Clinical presentation, course, and prognosis of multiple sclerosis in adults

INTRODUCTION — Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system.

The onset and phenotypes of MS will be reviewed here. Other aspects of MS are discussed separately:

● Pathogenesis and epidemiology of multiple sclerosis

● Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis

● Manifestations of multiple sclerosis in adults

● Evaluation and diagnosis of multiple sclerosis in adults

● Symptom management of multiple sclerosis in adults

● Treatment of acute exacerbations of multiple sclerosis in adults

● Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults

● Treatment of secondary progressive multiple sclerosis in adults

● Treatment of primary progressive multiple sclerosis in adults

● Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis

● Treatment and prognosis of pediatric multiple sclerosis

DISEASE ONSET AND PATTERN — The core MS phenotypes are those of relapsing-remitting and progressive disease [1]. The pattern and course of MS is further categorized into several clinical subtypes as follows [1,2]:

●Clinically isolated syndrome, often representing the first attack of MS

●Relapsing-remitting MS

●Secondary progressive MS

●Primary progressive MS

In addition, these phenotypes are modified by assessments of disease activity and disease progression over time [1,3]. Disease activity is determined by clinical relapses or magnetic resonance imaging (MRI) evidence of contrast-enhancing lesions and/or new or unequivocally enlarging lesions on T2-weighted images. Disease progression (as defined by increased neurologic disability) is a process that is largely independently quantified from relapses, and is characteristic of primary and secondary progressive MS. Secondary progressive MS is preceded by relapsing-remitting MS, hence the designation of "secondary." Importantly, these phenotypes are based on how MS presents over time, yet say nothing about which symptoms a patient experiences or the severity of these symptoms.

There are no clinical findings that are unique to MS, but some are highly characteristic of the disease (table 1). Common manifestations (table 2) include sensory loss in limbs or one side of the face, unilateral visual loss, acute or subacute motor weakness, diplopia often with an internuclear ophthalmoplegia, gait disturbance and balance problems, Lhermitte sign (electric shock-like sensations that run down the back and/or limbs upon flexion of the neck), vertigo, bladder problems, limb ataxia, acute transverse myelitis, and pain. Presenting symptoms and signs may be either monosymptomatic (consistent with a single lesion) or polysymptomatic (consistent with more than one lesion). Presentations due to cortical syndromes such as aphasia or visual field disturbances are possible, though uncommon. These presentations are most likely to be associated with a large area of inflammation, called tumefactive MS due to its tendency to mimic neoplasms both clinically and radiographically.

The typical patient presents as a young adult with one or more clinically distinct episodes of central nervous system dysfunction with at least partial resolution. While most MS cases follow a relapsing-remitting course at disease onset, approximately 10 percent of cases are characterized by steadily increasing neurologic disability independent of relapses, termed primary progressive MS. (See 'Primary progressive MS' below.)

Some cases may be presaged by a radiologically isolated syndrome, which is defined by incidental brain or spinal cord MRI findings that are highly suggestive of MS in a patient lacking any history, symptoms, or signs of MS. By definition the MRI has been obtained for a completely unrelated condition such as headache or trauma. The main factors that predict conversion to clinically definite MS are male sex, age less than 37 years, and spinal cord lesions on MRI [4]. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'For a radiologically isolated syndrome' and "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)

Typical findings on brain MRI in patients with MS include hyperintense white matter lesions on T2 sequences (image 1A-B) in characteristic locations (periventricular, cortical or juxtacortical, infratentorial, and spinal cord), as described elsewhere. Active lesions enhance with the addition of gadolinium (image 2), while older lesions appear hypointense on T1 sequences, so-called "black holes" (image 3). (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Magnetic resonance imaging'.)

CLINICALLY ISOLATED SYNDROME — A clinically isolated syndrome (CIS) is the first clinical episode that is suggestive of MS, as characterized by the following features [1,5,6]:

●Presents as a monophasic clinical episode with symptoms and objective findings that reflect a focal or multifocal inflammatory demyelinating event in the central nervous system

●Develops acutely or subacutely, with a duration of at least 24 hours, with or without recovery

●Occurs in the absence of fever or infection

●Resembles a typical MS relapse (attack and exacerbation) but occurs in a patient not known to have MS

In CIS there is no evidence of previous episodes of demyelination from the patient's history or examination.

