MULTIPLE SCLEROSIS RESEARCH IN LATIN AMERICA is it p0.05 significant

1. MULTIPLE SCLEROSIS RESEARCH IN LATIN AMERICA�is it (p<0.05) �significant� ? VICTOR M. RIVERA, M.D. Professor of Neurology Baylor College of Medicine Houston, Texas

2. CURRENT STUDIES IN LATINAMERICA Buenos Aires, Argentina CMSC PRECEPTORSHIP June 9 � 11, 2004

3. � significance� �Meaningful� ? Grammatical �Important� ? Connotations �Place of Emphasis�? OR ? Statistical analysis term

4. LACTRIMS (lecture) MISSION, VISION and the PASSION of LACTRIMS�

5. LACTRIMS LACTRIMS Represents 21 countries Languages: Spanish Portuguese English Final directives are provided by a Multinational Assembly (>300 registered neurologist members) represented by 2 Delegates per country.. Executive Committee Scientific Committee Steering Committee Working Groups

6. LACTRIMS HISTORY GEO-SOCIAL POLITICS THE FOUNDATION THE FUTURE

7. HISTORY EARLY STUDIES IN LATIN AMERICA EVOLUTION OF THE UNDERSTANDING OF MS IN THE CONTINENT

8. Early Observations - BRAZIL Marques, A �Esclerosis en Placas� Jornal de Pernambuco, Junho, 1923 (Tesis Doctoral) first documented report on MS in Latin America General Description of the understanding of the disease at that time�

9. Early Observations - BRAZIL Vampre, Prado, Austreg�silo, Costa-Rodriguez� Descriptions of cases, clinical diagnostic techniques (examination), treatment (1925, 1926, 1936, 1939)

10. Early Observations - URUGUAY Saron, JAMA, 1924 General description of the clinical manifestations of the disease

11. Early Observations - ARGENTINA Camaller, Sac�n, Negri� Prensa M�dica Argentina, 1931, 1933 Pseudoencephalitic onset, hemiplegic form and discussion of �atypical� manifestations

12. Early Observations - ARGENTINA Between 1934 � 1965: 26 local publications Differential Diagnosis Associated Disorders Treatments Attempts Biochemical Essays

13. Early Observations - PERU Lastre Rev Med Per, 1935 Description of four cases detected and diagnosed in Lima�

14. No articles or works published between 1935 � 1945

15. Early Observations - MEXICO Ramos Murgu�a (Neurosurgeon) Rev Med Mex, 1946 : 19 Cases (� 2.5% admissions�) ( ! ) Central Military Hospital 1946 : Sylvia Lawry founds the NMSS in New York

16. Early Observations - CHILE Arce Bol Hosp Viha , 1949 One Case�.

17. Influential �landmark� report(21 years later) Alter M, Olivares L �Multiple Sclerosis in Mexico�. Arch Neurol 1970 ; 23 : 451�459 �Prevalence 1.6 / 100,000 � one of the lowest in the world�

19. Published General Reviews Between 1965 � 1990 (25 years) CUBA 3 MEXICO 1 JAMAICA 1

20. Significant paper LACK OF IDENTIFICATION OF MS IN NON-MIXED AMERICAN INDIANS� First Published Observation : Corona, Rodriguez, Otero, Stopp.. �Multiple Sclerosis in Mexico:�� Neurolog�a 1996 MEXICO

21. Genetics and MS MS is a polygenic disease associated to Class I and Class II � HLA antigens Most common candidates for MS are groups with HLA A3, B7,DR2/DQW1 haplotypes

22. Genetics and MS Facts HLA A3,B7,DR2/DQW1 VERY PROMINENT IN NORTHERN AND CENTRAL EUROPEAN population groups (CAUCASIANS or �CAUCASOIDS�)

23. Genetics and MS Facts HLA A3,B7,DR2/DQW1 RARE IN EAST ASIANS (Mongoloid), BLACK AFRICANS & AUSTRALIANS�..

24. Genetics, MS and LA NATIVE AMERICAN INHABITANTS (Amerindians) Have ancestral Mongoloid genes Peopling of the Americas: 17,000 years ago, from Siberia by way of the Bering land bridge��melting glaciers 12 � 15,000 years ago, Ainu of Sakhalin Islands, north of Japan�.by canoes all the way down the Pacific littoral to Chile�s Monte Verde..by steps for centuries. Polynesians to Chile�s Easter Islands during the XII century ???

