The course of MS is highly variable. Lublin and Reingold (174), after polling many MS experts, defined four temporal patterns. In most patients (80-85%), the disease initially follows a relapsing pattern of acute exacerbations (attacks) punctuated, usually after some improvement, by periods of stability (remissions). This form of disease, in which the baseline is stationary between attacks, is referred to as "relapsing-remitting MS.'' Approximately, 10% to 15% of patients never manifest acute attacks. Rather, from the onset they follow a course of steady worsening, perhaps with occasional plateaus. This type is referred to as, "primary progressive MS.'' A very small proportion of patients (probably fewer than 5%) start off as if they are going to have primary progressive disease. However, the course is then interrupted by discrete exacerbations. This form is thus referred to as "progressive-relapsing MS.'' Of those patients presenting initially with the relapsing-remitting form of the disease, many (probably 50-60%), after some years, begin to steadily worsen between attacks. Some of them do continue to have discernible exacerbations, but the hallmark of this form of the disease, which is referred to as "secondary progressive MS,'' is that the baseline does not remain stable, as the patient gradually deteriorates.

In usual cases, the initial attack of MS resolves completely, or nearly so, and the patient remains entirely well until the next discrete episode. In one series, more than 25% of patients relapsed within one year and more than 50% within three years (36). However, Muller (37) found a latent phase of at least 15 years in 6% of patients followed for that period. The attack rate varies from 0.1 to 0.85/yr in the early stages of the illness, according to several series (36,175-179). In several recent clinical trials that selected patients experiencing recently active disease, attack rates in placebo-treated groups ranged from 0.87 to 1.3 annually (180-182). However, in most studies, the frequency of identifiable attacks appears to diminish with increasing duration of illness (36,175,183,184).

Exacerbations most often develop over hours to days. However, the onset may at times be abrupt (strokelike) and in other cases more indolent. Remission of symptoms tends to occur within weeks to a few months. Muller (37) reported that up to 85% of patients seen within two months of relapse remitted completely, but the rate fell to 30% at three months and 10% at six months. Recent MRI studies indicate that Gad enhancement, currently the best imaging marker of new activity, usually disappears within four to six weeks (185). Once progression has begun, it generally continues, but at a relatively slow rate. Natural history studies by Weinshenker et al. (186) found that 50% of patients required assistance to walk by 15 years after the onset of symptoms. In one series of patients scored with the widely used Kurtzke expanded disability status scale (EDSS), those who were ambulatory when first examined worsened by 1 to 1.5 steps over the next five years (187). Those who required assistance to walk or were wheelchair-dependent worsened 0.3 to 0.7 steps over that period. Even in progressing patients, the disease course may appear to stabilize for long periods. In one clinical trial, approximately 20% of patients selected because of their progressive course showed little or no worsening during serial examinations over the next 12 months (188). Wynn et al. (189) reported a 74% survival rate at 25 years, compared with an expected 86%, and Kurtzke et al. (190) similarly found about 75% of normal survival in that interval. A recent Danish report noted that the excess mortality from MS has been halved over the past half century (191).

At times MS follows an extremely benign course. The patient experiences two or more attacks with complete remissions and no cumulative disability over many years (36). In Weinshenker's cohort, 10% to 20% of MS patients remained mildly affected after 25 years (186). However, most studies show only 11% to 34% of patients are able to work within 15 years (36,178,192). A recent population-based study in Olmsted County, Minnesota, found that among 39 patients with an EDSS score <2, five or more years after the onset of MS, only one needed a cane after another decade (193).

Unfortunately, predicting the course of MS in an individual patient is virtually impossible. Generally, patients whose initial attacks are marked by sensory symptoms have a better prognosis than those who early manifest corticospinal tract or cerebellar dysfunction (36,194,195). The course of the disease over the first five years provides a clue, on a statistical basis, to the subsequent progression. Thus, in a group of U.S. servicemen, nearly 90% of those with minimal disability at five years after onset continue to be ambulatory at 15 years. Of those with moderate disability, but walking unaided at five years, 60% were walking independently at 15 years (196). Age of onset also influences prognosis, with patients experiencing their first symptoms after age 40 tending to follow a more rapidly progressive course.

No factors have been clearly recognized to alter the long-term course of MS. However, certain conditions may tend to precipitate acute exacerbations. Viral infection seems to trigger attacks (197,198). This may occur by stimulation of interferon gamma which, in turn, leads to increased antigen presentation precipitating the episode (198).

The role of stress, both physical and psychological, in precipitating exacerbations of MS has been controversial (199). Early reports suggested that physical trauma may lead to worsening, but in a detailed controlled study no significant associations were found between any form of trauma and an increased frequency of attacks (200). Similarly, surgery and anesthesia do not appear to aggravate the condition, despite earlier suggestions to the contrary (199,201). A recent review by a committee of the American Academy of Neurology concluded that physical trauma was not associated with MS exacerbation (202). However, the group found that evidence about the relationship to psychological stress was inconclusive. In a recent meta-analysis of 14 studies, Mohr et al. (203) did find a significant increase in the risk of exacerbations after stressful life events. However, they were not able to identify specific stressors.

Measurement of psychological stress and its role in worsening of MS has been extremely difficult. Methodological problems have included retrospective study design, which is subject to recall bias; small or highly selected samples; and inadequate psychological tests (204-207). Thus, this issue remains unresolved despite recent studies suggesting that psychological stress may influence the course of MS (203,207). This could result from changes in the immune system associated with psychological factors. Interestingly, however, attack rate declined among Israeli MS patients during the period of SCUD missile attacks on the country in the Gulf War (208).

Sudden and transient neurological deterioration often results from situations that elevate body temperature (209). Such worsening is most often associated with febrile illness, but may also occur with physical exertion. Even moderate exercise may be associated with an aggravation or precipitation of neurological symptoms, with blurring of vision most frequently reported (Uhthoffs phenomenon) (210,211). Provocation of neurological signs by raised body temperature has been the basis of a clinical tool, the "hot-bath test'' (212). Although seldom performed today, this technique can be used to uncover additional anatomical lesions in mono-symptomatic patients. However, a reported patient developed a persistent neurological deficit following the test (213). The basis for the neurological worsening seems to be the development of conduction block in partially demyelinated axons with elevated temperature (214).

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