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`A reappraisal of the epidemiology
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`of multiple sclerosis in
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`Olmsted County, Minnesota
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`Daniel R. Wynn, MD; Moses Rodriguez, MD; W. Michael O’Fallon, PhD; and Leonard T. Kurland, MD, DrPI-I
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`Article abstract—A review of multiple sclerosis (MS) case reports, using the unified record system at the Mayo Clinic for the
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`Olmsted County population, revealed age- and sex-adjusted prevalence rates per 100,000 persons of 160 for Olmsted County and
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`173 for Rochester, Minnesota, on January 1, 1985. The annual age— and sex-adjusted incidence rate per 100,000 person-years from
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`1975 to 1984 for Olmsted County was 6.2 and for Rochester, 6.3. This incidence rate is significantly higher than what had been
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`reported previously in Rochester (3.6/100,000) or in other communities. The estimated 25-year survival of the MS population was
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`76.2% i 4.5% compared with 87.7% for the general US white population of a similar age and sex. Survival for men was less than
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`for women. There was no increase in survival for patients diagnosed with MS in more recent decades. No significant increase was
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`found in cancer or autoimmune disease rates in the MS patients.
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`NEUROLOGY 1990;40:780-786
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`In 1950, MacLean et a]1 reported the lst epidemiologic
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`study of multiple sclerosis (MS) in the United States for
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`the population of Rochester, Minnesota. Prevalence of
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`MS has now been studied in many different popula-
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`tions. In locations where such surveys have been re-
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`peated, prevalence appears to be increasing, most likely
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`reflecting improved case ascertainment or increased
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`survival, or both, among MS patients.2 There are, how-
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`ever, fewer incidence studies of MS, reflecting the diffi-
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`culty of identifying over a period of several years all
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`newly diagnosed cases in any population, but particu-
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`larly in those with diverse sources of health care. Inci-
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`dence rates of MS are available for only a few
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`populations, including Rochester, Minnesota”;
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`Orkney and Shetland Islands‘; Winnipeg“; New Or-
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`leans“; Iceland7; London/Middlesex County of Ontario,
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`Canada“; Norway9; Newfoundland and Labrador“);
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`Sassari, Sardinia“; and 3 Australian cities.12 Most stud-
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`ies have found the local incidence rate for MS to be a
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`stable phenomenon.13
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`We updated the epidemiology of MS in Rochester,
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`MN, and Olmsted County, and tested the hypothesis
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`that increased prevalence of MS in Olmsted County is
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`the result of increased incidence, not merely a result of
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`increased survival among MS patients. We also exam—
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`ined whether MS is associated with increased risk of
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`development of cancer or autoimmune disorders.
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`Methods. This study identified the cases of MS in Olmsted
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`County from 1905 through 1984 by using the centralized diag-
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`nostic index at the Mayo Clinic. The diagnostic retrieval
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`system of the Rochester Epidemiology Program Project“ al-
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`lowed identification and retrieval of medical charts of
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`Rochester or Olmsted County residents. Patients were re-
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`quired to have established residence in Olmsted County for at
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`least 1 year prior to the diagnosis of MS, thus excluding
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`anyone who might have moved to the area to facilitate diagno-
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`sis or treatment. Diagnoses of all cases considered eligible for
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`study had been made by at Mayo Clinic neurologist. However,
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`each chart was reviewed and classified by 2 of us (D.R.W. and
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`MR.) to confirm the diagnosis. We categorized cases as clini—
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`cally definite, laboratory-supported definite, clinically proba-
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`ble, laboratory-supported probable, or not MS by using
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`diagnostic criteria for MS outlined in the Workshop on the ‘
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`Diagnosis of Multiple Sclerosis.15 Patients with isolated retro-
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`bulbar neuritis were excluded from study.
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`Data regarding basic demographic characteristics, age at
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`onset, age at diagnosis, presence of associated medical diag-
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`noses (ie, diabetes, autoimmune disease, and neoplasia), and
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`follow-up status were abstracted from the medical record of
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`each patient by using precoded abstracting forms. Date of
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`onset was defined as the date of lst verified symptom. For
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`patients who experienced optic neuritis as the heralding sign
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`of MS, the date of diagnosis of optic neuritis was taken as the
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`date of onset of MS. On the basis of clinical documentation,
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`the date of onset was assigned retrospectively, frequently sev-
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`eral years before the date of diagnosis of MS. The date used for
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`prevalence study was January 1, 1985. The population of
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`From the Department of Neurology (Drs. Wynn and Rodriguez), the Section of Biostatistics (Dr. O’Fallon), and the Section of Clinical Epidemiology (Dr. Kurland),
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`Mayo Clinic and Mayo Foundation, Rochester, MN.