27. Genetics, MS and LA DNA studies have shown a rare genetic mutation in the chromosome of a son of a very ancestral American (or Asiatic ?) man : 90 % of male South American Indians and 50% of male North American tribesman share now that genetic mark�not present in any other male population ! HLA DR6 is common in Japanese and Mexican Mestizos

30. Significant paper SOUTH ATLANTIC PROJECT Multicentric Study in Prevalence Cohort. Observations in Ethnic prevalence. Impact in Afro-Brazilians (1995 � 1998). Rev Neurol Arg 2000 Papais-Alvarenga, Alves-Leon, Miranda Santos, Tilbery, Andrade, Poser BRAZIL

32. Genetics and MS in LA AFRICAN AMERICANS Mostly represented by Mulattos and probably more complex genetically than even the Mestizo cohort.. Africans Appear in the continent during the XVIII and XIX centuries and start to have a population impact in North America (except Mexico), Caribbean Islands, Central America, top geographic portion of South America and Brazil. Not so much in Chile and Argentina and small in Uruguay and Paraguay.

33. Genetics and MS in LA BLACK AMERICA ( Africa in America ) Another Genetic Phenomenon: Caribe Indians and other indigenous groups in other parts of America become extinguished in the XVIII century (part due to decimation, part due to epidemics of diseases brought by the Europeans). Africans are brought by the thousands for labor in mines, agriculture and house holds.

34. African Americans 40% less MS than caucasians North/South gradient ? Doubtful : Cuban, Colombian, Brazilian observations do not identify geographic gradient� Rather, these observations suggest local genetic influences� Almost half of patient in Rio de Janeiro are Afro Brazilian (Papais, Moreira, Tilbery; Liem et al)

35. Significant event I SIMPOSIO INTERNACIONAL DE ESCLEROSIS MULTIPLE Baylor International MS Center HOUSTON, 1999 U.S.A., Spain and Latin America 130 neurologists 11 countries Historically the First MS Event held in Spanish and Portuguese� �BIRTH OF LACTRIMS CONCEPT� Rev Neurol 2000, 31 (5) 469 -478

36. Geo � SocialP O L I T I C S � �have to be factual, objective, unbiased and educational��

37. USA POPULATION BORN ABROAD 1960 ITALY 1,257,000 GERMANY 990,000 CANADA 953,000 UK 833,000 POLLAND 748,000 2000 MEXICO 7,841,000 �? CHINA 1,391,000 PHILIPPINES 1,222,000 INDIA 1,007,000 CUBA 952,000 �?

38. ARE TERMS TOO (unnecessarily) ETHNIC ? �HISPANICS ?� Preferred by Democrats and Mexican-Americans.. (U.S. Census, 1975, Grace Flores-Hugues) Excludes Brazilians, African Americans, many Caribbeans.. �LATINOS ?� (Ital, Fr, Sp, Port, Ru) Preferred by Republicans �LATIN AMERICANS ?� Term derived during the Mexican war against the Napoleon III forces (1862, cinco de Mayo), this invasion was planned in part to �contra rest� the �United States Americanism� influence in the region

39. �A M E R I C A N S� Term formerly adjudicated to all people that lived in the American continent, from Alaska to the Tierra de Fuego (Patagonia) In December 23, 1823, John Quincy Adams promulgated the MONROE DOCTRINE : �America for the Americans� to prevent the European powers to continue their influence in the continent. The Monroe Doctrine received absolute solidarity from all the LIBERATORS of the Americas that were fighting Spain for independence

40. � A M E R I C A N S� By 1825 most countries in the continent have become independent, making reality the �Monroe Doctrine� (�America for the Americans�), however, 24 years later (1847) United States invaded Mexico (against protests from Quincy Adams himself and Abraham Lincoln) and took 40% of its territory. Since the last part of the XIX century the term �American� became practically synonymous (IF NOT EXCLUSSIVE) of a person from United States of North America

42. N O T E S� From LOS ANGELES, CAL., : �welcome to Mexifornia� �I am an immigrant in a land of immigrants and the place where I live every day looks more like me � Chicanos in CALIFORNIA, ARIZONA, NEW MEXICO, TEXAS,ILLINOIS, GEORGIA, ALASKA From EL PASO, TEXAS :�we are Tejanos..� Tex-Mex culture� From NOGALES, ARIZONA : �we did not come to United States; United States came to us�� Cuban-Americans and Central Americans in Florida Puerto Ricans in NY

43. USA Populations and Ethnic Shifts 2000 282 million �HISPANIC� 13 % NON-HISPANIC * 69 % 2050 420 million �HISPANIC� 24 % NON-HISPANIC * 50 % * Caucasian non-hispanic

