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

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MULTIPLE SCLEROSIS RESEARCH IN LATIN
AMERICAis it (plt0.05) significant ?

• VICTOR M. RIVERA, M.D.
• Professor of Neurology
• Baylor College of Medicine
• Houston, Texas

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CURRENT STUDIES IN LATINAMERICA

• Buenos Aires, Argentina
• CMSC PRECEPTORSHIP
• June 9 11, 2004

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significance

• Meaningful ? Grammatical
• Important ? Connotations
• Place of Emphasis?
• OR
• ? Statistical analysis term

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LACTRIMS (lecture)

• MISSION,
• VISION and the
• PASSION of
• LACTRIMS

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LACTRIMS

• LACTRIMS Represents 21 countries
• Languages Spanish
• Portuguese
• English
• Final directives are provided by a
• Multinational Assembly (gt300 registered
  neurologist members) represented by 2 Delegates
  per country..
• Executive Committee
• Scientific Committee
• Steering Committee
• Working Groups

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LACTRIMS

• HISTORY
• GEO-SOCIAL POLITICS
• THE FOUNDATION
• THE FUTURE

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HISTORY

• EARLY STUDIES IN LATIN AMERICA EVOLUTION OF
  THE UNDERSTANDING OF MS IN THE CONTINENT

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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

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Early Observations - BRAZIL

• Vampre, Prado, Austregésilo, Costa-Rodriguez
• Descriptions of cases, clinical
  diagnostic techniques
  (examination), treatment (1925, 1926,
  1936, 1939)

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Early Observations - URUGUAY

• Saron,
• JAMA, 1924
  General description of the
  clinical manifestations of the disease
• 
  
  

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Early Observations - ARGENTINA

• Camaller, Sacón, Negri
• Prensa Médica Argentina, 1931, 1933
• Pseudoencephalitic onset, hemiplegic form and
  discussion of atypical manifestations

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Early Observations - ARGENTINA

• Between 1934 1965
• 26 local publications
• Differential Diagnosis
• Associated Disorders
• Treatments Attempts
• Biochemical Essays

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Early Observations - PERU

• Lastre
• Rev Med Per, 1935
• Description of four cases detected and diagnosed
  in Lima

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No articles or works published between 1935
1945
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Early Observations - MEXICO

• Ramos Murguía (Neurosurgeon)
• Rev Med Mex, 1946
• 19 Cases ( 2.5 admissions) ( ! ) Central
  Military Hospital
  
• 1946 Sylvia Lawry founds the NMSS in New York
  

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Early Observations - CHILE

• Arce
• Bol Hosp Viha , 1949
• One Case.

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Influential landmark report(21 years later)

• Alter M, Olivares L
• Multiple Sclerosis in Mexico. Arch Neurol 1970
  23 451459
• Prevalence 1.6 / 100,000 one of the lowest in
  the world

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Published General Reviews

• Between 1965 1990 (25 years)
• CUBA 3
• MEXICO 1
• JAMAICA 1

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Significant paper

• LACK OF IDENTIFICATION OF MS IN NON-MIXED
  AMERICAN INDIANS
• First Published Observation Corona,
  Rodriguez, Otero, Stopp.. Multiple Sclerosis in
  Mexico Neurología 1996
• MEXICO

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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

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Genetics and MS

• Facts
• HLA A3,B7,DR2/DQW1
  
• VERY PROMINENT IN NORTHERN AND CENTRAL EUROPEAN
  population groups (CAUCASIANS or CAUCASOIDS)

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Genetics and MS

• Facts
• HLA A3,B7,DR2/DQW1
• RARE IN EAST ASIANS (Mongoloid), BLACK AFRICANS
  AUSTRALIANS..

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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 bridgemelting
  glaciers 12 15,000 years ago, Ainu of Sakhalin
  Islands, north of Japan.by canoes all the way
  down the Pacific littoral to Chiles Monte
  Verde..by steps for centuries. Polynesians to
  Chiles Easter Islands during the XII century ???
  

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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 marknot present
  in any other male population !
• HLA DR6 is common in Japanese and Mexican
  Mestizos

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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

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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.

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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.

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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)

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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

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Geo SocialP O L I T I C S

• have to be factual, objective, unbiased and
  educational

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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 ?

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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

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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

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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

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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

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USA Populations and Ethnic Shifts

• 2000 282 million
• HISPANIC 13
• NON-HISPANIC 69
• 2050 420 million
• HISPANIC 24
• NON-HISPANIC 50
• Caucasian non-hispanic

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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

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LACTRIMS

• THE FOUNDATION

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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

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First XXI Century Review

• Rivera VM, Cabrera JA
• Avance de la Esclerosis Múltiple en Latinoamérica
• (INCREASING PREVALENCE IN LATIN AMERICA)
• MEDICO Interamericano 2000,Vol 19 No. 10, 458 -
  465 (96 references)
  

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Prof. Posers observations

• SINCE THE INCEPTION OF THE CONCEPT ON INDEXED
  JOURNALS, gt 40,000 MS RELATED ARTICLES HAD BEEN
  PUBLISHED UNTIL NOVEMBER 2003.
• THE SHARPEST INCREASE OCCURRING WITHIN THE LAST
  10 YEARS..