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`Supported by the Neuroepidemiology Program Project NS 17750-P2 from the National Institutes of Health. Moses Rodriguez is the recipient of Teacher Investigator
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`Award NS 00849 from the NINCDS and is the John G. Searle Scholar of the Chicago Community Trust.
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`Presented in part at the 39th annual meeting of the American Academy of Neurology, New York, NY, April 1987, and in part at the 40th annual meeting of the
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`American Academy of Neurology, Cincinnati, OH, April 1988.
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`Received August 14, 1989. Accepted for publication in final form October ‘25, 1989.
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`Address correspondence and reprint requests to Dr. Moses Rodriguez, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
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`780 NEUROLOGY 40 May 1990
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`Page 1 0f 7
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`Biogen Exhibit 2086
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`Mylan v. Biogen
`IPR 2018-01403
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`Page 1 of 7
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`Biogen Exhibit 2086
`Mylan v. Biogen
`IPR 2018-01403
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`

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`Table 1. Prevalence‘ of multiple sclerosis in Olmsted County, Minnesota, January 1, 1985
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`Rate
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`37.9
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`124.0
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`281.5
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`290.5
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`491.7
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`265.7
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`159.8
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`Population
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`Women
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`Cases
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`Rate
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`Both sexes
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`Population
`Cases
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`22,143
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`15,848
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`18,555
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`13,144
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`9,293
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`7,118
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`9,033
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`95,134
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`0
`6
`23
`37
`27
`35
`24
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`152
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`_ 4
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`8.0
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`167.9
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`432.6
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`431.8
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`675.7
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`369.1
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`231.9
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`0
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`17
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`29
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`20
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`25
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`21
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`116
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`10,830
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`8,333
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`10,128
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`6,704
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`4,632
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`3,700
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`5,690
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`50,017
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`Age
`(yrs)
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`0-14
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`15-24
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`25—34
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`35-44
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`45-54
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`55-64
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`265
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`Total
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`Population
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`Men
`Cases
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`1 1,313
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`7,515
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`8,427
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`6,440
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`4,661
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`3,418
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`3,343
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`45,117
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`Rate
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`26.6
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`71.2
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`124.2
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`150.2
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`292.6
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`89.7
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`79.8
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`Table 2. Prevalence“ of multiple sclerosis in Rochester, Minnesota, January 1, 1985
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`'Prevalence rate per 100,000 population. Overall sex- and age-adjusted prevalence per 100,000 to the 1950 US white population was 170.8 (95% Cl, 143-198).
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`Age
`(yrs)
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`0—14
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`15—24
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`25—34
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`35-44
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`45-54
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`55-64
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`265
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`Total
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`Population
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`Men
`Cases
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`6,362
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`4,557
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`5,549
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`3,636
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`2,717
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`2,120
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`2,126
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`27,067
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`Rate
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`43.9
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`72.1
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`165.0
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`73.6
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`330.2
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`47.0
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`81.3
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`Women
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`Cases
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`Population
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`6,156
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`5,806
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`6,761
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`3,905
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`2,899
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`2,461
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`4,365
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`32,353
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`0
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`4
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`8
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`21
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`14
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`16
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`17
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`80
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`Rate
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`_
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`68.9
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`1 18.3
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`537.8
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`482.9
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`650.1
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`389.5
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`247.3
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`Both sexes
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`Population
`Cases
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`12,518
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`10,363
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`12,310
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`7,541
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`5,616
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`4,581
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`6,491
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`59,420
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`6
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`12
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`27
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`16
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`23
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`18
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`102
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`Rate
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`57.9
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`97.5
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`358.0
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`284.9
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`502.1
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`277.3
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`173.3
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`‘Prevalence rate per 100,000 population. Overall sex- and age-adjusted prevalence per 100,000 to the 1950 US white population was 177.3 (95% Cl, 142-212).
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`Rochester, Minnesota, is primarily middle class and 98%
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`white. The majority of patients received their medical care at
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`the Mayo Clinic; others received their care at the Olmsted
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`Medical Group or at the Olmsted Community Hospital. How-
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`ever, the indexes of the Rochester Epidemiology Project al-
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`lowed retrieval of all diagnoses regardless of health-care
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`provider. The pathology archives were also examined to in-
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`clude all histologically confirmed cases of MS.