44. How long current racial and ethnic categories will remain relevant? and, ARE THEY really MEANINGFUL FOR �Latin American� MS ? : There may be phenotypic and genotypic differences affecting clinical characteristics and therapeutic responses Increasing MS prevalence in Latin America will reflect in ? group prevalence in USA Genetic dissemination appears to increment the presence of MS

45. LACTRIMS THE FOUNDATION

46. LATIN AMERICAN COMMITTEE FOR TREATMENT AND RESEARCH IN MS L A C T R I M S Preliminary meetings Houston, Basel, Philadelphia� Founded in 1999 (PanAmerican Congress, Cartagena de Indias, Colombia) Congresses: I Buenos Aires 2000 II Monterrey 2002

47. First XXI Century Review Rivera VM, Cabrera JA Avance de la Esclerosis M�ltiple en Latinoam�rica (�INCREASING PREVALENCE IN LATIN AMERICA�) MEDICO Interamericano 2000,Vol 19 No. 10, 458 - 465 (96 references)

48. Prof. Poser�s observations SINCE THE INCEPTION OF THE CONCEPT ON �INDEXED� JOURNALS, > 40,000 MS RELATED ARTICLES HAD BEEN PUBLISHED UNTIL NOVEMBER 2003. THE SHARPEST INCREASE OCCURRING WITHIN THE LAST 10 YEARS..

49. Main Topics of Original Papers *1990 � 2000 MEDLINE & LILACS * Data Base Publications PREVALENCE (EPIDEMIOLOGY) 26 CUBA 7 JAMAICA/HAITI 2 BRAZIL 5 COLOMBIA 1 ARGENTINA 4 PERU 1 MEXICO 3 URUGUAY 3

50. INFORMATIVE PAPER (1990�S) Example Calegaro D, Goldbaum M, Morais L, Tilbery CP, Moreira MA, Gabbai AA, Scaff M. THE PREVALENCE OF MULTIPLE SCLEROSIS IN THE CITY OF S�O PAULO, BRAZIL, 1997. Acta Neurol Scand 2001: 104: 208 � 213 Describes increase prevalence in S�o Paulo from 1990 (5/100,000) to 1997 (15/100,000) attributed to more detailed recording methods and improvement in diagnosis and treatment.

51. Main Topics of Original Papers *1990 - 2000 MEDLINE & LILACS * Data Base Publications GENETICS 3 BRAZIL 2 COLOMBIA 1 BIOCHEMISTRY AND CSF URUGUAY 1

52. ORIGINAL PAPERS FROM THE N.I.N.N., (Public Health), MEXICO Tarrats R, Ordo�ez G, Rios C, Sotelo J. �VARICELLA, EPHEMERAL BREASTFEEDING AND ECZEMA AS RISK FACTORS FOR MS IN MEXICANS�. Acta Neurol Scand 108, 2002 VZV infection antecedent, most significant risk factor in Mexicans Ordo�ez G, Pineda B, Garc�a-Navarrete R, Sotelo J. �BRIEF PRESENCE OF VZV VIRAL DNA IN MONONUCLEAR CELLS DURING RELAPSES OF MS�. Arch Neurol 61, 2004 ? VZV infection ethiopathogenesis of MS or epiphenomenon

53. ORIGINAL PAPERS FROM THE N.I.N.N., (Public Health), MEXICO Leon C, Violante A, Arriada N, Santana HR, Corona T � EL INTERFERON-beta 1a EN EL TRATAMIENTO DE LA EM (RR)�. Rev Neurol 31, 2003 First description of INF therapy in a Mexican population Corona T, Leon T, Ostrosky-Zeichner �L. SEVERE ANAPHYLASIS WITH RECOMBINANT INTERFERON INTERFERON BETA�. Neurology 1999 Corona T, Ruiz L Letter to the Editor. �Pearls and pitfalls�� Acevedo AR, Nava C, Arriada N, Violante A, Corona �T. CARDIOVASCULAR DYSFUNCTION IN MS�. Acta Neurol Scand 100, 1999

54. Significant paper from the N.I.N.N. (Public Health), Mexico Gonzalez O, Sotelo J. �IS THE FREQUENCY OF MULTIPLE SCLEROSIS INCREASING IN MEXICO?� J Neurol Neurosurg Psychiatry, 1995

55. Significant paper Alvarado de la Barrera, Z��iga Ramos, et al HLA Class II genotypes in Mexican Mestizos with familial and no familial MS Neurology 55, 2000 Mexican Mestizos with MS share HLA-DR2 and DR3 similar to European populations at high risk

56. Important Genetic Studies C O L O M B I A National Prevalence Studies are not available� Medell�n (JL S�nchez et al, 1998): �.. more frequent HLA: DQ alpha 1.1, 1.2; allele 3 significantly less frequent (<0.05) similar to Caucasians residing in non-tropical areas..� 85% Caucasians, 10% mestizos, 5% Afro-Colombians NO CASES IN LOCAL INDIANS

