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Semin Neurol 2008; 28(1): 007-016
DOI: 10.1055/s-2007-1019125
© Thieme Medical Publishers

Genetics and Natural History of Multiple Sclerosis

Orhun H. Kantarci1
  • 1Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota
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Publication History

Publication Date:
07 February 2008 (online)

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ABSTRACT

Recent studies have better defined the association between the human leukocyte antigen (HLA)-DR, cytotoxic T-lymphocyte antigen-4, interleukin-7 receptor, and interferon-gamma polymorphisms and susceptibility to multiple sclerosis (MS), while many more studies have been added to the controversial pool of likely false-positive and false-negative genetic association and linkage studies. Apolipoprotein E alleles may yet play an important role in disease course and cognitive impairment, although largely refuted as being directly associated with ambulatory measures of disease severity. Natural history studies have started to better define the clinical phenotypic heterogeneity of idiopathic inflammatory diseases of the central nervous system, fueling new hypotheses about immunopathogenesis of MS. Our understanding of phenotype measurement tools is improving. However, despite all the ongoing effort, the cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown. As advances in our understanding of the immunobiology of MS start to bridge the gap between pathological and clinical natural history of the disease, biologically relevant phenotypes of MS will hopefully emerge to allow more specific treatment modalities to be developed and brought to practice.