Typical presentations include the following [5,7]:

●Unilateral optic neuritis, manifesting with painful, monocular visual loss consisting of visual blurring or scotoma

●Painless diplopia due to internuclear ophthalmoplegia (occasionally bilateral) or, less commonly, a sixth nerve palsy

●Brainstem or cerebellar syndrome, such as diplopia described above, ataxia with gaze-evoked nystagmus, vertigo, facial numbness, or paroxysmal episodes of dysarthria or vertigo

●Partial transverse myelitis, usually with predominant sensory symptoms, including a partial Brown-Sequard syndrome, or Lhermitte sign; other manifestations can include sphincter symptoms, with bladder involvement (eg, urge incontinence) more common than bowel, and erectile dysfunction

Symptoms usually develop over the course of hours to days and then gradually remit over the ensuing weeks to months, though remission may not be complete. Presenting symptoms and signs may be either monofocal (consistent with a single lesion) or multifocal (consistent with more than one lesion). CIS is best thought of as a precursor to MS in most patients, and fewer patients can be diagnosed with CIS as the diagnostic criteria for MS have become less stringent. As an example, a patient with a single clinical demyelinating event will be diagnosed with MS if their MRI shows both enhancing and non-enhancing brain or spinal cord lesions, indicative of inflammation separated in space and time.

RELAPSING-REMITTING MS — Relapsing-remitting MS is the most common type of MS at disease onset, especially in young people, accounting for 85 to 90 percent of cases at onset [8]. It is characterized by clearly defined attacks (also known as relapses, flares, or exacerbations) with full or incomplete recovery. There is minimal disease progression between disease relapses, at least as traditionally understood, though relapses themselves may leave residual disability, which can be severe on occasion.

Diagnosing relapsing-remitting MS depends on showing evidence of dysfunction in separate parts of the central nervous system on two separate times. The initial attack is an isolated neurologic problem, similar to clinically isolated syndrome (CIS), though patients may meet the formal definition of MS with a single clinical episode if their MRI reveals the simultaneous presence of enhancing and non-enhancing lesions. Oligoclonal bands that are present in cerebrospinal fluid but absent in the serum can also be used to make the diagnosis, though a spinal tap is generally not indicated in patients whose history, exam, and imaging are highly consistent with MS. The 2017 revisions to the McDonald Criteria are show in the table (table 3). The diagnosis of MS is reviewed in detail elsewhere. (See "Evaluation and diagnosis of multiple sclerosis in adults".)

Symptoms and signs associated with a relapse usually reach a peak in days to weeks, followed by a remission during which the symptoms and signs resolve to a variable extent. The minimum duration for a relapse has been arbitrarily established at 24 hours, though most are much longer. Clinical symptoms of shorter duration are less likely to represent new lesion formation or extension of previous lesion size. Devastating relapses that lead to permanent disability are rare. Only seven patient had relapses that permanently resulted in them needing a cane, crutch or brace to walk 100 meters with or without resting [9].

At different points in time, relapsing-remitting MS can be further characterized as either active (with relapses and/or evidence of new MRI activity) or not active, as well as worsening (a confirmed increase in disability over a specified period of time following a relapse) or not worsening.

Analysis of prospectively collected data from a cohort of 195 patients suggests that symptomatic demyelinating events in early relapsing-remitting MS have a tendency to recur in the same location (eg, spinal cord, optic nerve, brainstem) [10]. However, relapses can present with any of the typical clinical manifestations of MS, and there are no specific clinical features that can reliably distinguish the initial clinical attack of MS from a relapse in the same location, other than history.

In the absence of a new demyelinating event, previous clinical deficits may temporarily worsen in the setting of any elevated physiological temperature, including fever (see "Manifestations of multiple sclerosis in adults", section on 'Heat sensitivity'), physical activity, high environmental temperature, or metabolic upset, and may last for hours to a day or more. Such worsening, termed "pseudorelapses," is thought to reflect conduction block in previously demyelinated axons.

SECONDARY PROGRESSIVE MS — Secondary progressive MS is characterized by an initial relapsing-remitting MS disease course followed by gradual worsening with or without occasional relapses, minor remissions, and plateaus. However, there are no established criteria to determine when relapsing-remitting MS converts to secondary progressive MS, and the diagnosis of secondary progressive MS is made retrospectively [1]. The transition from relapsing-remitting MS to secondary progressive MS usually occurs 10 to 20 years after disease onset. In one report, the median time from the first symptoms of MS (a clinically isolated syndrome) to the development of secondary progressive MS was 19 years, while the median time from MS diagnosis to secondary progressive MS was 12 years [11].