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`Survival curves were estimated with use of the Kaplan-
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`Meier product-limit method.16 Comparisons of survival
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`curves were made with the log-rank test.”
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`Results. On January 1, 1985, there were 152 prevalence
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`cases of MS in Olmsted County, of which 102 were for
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`Rochester residents (tables 1 and 2). Age- and sex-
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`adjusted prevalence rates were 170.8/100,000 for
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`Olmsted County (95% confidence interval, 143 to
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`198/100,000) and 177.3/100,000 for Rochester (95% CI,
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`142 to 212/100,000). The overall sex- and age-adjusted
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`prevalence rate for Olmsted County, excluding
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`Rochester, was 159.8/100,000 (95% CI, 113 to
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`207/100,000). The prevalence rates were significantly
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`higher for women than for men, and this relationship
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`was the same when adjusted for age.
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`During the 80-year period between January 1, 1905,
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`and January 1, 1985, 206 incidence cases of MS were
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`diagnosed in Olmsted County: 57 men and 149 women.
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`The age-adjusted incidence rates were 2.8 and
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`6.8/100,000 for men and women, respectively (table 3).
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`Page 2 0f 7
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`Slightly higher incidence rates were noted for
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`Rochester: 3.4 and 77/100,000 for men and women,
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`respectively (table 4). Analysis of average annual inci-
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`dence of MS by years showed a trend toward increasing
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`incidence, especially for women (tables 3 and 4). Me-
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`dian age at diagnosis was 34 years for men, 32 years for
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`women, and 33 years overall (table 5). Median follow-up
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`interval was 13.8 years for men, 14.2 years for women,
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`and 14.0 years overall. Follow-up information covering
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`3,469 person-years was available for review. Autopsy
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`information was available on 20 of 43 individuals (47 %)
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`who died during the study interval (table 5); all had
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`pathologic evidence of MS.
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`Distribution of category of MS diagnosis by the cri-
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`teria of Poser et al15 is shown in table 6. More than 90%
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`of patients were classified as having clinically definite
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`MS (CDMSAI). This high percentage of clinically defi-
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`nite cases is most likely related to long median duration
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`of follow-up. Because previous epidemiologic studies of
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`MS in Rochester and other communities used only
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`clinical criteria, we also analyzed the data by using only
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`the 192 clinically definite cases (CDMSAI and
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`CDMSA2). Age-adjusted incidence rates for clinically
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`definite cases in Olmsted County (1905-1984) were 6.4
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`
`(95% CI, 5.4 to 7.6) for women and 3.0 (95% CI, 2.2 to
`
`
`
`
`
`
`
`
`
`
`3.8) for men. The overall sex- and age-adjusted rate was
`
`
`
`
`
`
`
`
`
`
`
`
`4.8 (95% CI, 4.1 to 5.4). From 1950 to 1984 the age-
`
`
`
`
`
`
`
`
`
`
`adjusted incidence rate for women was 8.3 (95% CI, 6.7
`
`
`May 1990 NEUROLOGY 40 781
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`Page 2 of 7
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`Table 3. Average annual incidence rates of multiple sclerosis in Olmsted County, Minnesota,
`
`
`
`
`New cases (no.)
`
`
`Women
`Men
`
`
`Crude rate 100,000
`
`
`Men
`Women
`
`
`
`
`
`1905-1984
`
`
`
`Total
`rateT/ 100,000
`
`95%
`
`CI
`
`
`
`
`
`
`Years
`
`
`Men
`
`
`Women
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.6
`
`0.7
`
`7.3
`
`3.7
`
`6.9
`
`5.1
`
`10.9
`
`9.0
`
`
`6.8
`
`7.4
`
`8.3
`
`
`1.2
`
`1.4
`
`3.5
`
`2.4
`
`5.3
`
`4.4
`
`7.9
`
`6.2
`
`
`4.9
`
`5.6
`
`6.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`13
`
`8
`
`17
`
`17
`
`47
`
`43
`
`33
`
`
`
`
`
`149
`137
`18
`1
`
`114,266
`140,609
`177,351
`213,958
`246,132
`331,335
`429,770
`477,647
`
`
`
`
`
`
`
`
`
`
`2,181,085
`1,844,000
`1,419,150
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Decade
`1905-1914
`1915-1924
`1925-1934
`1935-1944
`1945-1954
`1955-1964
`1965-1974
`1975-1984
`
`Interval
`1905-1984
`1930-1984
`1950-1984
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`116,965
`136,824
`167,848
`197,005
`220,265
`298,869
`387,244
`431,917
`
`2,002,053
`1,670,3 12
`1,2 79,774
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘ Expressed as person-years.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Table 4. Average annual incidence rates of multiple sclerosis in Rochester, Minnesota, 1905-1984
`
`
`
`Years
`
`
`
`
`Population‘
`
`
`Men
`Women
`
`
`
`
`New cases (no.)
