours acted cumulatively. In some communities, there was evidence of ‘clustering’ of seropositive persons in households of persons with histories of or current taeniasis28,29,30,37. In Guatemala, for example, one-third of all seropositive persons were clustered within the same households30. These observations suggest a ‘focal’ pattern of transmission associated with the presence of a tapeworm carrier. There is a need for further studies in other areas where T. solium is currently transmitted to be able to provide baseline epidemiological data and suggest strategies for control.

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Imported and introduced disease Imported cases of T. solium taeniasis/cysticercosis are those acquired in a foreign country. Onset of illness in NC typically occurs a year or more after initial acquisition of the infection; therefore, among internationally mobile persons exposed to infection, it is not uncommon that development of the disease occurs in a country different from that in which the infection was acquired (‘imported case’). Returning tourists or immigrants can also import intestinal-stage T. solium infections into the country; when the tapeworm carrier travels home or emigrates to a foreign country and inadvertently transmits the infection to another person, or to a pig, the infection has been ‘introduced’ to the host country. More rarely, the infection can be introduced by international transport of infected pigs and subsequent consumption of their infected meat.10,12 Imported disease A unique historical epidemic of imported NC was that which occurred in British troops stationed in India. In at least 450 cases soldiers or their family members developed symptoms 1–30 years (average: 5 years) following their deployment in India48. Approximately a quarter of these patients reported a history of taeniasis; however, little other information was reported on their possible sources of infection. More recently, imported cases of NC are diagnosed every year in countries throughout the world in immigrants or tourists returning from countries where T. solium infection is endemic. This phenomenon is fed by the recent increase in international movement as a result of tourist and business travel and emigration (the World Tourist Organization currently estimates that at least 400 million international border crossings occur each year). In recent years, imported cases of NC have been reported from Australia49–51, Norway52, Spain23, Argentina53, Denmark54 and the USA55. By virtue of the number of immigrants entering the USA every year from countries where T. solium infection is endemic, more cases of imported NC are diagnosed in that country every year

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than in all other non-endemic countries combined. The recently completed 2000 US Census recorded 35.3 million persons of Hispanic origin living in the USA representing an increase of 12.9 million in the past decade56. Because immigration to the USA from countries where T. solium infection is endemic continues to rise, the numbers of imported cases of NC as well as local transmission from imported tapeworm carriers are likely to increase. Aspects of the impact of this continuing wave of immigration into the USA on the epidemiology of T. solium infection are discussed in greater detail elsewhere in this volume (see Chapter 14) Introduced disease On rare occasions, T. solium has been introduced into a new area and spread epidemically. Such was the case in West Papua (Irian Jaya) where the infection was introduced through swine brought from Bali and given to the local people (Ekari tribals) by the Indonesian government as part of an effort to induce them to accept Indonesian control. Unfortunately, these gift pigs turned out to be a ‘Trojan horse’, because the swine were infected by cysticerci of T. solium and the human population also became infected, with disastrous consequences (see Chapter 12). Local cultural customs and pig husbandry practices facilitated the transmission and rapid spread of the cestode. The first indication of the problem was noted in 1971 when many of the people suffered seizures and burns caused by NC12. As a result of extensive migrations of people with their pigs, the infection has spread throughout the island, possibly including Papua New Guinea, and is now considered a serious emerging health problem10,11. There are no other documented instances of foreign ‘introduction’ and continued transmission of T. solium via infected pigs, however, imported cases of human taeniasis occasionally are linked epidemiologically to clusters of infected pigs in the United States. Such ‘outbreaks’ have been identified by detection of infected swine during routine inspection at slaughter and limited to the exposed cohorts of pigs (Peter M. Schantz, unpublished observations).

Conclusions The only effective solution to the public health problem of T. solium cysticercosis is to prevent transmission of the zoonotic cestode in the thousands of rural communities in Latin America, Africa and Asia where conditions exist to permit the life cycle of T. solium to be completed. Taenia solium infection is widely endemic in rural areas of developing countries where political, socioeconomic and environmental conditions permit the tapeworm’s life cycle in pigs and humans to be completed. Active intervention for control of T. solium infection is still at its infancy and there are many economic and social problems existing in most disease-endemic areas that hinder implementation of these programmes. Even though special studies reveal that morbidity caused by NC can be severe in disease-endemic populations, the nature of the disease and the lack of locally available diagnostic facilities often make NC an essentially silent and unrecognized disease of humans within many affected communities; these realities complicate attempts to motivate and empower the community to initiate measures to control the disease. Pig owners, however, easily recognize the infection in their animals and are aware that cysticercosis reduces the market value of infected pigs and the infection in this valuable meat animal suggests a possible focus for education and prevention measures. In contrast, people rarely understand the relationship between cysticercosis in pigs and taeniasis or cysticercosis in humans and thus lack knowledge and incentive to change behaviour that fosters transmission. In many, if not most, communities where T. solium infection is endemic there is an absence of piped water, sanitary infrastructure, waste disposal, and other basic services; consequently, to be effective in the short-term, intervention measures must be designed to circumvent these deficiencies to the extent possible (see Chapters 41–44). Primary health care facilities are also often lacking or inadequate. Since the disease is generally related to poverty and all its associated manifestations, strategies

Global Distribution and Transmission

to control the disease must consider costs and locally available resources. Nevertheless, the many recent advances in diagnosis and treatment of the disease, and the

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new knowledge of the impact of the zoonotic disease on local health and the economy, provide incentive and improved means to undertake these tasks57–59.

References 1. Flisser, A. (1994) Taeniasis and cysticercosis due to Taenia solium. Progress in Clinical Parasitology 4, 77–115. 2. Grove, D.I. (1990) Taenia solium taeniasis and cysticercosis. In: A History of Human Helminthology. CAB International, Wallingford, UK, pp. 335–383. 3. Henneberg, R. (1912) The animal parasites of the central nervous system. Handbook of Neurology (German) 3, 642–683. 4. Anonymous (1997) PAHO/WHO Informal Consultation on the Taeniasis/Cysticercosis Complex. Pan American Organization Series HCT/AIEPI-5. Washington, DC, pp. 1–20. 5. Schenone, H.R., Ramirez, A., Rojas, F., et al. (1982) Epidemiology of human cysticercosis in Latin America. In: Flisser, A., Willms, K., Laclette J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 25–38. 6. Banerjee, P.S., Bhatia, B.B., Pandit, B.A. (1994) Sarcocystis suihominis infection in human beings in India. Journal of Veterinary Parasitology 8, 57–58. 7. Singh, S., Singh, N.R., Pandav, C.S., et al. (1994) Toxoplasma gondii infection and its association with iodine deficiency in a residential school in a tribal area of Maharashtra. Indian Journal of Medical Research 99, 27–31. 8. Thakur, L.C., Anand, K.S. (1991) Childhood neurocysticercosis in South India. Indian Journal of Pediatrics 58, 815–819. 9. Wadia, N.H., Desai, S., Bhatt, M.B. (1988) Disseminated cysticercosis. New observations including CT scan findings and experience with treatment by praziquantel. Brain 11, 597–614. 10. Simanjuntak, G.M., Margono, S.S., Okamoto, M., et al. (1997) Taeniasis/Cysticercosis in Indonesia as an emerging disease. Parasitology Today 13, 321–322. 11. Wandra, T., Subahar, R., Simanjuntak, G.M., et al. (2000) Resurgence of epileptic seizures and burns associated with cysticercosis in Assologaima, Jayawijaya, Irian Jaya, Indonesia, 1991–95. Transactions of the Royal Society of Tropical Medicine and Hygiene 94, 46–50. 12. Gadjusek, D.C. (1978) Introduction of Taenia solium into West New Guinea with a note on an epidemic of burns from cysticercus epilepsy in the Ekari people of the Wissel Lake area. Papua New Guinea Medical Journal 21, 329–342. 13. Preux, P.M., Avode, G., Bouteille, B.M., et al. (1996) Cysticercosis and neurocysticercosis in Africa: current status. Neurological Infections and Epidemiology 1, 63–68. 14. Graber, M., Chailloux, A. (1970) Existence in Chad of porcine cysticercosis caused by Cysticercus cellulosae (Rudolphi). Revue d’ Elevage et de Medecine Veterinaire de Pays Tropicaux (Paris) 23, 49–55. 15. Permin, A., Yelifari, L., Bloch, P., et al. (1999) Parasites in cross-bred pigs in the upper east region of Ghana. Veterinary Parasitology 87, 63–71. 16. Gelfand, M., Jeffrey, C. (1973) Cerebral cysticercosis in Rhodesia. Journal of Tropical Medicine and Hygiene 76, 87–89. 17. Mafojane, N.A. (1994) The neurocysticercosis project in Atteridgeville-Mamelodi townships. South African Medical Journal 84, 208–211. 18. Powell, S.J., MacLeod, I.N., Proctor, E.M., et al. (1966) Cysticercosis and epilepsy in Africans: a clinical and serological study. Annals of Tropical Medicine and Parasitology 60, 152–158. 19. Sachs, L.V., Berkowitz, I. (1991) Cysticercosis in an urban black South African community: prevalence and risk factors. Tropical Gastroenterology 11, 30–33. 20. Michel, P., Callies, P., Genin, C., et al. (1992) Cysticercosis in Madagascar: diagnostic and therapeutic improvement. Dakar-Médical (Dakar) 37, 191–197. 21. Boa, M.E., Bogh, O.H., Kassuku, A.A., et al. (1995) The prevalence of Taenia solium metacestodes in pigs in northern Tanzania. Journal of Helminthology 69, 113–117. 22. Chinchilla, N., De Andres, D., Gimenez-Roldan, S. (1989) Neurocysticercosis in the urban area of Madrid. Archivos de Neurobiology 52, 287–294.

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23. Terraza, S., Pujol, T., Gascon, J., et al. (2001) Neurocysticercosis: an imported disease? Medicina Clinica (Barcelona) 116, 261–263. 24. Santos Meneses Monteiro, L.A. (1995) Neurocisticercose no norte de Portugal: Doctoral Disssertation, Institute Ciencias Biomed A. Salazar (ISBN 972–96591–0-9-DL No. 87526/95), 247 pp. 25. Saporiti, A., Brocchieri, A., Grignani, G. (1994) Neurocysticercosis as a cause of epilepsy. A case report. Minerva Medica (Torino) 85, 403–407. 26. Tsang, V.C.W., Boyer, A.E., Brand, J.A. (1989) An enzyme-linked immunotransfer blot assay and glycoprotein antigens for diagnosing human cysticercosis (Taenia solium). Journal of Infectious Diseases 159, 50–59. 27. Sarti, E., Plancarte, A., Schantz, P.M., et al. (1994) Epidemiological investigation of Taenia solium taeniasis and cysticercosis in a rural village of Michoacan state, Mexico. Transactions of the Royal Society of Tropical Medicine and Hygiene 88, 49–52. 28. Sarti, E., Aguilera, J., Lopez, A., et al. (1992) Epidemiologic observations on porcine cysticercosis in a rural community of Michoacan State, Mexico. Veterinary Parasitology 41, 195–201. 29. Sarti, E., Flisser, A., Guiterrez, I.O., et al. (1992) Prevalence and risk factors for Taenia solium taeniasis and cysticercosis in humans and pigs in a village in Morelos, Mexico. American Journal of Tropical Medicine and Hygiene 46, 677–685. 30. Allan, J.C., Soto de Alfaro, H., Torres-Alvarez, R., et al. (1996) Epidemiology of intestinal taeniasis in four rural Guatemalan communities. Annals of Tropical Medicine and Parasitology 90, 157–165. 31. Garcia-Noval, J., Moreno, E., De Mata, F., et al. (2001) An epidemiological study of epilepsy and epileptic seizures in two rural Guatemalan communities. Annals of Tropical Medicine and Parasitology 95, 167–175. 32. Sanchez, A.L., Medina, M.T., Ljungstrom, I. (1998) Prevalence of taeniasis and cysticercosis in a population of urban residence in Honduras. Acta Tropica 69, 141–149. 33. Sanchez, A.L., Gomez, O., Allebeck, P., et al. (1997) Epidemiological study of Taenia solium infections in a rural village in Honduras. Annals of Tropical Medicine and Parasitology 91, 163–171. 34. Sanchez, A.L., Lindback, J., Schantz, P.M., et al. (1999) A population-based case-control study on Taenia solium taeniasis and cysticercosis. Annals of Tropical Medicine and Parasitology 93, 247–258. 35. Sakai, H., Sone, M., Castro, D.M., et al. (1998) Seroprevalence of Taenia solium cysticercosis in pigs in a rural community of Honduras. Veterinary Parasitology 78, 233–238. 36. Tsang, V.C.W., Wilson, M. (1995) Taenia solium: an under recognized but serious public health problem. Parasitology Today 11, 124–126. 37. Cruz, M.E., Schantz, P.M., Cruz, I., et al. (1998) Epilepsy and neurocysticercosis in an Andean community. International Journal of Epidemiology 28, 799–803. 38. Diaz, J.F., Carcamo, C., Castro, M., et al. (1992) Epidemiology of taeniasis and cysticercosis in a Peruvian village. American Journal of Epidemiology 185, 875–882. 39. García, H.H., Gilman, R.H., Gonzales, A.E., et al. (1996) Epidemiologia de la cysticercosis en el Peru. In: García, H.H., Martinez, S.M. (eds) Taeniasis/Cisticercosis por T. solium. Editorial Universo SA, Lima, Peru, pp. 313–326. 40. García, H.H., Araoz, R., Gilman, R.H., et al. (1999) Increased prevalence of cysticercosis and taeniasis among professional fried pork vendors and the general population of a village in the Peruvian highlands. American Journal of Tropical Medicine and Hygiene 59, 902–905. 41. Schantz, P.M., Criales, J.L., Flisser, A., et al. (1994) Community-based epidemiological investigations of cysticercosis due to Taenia solium: comparison of serological screening tests and clinical findings in two populations in Mexico. Clinical Infectious Diseases 18, 879–885. 42. Bern, C., García, H.H., Evans, C., et al. (1999) Magnitude of the disease burden from neurocysticercosis in a developing country. Clinical Infectious Diseases 29, 1203–1209. 43. Canelas, H.M. (1962) Neurocisticercose: incidencia diagnostico y formas. Arquivos de Neuropsiquiatria 20, 1–15. 44. Allan, J.C., Fletes, C., Velasquez-Tohom, M., et al. (1997) Mass chemotherapy for intestinal Taenia solium infection: effect on prevalence in humans and pigs. Transactions of the Royal Society of Tropical Medicine and Hygiene 91, 595–598. 45. Garcia-Noval, J., Allan, J.C., Craig, P.S., et al. (1996) Epidemiology of Taenia solium taeniasis and cysticercosis in two rural Guatemalan communities. American Journal of Tropical Medicine and Hygiene 55, 282–289. 46. Cysticercosis Working Group in Peru (1993) The marketing of cysticercotic pigs in the Sierra of Peru. Bulletin of the World Health Organization 71, 223–228.

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47. Diaz, J.F., Gallo, C., García, H.H., et al. (1992) Immunodiagnosis of human cysticercosis: a field comparison of an antibody enzyme-linked immunosorbent assay (ELISA), and an enzyme-linked immunoelectrotransfer blot (EITB) assay in Peru. American Journal of Tropical Medicine and Hygiene 46, 610–615. 48. Dixon, H.B.F., Lipscomb, F.M. (1961) Cysticercosis: an analysis and follow-up of 450 cases. Medical Research Special Report Series. Her Majesty’s Stationery Office, London, 229, 1–58. 49. Oman, K.M., Grayson, M.L., Kempster, P. (1994) Neurocysticercosis and new-onset seizures in short term travelers to Bali. Medical Journal of Australia 161, 399. 50. Yong, J.L.C., Warren, B.A. (1994) Neurocysticercosis: a report of four cases. Pathology 26, 244–249. 51. McDowell, D., Harper, C.G. (1990) Neurocysticercosis – two Australian cases. Medical Journal of Australia.152, 217–218. 52. Dietrichs, E., Aanonsen, N.O., Bakke, S.J., et al. (1994) Tapeworms in the brain – current problem in Norway. The Journal of the Norwegian Medical Association 114, 3089–3092. 53. Villa, A.M., Monteverde, D.A., Rodriguez, W. (1993) Neurocisticercosis en un hospital de la ciudad de Buenos Aires: estudio de once casos. Arquivos de Neuropsiquiatria 51, 333–336. 54. Hansen, N.J.D., Christensen, T., Hagelskjaer, L.H. (1992) Neurocysticercosis: a short review and presentation of a Scandinavian case. Scandinavian Journal of Infectious Diseases 24, 255–262. 55. Schantz, P.M., Wilkins, P.P., Tsang, V.C. (1998) Immigrants, imaging and immunoblots: the emergence of neurocysticercosis as a significant public health problem. Emerging Infections, Vol. 2. ASM Press, Washington, DC, pp. 213–242. 56. Guzman, B. (2001) The Hispanic population. Census 2000 brief. United States, Department of Commerce, C2KBR/01-3, 8 pp. (www.census.gov) 57. Centers for Disease Control and Prevention (1993) Recommendations of the International Task Force for Disease Eradication. Morbidity and Mortality Weekly Report 42 (No. RR-16), 1–27. 58. Gilman, R.H., Dunleavy, M., Evans, C.A.W., et al. (1996) Methods for the control of taeniasis-cysticercosis. In: García, H.H., Martinez, M. (eds) Taeniasis/Cisticercosis por T. solium. Editorial Universo SA, Lima, Peru, pp. 327–340. 59. Schantz, P.M., Cruz, M., Pawlowski, Z., et al. (1993) Potential eradicability of taeniasis and cysticercosis. Bulletin of Pan American Health Organization 27, 397–403.

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What Have We Learnt From Epidemiological Studies of Taenia solium Cysticercosis in Peru? Hector H. García, Robert H. Gilman, Armando E. Gonzalez, Manuela Verastegui, Victor C.W. Tsang, and The Cysticercosis Working Group in Peru

Introduction Taenia solium taeniasis/cysticercosis has been known since antiquity (it is probable that suspicion as to its origins led some religions to expressly forbid the consumption of pork), but the epidemiology of human and porcine infection and disease has been poorly understood until recently. The lack of an accurate screening tool in the community setting was a barrier to the understanding of the magnitude of infection burden. The design of the enzyme-linked immunoelectrotransfer blot (EITB), the most sensitive and specific serological assay so far available, was a turning point in population studies of cysticercosis. In Peru, South America, the Cysticercosis Working Group (CWG) was formed through the efforts of professionals of different disciplines (biologists, biochemists, clinicians, epidemiologists and others), institutions and countries. The group performed a series of studies oriented to describe the epidemiological characteristics of taeniasis/cysticercosis for T. solium. This information is summarized in the present chapter.

Studies in General Population Overview of seroprevalence studies in Peru Peru, located in South America has 24 million inhabitants. The population is of mixed

ethnicity; most people are Catholic. The country is divided into three clearly defined zones by the Andean mountains: the arid Coast, the Highlands and the tropical Jungle. The geographic divisions served well as a guide to define regional prevalence of T. solium infection within Peru. Cysticercosis was believed to be endemic in the Highlands, and certain zones of the Coast and Jungle. The earliest surveys by the CWG were carried out in communities that were believed to be highly endemic for T. solium cysticercosis1–3. In 1988, two Jungle communities, Maceda (population: 421; altitude: 500 m)1 and Churusapa (population: 275; altitude: 500 m) were sampled. Both were typically representative of the High Jungle communities: each was located close to a river, had an agriculture-based economy and a tropical climate. The survey found that houses were made of adobe, with dirt floors. There was no electricity or water supply; water for consumption was obtained from the river. Further, pigs and other domestic animals were raised free (rarely corralled) and had access to human dwellings. Only a few houses had latrines. Census, mapping, human stool sampling, human and porcine blood sampling, and porcine tongue examination were performed after obtaining population consent. A total of 25 soil samples (five in Maceda and 20 in

© CAB International 2002. Taenia solium Cysticercosis (eds G. Singh and S. Prabhakar)

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Churusapa) and five water samples (each after concentrating 250–500 l of river water) were obtained. The study determined that the EITB-human seroprevalence was 8% and porcine seroprevalence, 45% (Table 8.1). The coproparasitological survey detected Taenia eggs in about 1% of the human population. Most seropositive individuals were neurologically asymptomatic. Taenia ova were not found in any soil or water sample. Subsequently, the CWG focused upon a different geographical environment, the Highlands. A survey was carried out in Haparquilla (population: 371; altitude: 3400 m), a village in the southern Highlands, close to Cusco, in 19903. The Highlands are different from the jungle in that the weather is much colder. Moreover, the survey found that pigs were mostly corralled in the backyards. There were virtually no latrines and villagers defecated in their backyards. Electricity supply existed, however there was no facility of potable water. Human seroprevalence in the Highland community was found to be 13% and was comparatively higher than in the jungle communities. Porcine seroprevalence was similarly high (Table 8.1)2. Two years later, we performed a survey in Saylla, another community in the Highlands, with the help

of the Mother’s Club of the village, and obtained similar findings3. In order to obtain a thorough assessment of the geographical prevalences within Peru, the CWG studied an endemic community (Monteredondo) in the Coastal zone (population: 1200; altitude: 300 m)4. An inspection of this region noted that pigs were kept tied, and human faeces were disposed in the fields, but usually in fixed places. A total of 489 individuals were sampled and human seroprevalence was estimated at 16%. However, interestingly, seroprevalence in pigs (13%) was considerably less than human seroprevalence as well as prevalence figures in porcine populations in other geographic locations (Table 8.1)4. The low prevalence in pigs was somewhat unexpected. When the CWG attempted to analyse the reasons behind the low rates of porcine infection in this community, it found that the Monteredondo community began to grow rice, 3 years before the survey. This led the villagers to tether pigs in order to protect the rice crop. Therefore, at the time of the survey, all pigs were less than 3 years of age and were tethered; accordingly seropositvity rates were low. Serological status in humans remained high since it represented the cumulative effects of exposure over a

Table 8.1. Characteristics of human and porcine populations and EITB based seroprevalence of Taenia solium cysticercosis in Peru. Jungle villages Community Population sampled

Maceda

Highland villages

Coastal village

Churusapa

Haparquilla

Saylla

Monteredondo

371 (88%)*

134 (48%)*

108 (30%)*

99 (20%)*

489

General population

General population

General population

Mothers’ Club and relatives

General population

Human seroprevalence Males Females

8% 7% 9%

7% 6% 7%

13% 10% 15%

24% 41% 18%

16% 13% 20%

Stool disposal

Open field

Open field

Backyard

Backyard

Defined

Type of sample

Porcine seroprevalence

43% (57/133)

49% (43/87)

46% (51/110)

36% (19/53)

13%

Pig raising

Free

Free

Free/corralled

Free/corralled

Tied

*Figures in parentheses represent the percentage of the total population of the village that was sampled.

Lessons from Epidemiological Studies in Peru

much longer period of time. Other community surveys have similarly described high seroprevalence rates in endemic communities within Peru; 15 (13%) out of 112 individuals attending a health centre in Pomabamba, Ancash, and 72 (21%) out of 334 in Vichaycocha, Central Highlands were seropositive. Two large-scale surveys in a population of 3000 in Quilcas (Huancayo, Central Highlands) and 4500 in Andahuaylas (Apurimac, southern Highlands) established seroprevalence rates of 12–15%. In addition, a recent survey in Tumbes in the northern Coast, found 22% of individuals sampled to be seropositive. The above findings are representative of the prevalence in T. solium endemic regions of Peru. In non-endemic areas, the seroprevalence has been consistently found to be less than 1% (1% in unselected urban groups in Lima5 and a specialized sheep-raising cooperative farm in the Highlands6 and no seropositive cases among the low-Jungle communities in Iquitos and La Merced).

Longitudinal studies of seroprevalence The high seroprevalence rates of T. solium antibodies with EITB in disease-endemic populations contrasts with the relatively small number of symptomatic cases of NC among seropositive individuals as well as a large number of putatively inactive brain lesions (mainly calcifications) in seronegative controls. These findings have been borne out in epidemiological studies of T. solium cysticercosis in Peru in common with data from Mexico (see Chapter 9) and Central America (see Chapter 10). The discrepancies have often been a source of confusion. When longitudinal serological data from general population serosurveys in disease-endemic areas were analysed, it was noted that about 40% of initially seropositive individuals became seronegative when resampled after one year7. This phenomenon was first observed between 1993 and 1994 in Monteredondo4,7. Between two consecutive serosurveys, 1 year apart, six (32%, 95%CI: 11–52%) out of 19 initially seropositive individuals in the community reverted to seronegative. In a different

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location (Quilcas, Central Highlands), 398 villagers were sampled in 1996; 140 were found to seropositive while 258 were seronegative. Three years later, in 1999, 69 out of the 140 that were initially seropositive (50%; 95%CI: 41–58%) were now seronegative. These data demonstrated that many newly infected (or exposed) individuals developed only transient serologic antibody reactions. These individuals may have been exposed to T. solium, but did not eventually develop viable infection, or they may have had cysticercosis that spontaneously resolved. This could also explain the discrepant finding of high background levels of putatively inactive, calcified brain lesions in seronegative controls8–10; it may be surmised that these currently seronegative individuals had transient seropositivity in association with active or transitional cysticercosis that eventually resolved with calcification.

From initial evaluation to intervention The CWG also studied the feasibility of control of T. solium with combined mass human and porcine chemotherapy in the Central Highlands. The prevalence of porcine infection did decrease temporarily; however it soon returned to the pre-intervention levels (CWG, unpublished data). The reader is referred to Chapters 41 and 43 for more comprehensive descriptions of these studies. Geographic position system analysis demonstrated clustering of new infections in pigs around the houses with Taenia carriers (see Chapter 15). Moreover, the pattern of appearance of new cases suggested that immigration from other endemic areas was the major contributor to control failure (CWG, unpublished data).

Studies in Hospital-based Population In order to determine the relationship between EITB-based T. solium seropositive status and neurological disease, 204 of 231 patients consecutively admitted to a neurology ward in Lima were studied5. Twentyone (12%) of 173 patients, who agreed to

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give blood samples were seropositive. There was however, discordance between clinical and serological diagnoses: over half of the patients clinically diagnosed as having cysticercosis were seronegative. On the other hand, ten seropositive patients had diagnoses other than cysticercosis. One of them had intestinal Taenia infection and another previously had surgery for cerebral cysticercosis (antecedent was not recorded in the current clinical chart). Three seropositive subjects were diagnosed to have NC by computed tomography (CT) scan (showing multiple cysts) upon follow-up, one had a lesion diagnosed on CT as ‘expansive temporal lesion’, and another patient had hydrocephalus5. Another serological survey was performed upon patients visiting a private radiology centre for brain CT scan10. Seroprevalence was 8% in this population. Again, there were discrepancies between radiological diagnoses and seropositive status. Moreover, when the scans were interpreted by a second neuroradiologist (masked to the original interpretation), only one of ten scans was confirmed as having ‘active’ NC, and five of 14 were not recognized as having NC. At the Instituto de Ciencias Neurológicas, Lima, 498 neurological outpatients were examined by EITB11. Of patients with seizures, 12% were seropositive, compared with 3% of those with other neurological symptoms. Seroprevalence increased to 20% if patients had late-onset epilepsy or were born outside Lima, and to 29% if they had both risk factors. The relationship between serological status and seizures was also evaluated in the community setting during a survey in Monteredondo12. Of 52 individuals who were evaluated, 49 had neurological symptoms. Fourteen (34%) of 41 epileptic individuals were found to be seropositive, in comparison to one (12.5%) of eight with headache and/or dizziness. Of the 14 seropositive epileptic individuals, 13 agreed to undergo CT. Seven of these 13 scans revealed evidence of NC: single cyst (2), multiple cysts (1), two calcifications (2), and multiple calcifications (2). In a different community in Huaraz, five (35%)

seropositive cases were found among 16 individuals with history of seizures13. Eight of them (four seropositive and four seronegative) agreed to undergo complete neurological and CT examination at a reference centre. All four seropositive individuals had evidence of NC upon CT: single enhancing lesion (1), multiple live cysts and calcifications (1) and multiple calcifications (2). The four seronegative individuals had normal cerebral CT scans. Age of onset of seizures was 17 or older in seven of the eight patients (excepting one seropositive case). When results of consecutive EITB-based serological studies at a serological laboratory of a large hospital were evaluated, the overall proportion of positive cases was 18% in serum samples and 28% in CSF samples14. Factors potentially associated with seropositivity were analysed using logistic regression techniques. Four factors were significantly associated with a positive test: to be born outside Lima, to have raised pigs, age older than 20, and a history of taeniasis. We have also studied the time to disappearance of antibodies in a series of 50 patients with NC treated with albendazole15,16. Only three of the 14 cured patients became seronegative at one year after successful treatment. In most patients, who had strong baseline serology (displaying all seven reactive bands on EITB), the reactive bands persisted at the end of 1 year of follow-up. Interestingly, an increase in the number of bands was observed around the second week of therapy in patients with viable cysts. A careful coproparasitological evaluation of a prospective series of patients with NC identified intestinal taeniasis in 15%. This prevalence was higher than expected. A direct correlation between the number of cysticerci and the presence of intestinal T. solium was noted, suggesting that heavy infections were commonly the result of autoinfection17. Furthermore, we have confirmed elsewhere that the frequency of adult T. solium infection is high among patients with massive cysticercus infection18. When imaging features in seropositive individuals were analysed it was found that individuals with transitional (enhancing)

Lessons from Epidemiological Studies in Peru

lesions were younger in comparison to those with active (viable) cysts; at older ages both active (viable) cysts and calcified lesions were frequent. This suggested that some infections (probably those with lesser numbers of parasites) were controlled by the host immune response resulting in early death of parasites, whereas others persisted for long periods. Patients with hydrocephalus were older than those with viable cysts, enhancing lesions, or calcifications alone (CWG, unpublished data).