Secondary progressive MS can be further characterized at different points in time as either active (with relapses and/or evidence of new magnetic resonance imaging [MRI] activity) or not active, as well as with progression (evidence of disease worsening on an objective measure of change over time, with or without relapses) or without progression. Disease-modifying therapy is available for active secondary progressive MS. (See "Treatment of secondary progressive multiple sclerosis in adults".)

PRIMARY PROGRESSIVE MS — Primary progressive MS is characterized by progressive accumulation of disability from disease onset with occasional plateaus, temporary minor improvements, or acute relapses still consistent with the definition. A diagnosis of primary progressive MS is made exclusively on patient history, and there are no imaging or exam findings that distinguish primary progressive MS from relapsing-remitting MS. Primary progressive MS represents approximately 10 percent of adult MS cases at disease onset [12]. The mean age at onset is approximately 40 years, which is approximately 10 years older than the mean age of patients presenting with relapsing-remitting MS. Some evidence suggests that MS is progressive in over 60 percent of patients when onset is after the age of 40 years [8]. Unlike relapsing-remitting MS, primary progressive MS occurs equally in males and females [13].

The most common clinical presentation is a spinal cord syndrome that worsens over months or years with asymmetric spastic paraparesis and no clear sensory level [14]. Less often, primary progressive MS develops as a progressive cerebellar ataxia, and rarely with cognitive, brainstem, or visual symptoms. Enhancing lesions may be seen on the MRI in patients with primary progressive MS [15]. These patients have a worse prognosis for ultimate disability in comparison with patients who have relapsing-remitting MS.

Primary progressive MS can be further characterized at different points in time as either active (with an occasional relapse and/or evidence of new magnetic resonance imaging [MRI] activity) or not active, as well as with progression (evidence of disease worsening on an objective measure of change over time, with or without relapse or new MRI activity) or without progression. Disease-modifying therapy for primary progressive MS is reviewed separately. (See "Treatment of primary progressive multiple sclerosis in adults".)

The term progressive-relapsing MS, previously used to characterize patients who had progressive disease from onset and clear acute relapses [2], is now obsolete [1]. An acute attack in a patient with progressive disease from onset is now considered to be primary progressive MS with active disease, whereas those with progressive disease from onset without acute attacks (relapses) are considered to have primary progressive MS, not active but with progression [1].

DISEASE SEVERITY — Neurologic disability resulting from MS is highly variable (see 'Rate of worsening' below). The impact of MS on any one individual varies according to a number of measures, including severity of signs and symptoms, frequency of relapses, rate of worsening, and residual disability. From a patient's perspective, worsening of disability over time is probably the most important issue in MS.

Most patients have relapsing-remitting MS at onset, and the clinical course often evolves to secondary progressive MS [8,16]. Over time, the proportion of patients with relapsing-remitting MS falls steadily, so that, absent therapy, only one-half are still relapsing by nine years from onset [8]. Patients with an initial relapsing-remitting MS course who have active disease tend over time to have incomplete recovery between attacks, and the level of disability begins to increase. Eventually, patients continue to worsen even in the absence of relapses and the disease is then said to convert to secondary progressive MS.

At the extreme ends of the severity spectrum, there are "benign" and "malignant" forms of MS (see 'Benign MS' below and 'Aggressive MS' below). However, these designations, especially of benign MS, are always retrospective and should be used cautiously, since the severity and activity of MS can change in significant and unpredictable ways [1].

Disability measures — The Kurtzke disability status scale (table 4), or Disability Status Scale (DSS), and the expanded version known as the expanded disability status scale (table 5) or Expanded Disability Status Scale (EDSS), are commonly used indices of clinical disability in MS [17,18]. These indices use numbers ranging from 0 for normal examination and function to 10 for death due to MS. The scales are nonlinear, with great emphasis on ambulation capabilities with scores above 4.

An alternative to the EDSS is the Patient-Determined Disease Steps (PDDS) scale (table 6), which utilizes patient-reported outcomes to derive a disability score [19].

Most MS cohort studies have found bimodal distributions of EDSS scores, with peaks at values of 1 (no disability with minimal neurologic signs) and 6 (unilateral assistance or cane necessary for ambulation). The time spent by a patient at a given level of disability varies with the score. The median time spent with a DSS score of 4 or 5 is 1.2 years, while the median time spent at DSS 1 is four years and at DSS 6 three years [8].