`
`
`Women
`Men
`
`
`
`
`
`
`
`
`
`’r Total rates were sex- and age-adjusted to the 1950 US white population.
`
`
`
`
`
`
`* Expressed as person-years.
`
`
`
`
`
`
`
`
`
`
`‘1 Total rates were sex- and age-adjusted to the 1950 US white population.
`
`
`
`
`
`
`
`
`
`
`Table 5. Multiple sclerosis cohort in Olmsted County,
`
`Minnesota
`
`
`
`Men
`
`
`
`Women
`
`
`
`Total
`
`
`
`
`
`
`
`
`
`Median age at diagnosis (yrs)
`
`
`
`
`Median follow-up interval (yrs)
`
`
`Person-years of follow-up
`
`
`Autopsy information
`
`
`
`34
`
`
`
`32
`33
`14.0
`14.2
`13.8
`
`
`
`
`
`
`871
`3,469
`2,598
`
`
`
`
`
`9/17 (53%) 11/26 (42%) 20/43 (47%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to 9.9); for men, 4.0 (95% CI, 2.8 to 5.2); and overall sex-
`
`
`
`
`
`
`
`
`
`and age-adjusted rate, 6.2 (95% CI, 5.2 to 7.1). For
`
`
`
`
`
`
`
`
`Rochester from 1950 to 1984, the age-adjusted rate for
`
`
`
`
`
`
`
`
`
`
`
`women was 8.5 (95% CI, 6.4 to 10.4); men, 4.1 (95% CI,
`
`
`
`
`
`
`
`
`
`2.6 to 5.6); and overall sex- and age-adjusted rate, 6.3
`
`
`
`
`
`(95% CI, 5.0 to 7.6).
`
`
`
`
`
`
`
`Survival of MS patients was estimated by using Kap-
`
`
`
`
`
`Ian-Meier product—limit estimation16 and was com-
`
`
`
`
`782 NEUROLOGY 40 May 1990
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`
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`
`
`
`
`Page 3 0f 7
`
`
`
`
`
`
`
`
`
`
`
`pared with that of the general population by a log-rank
`
`
`
`
`
`
`
`
`
`
`test (p < 0.001) (figure 1). When analyzed by sex (figure
`
`
`
`
`
`
`
`
`
`2), survival for men was significantly worse than for
`
`
`
`
`
`
`
`
`
`
`women (p = 0.001). To address the question of whether
`
`
`
`
`
`
`
`
`
`increase in survival of the MS cohort explained the
`
`
`
`
`
`
`
`increase in prevalence, we compared survival with
`
`
`
`
`
`
`
`
`
`death as a function of year of diagnosis. No differences
`
`
`
`
`
`
`
`
`
`were found in survival in patients diagnosed with MS
`
`
`
`
`
`
`
`
`
`
`from 1905 to 1933, 1934 to 1959, or 1960 to 1984 (p =
`
`
`
`
`
`
`
`
`
`
`0.875) (table 7). It is estimated that 25 years after
`
`
`
`
`
`
`
`
`
`
`disease onset, 76.2% i 4.5% of the MS cohort will
`
`
`remain alive.
`
`
`
`
`
`
`
`
`We analyzed whether MS was associated with cancer
`
`
`
`
`
`
`
`or autoimmune disorders. Diseases associated with this
`
`
`
`
`
`
`
`
`
`
`
`MS cohort are shown in table 8. No definite increase in
`
`
`
`
`
`
`
`
`
`risk was found for cancer or specific autoimmune disor-
`
`
`
`
`
`
`
`
`ders compared with rates in the Rochester population
`
`
`(table 9).