Porcine Cysticercosis Porcine cysticercosis has been reviewed by Gonzalez et al. (Chapter 15). Certain features that are specifically relevant to the understanding of the epidemiology of T. solium cysticercosis in Peru are discussed here. Before 1990, the veterinary team of the CWG evaluated the sensitivity and specificity of tongue palpation vis-à-vis EITB serology, in a controlled design. When evaluated against necropsy, tongue palpation was over 70% sensitive and highly specific, whereas EITB detected all necropsy-positive pigs19. The veterinary team also studied and identified the pig marketing circuits in Peru. They noted that official marketing and slaughtering facilities were completely circumvented by peasants particularly in the Central Highlands. Slaughtering was performed under clandestine conditions; infested carcasses thus obtained were later introduced into the formal market. A significant proportion of commercialized pork was infected in the Highlands. Infected pork was sold at cheaper prices and often mixed and disguised with clean meat in order to facilitate its sale to public eating facilities20. Other major accomplishments of the veterinary team of the CWG include the establishment of the feasibility of using sentinel pigs as an indicator of the burden of infection in a given area21, demonstration of the passive transplacental transfer of immunity and seropositivity22, the use of drugs such as albendazole and oxfendazole for treatment in control measures23–27 and of intramuscular inoculation in an experimental model of porcine cysticerco-

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sis28. The reader is referred to Chapter 15 for a comprehensive review of these studies.

Conclusions After more than a decade of studies by the CWG, several concepts have emerged while others have been clarified. The most significant of these is that taeniasis/cysticercosis is extremely common in Peru. The magnitude of transmission may be as high as 25% of humans infected at a given time in hyperendemic villages, and may easily be over 10% in many endemic zones. While seroprevalence rates are high, neurologically symptomatic individuals constitute the tip of the iceberg. Also, a proportion of asymptomatic individuals has imaging abnormalities suggestive of NC7–9; these are mainly seronegative individuals with residual, inactive calcified brain lesions. On a converse note, it is also common to encounter asymptomatic seropositive individuals in community studies. As for many other infectious diseases, seropositivity in asymptomatic individuals is generally interpreted as a marker of current subclinical or past infection. A common pitfall in the interpretation of serological data is to compare different kinds of populations. A 10% prevalence in neurological patients at a large urban medical facility (where the overall seroprevalence is likely to be below 10%) cannot be equated to a 10% prevalence in the general population of an endemic community (where surveying epileptic patients may reveal seroprevalence rates of 30–35%). Another pitfall is to assume that, since the majority of seropositive individuals in endemic communities are asymptomatic, seropositivity has no relationship with neurological symptoms. Some authors have questioned the role of NC in the aetiology of seizure disorders. However, studies by the CWG in Peru have demonstrated that seroprevalence rates in neurological patients are consistently much higher than in comparable general populations. This increases further when specific subgroups, for instance, those with late onset seizures are examined. Another important outcome of the work done by the CWG is the realization of the intimate

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relationship between domestic pig raising, taeniasis and human cysticercosis. Porcine seroprevalence reflects recent infection and porcine serosurveys are the fastest and least expensive method to document levels of ongoing transmission. Pigs are infected early in life29 and are usually slaughtered by the age of 1 year. In a survey in an urban commercial pig slaughterhouse, no animals had cysticercosis. Usually porcine seroprevalence is twice that of human seroprevalence. However, Monterendondo was an exception. Thus human seroprevalence reflects cumulative effect of past exposure, while porcine seroprevalence is an indicator of recent trends in infection burden in a given community.

The CWG is now in the concluding phase of a randomized study designed to evaluate the clinical benefits of anticysticercal therapy for NC, along with radiological (CT/MRI) and immunological (clinical significance of individual antibodies, antigen detection30,31, cytokine pathways32) studies in the natural and post-treatment evolution of human NC.

Acknowledgements Support from grants FD-R-001107 from the Food and Drug Administration, and U19A145431 from NIAID/NIH (USA) is acknowledged.

References 1. Diaz, F., García, H.H., Gilman, R.H., et al. (1992) Epidemiology of taeniasis and cysticercosis in a Peruvian village. American Journal of Epidemiology 135, 875–882. 2. García, H.H., Araoz, R., Gilman, R.H., et al. (1998) Increased risk for cysticercosis and taeniasis among professional fried pork vendors and the general population of a village in the Peruvian highlands. American Journal of Tropical Medicine and Hygiene 59, 902–905. 3. García, H.H., Gilman, R.H., Gonzalez, A.E., et al. (1999) Human and porcine T. solium infection in a village in the Highlands of Cusco, Peru. Acta Tropica 73, 31–36. 4. Gilman, R.H., García, H.H., Gonzalez, A.E., et al. (1999) Shortcuts to development: methods to control the transmission of cysticercosis in developing countries. In: García, H.H., Martínez, S.M. (eds) Taenia solium Taeniasis/Cysticercosis, 2nd edn. Editorial Universo SA, Lima, Peru, pp. 313–326. 5. García, H.H., Martinez, M., Gilman, R.H., et al. (1991) Diagnosis of cysticercosis in endemic regions. Lancet 338, 549–551. 6. Moro, P.L., Guevara, A., Verastegui, M., et al. (1994) Distribution of hydatidosis and cysticercosis in different Peruvian populations as demonstrated by an enzyme-linked immunoelectrotransfer blot (EITB) assay. American Journal of Tropical Medicine and Hygiene 51, 851–855. 7. García, H.H., Gonzalez, A.E., Gilman, R.H., et al. (2001) Transient antibody response in Taenia solium infection in field conditions: a major contributor to high seroprevalence. American Journal of Tropical Medicine and Hygiene (in press). 8. Cruz, M.E., Schantz, P.M., Cruz, I., et al. (1999) Epilepsy and neurocysticercosis in an Andean community. International Journal of Epidemiology 28, 799–803. 9. Sanchez, A.L., Lindback, J., Schantz, P.M., et al. (1999) A population-based, case-control study of Taenia solium taeniasis and cysticercosis. Annals of Tropical Medicine and Parasitology 93, 247–258. 10. García, H.H., Herrera, G., Gilman, R.H., et al. (1994) Discrepancies between cerebral computed tomography and western blot in the diagnosis of neurocysticercosis. American Journal of Tropical Medicine and Hygiene 50, 152–157. 11. García, H.H., Gilman, R., Martinez, M., et al. (1993) Cysticercosis as a major cause of epilepsy in Peru. Lancet 341, 197–200. 12. García, H.H., Gilman, R.H., Tsang, V.C.W., et al. (1997) Clinical significance of neurocysticercosis in endemic villages. Transactions of the Royal Society of Tropical Medicine and Hygiene 91, 176–178. 13. García, H.H., Talley, A., Gilman, R.H., et al. (1999) Epilepsy and neurocysticercosis in a village in Huaraz, Perú. Clinical Neurology and Neurosurgery 101, 225–228. 14. García, H.H., Gilman, R.H., Tovar, M., et al. (1995) Factors associated with T. solium cysticercosis. Analysis on 946 Peruvian neurologic patients. American Journal of Tropical Medicine and Hygiene 52, 147–150.

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15. García, H.H., Gilman, R.H., Horton, J., et al. (1997) Albendazole therapy for neurocysticercosis: a prospective double blind trial comparing 7 vs. 14 days of treatment. Neurology 48, 1421–1427. 16. García, H.H., Gilman, R.H., Catacora, M., et al. (1997) Serological evolution of neurocysticercosis patients after antiparasitic therapy. Journal of Infectious Diseases 175, 486–489. 17. Gilman, R.H., Del Brutto, O.H., García, H.H., et al. (2000) Prevalence of taeniasis among neurocysticercosis patients is related to the severity of cerebral infection. Neurology 55, 1062. 18. García, H.H., Del Brutto, O.H. and The Cysticercosis Working Group in Perú (1999) Heavy nonencephalitic cerebral cysticercosis in tapeworm carriers. Neurology 53, 1582–1584. 19. Gonzalez, A.E., Cama, V., Gilman, R.H., et al. (1990) Prevalence and comparison of serologic assays, necropsy, and tongue examination for the diagnosis of porcine cysticercosis in Peru. American Journal of Tropical Medicine and Hygiene 43, 194–199. 20. Cysticercosis Working Group in Peru (1993) The marketing of cysticercotic pigs in the sierra of Peru. Bulletin of the World Health Organization 71, 223–228. 21. Gonzalez, A.E., Gilman, R.H., García, H.H., et al. (1994) Use of sentinel pigs to monitor environmental Taenia solium contamination. American Journal of Tropical Medicine and Hygiene 51, 847–850. 22. Gonzalez, A.E., Verastegui, M., Noh, J.C., et al. (1999) Persistence of passively transferred antibodies in porcine Taenia solium cysticercosis. Veterinary Parasitology 86, 113–118. 23. Gonzalez, A.E., García, H.H., Gilman, R.H., et al. (1995) Treatment of porcine cysticercosis with albendazole. American Journal of Tropical Medicine and Hygiene 53, 571–574. 24. Gonzalez, A.E., García, H.H., Gilman, R.H., et al. (1996) Effective, single dose treatment of porcine cysticercosis with oxfendazole. American Journal of Tropical Medicine and Hygiene 54, 391–394. 25. Gonzalez, A.E., Falcon, N., Gavidia, C., et al. (1997) Treatment of swine cysticercosis with oxfendazole: a dose-response trial. Veterinary Record 141, 420–422. 26. Gonzalez, A.E., Falcon, N., Gavidia, C., et al. (1998) Time–response curve of oxfendazole in the treatment of swine cysticercosis. American Journal of Tropical Medicine and Hygiene 59, 832–836. 27. Verastegui, M., Gonzalez, A.E., Gilman, R.H., et al. (2000) Experimental infection model for Taenia solium cysticercosis in swine. Veterinary Parasitology 94, 33–44. 28. Gonzalez, A.E., Gavidia, C., Falcon, N., et al. (2001) Cysticercotic pigs treated with oxfendazole are protected from further infection. American Journal of Tropical Medicine and Hygiene 65, 15–18. 29. Diaz, F., Verastegui, M., Gilman, R.H., et al. (1992) Immunodiagnosis of human cysticercosis (Taenia solium): a field comparison of an antibody-enzyme-linked immunosorbent assay (ELISA) an antigen-ELISA and an enzyme-linked immunoelectrotransfer blot (EITB) assay in Peru. American Journal of Tropical Medicine and Hygiene 46, 610–615. 30. García, H.H., Harrison, L.J.S., Parkhouse, R.M.E., et al. (1998) Application of a specific antigen detection ELISA to the diagnosis of human neurocysticercosis. Transactions of the Royal Society of Tropical Medicine and Hygiene 92, 411–414. 31. García, H.H., Parkhouse, R.M.E., Gilman, R.H., et al. (2000) Serum antigen detection in the diagnosis, treatment, and follow-up of neurocysticercotic patients. Transactions of the Royal Society of Tropical Medicine and Hygiene 94, 673–676. 32. Evans, C.A.W., García, H.H., Hartnell, A., et al. (1998) Elevated concentrations of eotaxin and interleukin-5 in human neurocysticercosis. Infection and Immunity 66, 4522–4525.

9

Epidemiology of Taenia solium Taeniasis and Cysticercosis in Mexico Elsa Sarti

Introduction Taenia solium taeniasis and cysticercosis are important public health problems in several developing countries of Latin America, Africa and Asia. Mexico has one of the highest frequencies of disease in the Americas1–4. It also has a long history, spanning over three decades, of the development of surveillance, preventive and control strategies with specific reference to T. solium cysticercosis. These and several other aspects of epidemiology of human and porcine cysticercosis and human taeniasis in Mexico are reviewed in this chapter. Mexico is the third largest country in Latin America (after Brazil and Argentina), with an area of 1,972,550 square kilometres. It has a population of almost 100 million, 35% of which live under marginal conditions. Ethnically, most (60%) Mexicans are of Mestizo origin. The official literacy rate was 88% in 1990. Health care personnel and facilities are generally concentrated in urban areas; care in rural areas consists of understaffed clinics operated mostly by medical graduates. Leading causes of death are infections, including parasitic diseases, and respiratory and circulatory failure. Spanish is the official language, spoken by nearly all. However, knowledge of English is increasing rapidly, especially among business people,

the middle class, returned emigrants and the young. The annual population growth rate is 1.96%. The nation underwent a rapid change in the last few decades of the 20th century and Mexicans are viewed as urban, opening to democracy and market-oriented.

Human Intestinal Taeniasis The reported prevalence of intestinal T. solium infection in Mexico is between 0.2% and 3.4%2,3,5–9. This amounts to nearly 1.5 million potential transmitters of Taenia eggs, capable of producing new cases of neurocysticercosis (NC). An average of 13,000 cases of Taenia sp. infection were reported every year during the last 5 years by the National Epidemiological Surveillance System, giving an incidence of 3.8 per 100,000 inhabitants (Fig. 9.1)7,10. Official statistics reveal highest frequency in individuals under 14 years of age with no statistical difference by gender7,10. In comparison, several epidemiological surveys have established peak levels between 16 and 45 years of age (economically productive life) with predominance in women2,5–9,11. These discrepancies reflect differences in ‘taeniasis’ case definitions and methodologies adopted by the two sources of data. While surveillance systems consider only patients

© CAB International 2002. Taenia solium Cysticercosis (eds G. Singh and S. Prabhakar)

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11.49 –13.1 (1 state)

5.75 – 11.48 (3 states)

2.88 – 5.74 (13 states)

0.19 – 2.87 (15 states)

*Incidence rate by 100,000 inhabitants in Mexico (average 3.0)

Fig. 9.1. State-wise and age-wise incidence of Taenia sp. infection in México, 1994–2000 (Source: National epidemiological surveillance system)10.

Older than 65 years

45–64

Less than 1 year old 1 –4 5 –14 15–24 25–44

0

25

43

*Incidence rates by group of age (100,000 inhabitants)

84 E. Sarti

Epidemiology of Taeniasis and Cysticercosis in Mexico

requesting assistance in local health units, planned epidemiological studies obtain data from house-to-house surveys. The latter, apparently, are more representative of the community burden.

Human Cysticercosis Initially, considerable information on human cysticercosis was derived from cases seen in neurological services of hospitals and necropsy series of general hospitals in Mexico. The frequency of NC from hospital facilities in Mexico appeared to be as high as 8.6 per 100 patients1,3,12. Cysticercosis was detected in 4–13% of large hospital-based autopsy series1,2,13. Neurocysticercosis was listed as the cause of death in 40–80% of autopsy protocols that reported cysticercal infestation. Official sources from Mexican surveillance currently estimate an average of 500 new cases every year, giving a nationwide incidence of 0.6 per 100,000. These projections underestimate the incidence and prevalence of human cysticercosis in Mexico, since a number of cases in rural areas, where facilities for contemporary diagnosis (like computed tomography, magnetic resonance imaging and serology) do not exist, are not registered. Nevertheless, official registers do give us a general idea about the geographical and demographic predilections of human cysticercosis in Mexico (Fig. 9.2). The seroprevalence of cysticercosis using immunoelectrophoresis (IEF) and indirect haemagglutination (IHA) was 1–3% of the population studied. With newer techniques such as the ELISA and EITB (enzyme-linked immunoelectrotransfer blot, better known as ‘blot’), the prevalence has been estimated at around 10%5–9,14,15. Seroprevalence rates are highest between 15 and 45 years of age and in women.

Swine Cysticercosis The reported average prevalence of cysticercosis in swine, from official registered slaughterhouses in Mexico is 0.2%3,16. This

85

figure is at best, an underestimate. It is common to find a large number of informal slaughterhouses without veterinary inspection, in addition to the registered ones in the country. No information on the status of porcine infection in these unauthorized facilities is available. Swine in registered slaughterhouses represent only 40% of the total swine slaughtered3,16. Besides, infected pigs are unlikely to be brought to abattoirs for slaughter. Undernotification may also occur on account of lack of trained personnel in slaughter facilities and of standardized screening practices among meat vendors. In addition to slaughterhousebased data, information has been collected from sampling domestic and free-ranging pigs in Mexico. Tongue inspection and palpation and EITB have been used as methods of evaluation in such studies. The prevalence of porcine cysticercosis was found to vary between 1.4 and 4.0% using tongue inspection or palpation and from 4.1% to 7.0% with EITB6,9,16–17,18. Seroprevalence rates increased with age and peaked at 11 months.

An Overview of Epidemiological Studies from Mexico The study of the taeniasis–cysticercosis complex in Mexico has progressed through logical and sequential steps. It began with investigations into disease frequency at necropsy and later, in clinical series at neurological and neurosurgical services. Studies then progressed towards the search of an adequate, reliable, and convenient diagnostic and screening test, available for use, both in hospital facilities and the community. In the 1970s, epidemiological studies were directed towards the study of prevalence of T. solium. In the 1980s, research looked into risk factors for transmission. Simultaneously, standardization of methods for the diagnosis of taeniasis and cysticercosis, for instance the use of EITB and sound statistical techniques, was undertaken. Finally in the 1990s, intervention studies began examining strategies for control of taeniasis–cysticercosis.

0– 0.19 (4 states) 0.20 – 0.63 (14 states) 0.64 – 2.52 (9 states) 2.53 – 3.94 (5 states)

*Incidence rate by 100,000 inhabitants in Mexico (average 0.5)

Fig. 9.2. State-wise and age-wise incidence of neurocysticercosis in México, 1994–2000 (Source: National epidemiological surveillance system)10.

0 Less than 1 year old 1 –4 5 –14 15 –24 25 –44 45 –64 Older than 65 years

6

12

*Incidence rates by group of age (100,000 inhabitants)

86 E. Sarti

Epidemiology of Taeniasis and Cysticercosis in Mexico

Step 1 (Estimation of disease prevalence) A national survey with urban representation was carried out in 197419. Blood samples of 18,417 individuals were examined for anticysticercus antibodies by IEF; 1% of the population was found to be positive. Earlier, a survey in Oaxaca in 1971 revealed a seropositivity of 3.3% by IHA20. In several communities of Chiapas, seroprevalence by IEF ranged between 0.4% and 7.6%21. Some of the early epidemiological investigations were criticized for not having used rigorous epidemiological methods. Nevertheless, a general idea of disease frequency could be drawn. In 1992, a second nationwide seroepidemiological survey was conducted using a systematic approach. From 66,754 blood samples analysed by IHA, anticysticercus antibodies were detected in 1.2%22. The highest prevalences were noted in West and Southeast Mexico. Our studies using EITB vis-à-vis ELISA for screening established an association of EITB positivity (but not ELISA positivity) with late-onset convulsions6,14,23. Neuroimaging abnormalities compatible with NC were significantly more common in individuals with late-onset convulsions. This led us to infer a risk factor association between cysticercosis and late-onset convulsions and established the superiority of EITB over ELISA as a tool for community screening. It was also found that immunological tests detect exposure to the parasite besides the infection and active disease. Therefore, in the 1990s, EITB was employed for further human sero-surveys. Coproparasitological examinations of faeces with Ritchie, Katz and Faust techniques and faecal antigen assays have been used for screening of intestinal taeniasis24,25. However, both techniques yielded poor results. Incidentally, a simple inquiry about having passed proglottides was found to be a fairly reliable indicator of intestinal taeniasis. This inquiry is simpler and more effective than sophisticated, expensive and timeconsuming faecal tests. Therefore, therapeutic taeniacidal intervention on the basis of this inquiry alone is recommended.

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The prevalence of intestinal taeniasis using standard coproparasitological evaluations was 0.2–0.4%5,6,8,9,14,17,23,26–29. EITB based seroprevalence of human cysticercosis varied between 4.9% and 10.9%5,6,8,9,14,17,23,26– 29. The prevalence of porcine cysticercosis based on tongue inspection and palpation was 1.4% to 23.8% and using EITB was around 4%6,9,16,18.

Step 2 (Determination of risk factors) In the 1980s, a number of epidemiological and statistical investigations focused on determination of magnitude of disease and risk factors. The first such study was undertaken in ‘El Sótano’, a small community of 150 inhabitants in 19845. An association between ELISA seropositivity and tapeworm carriage, symptoms compatible with cysticercosis (generalized convulsions), swine cysticercosis, and presence of latrines in homes was observed in this study5. Clusters of infection in the ‘El Sótano’ study, suggested that the source of transmission of infection lay within the household (living closely with the tapeworm carrier) rather than the environment. Subsequent studies from Mexico and Central America using EITB and structured questionnaires have confirmed the observations6,9,26,27,30,31. In these studies, cardinal risk factors for human taeniasis included: (i) history of having passed proglottides in stools; and (ii) consumption of uncooked or infected pork. Risk practices that were associated with human cysticercosis included: (i) drinking unboiled water; and (ii) not washing hands before eating food and after defecation. On the other hand, rates of swine cysticercosis were determined by numbers of free-ranging pigs with access to human faeces. The above mentioned human and porcine behaviours facilitate the ‘human–environment–pig–human’ cycle. Modifications of these behaviours were considered as potential strategies for control of the taeniasis–cysticercosis complex. Transmission, other than the human– environment–pig–human cycle has been suggested, for instance, through flies and by ingestion of fruits and vegetables contami-

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nated by Taenia eggs32. These modalities of transmission have not been confirmed by studies in Mexico6,17,33.

Step 3 (Developing interventions for control) An evaluation of the efficacy of mass taeniacidal treatment was carried out during 1990, in a community in Sinaloa26. Praziquantel treatment was administered to the population of approximately 2000 inhabitants. Before treatment, 1.3% of the individuals had taeniasis and only one out of the 72 pigs examined had cysticercosis. Treatment lead to complete eradication of intestinal taeniasis but data on porcine cysticercosis was inadequate. By comparison, another study in 1987 provided insights into the role of health education, and demonstrated that health promotion could be a short-term alternative26,27. A promotional campaign emphasizing upon the need to construct latrines in every home and the hazards of open-air defecation was conducted in schools. The study demonstrated that the campaign created awareness about the parasite; unfortunately, mass taeniacidal treatment of members of this community was not successful as the prevalence of porcine cysticercosis had doubled 1 year after intervention. It must be mentioned that this study was not oriented to community intervention, but to the identification of the risk factors. We have evaluated two alternative strategies for control of T. solium in the last decade: (i) mass taeniacidal drug administration; and (ii) health education28,29,34. Both measures were applied to three rural communities of Mexico with similar social, economical and cultural characteristics. Community ‘A’ received mass praziquantel treatment (5 mg kg1), community ‘B’ received health education and community ‘C’ received both mass praziquantel treatment and health education. Demographic, epidemiological, clinical, sanitary and sociological data from 98% of the inhabitants were obtained. Evaluations were performed 6 and 42 months after intervention. Prevalence and incidence rates of taeni-

asis were measured by the frequency of Taenia coproantigens and Taenia eggs in faeces. Swine cysticercosis was measured by palpating tongue and the presence of serum antibodies. Changes in knowledge, attitudes and practices in the communities were evaluated by questionnaires prepared ex professo as well as by direct observation by interviewers. Praziquantel treatment reduced rates of taeniasis by 66%. However, treatment alone, had no impact on swine cysticercosis. A 66–77% decrease in swine cysticercosis was observed in communities where health education was provided (‘B’ and ‘C’). Evaluation of long-term outcome (42 months after the intervention) revealed a reduction of 48% of taeniasis in community ‘B’. This underscored the importance of health education in the effective control of taeniasis–cysticercosis. Health education had a twofold effect. Improved sanitary practices and curtailing free-ranging pigs led to a decrease in the frequency of porcine cysticercosis and ultimately human taeniasis. Secondly, awareness of the utility of taeniacidal treatment and its use prevented human and porcine cysticercosis. Results of our studies suggested that health educational programmes are effective for T. solium control.

Mexican Surveillance to Monitor and Control Taeniasis–Cysticercosis Mexico has a Unique Information System for Epidemiological Surveillance (SUIVE) generating information on community healthrelated risk factors, treatment and control at all operative levels. Information on several diseases subject to epidemiological surveillance, including taeniasis and cysticercosis is collected in a specifically prepared format by some 17,000 primary health care units and is transmitted to State and Federal health authorities for analysis at a national level. Health care personnel manning the primary health care units are imparted continuing education regarding simple and effective screening and treatment of taeniasis and cysticercosis. It is recommended that all individuals presenting to these centres for health

Epidemiology of Taeniasis and Cysticercosis in Mexico

check-ups and treatment for any ailment should be screened for taeniasis–cysticercosis. As mentioned earlier, a simple inquiry about the passage of proglottides suffices as a screening tool. Both cases that are identified as positive by screening and their families should be offered taeniacidal treatment.

Conclusions The prevalence of human taeniasis in Mexico varies between 0.2% and 0.4%, while that of human cysticercosis is 4.9–10.9% and that of

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swine cysticercosis may be as high as 23.8%. Risk behaviours for taeniasis include freeranging pigs with access to human faeces and poor personal hygiene. Human cysticercosis, on the other hand, is clustered around intestinal adult T. solium carriers. Currently intervention trials focusing on the modification of these risks are underway. The impact of health education and improving sanitary infrastructure is considered important. Finally strategies employing the above interventions both individually as well as in combination, must be evaluated in order to develop a unified national control policy.

REFERENCES 1. Sarti, E., Gutiérrez, I. (1986) La teniasis y cisticercosis en México (Revisión Bibliográfica). Salud Púbica de México 28, 556–563. 2. Sarti, E. (1997) La teniosis y cisticercosis en México. Salud Pública de México 39, 225–231. 3. Organización Panamericana de la Salud (1994) Epidemiología y control de la teniosis y cisticercosis en América Latina. OPS/OMS, Washington, DC. 4. Schantz, P., Cruz, M., Sarti, E., et al. (1993) Potential erradicability of taeniasis and cysticercosis. Bulletin of the Pan American Health Organization 27, 397–403. 5. Sarti, E., Schantz, P., Lara, R., et al. (1988) Taenia solium taeniasis and cysticercosis in a Mexican village. American Journal of Tropical Medicine and Hygiene 39, 194–198. 6. Sarti, E., Schantz, P., Plancarte, A., et al. (1992) Prevalence and risk factors for Taenia solium taeniosis and cysticercosis in humans and pigs in a village in Morelos, Mexico. American Journal of Tropical Medicine and Hygiene 46, 677–684. 7. Correa, M.D., Flisser, A., Sarti, E. (1994) Teniasis y cisticercosis. In: Valdespino-Gomez, J.L. (ed.) Enfermedades Tropicales. Secretaría de Salud, México, DF, Mexico, pp. 335–345. 8. Díaz, S., Candil, R., Uribe, M., et al. (1990) Serology as an indicator of Taenia solium tapeworm infections in a rural community in Mexico. Transactions of the Royal Society of Tropical Medicine and Hygiene 84, 563–566. 9. Sarti, E., Schantz, P., Plancarte, A., et al. (1994) Epidemiological investigation of Taenia solium taeniosis and cysticercosis in a rural village of Michoacan State, Mexico. Transactions of the Royal Society of Tropical Medicine and Hygiene 68, 49–52. 10. Secretaría de Salud (2000) Boletín Semanal de Epidemiología, 1994–2000. Dirección General de Epidemiología, México DF, Mexico. 11. Schantz, P., Sarti, E. (1989) Diagnostic methods and epidemiologic surveillance of Taenia solium infection. Acta Leidensia 57, 153–163. 12. Medina, M.T., Rosas, E., Rubio-Donnadieu, F., et al. (1990) Neurocysticercosis as the main cause of late onset epilepsy in Mexico. Archives of Internal Medicine 150, 325–327. 13. Rabiela, M.T., Rivas, A., Rodriguez, I.J. (1979) Consideraciones anatomopatológicas de la cisticercosis cerebral como causa de muerte. Patología (México) 17, 119–124. 14. Schantz, P., Sarti, E., Plancarte, A., et al. (1994) Community based epidemiological investigations of cysticercosis due to Taenia solium. Comparison of serological screening tests and clinical findings in two populations in Mexico. Clinical Infectious Diseases 18, 879–885. 15. Flisser, A., Correa, D., Plancarte, A., et al. (1990) New approaches for the diagnosis of Taenia solium taeniasis/cysticercosis. Annals of Human and Comparative Parasitology 65, 95–98. 16. Aluja, A.S. (1982) Frequency of porcine cysticercosis in Mexico. In: Flisser, A., Willms, K., Laclette, J., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 47–50.