The EDSS is universally used in clinical trials, often with additional measures, but it has a number of serious limitations. Inter- and intra-rater variations in scoring are common. EDSS scores of 4 and higher depend almost entirely on the ability to walk. Problems such as the development of cognitive impairment, visual loss, or hand weakness may pass relatively undetected by the scoring. Additionally, the scale is non-linear and not all increases have an equal impact on a patient's life. As an example, a one-point increase in the EDSS may mean the patient has developed a sign apparent only to the examining doctor, or it may mean the patient has transitioned from being able to walk with a walker to using a wheelchair. Thus, other outcome measures such as the PDDS should also be used; minor changes in the EDSS alone should not be over-interpreted.

Rate of worsening — Worsening of neurologic function due to MS is highly variable [20], but accumulating evidence suggests that it is slow in most patients [12,21-25]. One of the largest longitudinal studies followed 2319 patients from British Columbia for 22,723 patient years [23]. Disability scores were prospectively assigned in greater than 95 percent of the patients.

The following observations were reported [23]:

●The median time from disease onset to EDSS 6 (unilateral assistance necessary for ambulation) was 27.9 years; the median age from birth to EDSS 6 was 59 years.

●A primary progressive course was associated with more rapid disease progression than a relapsing course and was a risk factor in multivariate analysis for time to use of a cane or equivalent (EDSS 6) from both MS onset (hazard ratio [HR] 2.90, 95% CI 2.39-3.52) and from birth (HR 2.68, 95% CI 2.20-3.26).

●Although adult males progressed more quickly than adult females from onset, both required a cane at similar ages (58.8 and 60.1 years, respectively), and male sex was not associated with a worse outcome after controlling for other factors.

●After controlling for other factors, the type of symptoms at onset (eg, motor, sensory, optic neuritis, cerebellar, ataxia, or brainstem) did not predict disease progression.

●A younger age at onset was associated with slower progression, but patients older at onset were consistently older when they progressed to EDSS 6 than patients younger at onset (figure 1). Similar results were found in a large epidemiology study from France [26].

Some earlier studies had suggested that MS was more rapidly progressive. As an example, a 25-year follow-up study of 308 patients with MS published in 1993 found that 50 percent of the patients reached EDSS 6 within 16 years of onset [27]. By contrast, a prospective report from 2016 of 517 patients with MS who were managed at a single MS center found that only 11 percent of patients had reached an EDSS ≥6 at a median of approximately 17 years after disease onset [28]. These data suggest but do not prove that disease-modifying therapies (DMTs), first introduced in the 1990s, have led to improved long-term outcomes. While DMTs are effective for reducing the frequency of relapses in patients with relapsing-remitting MS, it has been difficult to confirm that they alter the course of disability development, as discussed elsewhere. The difference found in these studies may also reflect different diagnostic criteria for the disease and an increased motivation to make the diagnosis in an era of effective treatments. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

Frequency of relapses — The frequency of MS relapses (ie, attacks, exacerbations) is highly variable. Summaries of many studies provide an average figure of 0.4 to 0.6 relapses per year. Relapses tend to be more frequent during the first years of the disease and wane in later years [29]. Some data suggest that a high relapse frequency in the first two to five years following the diagnosis of MS is associated with increased risk of secondary progression and disability [11,30,31].

In a single center study that analyzed data from 2587 relapses occurring in 1078 patients during an average follow-up of 7.4 years, relapses causing permanent disability were rare [9].

Relapses may be more common after stressful life events [32-34]. Perhaps the strongest evidence comes from a meta-analysis of 14 observational studies that found a significant association between stress and MS exacerbations [32]. However, patients may suffer from a recall bias, and the authors cautioned that the study does not offer absolute evidence of a causal association.

Mortality — Mortality due to MS is difficult to determine because of poor data collection and reporting. Nevertheless, the following reports illustrate that mortality is increased patients with MS:

●A review of large MS cohort registries assessing mortality found that, compared with the general healthy population, life expectancy in patients with MS was reduced by 7 to 14 years [35]. One-half or more of the deaths among patients with MS were directly related to complications of MS.

●A meta-analysis of 12 studies, with data from over 28,000 patients with MS, found that the pooled all-cause standardized mortality ratio (SMR) was 2.8 (95% CI 2.7-2.9). Compared with the general population, patients with MS had increased rates of death from infection and respiratory diseases, suicide, and cardiovascular disease [36].

●Using excess death rates (EDRs) rather than SMR, a retrospective study of data from 18 French MS centers with over 37,500 patients found no excess mortality caused by MS during the first 10 years after MS onset [37]. Thereafter, the EDRs increased with age up to age 70 years. Beyond age 70 years, the EDRs were similar regardless of the age at disease onset, suggesting that disease duration was no longer a factor in excess mortality.