`
`
`Crude rate[100,000
`
`
`Men
`Women
`
`
`Total
`rateT/ 1 00,000
`
`
`2.8
`
`2.9
`
`5.2
`
`2.3
`
`6.5
`
`4.9
`
`7.4
`
`6.3
`
`
`5.5
`
`5.8
`
`6.6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`6.8
`
`1.4
`
`12.2
`
`3.7
`
`7.5
`
`5.2
`
`11.3
`
`8.7
`
`
`7.7
`
`7.7
`
`8.5
`
`
`
`
`13
`
`5
`
`12
`
`11
`
`32
`
`27
`
`3 1
`
`104
`92
`78
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`031 1 8 77 1
`
`1
`
`
`38
`
`35
`
`29
`
`Decade
`
`
`1905-1914
`
`1915-1924
`
`1925-1934
`
`1935-1944
`
`1945-1954
`
`1955-1964
`
`1965-1974
`
`1975-1984
`
`Interval
`
`1905-1984
`
`1930-1984
`
`1950-1984
`
`38,582
`61,138
`86,039
`108,994
`123,449
`172,517
`234,374
`261,141
`
`
`
`
`
`
`
`
`
`
`44,041
`72,271
`106,421
`136,975
`159,003
`212,364
`282,529
`312,01 1
`
`
`
`
`
`
`
`
`
`
`1,357,968
`974,895
`760,610
`
`
`
`
`
`1,113,301
`1,193,607
`923,113
`
`
`
`
`
`Page 3 of 7
`
`

`

`Years since diagnosis of MS
`
`
`
`
`
`
`
`10
`
`
`
`
`15
`
`
`
`
`
`20
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 2. Kaplan-Meier curves for males and females with
`
`
`
`
`
`
`
`
`MS in Olmsted County. Males had decreased survival
`
`
`
`
`
`
`
`
`
`compared with females (p = 0.001). This became most
`
`
`
`
`
`
`
`apparent 10 years after diagnosis of MS.
`
`
`
`
`
`
`
`
`
`
`
`Table 7. Survival of patients with multiple sclerosis
`
`
`
`
`
`
`in Olmsted County, Minnesota: Incidence cases as a
`
`
`
`
`
`function of year of diagnosis‘
`
`
`Females-observed
`
`
`
`--------------- Males-expected
`Males--observed
`
`
`
`o\°
`Ci)
`
`5.
`
`2Z3
`
`CD
`
`
`
`
`
`
`
`
`
`Table 6. Diagnostic category of multiple sclerosis in
`
`
`
`
`
`cohort from Olmsted County, Minnesota, 1905-1984
`
`
`
`Category of
`multiple sclerosis'
`
`Frequency
`
`Total
`
`Men
`
`Women
`
`No.
`
`
`
`Clinically definite
`55
`CDMSA 1
`
`
`
`1
`CDMSA2
`
`
`
`
`Laboratory-supported definite
`
`LSDMSBI
`l
`
`
`
`LSDMSBZ
`0
`
`LSDMSB3
`0
`
`
`Clinically probable
`
`
`0
`CPMSCI
`
`
`0
`CPMSCZ
`
`
`0
`CPMSC3
`
`Laboratory-supported probable
`
`
`LSPMSDl
`0
`
`
`Total
`
`
`
`57
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`149
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘ Poser et 31 criteria for multiple sclerosis.l5
`
`
`
`
`/
`
` ------ Females-expected
`
`some000
`saw00
`
`
`
`
`
`
`
`
`wa..5woooo
`
`o
`
`
`
`nz—<—<2:Cm«zmozrfi-u
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Year of
`diagnosis
`
`1905-1933
`1934-1959
`1960-1984
`
`
`Total
`
`
`
`
`
`
`
`
`
`Cases of
`
`multiple
`
`sclerosis
`
`(no.)
`
`
`17
`
`49
`
`140
`
`
`206
`
`
`
`
`
`
`
`
`
`
`
`
`‘ l2 = 0.28; df = 2; 2-tailed,p = 0.87.
`
`
`
`
`
`
`
`
`
`
`
`
`and associates extended incidence estimates through
`
`
`
`
`
`
`
`
`
`1974 and prevalence through 1978.3 They noted, as had
`
`
`
`
`
`
`
`been observed in other communities where repeated
`
`
`
`
`
`
`
`surveys have been performed, an increasing prevalence
`
`
`
`
`
`
`
`
`
`
`
`rate from 46/100,000 as calculated by Percy et al for 1915
`
`
`
`
`
`
`
`
`
`
`to 108/100,000 for 1978. They noted an incidence rate of
`
`
`
`
`
`
`
`
`3.6/100,000 for the 10-year interval from 1965 to 1974,
`
`
`
`
`
`
`
`
`
`
`which was identical to that calculated by Percy et al for
`
`
`
`
`
`
`
`the entire time from 1905 to 1964.