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17. Sarti, E., Schantz, P., Aguilera, J., et al. (1992) Epidemiologic observations in a rural community of Michoacan State, Mexico. Veterinary Parasitology 41, 195–201. 18. Aluja, A., Villalobos, N., Plancarte, A., et al. (1996) Experimental Taenia solium cysticercosis in pigs. Characteristics of the infection and antibody response. Veterinary Parasitology 61, 49–58. 19. Woodhouse, E., Flisser, A., Larralde, C. (1982) Seroepidemiology of human cysticercosis in Mexico. In: Flisser, A., Willms, K., Laclette, J., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 11–23. 20. Goldsmith, R.S., Kagan, I.G., Reyes-González, M.A., et al. (1971) Estudios serepidemiológicos realizados en Oaxaca, Mexico. I. – Encuesta de anticuerpos parasitarios mediante la prueba de hemaglutinación indirecta. Boletin de la Oficina Sanitaria Panamericana (Washington DC) 71, 500. 21. Flisser, A., Bulnes, I., Díaz, M.L., et al. (1976) Estudio seroepidemiológico de la cisticercosis humana en poblaciones predominantemente indígenas y rurales del estado de Chiapas. Archives of Internal Medicine (México) 7, 107–113. 22. Larralde, C., Padilla, A., Hernández, M., et al. (1992) Seroepidemiology of cysticercosis in Mexico. Salud Pública de México 34, 197–210. 23. Schantz, P., Sarti, E., Plancarte, A., et al. (1991) Clinical, radiological and epidemiological correlation of ELISA and immunoblot assays for Taenia solium cysticercosis in 2 populations. Mexico. American Journal of Tropical Medicine and Hygiene 45, 130–131. 24. Alan, J.C., Avila, G., Garcia-Noval, J., et al. (1990) Immunodiagnosis of taeniasis by coproantigen detection. Parasitology 101, 473–477. 25. Díaz, S., Candil, R., Suate, P., et al. (1991) Epidemiologic study and control of Taenia solium infections with praziquantel in a rural village of Mexico. American Journal of Tropical Medicine and Hygiene 45, 522–531. 26. Keilbach, N., Aluja, S., Sarti, E. (1989) A program to control taeniosis and cysticercosis (Taenia solium). Experiences in a Mexican village. Acta Leidensia 57, 181–189. 27. Rodriguez Canul, R., Fraser, A., Allan, J.C., et al. (2000) Epidemiological study of Taenia solium taeniasis/cysticercosis in a rural village in Yucatan state, Mexico. Annals of Tropical Medicine and Parasitology 93, 57–67. 28. Sarti, E., Flisser, A., Schantz, P.M., et al. (1997) Development and evaluation of health education intervention against Taenia solium in a rural community in Mexico. American Journal of Tropical Medicine and Hygiene 56, 127–132. 29. Sarti, E., Schantz, P., Avila, G., et al. (2000) Mass treatment against human taeniosis for the control of cysticercosis. A population based intervention study. Transactions of the Royal Society of Tropical Medicine and Hygiene 94, 85–89. 30. García, H.H., Gilman, R., Tovar, M., et al. (1995) Factors associated with Taenia solium cysticercosis: analysis of nine hundred forty-six Peruvian neurologic patients. American Journal of Tropical Medicine and Hygiene 52, 145–148. 31. Lawson, J.R., Gemmel, M.A. (1983) Hydatidosis and cysticercosis: the dynamics of transmission. Advances in Parasitology 22, 261–308. 32. Spindola Feliz, N., Rojas Wastanino, G., de Haro, Arteaga, L., et al. (1996) Parasite search in strawberries from Irapuato, Guanajuato and Zamora, Michoacán (México). Archives of Medical Research 27, 229–231. 33. Sarti, E., Bronfman, M., Schantz, P., et al. (1993) Estructuración de un proyecto epidemiológico para el control de la Taenia solium. Comparación del uso de quimioterapia masiva contra la teniasis y de la impartición de educación para la salud, como método de intervención de mayor utilidad. Conmemoración Jubileo. Instituto de Investigaciones Biomédicas. UNAM. México DF, México 2, pp. 413–415. 34. Sarti, E. (1989) Epidemiología de la teniasis y cisticercosis. In: Flisser, A., Malagón, F. (eds) Cisticercosis Humana y Porcina, su Conocimiento e Investigación en México. Limus Noriega, México DF, México, pp. 233–242.

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Taenia solium Taeniasis and Cysticercosis in Central America

José Garcia-Noval, Ana L. Sanchez and James C. Allan

Introduction The Central American region, lying between Mexico and Colombia consists of seven countries: Belize, Guatemala, Honduras, El Salvador, Nicaragua, Costa Rica and Panama (Fig. 10.1). The region occupies approximately 524,000 km2 and had a population of approximately 36 million in 1999. Slightly less than one-third of this population lives in Guatemala. Over half the population is rural and the United Nations classified 46% as living in extreme poverty in 1994. In 1999, rates of access to health services varied from 46% (Honduras) to 96% (Costa Rica)1. The region is ethnically diverse: two-thirds of the population being of mixed race, 49% of the Guatemalan population being classified as indigenous American, up to 9% of the population of Nicaragua being Afro-Caribbean and 87% of the population of Costa Rica being of European origin. The region has an estimated population of 3 million pigs. Taenia solium has been recognized in Central America for over a century2. Neurocysticercosis (NC) was reported in Guatemala and Honduras in 1940 and 1956, respectively, and periodically thereafter over the next quarter-century3–8. The first Panamanian report of NC was made in 1984, though T. solium was known to be endemic in Panama for decades prior to this9–12.

The presence of the parasite within the region also has an impact further afield. Data from both Guatemala and Honduras indicate that a significant number of individuals from rural communities, where T. solium is highly prevalent, travel either to Guatemala City or Tegucigalpa for work13,14. Furthermore, migration also occurs to the United States, such that in one study, 9.7% of a rural population, 100 km from Guatemala City were travelling on a regular basis to Guatemala City or the United States for work13. There have been numerous reports of cysticercosis either in Central American immigrants or in visitors to Central America made in the United States, Europe and Japan15–19. Recently, the employment of domestic help from Latin America and in particular Central America has been implicated in an outbreak of cysticercosis in the United States20,21.

Taeniasis From 1951 to 1960, a mean prevalence of 1.13% of T. solium taeniasis was detected in the 157,085 faecal samples examined in the Institute of Tropical Diseases ‘Rodolfo Robles’, Guatemala City10. Of these cases, 83% were aged between 18 and 45 years old and 42% came from rural areas near Guatemala City. From 1983 to 1989, data

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N Belmopan

Belize Caribbean Sea

Guatemala

Honduras

Guatemala City

Tegucigalpa San Salvador

El Salvador

Nicaragua Managua

Pacific Ocean

Costa Rica San Jose Panama City

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Fig. 10.1. Map of Central America showing countries and capital cities.

from health centres in Honduras indicated a mean prevalence of 0.47% of intestinal taeniasis in 365,400 faecal samples22. The Honduran data also brought out significant regional variation in prevalence with rates between 0.06% and 1%. From 1978 to 1987, a survey by the Ministry of Health, Costa Rica recorded a relatively low rate of intestinal taeniasis, with a mean prevalence of 0.05% in 1,176,332 faecal samples examined23. Recent data on rates of taeniasis from rural Central America are available from Honduras and Guatemala13,22,24–26. Rates of up to 6.2%, with an average prevalence of 2% of intestinal taeniasis have been recorded by microscopy in Honduran communities22,25,26. Rates of approximately 1% have been detected by microscopy in Guatemala13,24,27. These data appear to indicate that, in comparison to countries in Latin America, rates in these two countries are high. For instance, average prevalence in Mexico is typically below 0.5%28–33. Interestingly, a study carried out in the United States indicated a prevalence of 4.4% of intestinal taeniasis in Central American migrant workers to North

Carolina but none in migrants from Mexico or Haiti34. Data from field studies in rural areas of Honduras and Guatemala have indicated that T. solium is responsible for 75–100% of all Taenia species worms identified to the species level22,24–26. This contrasts with hospital data from large urban centres where typically no diagnosis to the species level is carried out10,22. There are clear patterns in the distribution of cases of taeniasis within the population of the region. Rates have been demonstrated to vary considerably between, closely situated, communities. For instance, in one study of four similarly sized rural communities, all within 5 km of each other, prevalence rates of taeniasis varied between 1% and 5.7%, with statistically significant differences in prevalence between the communities13. The variations may be linked to socio-economic factors such as sanitation, pig husbandry techniques and rates of pork consumption. Furthermore, within individual communities the inter-household distribution of intestinal taeniasis has been shown to be clustered13,24,25. In the same Guatemalan study,

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rates of taeniasis in household members of indicator cases of the taeniasis were shown to be nearly double that of the general rate of taeniasis in the population (4.7% vs. 2.7%)13. This is consistent with the clustered pattern of intestinal taeniasis reported elsewhere in Latin America28,30,31. Data from both hospitals and rural communities within the region suggest that the highest rates of intestinal taeniasis are in individuals in their late teens to early forties (Fig. 10.2)10,13. Some data suggest that females may be at higher risk than males13,22. Similar sex-biased distributions of intestinal taeniasis have been reported in Ecuador and in Latin American immigrants to the United States35,36. Once again the reasons for this are unknown.

Human Cysticercosis, Neurocysticercosis and Seizures From 1952 to 1961, in a study of hospital records from El Salvador and Guatemala, 118 cases of cysticercosis were detected by autopsy, of which 71 were shown to involve cysts in the brain10. In 1967, a retrospective

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study of 10,600 Costa Rican autopsy reports showed 24 cases of NC (0.23%)37. All the cases were aged above 7 years and the number of the cysts was overdispersed, with 11 of the 24 autopsies (41.6%) disclosing only one cyst, a median of two cysts per person and a maximum of 17 cysts (Fig. 10.3)37. Retrospective review indicated that 11 cases (45.8%) had apparently been neurologically asymptomatic, intracranial hypertension had been diagnosed in 7 cases (29.1%), convulsive crisis in three cases (12.5%) and motor deficit in two cases (8.3%). One case was not classified37. More recent hospital data from Costa Rica demonstrates the continued presence of low levels of human cysticercosis in that country23. When computed tomography (CT) scanning was introduced to Guatemala in 1980, the number of cases of NC diagnosed increased greatly, resulting in the finding that NC accounted for at least 8% of all admissions to neurological wards in Guatemala City38. Similarly, the introduction of CT and ELISA to Honduras in the middle of the 1980s led to a fivefold increase in the number of diagnoses of NC made in University Hospital, Tegucigalpa22.

5.0 4.5 Percentage prevalence

4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 0–4

5–9

10–19

20–29

30 – 39

40 – 49

50 – 59

60 – 80

Age cohort (years) Fig. 10.2. Age prevalence of intestinal taeniasis from a study of four rural communities in Guatemala13. A total of 92 cases were diagnosed from a sample size of 3399 individuals (2.7% prevalence). Of the cases 56 were Taenia solium, one case was T. saginata and in 35 cases it was not possible to determine the species present.

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Number of individuals

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6

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0 1

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3

4

5

6

7

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10 11 12 13 14 15 16 17

Number of cysticerci Fig. 10.3. Distribution of intracerebral Taenia solium cysticerci detected in a retrospective study of autopsy results carried out in Costa Rica37.

Seroepidemiology of human cysticercosis in Central America Studies with the glycoprotein antigen based enzyme-linked immunoelectrotransfer blot (EITB) have provided important insights into the burden of cysticercosis in Central America39. For instance, seroprevalence rates were 10% and 17%, respectively, in two rural communities in Guatemala, whilst seroprevalence rates were 17%, 22% and 34%, respectively, in three different rural populations and 15% in an urban population from Tegucigalpa in Honduras14,24–26,40. These rates would suggest that infection rates in Guatemala and Honduras are higher than those routinely reported from the remainder of Latin America such as Mexico, Peru, Colombia or Bolivia, where rates are generally below 10%31,32,41–45. Indeed, a recent assessment of data from Peru suggested a mean seroprevalence of between 6% and 10% there, although seroprevalence rates of up to 35% have been reported43,46. Studies within Central America have indicated, in common with data from other regions, that infection with intestinal taeniasis

or sharing a house with an intestinal taeniasis carrier are significant risk factors for cysticercosis24. In the Honduran study, several socioeconomic factors were associated with seropositivity including lack of potable water, lack of a sanitary toilet, raising pigs and an earthen floor in the home14. In Guatemala females have been shown to be at higher risk of being seropositive (15% seropositive females vs. 11% seropositive males, odds ratio = 1.45, P0.016)24. Whether this reflects greater exposure to infective eggs in the home environment, or is a reflection of the higher rates of intestinal taeniasis seen in females, reported above, is unknown. This sex-specific difference has, however, not been generally reported elsewhere, even within the region, and so may represent a local phenomenon14,26.

Epidemiology of seizure disorders in Central America Prevalence rates of seizure disorders are high among rural communities throughout the region24,26,47,48. The lowest rate reported to date has been in one Guatemalan study that

Taeniasis and Cysticercosis in Central America

neuroimaging studies than apparently neurologically normal controls (47% vs. 24%, P  0.007) (Fig. 10.4)24. In Honduras, one study in a rural community found 41% of 90 epileptics having lesions compatible with NC40. A second Honduran community study found a 17.6% rate of intracranial lesions suggestive of NC in persons with a normal neurological examination26. Finally, an evaluation of family contacts of an indicator case of cerebral cysticercosis at an urban Panamanian hospital resulted in the detection of three of six other family members as EITB positive and two of six (including one of the three seropositives) as having calcified lesions indicative of NC by CT (Fig. 10.4)52. In the clinical setting, a study in Honduran neurological patients indicated that 84% of individuals with seizures and 69% of those with neurological problems other than seizures had lesions suggestive of NC (Fig. 10.4)53. Furthermore, recent data from Honduras indicate that the two major causes of seizures in that country were neonatal hypoxia, as a result of lack of medical attention during delivery, and NC (Ada Zelaya, National University of Honduras, personal communication). Finally, there is evidence from a Honduran study to suggest

indicated a prevalence of 5.8 cases of active epilepsy per 100048. Combined rates of active and inactive epilepsy in rural Honduras have been recorded at 22.7 per 100049. High rates of active epilepsy have been detected in other studies. For instance, prevalence rates of 29 per 1000 in rural Honduras26 and 18 per 1000 in rural Guatemala50 have been detected. Furthermore, the estimated prevalence in a rural population of Guaymi Indians, living on the Caribbean coast near Costa Rica, was up to 57 per 1000, much higher than the rate of active epilepsy in the lower social class population of Panama City (22 per 1000)51.

Neurocysticercosis and seizure disorder: imaging studies Central American studies carried out in urban centres, rural populations and among neurological patients have all established that cysticercosis is a major cause of morbidity due to seizure disorders throughout the region24–26,40,50,51. Data from two rural Guatemalan communities revealed that individuals with history of seizures had a significantly greater chance of exhibiting abnormal intracranial lesions suggestive of NC upon

Neurological status

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Neurological patients (Honduras)

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Number of individuals

Punctate calcification

Active/mixed lesions

Any abnormality

Seizures

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31 (41%)

9 (12%)

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10 (20%)

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6 (19%)

26 (84%)

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12 (41%)

8 (28%)

20 (69%)

Seizures

1

1 (100%)

No seizures

6

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Fig. 10.4. Correlation between history of seizures and neuroimaging abnormalities detected by CT scan in different populations in Central America: rural village population24; neurological patients52 and trace back to family members of an individual in whom NC was diagnosed51.

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that headache may also be linked to NC53. This link has previously been reported from a rural population in Ecuador and may bear further investigation54. In both field epidemiological studies and studies of neurological patients the most common type of abnormal intracerebral lesions seen by CT scanning have been punctate calcifications (Fig. 10.4)24,26,50,53. Furthermore, studies from the region have indicated that, besides imposing a burden of neurological disease, that, conversely, significant numbers of apparently neurologically normal individuals have abnormal intracranial lesion suggestive of NC14,24–26,50,52. This has led to the suggestion that the majority of cases may, in fact, be asymptomatic as has been suggested in other endemic regions24,26,54,55.

Human cysticercosis and seizure disorder: serological observations Serological testing, particularly using the EITB has been useful in detecting areas of transmission, identifying risk factors associated with infection and producing data that allow comparison both within the region and between Central America and other endemic areas39. In the hospital-based setting, clear associations have been shown between T. solium specific serological status and seizure disorder. This sometimes represents the only recently available data from some countries. For instance, in an ongoing study in Nicaragua, 14.7% of 88 epileptic patients and 2.94% of 102 controls from Leon had antibodies detected by EITB (P0.05, odds ratio = 4.25) (Felix Espinoza, National Autonomous University of Nicaragua, personal communication). Epidemiological studies in the region, and particularly those carried out in endemic communities, have, however, not generally shown an association between either epilepsy or abnormal CT images suggestive of cysticercosis and serological status in this test14,24–26. This contrasts with studies in other areas41,42,46. These interregional variations may be related to the study design. There may, however, be some differences caused by the underlying prevalence and intensity and

location of cystic infections. For instance in Central America there appears to be a relatively high frequency of single active lesions and calcified lesions detected by CT scan in rural populations (see Figs 10.3 and 10.4). It is known that the EITB, though essentially 100% specific for T. solium, is less sensitive in infections involving single cysts and in individuals with calcified lesions56. Furthermore, the high rates of NC in apparently asymptomatic individuals in Central America and the frequency of extraneural infection may further explain the apparent lack of association between serological status and epilepsy in rural Central America. Some studies carried out within the region have, however, demonstrated association between epilepsy and serological status in rural populations. Indeed Panamanian data, collected before the introduction of the glycoprotein-based EITB using an ELISA, demonstrated that significantly more active epileptics were seropositive for cysticercosis than age- and sexmatched controls in a population of Guaymi Indians (44% vs. 6%, relative risk = 14)51.

Porcine Cysticercosis For many years there has been an understanding that porcine cysticercosis imposes a significant economic burden on Central American pork producers10,57,58. In a study carried out across the whole region, except Belize, from 1959 to 1961, it was reported that 68% of all the hogs condemned for any reason in the six main abattoirs serving the capital cities of Guatemala City, San Salvador, Tegucigalpa, Managua, San José and Panama City, were condemned because of cysticercosis10. This represented 2.13% of all the pigs slaughtered over this period in these abattoirs. This situation does not appear to have improved: Honduran figures indicate that, from 1981 to 1986, an average of 4.8% of all pigs slaughtered at the main abattoir serving Tegucigalpa were condemned due to cysticercosis22. Furthermore, in 1994 and 1995 respectively, in the same abattoir, 2.8% and 3% of pigs slaughtered were condemned due to cysticercosis (Alexis Mendoza, PROMDECA, personal communication).

Taeniasis and Cysticercosis in Central America

The failure of the meat inspection process to control this parasite can be seen in data from the mid 1960s, where 6% and 6.5% respectively, of 99 pork sausages and 107 ‘chorizo’ (Spanish type) sausages purchased from a range of randomly selected establishments in Guatemala City were found to harbour cysticerci57. More recent studies from Guatemala revealed that 4% and 14%, respectively, of pigs in two rural communities had cysts present in their tongues ante mortem24. In these respective communities, 22% and 55% of families raised pigs and 77% and 83% of those families that raised pigs allowed them to roam freely in the village. At least 75% of families stated that their main source of pork was pigs killed either at home or in the village with no official meat inspection. In one village 27% of families were aware of having purchased pork containing cysts while in the other community, 6% were aware of this24. Further studies in Guatemala have indicated seroprevalences of antibodies to T. solium antigens using the glycoprotein-based EITB59 of 40% and 64% in pigs from two communities60. Data from Honduras indicate that 27.1% of pigs in one community were seropositive in this test and that pigs may be infected soon after birth, although recent data on the passive transfer of antibodies from infected sows to piglets complicates the interpretation of the serological data61,62.

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Conclusions: Prospects for Control The prospects for control of T. solium within Central America remain poor. None of the countries has a formal comprehensive control system and abattoir meat inspection is ineffective due to slaughter of significant numbers of pigs outside the formal, regulated, system. Further to this, for much of the region, there is a lack, or indeed complete absence of epidemiological data. Without such data to assess the magnitude of the problem, control programmes cannot be either properly planned or implemented. Within the region, one study, carried out in Guatemala, has indicated that mass chemotherapy with niclosamide significantly reduced prevalence of intestinal taeniasis and seroprevalence of cysticercosis in pigs 10 months later60. Whether such an approach is economically or logistically feasible is, in the current economic climate of much of the region, questionable. If regional governments were to identify T. solium as a problem that needed attention, this might improve the situation. The authors are unaware of any initiatives on this parasite backed by any of the regional governments. Similarly, there appears to have been relatively little work undertaken on this parasite by the local scientific, veterinary or public health communities.

References 1. Pan American Health Organization. (1999) Health Situation in the Americas. Basic Indicators. Special Programme for Health Analysis, PAHO, Washington, DC. 2. Herrera, C.T. (1894) Frequent Endemics and Infections in Guatemala. Thesis, Faculty of Medicine, University of San Carlos, Guatemala. 3. Aguilar, F.J. (1989) Natural history of cysticercosis. In: Aguilar, F.J., Masselli, R., Samayao, A. (eds) Cisticercosis. Asociacion Guatemalteca de Parasitologia y Medicina Tropical, Guatemala, pp. 11–15. 4. Aguilar, F.J., Vizcaino, C. (1954) Cysticercosis in Guatemala. Revista del Collegio Medico (Guatemala) 5, 92–98. 5. Alvarez Rubio, O.A., Nazar, H.N. (1989) Neurocysticercosis in the Hospital Escuela. Revista Medica Hondureña 57, 246–260. 6. Cueva, J.A. (1956) Cysticercosis in Honduras. Revista Medica Hondureña 24, 101–111. 7. Duron, R.A. (1967) Human cysticercosis in Honduras. A statistical review. Revista Medica Hondureña 35, 126–131. 8. Hernandez-Gonzalez, L.A., Arrredondo-Mendoza, F., Prado-Castro, J.A. (1990) Racimedullar neurocysticercosis in Guatemala. Description of the ‘floating cystic lesion’ sign. Revista Mexicana Radiologica 44, 165–169. 9. Acuna, E.R., Velasco Aparicio, G., Guzman Aranda, G. (1988) Neurocysticercosis in Panama. Revista Medica Panama de 13, 9–16.

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10. Acha, P.N., Aguilar, F.J. (1964) Studies on cysticercosis in Central America and Panama. American Journal of Tropical Medicine and Hygiene 13, 48–53. 11. Garrick, D. (1967) Current status of brucellosis, tuberculosis, rabies and cysticercosis in Central America and Panama. Bulletin of the Pan American Health Organization 63, 142–150. 12. Paz, J.R. (1973) Present status of cysticercosis in Panama. Boletin Chileno de Parasitologia 28, 100–102. 13. Allan J.C., Velasquez Tohom, M., Garcia Noval, J., et al. (1996) Epidemiology of intestinal taeniasis in four rural Guatemalan communities. Annals of Tropical Medicine and Parasitology 90, 157–165. 14. Sanchez, A.L., Medina, M.T., Ljungström, I. (1998) Prevalence of taeniasis and cysticercosis in a population of urban residence in Honduras. Acta Tropica 69, 141–149. 15. Shimizu, Y., Kagawa, S., Onuma, T. (1986) Cerebral cysticercosis – report of an operated case. No Shinkei Geka 14, 209–213. 16. Ciesielski, S., Seed, J.R., Estrada, J., et al. (1993) The seroprevalence of cysticercosis, malaria, and Trypanosoma cruzi among North Carolina migrant farmworkers. Public Health Reports 108, 736–741. 17. Steinmetz, R.L., Masket, S., Sidikaro, Y. (1989) The successful removal of a subretinal cysticercus by pars plana vitrectomy. Retina 9, 276–280. 18. Chatel, G., Gulletta, M., Scolari, C., et al. (1999) Neurocysticercosis in an Italian traveller to Latin America. American Journal of Tropical Medicine and Hygiene 60, 255–256. 19. Prosser, P.R., Wilson, C.B., Forsham, P.H. (1978) Intrasellar cysticercosis presenting as a pituitary tumor: successful transsphenoidal cystectomy with preservation of pituitary function. American Journal of Tropical Medicine and Hygiene 27, 976–978. 20. Schantz, P.M., Moore, A.C., Munoz, J.L., et al. (1992) Neurocysticercosis in an Orthodox Jewish community in New York City. New England Journal of Medicine 327, 692–695. 21. Moore, A.C., Lutwick, L.I., Schantz, P.M., et al. (1995) Seroprevalence of cysticercosis in an Orthodox Jewish community. American Journal of Tropical Medicine and Hygiene 53, 439–442. 22. Kaminsky, R.G. (1991) Taeniasis–cysticercosis in Honduras. Transactions of the Royal Society of Tropical Medicine and Hygiene 85, 531–534. 23. Arroyo, R. (1989) Taeniasis/cysticercosis in Costa Rica. In: Aguilar, F.J., Masselli, R., Samayao, A. (eds) Cisticercosis. Asociacion Guatemalteca de Parasitologia y Medicina Tropical, Guatemala, pp. 75–79. 24. Garcia-Noval, J., Allan, J.C., Fletes, C., et al. (1996) Epidemiology of Taenia solium taeniasis and cysticercosis in two rural Guatemalan communities. American Journal of Tropical Medicine and Hygiene 55, 282–289. 25. Sanchez, A.L., Gomez, O., Allebeck, P., et al. (1997) Epidemiological study of Taenia solium infections in a rural village in Honduras. Annals of Tropical Medicine and Parasitology 91, 163–171. 26. Sanchez, A.L., Lindbäck, J., Schantz, P.M., et al. (1999) A population-based case-control study for T. solium taeniasis and cysticercosis. Annals of Tropical Medicine and Parasitology 93, 247–258. 27. Allan, J.C., Velasquez Tohom, M., Torres Alvarez, R., et al. (1996) Field trial of diagnosis of Taenia solium taeniasis by coproantigen enzyme linked immunosorbent assay. American Journal of Tropical Medicine and Hygiene 54, 352–356. 28. Diaz Camacho, S.P., Candil Ruiz, A., Suate Peraza, V., et al. (1991) Epidemiologic study and control of Taenia solium infections with praziquantel in a rural village of Mexico. American Journal of Tropical Medicine and Hygiene 45, 522–531. 29. Diaz Camacho, S., Candil Ruiz, A., Uribe Beltran, M., et al. (1990) Serology as an indicator of Taenia solium tapeworm infections in a rural community in Mexico. Transactions of the Royal Society of Tropical Medicine and Hygiene 84, 563–566. 30. Sarti-Gutierrez, E.J., Schantz, P.M., Lara-Aguilera, R., et al. (1988) Taenia solium taeniasis and cysticercosis in a Mexican village. Tropical Medicine and Parasitology 39, 194–198. 31. Sarti, E., Schantz, P.M., Plancarte, A., et al. (1992) Prevalence and risk factors for Taenia solium taeniasis and cysticercosis in humans and pigs in a village in Morelos, Mexico. American Journal of Tropical Medicine and Hygiene 46, 677–685. 32. Sarti, E., Schantz, P.M., Plancarte, A., et al. (1994) Epidemiological investigation of Taenia solium taeniasis and cysticercosis in a rural village of Michoacan state, Mexico. Transactions of the Royal Society of Tropical Medicine and Hygiene 88, 49–52. 33. Rodriguez-Canul, R., Fraser, A., Allan, J.C., et al. (1999) Epidemiological study of Taenia solium taeniasis/cysticercosis in a rural village of Yucatan, Mexico. Annals of Tropical Medicine and Parasitology 93, 57–67. 34. Ciesielski, S., Seed, J.R., Ortiz, J.C., et al. (1991) Intestinal parasites among North Carolina migrant farmworkers. American Journal of Public Health 82, 1258–1262.