KEYWORDS

Genetic epidemiology - natural history - prognosis - multiple sclerosis

REFERENCES

  • 1 Lucchinetti C F, Parisi J, Bruck W. The pathology of multiple sclerosis.  Neurol Clin. 2005;  23(1) 77-105
    CrossrefPubMedGoogle Scholar
  • 2 Kantarci O H, Weinshenker B G. Natural history of multiple sclerosis.  Neurol Clin. 2005;  23(1) 17-38
    CrossrefPubMedGoogle Scholar
  • 3 McDonald W I, Compston A, Edan G et al.. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.  Ann Neurol. 2001;  50(1) 121-127
    CrossrefPubMedGoogle Scholar
  • 4 Poser C M, Paty D W, Scheinberg L et al.. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.  Ann Neurol. 1983;  13(3) 227-231
    CrossrefPubMedGoogle Scholar
  • 5 Kantarci O H, de Andrade M, Weinshenker B G. Identifying disease modifying genes in multiple sclerosis.  J Neuroimmunol. 2002;  123(1-2) 144-159
    CrossrefPubMedGoogle Scholar
  • 6 Oksenberg J R, Barcellos L F. The complex genetic aetiology of multiple sclerosis.  J Neurovirol. 2000;  6(S2) S10-S14
    PubMedGoogle Scholar
  • 7 Ebers G C, Sadovnick A D, Risch N J. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group [see comment].  Nature. 1995;  377(6545) 150-151
    CrossrefPubMedGoogle Scholar
  • 8 Weinshenker B G. Epidemiology of multiple sclerosis.  Neurol Clin. 1996;  14(2) 291-308
    CrossrefPubMedGoogle Scholar
  • 9 Ebers G C. A twin consensus in MS [see comment].  Mult Scler. 2005;  11(5) 497-499
    CrossrefPubMedGoogle Scholar
  • 10 Kantarci O H, Barcellos L F, Atkinson E J et al.. Men transmit MS more often to their children vs women: the Carter effect.  Neurology. 2006;  67(2) 305-310
    CrossrefPubMedGoogle Scholar
  • 11 Ebers G C, Sadovnick A D, Dyment D A et al.. Parent-of-origin effect in multiple sclerosis: observations in half-siblings.  Lancet. 2004;  363(9423) 1773-1774
    CrossrefPubMedGoogle Scholar
  • 12 Herrera B M, Ramagopalan S V, Orton S et al.. Parental transmission of MS in a population-based Canadian cohort [see comment].  Neurology. 2007;  69(12) 1208-1212
    CrossrefPubMedGoogle Scholar
  • 13 Hensiek A E, Seaman S R, Barcellos L F et al.. Familial effects on the clinical course of multiple sclerosis.  Neurology. 2007;  68(5) 376-383
    CrossrefPubMedGoogle Scholar
  • 14 Weiss K M, Terwilliger J D. How many diseases does it take to map a gene with SNPs?.  Nat Genet. 2000;  26(2) 151-157
    PubMedGoogle Scholar
  • 15 GAMES; Transatlantic Multiple Sclerosis Genetics Cooperative . A meta-analysis of whole genome linkage screens in multiple sclerosis.  J Neuroimmunol. 2003;  143(1-2) 39-46
    CrossrefPubMedGoogle Scholar
  • 16 Sawcer S, Compston A. The genetic analysis of multiple sclerosis in Europeans: concepts and design [see comment].  J Neuroimmunol. 2003;  143(1-2) 13-16
    CrossrefPubMedGoogle Scholar
  • 17 Sawcer S, Ban M, Maranian M et al.. A high-density screen for linkage in multiple sclerosis.  Am J Hum Genet. 2005;  77 454-467
    CrossrefPubMedGoogle Scholar
  • 18 Oksenberg J R, Barcellos L F, Cree B A et al.. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans.  Am J Hum Genet. 2004;  74(1) 160-167
    CrossrefPubMedGoogle Scholar
  • 19 Lincoln M R, Montpetit A, Cader M Z et al.. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis.  Nat Genet. 2005;  37(10) 1108-1112
    PubMedGoogle Scholar
  • 20 Barcellos L F, Sawcer S, Ramsay P P et al.. Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.  Hum Mol Genet. 2006;  15(18) 2813-2824
    CrossrefPubMedGoogle Scholar
  • 21 Reich D, Patterson N, De Jager P L et al.. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility.  Nat Genet. 2005;  37(10) 1113-1118
    PubMedGoogle Scholar
  • 22 Gough S C, Walker L S, Sansom D M. CTLA4 gene polymorphism and autoimmunity.  Immunol Rev. 2005;  204 102-115
    CrossrefPubMedGoogle Scholar
  • 23 Harbo H F, Celius E G, Vartdal F, Spurkland A. CTLA4 promoter and exon 1 dimorphisms in multiple sclerosis.  Tissue Antigens. 1999;  53(1) 106-110