Benign MS — Benign MS refers to disease in which the patient remains fully functional in all neurologic systems 15 years after the disease onset; it is always a retrospective diagnosis. Approximately 15 percent of patients with a single demyelinating event will never experience a second relapse, although the exact frequency of this benign form of disease is unknown since many of these individuals either never come to medical attention or are lost to follow up after the initial event. Among patients in a population-based cohort study who had MS for 10 or more years, approximately 17 percent had minimal or no disability [22].

Autopsy studies have found a number of cases with central nervous system pathology consistent with MS but no documented clinical evidence of disease [38-41]. MRI studies of asymptomatic relatives of MS patients have discovered lesions consistent with demyelination in up to 15 percent of these relatives [42]. The use of MRI may expand the spectrum of MS by detecting milder cases that previously were not included in prognosis studies. Prospective MRI studies are needed to determine if there are reliable imaging features that can distinguish benign MS from relapsing-remitting MS and progressive types of MS [43].

In our experience and that of most others, patients who have had a known benign course for 15 years will only rarely develop a more severe course [22,27]. However, evidence is conflicting, and some have found that patients with benign MS for 10 years still have a substantial risk of disease worsening and increased disability [44]. The range of evidence is illustrated by the following reports, which likely include patients who enrolled in the era before DMT for MS was available:

●In one long-term cohort published in 1993, only 8 percent of patients with mild disease (EDSS score 0 to 3) five years after diagnosis progressed to severe disease (EDSS score 6) by 10 years, and only 12 percent by 15 years [27].

●Similar results from a 2004 study were noted in a second cohort, 17 percent of whom had minimal or no disability (EDSS score of 2 or lower) at study onset despite a 10-year or longer history of MS [22]. The longer the duration of MS and the lower the disability, the more likely the patient was to remain stable and not progress.

●By contrast, a cohort study published in 2007 of 169 patients with EDSS scores ≤3 at 10 years from MS onset found progression to EDSS scores of ≥6 at 20 years after onset in 21 percent [44]. The EDSS score at 10 years was the only independent predictor of score at 20 years.

Aggressive MS — Aggressive MS or malignant MS refers to disease with a rapidly progressive course, leading to significant disability in multiple neurologic systems in a relatively short time after disease onset. In a single center study of 487 patients with MS that defined aggressive MS by the need for assistance with ambulation (ie, an EDSS score ≥6) within five years from symptom onset, an aggressive course was observed in 12 percent [45]. Using the same definition for one model of aggressive MS, a population-based study of over 4000 subjects with adult-onset MS identified an aggressive course in 6 percent [46]. Another report, which defined aggressive MS by an EDSS score ≥6 reached within 10 years of symptom onset and analyzed data from the a registry of over 58,000 patients with MS [47], also found that aggressive MS developed in 6 percent [48]. Predictors for aggressive MS in one or more of these studies were older age at onset, a progressive disease course, greater disability within the first year, and pyramidal signs in the first year after onset [45,46,48].

PROGNOSTIC FACTORS — A variety of factors have been identified as possible prognostic indicators in MS that may modify the disease course or predict exacerbations. However, none are established as reliable, and our ability to accurately predict outcome for individual patients with MS is quite limited [49].

Relapsing versus progressive disease — Relapsing-remitting MS is generally associated with a better prognosis than progressive types of MS [8,23]. An observational natural history study found that irreversible disability occurred sooner in patients in whom the disease was progressive from the onset than in those in whom the onset was relapsing-remitting [21]. Once irreversible disability occurred, however, the time course of progressive disability was similar in the two groups.

However, there are data suggesting that most untreated and many treated patients with relapsing MS will eventually enter a secondary progressive phase of disease [8,16] where neurologic function gradually worsens regardless of the presence or absence of superimposed attacks. The development of a progressive course may be the single most adverse factor that influences prognosis [16,27,50-55]. One natural history study found that the progressive phase of MS appeared to be independent of relapses that occurred before or after the onset of relapse-free progression [16]. In addition, disability in MS may be more dependent on patient age than on the initial course, whether relapsing or progressive from onset [26,56].

An analysis of the Novartis-Oxford multiple sclerosis (NO.MS) clinical trial (observational and randomized) data set, with approximately 200,000 Expanded Disability Status Scale (EDSS) transitions from over 27,000 patients who had up to 15 years of follow-up, evaluated the two main mechanisms leading to accrual of disability [57]:

●Relapse-associated worsening (RAW), defined as confirmed disability worsening over three to six months beginning within 90 days from the onset of a relapse (ie, incomplete recovery from a relapse).