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35. Cruz, M., Davis, A., Dixon, H., et al. (1989) Operational studies on the control of Taenia solium taeniasis/cysticercosis in Ecuador. Bulletin of the World Health Organization 67, 401–407. 36. Richards, F.O. Jr, Schantz, P.M., Ruiz-Tiben, E., et al. (1985) Cysticercosis in Los Angeles County. Journal of the American Medical Association 254, 3444–3448. 37. Piza, J., Fernandez, A., Soto, M., et al. (1967) Cerebral cysticercosis. a clinico–anatomical study of 24 cases in Costa Rica. Acta Medica Costaricense 10, 5–17. 38. Arredondo, F. (1989) Computerised tomography in the diagnosis of neurocysticercosis. In: Aguilar, F.J., Masselli, R., Samayao, A. (eds) Cisticercosis. Asociacion Guatemalteca de Parasitologia y Medicina Tropical, Guatemala, pp. 51–55. 39. Tsang, V., Brand, A.J., Boyer, A.E. (1989) An enzyme imunoelectrotransfer blot assay and glycoprotein antigens for diagnosing human Taenia solium cysticercosis. Journal of Infectious Diseases 159, 50–59. 40. Sánchez, A.L., Duron, R., Osorio, J.R., et al. (1998) Evaluation of the enzyme-linked immunoelectrotransfer blot (EITB) assay in epileptic patients from a rural community in Honduras. In: Proceedings of the International Congress of Parasitology, ICOPA IX. Italy, pp. 185–189. 41. Diaz, J.F., Verastegui, M., Gilman, R.H., et al. (1992) Immunodiagnosis of human cysticercosis (Taenia solium): a field comparison of an antibody-enzyme-linked immunosorbent assay (ELISA), an antigen-ELISA, and an enzyme-linked immunoelectrotransfer blot (EITB) assay in Peru. The Cysticercosis Working Group in Peru (CWG). American Journal of Tropical Medicine and Hygiene 46, 610–615. 42. Moro, P.L., Guevara, A., Verastegui, M., et al. (1997) Distribution of hydatidosis and cysticercosis in different Peruvian populations as demonstrated by an enzyme-linked immunoelectrotransfer blot (EITB) assay. The Cysticercosis Working Group in Peru (CWG). American Journal of Tropical Medicine and Hygiene 51, 851–855. 43. Bern, C., García, H.H., Evans, C., et al. (1999) Magnitude of the disease burden from neurocysticercosis in a developing country. Clinical Infectious Diseases 29, 1203–1209. 44. Palacio, L.G., Jimenez, I., García, H.H., et al. (1998) Neurocysticercosis in persons with epilepsy in Medellin, Colombia. The Neuroepidemiological Research Group of Antioquia. Epilepsia 39, 1334–1339. 45. Jafri, H.S., Torrico, F., Noh, J.C., et al. (1998) Application of the enzyme-linked immunoelectrotransfer blot to filter paper blood spots to estimate seroprevalence of cysticercosis in Bolivia. American Journal of Tropical Medicine and Hygiene 58, 313–315. 46. García, H.H., Talley, A., Gilman, R.H., et al. (1999) Epilepsy and neurocysticercosis in a village in Huaraz, Peru. Clinical Neurology and Neurosurgery 101, 225–228. 47. Gracia, F.J., Bayard, V., Triana, E., et al. (1988) Prevalence of neurologic diseases in Belisario Porras municipality, District of San Miguelito, Panama, 1986. Revista Medica de Panama 13, 40–45. 48. Mendizabal, J.E., Salguero, L.F. (1996) Prevalence of epilepsy in a rural community of Guatemala. Epilepsia 37, 373–376. 49. Duron, R., Osorio, J.R., Martinez, L., et al. (1997) Epilepsy in Salama, Honduras: first phase of an epidemiological study. Revista Hondureña de Neurociencias 1, 9–18. 50. Garcia-Noval, J., Moreno, E., de Mata, F., et al. (2001) An epidemiological study of epilepsy and epileptic seizures in two rural Guatemalan communities. Annals of Tropical Medicine and Parasitology 95, 167–175. 51. Gracia, F., de Lao, S.L., Castillo, L., et al. (1990) Epidemiology of epilepsy in Guaymi Indians from Bocas del Toro Province, Republic of Panama. Epilepsia 31, 718–723. 52. Gracia, F., Chavarria, R., Archbold, C., et al. (1990) Neurocysticercosis in Panama: preliminary epidemiologic study in the Azuero region. American Journal of Tropical Medicine and Hygiene 42, 67–69. 53. Sanchez, A.L., Ljungström, I., Medina, M.T. (1999) Diagnosis of human neurocysticercosis in an endemic area: a clinical study in Honduras. Parasitology International 48, 81–89. 54. Cruz, I., Cruz, M.E., Teran, W., et al. (1994) Human subcutaneous Taenia solium cysticercosis in an Andean population with neurocysticercosis. American Journal of Tropical Medicine and Hygiene 51, 405–407. 55. Schantz, P.M., Sarti, E., Plancarte, A., et al. (1994) Community-based epidemiological investigations of cysticercosis due to Taenia solium: comparison of serological screening tests and clinical findings in two populations in Mexico. Clinical Infectious Diseases 18, 879–885. 56. Wilson, M., Bryan, R.T., Fried, J.A., et al. (1991) Clinical evaluation of the cysticercosis enzyme linked immunotransfer blot (EITB) in patients with neurocysticercosis. Journal of Infectious Diseases 164, 107–109.

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57. Zapatel, J., Ubieto, A., Martinez, M. (1965) Cysticerci in processed meat in Guatemala. American Journal of Tropical Medicine and Hygiene 14, 113–116. 58. Schenone, H. (1973) Some considerations on the occurrence of cysticercosis in swine in Latin America. Boletin Chileno de Parasitologia 28, 106–107. 59. Gonzalez, A.E., Cama, V., Gilman, R.H., et al. (1990) Prevalence and comparison of serologic assays, necropsy, and tongue examination for the diagnosis of porcine cysticercosis in Peru. American Journal of Tropical Medicine and Hygiene 43, 194–199. 60. Allan, J.C., Velasquez-Tohom, M., Fletes, C., et al. (1997) Mass chemotherapy for intestinal Taenia solium taeniasis: effect on prevalence in humans and pigs. Transactions of the Royal Society of Tropical Medicine and Hygiene 91, 595–598. 61. Sakai, H., Sone, M., Castro, D.M., et al. (1998) Seroprevalence of Taenia solium in pigs in a rural community of Honduras. Veterinary Parasitology 78, 233–238. 62. Gonzalez, A.E., Verastegui, M., Noh, J.C., et al. (1999) Persistence of passively transferred antibodies in porcine Taenia solium cysticercosis. Cysticercosis Working Group in Peru. Veterinary Parasitology 86, 113–118.

11

Neurocysticercosis in Brazil: Epidemiological Aspects Svetlana Agapejev

Introduction Human and swine cysticercosis is a disease caused by the metacestode larval form (cysticercus cellulosae) of the parasite, Taenia solium. Factors contributing to the endemic nature of taeniasis–cysticercosis are many. Improper disposal of faeces from infected individuals in the absence of sanitary infrastructure, the existence of latrines and vegetable gardens and/or orchards in the vicinity of pig pens especially when irrigated with contaminated water or fertilized with human faeces, allow the swine access to human faeces. Rearing infected swine, manipulation of contaminated meat through unofficial markets, aberrant inspection at slaughterhouses and butchers’ shops and consumption of raw or poorly cooked pork are risk factors for acquiring human taeniasis. Finally, deficient health education and awareness, precarious personal hygiene such as ingestion of unwashed food and handling of food with dirty and contaminated hands, and possibly the use of water from rivers, streams or lakes, directly for consumption are risk factors for human cysticercosis. Several of these risk factors prevail in Brazil giving it one of the highest prevalences of taeniasis–cysticercosis in the world (Fig. 11.1). A review of Brazilian literature on neurocysticercosis (NC) from 1907 to 2000 reveals

a sizeable collection of papers describing the many aspects of the disorder. A major contribution of Brazilian work has been the generation of autopsy (Table 11.1)1–22 and clinical (Table 11.2)23–52 data. In comparison, seroepidemiologic studies are few but nevertheless available (Table 11.3)53–59. This chapter is based on reports selected from an extensive review of papers from accessible Brazilian literature and from more than 25 years of personal observations60. Together, the autopsy, clinical and epidemiological information reflect the epidemiological characteristics of T. solium cysticercosis in Brazil.

Geographical Prevalences Brazil: geography, people and habits Brazil is the fifth largest country in the world and the largest in South America. It has an area of 8512 million km2 and a population of 172,535 million. Most Brazilians are Catholic Christians. Food habits differ regionally and with economic conditions within Brazil. Meat is an important dietary item, although beef is eaten more frequently than pork. However, sausages made of pork are often consumed raw or undercooked. It is traditional practice in North and Northeast Brazil to eat meat after salting it and then drying it

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Fig. 11.1. Some endemic factors for the maintenance of taeniasis/cysticercosis complex: (a) Rubbish near a sign (arrow) saying ‘No rubbish disposal ’. (b) Lake water used for drinking and hygiene for humans (arrows) and swine (foreground). (c) Vegetable garden irrigated with contaminated water from the river (arrow). (d) Contaminated pork at a clandestine slaughterhouse.

in the hot sun. In South and Southeast Brazil, pork is roasted or fried. Brazil is a rapidly developing country, making great strides in industrialization. Piped water supply exists in three-quarters and sewer or septic cesspool facilities in one-half of the homes. The Brazilian Association of Pig Producers has 12 million pigs registered in South Brazil, 9 million in Northeast Brazil, 7 million in Southeast Brazil and 6 million in CentralWest Brazil. This, however, is not a true estimate of the porcine population, since a large number of pigs are raised in backyards or are free ranging. Official data from government sources revealed that the prevalence of swine cysticercosis for the period 1952–91 was 0.03–6.9%, through several regions in Brazil. However, epidemiological surveys estimate that the actual prevalence may be as high as 13–28% in certain regions within Brazil.

Geographic prevalence of NC within Brazil While NC is endemic throughout most of Brazil, definite information about the endemic nature of the disease is available from several states (shown in Fig. 11.2). Other states have non-confirmed occurrence of NC. These projections are mostly derived from hospital-based reports and these may not reflect the true prevalence of disease. For instance, Northeast Brazil is an economically underprivileged area and one would expect large number of cases to be reported from this region. However, this might not be the case as a large proportion of cases may be undiagnosed on account of the lack of investigative facilities like computed tomography (CT). Similarly, it appears from the review of literature that more severe cases like intracra-

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Fig. 11.2. Frequency of human neurocysticercosis in the Brazilian states. (RS: Rio Grande do Sul; SC: Santa Catarina; PR: Paraná; MS: Mato Grosso do Sul; SP: São Paulo; MT: Mato Grosso; MG: Minas Gerais; RJ: Rio de Janeiro; ES: Espírito Santo; TO: Tocantins; FD: Federal District; GO: Goiás; BA: Bahia; SE: Sergipe; AL: Alagoas; PI: Piauí; PE: Pernambuco; PB: Paraíba; AC: Acre; AM: Amazonas; PA: Pará; MA: Maranhão; CE: Ceará; RN: Rio Grande do Norte; RR: Roraima; AP: Amapá.)

nial hypertension and racemose cysticercosis are frequently seen in hospital services in Southern and Southeast Brazil in comparison to North and Northeast Brazil, where most of the hospital-based reports are those of milder varieties of NC. These differences may merely reflect different referral patterns, access to medical care and of expertise in the treatment of more difficult cases in South and Southeast Brazil. Therefore geographical differences in clinical presentations may be more apparent than real (Figs 11.2 and 11.3). From a review of published autopsy and clinical service-based data from 1907 to 2000 and 1915 to 2000, respectively, an average of 600 autopsy diagnoses of NC and 500 clinicoradiological diagnoses of NC were made every year60. Similarly, data available from general

hospitals in Brazil indicate that NC was responsible for about two admissions every month there. These data are at best an underestimate especially since the reporting of taeniasis–cysticercosis is not obligatory in Brazil.

Epidemiological Characteristics Inferred from Autopsy Autopsy is an important tool to confirm clinical diagnosis and estimate disease frequency. Unfortunately, however, resort to autopsy is infrequent in Brazil, primarily owing to factors such as excessive trust in laboratory diagnoses, difficulty in obtaining family authorization, lack of systematic

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(a) North-Northeast Central-West South-Southeast

12.9%

Viable cysts 26%

1.6%

5.2% 4.6%

67%

2.0%

4.0%

1.8%

1.5%

0.4% Autopsy

Clinical series

Seroepidemiology

North-Northeast

(b) 77%

South-Southeast

57% 50% 48%

47%

28%

10% 5% Epilepsy

Intracranial hypertension

Psychiatric disturbance

Headache

Fig. 11.3. Brazilian regional differences in the frequency of neurocysticercosis: (a) and clinical manifestations (b) expressed by the average of the reported incidences.

requirement of obligatory autopsy even in university hospitals, and a high frequency of domiciliary deaths. Since autopsy is difficult to perform in many areas, many cases of disease go unnoticed. There is a lack of uniform protocol for organ examination at autopsy services. Furthermore, slices are usually made at more than 1 cm at autopsy; and as a result, a small pathological lesion may escape detection leading to an underestimation of disease frequency. Survey of necropsy at Legal Medicine institutes and in the popula-

tion may provide a more realistic estimate of the prevalence of NC since ocular globes, skeletal muscles and spinal cord with the nerve roots are analysed in addition to the brain. Nevertheless, NC ranked 19 among pathological diagnoses at autopsy in a general hospital in the city of São Paulo15. The frequency of detection of NC at autopsy in different series in Brazil from 1915 onwards is shown in Table 11.1. A range of frequency from 0.12% to 9.0%, giving an average of 1.5% has been reported1–22,60.

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Table 11.1. Neurocysticercosis in Brazil – frequency based on autopsy studies. Author (publication year) Almeida§1 (1915) Trétiakoff and Silva§2 (1924) Galvão§3 (1928) Povoa§4 (1934) Salles5 (1934) Pinheiro and Mello§6 (1941) Pupo et al.§7 (1945/1946) Montenegro8 (1946) Hellmeister and Faria9 (1973) Guidugli-Neto and Matosinho-França10 (1977) Queiroz and Martinez11 (1979) Gobbi et al.12 (1980) Almeida and Lima13 (1988) Tavares et al.14 (1988) Almeida et al.15 (1989) Vianna et al.16 (1991) Tavares§17 (1994) Agapejev‡18 (1995) Costa-Cruz et al.19 (1995) Chimelli et al.20 (1998) Lino et al.21 (1999) Montemór-Netto et al.22 (2000)

State*

Frequency (%)

Total number of cases†

SP SP SP SP SP SP SP SP SP SP BA MG CE MG SP FD SP MG MG SP MG PR

0.71 3.6 1.6 1.03 0.12 0.43 1.5 2.5 1.78 0.86 0.30 1.60 0.45 9.0 1.5 1.6 1.85 0.77 1.22 1.5 3.3 3.1

1,822 250 997 1,073 4,000 465 1,000 312 1,013 3,587 4,000 2,306 1,773 1,160 200 1,520 3,681 20,741 2,862 2,522 1,596 901

Note: The data refer to frequency of neurocysticercosis and not to cysticercosis in general. *Federal State of Brazil in which the study was conducted (see Fig. 11.2). †Number of studied cases from which those with neurocysticercosis were selected. ‡Studies in general hospitals. §Studies conducted on psychiatric patients.

Numbers reported depend primarily upon the autopsy protocol adopted, the repute of the medical facility in treatment of disease and possibly on the geographical location within Brazil. For instance, high rates of detection of NC have been noted in autopsy series reported from Southeast Brazil (0.1–9.0%) in comparison with Northeast Brazil (0.30–0.45%). Dichotomy also exists in the relative proportions of viable, asymptomatic and symptomatic cysticercosis. In a large series from the state of Bahia in North Brazil, 67% of examined parasites were viable and there was a high proportion of asymptomatic NC11. The latter refers to those autopsies in which the individuals had no symptoms related to NC during life and autopsy revealed incidental cysts. In comparison, data from our centre in Southeast Brazil revealed viable cysticerci in 26% of the autopsies18.

Autopsy data from Brazil also indicate that NC is the primary cause of death in 16–34% of those cases in which it was detected1–22,60. The final cause of death was found to be intracranial hypertension in 47–69% of these cases18,20. Even in autopsies performed in those who had neurological symptoms during life, NC may be an incidental finding in about 26%18. While parenchymal calcifications and viable cysts are the most common incidental findings, autopsy could occasionally reveal asymptomatic intraventricular or cisternal cysticercosis. NC may also be diagnosed at autopsy in those patients who die as a result of other infectious and parasitic diseases such as pulmonary tuberculosis, paracoccidiomycosis, Chagas’ disease and AIDS18,20. Co-infection probably reflects poor socio-economic and health-related conditions that predispose to both infections.

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Prior to the 1980s, when CT was not available, a diagnosis of NC was often made only after death during necropsy. For instance, a definite ante-mortem diagnosis of NC was made on the basis of cerebrospinal fluid examination in only 3.6% of cases in whom autopsy revealed NC. With the advent of CT, this figure rose to 50–63%, demonstrating the dramatic impact of CT upon the diagnosis of NC15,18,43.

Epidemiological Characteristics Inferred from Hospital-based Studies Several large clinical series of patients with NC have been reported from Brazil (Table 11.2). The frequency of NC, the demographic profile and clinical manifestations depend upon the source of the series. For instance, in four general hospitals in São Paulo state, two

Table 11.2. Neurocysticercosis in Brazil – frequency in clinical series. Author (publication year)

State*

Lange¶|23 (1940) Pupo et al.¶|7 (1945/1946) Brotto24 (1947) Spina-França25 (1956) Canelas26 (1962) Silva et al.27 (1965) Camargo-Lima28 (1966) Mega and Lison ¶|29 (1967) Benício** (1970) Reis31 (1970) Manreza§32 (1982) Takayanagui and Jardim33 (1983) Machado et al.‡34 (1988) Chequer and Vieira35 (1990) Clemente and Werneck36 (1990) Vianna et al.37 (1990) Spina-França et al.¶|39 (1993) Agapejev‡18 (1995)

SP SP SP SP SP PE SP SP PE SP SP SP SP ES RJ FD SP SP

Ferreira et al.§40 (1994) Tavares***17 (1994) Azambuja et al.¶|41 (1995) Camargo¶|42 (1995) Gonçalves-Coêlho and Coêlho¶|43 (1996) Freitas and Palermo44 (1996) Takayanagui et al.45 (1996) Andrade46 (1997) Forlenza et al.***40 (1997) Narata et al.¶|48 (1998)

FD MG RS PR PB PA SP BA SP PR

Agapejev49 (1999) Pfuetzenreiter and Ávila-Pires50 (1999) Gomes et al.¶|51 (2000) Silva et al.¶|52 (2000)

SP SC BA RS

Frequency (%)

Total number of cases†

0.31 0.36 2.98 3.39 0.06 3.08 0.03 1.15 1.76 7.5 0.19

12.9 1.13 0.3 6.1 12.2 13.4 4.8 1.02

9.2 3.3

5.0 1.27

Note: The data refer to frequency of neurocysticercosis and not to cysticercosis in general. *Federal State of Brazil in which the study was conducted (see Fig. 11.2). †Number of studied cases from which those with neurocysticercosis were selected. ‡Studies in general hospitals. §Studies limited to paediatric cases. ***Studies conducted on psychiatric patients. **Cited by Schenone et al.30. ¶| Studies based upon complementary tests (e.g. CT, CSF, etc.).

4,200 10 12,361 2,273 4,900 4,600 355 2,500 9,077

500 126,968 45 100 520 135,000 132,480 3,225 10 188 1,088 51,694 4,011 12 262 157 38 2,554 973 299 57 200 6,300

Neurocysticercosis in Brazil

in the capital city and two outside the capital, NC was responsible for 0.1–0.2% and 0.3–2.5% of hospital admissions, respectively60. In comparison, this disorder was responsible for up to 13% of admissions to neurology and neurosurgery services. Headaches and seizures are the most commonly reported symptoms; headaches are more frequent in women, while seizures are more common in men. Seizures occur more frequently in series collected from outpatient departments in Brazil. In available hospital-based reports of series of patients with NC from Brazil, patients are mostly of rural origin (30–79%). However, urban origin becomes more frequent when more severe clinical presentations of NC in children and adults are considered60–62. Skin colour does not seem to be a selection factor since its frequency was proportional to the studied populations, with no significant statistical difference18,46. In the majority of published studies, the most affected age group is 11–60 years, with a frequency of 22–67% between 21 and 40 years60. In general, there is a predominance of males (51–80%) in most series20,22,46,51,60,61. However, severe manifestations are more commonly reported among females47,48,50,60,63. The period of hospitalization for patients with NC ranges from 1 to 254 days. Most patients require hospitalization for about a week18,34. Nearly one half of the patients require multiple admissions (up to nine, in Brazilian literature)18,34,35. The mortality rate in several of the general hospital based series in Brazil is low (approximately 0.3%). However, among patients with NC, the mortality rate is 4.8–25.9%18,25,26,33,34,37. NC is responsible for 0.6–3.6% of hospital deaths due to neurological disorders in Brazil. When studies from neurosurgical departments are evaluated, the mortality may be as high as 60%64.

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quency of 2–6% in radiological investigations20,22,45,60. Several studies have addressed the frequency of diagnosis of NC among patients referred to CT scan units38,41,43,48,52,61. While these numbers give us an idea of the frequency of NC in comparison to other neurological disorders, they cannot be extrapolated to establish prevalence of the disease in the community. In addition, the frequency may depend upon whether the CT unit is that of a general hospital or a specialized neurological facility. In most of such published series from Brazil, a diagnosis of NC was made in 1–2% of the CT examinations38,41,43,48,52,61. More meaningful is the fact that the commonest CT abnormality in these reports has been either single or multiple parenchymal calcifications38,41,43,48,52,61.

Compulsory Notification The study of frequency and manifestations of NC seen in a single hospital does not reflect actual disease prevalence and patterns, since they are largely dependent on the pattern of referral to that hospital. Compulsory notification is a more accurate estimate of disease frequency and patterns45. Compulsory notification in Ribeirão Preto, São Paulo, established a prevalence of 54/100,000 inhabitants45. While compulsory notification is useful in estimating the prevalence of clinically overt NC, it would not be able to detect the large number of asymptomatic cases known to exist.

Community-based Serological Studies The seroepidemiology of human cysticercosis has not been systematically studied with the help of contemporary methods of evaluation. Some of the earlier studies have been based upon indirect haemagglutination and ELISA (reviewed in Table 11.3)52–59.

Epidemiological Data Inferred from Imaging Facilities Conclusions While asymptomatic forms of NC (cases with no neurological manifestations during life) are often diagnosed at autopsy, they can also be detected as an incidental finding with a fre-

A plethora of clinical, hospital-based and autopsy reports of human cysticercosis are available from Brazil. These reports suggest

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Table 11.3. Neurocysticercosis in Brazil – seroepidemiological studies. Author (publication year)

State*

Ueda et al.53 (1984) Vianna et al.54 (1986) Arruda et al.55 (1990) Vaz et al.56 (1990) Silva-Vergara57 (1995) Lonardoni et al.58 (1996) Biondi et al.‡ (1998) Pires et al.59 (2000)

SP FD PR SP MG PR AL MA

Total number of cases†

Frequency (%)

824 1122 1168 821 1080 2180 736 756

0.87 5.2 0.68 2.30 1.94 3.2 1.9 6.22

Note: The data refer to incidence of positive reactions for cysticercosis in serum. * Federal State of Brazil in which the study was conducted (see Fig. 11.2). †Number of studied cases from which those with cysticercosis were selected. ‡Biondi, G.F., Nunes, C.M., Cruz, J.M.C., et al., 1998 – unpublished observations.

that human cysticercosis is an important public health problem there; however, they do not provide a true estimate of the disease prevalence. Compulsory notification of the disease is a useful method that has been

evaluated on a preliminary basis in Brazil. It needs to be applied on a wider basis in order to determine areas of high prevalence. Once this is done, control measures may be preferentially applied to these areas.

References 1. Almeida, W. (1915) [Contribution of autopsy to clinical study of cerebral cysticercosis.] Archivos Brasileiros de Psychiatria, Neurologia e Medicina Legal 11, 229–264. 2. Trétiakoff, C., Silva, A.C.P. (1924) [Contribution to the study of cerebral cysticercosis and in details the farther toxic brain lesions in this infection.] Memorias do Hospício de Juquery 1, 37–66. 3. Galvão, S.T. (1928) [Incidence and Prophylaxis of Cysticercosis and Hydatidosis in São Paulo.] Thesis, University of São Paulo, Brazil. 4. Povoa, H. (1932) [Cerebral cysticercosis.] Folha Médica 13, 241–246. 5. Salles, J.M.M. (1934) [Cerebral Cysticercosis.] Thesis, University of São Paulo, Brazil. 6. Pinheiro, J., Mello, A.R. (1941) [Considerations about cerebral cysticercosis.] Archivos Brasileiros de Medicina 31, 192–212. 7. Pupo, P.P., Cardoso, W., Reis, J.B., et al. (1945/1946) [On brain cysticercosis. Its clinic, pathology, radiology and cerebrospinal fluid syndrome.] Arquivos de Assistência aos Psicopatas do Estado de São Paulo 10/11, 3–123. 8. Montenegro, J. (1946) [Blindness caused by brain cysticercosis.] Revista Paulista de Medicina 29, 348–356. 9. Hellmeister, C.R., Faria, J.L. (1973) [Neurocysticercosis. Necropsy details.] Revista da Associação Médica Brasileira 19, 281–282. 10. Guidugli-Neto, J., Matosinho-França, L.C. (1977) [Neurocysticercosis: necroscopic study.] Revista Médica do IAMSPE 8, 65–67. 11. Queiroz, A.C., Martinez, A.M.B. (1979) [The involvement of the central nervous system in cysticercosis.] Arquivos de Neuropsiquiatria 37, 34–41. 12. Gobbi, H., Adad, S.J., Neves, R.R., et al. (1980) [Occurrence of cysticercosis (Cysticercus cellulosae) in necropsied patients in Uberaba – MG, Brazil.] Revista de Patologia Tropical 9, 51–59. 13. Almeida, Y.M., Lima, J.H.C. (1988) [Neurocysticercosis in the state of Ceará: necropsy findings.] Revista da Sociedade Brasileira de Medicina Tropical 11 (Suppl.), 97. 14. Taveras, A.R., Valadares-Neto, D., Pittella, L.E.M. (1988) [Frequency of neurocysticercosis at the Hospital of Clinics of the Federal University of Minas Gerais confirmed by neuropathologic examination.] Arquivos de Neuropsiquiatria 46 (Suppl.), 75.