    CrossrefPubMedGoogle Scholar
  • 24 Ligers A, Xu C, Saarinen S, Hillert J, Olerup O. The CTLA-4 gene is associated with multiple sclerosis.  J Neuroimmunol. 1999;  97(1-2) 182-190
    CrossrefPubMedGoogle Scholar
  • 25 Fukazawa T, Yanagawa T, Kikuchi S et al.. CTLA-4 gene polymorphism may modulate disease in Japanese multiple sclerosis patients.  J Neurol Sci. 1999;  171(1) 49-55
    CrossrefPubMedGoogle Scholar
  • 26 Kantarci O H, Hebrink D D, Achenbach S J et al.. CTLA4 is associated with susceptibility to multiple sclerosis.  J Neuroimmunol. 2003;  134(1-2) 133-141
    CrossrefPubMedGoogle Scholar
  • 27 Suppiah V, Alloza I, Heggarty S et al.. The CTLA4 + 49 A/G*G-CT60*G haplotype is associated with susceptibility to multiple sclerosis in Flanders.  J Neuroimmunol. 2005;  164(1-2) 148-153
    CrossrefPubMedGoogle Scholar
  • 28 Dincic E, Zivkovic M, Stankovic A et al.. Association of polymorphisms in CTLA-4, IL-1ra and IL-1beta genes with multiple sclerosis in Serbian population.  J Neuroimmunol. 2006;  177(1-2) 146-150
    CrossrefPubMedGoogle Scholar
  • 29 Malferrari G, Stella A, Monferini E et al.. Ctla4 and multiple sclerosis in the Italian population.  Exp Mol Pathol. 2005;  78(1) 55-57
    CrossrefPubMedGoogle Scholar
  • 30 Alizadeh M, Babron M C, Birebent B et al.. Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients.  Ann Neurol. 2003;  54(1) 119-122
    CrossrefPubMedGoogle Scholar
  • 31 Roxburgh R H, Sawcer S, Maranian M et al.. No evidence of a significant role for CTLA-4 in multiple sclerosis.  J Neuroimmunol. 2006;  171(1-2) 193-197
    CrossrefPubMedGoogle Scholar
  • 32 Fukazawa T, Kikuchi S, Miyagishi R et al.. CTLA-4 gene polymorphism is not associated with conventional multiple sclerosis in Japanese.  J Neuroimmunol. 2005;  159(1-2) 225-229
    CrossrefPubMedGoogle Scholar
  • 33 Teutsch S M, Booth D R, Bennetts B H, Heard R N, Stewart G J. Association of common T cell activation gene polymorphisms with multiple sclerosis in Australian patients.  J Neuroimmunol. 2004;  148(1-2) 218-230
    CrossrefPubMedGoogle Scholar
  • 34 Lorentzen A R, Celius E G, Ekstrom P O et al.. Lack of association with the CD28/CTLA4/ICOS gene region among Norwegian multiple sclerosis patients.  J Neuroimmunol. 2005;  166(1-2) 197-201
    CrossrefPubMedGoogle Scholar
  • 35 Masterman T, Ligers A, Zhang Z et al.. CTLA4 dimorphisms and the multiple sclerosis phenotype.  J Neuroimmunol. 2002;  131(1-2) 208-212
    CrossrefPubMedGoogle Scholar
  • 36 Barcellos L F, Kamdar B B, Ramsay P P et al.. Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study [see comment].  Lancet Neurol. 2006;  5(11) 924-931
    PubMedGoogle Scholar
  • 37 Goris A, Heggarty S, Marrosu M G et al.. Linkage disequilibrium analysis of chromosome 12q14-15 in multiple sclerosis: delineation of a 118-kb interval around interferon-gamma (IFNG) that is involved in male versus female differential susceptibility.  Genes Immun. 2002;  3(8) 470-476
    CrossrefPubMedGoogle Scholar
  • 38 Reboul J, Mertens C, Levillayer F et al.. Cytokines in genetic susceptibility to multiple sclerosis: a candidate gene approach.  French Multiple Sclerosis Genetics Group . J Neuroimmunol. 2000;  102(1) 107-112
    CrossrefPubMedGoogle Scholar
  • 39 Vandenbroeck K, Cunningham S, Goris A et al.. Polymorphisms in the interferon-gamma/interleukin-26 gene region contribute to sex bias in susceptibility to rheumatoid arthritis.  Arthritis Rheum. 2003;  48(10) 2773-2778
    CrossrefPubMedGoogle Scholar
  • 40 Kantarci O H, Goris A, Hebrink D D et al.. IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis.  Genes Immun. 2005;  6(2) 153-161
    CrossrefPubMedGoogle Scholar
  • 41 Dai Y, Masterman T, Huang W X et al.. Analysis of an interferon-gamma gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients.  Mult Scler. 2001;  7(3) 157-163
    PubMedGoogle Scholar