●Progression independent of relapse activity (PIRA), defined as confirmed disability worsening over three to six months with either no prior relapse or beginning more than 90 days after the start of the last relapse.

The study found that RAW contributed to disability progression primarily in the early stages of MS and was the main driver of worsening in pediatric-onset MS [57]. PIRA was also present early in the course of MS in all phenotypes (pediatric-onset MS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS) and became the main driver of disability in the later stages of MS. The main risk factors for accumulating disability were pre-existing disability and older age.

In an analysis of a subset of NO.MS data from placebo-controlled randomized trials (n = 4970), the use of disease-modifying therapy (DMT) delayed disability progression by several years; as an example, the estimated average time to reach an EDSS score of 4, signifying increased limitation in walking ability, was shorter for patients who received placebo compared with patients who used DMTs (9.0 versus 12.5 years) [57]. This finding supports the importance of starting DMT early in the course of MS. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults" and "Treatment of secondary progressive multiple sclerosis in adults" and "Treatment of primary progressive multiple sclerosis in adults" and "Treatment and prognosis of pediatric multiple sclerosis".)

Neurodegeneration and silent progression — While some data suggest that recurrent relapses are the main cause of disability progression in relapsing forms of MS [58], there also is evidence that disability progression occurs because of clinically silent neurodegeneration of brain and spinal cord that is independent of relapse activity [59-61]. In a longitudinal prospective cohort study of 372 patients with relapsing-remitting MS or a clinically isolated syndrome (CIS) and 10-year follow-up data, relapses were associated with a temporary increase in disability but not with confirmed disability progression [59]. Rather, disability progression correlated with declines in relative brain volume measured by magnetic resonance imaging (MRI), suggesting that underlying neurodegeneration with brain atrophy is an important mechanism. The authors proposed the term "silent progression" to characterize the insidious disability that accumulates in many patients with relapsing-remitting MS.

In a subsequent longitudinal case-control study from the same investigators, faster cervical spinal cord atrophy (measured from sagittal brain MRI) was associated with a shorter time to silent progression and a shorter time to secondary-progressive MS conversion [60]. Patients who converted to secondary-progressive MS had faster annualized rates of cervical cord atrophy beginning at least four years prior to conversion compared with matched patients who remained relapsing-remitting (-2.19 versus -0.88 percent, mean difference -1.30 percent, 95% CI -1.84 to -0.80). These findings suggest that secondary-progressive MS represents a late recognition of silent progression rather than a distinct disease phase.

Early symptoms — In a systematic review of 27 eligible studies published by May 2005 that evaluated patients with relapsing-remitting MS, bowel and/or bladder symptoms at onset and incomplete recovery from a first attack had the strongest and most consistent associations with poor prognosis. Additional factors that predicted long-term disability in those with relapsing-remitting MS were a short interval between the first and second attack, and early accumulation of disability [62].

Other MS symptoms and signs at disease onset were once thought to predict a favorable (sensory symptoms, optic neuritis) or unfavorable (pyramidal, brainstem, and cerebellar symptoms) prognosis [8]. However, subsequent data suggested that none of these onset symptoms were independent prognostic factors [23,62].

A long-term observational study of patients with progressive types of MS found that polysymptomatic compared with monosymptomatic onset of MS was associated with a significantly shorter time to the development of progressive disease [16]. (See 'Rate of worsening' above.)

MRI markers — In a longitudinal study of 166 patients who presented with a CIS, as defined some years ago, and were followed for 15 years, baseline MRI findings of gadolinium-enhancing lesions and spinal cord lesions were each independently associated with greater physical disability and with progression to secondary progressive MS at 15 years [63]. While many of the patients would in retrospect be classified as already having MS, this study is useful in identifying the key elements associated with progression.

The main MRI markers of MS disease activity and pathology are lesion load and cerebral atrophy [64,65]. The lesion load is assessed on conventional T2-weighted, fluid-attenuated inversion recovery (FLAIR), and pre- and post-contrast T1-weighted MRI sequences. The degree of brain atrophy affecting gray and white matter, as well as the presence of so-called "black holes" (ie, areas of abnormal hypointensity on T1-weighted MRI) can be quantified using T1-weighted MRI sequences, and may correlate better with clinical disability than lesion volume on T2-weighted MRI. Although not routinely assessed in clinical practice, spinal cord atrophy is also associated with disability [66-68].