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15. Almeida, M.C., Couto, L.A.A.M., Silva, L.H.F., et al. (1989) [Correlation between anatomo-clinical diagnosis and retrospective assessment of clinical diagnosis in post mortem.] Revista de Saúde Pública (São Paulo) 23, 285–291. 16. Vianna, L.G., Macedo, V., Costa, J.M. (1991) Musculocutaneous and visceral cysticercosis: a rare disease? Revista do Instituto de Medicina Tropical de São Paulo 33, 129–136. 17. Taveras, A.R. (1994) [Neuropsychiatric Aspects in Human Neurocysticercosis.] Thesis, Federal University of São Paulo, Brazil. 18. Agapejev, S. (1995) Incidence of Neurocysticercosis at the University Hospital, Faculty of Medicine, State University of São Paulo. (Abstract). Thesis. University of São Paulo, Brazil. Arquivos de Neuropsiquiatria 53, 170–171. 19. Costa-Cruz, J.M., Rocha, A., Silva, A.M., et al. (1995) [Occurrence of cysticercosis in autopsies performed in Uberlândia, Minas Gerais, Brazil.] Arquivos de Neuropsiquiatria 53, 227–232. 20. Chimelli, L., Lovalho, A.F., Takayanagui, O.M. (1998) [Neurocysticercosis: contribution of autopsies to consolidation of the compulsory notification in Ribeirão Preto – SP, Brazil.] Arquivos de Neuropsiquiatria 56, 577–584. 21. Lino, R.S., Reis, M.A., Teixeira, V.P.A. (1999) [Occurrence of encephalic and cardiac cysticercosis (Cysticercus cellulosae) in necropsy.] Revista de Saúde Pública (São Paulo) 33, 495–498. 22. Montemór-Netto, M.R., Gasparetto, E.L., Faoro, L.N., et al. (2000) [Neurocysticercosis: a clinical and pathological study of 27 necropsied cases.] Arquivos de Neuropsiquiatria 58, 883–889. 23. Lange, O. (1940) [Cerebrospinal fluid syndrome in encephalic and meningeal cysticercosis.] Revista de Neurologia e Psiquiatria de São Paulo 6, 35–48. 24. Brotto, W. (1947) [Neurologic aspects of cysticercosis.] Arquivos de Neuropsiquiatria 5, 258–294. 25. Spina-França, A. (1956) [Central nervous system cysticercosis. Considerations about 50 cases.] Revista Paulista de Medicina 48, 59–70. 26. Canelas, H.M. (1962) [Neurocysticercosis: incidence, diagnosis and clinical pictures.] Arquivos de Neuropsiquiatria 20, 1–16. 27. Silva, W.F., Ataide, L., Chiappetta, J. (1965) [Neurocysticercosis: a proposal of 3 cases.] Neurobiologia 28, 51–58. 28. Camargo-Lima, J.G. (1966) [Brain Cysticercosis. Clinical Aspects.] Thesis. Federal University of São Paulo, Brazil. 29. Mega, D., Lison, M.P. (1967) [Hypoglycorachie et cysticercose cérébro-méningée.] Schweizerisch Archiv für Neurologie, Neurochirurgie und Psychiatrie 100, 425–430. 30. Schenone, H., Ramirez, R., Rojas, A. (1973) [Epidemiological aspects of neurocysticercosis in Latin America.] Boletin Chileno de Parasitologia 28, 61–72. 31. Reis, J.B. (1970) [Incidence of Neurocysticercosis at the Department of Neurology and Neurosurgery of the São Paulo School of Medicine During the Period of 1939–1969.] Thesis. Federal University of São Paulo, Brazil. 32. Manreza, M.L.G. (1982) [Neurocysticercosis in childhood: clinical aspects and diagnosis.] Revista do Hospital das Clínicas da Faculdade de Medicina de São Paulo 37, 206–211. 33. Takayanagui, O.M., Jardim, E. (1983) [Clinical aspects of neurocysticercosis: study of 500 cases.] Arquivos de Neuropsiquiatria 41, 50–63. 34. Machado, A.B.B., Pialarissi, C.S.M., Vaz, A.J. (1988) [Human cysticercosis in a general hospital in S. Paulo, Brazil.] Revista de Saúde Pública (São Paulo) 22, 240–244. 35. Chequer, R.S., Vieira, V.L.F. (1990) [Neurocysticercosis in the state of Espírito Santo, Brazil: evaluation of 45 cases.] Arquivos de Neuropsiquiatria 48, 431–440. 36. Clemente, H.A.M., Werneck, A.L.S. (1990) [Neurocysticercosis: incidence in the Rio de Janeiro State.] Arquivos de Neuropsiquiatria 48, 207–209. 37. Vianna, L.G., Macedo, V., Mello, P., et al. (1990) [Clinical and laboratory study of neurocysticercosis in Brasília.] Revista do Brasileira de Neurologia 26, 35–40. 38. Bruck, I., Antoniuk, A.S., Wittig, E., et al. (1991) [Neurocysticercosis in childhood I. Clinical and laboratory diagnosis.] Arquivos de Neuropsiquiatria 49, 43–46. 39. Spina-França, A., Livramento, J.A., Machado, L.R. (1993) Cysticercosis of the central nervous system and cerebrospinal fluid. Immunodiagnosis of 1573 patients in 63 years (1929–1992). Arquivos de Neuropsiquiatria 51, 16–20. 40. Ferreira, M.S., Costa-Cruz, J.M., Nishioka, S.A., et al. (1994) Neurocysticercosis in Brazilian children: report of 10 cases. Tropical Medicine and Parasitology 45, 49–50. 41. Azambuja, N.D., Ambrós, S., Vanzin, J., et al. (1995) [Neurocysticercosis calcifications in computed tomography: a report of the Department of Radiology of HSVP.] Revista do Hospital São Vicente de Paula 7, 14–19.

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42. Camargo, N.J. (1995) Epidemiological situation of taeniasis/cysticercosis in the state of Paraná (Southern part of Brazil) and strategie for its control. PAHO/AMRO WHO Informal Consultation. 43. Gonçalves-Coêlho, T.D., Coêlho, M.D.G. (1996) Neurocysticercosis in Paraíba, Northeast Brazil – an endemic area? Arquivos de Neuropsiquiatria 54, 565–570. 44. Freitas, J., Palermo, E.N. (1996) [Taeniasis–cysticercosis complex in Northern Brazil.] Brazilian Journal of Veterinary Research and Animal Science 33, 270–275. 45. Takayanagui, O.M., Castro e Silva, A.A.M.C., Santiago, R.C., et al. (1996) [Compulsory notification of cysticercosis in Ribeirão Preto – SP.] Arquivos de Neuropsiquiatria 54, 557–564. 46. Andrade, A.S. (1997) [Neurocysticercosis: Clinical, Epidemiological and Diagnostic Aspects – Prospective Study of 157 Patients in Northeastern Region – Bahia, Brazil.] Thesis. Federal University of Rio de Janeiro, Brazil. 47. Forlenza, O.V., Guerra-Vieira, A.H., Nóbrega, J.P.S., et al. (1997) Psychiatric manifestations of neurocysticercosis: a study of 38 patients from a neurology clinic in Brazil. Journal of Neurology, Neurosurgery and Psychiatry 62, 612–616. 48. Narata, A.P., Arruda, W.O., Uemura, E., et al. (1998) [Neurocysticercosis: a CT-scan study in a series of neurological patients.] Arquivos de Neuropsiquiatria 56, 245–249. 49. Agapejev, S. (1999) Standardization of tomographic indexes of the fourth ventricle and its characteristics in patients with neurocysticercosis (Abstract). Thesis. University of the State of São Paulo, Brazil. Arquivos de Neuropsiquiatria 57, 147–148. 50. Pfuetzenreiter, M.R., Ávila-Pires, F.D. (1999) [Clinical manifestations in patients with computerized tomography diagnosis of neurocysticercosis.] Arquivos de Neuropsiquiatria 57, 653–658. 51. Gomes, J., Veiga, M., Correa, D., et al. (2000) Cysticercosis in epileptic patients of Mulungo do Morro – Northeastern Brazil. Arquivos de Neuropsiquiatria 58, 621–624. 52. Silva, J.E., Diefenthaler, A.P., Palma, J.K. (2000) Frequency of suspected cases of neurocysticercosis detected by computed skull tomography in Santa Maria, RS Brazil. Revista do Instituto de Medicina Tropical de São Paulo 42, 57–58. 53. Ueda, M., Nakamura, P.M., Waldman, E.A., et al. (1984) [Frequency of anti-Cysticercus cellulosae antibodies in a population with risk of cysticercosis in a considered normal population segment in regions of the state of São Paulo, Brazil.] Revista do Instituto Adolfo Lutz 44, 25–28. 54. Vianna, L.G., Macedo, V., Costa, J.M., et al. (1996) [Seroepidemiologic study of human cysticercosis in Brasília, Distrito Federal.] Revista da Sociedade Brasileira de Medicina Tropical 19, 149–153. 55. Arruda, W.O., Camargo, N.J., Coelho, R.C. (1990) Neurocysticercosis. An epidemiological survey in two small rural communities. Arquivos de Neuropsiquiatria 48, 419–424. 56. Vaz, A.J., Hanashiro, A.S.G., Chieffi, P.P., et al. (1990) [Frequency of patients with anti-Cysticercus cellulosae antibodies in 5 municipalities of the state of São Paulo.] Revista da Sociedade Brasileira de Medicina Tropical 23, 97–99. 57. Silva-Vergara, M.L., Aluizio, P., Vieira, C.O., et al. (1995) [Epidemiological aspects of cysticercosis due to Taenia solium in the endemic area of Lagamar, MG.] Revista da Sociedade Brasileira de Medicina Tropical 28, 345–349. 58. Lonardoni, M.C.V., Bertolini, D.A., Silveira, T.G.V., et al. (1996) Frequency of anti-Cysticercus cellulosae antibodies in individuals from five counties in the southern region of Brazil. Revista de Saúde pública (São Paulo) 30, 273–279. 59. Pires, M.A.S., Barbosa, S.P.F., Gonçalves-Pires, M.R.F., et al. (2000) Frequency of IgG anti-cysticercus cellulosae antibodies in a human population of the São Luiz Island – MA, between March and June. Annals of the XIII Sao Paulo State Journal of Parasitology, p. 35. 60. Agapejev, S. (1996) Epidemiology of neurocysticercosis in Brazil. Revista do Instituto de Medicina Tropical de São Paulo 38, 207–216. 61. Trevisol-Bittencourt, P.C., Silva, N.C., Figueredo, R. (1998) [Prevalence of neurocysticercosis among epileptic in-patients in the west of Santa Catarina – southern Brazil.] Arquivos de Neuropsiquiatria 56, 53–58. 62. Morales, N.M.O., Agapejev, S., Morales, R.R., et al. (2000) Clinical aspects of neurocysticercosis in children. Pediatric Neurology 22, 287–291. 63. Dantas, F.L.R., Fagundes-Pereira, W.J., Souza, C.T., et al. (1999) [Intramedular cysticercosis: Case report.] Arquivos de Neuropsiquiatria 57, 301–305. 64 Colli, B.O., Martelli, N., Assirati, J.A. Jr, et al. (1994) Cysticercosis of the central nervous system. I. Surgical treatment of cerebral cysticercosis. A 23 years experience in the Hospital das Clínicas of Ribeirão Preto Medical School. Arquivos de Neuropsiquiatria 52, 166–186.

12

Taenia solium Taeniasis and Cysticercosis in Asia

Gagandeep Singh, Sudesh Prabhakar, Akira Ito, Seung Yull Cho and Dong-Chuan Qiu

Introduction

Indonesia

Taenia solium infections remain widely prevalent throughout Asia, Africa and South and Central America. A large number of community-based, epidemiological surveys carried out in several Latin American countries, provide accurate information on the burden of T. solium taeniasis and cysticercosis in these countries (see Chapters 8–10). In this regard, a series of investigations in Peru stands apart in terms of their completeness and accuracy of portrayal of the status of disease there (see Chapter 8). In contrast, precise epidemiological proportions of T. solium infection have not been defined adequately in most Asian countries. All we know is that the disease does exist in several countries like Indonesia, China, India and Nepal. More accurate data are, however, lacking. Information regarding taeniasis–cysticercosis is now available from Indonesia1. In the present review, several researchers review available knowledge about the situation of T. solium cysticercosis in their countries, with particular emphasis upon Indonesia, India, Korea, China and Japan.

Geography, people, customs and food habits Indonesia comprises 17,000 islands, of which 6000 are inhabited2. The islands are situated on the archipelago between the Indian and Pacific Oceans, straddling the equator. Important islands include Java, Sumatra, Borneo, Bali and Irian Jaya (now called West Papua Guinea). The last mentioned comprises the western half of New Guinea, the other eastern half of which is a separate country, namely Papua New Guinea (formerly East Irian Jaya) (Fig. 12.1). Indonesia has a landed area of 1.8 million km2 and a population of 21 million. About 88% of the population is Moslem, the remaining 12% consists of Christians, Hindus and Buddhists2. Certain islands have a majority of non-Moslem communities, for instance of Christians in Irian Jaya and Hindus in Bali. Some 80% of the people live in the countryside. Reliance upon traditional sanitary practices and inadequate cooking of infested pork are principal reasons for the high prevalence of T. solium taeniasis and cys-

© CAB International 2002. Taenia solium Cysticercosis (eds G. Singh and S. Prabhakar)

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Philippines Pacific Ocean Malaysia

Irian Jaya Borneo

Sumatra

Papua New Guinea South Sulawesi Flores

Java Indian Ocean

Bali

Timor Australia Traditionally endemic areas

0

500

km

INDONESIA

Areas rendered highly endemic after introduced disease Areas threatened to become endemic

Fig. 12.1. Geographical representation of Taenia solium endemic regions in Indonesia.

ticercosis in Indonesia. For instance, the tribal inhabitants of Bali use the dwellings of their domestic animals, called ‘teba’, for ablution3. In Irian Jaya, an undeveloped tribal habitat with complete lack of sanitary understructure, people defecate in their house-yards and gardens and allow freeranging pigs to clear the excrement at nighttime. As if to complete the human– pig–human cycle, the Balinese traditional festival dish, ‘lavar’ is made from minced raw pork, mixed with coconut and spices4. In Irian Jaya, male tribals frequently feast upon pork that is inadequately cooked with cassava in earthen ovens during tribal ceremonies5. Women are permitted to consume the dish only after childbirth. Human and porcine cysticercosis are infrequent in the Moslem dominated regions of Indonesia1. However, they constitute major health and economic problems in Irian Jaya, Bali, Timor, Flores, Samosir Island of North Sumatra, Lampung in South Sumatra, West Kalimantan and Sulawesi (Fig. 12.1)1,6,7. In these islands, the estimated prevalence varies between 2% in Bali and 48% in Irian Jaya, the latter being one of the highest reported figures in the world1,6,7.

Intestinal taeniasis Intestinal taeniasis is common in Bali, Sumatra and Samosir Island, but beef Taenia sp. and Asian Taenia sp. are believed to be more common than pork Taenia sp.5,8–11. Recent data is available from a study by Sutisna and co-workers12. They reported three instances of Taenia sp. infection among 415 faecal samples surveyed in Bali; at a species level, one was T. solium, while the other two were T. saginata. The occurrence of T. solium taeniasis in Irian Jaya has been recognized only lately. Indeed several of the surveys of intestinal parasitism, which were undertaken in the 1950s and 1960s, indicated a complete absence of T. solium infection in this region. Thus, in at least two separate communitybased coproparasitic surveys, van der Hoeven and Rijpstra13 (1957), and Kelly and Vines14 (1966), could not find a single case of T. solium infection in Central Irian Jaya and neighbouring Papua New Guinea. The earliest report of human intestinal T. solium infection in the Wissel Lakes area of Irian Jaya was probably made in 197315. Several workers have recently examined the prevalence of intestinal T. solium infection in Irian Jaya. Margono and

Taeniasis and Cysticercosis in Asia

co-workers6,7,16, and other workers17,18, have reviewed these studies and found that the reported prevalence varied from 8% to 51%. The prevalence of intestinal taeniasis in other islands has not been studied in a comprehensive manner, but rates in excess of 5% of the faecal samples examined have been noted in North Sumatra and Timur16,19,20.

Porcine cysticercosis High levels of porcine infection have been noted throughout Indonesia, particularly Bali and Irian Jaya. More accurate data to indicate the prevalence of porcine cysticercosis is recently available from Irian Jaya17. Approximately 24% of pigs examined in Jayawijaya, Irian Jaya were noted to be heavily infected and 74% (50 of 71 examined) demonstrated serological evidence of exposure to T. solium17. The spread of a zoonotic disorder through transport of animals across geographical boundaries is typically exemplified by the story behind the occurrence of T. solium cysticercosis in Irian Jaya. Porcine cysticercosis was not known to occur in Irian Jaya prior to the 1970s. A mass transport of cysticercotic pigs was undertaken from Bali to Irian Jaya in the early 1970s and the taeniasis–cysticercosis epidemic in Irian Jaya followed.

Dog cysticercosis The consumption of canine meat and brain is customary among tribals of Irian Jaya. It might be interesting to speculate that the dog may also be involved in the transmission cycle of T. solium. In this context, parallel may be drawn from evidence of T. saginata taeniasis arising from consumption of undercooked reindeer brain in the former USSR21. Indeed, some recent studies using serological markers suitable for humans and swine have demonstrated serological evidence of exposure (to T. solium) among dogs in Indonesia22,23. Moreover, T. solium cysticerci have also been recovered from seropositive dogs (Ito et al., Jakarta, Indonesia, unpublished data).

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Human cysticercosis In 1983, Coker-Vann and co-workers, reported an estimated prevalence of 21% of anticysticercus antibodies in sera based upon ELISA among inhabitants of Bali24. In other regions, such as Samosir and Nias, the prevalence of seropositivity was lower, in the range of 3–4%24. More recent data have revealed the continued presence, in low to moderate levels, of anticysticercus seropositive status in Bali. Thus, Theis et al. reported an immunoblot-based seropositivity to be 13%25. Serological prevalence was highest in the age group 21–30 years, with no preference for any gender. In comparison to the high prevalence found by Theis et al.25, Sutisna and co-workers12 determined a seropositive status in only 1.65% of a population surveyed in Bali. All seropositive cases were from one district only, suggesting regional variations with regard to the seroprevalence of cysticercosis on the island of Bali. While human cysticercosis has been known in Bali since at least the 1920s9,26–28, its occurrence in Irian Jaya is a recent phenomenon1. Tumada and Margono were the first to report T. solium cysticercosis in 12 patients in the Wissel Lakes area of Central Irian Jaya in 197315. Several other authors followed with reports of widespread infection among Ekari tribals of this region29–32. In 1978, Subianto et al. reported an unprecedented increase in hospital admissions due to high-degree burns between 1973 and 1976 in Central Irian Jaya31. Burns were believed to be caused by nocturnal seizures in tribals who slept by community fires during winter nights. Seizures were recorded in 63%, subcutaneous nodules were found in 33% and intestinal T. solium infection was demonstrated in 16% of 157 individuals, who were hospitalized with burns31. To build up on the story of the epidemic, while cysticercosis was recognized in Central Irian Jaya in the 1970s it was then unheard of in West Irian Jaya or the neighbouring Papua New Guinea. However, there is recent evidence of the spread of the epidemic to East and South Irian Jaya.

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Wandra et al. reported 120 burn casualties and new onset seizures in 293 individuals among a community of 15,000 in Jayawijaya district in East Irian Jaya33. Histopathological examination of subcutaneous cysts removed from a number of affected individuals confirmed the diagnosis of cysticercosis. Over the years, cross-border migration between Indonesian Irian Jaya and Papua New Guinea has given rise to concerns about the disease getting established in Papua New Guinea34. In fact, in 1990, Fritzsche et al. detected a serologically confirmed cases of cysticercosis among Irianese refugees in Papua New Guinea35. More recently, however, a survey found 3% of the population of Papua New Guinea to be seropositive and among them, local inhabitants were also positive18.

Philippines The estimated prevalence of T. solium taeniasis in Philippines is about 2%36. In one survey of over 200,000 stool examinations in Manila and elsewhere within the country, the prevalence of T. solium infection was 0.02%37. The estimated prevalence of porcine cysticercosis is 0.16%38. A Medline search indicated several reports of isolated cases and series of NC originating from Philippines39,40.

Hong Kong and Singapore Published reports indicate the occurrence of both indigenous and imported cases in Hong Kong, now part of China41,42. Local or indigenous cases result from consumption of pork imported from the Chinese mainland42. With specific reference to exotic cases, Heap reported that a diagnosis of cysticercosis was quite common in Nepalese Gurkha recruits in the Territorial Army43. The Gurkhas presumably acquired infection while in Nepal. CokerVann et al. surveyed three different ethnic communities using an anticysticercus ELISA and determined an overall prevalence of 8%24. Rates were highest among individuals of Chinese origin (13%) in comparison to those of Indian (5%) or Malay (3%) origin24. While

Singapore is a developed country, it is ‘at-risk’ for T. solium cysticercosis, given the high volume of travel to and from this country.

Vietnam, Cambodia and Laos Studies in the post-Vietnam war period focused on morbidity patterns among war veterans and refugees. Among various illnesses, a high rate of helminthiasis was described in war veterans and refugees by several authors44–47. Several case reports from medical facilities affirmed the occurrence of T. solium cysticercosis in good numbers in Vietnam48–50. In 36 children convalescing from a flu-like illness in Vietnam, 3% of the serum samples were positive for anticysticercus antibodies, when tested in an ELISA in 1972–197324. Contemporary data is now available; Brandt et al. reported reported a seropositivity of 5.7% among inhabitants of North Vietnam51, while reliable estimates of seropositivity are around 8% in Hanoi and 10% in Cambodia and Laos (Carlo Urbani, Hanoi, Vietnam, personal communication).

Thailand According to Vejjajiva, T. solium infestation is uncommon in Thailand52. However, reports of sporadic case and series have been made from several hospitals located throughout Thailand53–57. These indicate that low levels of infection do exist in this country. A recent report from a provincial general hospital in Surin, in Northeast Thailand, alluded to the frequent occurrence of solitary cysticercus granulomas57. There, a solitary cysticercus granuloma was identified in 110 (11%) of 972 patients with a seizure disorder over a 3-year period.

Myanmar One of the earliest Asian reports of cysticercosis was made from Myanmar (Burma) (1912)58. However, a review of literature, including a Medline search did not

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reveal a single recently published report of the disorder originating from Myanmar. Surely, this must be because of lack of awareness rather than the lack of occurrence of T. solium infections. Coker Vann et al. performed a serological study in a local population using an ELISA format and found anticysticercus antibodies in 6% of the samples surveyed24.

Malaysia and Bangladesh Malaysians are mostly Moslems and hence do not consume pork. Accordingly T. solium cysticercosis is recognized only infrequently in this country (Zim Abdul Rashid, Kuala Lumpur, Malaysia, personal communication). Similarly, Islam is the official and most widely endorsed religion in Bangladesh. Hence, indigenous cases of T. solium taeniasis and cysticercosis do not occur (Muzuharal Mannan, Dhaka Neurological Foundation, personal communication).

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India Geography, people, customs and food habits India is located in subtropical South Asia. With a population of over one billion, it is the second most populated nation in the world. About 80% of the population is Hindu, 14% is Moslem and the remaining 6%, of several religions. The average literacy rate is 52%. About 80% of the people live in villages2. A good majority of the population in India is vegetarian59. Animal proteins account for about 20% of protein intake in India, in comparison with 58% in developed countries60. An unimaginable disparity exists in the geography, ethnicity, religion, food and personal habits, level of education and standards of living within the country. The above listed factors have direct bearing on the frequency of T. solium infection and, consequently, there is significant variation in the frequency of T. solium cysticercosis throughout the country (Fig. 12.2).

Jammu and Kashmir New Delhi Uttar Pradesh Bihar Assam

Calcutta

Kerala

Areas believed to be endemic Areas where transmission possibly exists Areas with no or very few local cases

Fig. 12.2. Geographical representation of regions within India, from where Taenia solium taeniasis and cysticercosis have been reported in considerable numbers.

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Porcine cysticercosis The estimated pig population in India is 15.4 million59. The density of pigs in the plains of North India (states of Uttar Pradesh, Bihar, Haryana and Punjab) is high and is estimated at 10–18 km2 61. Here, the pig industry largely consists of domestic pig rearers who follow the scavenging system, where pigs are allowed to free range in the morning and are enclosed in unhygienic pens at night61. Data collected from abattoirs from several locations in Uttar Pradesh in the northern plains revealed cysticercal infestation in the muscles of 8–12% of the slaughtered pigs62. Another survey of slaughterhouses in Calcutta in eastern India revealed cysticercus cellulosae infestation in 7% of the slaughtered pigs63.

Human taeniasis Public health and hospital records of British soldiers posted in India in the early part of the 19th century were extremely useful for calculation of the incidence of T. solium taeniasis64. At that time, it was customary to admit individuals with diagnosed taeniasis to hospital on account of the complexity and toxicity of its treatment. Thus, between 1928 and 1932, a total of 774 British soldiers were admitted to hospital because of taeniasis. All of them were assumed to have acquired the infection while in India, because T. solium infection did not exist in Britain at that time. Therefore, all cases were presumed to be new and not existing cases. During this period, approximately 58,000 British troops were stationed in India. This gave a calculated incidence of at least 1.3%. Infection was most commonly reported from the United Provinces (presently, Uttar Pradesh) (Fig. 12.2)64. More recent data has indicated the persistence of T. solium infestation in significant proportions in the areas mentioned above as well a variation in the prevalence throughout the country. A stool survey of 1074 outpatients and inpatients in a hospital in Calcutta revealed Taenia sp. infestation in 12 (1.11%)63. When identified to a species level, T. solium could be identified in only a single instance.

Another hospital-based evaluation of nearly 250,000 faecal samples in Northwest India revealed a prevalence of T. solium of 0.5–2%65. When faecal samples were examined in a community-based survey in Uttar Pradesh, a prevalence of 2% was determined62. A survey of 2559 faecal samples in Sikkim in East India indicated a prevalence of 3.9%66. Prevalence was highest among Lepkhas, Tibetians and Bhotiyas and was comparatively less among Hindus and Nepalese66. Taenia solium taeniasis is less of a problem in South India67,68and in the northern state of Kashmir69. Community based surveys in Tamil Nadu67and the Andaman and Nicobar Islands68 have revealed a high prevalence of geohelminthiasis but no cases of Taenia sp. infection. On the other hand, in Kashmir, where the population is predominantly Moslem, high prevalence of T. saginata infestation was found but no cases of T. solium were encountered in one survey69.

Human cysticercosis There is virtually no population-based data that gives information about the community burden, risk behaviours and geographical predilections of T. solium cysticercosis in India. Medical facility-based data is however available in the form of large series of patients with neurocysticercosis (NC). Health care providers all over the country with the exception of a few states such as Kerala70 in the extreme Southeast and Kashmir (Sushil Razdan, Jammu, India, personal communication) in the extreme north (Fig. 12.2), do see large number of patients with NC. Thus, when pre-computed-tomography (CT) era hospital records of a large referral hospital in Madras, South India were analysed, NC accounted for 0.005% of all neurological admissions71. At a tertiary care neurological referral service in the capital, New Delhi, NC constituted 2.5% of all intracranial spaceoccupying lesions72. In another tertiary hospital in Northwestern India, a survey of over 6000 consecutive autopsy protocols revealed cerebral cysticercosis in 48 (0.75%)65. Intensive evaluations of an unselected series of epileptics at a tertiary-care neurological

Taeniasis and Cysticercosis in Asia

facility in Banglore, South India, in the period when CT and magnetic resonance imaging (MRI) were not accessible, revealed a diagnosis of cerebral cysticercosis in 2%73. With the availability of CT and MRI, the proportion of seizures due to cerebral cysticercosis rose. Thus Murthy and Ravi, from Hyderabad in South India, diagnosed cerebral cysticercosis in 220 (8.7%) of an unselected group of 2537 consecutive patients with seizure disorder74. Similarly, Sawhney et al. noted cerebral cysticercosis in 49 (31%) of 158 patients among a series of 407 patients with seizure disorder in whom a CT scan was done75. In both series, solitary cerebral cysticercus granulomas predominated. Within the country, NC appears to be more prevalent in the northern region including the states of Bihar, Uttar Pradesh through Punjab. Other states also have a fair proportion of disease with the possible exception of Kerala, where low levels of disease reflect efficient sanitation, pig husbandry and a superior socio-economic and educational status and in Kashmir with its predominant Moslem population, where the consumption of pork is forbidden. Experience with contemporary tools of epidemiogical evaluation such as the enzyme-linked immunoelectrotransfer blot (EITB) is limited76. An EITB-based sero-survey of household family contacts of children with solitary cysticercus granulomas found anticysticercus antibodies in 27% of the family contacts. These figures are high because they are from a population that is at risk of exposure, possibly due to consumption of common food items and similar socio-economic and sanitary conditions as with index cases with solitary cysticercus granuloma.