`
`
`
`
`
`
`This reappraisal of the epidemiology confirms a fur-
`
`
`
`
`
`
`
`
`ther increase in prevalence of MS in Olmsted County,
`
`
`
`
`
`
`
`
`but it also documents an increase in incidence. In-
`
`
`
`
`
`
`
`creases in MS prevalence have been attributed previ-
`
`
`
`
`
`
`
`
`ously to increased survival of MS patients, changes in
`
`
`
`
`
`
`
`population age structure, migration, and miscellaneous
`
`
`
`
`
`
`efl'ects of restudy.4 Important effects of restudy include
`
`
`
`
`
`improved case-finding methods as a result of advances
`
`
`
`
`
`
`in technology of diagnosis and computerization and
`
`
`
`
`
`
`long-term maintenance of medical records, which fur-
`
`
`
`
`
`
`ther increase completeness of case ascertainment. Al-
`
`
`
`
`
`
`
`
`though it is likely that these factors have contributed to
`
`
`
`
`
`
`
`increased prevalence rates in Olmsted County, we were
`
`
`
`
`
`
`
`suspicious that these factors might be insufficient to
`
`
`
`
`
`
`
`
`explain the entire difference noted and we looked to
`
`
`
`
`
`
`another possible cause—an increase in disease inci-
`
`dence.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`May 1990 NEUROLOGY 40 783
`
`
`
`
`
`
`
`
`I""""'H 1
`Ty—v—v—i
`r—T—v—1—V—Y—V—1—t
`
`25
`10
`15
`20
`
`
`
`
`YEARS SINCE DIAGNOSIS OF M,S.
`
`
`
`
`
`rrrrrrr EXPECTED — OBSERVED
`
`
`
`GROUP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 1. Kaplan-Meier survival curve for the entire cohort
`
`
`
`
`
`
`
`
`
`
`
`with MS (n = 206) compared with an age- and sex-
`
`
`
`
`
`
`
`
`
`matched cohort from the US white population. There was
`
`
`
`
`
`
`
`decreased survival in the multiple sclerosis cohort compared
`
`
`
`
`
`with expected (p < 0.001).
`
`
`
`
`
`
`
`
`
`Discussion. The development of neuroepidemiology
`
`
`
`
`
`
`
`
`
`as a distinct specialty can be traced to 1950 with pub-
`
`
`
`
`
`
`
`
`
`lication of the 1st population-based study of MS in the
`
`
`
`
`
`
`
`
`United States by MacLean et al.1 This initial multi-
`
`
`
`
`
`
`disciplinary study of incidence, prevalence, and survival
`
`
`
`
`
`
`
`
`of MS patients in the population of Rochester, Min-
`
`
`
`
`
`
`
`
`nesota, showed that prevalence of MS was more than
`
`
`
`
`
`
`twice that previously reported anywhere, and prognosis
`
`
`
`
`
`
`
`was far more optimistic than estimated from previous
`
`
`
`
`
`
`hospital-based studies. There have been 2 subsequent
`
`
`
`
`
`
`surveys of frequency of MS performed in Rochester?-3
`
`
`
`
`
`
`
`
`
`Percy et al2 updated and extended the earlier study by
`
`
`
`
`
`
`
`MacLean et al, estimating the prevalence rate in
`
`
`
`
`
`
`
`
`Rochester at 10-year intervals from 1915 to 1964. They
`
`
`
`
`
`
`
`also calculated average annual incidence rates for each
`
`
`
`
`
`
`
`
`
`decade from 1905 to 1914 through 1955 to 1964. Kranz
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 4 0f 7
`
`Page 4 of 7
`
`

`

`
`
`
`
`
`
`
`
`
`The increase in MS incidence for both Rochester and
`
`
`
`
`
`
`
`
`
`
`
`Olmsted County (tables 3 and 4) may be real or may be
`
`
`
`
`
`
`
`explained by methodologic issues or technologic ad-
`
`
`
`
`
`
`
`
`vances that have facilitated diagnosis in recent decades.