57. MS still not identified in non-mixed American Indians : Surveys by Rivera and Cabrera*,** � MEXICO: 10% Indian (7% total pop. does not speak Spanish): N�huatl,huastecos, otom�es, pur�pechas (central M�xico), tarahumaras, tepehuanes, pimas, mazahuas, guarijios (north). No information on mayas,tzentales,mixtecos,lacandones (south) � GUATEMALA (>80% Indian): Maya quich� � COLOMBIA: Kogis � BRAZIL: Guatos, ipicas, guaran�es (Rio Paraguay/Paran�),xing�s, yanomanis (central Brazil), kaigang (south), tembers, timbiras, kaapor (east), kalungas � PERU : Aymaras (Titicaca lake) (* Rivera VM, Cabrera JA. MEDICO Interamericano. October 2000) � CANADA : Algonkians (** Rivera VM, Cabrera JA. Aborigenals with MS.Letter to theEditor, NEUROLOGY 2001)

58. Significant Study First epidemiological INCIDENCE studies in Latin America : Cristiano E and collaborators, ARGENTINA 2002 - 2003

60. Socioeconomic Search Paper Lana-Peixoto MA STUDIES ON MS: THE GROSS DOSMETIC PRODUCT PER CAPITA (GDPpc) OF A COUNTRY AS AN INDEX OF RESEARCH PRODUCTIVITY (publications 1991-2000), BCTRIMS 2003, S�o Paulo, Brazil USA first with 35 % of the world�s total publications; Italy second (11%), UK (10%), Canada (6%)

61. Socioeconomic Search Paper (Lana-Peixoto, BCTRIMS 2003) Higher GDPpc was not necessarily related to MS scientific production: USA first in GDPpc and first in % of publications; Switzerland second in GDP, 18th in production; Norway third in GDP, 16th in production. 25 countries responsible for 99.6% of the world publications (including Brazil, Turkey and Mexico, but the former �Br and Tur- despite lower GDP�s fared better that Switzerland and Norway).

62. XIX Congreso Brasileiro de Neurologia SALVADOR, BAHIA, 2000 48 abstracts pertaining to MS or related topics Epidemiology, MR, Case Reports, NMO, MS in children, Psychological and Social Issues, Interferon Therapy, Cognition and QOL

63. XXVI Academia Mexicana de Neurolog�a PUEBLA, PUEBLA, 2002 4 MS abstracts (from a total of 77 papers on general neurology) Case Reports 2 Epidemiology 1 Electrophysiology 1

64. 54th Annual Meeting  American Academy of Neurology DENVER, COL., 2002 1 Scientific Paper ( From a LACTRIMS member, ARGENTINA ) Correale J, Bassani Molinas JC. Temporal Variations of Adhesion Molecules and Matrix Metalloproteinases (MMP) during the course of MS.

65. 55th Annual MeetingAmerican Academy of Neurology HONOLULU, HAWAii, 2003 3 abstracts Basic Research 1 (Argentina) Cognitive Dysfunction 1 (Argentina) Therapy of NMO in Children 1 (Argentina)

66. 56th Annual Meeting American Academy of Neurology SAN FRANCISCO, 2004 2 abstracts Basic research: 1 (Argentina) Correale J, Filol MP. Humoral Immunity and Eosinophilic Activation in NMO Therapy: 1 (Argentina) Tenebaum SN, Segura MJ. Modifying Therapies in Early-Onset MS

67. Consortium of MS Centers DALLAS/FORT WORTH, TEXAS, 2001 3 abstracts Epidemiology 2 (Caribe; New Mexico, USA*) Social Issues 1 (USA*) ( * LACTRIMS members )

68. Consortium of MS Centers CHICAGO, ILL., 2002 8 abstracts Epidemiology 2 (Canada * ; Cuba) Social Issues 2 (Brazil � ABEM) Psychol. � 1 (Brazil � ABEM) QOL 1 (Brazil � ABEM) PT 1 (Brazil � ABEM) Therapeutics 1 (USA *)

69. Consortium of MS Centers SAN DIEGO, CAL., 2003 2 abstracts Immunology 1 (Argentina) LACTRIMS II Award Clinical Cases 1 (Cuba)

70. ECTRIMS 2001* ACTRIMS/ECTRIMS 2002** DUBLIN 2001* 7 abstracts (Brazil) BALTIMORE 2002** 7 abstracts (Brazil) Epidemiology, Genetics, Clinical Aspects.