Nepal A systematic evaluation of the dimensions of the problems related to T. solium cysticercosis has not been undertaken in this Himalyan nation with an area of 140,000 km2 and a population of 24 million. The disorder has been recognized as a major health hazard in the country only lately as is evident from few recent reports from major referral hospi-

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tals77,78. Amatya and Kimula collected 62 cases of cysticercus skin mucosal and breast nodules out of a total of 23,402 biopsies over a 5-year period at the Patan Hospital in the capital city of Kathmandu77. Cases were drawn from all over the country, though the majority were from the capital city itself. Most patients were less than 30 years of age. Data from neurological facilities indicate that NC is the commonest cause of symptomatic seizures in Nepal79. Both solitary and multiple forms of cerebral cysticercosis are seen, though the former predominates.

Sri Lanka According to Senanayake (Peradinya, Sri Lanka, personal communication), NC, including the solitary cysticercus granuloma, which occurs very commonly in several neighbouring countries, does not occur locally in Sri Lanka.

China China has an area of 9.5 million km2 and a population of 1.2 billion. The country is divided by the river Yangtze into two: the warm tropical south and the cold and dry north. About 70% of the population is rural. There is a substantial portion of the population that is Buddhist, Taoist or Moslem, important because these communities do not consume pork. China also has the largest pig population in the world. The Food and Agricultural Organization estimated in 1997 that there were 4.6 billion pigs in China59. Despite this, levels of pork consumption do not approach those noted in the Western Hemisphere. Nevertheless, the conditions do exist in China that may perpetuate the pig–human–environment cycle. Surveys in Yunnan Province indicated that significant numbers of the Pumi and Bai minorities ate raw meat80,81. Surveys in rural portions of the Shandong Province revealed that pigs were rarely corralled, human defecation was indiscriminate and awareness of the means to recognize infected pork was lacking82,83.

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Neurocysticercosis has been reported from hospitals all over China. Yingkun et al. collected a series of 158 cases between 1956 and 1974 at a large hospital in Beijing84. Most clinic-based data is however not published or is published in Chinese scientific literature, to which the rest of the world’s scientific community has poor access.

Intestinal taeniasis Adult T. solium infection is distributed broadly throughout China. Confirmed cases have been noted in at least 28 provinces. Neimeng, Henan, Shandong, Hebei and Anhui are considered hyperendemic, while other provinces like Guangxi, Guizhou, Yunnan, Sichuan and Tibet have moderate prevalence of intestinal infection85. The National Investigation of Human Parasitic Diseases estimated an average prevalence of 0.112%; however, in certain regions, local prevalence rates were as high as 0.66–6.0%86. The investigation estimated that there were approximately 1.26 million persons with adult T. solium in the entire country. Several regional surveys have indicated varying levels of infection in different provinces within China. For instance, between 1975 and 1987, a coproparasitological evaluation of over 34,000,000 individuals in Henan Province revealed T. solium taeniasis in 0.55%87. Investigations in other regions have yielded similar results: Shandong – 0.8%88; Jinan, Taian and Laiwu City – 0.1%89; Yunnan – 6.93%; Dali City (Louyi village of Eryuan county) – 19.5%; Jilin (Yanji City) – 0.11%; Liaoning (Shengyang and Dalian cities) – 0.005%80; Sichuan (Xide county) – 4.0%90 and Fujian (Xianyou county) – 0.13%91.

Human cysticercosis The earliest report of confirmed human cysticercosis from China was made in 193092. The National Investigation of Human Parasitic Diseases revealed that T. solium cysticercosis was reported from 671 counties in 29 provinces within China93. Five zones of high endemicity have been described: (i) Northeast provinces; (ii) North China (including Hebei,

Neimeng and Shanxi), (iii) Northwest China (including Ganxu, Ningxia and Qinghai); (iv) a fourth zone comprising of Shandong, Henan, Anhui and Hubei; and (v) finally, a fifth zone comprising of Guangdong, Guangxi, Hainan, Yunnan and Sichuan (Fig. 12.3). Sporadic cases have also been reported from the provinces of Jiangshu, Shanghai, Zhejiang, Fujian, Taiwan, Guizhou, Xinjiang and Tibet. Most epidemiological studies have focused on the prevailing situation in Shandong Province82,83,89. Here, 38 clinical cases were detected among 35,512 patients examined in 2000, giving a frequency of 0.2%89. In this province, a seroprevalence (with a specific IgG4 antibody) of 2.2% was noted89. In another study using the indirect fluorescent antibody assay, a seroprevalence of 3.2% was found83. Seropositivity rates increased with age and were highest in persons over 60 years of age. Other factors that were significantly associated with seropositivity were indiscriminate defecation, inability to identify diseased pork and raising pigs. Outside the Shandong Province seropositivity rates are reportedly low94: Haerbin city of Helongjiang Province – 4.3%95; Liaoning Province – 0.02%96; Henan Province – 0.1–1.2%97,98 and Sichuan – 0.8%97. Higher seroprevalence rates have however been noted in the Pumi nation area of Yunnan Province (11.2%)81 and Guangxi (9.5%)99.

Korea Intestinal taeniasis During the past three decades, Taenia infection has decreased steadily in Korea. In a series of national surveys for intestinal helminth infections, undertaken every 5 years, the egg positive rates of Taenia species were 1.9% in 1971, 0.7% in 1976, 1.1% in 1981, 0.3% in 1986, 0.06% in 1992 and 0.002% in 1997, respectively, when one random sample of 1000 people was examined by stool microscopy100. In interpreting these data, low sensitivity of stool microscopy for detecting Taenia infection should be considered. However, the decreasing trend has well been depicted in the consecutive surveys.

Fig. 12.3. Geographical representation of Taenia solium endemic regions in China.

Zone 5

Zone 4

Zone 3

Zone 2

Zone 1

Non-endemic area

300

0

300

600

Miles

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ally before the 1990s. The egg positive rate has always been the highest in Cheju Province, although the infections were found throughout the country (Fig. 12.4). Except for a few academic surveys, mass chemotherapeutic control has not been undertaken in Korea against intestinal Taenia infections. Instead, taeniafuges such as bithionol (marketed since 1964), niclosamide (since 1976) and praziquantel (since 1981) were allowed to be available to the public, and infected individuals can purchase the drug without prescription.

By examining morphology of Taenia expelled after chemotherapy, the proportion of T. solium was found in the wide range of 4.1–36.7%101 among the Taenia egg passers. As of 1997, the least number of infected people with two species of Taenia was about 9000, which were mostly aged people older than 60 years, living in rural Korea. From them, nationwide number of T. solium infection could be estimated as being in the range of 400–3200 out of 46 million people in Korea. The present intestinal infections are regarded as persisting ones contracted actu-

Pyongyang

Seoul

Not surveyed < 2.5% 2.5–4.9%

Pusan

5.0–7.4% > 7.5%

Cheju Fig. 12.4. Geographic map of Korea depicting major geographical foci of Taenia solium taeniasis and cysticercosis.

Taeniasis and Cysticercosis in Asia

Porcine cysticercosis Porcine infections with T. solium metacestodes had been as high as 7.4% in Cheju Province where pigs had been reared in pigpens in each household102. Swine infection rates also decreased steadily throughout the 1970s to 0.4–0.5%. After 1986, no more swine infections were found when the Governor of Cheju Province banned the use of pigpens. However, the principal reason of disappearance of measly pork in the Korean market was the modernization of the pig breeding industry. In 1980, about half of the pigs came to market from farm households. However, industrialized pig breeding, which started in the 1960s by instigation of an Irish Catholic Mission, has dominated the market since the mid-1980s. It is believed that the transmission cycle from pig to human infection of T. solium ceased in 1985.

Human cysticercosis The earliest report of human cysticercosis in Korea was made in 1937. Thereafter, sporadic case reports continued. Since the 1960s when the industrialization drive began and farmers migrated to industrial areas, the demand for animal proteins increased. During the same period, modernized pig breeding also began, but most pigs originated from farmhouses. Therefore in addition to sporadic cases of cysticercosis from rural areas, urban cases of subcutaneous cysticercosis, orbital and intraocular cysticercosis (which represented recent transmission and active infections) were frequently reported in literature in the 1970s103. One such report described that out of 657 patients with benign and malignant skin tumours, observed in Seoul during 1960–1972, 114 (24.3%) were caused by T. solium cysticercosis104. Out of 174,770 biopsy specimens submitted to the surgical pathology department of a University hospital in Seoul during 1968–1987, 580 cases (0.33%) were diagnosed as parasitic diseases. Of them, 216 (37.2%) were due to cysticercosis105. Cases of NC were also reported during the 1970s.

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In the 1980s, innovative progress was achieved in diagnosis and patient management of NC including brain imaging by CT/MRI106, chemotherapeutics such as praziquantel107, and antibody test by ELISA108. As a result of the progress, it was found that at least 12.6% of 206 adult-onset epilepsy patients in 1982–1985 were diagnosed as due to cysticercosis109. An epidemiological study for anti-T. solium metacestode antibodies was also undertaken. The antibody positive rate was 3.1% in epilepsy patients while that in normal population was 1.8%110. Since 1984, a multi-antigen screening system has been set up for specific antibodies to three helminth parasites. During 7 years from 1990 to 1997, a total of 10,802 neurological patients with abnormal brain images were examined for the antibody levels. Of them, 1580 (14.6%) were positive for anti-T. solium antibodies in either serum or cerebrospinal fluid or both111. After experiencing epidemic cysticercosis in the early industrialization period, the situation of T. solium cysticercosis in Korea has improved nowadays because of progress in sanitation and pig husbandry. Innovative diagnostics and chemotherapeutics, together with improved patient care, have lessened the social burden caused by the disease. However, even if the transmission cycle of intestinal T. solium infection is stopped, morbidity and mortality due to NC will continue for decades because of the long-term nature of this larval disease.

Japan Masuda et al. reviewed available published and unpublished information on 345 cases of T. solium cysticercosis reported in Japan112. Subsequently, Nishiyama and Araki added more cases to their review, giving a total of 389 cases from 1908 till 1999. Of these 325 were Japanese; 168 were from the Okinawa Island, where an endemic focus existed before the Second World War. Among others, there were 20 Chinese, 22 Koreans, one Indian and 21 of whom no record of nationality was available112,113. In most of the cases reviewed, there was no evidence to suggest adult Taenia infection;

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presumably these cases acquired infection either during overseas travel or through persons of foreign origin in Japan. Over the last few years, between five and ten cases were detected every year in Japan114–117. At the Asahikawa Medical College, most cases were in workers who visit endemic countries115,117,118. However, two cases reported by Masuda et al. and Ohnishi et al. are of interest since both had no history of overseas travel and apparently acquired the disease locally in Japan112,116. This raises the possibility of an outbreak of cysticercosis such as the one reported in New York in an orthodox Jewish community that never travelled abroad but nevertheless acquired cysticercosis through household food handlers from endemic countries119,120.

West Asia (including Pakistan, Afganistan, Iran, Iraq and the Arabian Peninsula) Most of West Asia is almost exclusively Moslem. Human and porcine cysticercosis does not occur in these locations, though, given the high rate of travel to Arabia, the diagnostic possibility may be considered in foreigners who present with appropriate clinical features121.

Conclusions Asia is a colossal mix of contrasting geographies, cultures, religions and economies. Understandably, therefore, remarkable variations are observed in the prevalence of T. solium-taeniasis and cysticercosis in the continent. There are developed countries with high standards of sanitation such as Japan and Singapore, where T. solium infection is virtually non-existent, apart from an occasional imported case in overseas travellers or immigrants. There are also a number of Moslem countries in West Asia, but also others such as Malaysia, where the consumption of pork is forbidden on religious grounds. Here again, though for a different reason, T. solium infection does not occur. There are also few rapidly developing economies such as Korea, Thailand and Taiwan, where T. solium infection was a major health problem in the past, but its impact is now on the decline. In contrast, there are a number of developing countries such as Indonesia, China, India and Nepal, where a significant burden of disease is believed to exist. Finally, there are a number of countries such as Vietnam, Cambodia, Myanmar and Bhutan for which no current information is available about the status of T. solium infection but levels of infection can be imagined to be high.

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McManus, D.P. (1995) Improved diagnosis as an aid to better surveillance of Taenia solium cysticercosis, a potential public health threat to Papua New Guinea. Papua New Guinea Medical Journal 38, 287–294. Fritzsche, M., Gottstein, B., Wigglesworth, M.C., et al. (1990) Serological survey of human cysticercosis in Irianese refugee camps in Papua New Guinea. Acta Tropica 47, 69–77. Cross, J.H. (1988) Biotechnology research on cestodes in the Philippines, Malaysia and Indonesia. Southeast Asian Journal of Tropical Medicine and Public Health 19, 41–45. Hinz, E. (1984) Human Helminthiases in the Philippines. The Epidemiology and Geomedical Situation. Springer-Verlag, Berlin, pp. 166–170, 266–268. Arambulo, P.V., Cabrera, B.D., Tongson, M.S. (1976) Studies on the zoonotic cycle of Taenia saginata taeniasis and cysticercosis in the Philippines. International Journal of Zoonoses 3, 77–104. Quimosing, E.M., Conde, J., Cross, J.H. (1984) Subcutaneous and cerebral cysticercosis treated with praziquantel. Southeast Asian Journal of Tropical Medicine and Public Health 15, 201–205. Jarin, P. Cysticercosis presenting as a tongue mass. UP-PGH ENT Journal. http://www.cm.upm.edu. ph/dept/ent/journal 2.html Ko, R.C. (1991) Current status of food-borne parasitic zoonoses in Hong Kong. Southeast Asian Journal of Tropical Medicine and Public Health 22, 42–47. Woo, E., Yu, Y.L., Huang, C.Y. (1988) Cerebral infarct precipitated by praziquantel in neurocysticercosis – a cautionary note. Tropical Geographic Medicine 40, 143–146. Heap, B.J. (1990) Cerebral cysticercosis as a common cause of epilepsy in Gurkhas in Hong Kong. Journal of Royal Army Medical Corps 136, 146–149. Colwell, E.J., Welsh, J.D., Boone, S.C., et al. (1971) Intestinal parasitism in residents of the Mekong delta of Vietnam. Southeast Asian Journal of Tropical Medicine and Public Health 2, 25–28. Berke, R., Wagshol, L.E., Sullivan, G. (1972) Incidence of intestinal parasites in Vietnam veterans. Eosinophilia – a guide to diagnosis. American Journal of Gastroenterology 57, 63–67. Picher, O., Aspock, H. (1980) Frequency and significance of parasitic infections in refugees from Vietnam. Wiener Medizinische Wochenschrift 130, 190–193. King, P.A., Duthie, S.J., Ma, H.K. (1990) Intestinal helminths in pregnant Vietnamese refugees. Transactions of the Royal Society for Tropical Medicine and Hygiene 84, 723. Pham, H.T., Van Knapen, F. (1989) Preliminary report of praziquantel treatment of cysticercosis patients in Vietnam. Acta Leiden 57, 229–233. Pascoe, M., Saines, N., Lyall, I., et al. (1987) Cerebral cysticercosis: a case report with particular reference to recent advances in diagnosis and treatment. Australian and New Zealand Journal of Medicine 17, 55–57. Perry, H.D., Font, R.L. (1978) Cysticercosis of the eyelid. Archives of Ophthalmology 96, 1255–1257. Brandt, L. (2000) Taenia solium cysticercosis in Northern Vietnam. Third Seminar on Food-borne Parasitic Diseases; Food, Water and Parasitic Zoonoses in the 21st Century, Bangkok, Thailand, 95pp. Vejajiva, A. (1977) Neurology in Thailand. In: Spillane, J.D. (ed.) Tropical Neurology. Oxford University Press, Oxford, UK, pp. 335–352. Vanijanouta, S., Bunnag, D., Riganti, M. (1991) The treatment of neurocysticersosis with praziquantel. Southeast Asian Journal of Tropical Medicine and Public Health 22, 275–278. Morakote, N., Nawacharoen, W., Sukonthasun, K., et al. (1992) Comparison of cysticercus extract, cyst fluid and Taenia saginata extract for use in ELISA for serodiagnosis of neurocysticercosis. Southeast Asian Journal of Tropical Medicine and Public Health 23, 77–81. Chotmongkol, V., Silarugs, S. (1992) Transient paralytic attacks with cerebral cysticercosis. Southeast Asian Journal of Tropical Medicine and Public Health 23, 165–166. Bhoopat, W., Poungarin, N., Issaragrisil, R., et al. (1989) CT diagnosis of cerebral cysticercosis. Journal of Medical Association of Thailand 72, 673–681. Yodnopaklow, P., Mahuntussanapong, A. (2000) Single small enhancing CT lesions in Thai patients with acute symptomatic seizures: a clinico-radiological study. Tropical Medicine and International Health 5, 250–255. Krishnaswami, C.S. (1912) Case of Cysticercus cellulosae. Indian Medical Gazette 47, 43–44. Anonymous. FAO Production Yearbook, 1997–98. Food and Agriculture Organization of the United Nations, Rome, Italy 1998. Griggs, D. (1993) International variations in food consumption. Geography 3, 251–266. Sastry, N.S.R. (1995) Livestock Sector of India: Regional Aspects. International Book Distributing Co., Lucknow, India. Pathak, K.N., Gaur, S.N. (1989) Prevalence and economic implications of Taenia solium taeniasis and cysticercosis in Uttar Pradesh state of India. Acta Leiden 57, 197–200.

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63. Ratnam, S., Khanna, P.N., Bandyopadhyay, A.K. (1983) Incidence of taeniasis in man. Indian Journal of Public Health 27, 70–74. 64. Dixon, H.B.F., Lipscomb, F.M. (1961) Cysticercosis: an analysis and follow-up of 450 cases. Medical Research Council Special Report Series 299, 1–58. 65. Mahajan, R.C. (1982) Geographical distribution of human cysticercosis. In: Flisser, A., Willms, K., Laclette, J.P., et al. (eds) Cysticercosis: Present State of Knowledge and Perspectives. Academic Press, New York, pp. 39–46. 66. Mitra, S., Patwari, A. (1998) Intestinal taeniasis in Sikkim. Journal of the Association of Physicians of India 45, 124–126. 67. Kang, G., Mary, S., Mathew, D., et al. (1998) Prevalence of intestinal parasites in rural southern Indians. Tropical Medicine and International Health 3, 70–75. 68. Sugunan, A.P., Murhekar, M.V., Sehgal, S.C. (1996) Intestinal parasitic infection among different population groups of Andaman and Nicobar Islands. Journal of Communicable Diseases 28, 253–259. 69. Patwari, A., Aneja, S., Singh, G., et al. (1980) A study of taeniasis in children. Indian Pediatrics 17, 515–517. 70. Kuruvilla, A., Pandian, J.D., Nair, M.D., et al. (2001) Neurocysticercosis: a clinico-radiological appraisal from Kerala state, South India. Singapore Medical Journal 42, 297–303. 71. Ramamurthi, B., Balasubramaniam, V. (1970) Experience with cerebral cysticercosis. Neurology India 18, 89–91. 72. Wani, M.A., Banerjee, A.K., Tandon, P.N., et al. (1981) Neurocysticercosis – some uncommon presentations. Neurology India 29, 58–63. 73. Mani, A., Ramesh, C.K., Ahuja, G.K., et al. (1974) Cysticercosis presenting as epilepsy. Neurology India 22, 30. 74. Murthy, J.M.K., Ravi, Y. (1995) The syndromic classification of the International League Against Epilepsy: a hospital based study from South India. In: Chopra, J.S., Sawhney, I.M.S. (eds) Progress in Neurology. BI Churchill Livingstone, New Delhi, India, pp. 53–67. 75. Sawhney, I.M.S., Lekhra, O.P., Chopra, J.S. (1995) Evaluation of epilepsy management and future guidelines for a developing country. In: Chopra, J.S., Sawhney, I.M.S. (eds) Progress in Neurology. BI Churchill Livingstone, New Delhi, India, pp. 28–37. 76. Singh, G., Ram, S., Kaushal, V., et al. (2000) Risk of seizures and neurocysticercosis in household family contacts of children with single enhancing lesions. Journal of the Neurological Sciences 176, 131–135. 77. Amatya, B.M., Kimula, Y. (1999) Cysticercosis in Nepal: a histopathologic study of sixty-two cases. American Journal of Surgical Pathology 23, 1276–1279. 78. Shrestha, S.P., Henning, A., Pradhan, D., et al. (1999) Subconjunctival and intraocular cysticercosis in Nepal. Tropical Doctor 29, 251–253. 79. Rajbhandari, K.C. (2000) Clinical profile of epilepsy with neurocysticercosis in Nepal. In: Proceedings of the Third Congress of Asian Oceanian Epilepsy Organization, New Delhi, pp. 18. 80. Fang, W., Lian, Z.Q., Fang, C., et al. (1996) The investigation of infection actuality and epidemic factors of Taenia solium taeniasis/cysticercosis in Bai minority of Dali, Yunnan. Journal of Practical Parasitic Diseases 4, 62. 81. Wang, H.Z., Zhang, H.M., Zhang, L.L., et al. (1997) The seroepidemiological survey of cysticercosis in Pumi minority focusing region of Yunnan Province. The Chinese Journal of Prevention and Care of Parasitic Diseases 10, 306. 82. Cao, W., van der Ploeg, C.P., Xu, J., et al. (1997) Risk factors for human cysticercosis morbidity: a population-based case control study. Epidemiology and Infections 119, 231–235. 83. Cao, W., van der Ploeg, C.P., Gao, C.L., et al. (1996) Seroprevalence and risk factors of human cysticercosis in a community of Shandong, China. Southeast Asian Journal of Tropical Medicine and Public Health 27, 279–285. 84. Yingkun, F., Shan, O., Xiuzhen, Z., et al. (1979) Clinicoelectroencephalographic studies of cerebral cysticercosis, 158 cases. Chinese Medical Journal 92, 770–786. 85. Li, W., Ma, Y. (1995) The epidemiological status of Taenia solium taeniasis in China. Henan Preventive Medicine Journal 6, 44–45. 86. Wang, Z. (1991) The Address to the Meeting of National Antiparasitic Diseases. Guilin, pp.1–4. 87. Ma, Y.X. (1991) The status and countermeasure of prevention and cure of echinococcosis and cysticercosis in China. The Chinese Journal of Prevention and Care of Parasitic Diseases (Suppl.) 4, 50–52.

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88. Liu, X., Deng, X.L., Zhao, Z.P., et al. (2000) The epidemiological survey of Taenia solium taeniasis/cysticercosis in the center of Shangdong Province. The Chinese Journal of Prevention and Care of Parasitic Diseases 13, 34–36. 89. Zhou, K.X. (1998) The epidemiology and prevention of Taenia solium taeniasis/cysticercosis in China. The Chinese Journal of Prevention and Care of Parasitic Diseases 11, 344–345. 90. Zhou, G.X., Zhang, G.H., Wang, S.Y., et al. (1993) The epidemiological survey of Taenia solium taeniasis/cysticercosis in Xide County of Sichuan. Journal of Practical Parasitic Diseases 1, 25–27. 91. Xu, X.R., Yin, H.Z., Chen, B.J., et al. (1998) The prevention and cure of Taenia solium taeniasis/cysticercosis in Xianyou County. The Haixia Journal of Preventive Medicine 4, 53–54. 92. Zhao, W.X. (1983) The Human Parasitology, 1st edn. People’s Sanitation Publishing Co., Beijing, China, pp. 492–509. 93. Xu, L.Q., Jiang, Z.X., Zhou, C.H., et al. (1999) The investigation of cysticercosis’s distribution in China. The Chinese Journal of Prevention and Care of Parasitic Diseases 12, 30–32. 94. Li, X.C., Sun, D.P., Hu, B.Y., et al. The epidemiological survey of Taenia solium taeniasis/cysticercosis and the study of corresponding countermeasure in Gunzhou City. The Chinese Journal of Prevention and Care of Parasitic Diseases 12, 150. 95. Ji, K.B., Tong, S.F., Liu, Y.L., et al. (1996) The seroepidemiological survey of cysticercosis in Ha Erbin City. The Chinese Journal of Prevention and Care of Parasitic Diseases 9, 313. 96. Li, F.H., Xu, J.T., Sun, T., et al. (1998) The epidemiological investigation of human Taenia solium taeniasis/cysticercosis in Liaoning Province. The Chinese Public Health Journal 14, 227–228. 97. Li, Y., Mo, Q.X., Wang, H., et al. (1997) The investigation of epidemic situation and epidemic factors of Taenia solium taeniasis/cysticercosis in Xiayi county. The Henan Journal of Preventive Medicine 8, 9–10. 98. Wang, Z.Q., Ma, Y.X., Cui, J., et al. (1999) The seroepidemiological survey of human Taenia solium taeniasis/cysticercosis in Weishi County of Henan Province. The Chinese Journal of Prevention and Care of Parasitic Diseases 12, 236–237. 99. Mai, F.Z., Xie, Z.Y., Lu, X.G., et al. (1999) The seroepidemiological survey of Taenia solium taeniasis/cysticercosis in the minority focusing region of Guangxi. The Guangxi Journal of Preventive Medicine 5, 121. 100. Ministry of Health and Welfare, Korea Association of Health (1997) Prevalence of Intestinal Parasitic Infections in Korea: the Sixth Report, pp. 1–287. 101. Rim, H.J., Song, K.W., Joo, K.H., et al. (1980) An epidemiological note on the taeniasis in Korea. Korean Journal of Parasitology 18, 235–240. 102. Han, H.R. (1969) A survey on Cysticercus cellulosae infection in swine of Cheju-Do. Korean Journal of Public Health 6, 23–28. 103. Lee, K.T., Kim, C.H., Park, C.T., et al. (1966) Cysticercosis and taeniasis in Chollapukdo Province. Korean Journal of Parasitology 4, 39–45. 104. Cho, B.K., Houh, W., Shim, S.I., et al. (1973) A study on 657 skin tumors. Korean Journal of Dermatology 11, 3–8. 105. Chi, J.G., Sung, R.H., Cho, S.Y. (1988) Tissue parasitic diseases in Korea. Journal of Korean Medical Science 3, 51–62. 106. Chang, K.H., Kim, W.S., Cho, S.Y., et al. (1988) Comparative evaluation of brain CT and ELISA in the diagnosis of neurocysticercosis. American Journal of Neuroradiology 9, 125–130. 107. Rim, H.J., Lee, J.S., Joo, K.H., et al. (1982) Therapeutic trial of praziquantel (Embay 8440; Biltricide) on the dermal and cerebral human cysticercosis. Korean Journal of Parsitology 20, 169–190. 108. Cho, S.Y., Kim, S.I., Kang, S.Y., et al. (1986) Evaluation of enzyme-linked immunosorbent assay in serological diagnosis of human neurocysticercosis using paired samples of serum and cerebrospinal fluid. Korean Journal of Parasitology 24, 25–41. 109. Han, S.H., Myung, H.J. (1986) A clinical study on epileptic seizures of late onset. Journal of Korean Neurological Association 4, 218–226. 110. Kong, Y., Cho, S.Y., Cho, M.S., et al. (1993) Seroepidemiological observation of Taenia solium cysticercosis in epileptic patients in Korea. Journal of Korean Medical Science 8, 145–152. 111. Cho, S.Y., Kong, Y., Kang, S.Y., et al. (1997) Multi-antigen screening for antibodies to three helminthes parasites in neurologic patients in Korea. Proceedings of the Third Korea-Japan Parasitologists’ Seminar, pp. 39–41. 112. Masuda, H., Niida, M., Nakamura, N., et al. (1980) Cysticercosis in Japan: one case after 30 years of infection with reference of 345 reported cases. Showa Medical College Journal 40, 669–688.