The lesion load on T2-weighted MRI scan has been associated with an increased risk of disability in some studies but not others [49]. As an example, a serial MRI study in 71 patients followed for a mean of 14 years found that lesion volume at 5 years and the change in volume during the first 5 years of illness correlated more strongly with disability scores at 14 years than measures of volume at earlier or later times, suggesting that the development of lesions in the early years may have an important influence on long-term disability [69].

However, there is only weak correlation between MRI lesion load and age at disease onset, disease duration, and progression, as shown in an analysis of 1312 placebo subjects with MS in pooled data from 11 randomized controlled trials [70]. The correlation appears to plateau at higher levels of disability, suggesting that MRI lesion burden is a poor measure of disease progression in patients with advanced disease.

Furthermore, the extent of cranial MRI abnormalities in individual patients does not necessarily correlate with the degree of clinical disability. Patients with small numbers of lesions may be quite disabled, while others can function well despite a large burden of disease detected by MRI. There are several possible explanations for this observation: some lesions may occur in areas that are clinically silent, while others may involve clinically eloquent areas and cause specific disabilities [71]; small lesions in the spinal cord or brainstem can cause major disability in the absence of cerebral lesions; MRI may miss or underestimate lesions that are clinically relevant such as those in cortex, basal ganglia, and brainstem; and large plaques detected by MRI may not have functional correlates but reflect increased tissue water without impairment of neural function.

The amount of ongoing MRI activity, as determined by the appearance of new or enlarging lesions and/or gadolinium-enhancing lesions, exceeds the observed clinical activity in MS by a factor of 5 to 10 [64]. This may reflect not only the issues discussed above, but also underreporting of minor symptoms and under-recognition of minor signs in patients with MS. It does, however, suggest that MS is a much more dynamic and active disease than is clinically apparent.

Optical coherence tomography markers — In several prospective studies, thinning of the peripapillary retinal nerve fiber layer (pRNFL) or the ganglion cell layer plus inner plexiform layer (GCIPL), measured using optical coherence tomography (OCT) in eyes without a prior history of optic neuritis, has been associated with disability progression in patients with MS or a clinically isolated syndrome (CIS) [72]. Thus, the thinning is likely a marker of neurodegeneration due to MS rather than a reflection of focal nerve injury related to optic neuritis. In one report of 879 patients with CIS or MS, patients with a baseline pRNFL thickness of ≤87 or ≤88 µm, depending on the OCT device used, had a nearly four-fold increased risk of disability worsening at four to five years of follow up [73]. Similarly, a study of 151 patients with MS found that pRNFL thickness ≤88 µm was associated with an increased risk of disability progression within three years [74]. Spectral-based (as opposed to time-domain based) OCT provides a more precise measurement of GCIPL and thus may be more precise in determining the potential usefulness of OCT in predicting disability. A report of 132 patients with MS followed for a median duration of 10 years, a lower baseline thickness of the GCIPL (≤70 µm) on OCT was associated with a four-fold increase in the odds of long-term disability progression [75]. At present, it is not clear how to integrate OCT in making treatment recommendations for patients. However, these results suggest that OCT, in conjunction with clinical data and MRI findings, may have a future role in guiding risk assessment and treatment decisions for patients with MS [76].

Neurofilament light chain — A number of studies suggest that serum neurofilament light chain concentration (sNFL), a marker of neuronal injury, is associated with acute MS disease activity and treatment response and may predict future risk of disability [77-79]. However, sNFL is not specific for MS, and further study is needed to establish its clinical utility as an MS biomarker [79].

Pregnancy — MS predominantly affects women and has its maximum incidence during childbearing years. Pregnancy appears to have a protective effect against MS relapses, but there is an increased risk of disease exacerbation in the early postpartum period. When the protective effect during pregnancy and the increased risk in the early postpartum period are combined, the net effect is no increase in the risk of exacerbation or long-term disability [80].

The available evidence suggests that maternal MS is associated with a modestly increased rate of caesarean delivery and lower infant birth weights. However, birth outcomes have not been systematically studied. The choice of anesthesia for delivery in mothers with MS should be based upon obstetric concerns. Breastfeeding is safe in MS and women who breastfeed their baby may even have a lower risk of MS [81]. These issues are discussed in greater detail separately. (See "Neurologic disorders complicating pregnancy", section on 'Multiple sclerosis'.)