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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

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INFORMATIVE PAPER (1990S)

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

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Main Topics of Original Papers 1990 - 2000

• MEDLINE LILACS
• Data Base Publications
• GENETICS 3
• BRAZIL 2
• COLOMBIA 1
• BIOCHEMISTRY AND CSF
• URUGUAY 1
  

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ORIGINAL PAPERS FROM THE N.I.N.N., (Public
Health), MEXICO

• Tarrats R, Ordoñez 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
• Ordoñez G, Pineda B, García-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

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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

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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

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Significant paper

• Alvarado de la Barrera, Zúñiga 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

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Important Genetic Studies

• C O L O M B I A
• National Prevalence Studies are not available
• Medellín (JL Sánchez et al, 1998) .. more
  frequent HLA DQ alpha 1.1, 1.2 allele 3
  significantly less frequent (lt0.05) similar to
  Caucasians residing in non-tropical areas..
• 85 Caucasians, 10 mestizos, 5 Afro-Colombians
• NO CASES IN LOCAL INDIANS

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MS still not identified in non-mixed American
Indians Surveys by Rivera and Cabrera,

• MEXICO 10 Indian (7 total pop. does not
  speak Spanish) Náhuatl,huastecos, otomíes,
  purépechas (central México), tarahumaras,
  tepehuanes, pimas, mazahuas, guarijios (north).
  No information on mayas,tzentales,mixtecos,lacando
  nes (south)
• GUATEMALA (gt80 Indian) Maya quiché
• COLOMBIA Kogis
• BRAZIL Guatos, ipicas, guaraníes (Rio
  Paraguay/Paraná),xingús, 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)

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Significant Study

• First epidemiological INCIDENCE studies in Latin
  America
• Cristiano E and collaborators,
• ARGENTINA 2002 - 2003

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John F. Kurtzke, M.D. 7509 Salem Road Falls
Church, VA 22043-3240 U.S.A. Nov 2002
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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, São Paulo, Brazil
• USA first with 35 of the worlds total
  publications Italy second (11), UK (10),
  Canada (6)

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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 GDPs fared better that
  Switzerland and Norway).

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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

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XXVI Academia Mexicana de Neurología

• PUEBLA, PUEBLA, 2002
• 4 MS abstracts
• (from a total of 77 papers on general
  neurology)
• Case Reports 2
• Epidemiology 1
• Electrophysiology 1

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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.

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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)

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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

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Consortium of MS Centers

• DALLAS/FORT WORTH, TEXAS, 2001
• 3 abstracts
• Epidemiology 2 (Caribe New Mexico, USA)
• Social Issues 1 (USA)
• ( LACTRIMS members )

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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 )

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Consortium of MS Centers

• SAN DIEGO, CAL., 2003
• 2 abstracts
• Immunology 1 (Argentina)
• LACTRIMS II Award
• Clinical Cases 1 (Cuba)

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ECTRIMS 2001 ACTRIMS/ECTRIMS
2002

• DUBLIN 2001 7 abstracts (Brazil)
• BALTIMORE 2002 7 abstracts (Brazil)
• Epidemiology, Genetics, Clinical Aspects.

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LACTRIMS meetings

• BUENOS AIRES I 48 Abstracts
• 2000 Rev Neurol Arg
• MONTERREY II 73 Abstracts
• 2002 Rev Neurol (Sp)
• (indexed)
• 
  
  
  

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LACTRIMS meetings

• IGUAçU Falls , Brazil LACTRIMS
  III
• August 25 28, 2004
• (Borders between Brazil, Argentina, Paraguay)

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TEXT BOOKS

• ESCLEROSIS MULTIPLE (Manejo Integral)
  
  Asociación Médica Mexicana para el Estudio de la
  Esclerosis Múltiple (AMMEEM)
• Editorial Prado México, 2002
• ESCLEROSIS MULTIPLE. UNA MIRADA IBEROAMERICANA
  Camilo Arriagada, Jorge Nogales-Gaete, Editores
  Arrynog Ediciones Santiago,
  Chile, 2002
• SPONSORED BY LACTRIMS

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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

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NATIONAL CONSENSUS ON TREATMENT

• ARGENTINA
• BRAZIL
• COSTA RICA
• GUATEMALA
• MEXICO
• URUGUAY
• VENEZUELA

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PRELIMINARY CONCLUSIONS(Factors influencing
Research)

• INCREASING PREVALENCE OF MS IN LATIN AMERICA
• INCREASING PUBLIC AWARENES OF THE DISEASE
• MODERNIZATION OF NEUROLOGICAL EDUCATION
• AVAILABILITY OF DMTS (A,B,C,R,)
• RESULTS more interest in MS more studies

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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

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LACTRIMS

• THE FUTURE

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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
  
  

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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

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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 AMs AMs have more
  aggressive disease the Asian Optic Spinal Form
  of MS, etc.

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GENETIC CHARACTERIZATIONS

• LATIN AMERICAN MESTIZOS
• (admixture between Caucasians and Amerindians)
• REPRESENT A GROUP OF RECENT APPEARANCE (lt500
  years). The European genetic contribution
  PROBABLY HAS INCREASED THE RISK OF DEVELOPING MS
• HLA Colombian Studies (gtfrequency of HLA alleles
  DQA-alpha 1.1,1.2 and ltfrequency allele 3),
  similar to Caucasian populations residing in
  non-tropical areas (Sanchez JL et al, 1998)

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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.