`
`
`
`
`
`
`
`
`
`The majority of patients not considered “cases” in pre-
`
`
`
`
`
`
`
`
`vious studies from Rochester had initial symptoms that
`
`
`
`
`
`
`
`
`
`
`were transient or mild, such that diagnosis of MS was
`
`
`
`
`
`
`
`not initially entertained. Some had more worrisome
`
`
`
`
`
`
`
`initial symptoms (ie, retrobulbar neuritis or myelopa-
`
`
`
`
`
`
`
`
`thy) without evidence of additional lesions on examina-
`
`
`
`
`
`
`
`
`tion or history of prior neurologic dysfunction. Since
`
`
`
`
`
`
`
`
`the last study, these patients have experienced addi-
`
`
`
`
`
`
`
`tional attacks of neurologic dysfunction, changing their
`
`
`
`
`
`
`
`
`
`diagnoses to definite MS and qualifying them for inclu-
`
`
`
`
`
`
`
`
`
`sion in our study. The number of newly ascertained
`
`
`
`
`
`
`
`Table 8. Associated cancers and autoimmune
`
`
`
`
`
`
`disorders in the cohort with multiple sclerosis
`
`
`
`(n = 206)
`
`
`
`Disease
`
`Frequency
`
`
`
`
`
`Diabetes mellitus
`
`
`Insulin dependent
`
`Noninsulin dependent
`
`
`Thyroid diseases
`
`
`Graves’ disease
`
`Hashimoto’s thyroiditis
`
`
`Rheumatic diseases
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`Rheumatoid arthritis
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`Ankylosing spondylitis
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`Pemicious anemia
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`Cancer (malignant)
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`Breast
`Ovarian
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`Multiple myeloma
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`Carcinoid
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`Cervical (invasive)
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`Colon
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`Lung
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`Stomach
`Thymoma
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`Thyroid
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`Uterus
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`Vulva (invasive)
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`1
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`cases was greatest during the last 2 decades of study. We
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`know from prior studies of MS in this community that
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`there is, on average, 4 years between onset of MS and its
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`diagnosis. Although this may be less now because of new
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`diagnostic techniques, we suspect there are additional
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`cases in the population that have not yet come to diag-
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`nosis. All newly ascertained cases were reviewed by
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`multiple neurologists to verify the diagnosis. Inclusion
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`of these additional patients was not a function of poor
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`case ascertainment in previous studies, but rather a
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`reflection of a longer period of follow-up that influenced
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`incidence and prevalence rates. Whether this implies a
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`general trend toward increasing risk of MS elsewhere
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`awaits study in other communities. However, the in-
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`crease in incidence may explain, in part, the increase in
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`prevalence noted previously in this community.
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`A criticism can be raised that the increase in inci-
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`dence noted in this study is a result of change in diag-
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`nostic criteria for MS.18 Other studies have used purely
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`clinical criteria for diagnosis,”21 whereas we elected to
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`use an established set of criteria that use both labora-
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`tory and clinical data.15 Diagnostic investigations of
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`immunoglobulins and oligoclonal bands in CSF have
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`been routinely available only in the last 2 decades; past
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`patients with “suspected” MS could not be further
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`classified and were not eligible as “cases” in earlier
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`studies. Even though some of our patients had CT and
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`MRI of the head, we did not use those results for classifi-
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`cation. It is unlikely that a change in diagnostic criteria
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`accounts for increased incidence because the great ma-
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`jority of our patients (92%) had clinically definite MS.
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`In addition, the long average length of follow-up (14
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`years), the high autopsy rate in the MS population
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`(47%), and the uniform correlation between clinical
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`diagnosis and pathologic examination make this less
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`likely. Analysis of the data in only the “clinically defi-
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`nite” category shows only minor differences in our over-
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`all results.
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`In the search for clues to the cause of MS, attempts
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`have been made to determine whether MS is linked
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`with other diseases. Of particular interest have been
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`associations between MS and autoimmune diseases”40
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`and neoplasia.“46 Anecdotal evidence and small case
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`series have suggested an association between MS and
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`Table 9. Rate of certain diagnoses between 1930 and 1984 in cohort with multiple sclerosis (n = 191)
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`Diagnosis
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`Prevalence‘
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`Person-years
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`Observed?