Demographics — Racial differences may also exist for the clinical features and prognosis of MS, although this is less well established than for differences in the risk of developing MS (see "Pathogenesis and epidemiology of multiple sclerosis", section on 'Geographic factors'). A retrospective study found that Black Americans with MS have a later age of disease onset than White Americans (age 33.7 versus 31.1 years, respectively) and are more likely to develop ambulatory disability than White Americans with MS [82]. Since the median time to both MS diagnosis and MS onset to treatment was significantly shorter for Black compared with White subjects in this study population, it is possible that the increased risk of disability for Black patients was independent of health care access.

The same report, from 2004, noted that Black Americans with MS were more likely to present with multifocal signs and symptoms, were more likely to have clinical involvement restricted to the optic nerves and spinal cord (ie, probable neuromyelitis optica spectrum disorders [NMOSD] by modern criteria), and were more likely to develop transverse myelitis compared with White Americans with MS [82]. While 63 Black Americans in the study had opticospinal MS (defined as relapses or clinical signs restricted to the optic nerves and spinal cord), only three met the criteria for NMOSD in place at the time [83]. Nevertheless, there may have been some additional overlap with NMOSD, since this report from 2004 predates the development of more precise laboratory studies and clinical criteria for NMOSD. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'NMOSD' and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Epidemiology'.)

Data regarding the effect of biological sex in MS activity and progression are inconsistent. One longitudinal study that followed 2319 patients prospectively for 22,723 patient years found that sex and age of onset were not independent prognostic factors [23]. By contrast, male sex was associated with more rapid progression of disability in one natural history study with 5778 patients and another with 1844 patients [25,84].

Several studies have found that patients who present at an older age (over 30 to 35 years) develop disability more rapidly compared with those diagnosed at a younger age [85]. However, as younger patients have longer to live with the disease, they are likely to develop disability milestones (such as needing a cane or walker) at an earlier age.

Other factors — Physical trauma does not appear to be related to disease induction or relapse [33]. However, there is some evidence that repeated concussions can increase the MS risk [86]. Neurologic diagnostic procedures such as myelography and lumbar puncture have not been linked with aggravation of the disease course, nor has administration of local or general anesthetics. Cigarette smoking has been associated with an increased rate of transition from relapsing-remitting MS to secondary progressive MS [87]. Treatment with anti-tumor necrosis factor alpha medications has been associated with the onset of MS [88,89]. Obesity in childhood and adolescence may also increase the risk of MS [90].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

SUMMARY

●Core MS phenotypes – The core multiple sclerosis (MS) phenotypes are those of relapsing and progressive disease. The pattern and course of MS is further categorized into several phenotypes or clinical subtypes as follows (see 'Disease onset and pattern' above):

•A clinically isolated syndrome – This is the first potential attack of a disease compatible with MS that exhibits characteristics of inflammatory demyelination but has yet to fulfill MS diagnostic criteria. The typical patient presents as a young adult with a clinically distinct episode of central nervous system dysfunction (eg, optic neuritis, diplopia, brainstem or cerebellar syndrome, or partial transverse myelitis) with at least partial resolution. (See 'Clinically isolated syndrome' above.)

•Relapsing-remitting MS – This phenotype is characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery. There is no or minimal disease progression during the periods between disease relapses. This type of MS accounts for approximately 85 to 90 percent of MS cases at onset. However, most patients with relapsing-remitting MS will eventually enter a secondary progressive phase. (See 'Relapsing-remitting MS' above.)

•Secondary progressive MS – This phenotype is characterized by an initial relapsing-remitting MS disease course followed by progression with or without occasional relapses, minor remissions, and plateaus. Some studies suggest that secondary progressive MS ultimately develops in most patients with relapsing-remitting MS and is the stage in which patients accumulate the greatest amount of neurologic disability. (See 'Secondary progressive MS' above.)

•Primary progressive MS – This phenotype is characterized by disease progression from onset with occasional plateaus and temporary minor improvements allowed; acute attacks may also occur. This type represents approximately 10 percent of adult cases at disease onset. (See 'Primary progressive MS' above.)

●Disability progression – Progression of disability due to MS is highly variable. The impact of MS varies according to a number of measures, including severity of signs and symptoms, frequency of relapses, rate of worsening, and residual disability. Accumulating evidence suggests that, in most patients, worsening is slow. At the extreme ends of the severity spectrum, there are benign and malignant forms of MS, but the determination of these is always retrospective and must be made cautiously. (See 'Disease severity' above.)

●Predicting outcome – There are a variety of possible prognostic indicators in MS. However, none are established as reliable, and our ability to accurately predict outcomes for individual patients with MS is quite limited. The development of a progressive course of MS may be the single most adverse factor influencing prognosis. (See 'Prognostic factors' above.)