  • 42 Goris A, Epplen C, Fiten P et al.. Analysis of an IFN-gamma gene (IFNG) polymorphism in multiple sclerosis in Europe: effect of population structure on association with disease.  J Interferon Cytokine Res. 1999;  19(9) 1037-1046
    CrossrefPubMedGoogle Scholar
  • 43 Schrijver H M, Hooper-van Veen T, van Belzen M J et al.. Polymorphisms in the genes encoding interferon-gamma and interferon-gamma receptors in multiple sclerosis.  Eur J Immunogenet. 2004;  31(3) 133-140
    CrossrefPubMedGoogle Scholar
  • 44 Bergkvist M, Olsson M, Sandberg-Wollheim M. No evidence for genetic linkage between development of multiple sclerosis and components of the IFN system and the JAK-STAT pathway.  Mult Scler. 2004;  10(1) 87-88
    CrossrefPubMedGoogle Scholar
  • 45 Gee J R, Keller J N. Astrocytes: regulation of brain homeostasis via apolipoprotein E.  Int J Biochem Cell Biol. 2005;  37(6) 1145-1150
    CrossrefPubMedGoogle Scholar
  • 46 Laskowitz D T, Horsburgh K, Roses A D. Apolipoprotein E and the CNS response to injury.  J Cereb Blood Flow Metab. 1998;  18(5) 465-471
    PubMedGoogle Scholar
  • 47 Enzinger C, Ropele S, Strasser-Fuchs S et al.. Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele [see comment].  Arch Neurol. 2003;  60(1) 65-70
    PubMedGoogle Scholar
  • 48 Schmidt S, Barcellos L F, DeSombre K et al.. Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis.  Am J Hum Genet. 2002;  70(3) 708-717
    CrossrefPubMedGoogle Scholar
  • 49 Kantarci O H, Hebrink D D, Achenbach S J et al.. Association of APOE polymorphisms with disease severity in MS is limited to women [see comment].  Neurology. 2004;  62(5) 811-814
    PubMedGoogle Scholar
  • 50 Cocco E, Sotgiu A, Costa G et al.. HLA-DR, DQ and APOE genotypes and gender influence in Sardinian primary progressive MS.  Neurology. 2005;  64(3) 564-566
    PubMedGoogle Scholar
  • 51 Savettieri G, Messina D, Andreoli V et al.. Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis.  J Neurol. 2004;  251(10) 1208-1214
    PubMedGoogle Scholar
  • 52 Burwick R M, Ramsay P P, Haines J L et al.. APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers.  Neurology. 2006;  66(9) 1373-1383
    CrossrefPubMedGoogle Scholar
  • 53 Koutsis G, Panas M, Giogkaraki E et al.. APOE epsilon4 is associated with impaired verbal learning in patients with MS.  Neurology. 2007;  68(8) 546-549
    CrossrefPubMedGoogle Scholar
  • 54 Ebers G C, Kukay K, Bulman D E et al.. A full genome search in multiple sclerosis [see comment].  Nat Genet. 1996;  13(4) 472-476
    PubMedGoogle Scholar
  • 55 Zhang Z, Duvefelt K, Svensson F et al.. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis.  Genes Immun. 2005;  6(2) 145-152
    CrossrefPubMedGoogle Scholar
  • 56 Hafler D A, Compston A, Sawcer S International Multiple Sclerosis Genetics Consortium et al.. Risk alleles for multiple sclerosis identified by a genomewide study.  N Engl J Med. 2007;  357(9) 851-862
    CrossrefPubMedGoogle Scholar
  • 57 Lundmark F, Salter H, Hillert J. An association study of two functional promotor polymorphisms in the myeloperoxidase (MPO) gene in multiple sclerosis.  Mult Scler. 2007;  13(6) 697-700
    CrossrefPubMedGoogle Scholar
  • 58 Lucchinetti C, Bruck W, Parisi J et al.. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination [see comment].  Ann Neurol. 2000;  47(6) 707-717
    CrossrefPubMedGoogle Scholar
  • 59 CHAMPS Group Study . Interferon beta-1a for optic neuritis patients at high risk for multiple sclerosis.  Am J Ophthalmol. 2001;  132(4) 463-471
    CrossrefPubMedGoogle Scholar
  • 60 Beck R W, Chandler D L, Cole S R et al.. Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses.  Ann Neurol. 2002;  51(4) 481-490
    CrossrefPubMedGoogle Scholar
  • 61 Beck R W, Trobe J D, Moke P S et al.. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial [see comment].  Arch Ophthalmol. 2003;  121(7) 944-949
    CrossrefPubMedGoogle Scholar
