Ann Neurol 1994;36:S25-S28
Numerous exogenous events have been proposed as triggering factors for exacerbations of multiple sclerosis (MS), e.g., "stress," trauma, infection, immunization, pregnancy, climatic changes, and physical exemon. The only ones that have been well documented are infection, delivery after pregnancy, and trauma in the form of electrical shock or direct penetrating injury to the central nervous system (CNS) El].
In 1985 Sibley and colleagues [2] published a landmark prospective study showing that minor infectious illnesses, presumably viral in origin, were a potent trigger of MS attacks (Table 1) . Twenty-seven percent of documented attacks were preceded or accompanied by such infections, and more than 8% of infections were associated with attacks. These were usually upper respiratory or gastrointestinal in nature. Interestingly, bacterial infections, especially urinary tract infections (UTIs), were not a sgdicant trigger.
At about the same time, we were conducting a clinical trial of interferon-? (IFN-)I) in a small number of patients with relapsing-remitting MS, and in 1987 [3] published the disappointing but interesting result that administration of 1FN-y seemed to precipitate exacerbations of MS. This led to the hypothesis that infections might trigger attacks via release of cytokines such as IFN--y which then acted on the immune system to induce or enhance an autoreactive response to CNS antigens. Since then other investigators 141 have noted a connection with viral infections. No specific virus has been consistently implicated, although adenoviruses and herpesviruses such as Epstein-Barr virus (EBV) have been suggested. In addition, cytokines, especially IFN-y and tumor necrosis factor (TNF), seem to be produced in increased amounts just before acute attacks, or in conjunction with progression of MS 153.
The data presented here were collected prospectively during the first 2 years of the recently completed trial of IFN-p l b (Betaseron) in MS at the University of Maryland, where we followed 30 of the 372 patients. The study design called for three groups treated systemically with either hgh dose (8 MIU), low dose (1.6 MIU), or placebo by subcutaneous injection every other day. The results {b] showed that the hgh dose of IFN-p significantly reduced the frequency of MS attacks. The question we asked at the outset was whether this would simply be a trivial phenomenon (i.e., I F N prevented attacks by preventing the viral infections that induced them) or did it have an immunological basis that did not involve prevention of viral infections but somehow blocked their triggering effect on the immune system.
We developed a questionnaire that the patients filled Information on upper respiratory infections (URIs) and multiple sclerosis (MS) exacerbations was collected over 8 years in 170 patients with MS. The period "at risk" extended from 2 weeks before to 5 weeks after onset of URI symptoms. All other periods were considered "not at risk." Attack rate = exacerbations per patient per year.
out with each injection and submitted every 3 months.
They recorded their oral temperature prior to the injection and noted any symptoms of infection in themselves, family members, and co-workers. Almost all the infections recorded turned out to be upper respiratory (URIs). To analyze the data, we followed the procedure published by Sibley and colleagues of dividing the time on study into periods "at risk" and "not at risk." The periods at risk extended from 1 week prior to the onset of infection to 5 weeks after onset. Any MS attack occurring in that time period was considered temporally related to the infection. In addition, we drew blood before the study began and every 3 months 
in the first year and tested the serum for a panel of antibodies to common respiratory pathogens ( Table 2) .
The results are shown in Figures 1 through 6 and in Table 3 . A strong correlation was found between MS attacks and URIs. Nearly two-thirds of exacerbations occurred in periods at risk, and one-third of infections were accompanied or followed by exacerbations. Attack rates for the entire group, irrespective of treatment, were 2.92 per year in weeks at risk compared with 1.16 per year in weeks not at risk (see Fig 1) . The difference is significant at the 0.001 level. These figures are much hgher than those found in previous studies, probably because the data were collected prospectively and noted daily by the patients. Figure 2 shows the temporal relationship to exacerbations, with a peak at 1 week after the onset of clinical symptoms of infections. The exacerbations are divided into documented attacks and minor or nonreported attacks. The were considered to be genuine attacks, but either the patient was not examined at the time or the findings did not fulfill the criteria for documentation as a definite attack (i.e., they consisted of sensory symptoms alone or other symptoms without objective findings on neurological examination, which lasted a week or less and resolved completely with no treatment). When URIs and other infectious illnesses were compared between study subjects and family members or co-workers, there was no difference in seasonal incidence (see Fig 3) . The same spring and fall peaks were seen in both groups, phenomena also found by other investigators El}. There were also no significant differences between the incidence of or seasonal pattern of URls in the three treatment groups, indicating that systemic IFN treatment had no effect on the occurrence of infections. In conuast, we did not find a seasonal pattern for exacerbations of MS, suggesting that IFN treatment prevented at least some of the URIs from triggering attacks (see Fig 4) . Figure 5 shows the pattern of attacks in periods at risk and not at risk by treatment group. In this figure, only documented attacks are shown, with the highest attack rate in the placebo group and a lower rate in the 8 MIU group, irrespective of whether the patients were in the critical at risk periods surrounding U R I s . Finally, the number of attack-free patients was greatest in the 8 MIU group throughout the study (see Fig 6) .
Serum antibody titers to a variety of common, predominantly viral, respiratory pathogens did not implicate a specific agent as being more likely to precipitate an attack (Table 3) . Although titers of IgG antibody to Panitch: Exacerbations of MS S27 EBV generally fluctuated in parallel with attacks, we feel this is likely to resuit from nonspecific activation of the immune system. Herpes virus types I and I1 and adenovirus antibodies were found in the majority of patients, but titers fluctuated independently of clinical changes in neurological function. Titers of coronavirus and rhinovirus antibodies were not performed. IFN--y production by peripheral blood mononuclear cells was tested, but the results are not available at this time.
The attacks in periods at risk were not qualitatively different from those that occurred in periods not at risk. They were of approximately the same severity and duration and responded equally well to corticosteroids. There were also no obvious differences in proportions of new and recurrent symptoms in the two groups. It would have been useful to perform gadoliniumenhanced MRI scans at the time of each URI in selected patients to determine if changes in blood-brain barrier permeability heralded the development of clinical attacks; however, the resources to do this were not available.
We conclude that mild infectious illnesses, largely of nonspecific viral origin, are responsible for the majority of exacerbations in a population of patients with early relapsing-remitting MS. They probably act via systemic release of cytokines such as IFN-y and TNF that then activate the immune system and facilitate the entry of activated T cells into the CNS, leading to exacerbations. Treatment with IFN-p reduces the at-tack rate but not by preventing infections. Rather, its immunoregulatory effects probably tend to inhibit responses to viral infection that would otherwise lead to immune activation and clinical neurological symptoms.