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`Expectedt
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`RR = O/E
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`HHHHHHHHHMMOOQD-‘chwoown-‘me
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`95% CI
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`on RR
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`0.67-2.78
`0.41-1.57
`0.43-4.04
`0.27-3.87
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`2,874
`2,828
`2,905
`2,010
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`10
`4
`3
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`Diabetes
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`Cancer
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`Rheumatic diseases
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`Graves’ or Hashimow’s
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`disease§
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`Number of cases with a specific associated disease at time of diagnosis of multiple sclerosis.
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`Number of cases observed with a specific associated disease after diagnosis of multiple sclerosis.
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`All expected values were calculated with Rochester-based incidence rates.
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`Relative rate.
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`Observed.
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`Expected.
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`§ Women only (n = 137).
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`6.2
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`11.7
`2.54
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`2.26
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`1.46
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`0.86
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`1.58
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`1.33
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`784 NEUROLOGY 40 May 1990
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`Page 5 0f 7
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`Page 5 of 7
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`

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`myasthenia gravis,”28 systemic lupus erythemato-
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`sus,3°'32 ankylosing spondylitis,29 ulcerative colitis,3“v37
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`thyroid disease,35 scleroderma,33 diabetes mellitus,“0
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`and cancer.“”6 Interpretation of these reports is diffi-
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`cult given the nature of the studies, particularly non—
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`population-based selection of cases. Our study demon-
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`strates clearly that in a cohort it is not unusual to find
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`patients with MS and a presumed autoimmune disor-
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`der. However, when prevalence rates and observed-to-
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`expected risk ratios are compared with rates of these
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`disorders in Rochester,‘“-“9 there is no increased risk.
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`Analyses of the results for a possible association with
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`cancer are particularly important because concerns
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`have been raised regarding the emergence of malig-
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`nancy in MS patients treated with immunosup-
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`pression. In general, patients in this cohort received
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`supportive medical care and steroids during acute exac-
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`erbations, but they were not chronically immunosup-
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`pressed. Therefore, our study provides the framework
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`to determine whether cancer risk is increased in other
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`MS series in which more aggressive medical therapy has
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`been used.
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`Our study confirms the observation that the survival
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`rate for men with MS is lower than for women. The
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`argument has been made that men fare worse than
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`women chiefly because they are male and not because
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`they have MS.50 This is not the case, since survival for
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`female MS patients is similar to survival for women in
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`the entire population (figure 2). In contrast, male MS
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`patients do significantly worse than the male-adjusted
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`survival for the population. A recent report using a
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`“revised” hospital-based series50 concluded that there
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`was no difference in survival between male and female
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`MS patients. However, in that study, both men and
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`women did worse than each sex-adjusted expected sur-
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`vival. The difference in our results compared with those
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`of Poser et alt"0 emphasizes the important bias between a
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`hospital-based case series and an epidemiologic popula-
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`tion-based study.
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`Acknowledgments
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`We appreciate the secretarial assistance of Kathryn A. Jensen and the
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`programming services of Marie J. Eidem.
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`References
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`l. MacLean AR, Berkson J, Woltman HW, Schionneman L. Multi-
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`ple sclerosis in a rural community. Res Publ Assoc Res Nerv Ment
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`2. Percy AK, Nobrega FT, Okazaki H, Glattre E, Kurland LT.
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`Multiple sclerosis in Rochester, Minn: a 60-year appraisal. Arch
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`3. Kranz JM, Kurland LT, Schuman LM, Layton D. Multiple scle-
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`rosis in Olmsted and Mower Counties, Minnesota. Neuro-
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`epidemiology 1983;2:206-218.
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`4. Poskanzer DC, Prenney LB, Sheridan JL, Yon Kondy J. Multiple
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`sclerosis in the Orkney and Shetland Islands. I: Epidemiology,
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`clinical factors, and methodology. J Epidemiol Community
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`Health 1980;34:229-239.
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`5. Stazio A, Kurland LT, Bell LG, Saunders MG, Rogot E. Multiple
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`sclerosis in Winnipeg, Manitoba: methodological considerations
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`of epidemiologic survey: ten-year follow-up of a community wide
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`study, and population re-survey. J Chronic Dis 1964;17:415-438.
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`6. Stazio A, Paddison RM, Kurland LT. Multiple sclerosis in New
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`Orleans, Louisiana, and Winnipeg, Manitoba, Canada: follow-up
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`of a previous survey in New Orleans, and comparison between the
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`patient populations in the two communities. J Chronic Dis
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`7. Gudmundsson KR, Bergmann S, Bjorns