  • 62 Cordonnier C, de Seze J, Breteau G et al.. Prospective study of patients presenting with acute partial transverse myelopathy.  J Neurol. 2003;  250(12) 1447-1452
    PubMedGoogle Scholar
  • 63 Ford B, Tampieri D, Francis G. Long-term follow-up of acute partial transverse myelopathy [see comment].  Neurology. 1992;  42 250-252
    PubMedGoogle Scholar
  • 64 Weinshenker B G, Wingerchuk D M, Vukusic S et al.. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis.  Ann Neurol. 2006;  59(3) 566-569
    CrossrefPubMedGoogle Scholar
  • 65 Weinshenker B G. Plasma exchange for severe attacks of inflammatory demyelinating diseases of the central nervous system.  J Clin Apher. 2001;  16(1) 39-42
    CrossrefPubMedGoogle Scholar
  • 66 Keegan M, Konig F, McClelland R et al.. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange [see comment].  Lancet. 2005;  366(9485) 579-582
    CrossrefPubMedGoogle Scholar
  • 67 Wingerchuk D M. Neuromyelitis optica: current concepts.  Front Biosci. 2004;  9 834-840
    CrossrefPubMedGoogle Scholar
  • 68 Kantarci O, Siva A, Eraksoy M et al.. Survival and predictors of disability in Turkish MS patients.  Turkish Multiple Sclerosis Study Group (TUMSSG) . Neurology. 1998;  51(3) 765-772
    CrossrefPubMedGoogle Scholar
  • 69 Rodriguez M, Siva A, Ward J et al.. Impairment, disability, and handicap in multiple sclerosis: a population-based study in Olmsted County, Minnesota.  Neurology. 1994;  44(1) 28-33
    PubMedGoogle Scholar
  • 70 Frohman E M, Filippi M, Stuve O et al.. Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions [see comment].  Arch Neurol. 2005;  62(9) 1345-1356
    CrossrefPubMedGoogle Scholar
  • 71 Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up.  Brain. 1993;  116(Pt 1) 117-134
    PubMedGoogle Scholar
  • 72 Riise T, Gronning M, Fernandez O et al.. Early prognostic factors for disability in multiple sclerosis, a European multicenter study.  Acta Neurol Scand. 1992;  85(3) 212-218
    PubMedGoogle Scholar
  • 73 Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis [see comment].  N Engl J Med. 2000;  343(20) 1430-1438
    CrossrefPubMedGoogle Scholar
  • 74 Trojano M, Avolio C, Manzari C et al.. Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events.  J Neurol Neurosurg Psychiatry. 1995;  58(3) 300-306
    PubMedGoogle Scholar
  • 75 Bergamaschi R, Berzuini C, Romani A, Cosi V. Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis [see comment].  J Neurol Sci. 2001;  189(1-2) 13-21
    CrossrefPubMedGoogle Scholar
  • 76 Ann Marrie R, Rudick R A. Drug insight: interferon treatment in multiple sclerosis.  Nat Clin Pract Neurol. 2006;  2(1) 34-44
    CrossrefPubMedGoogle Scholar
  • 77 Fox E J. Management of worsening multiple sclerosis with mitoxantrone: a review.  Clin Ther. 2006;  28(4) 461-474
    CrossrefPubMedGoogle Scholar
  • 78 Kurtzke J F. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS).  Neurology. 1983;  33(11) 1444-1452
    CrossrefPubMedGoogle Scholar
  • 79 Rao S M, Leo G J, Haughton V M, St Aubin-Faubert P, Bernardin L. Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis.  Neurology. 1989;  39(2 Pt 1) 161-166
    CrossrefPubMedGoogle Scholar
  • 80 Rudick R A. Clinical outcomes assessment in multiple sclerosis: Part I.  Mult Scler. 1996;  2(5) 244-246
    PubMedGoogle Scholar
  • 81 Fischer J S, Rudick R A, Cutter G R, Reingold S C. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force.  Mult Scler. 1999;  5(4) 244-250
    CrossrefPubMedGoogle Scholar
  • 82 Goodkin D E, Hertsgaard D, Seminary J. Upper extremity function in multiple sclerosis: improving assessment sensitivity with box-and-block and nine-hole peg tests.  Arch Phys Med Rehabil. 1988;  69(10) 850-854
    PubMedGoogle Scholar
  • 83 Miller D M, Rudick R A, Cutter G, Baier M, Fischer J S. Clinical significance of the multiple sclerosis functional composite: relationship to patient-reported quality of life.  Arch Neurol. 2000;  57(9) 1319-1324
