Objectives: To determine the relationship between baseline CSF immunologic abnormalities and MS disease progression; To determine progression rates in an untreated, recently-diagnosed MS sample using several validated clinical measures.
Background: CSF immune abnormalities are common in MS but have not been linked to disease progression.
Design Methods: Thirty-six patients with definite (n=28), probable (n=2), or possible (n=6) MS were studied prospectively. Baseline CSF was analyzed for free kappa and lambda light chains, myelin basic protein, IgG synthesis rate, and IgG index. MS patients were entered into the study within 5 years of symptom onset and examined semiannually for as long as 53.4 months (median length offollow up 38.9 months). MS progression was defined as sustained worsening on the following clinical measurement instruments: the Expanded Disability Status Scale (EDSS), the Ambulation Index (AI), the 9 Hole Peg Test (9HT) and the Box and Blocks test (BBT). Kaplan-Meier estimates of disease progression were calculated and the relationship between baseline CSF values and disease progression was determined using Cox proportional hazards regression models.
Results: By 36 months, 33% (95% Cl-10.3, 55.7) of patients had progressed on EDSS and 49.7% (95% Cl=27.7, 71.7) had progressed on at least one of the outcome measures. Patients with CSF free kappa chain levels in the upper quartile had a significantly higher risk of progression on EDSS (Hazard Ratio 3.78; p=0.04) and 9HT (Hazard Ratio 10.77, p=0.04).
Conclusions: In this study, CSF free kappa light chains predicted subsequent physical deterioration in prospectively evaluated MS patients. If this is confirmed by larger studies, then CSF free kappa light chains could serve as a target for intervention in therapeutic trials.
7 Detels R, et al. (1982) Factors associated with a rapid course of multiple sclerosis. Arch Neurol39: 337–341.
8.
8 Ellison GW, et al. (1981) A placebo-controlled rando mized, double-masked, variable dosage, clinical trial of azathioprine with and without methylprednisolone in multiple sclerosis. Neurol39: 1018–1026.
9.
9 Filippi M, et al. (1994) Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis. Neurol44: 635–641.
10.
10 Folkman S, Lazarus RS. (1973) Manual for the ways of coping questionnaire.Palo Alto: Consulting Psychologists Press.
11.
12 Goodkin DE, et al. (1995) Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol37: 30–40.
12.
13 Goodkin DE, et al. (1991) The efficacy of azathioprine in relapsing remitting multiple sclerosis. Neurol41: 20–25.
13.
14 Goodkin DE, Hertsgaard D, Rudick RA. (1989) Exacerbation rates and adherence to disease type in a prospectively followed-up population with multiple sclerosis: implications for clinical trials. Arch Neurol46: 1107–1112.
14.
15 Gulick EE. (1987) Parsimony and model confirmation of the ADL self-care for multiple sclerosis persons. Nursing Res36: 278–283.
15.
16 Gupta MK, Whitaker JN, Johnson C, Goren H. (1988) Measurement of immunoreactive myelin basic protein peptides (45–89) in cerebral spinal fluid. Annals Neurol23: 274–280.
16.
17 Hauser SL, et al. (1983) Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. NEJM308: 173–180.
17.
18 Kaplan EL, Meier P. (1958) Nonparametric estimation from incomplete observations. J Am Statistical Assoc53: 457–481.
18.
19 Kurtzke JF, et al. (1977) Studies on the natural history of multiple sclerosis-8. Early prognostic features of the later course of the illness.J Chron Dis330: 819–130.
19.
20 Kurtzke JF. (1983) Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)Neurol33: 1444–1452.
20.
21 LaRocca NG, Scheinberg LC, Slater RJ. (1984) Field testing of a minimal record of disability in multiple sclerosis: The United States and Canada. Acta Neurol Scand70: 126–138.
21.
22 Mahler ME, Davis RJ, Benson DF. (1989) Screening multiple sclerosis patients for cognitive impairment. In: Jensen K, Knudsen L, Stenager E, Grant I, eds. Mental disorders and cognitive deficits in multiple sclerosis. London: Libbey pp. 11–14. (Current problems in neurology; vol. 10).
22.
23 Mathiowetz V, Weber K, Kashman N, Volland G. (1985) Adult norms for the nine hole peg test offinger dexterity. The Occupational Therapy Journal of Research5: 24–38.
23.
24 Mathiowetz V, Volland G, Kashman N, Weber K. (1985) Adult norms for the box and block test of manual dexterity. Am Journal Occupational Therapy39: 386–391.
24.
25 McAlpine D. (1961) The benign form of multiple sclerosis. A study based on 241 cases seen within three years of onset and followed up until the tenth year or more of the disese. Brain84: 186–203.
25.
26 Myers LW, Ellison GW. (1992) Use of survival analysis to describe the course of multiple sclerosis. Ann Neurol32: 259.
26.
27 Noseworthy JN, et al. (1993) TNF-Alpha in multiple sclerosis.Neurol43: A355.
27.
28 Poser CM, et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol13: 227–233.
28.
29 Poser S, Raun NE, Poser W. (1982) Age at onset, initial symptomatology and the course of multiple sclerosis. Acta Neurolog Scandinavia66: 355–362.
29.
30 Rudick RA, French CA, Breton D, Williams GW. (1989) Relative diagnostic value of cerebrospinal fluid kappa chains in MS: Comparison with other immunoglobulin tests. Neurol39: 964–968.
30.
31 Runmarker B, Anderson O. (1993) Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years offollow-up. Brain116: 117–134.
31.
32 Sarason IG, Johnson JH, Siegel JM. (1978) Assessing the impact of life changes: Development of the Life Experiences Survey. J Consult Clin Psychol46: 932–946.
32.
33 Sarason IG, Levine HM, Basham RB, Sarason BR. (1983) Assessing social support: The Social Support Questionnaire. J Pers Soc Psychol44: 127–139.
33.
34 Sharief MK, Hentges R. (1991) Association between tumor necrosis factorα and disease progression in patients with multiple sclerosis. N Engl J Med325: 467–472.
34.
35 Smith A. (1973) Symbol-Digit Modalities Test: Manual.Los Angeles: Western Psychological Services.
35.
36 Stanescu GL, Swick AR, Tuohy VK, Rudick RA. (1991) Sensitive competitive3-binding ELISAs for quantifying free kappa and lambda light chains in cerebrospinal fluid. J Clin Lab Anal5: 206–211.
36.
37 Tibbling G, Link H, Ohman S. (1977) Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest37: 385–390.
37.
38 Tourtellotte W. (1970) On cerebrospinal fluid immunoglobulin-G (IgG) quotients in multiple sclerosis and other diseases. A review and a new formula to estimate the amount of IgG synthesized per day by the central nervous system. J Neurol Sci10: 279–304.
38.
39 Trotter JL, et al. (1989) Correlation of immunological studies and disease progression in chronic progressive multiple sclerosis. Ann Neurol25: 172–178.
39.
40 Weinshenker BG, et al. (1989) The natural history of multiple sclerosis: A geographically based study. II. Predictive value of the early clinical course. Brain112: 1419–1428.
40.
41 Weinshenker BBG, et al. (1991) The natural history of multiple sclerosis: A geographically based study. 3 Multivariate analysis of predictive factors and models of outcome. Brain114: 1045–1056.
41.
42 Whitaker JN, McFarland HR, Rudge P, Reingold SC. (1995) Outcomes assessment in multiple sclerosis clinical trials: A critical analysis.Multiple Sclerosis, in press.
