EDITORIAL

The four seasons of multiple sclerosis

Anne H. Cross, MD Becky Jo Parks, MD

Address correspondence and reprint requests to Dr. Anne H. Cross, Department of Neurology and Neurological Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110 crossa@neuro.wustl.edu

Neurology 2010;75:762763

Multiple sclerosis (MS) affects 12 per 1,000 people in North America and has a complex etiology that is not fully understood (www.nmss.org), though the immune system plays a major role. Rapidly accumulating studies have identified several genes related to MS susceptibility; most of these encode proteins with immune functions. Furthermore, environmental factors affect both risk for MS development and MS activity. Perhaps the most well-known environmental factor affecting MS is geographic latitude.1 However, the latitudinal gradient appears to be decreasing with time, a finding that may be due to changing environmental factors.2 Interestingly, several regions of the world report an increasing female to male ratio, which has also been attributed to changing environmental factors that affect women differently than men. Environmental factors purported to play a role in risk of MS development or progression include viruses such as Epstein-Barr virus (EBV), vitamin D levels, and smoking, as well as diet, obesity, pregnancy, hormones, and stress. Of these, vitamin D and infections have the clearest seasonality. Vitamin D levels fluctuate along with ultraviolet light exposure, which changes with season.3 Regarding infections, Sibley and colleagues4 reported that the frequency of MS relapses is 3 times higher in periods related to viral infections. Such observations are in accord with the finding that interferon-, a cytokine that is often increased during infections, can lead to relapses when administered to patients with MS.5 Infection with EBV, increasingly implicated in MS causation, also has a seasonality of occurrence that varies among world regions.6 In this issue of Neurology, Meier et al.7 report a retrospective observation study, involving 44 patients with MS from the Boston area, that lends further support for an environmental effect on MS activity. Frequent MRI examinations revealed a strong seasonal variation in MS activity, based on new lesions on T2-

weighted MRI, with most activity in the spring and summer. New T2 lesions were strongly correlated with warmer temperature and solar radiation but not with precipitation. While the present study did not find a significant seasonal effect on enhancing lesion frequency, it is nonetheless similar to an earlier MRI study that found an increase in gadolinium-enhancing lesions in the spring and early summer in Germany.8 Several groups worldwide have noted seasonal variations in clinical attack rate, with seasons of highest clinical rate being most often the spring and summer. Associations of clinical attack rate with a particular season seemed related less to latitude than to geographic region. This was apparent in the United States, where Sibley and colleagues found that most relapses were observed in the late spring and summer months in both northeastern Ohio and southern Arizona.9,10 In contrast, Meier et al. did not find a significant seasonal variation in clinical attacks, which may have been due to the low numbers of attacks that occurred during their study. The study by Meier et al. provides new data that are in accord with prior studies that reported seasonal variation in clinical disease activity. The strengths of the present study are the large number (939 total MRI examinations) and frequency (median 22 per subject) of the MRI examinations, along with the objective nature of the MRI readings, the inclusion of meteorologic data, and the excellence and experience of the investigators. Because these data were acquired prior to the advent of Food and Drug Administrationapproved immunomodulatory medications for relapsing MS, the study was not confounded by medication effects. Studies such as this in patients with relapsing MS are unlikely to be repeated. Weaknesses of the study include the small total number of subjects and the lack of ancillary information on factors that may also have fluctuated with season, such as vitamin D levels, infections, and immune factors in blood and CSF.

See page 799

From the Department of Neurology and Neurological Surgery, Washington University School of Medicine, St. Louis, MO. Study funding: This publication was made possible by UL1 RR024992 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Disclosure: Author disclosures are provided at the end of the editorial. 762 Copyright 2010 by AAN Enterprises, Inc.

Two important points are underscored by this study. First, this study further supports the idea that the environment affects MS. If the critical environmental factors could be identified, this information would undoubtedly provide important clues regarding the mechanisms of disease progression in MS. Secondly, an issue of practical significance is raised by this study, the effect of the seasonal variation in MRI T2 lesion activity upon early phase clinical trials in MS that typically use MRI as the primary outcome measure. Such phase 12 studies are often of 6 9 month design, and sometimes use crossover or escalating dose protocols. The seasonal variability in MS activity detected by MRI could greatly bias results, either positively or negatively. Thus, seasonal variation in MS should be considered in the design of future studies that utilize imaging as an outcome measure. Taken together, the previous and current results constitute an imperative to identify the environmental factors most likely to play a role in MS, and to understand the mechanisms by which they modulate the disease process. To this end, future clinical trials should include in their design the serial measurements of proposed environmental factors, such as vitamin D and cytokines related to infections. Even so, it is unlikely that a single unifying factor will explain these seasonal fluctuations in the conundrum that is MS.
DISCLOSURE
Dr. Cross serves/has served on scientific advisory boards for Eli Lilly and Company, Genentech, Inc., Biogen Idec, and Roche; serves on the editorial boards of Brain Pathology and the Journal of Neuroimmunology; serves on speakers bureaus for Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., and Biogen Idec; has received speaker honoraria from Pfizer Inc.; receives research support from Sanofi-Aventis, Acorda Therapeutics Inc., Genentech, Inc., and Biogen Idec, the NIH (NINDS PO1

NS059560-01 [PI], NINDS UO1 NS45719-01A1 [Co-I], RO1 NS047592 [Co-I], and NINDS/National MS Society RO1 NS 051591/ NMSS RG 3915-A-15 [Co-I]), ICTS Washington University, the National MS Society USA, and the Barnes-Jewish Hospital Foundation; and owns stock in Affymetrix, Inc. Dr. Parks serves/has served on speakers bureaus for and has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, EMD Serono, Inc., and Teva Pharmaceutical Industries Ltd.; and receives/has received research support from Actelion Pharmaceuticals Ltd, Allergan, Inc., Biogen Idec, Teva Pharmaceutical Industries Ltd., BioMS Medical, and Novartis.

REFERENCES 1. Kurtzke JF. An evaluation of the geographic distribution of multiple sclerosis. Acta Neurol Scand 1966; 42(suppl 19):91. 2. Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 2008; 71:129 135. 3. Maxwell JD. Seasonal variation in vitamin D. Proc Nutr Soc 1994;53:533543. 4. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet 1985;1:13131315. 5. Panitch HS, Hirsch RL, Schindler J, Johnson KP. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 1987;37:10971102. 6. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis: part II: noninfectious factors. Ann Neurol 2007;61:504 513. 7. Meier DS, Balashov KE, Healy B, Weiner HL, Guttmann CRG. Seasonal prevalence of MS disease activity. Neurology 2010;75:799 806. 8. Auer DP, Schumann EM, Kumpfel T, Gossl C, Trenkwalder C. Seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2000;47:276 277. 9. Bamford CR, Sibley WA, Thies C. Seasonal variation of multiple sclerosis exacerbations in Arizona. Neurology 1983;33:697701. 10. Sibley WA, Foley JM. Seasonal variation in multiple sclerosis and retrobulbar neuritis in northeastern Ohio. Trans Am Neurol Assoc 1965;90:295297.

Neurology 75

August 31, 2010

763