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113. Nishiyama, T., Araki, T. (1999) Cysticercosis: clinical and epidemiological aspects. Progress in Medical Parasitology in Japan, 7, 263–274. 114. Miyake, H., Takahashi, K., Tsuji, M., et al. (1993) A surgical case of solitary cerebral cysticercosis. No Shinkei Geka 21, 561–565. 115. Ohsaki, Y., Matsumoto, A., Miyamoto, K., et al. (1999) Neurocysticercosis without detectable specific antibody. Internal Medicine 38, 67–70. 116. Ohnishi, K., Murata, M., Nakane, M., et al. (1993) Cerebral cysticercosis. Internal Medicine 32, 569–573. 117. Ito, A., Nakao, M., Itoh, Y., et al. (1999) Neurocysticercosis case with a single cyst in the brain showing a dramatic drop in specific antibody titers within 1 year after curative resection. Parasitology International 48, 95–99. 118. Ito, A., Nako, M., Sako, Y., et al. (2000) Neurocysticercosis and echinococcosis in Asia: recent advances in the establishment of highly reliable differential serodiagnosis for international collaboration. Southeast Asian Journal of Tropical Medicine and Public Health 31 (Suppl. 1), 16–20. 119. Schantz, P.M., Moore, A.C., Munoz, J.L., et al. (1992) Neurocysticercosis in an orthodox Jewish community in New York City. New England Journal of Medicine 327, 692–695. 120. European Commission (2000) Opinion of the Scientific Committee on Veterinary Measures Relating to Public Health of the Control of Taeniasis/Cysticercosis in Man and Animals. pp. 31. 121. Kak, V.K., Al-Joshi, A.A., Daftary, S.G., et al. (1994) Cerebral cysticercosis presenting as a ring enhancing lesion with partial seizures (A case report with review of literature). Baharin Medical Bulletin 16, 26–28.

13

Taenia solium Cysticercosis in Africa

Michel Druet-Cabanac, Bienvenue Ramanankandrasana, Sylvie Bisser, Louis Dongmo, Gilbert Avodé, Léopold Nzisabira, Michel Dumas and Pierre-Marie Preux

Introduction Taenia solium cysticercosis exists in Africa but published reports are scarce. Its spread is not well understood, owing to the lack of welldeveloped medical infrastructure, and of trained medical staff and diagnostic facilities. Several sub-Saharan African countries have high rates of cysticercosis, because of indiscriminate pork consumption, poor sanitary conditions, free-roaming pigs around residential areas, and lack of veterinary control at slaughter facilities. Even in South Africa, where sanitary and medical facilities are better developed, the disease is well recognized, with a high prevalence having been reported. In West Africa, similar high rates have been reported in countries where epidemiological studies have been carried out. This chapter, based on a previous review1, gives an account of available data concerning T. solium cysticercosis in Africa.

Geography, people and their habits and environment Africa covers more than 30 million km2 of area and, after Asia, it is the second largest continent. It is divided into two parts by the equator. One-third of the continent is desert. The Sahara, the largest desert in the world,

covers almost one-quarter of Africa. Twothirds of the continent has a tropical or subtropical climate. Africa has nearly 600 million inhabitants. Its rate of population growth is the highest in the world, but actually it is sparsely populated, the average population density being around 20 inhabitants per km2. Differences in language, religion, ethnic origin and culture are enormous but comparable to other continents. Regarding religious status, Africa can be divided in two parts: the Moslem dominated northern part and animist and Christian dominated sub-Saharan region. Owing to religious beliefs, pork is not consumed in Moslem dominated regions of Africa, resulting in a low prevalence of cysticercosis in these areas. We have chosen to include Madagascar, an island off the African coast, in this review because of the similarities of the environmental conditions between this country and the African continent. The overall socio-economic standard of the population in Africa is low, the illiteracy rate is high, and cultural backgrounds are difficult to modify. There is a dearth of robust sanitary and medical understructure and trained medical personnel. Access to improved sanitary facilities and training of qualified medical staff is dependent upon socio-economic standards of the society. The latter in turn are negatively influenced by the number of diseases existing in the African continent, resulting in

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an important loss of productivity. This forms a vicious cycle that is very difficult to break. In most rural areas, meat inspection is improper or absent. Even in localities where slaughterhouses exist, illegal channels of meat marketing exist. Moreover, slaughterhouses do not exist in villages and people butcher their own animals, offering the meat for sale. Free-ranging pigs with access to human faeces abound. Too many inhabitants in remote areas of the continent ignore the danger of eating meat infected with cysticerci. Different gastronomic customs and beliefs concerning meat consumption also play an important role in transmission of T. solium cysticercosis. In a few ethnic groups, pork infested with cysticercosis is believed to have a better taste than healthy meat. Raw or insufficiently cooked pork meat is consumed to ensure virility in certain other communities. In some tribes of South Africa, tapeworm proglottides are a component of the ‘muti’ administered by native herbalists to expel intestinal worms2. In Africa, maybe more than anywhere else, environment and disease are closely related. As with other communicable diseases, the geographic, demographic and cultural characteristics of the region influence the epidemiology of cysticercosis. For instance, T. solium egg survival in the external environment is influenced by temperature and humidity. The tropical climate of Africa favours egg survival. In addition, ova can be transported over many kilometres by streams and rivers, and mechanically over long distances by birds. Some insects may also transmit the disease. The use of irrigation water contaminated by animal wastes contributes to transmission of cysticercosis. Finally, a high rate of transmission is noted in specific familial environments.

Human Cysticercosis Hospital-based case reports and series In most African countries, neurologists are few and general practitioners are not aware of cysticercosis. Access to modern neuroimaging techniques and serological diagno-

sis is limited. The clinical presentation of neurocysticercosis (NC) is extremely variable and the diagnosis is easy to miss. It is interesting that diagnosis of the first case of NC in a country often follows the completion of training of the first neurologist in that country. The first autopsy report of human cysticercosis in Africa was made from Madagascar in 1910 by Andrianjafy3. Bettencourt in 1911, reported cysticerci in an Angolan individual who died of trypanosomiasis. In 1938, Gallais reported NC in an epileptic individual from Benin4. Review of international literature indicates that T. solium cysticercosis has been reported from many African countries. Cases have been reported from Senegal5–7, Benin8, Ivory Coast9–11, Togo12, Ghana13, Burkina Faso1 and Nigeria14 in West Africa, Democratic Republic of Congo (ex-Zaire)15–17, Cameroon18, Burundi19, Kenya20, Rwanda21–23, Tanzania1 and Uganda1 in Central and East Africa, and Zimbabwe24–26, South Africa27–35 and Madagascar36 in southern Africa. Human cysticercosis was found in 7% of 300 autopsies carried out at Butare, Rwanda23. Gelfand reported cysticercosis in 0.45% of 2148 autopsies conducted in Zimbabwe24. Proctor, identified 71 cases of taeniasis in an autopsy survey of 7597 cases, most of them also had cysticercosis25. In Togo, 38 (1.45%) of 2604 consecutive patients presenting for neurological consultation to the outpatient department of a teaching hospital, were found to have cysticercosis12. Mason et al. observed that 12% of 630 hospitalized patients were seropositive for anticysticercus antibodies with an ELISA26. Sacks and Berkowitz noted a seropositivity rate of 7.4% among hospitalized adult patients in Johannesburg with an ELISA test35. In Madagascar, Michel et al., using ELISA and enzyme-linked immunoelectrotransfer blot (EITB) reported a seroprevalence rate of 36% among 1132 neurologic patients36. Human NC and seizure disorder A review of published studies from Africa reveals that seizures are the most frequent presenting manifestation of NC in common with data available from other continents.

T. solium Cysticercosis in Africa

Powell et al. noted seizures in 58% of 48 patients with proven cysticercosis from Zimbabwe37. In Madagascar, seizures were the presenting symptom in 57% of 241 patients with NC38. A total of 33 (87%) of 38 patients with NC presented with seizures in Togo12. Shasha et al. analysed 141 cases of cysticercosis from South Africa and reported seizures with or without other neurological syndromes in 95 (67.4%) of them39. In a paediatric cohort of 61 cases of cerebral cysticercosis from South Africa, seizures were recorded in 43%30.

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Several studies from South and Central America indicate that NC is the most common cause of adult-onset seizures40–42. Studies from Africa have produced conflicting viewpoints on the association between NC and seizures (Tables 13.1 and 13.2)2,12,34,37,43–50. Dumas et al. demonstrated evidence of cysticercosis in 26 of 88 individuals with seizure disorder identified during a population-based survey in Togo48. The diagnosis of cysticercosis was based upon presence of one of the following findings: positive serology by ELISA; presence of

Table 13.1. Prevalence of cysticercosis among epileptic patients in sub-Saharan Africa. Number of epileptic patients

Prevalence (%)

45

98 103 93 200

2 37 46 47 34 48 12 49

200 180 70 106 578 88 305 170

40.8 11.7 18.3 12.8 5.5 15.5 34.4 30.0 50.9 28.0 29.5 10.8 13.5

Country

Year

Reference

Burundi

1992 1997 2000 1962

43 44

1965 1966 1987 1987 1991 1989 1995 2000

Cameroon South Africa

Togo

†

Diagnostic method * S, R, N S S S R S, R S, R, N CT CT CT S, R, N S, R, N, CT S

*S: serology; R: calcifications on standard radiographs; N: subcutaneous cysticercus nodules; CT: computerized tomography cerebral scan. †Louis Dongmo, Yaounde, Cameroon unpublished data.

Table 13.2. Seroprevalence of cysticercosis in case–control and transversal studies in sub-Saharan Africa.

Country

Year

Reference

Benin Burundi

2000 1997 2000 2000 1999 2000 2000

* 44

Cameroon Central African Republic Kenya Togo

† ‡

50 * 49

Number of epileptic patients

Prevalence in epileptics (%)

Number of controls

Prevalence in controls (%)

65 103 61 93 187 98 115

1.5 11.7 26.0 18.3 4.0 5.0 13.5

130 72 87 81 374 124 1343

1.5 2.8 24.0 14.8 2.4 2.4 3.8

*Pierre-Marie Preux, Limoges, France, unpublished data. †Nsengiyumva, Burundi, unpublished data. ‡Louis Dongmo, Yaounde, Cameroon, unpublished data.

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calcifications characteristic of cysticercosis on standard radiographs; proof of cysticerci in subcutaneous nodules by histology. Using the same criteria, evidence of cysticercosis was found in 40 of 98 individuals with seizures in Burundi43. Of these, 25 patients had a positive cerebrospinal fluid (CSF) serology. In a hospital-based study from Madagascar, Michel et al. reported 36% seropositivity for cysticercosis among 1132 consecutive hospitalized patients with neurological complaints38. Laurence and Levi also emphasized the aetiological role of cysticercosis in epilepsy in Zimbabwe, Malawi and Zambia51. However, in several other case-control studies, no difference was found between the seroprevalence rates in individuals with seizures and controls (Table 13.2). More studies with contemporary methods of case finding such as the EITB are needed in order to determine if these differences are real or only due to methodological discrepancies1, 41. Human NC and other neurological presentations Other presentations including intracranial hypertension (ICH), psychiatric symptoms and focal neurological deficits have been reported from Africa. ICH was a presenting symptom in 24% of 61 children with cerebral cysticercosis in South Africa30. In this report, headache and meningoencephalitis were noted in 28% and 13%, respectively. Meningoencephalitis was reported in two patients from Togo12. Some patients having NC present with multiple signs and symptoms. Avodé et al. reported a patient from Benin with diffuse cysticercosis, who presented with seizures, ICH, confusion, myositis and subcutaneous cysticercus nodules8. Spinal cord involvement or ocular cysticercosis has been rarely reported from Africa. Michel et al. reported ocular cysticercosis in 3% of 266 patients with cysticercosis36. Subcutaneous cysticercosis The finding of subcutaneous nodules in individuals with seizures may be taken as presumptive evidence of T. solium cysticercosis.

However, subcutaneous cysticerci need to be differentiated from onchocerciasis nodules in certain parts of Africa, where the latter is endemic. For example, cysticerci were found in 12 cases (22.7%), while onchocerci were found in 36 cases (67.9%) out of 53 biopsies of subcutaneous nodules in Togo48. The study further showed that clinical examination had excellent positive predictive value for onchocerciasis (100%) in comparison with cysticercosis (45.8%). Among the 12 individuals with subcutaneous cysticerci, a diagnosis of NC could not be confirmed in five. Interestingly, the study revealed that there were three epileptics among the 36 cases with histologically proven onchocercal subcutaneous nodules; two of them had intracranial calcifications typical of NC. This raises the possibility of co-infection in areas that are endemic for both disorders.

Community-based data on T. solium cysticercosis While there are several reports of NC in hospitalized patients from Africa, very few community-based studies have been undertaken. When available, studies are often subject to bias because of lack of random sampling or other appropriate epidemiological methods. This may explain the high variability of prevalence rates among different regions within Africa. Nevertheless, preliminary data has emerged to show that most sub-Saharan countries have a high prevalence of T. solium cysticercosis (Table 13.3)2,14,36,48–50,52–57. West Africa A population-based survey evaluated the prevalence of cysticercosis and epilepsy in the Kozah region of northern Togo in 198748,58. The study included 5264 randomly selected subjects above 15 years of age. In this population, the prevalence rate for epilepsy was 16.7 per 1000 (95%CI: 12.3–21.2 per 1000). The overall prevalence of cysticercosis was 2.4%. Serological studies were undertaken in part of this sample (i.e. among epileptic subjects, their relatives and

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Table 13.3. Prevalence of human cysticercosis in sub-Saharan Africa and Madagascar. Country

Year

Reference

Benin

1996 1998 1998 2000 1987 2002 2000 1999 1993 1965 1987

52 53 54

1991 1989 2000

57 48 49

Burundi Cameroon

Central African Republic Madagascar South Africa

Togo

‡

55 14 §

50 36 2 56

Population studied *

Prevalence (% )

Sample size

Diagnostic method†

GP GP GP GP GP GP GP GP GP GP SC: Transkei SC: KwaZulu SC GP GP

3.5 3.9 1.5 24.0 2.4 0.8 16.7 2.4 18.0 8.5 0.23 2.49 5.5 2.4 3.8

319 1443 2625 87 764 4128 174 374 1408 2124 736 677 1352 5264 1343

S S S S S S S S S S S S S S, R, N S

*GP: general population; SC: school children. serology; R: calcifications on standard radiographs; N: subcutaneous cysticercus nodules. ‡Nsengiyumva, Burundi, unpublished data. §Louis Dongmo, Yaounde, Cameroon, unpublished data. †S:

neighbours). In this subsample, seroprevalence was 8.4% (95%CI: 6.5–10.7%), and the difference in prevalence between epileptic individuals and others was statistically significant (P0.001). Another survey in the Tone region of Togo, found 170 individuals with seizure disorder among 9155 examined, giving a prevalence of 18.6 per 100049. The seroprevalence of cysticercosis was significantly higher (P106) in subjects with seizure disorder (135 per 1000) than in a control group consisting of 1343 randomly selected individuals (38 per 1000). Using similar methods and case definitions, a survey of 1443 subjects older than 5 years in the Savalou region of Benin, in 1993, indicated a prevalence rate of seizure disorder of 15.2 per 1000 (95%CI: 9.8–23.4 per 1000). Prevalence rates were comparable to those found in Togo52,54. The seroprevalence rate for cysticercosis was 3.9% (95%CI: 3.0–5.1%). No statistically significant difference was found between seropositivity rates among individuals with and without seizures. Two other studies were carried out in Benin by the same team. A serological study for cysticercosis on a representative sample of 319

subjects in Vekky, a lake-side village situated near Cotonou in the Atlantique province of Benin, found 11 (3.5%) positive cases (95%CI: 1.8–6.3%)52. Houinato et al. evaluated 2625 sera using ELISA and immunoblot collected from six regions within Benin by cluster sampling54. The sera, therefore, constituted a representative sample of the national population. A total of 35 (1.3%) subjects were seropositive for cysticercosis (95%CI: 0.9–1.9%). Two regions, Atacora (3.3%) and Atlantique (3.0%) had higher seroprevalence rates than the national average. The Moslem dominated regions of Borgou (0.3%), Ouémé (0.8%) had low seroprevalence rates. The prevalence rate was higher in men (1.9%; 95%CI: 1.2–2.7%) than in women (0.8%; 95%CI: 0.4–1.5%) (P0.05). Benin can then be considered as a country with medium endemicity for cysticercosis with several foci of hyper-endemicity53,59. East Africa In Kazanya, northern Burundi, 25% of individuals with seizure disorder were assigned

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a diagnosis of NC based on the finding of anticysticercus antibodies in CSF in a community-based survey43. To our knowledge, this is the only population-based study from East Africa. Southern Africa A serological survey using complement fixation and precipitin reactions found an overall prevalence rate of 8.5% of cysticercosis among a rural black population in South Africa2. In an ELISA based serosurvey, 22 of 736 school children from Transkei were found to be serologically positive while only eight of 677 KwaZulu children were positive56. These results, when corrected for the sensitivity and specificity of ELISA, indicate a prevalence rate for cysticercosis of 2.49% in Transkeian school children and 0.23% in the KwaZulu. The differences in prevalence between the two regions are in keeping with the meat-eating habits of the two communities. While KwaZulu is primarily a cattle and meatproducing area, the Transkei region has a large number of free-roaming pigs in addition to cattle. An earlier study in 1966 revealed that the frequency of porcine cysticercosis detected in slaughterhouses in the Transkei area was nearly seven times higher than in those close to the KwaZulu area60. Another ELISA based serosurvey, carried out on school children in Transkei in 1991, determined an overall seroprevalence rate of 5.5%57. The rates were similar for regions with different climatic conditions. An interesting revelation that emerged from this study was the lower seroprevalence rate in undernourished children (3.3%) in comparison with those with good nutritional status (7.3%). The authors attributed this discrepancy to an impaired antibody response associated with proteinenergy malnutrition. In Madagascar, 91 of 34,137 persons with neurological symptoms were found to have NC61. When 1408 sera from healthy individuals from six provinces of Madagascar were evaluated by the anticysticercus ELISA/EITB, a high seroprevalence rate of 18% was obtained36,38.

Porcine Cysticercosis Only few studies have examined the burden of porcine cysticercosis in Africa. In Burundi, the prevalence was found to be around 20%56. In northern Togo, 17% of pigs were reported to be infected58. In South Africa, prevalence of porcine cysticercosis was 4% in 198445. Similar data are also available from other African countries14,62. Veterinary meat inspection is an important method of prevention. Unfortunately, in most parts of Africa, only a very small percentage of pig carcasses undergo veterinary meat inspection. We believe that the situation in Africa is similar to that reported in Peru, where about 65% of the pork consumed is obtained through informal channels, in order to avoid financial losses from the condemnation of infected pigs63. One way to circumvent these problems would be to establish an official market for infected meat. The meat brought there, at a somewhat lower price, could then be processed using methods that would kill all cysts. The production of free-roaming pigs, which feed on domestic wastes and faecal matter, with minimal feeding and maintenance costs is a considerable source of income for small farmers. None of the peasants who raised pigs in Vekky (Benin) practised indoor husbandry52. Similarly, in Savalou (Benin), 92.6% of the pigs are produced using free-range methods53. In western Cameroon, pigs are raised in household pens but humans frequently defecate inside these pens64.

Intestinal Taeniasis Data on intestinal taeniasis in Africa is extremely limited. Furthermore, there are discrepancies between the low prevalence of intestinal taeniasis and the high prevalence of cysticercosis in the same area. For instance, Dumas et al. found T. solium eggs and proglottides in one case out of 1163 stool examinations and eggs alone in eight (0.5%) out of 1157 faecal samples48. Only one of these eight cases was seropositive (ELISA) for cysticercosis. Newell et al.

T. solium Cysticercosis in Africa

established a prevalence of taeniasis (both T. solium and T. saginata) of 0.16% in 1992, 0.25% in 1993 and 0.25% in 1994 among school children in Rumonge, Burundi44. The highest reported prevalence was reported from South Africa, where a survey found 10% prevalence of adult Taenia infection.

Conclusions While human and porcine cysticercosis have been recognized as major health and economic problems in Latin America and also in few developed countries, their impact upon health and economy in Africa has not been adequately appreciated. Preliminary epidemiological data indicate that sub-Saharan Africa may be a major focus of disease.

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Besides, cysticercosis has also been recognized in West Africa and southern Africa. Studies from Benin and Togo have succeeded in increasing the awareness of local political, administrative and public health authorities concerning cysticercosis and NC. In Benin, information on sanitation has been disseminated through a published handbook. More work of this nature on a collaborative basis involving countries within Africa and beyond are clearly required to assess and contain the situation in Africa.

Acknowledgements We would like to thank the Conseil Régional du Limousin for their financial help and Dr Bernard Bouteille for technical assistance.

References 1. Preux, P.M., Melaku, Z., Druet-Cabanac, M., et al. (1996) Cysticercosis and neurocysticercosis in Africa: current status. Neurological Infections and Epidemiology 1, 63–68. 2. Heinz, H.J., MacNab, G.M. (1965) Cysticercosis in the Bantu of Southern Africa. South African Journal of Medical Sciences 30, 19–31. 3. Andrianjafy, A. (1910) Cysticercose humaine. S S Mad 2, 53–60. 4. Gallais, P. (1938) Deux cas de cysticercose cérébrale avec manifestations épileptiques. Bulletin de la Société de Pathologie Exotique 31, 915–919. 5. Collomb, H., Lariviere, M., Philippe, Y. (1961) Cysticercose cérébrale (premier cas au Sénégal). Bulletin de la Société de Médicine d’African Noire 6, 695–700. 6. Dumas, M., N’Diaye, I.P., Daumens, J.P., et al. (1976) Cysticercose cérébrale (deux nouveaux cas sénégalais). Bulletin de la Société de Médicine d’African Noire 21, 203–211. 7. Collomb, H., Larivière, M., Phillipe, Y., et al. (1964) Foyer de cysticercose de la Basse Casamance (Sénégal). Bulletin et Mémoires de la Faculté Mixte de Médecine et de Pharmacie de Dakar, Sénégal 12, 148–155. 8. Avodé, D.G., Bouteille, B., Avimadjé, M., et al. (1994) Epilepsie, hypertension intracrânienne, syndrome confusionnel et cysticercose cutanée, à propos d’un cas observé en milieu hospitalier au Bénin. Bulletin de la Société de Pathologie Exotique 87, 186–188. 9. Heroin, P., Loubière, R., Doucet, J., et al. (1972) Un cas de cysticercose sous-cutanée en Côte d’Ivoire. Revue Médicale Côte d’Ivoire 8, 26. 10. Giordano, C., Vedrenne, H., Dago-Ekribi, A., et al. (1976) Cysticercose cérébrale à forme confusionnelle avec aspects périodiques à l’EEG, étude anatomo-clinique. Médicine d’Afrique Noire 23, 43 – 51. 11. Bullock, A. (1980) La cysticercose cérébrale. A Propos d’une Observation Clinique, Electrique et Anatomique. Medical thesis, Abidjan, Ivory Coast, 75 pp. 12. Grunitzky, E.K., Balogou, A.K., M’Bella, M., et al. (1995) La cysticercose chez des malades neurologiques en milieu hospitalier à Lomé, Togo. Annales de Médecine Interne 146, 419–422. 13. Odamtten, S.E., Laing, W.N. (1967) Cysticercosis of the brain. Ghana Medical 6, 97–105. 14. Geerts, S., Zoli, A., Wallingham, L., et al. (2002) Taenia solium cysticercosis in Africa: an under-recognised problem. In: Craig, P.S., Pawlowski, Z.S. (eds) Tapeworm Zoonoses: – an Emergent and Global Problem. IOS Press, Amsterdam, pp. 13–23. 15. Fain, A., Duren, P., Fels, P. (1956) Cysticercose généralisée et plasmocytose médullaire (myélome) associés chez une femme de race Muhutu. Annales de la Société de Belge Médecine Tropicale 36, 239–246.

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16. Denisoff, N., Haenecour, F. (1958) Nouveau cas de cysticercose généralisée dans l’Est Congolais. Annales de la Société de Belge de Médecine Tropicale 38, 529–530. 17. Lelo, T., Malenga, M., Ndoma, K., et al. (1992) La cysticercose cérébrale à Kinshasa, à propos de deux observations. African Journal of Neurological Sciences 11, 36–37. 18. Marty, P., Herzog, U., Marty-Jaussan, et al. (1985) 2 cas de cysticercose observés au Cameroun. Médecine Tropicale 45, 83–86. 19. Aubry, P., Ndayiragije, A., Kamamfu, G., et al. (1990) A propos de 2 cas de cysticercose au Burundi. Bulletin de la Société de Pathologie Exotique 83, 288–289. 20. Ruberti, R.F., Mwingi, S.M.G., Dekker, N., et al. (1985) Epilepsy in the Kenyan Africans. African Journal of Neurological Sciences 4, 1–3. 21. Kestelyn, P., Taelman, H. (1985) Effect of praziquantel in intraocular cysticercosis: a case report. British Journal of Ophthalmology 69, 788–790. 22. Gascon, J., Corachan, M., Ramirez, J. (1989) A propos de 5 cas de cysticercose au Rwanda. Médecine Tropicale 49, 77–80. 23. Vanderick, F.X., Moboryingabo, P. (1972) La cysticercose humaine au Rwanda. Annales de la Société de Belge de Médecine Tropicale 52, 153–155. 24. Gelfand, M. (1948) Cysticercosis of the brain in the Africans of Rhodesia. East African Medical Journal 25, 110–112. 25. Proctor, N.S.T. (1963) Problems associated with tapeworm infestation of the central nervous system. In: van Bogaert, L., Kafer, J.P., Poch, G.F. (eds) Tropical Neurology. Lopez Libreros Editores, Buenos Aires, Argentina, pp. 140. 26. Mason, P., Houston, S., Gwanzura, L. (1992) Neurocysticercosis: experience with diagnosis by ELISA serology and computerized tomography in Zimbabwe. Central African Journal of Medicine 38, 149– 154. 27. Becker, B.J.P., Jacobson, S. (1951) Infestation of the human brain with Coenurus cerebralis. Lancet 29, 1202–1204. 28. De Villiers, P.D. (1953) Cerebral cysticercosis: an aspect of the diagnosis. South African Medical Journal 27, 1097–1098. 29. Gelfand, M., Jeffrey, C. (1973) Cerebral cysticercosis in Rhodesia. Journal of Tropical Medicine and Hygiene 76, 87–89. 30. Thomson, A.J., De Villiers, J.C., Moosa, A., et al. (1984) Cerebral cysticercosis in children in South Africa. Annals of Tropical Paediatrics 4, 67–77. 31. Tuch, P.S., Saffer, D. (1984) Cerebral cysticercosis: a case report and review of literature. South African Medical Journal 65, 211–216. 32. Joubert, J., Joubert, M.J., Lombaard, C.M. (1985) Neurocysticercosis – a comprehensive approach to medical treatment. South African Medical Journal 68, 11–14. 33. Zini, D., Farrell, V.J.R., Wadee, A.A. (1990) The relationship of antibody levels to the clinical spectrum of human neurocysticercosis. Journal of Neurology, Neurosurgery and Psychiatry 53, 656–661. 34. Van As, A.D., Joubert, J. (1991) Neurocysticercosis in 578 black epileptic patients. South African Medical Journal 80, 327–328. 35. Sacks, L.V., Berkowitz, I. (1990) Cysticercosis in urban black South African community: prevalence and risk factors. Tropical Gastroenterology 11, 30–33. 36. Michel, P., Callies, P., Raharison, H., et al. (1993) Epidémiologie de la cysticercose à Madagascar. Bulletin de la Société de Pathologie Exotique 86, 62–67. 37. Powell, S.J., Proctor, E.M., Wilmot, A.J., et al. (1966) Cysticercosis and epilepsy in Africans: a clinical and serological study. Annals of Tropical Medicine and Parasitology 60, 152–158. 38. Michel, P., Callies, P., Raharison, H., et al. (1992) La cysticercose à Madagascar: mise au point diagnostique et thérapeutique. Dakar Médical 37, 191–197. 39. Shasha, W., Van Dellen, J., Cakata, E. (1986) Cysticercosis: an analysis of 141 cases in South Africa. South African Journal of Epidemiology and Infection 1, 94–97. 40. Medina, M.T., Rosas, E., Rubio-Donnadieu, F., et al. (1990) Neurocysticerosis as the main cause of late-onset epilepsy in Mexico. Archives of Internal Medicine 150, 325–327. 41. Carpio, A., Escobar, A., Hauser, W.A. (1998) Cysticercosis and epilepsy: a critical review. Epilepsia 39, 1025–1040. 42. Pal, D.K., Carpio, A., Sander, J.W.A.S. (2000) Neurocysticercosis and epilepsy in developing countries. Journal of Neurology, Neurosurgery and Psychiatry 68, 137–143. 43. Nzisabira, L., Nsengiyumva, G., Bouteille, B., et al. (1992) La cysticercose dans la province de Kayanza (Burundi). Bulletin de la Société de Pathologie Exotique 85, 374–377.