71. LACTRIMS meetings BUENOS AIRES I 48 Abstracts 2000 Rev Neurol Arg MONTERREY II 73 Abstracts 2002 Rev Neurol (Sp) * (*indexed)

72. LACTRIMS meetings IGUA�U Falls *, Brazil LACTRIMS III August 25 � 28, 2004 (*Borders between Brazil, Argentina, Paraguay)

76. TEXT BOOKS ESCLEROSIS MULTIPLE (Manejo Integral) Asociaci�n M�dica Mexicana para el Estudio de la Esclerosis M�ltiple (AMMEEM) Editorial Prado M�xico, 2002 ESCLEROSIS MULTIPLE. UNA MIRADA IBEROAMERICANA Camilo Arriagada, Jorge Nogales-Gaete, Editores Arrynog Ediciones Santiago, Chile, 2002 SPONSORED BY LACTRIMS

77. Established MS Research Laboratories in Latin America INSTITUTO FLENI, BUENOS AIRES HOSPITAL UNIVERSITARIO CLEMENTINO FRAGA FILHO, RIO DE JANEIRO NATIONAL INSTITUTE OF NEUROLOGY & NEUROSURGERY MANUEL VELASCO SUAREZ, MEXICO INSTITUTO DE NEUROLOGIA ANTIOQUIA, MEDELLIN CIREN, HAVANA INSTITUTO de NEUROLOGIA del HOSPITAL DE CLINICAS, MONTEVIDEO AND MANY OTHERS

78. NATIONAL CONSENSUS ON TREATMENT ARGENTINA BRAZIL COSTA RICA GUATEMALA MEXICO URUGUAY VENEZUELA

79. PRELIMINARY CONCLUSIONS(Factors influencing Research) INCREASING PREVALENCE OF MS IN LATIN AMERICA INCREASING PUBLIC AWARENES OF THE DISEASE MODERNIZATION OF NEUROLOGICAL EDUCATION AVAILABILITY OF DMT�S (A,B,C,R,) RESULTS : more interest in MS; more studies

80. TENDENCIES in Latin American MS Research EMPHASIS IN EPIDEMIOLOGICAL OBSERVATIONS (Most of them regional, institutional and limited in technical design) EMPHASIS IN CASE REPORTS (Although these are becoming less fashionable and more inclined towards regional clinical characterizations of the disease) INCREASING STUDIES IN QOL, COGNITIVE & PSYCOSOCIAL ISSUES and GENETICS�

81. LACTRIMS THE FUTURE

82. THE FUTURE BASIC RESEARCH Available in just a few centers in Latin America� Probable Contributing Factors: Lack of training Lack of Education Lack of Official Support --? results : NO MONEY ($) � NO RESEARCHERS� NO RESEARCH�

83. THE FUTURE GENETIC CHARACTERIZATION ADEQUATE EPIDEMIOLOGICAL STUDIES Including not only Prevalence but also Incidence Studies PARTICIPATION IN MULTICENTER CONTROLLED Phase II, III and IV STUDIES MR TECHNIQUES OF RELEVANCE

84. GENETIC CHARACTERIZATIONS Caucasians Native Americans (Amerindians) Mestizos African Americans* Mulattos All possible combinations Studies are important because genetic differences may influence clinical behavior and response to therapy : i.e. DR2 and GA; Betainterferon1-a and AM�s*; AM�s have more aggressive disease; the �Asian Optic Spinal Form� of MS, etc.

85. GENETIC CHARACTERIZATIONS LATIN AMERICAN MESTIZOS (admixture between Caucasians and Amerindians) REPRESENT A GROUP OF �RECENT� APPEARANCE (<500 years). The European genetic contribution PROBABLY HAS INCREASED THE RISK OF DEVELOPING MS HLA Colombian Studies (>frequency of HLA alleles DQA-alpha 1.1,1.2 and <frequency allele 3), �similar to Caucasian populations residing in non-tropical areas� (Sanchez JL et al, 1998)

86. MS RESEARCH IN LATIN AMERICA(Final Thoughts) ORIENTED MOSTLY TO CLINICAL ASPECTS AND EPIDEMIOLOGY. LACK OF TRAINING, EDUCATION AND OFFICIAL AND/OR INSTITUTIONAL SUPPORT TEND TO LIMIT POSSIBILITIES OF BASIC RESEARCH IN THE REGION. HOWEVER THE NUMBER OF MS- RELATED WORKS PRESENTED AT LOCAL, NATIONAL AND INTERNATIONAL EVENTS HAS NOTABLY INCREASED IN NUMBER AND QUALITY� Thank you for your significant work ! VICTOR M. RIVERA, M.D.