    CrossrefPubMedGoogle Scholar
  • 84 Deloire M S, Salort E, Bonnet M et al.. Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2005;  76(4) 519-526
    CrossrefPubMedGoogle Scholar
  • 85 Achiron A, Polliack M, Rao S M et al.. Cognitive patterns and progression in multiple sclerosis: construction and validation of percentile curves.  J Neurol Neurosurg Psychiatry. 2005;  76(5) 744-749
    CrossrefPubMedGoogle Scholar
  • 86 Roxburgh R HSR, Seaman S R, Mastermann T et al.. Multiple Sclerosis Severity Score. Using disability and disease duration to rate disease severity.  Neurology. 2005;  64 1144-1151
    PubMedGoogle Scholar
  • 87 Weinshenker B G, Bass B, Rice G P et al.. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.  Brain. 1989;  112(Pt 1) 133-146
    CrossrefPubMedGoogle Scholar
  • 88 Weinshenker B G, Bass B, Rice G P et al.. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course.  Brain. 1989;  112(Pt 6) 1419-1428
    CrossrefPubMedGoogle Scholar
  • 89 Pittock S J, McClelland R L, Mayr W T et al.. Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study.  Ann Neurol. 2004;  56(2) 303-306
    CrossrefPubMedGoogle Scholar
  • 90 Pittock S J. Does benign multiple sclerosis today imply benign multiple sclerosis tomorrow?: implications for treatment [see comment].  Neurology. 2007;  68 480-481
    CrossrefPubMedGoogle Scholar
  • 91 Langer-Gould A, Popat R A, Huang S M et al.. Clinical and demographic predictors of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review.  Arch Neurol. 2006;  63(12) 1686-1691
    CrossrefPubMedGoogle Scholar
  • 92 Confavreux C, Hutchinson M, Hours M M, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group [see comment].  N Engl J Med. 1998;  339(5) 285-291
    CrossrefPubMedGoogle Scholar
  • 93 Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process [see comment].  Brain. 2003;  126(Pt 4) 770-782
    CrossrefPubMedGoogle Scholar
  • 94 Cottrell D A, Kremenchutzky M, Rice G P et al.. The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis [see comment].  Brain. 1999;  122(Pt 4) 625-639
    CrossrefPubMedGoogle Scholar
  • 95 Tremlett H, Paty D, Devonshire V. The natural history of primary progressive MS in British Columbia, Canada.  Neurology. 2005;  65 1919-1923
    CrossrefPubMedGoogle Scholar
  • 96 Sadovnick A D, Eisen K, Ebers G C, Paty D W. Cause of death in patients attending multiple sclerosis clinics [see comment].  Neurology. 1991;  41(8) 1193-1196
    PubMedGoogle Scholar
  • 97 Phadke J G. Survival pattern and cause of death in patients with multiple sclerosis: results from an epidemiological survey in north-east Scotland.  J Neurol Neurosurg Psychiatry. 1987;  50(5) 523-531
    PubMedGoogle Scholar
  • 98 Riise T, Grønning M, Aarli J A, Nyland H, Larsen J P, Edland A. Prognostic factors for life expectancy in multiple sclerosis analysed by Cox-models.  J Clin Epidemiol. 1988;  41(10) 1031-1036
    CrossrefPubMedGoogle Scholar
  • 99 Poser S, Kurtzke J F, Poser W, Schlaf G. Survival in multiple sclerosis.  J Clin Epidemiol. 1989;  42(2) 159-168
    CrossrefPubMedGoogle Scholar
  • 100 Bronnum-Hansen H, Koch-Henriksen N, Hyllested K. Survival of patients with multiple sclerosis in Denmark: a nationwide, long-term epidemiologic survey.  Neurology. 1994;  44(10) 1901-1907
    PubMedGoogle Scholar
  • 101 Pekmezovic T, Jarebinski M, Drulovic J, Stojsavljevic N, Levic Z. Survival of multiple sclerosis patients in the Belgrade population.  Neuroepidemiology. 2002;  21(5) 235-240
    CrossrefPubMedGoogle Scholar
  • 102 Wallin M T, Page W F, Kurtzke J F. Epidemiology of multiple sclerosis in US veterans. VIII. Long-term survival after onset of multiple sclerosis.  Brain. 2000;  123(Pt 8) 1677-1687
    CrossrefPubMedGoogle Scholar

Orhun H KantarciM.D. 

Assistant Professor of Neurology, Mayo Clinic College of Medicine

200 First Street SW, Rochester, MN 55902

Email: kantarci.orhun@mayo.edu