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44. Newell, E., Vyungimana, F., Geerts, S., et al. (1997) Prevalence of cysticercosis in epileptics and members of their families in Burundi. Transactions of the Royal Society of Tropical Medicine and Hygiene 91, 389–391. 45. Bird, A.V., Heinz, H.J., Klintworth, G. (1962) Convulsive disorders in Bantu mine workers. Epilepsia 3, 175–187. 46. Naidoo, D.V., Pammenter, M.D., Moosa, A., et al. (1987) Seventy black epileptics: cysticercosis, computed tomography, and electroencephalography. South African Medical Journal 72, 837– 838. 47. Campbell, G.D., Farrell, V.J.R. (1987) Brain scans, epilepsy and cerebral cysticercosis. South African Medical Journal 72, 885–886. 48. Dumas, M., Grunitzky, E.K., Deniau, M., et al. (1989) Epidemiological study of neurocysticercosis in Northern Togo (West Africa). Acta Leidensia 57, 191–196. 49. Balogou, A.K., Grunitzky, E.K., Beketi, K.A., et al. (2000) Cysticercose et épilepsie au nord du Togo dans le Tone. Revue Neurologique (Paris) 156, 270–273. 50. Druet-Cabanac, M., Preux, P.M., Bouteille, B., et al. (1999) Onchocerciasis and epilepsy: a matched case-control study in Central African Republic. American Journal of Epidemiology 149, 565–570. 51. Laurence, F., Levi, S. (1990) Epilepsia in Rhodesia, Zambia and Malawi. African Journal of Medical Science 1, 291–303. 52. Adjidé, C.C., Bouteille, B., Josse, R., et al. (1996) Séroprévalence de la cysticercose dans la commune lacustre de Vekky, département de l’Atlantique (Bénin). Bulletin de la Société de Pathologie Exotique 89, 24–29. 53. Avodé, D.G., Bouteille, B., Houngbe, F., et al. (1998) Epilepsy, cysticercosis and neurocysticercosis in Benin. European Neurology 39, 60–61. 54. Houinato, D., Ramanankandrasana, B., Adjidé, C.C., et al. (1998) Seroprevalence of cysticercosis in Benin. Transactions of the Royal Society of Tropical Medicine and Hygiene 92, 621–624. 55. Zoli, A., Geerts, S., Vervoort, T. (1987) An important focus of porcine and human cysticercosis in West Cameroon. In: Geerts, S., Kumar, V., Brandt, J. (eds) Helminth Zoonoses. Martinus Nijhoff Publishers, Dordrecht, pp. 85–91. 56. Pammenter, M.D., Rossouw, E.J., Dingle, C.E. (1987) Serological detection of cysticercosis in two rural areas of South Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene 81, 242–244. 57. Shasha, W., Pammenter, M.D. (1991) Sero-epidemiological studies of cysticercosis in school children from two rural areas of Transkei, South Africa. Annals of Tropical Medicine and Parasitology 85, 349–355. 58. Dumas, M., Grunitzky, K., Belo, M., et al. (1990) Cysticercose et neurocysticercose: Enquête épidémiologique dans le nord du Togo. Bulletin de la Société de Pathologie Exotique 83, 263–274. 59. Avode, D.G., Capo-Chichi, O.B., Gandaho, P., et al. (1996) Epilepsie provoquée par la cysticercose. A propos d’une enquête sociologique et culturelle réalisée à Savalou au Bénin. Bulletin de la Société de Pathologie Exotique 89, 45–47. 60. Verster, A. (1966) Cysticercosis, hydatidosis and coenurosis in the republic of South Africa. Journal of South African Veterinary Medical Association 37, 37–45. 61. Andriamiandra, A., Cros, J., Dodin, A., et al. (1969) La cysticercose à Madagascar. Bulletin de la Société de Pathologie Exotique 62, 894–900. 62. Geerts, S. (1993) The taeniosis–cysticercosis complex in Africa. Bulletin Séances de l’Académie des Sciences d’Outre-Mer 38, 245–264. 63. Cysticercosis Working Group in Peru. (1993) The marketing of cysticercotic pigs in the Sierra of Peru. Bulletin of the World Health Organization 71, 223–228. 64. Marty, P., Mary, C., Pagliardini, G., et al. (1986) Courte enquête sur la cysticercose et le taeniosis à Taenia solium dans un village de l’ouest Cameroun. Médecine Tropicale 46, 181–183.

14

Taenia solium Cysticercosis: the Special Case of the United States

Wayne X. Shandera, Peter M. Schantz and A. Clinton White Jr.

Introduction Neurocysticercosis (NC) is commonly considered a disease of the developing world. Nonetheless, NC is also diagnosed in the developed world. By virtue of the number of immigrants entering the United States of America (USA) every year from countries where Taenia solium infection is endemic, more cases of imported NC are diagnosed in the USA every year than in all other developed countries combined. While NC cases in the USA occur primarily among immigrants from the developing world, a few cases arise autochthonously. In this chapter we discuss the epidemiology of NC in the developed world by focusing on the USA.

Early American Reports The earliest studies on NC were from Europe. These include descriptions of Taenia morphology, clarification of the animal hosts’ differences between T. solium (originally classified by Linnaeus) and T. saginata (classified by the German scientist, Johann Goeze in the 18th century) and the detailed elucidation of the Taenia life cycle by the 19th-century German scientist Karl Leuckart1. Many of the clinical manifestations were defined by British investigators studying clinical disease

acquired largely in India. Key insights included the observation of the protracted interval between acquisition of disease and onset of symptoms. For example, of over 450 British citizens who acquired infection primarily in India, clinical disease did not present until several years (average: 5 years, range 1–30 years) later in their homeland2. In the USA, T. solium cysticercosis has always been predominantly an imported disease. Even in the early 19th century, when ‘thousands of swine’ roamed streets in New York City and other communities, cysticercosis was rarely described in the USA. Occasional cases were reported in the late 19th century and early 20th century, but most patients were German and Eastern European immigrants who were infected before immigration. A review published in 1899, for example, describes only eight cases including the first case, a German woman reported from New York in 18573. Few cases were reported in the first half of the 20th century4. Two larger case series were published in the 1950s. The first described two new cases from Louisiana as well as a literature review of 40 additional American cases5. Overall, 31% showed ocular disease, and only 49% parenchymal brain disease, suggesting that neurological manifestations were often overlooked. Only three (7%) of the cases had clearly acquired their infection in the USA.

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Another American series of cysticercosis cases diagnosed in the USA involved two intraventricular cases and one parenchymal case6. The three patients were from Portugal, Guatemala (the intraventricular cases) and Angola (the parenchymal case). Subsequent articles broadened the clinical spectrum of disease, and showed that surgical intervention improved the outcome of selected cases7–9. Thus, the number of cases described before the 1970s was limited, perhaps due to limitations of diagnostic tests. In addition, the spectrum of disease was skewed towards cases that were obvious (e.g. patients with parasites visible in the eye) or more severe (e.g. intraventricular disease).

T. solium Infections: 1970 Onwards The spurt in T. solium cases in the 1970s In the late 1970s, computed tomography (CT) scanning became widely available in the USA. The result was that parasites in the central nervous system could be identified without invasive testing. At about the same time, the number of immigrants from endemic areas began to increase. Between 1960 and the 1990s, the proportion of the US population born in foreign countries doubled. Furthermore, there was a shift in the country of origin for US immigrants. Prior to the 1970s, most immigrants to the USA were of Canadian or European origin. Changes in immigration policy led to the influx of large numbers of immigrants from Latin America and Asia. The recently completed 2000 US Census recorded 35.3 million persons of Hispanic origin living in the USA, representing an increase of 12.9 million in the past decade10. US immigrants of Mexican origin now number over 20 million. There was also increased travel to endemic areas with an estimated 200 million persons crossing the US–Mexico border every year. Increased immigration plus widespread availability of non-invasive neuroimaging tests resulted in a dramatic increase in recognition of NC. This was initially noted in California. For example, review of hospital records from four large medical centres in Los Angeles for the period 1973–1983

revealed 447 cases diagnosed with NC11. The number of cases, however, only began to increase during the last few years of the 1970s. There was a fourfold increase in the number of cases diagnosed between l977 and l981, which was far greater than the increase in the number of immigrants. The major factor associated with the increased number of cases was the introduction and widespread utilization of CT scans. This technology so enhanced the clinician’s ability to identify and define the nature of intracerebral lesions that its introduction overshadowed any other factors. The vast majority of the patients reported during this period were Hispanic. Most were presumably from Mexico. Even in this early report, however, 12 of the cases (3%) had no history of travel to diseaseendemic areas outside of the USA11. Thus, their infections were presumably acquired locally. As the number of immigrants increased and the geographic range of Hispanic immigration broadened, so did the extent of NC. By the 1990s, we estimated that 1000 NC cases were diagnosed in the USA each year12. With the continued increase in immigration from, and travel to endemic areas, the number of cases is probably higher now. In support of this is the continuing increase in the number of cases in Los Angeles13. While cases were initially noted in southern California, large cases series have subsequently been reported from Colorado, Texas, Chicago and New York12,14–17. Interestingly, these case series are reported from cities with large immigrant populations, especially those from Mexico and Central America. However, up to 42% of the patients were persons born in the USA15,16. Reported sources of possible exposure in these persons included travel to Mexico or Central America (50%) or visitors in the home from Latin America (20%). To document the extent of disease, an ongoing multi-state surveillance project of 11 university-affiliated hospital emergency departments was begun in the late 1990s18. NC was documented as the apparent cause of approximately 2% of cases of seizures. Most cases were seen in the southwestern states. Patients with no travel history and in whom infections may have been locally acquired represented 8% of identified cases.

T. solium Cysticercosis in the USA

Risk factors for T. solium infection in USA To further characterize the epidemiology of NC, we interviewed NC cases diagnosed in Houston19. Of 35 immigrants questioned, 83% were from families that raised pigs, 43% had a history of taeniasis, and 54% had a family history of taeniasis. The median period from immigration to diagnosis was 28 months for the 13 patients who had not left the USA after immigration. Thus, NC cases were concentrated in immigrants from villages in known endemic regions. Travel between the endemic villages and cities in the USA was surprisingly frequent19,20. In the late 1980s, NC was made a reportable disease in southern California. Surveillance was started in 1988 and within 3 years the county health system in Los Angeles was notified of 138 cases21. The number of cases was significantly fewer than would be predicted from hospital surveys, suggesting significant underreporting. As might be expected the case rates were over 2.5 times higher in the Hispanic than in the non-Hispanic communities. In addition, many of the non-Hispanic patients were Asian immigrants. With the increase in numbers of cases, there was also a shift in the spectrum of disease. Most cases diagnosed after the widespread use of neuroimaging studies were due to parenchymal cysticerci. Previously, it was widely assumed that NC carried a grave prognosis and that patients would do poorly unless treated with anticysticercal drugs. Based on uncontrolled studies, praziquantel and subsequently albendazole became widely used. During the early 1980s, neither of these drugs was widely available in the USA. Several investigators in California followed the natural history of patients treated with only symptomatic therapy22,23. US investigators reported that most patients with NC presented with seizures and usually a single enhancing lesion on CT scans. These patients did very well with only symptomatic therapy. By contrast, ocular, ventricular and meningeal disease (which comprised most of the reported cases before the CT era) were only a small minority of cases. Thus, the poor prognosis reported in older series

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may have been due to ascertainment bias, with only more severe or obvious cases being diagnosed.

Locally acquired infections Locally acquired infections have also occasionally been noted. Pigs sold and consumed in the USA however, are infrequently infected with cysticercosis and among over 80 million swine slaughtered annually, fewer than 10 pigs show evidence of infection1. Thus, local acquisition of T. solium adult tapeworms (taeniasis) is unlikely to be a significant problem. By contrast, local acquisition of NC has been noted. Twelve US-born patients with NC who had not left the USA were identified in the hospital-based survey from Los Angeles21. Similarly, locally acquired cases were also identified in patients from Massachusetts and North Carolina24. A small series of patients with no travel outside of the USA was also reported from Chicago16. Direct or circumstantial evidence commonly links these cases to direct or indirect exposure to immigrants from Latin America, who presumably are (or were previously) carriers of adult-stage T. solium. This was most dramatically shown in a cluster of cases in four unrelated families of an Orthodox Jewish community in New York City25. The clue to the epidemiological puzzle in these cases was the employment of ‘live-in’ housekeepers in all of the exposed households. These female employees had recently emigrated from Latin American countries where T. solium is endemic and were considered the most likely sources of infection for the infected members of these households. Examination of six housekeepers currently or previously employed in the four case households revealed an active Taenia sp. infection in one and a positive serological test result in another. Employment of immigrants as domestic workers was very common in this community; a random telephone survey determined that 94% of the approximately 7000 households in the community employed housekeepers, almost all of whom had recently emigrated from rural areas of Mexico or countries of Central America.

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Each household employed an average of three such women per year. To further evaluate the extent of this problem, a serosurvey was conducted in the same community which sought to identify exposures and practices associated with acquisition of infection. Anticysticercus antibodies were detected by enyme-linked immunoelectrotransfer blot (EITB) in 23 (1.3%) of 1789 persons from 612 families26. All 23 seropositive persons were asymptomatic, and no intracerebral lesions were found in the 21 seropositive persons who underwent brain imaging. Seropositivity was significantly associated (P 0.05) with female sex, employment of domestic workers for child care duties, and with employment of persons from Central America. This cluster of patients within a community in New York that never ate pork and enjoyed modern hygienic facilities underscored the importance of faecal–oral hygiene in the transmission cycle. The prevalence of these risk factors among the US population in general is unknown. The prevalence of taeniasis among immigrant employees in surveyed households is unknown and may be difficult to determine. Most employees live in the households; many are undocumented aliens; access to the population is limited, and confidentiality of test results is difficult to ensure. A stool examination survey of migrant workers in North Carolina found taeniasis in Central American workers

(4.4%), but none in those from Haiti or Mexico27. Thus, widespread employment of domestic workers from disease-endemic regions and high employee turnover may contribute to exposure risk. It is unclear, however, whether local transmission is in fact rare or merely under-recognized. In Los Angeles, Sorvillo et al. attempted to identify tapeworms among contacts of NC patients21. They identified carriers in 1.1% of the household contacts of their patients. Among the subgroup of NC patients that were not from and had not travelled to endemic areas, 22% had tapeworm carriers among household contacts.

Conclusions Overall, NC is a growing public health problem in the USA. Initial recognition resulted from improved imaging studies and has included more cases of mild disease (e.g. single parenchymal cysticerci) than in most series from developing countries. NC in the USA is primarily a disease of immigrants infected abroad. Thus, as immigration and travel from Latin America and Asia increase, so the number of cases. In addition, small numbers of cases of locally acquired infections are recognized. While the number of such cases is small, the risk factors associated with locally acquired infection need better definition and the magnitude of this problem requires further study.

References 1. Schantz, P.M., Wilkins, P.P., Tsang, V.C.W. (1998) Immigrants, imaging, and immunoblots: the emergence of neurocysticercosis as a major public health problem. In: Scheld, W.M., Craig, W.A., Hughes, J.M. (eds) Emerging Infections 2. ASM Press, Washington, DC, pp. 213–242. 2. Dixon, H.B.F., Lipscomb, F.M. (1961) Cysticercosis: an analysis and follow-up of 450 cases. Medical Research Council Special Report Series. Her Majesty’s Stationery Office, London, pp. 1–58. 3. Diamond, I.B. (1899) Cysticercosis of brain and spinal cord. Journal of the American Medical Association 32, 1365–1369. 4. Dandy, W.E. (1950) Animal parasites invading the central nervous system: cysticercosis cellulosae. In: Lewis’ Practice of Surgery, Vol. 12. W. F. Prior Co, Hagertown, USA, pp. 377–382. 5. Campagna, M., Swartzwelder, C. (1954) Human cysticercosis in the United States. Journal of Parasitology 40 (Suppl.), 46. 6. White, J.S., Sweet, W.H., Richardson, E.P. (1957) Cysticercosis cerebri. New England Journal of Medicine 256, 479–486.

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7. Orihel, T.C., Gonzalez, F., Beaver, P.C. (1970) Coenurus from the neck of a Texas woman. American Journal of Tropical Medicine and Hygiene 19, 255–257. 8. Simms, N.M., Maxwell, R.E., Christenson, P.C., et al. (1969) Internal hydrocephalus secondary to cysticercosis cerebri: treatment with a ventriculoatrial shunt. Journal of Neurosurgery 30, 305–309. 9. Carmalt, J.E., Theis, J., Goldstein, E. (1975) Spinal cysticercosis. Western Journal of Medicine 123, 311–314. 10. Guzman, B. (2001) The Hispanic population. Census 2000 Brief. US Department of Commerce, 8 pp. 11. Richards, F.O., Schantz, P.M., Ruiz-Tiben, E., et al. (1985) Cysticercosis in Los Angeles county. Journal of American Medical Association 254, 3444–3448. 12. Shandera, W.X., White, A.C. Jr, Chen, J., et al. (1994) Cysticercosis in Houston, Texas: a report of 112 cases. Medicine 73, 37–52. 13. Zee, C.S., Go, J.L., Kim, P.E., et al. (2000) Imaging of neurocysticercosis. Neuroimaging Clinics of North America 10, 391–407. 14. Earnest, M.P., Reller, L.B., Filley, C.M., et al. (1987) Neurocysticercosis in the United States: 35 cases and a review. Reviews in Infectious Diseases 9, 961–979. 15. Rosenfeld, E.A., Byrd, S.E., Shulman, S.T. (1996) Neurocysticercosis among children in Chicago. Clinical Infectious Diseases 23, 262–268. 16. Stamos, J.K., Rowley, A.H., Hahn, Y.S., et al. (1996) Neurocysticercosis: report of unusual paediatric cases. Pediatrics 98, 974–977. 17. Buitrago, M., Edwards, B., Rosner, F. (1995) Neurocysticercosis: report of fifteen cases. Mount Sinai Journal of Medicine 62, 439–444. 18. Ong, S., Moran, G.J., Talan, D.A., et al. (1998) Radiographically-imaged seizures and neurocysticercosis. Program and abstracts of the International Conference on Emerging Infectious Diseases, Atlanta, Georgia (abstract 28.4). 19. de la Garza, Y., Graviss, E., Shandera, W., et al. (1998) Epidemiology of neurocysticercosis in Houston, Texas. International Conference on Emerging Infectious Diseases, Atlanta, Georgia (abstract). 20. Allan, J.C., Velasquez-Tohom, M., Garcia-Noval, J., et al. (1996) Epidemiology of intestinal taeniasis in four, rural, Guatemalan communities. Annals of Tropical Medicine and Parasitology 90, 157–165. 21. Sorvillo, F.J., Waterman, S.H., Richards, F.O., et al. (1992) Cysticercosis surveillance: locally acquired and travel-related infection and detection of intestinal tapeworm carriers in Los Angeles. American Journal of Tropical Medicine and Hygiene 47, 365–371. 22. Mitchell, W.G., Crawford, T.O. (1988) Intraparenchymal cerebral cysticercosis in children: diagnosis and treatment. Pediatrics 82, 76–82. 23. Kramer, L.D., Locke, G.E., Byrd, S.E. (1989) Cerebral cysticercosis: documentation of natural history with CT. Radiology 171, 459–462. 24. Centers for Disease Control and Prevention (1992) Locally acquired neurocysticercosis – North Carolina, Massachusetts, and South Carolina, 1989–1991. Morbidity and Mortality Weekly Report 41, 1–4. 25. Schantz, P.M., Moore, A.C., Muñoz, J.L., et al. (1992) Neurocysticercosis in an Orthodox Jewish community in New York City. New England Journal of Medicine 327, 692–695. 26. Moore, A.C., Lutwick, L.I., Schantz, P.M., et al. (1995) Seroprevalence of cysticercosis in an Orthodox Jewish community. American Journal of Tropical Medicine and Hygiene 53, 439–442. 27. Ciesielski, S.D., Seed, J.R., Ortiz, J.C., et al. (1992) Intestinal parasites among North Carolina migrant farmworkers. American Journal of Public Health 82, 1258–1262.

15

Porcine Cysticercosis

Armando E. Gonzalez, Patricia P. Wilkins and Teresa Lopez

Introduction Porcine cysticercosis visibly affects the quality of pork and results in widespread economic losses in areas where Taenia solium is endemic. The rates of porcine infection are variable, but in highly endemic regions, over 20% to 42% of pigs may be infected1. Figures obtained from slaughterhouse inspection generally provide lower levels of infection because obviously infected pigs are not brought to the abattoir for slaughter2.

Diagnostics Infection by T. solium in pigs can be detected by one of three methods: necropsy, palpation or visualization of cysts in the tongue, and immunological assays to demonstrate either antibodies or circulating antigen. The first is not practically useful, as most infected pigs are killed in a clandestine manner2. Tongue examination, although specific, is only moderately sensitive, requires highly trained personnel, is time-consuming and involves the risk of being bitten3,4. Immunological assays appear to be best suited for field surveys. Pigs can be bled rapidly from the anterior vena cava, a task that requires less training, and involves less danger than examination of the tongue3.

Before development of the enzymelinked immunoelectrotransfer blot (EITB), serological diagnosis of porcine cysticercosis was hampered by the lack of a reliable test to establish previous exposure to T. solium eggs. The EITB, which utilizes purified glycoprotein antigens, is highly specific and more sensitive than either ELISA or tongue examination for the detection of T. solium infection in pigs3,5. Other serological methods have also been developed for the surveillance, control and prevention of porcine cysticercosis (reviewed in Chapters 33 and 34). Glycoproteins purified from T. solium cysts by isoelectric focusing6, as also four polypeptides found in the soluble fraction prepared from T. solium cysts7, were shown to react with sera from pigs with confirmed cysticercosis in ELISA and immunoblot formats. Four antigen preparations from T. solium and T. crassiceps were evaluated for the diagnosis of porcine cysticercosis8–10. These studies found that antigens from T. crassiceps cyst fluid were superior to crude extracts prepared from T. solium. Also, an ELISA that used excretory–secretory antigens, prepared from in vitro cultured T. solium cysticerci, was shown to be highly sensitive and specific11. The presence of T. solium specific antibodies does not always correlate with the detection of parasites at necropsy; often, positive

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serological results are obtained and subsequent necropsy results are negative. D’Souza and Hafeez described that 33.33% of freeranging pigs, in which parasites could not be detected at meat inspection, were positive using ELISA11. This problem affects any antibody-based diagnostic test, including the highly sensitive and specific EITB assay. Sciutto et al. reported that antigen and antibody detection assays showed lower sensitivity and specificity when used in pigs that were reared in rural environments versus those raised on commercial farms12. These data demonstrate that it is not uncommon to detect specific antibody responses in pigs from endemic areas, especially if pigs are free ranging. A positive serological result in the face of a negative necropsy could occur from either prior effective treatment, past infection that has cleared, or exposure to T. solium, among other explanations. In the past, when investigators used the EITB to diagnose porcine cysticercosis, the problem of passively transferred maternal antibodies was recognized as a potential source of bias13. The presence of passive antibodies hampers the use of cohort studies for porcine cysticercosis because in highly endemic villages most piglets must be excluded due to the presence of maternal antibodies, which cannot be differentiated from acquired antibodies. Investigators addressed this issue by sampling only pigs that were older than 3 months. Later, the presence of maternal anticysticercal antibodies was noted in sentinel pigs that were older than 3 months14. Seropositive results that did not correlate with age were also reported by

others, suggesting that maternally transferred antibodies may confound results obtained by using serological methods15,16. Subsequently, it was demonstrated that passive humoral immunity persists in piglets born to seropositive sows up to 35 weeks postpartum4. Infection-specific antibody patterns in the piglets are indistinguishable from maternally transferred antibody reactions. In contrast, new reaction bands produced by the piglet alone most certainly represent a new antigenic stimulus, and therefore are presumed to be the result of new infection14. Although the presence of antibodies in necropsy-negative pigs may, in some ways, limit the use of EITB, the number of bands in the infected animals suggests that diagnostic patterns do not happen at random and that these results may be related to the final infection outcome (A.E. Gonzalez, unpublished data). A study was designed to answer some of these questions to enable a better understanding of the EITB results. A total of 482 pigs were sampled from an endemic area in Huancayo, in the Peruvian Central Highlands. A total of 279 pigs were found to be EITB positive. The prevalence of seropositive pigs in the area was therefore calculated to be 53.59–62.41% (95%CI). A subset of 84 from the 279 EITB-positive pigs were bought and necropsied. The number of EITB bands and necropsy results were registered by age and have been tabulated (Table 15.1). The information (Table 15.1) was used to develop a stochastic model in a spreadsheet (Excel 2000) format using simulation software @risk (Palisade). The probability function of having a necropsy-positive result

Table 15.1. Distribution of necropsy-positive animals by EITB reaction and age. Age Number of EITB bands diagnosed 1–2 3 4+ Total

 8 months

 8 months

Positive

Negative

Positive

Negative

7 5 2 14

13 7 1 21

3 20 3 26

15 7 1 23

EITB: enzyme-linked immunoelectrotransfer blot.

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given a band and age combination was simulated using  distributions. The original 279 positive pigs were also organized by age and number of bands (Table 15.2). The confidence limits for the number of expected positive pigs for each group were simulated using binomial distributions that considered the number of positive pigs observed in each group and the  probability previously calculated. The distributions above described were then used to simulate the number of necropsy-positive pigs in each stratum in 500 interactions. The simulation results showed that the mean prevalence of EITB seropositivity was 28% (90%CI: 22–33%) (Fig. 15.1). Antigen detection assays (reviewed in Chapter 34) have also been evaluated in pigs. Monoclonal antibodies (MAbs) produced against T. saginata excretory–secretory products were unable to detect lightly infected animals17. Brandt et al. developed an assay using two MAbs that recognized antigenic components of T. saginata18. Although the sensitivity of the test varied from one animal

Table 15.2. Frequency of positive pigs by age. Bands

 8 months

 8 months

78 39 15

47 75 25

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to another, the minimum number of living cysticerci that could be detected was 88. Animals harbouring only dead cysticerci gave negative reactions and cross-reactions were observed with sera infected by other taeniids. The test was also able to detect circulating antigen in sheep and pigs, infected with T. ovis and T. solium respectively, and in serum samples of confirmed cases of human cysticercosis18. Another MAb, the HP10, generated against a repetitive epitope present on the surface and in excretory–secretory antigens of T. saginata cysticerci was selected for its ability to detect circulating antigen in a double antibody sandwich ELISA19. The assay was evaluated in a randomized study using control, positive, negative and heterologous infection sera (A.E. Gonzalez, unpublished data). Sensitivity and specificity values were calculated using sera (that served as control) from 40 necropsy-positive pigs with varying infection burdens and 40 necropsy-negative pigs from non-endemic areas. Cross-reactions were evaluated using sera from pigs infected with Cysticercus tenuicollis, hydatid cysts and liver flukes. Sensitivity was 83% (95%CI: 71–94%) with a specificity of 88% (95%CI: 77–98%). After grouping positive sera according to infection burden, it was found that 10 of 15 (67%) sera from mild infections, 10 of 12 from moderate infections (83%) and 13 of 13 from heavy infections gave positive results. Also, 24 of 27

Distribution for prevalence/H27

16 Mean = 0.2790083 14 12 10 8 6 4 2 0 0.18

0.23

0.28

0.33

90%

5% 0.23

0.38 5%

0.33

Fig. 15.1. Simulated prevalence of Taenia solium cysticercosis in swine.

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sera from pigs infected with C. tenuicollis reacted in the antigen detection ELISA. Cross-reactions with hydatid, liver fluke and mixed infections (C. tenuicollis and either hydatid or liver fluke) occurred with 1 of 13 (8%), 0 of 4 (0%) and 25 of 28 (89%) samples, respectively. Although this antigen detection assay may be potentially used to monitor treatment and experimental infections, the use of the test is limited to those areas with a low prevalence of T. hydatigena infections (A.E. Gonzalez, unpublished data).

Epidemiology Field epidemiology The prevalence and risk factors for T. solium infection in pigs were studied in a rural population in Michoacan State, Mexico20–22. Visual inspection of the tongues of 216 pigs revealed cysticerci in 14 (6.5%). The prevalence was slightly but not significantly higher in male (10 of 105) than female pigs (4 of 110). The most important risk factors for infection in pigs were access to human faeces, the presence of an indoor latrine, and indiscriminate disposal of human faeces around the pig owner’s h