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. Clinical symptoms and signs of MS are reviewed elsewhere. (See "Manifestations of multiple sclerosis in adults".)

Other aspects of MS are discussed separately:

●Pathogenesis

•(See "Pathogenesis and epidemiology of multiple sclerosis".)

●Diagnosis

•(See "Evaluation and diagnosis of multiple sclerosis in adults".)

●Treatment

•(See "Treatment of acute exacerbations of multiple sclerosis in adults".)

•(See "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)

•(See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

•(See "Treatment of secondary progressive multiple sclerosis in adults".)

•(See "Treatment of primary progressive multiple sclerosis in adults".)

•(See "Symptom management of multiple sclerosis in adults".)

●Pediatric multiple sclerosis

•(See "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".)

•(See "Treatment and prognosis of pediatric multiple sclerosis".)

DISEASE ONSET — 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 multiple sclerosis' below.)

Prodromal multiple sclerosis — The concept of a prodromal phase of MS holds that early, nonspecific clinical symptoms and signs precede the typical symptoms and signs of MS that enable diagnosis [1-3].

Prodromal MS is a relatively novel concept that is not fully defined or characterized. However, a prodromal phase of MS is supported by evidence that individuals who will go on to develop MS have an increased prevalence of health problems and nonspecific clinical findings 5 to 10 years before the onset of MS compared with age-matched controls who do not develop MS. These studies have found an increased use of health care services (hospitalizations, clinician visits, prescription medications) [4-6], worsening mental health [7,8], a variety of somatic complaints [7,9], diminished cognitive performance [7], fewer pregnancies [5], and increased serum levels of neurofilament light chain [10], a biomarker of neuronal injury. Given that the symptoms and findings associated with prodromal MS are nonspecific, evaluation with imaging is not warranted in the absence of more specific markers of MS.

Radiologically isolated syndrome — Some MS cases may be presaged by a radiologically isolated syndrome (RIS), which is defined by incidental brain or spinal cord magnetic resonance imaging (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 presumably unrelated condition such as headache or trauma [11,12]. In one review, the main factors that predicted conversion from RIS to clinically definite MS were male sex, younger age (less than 37 years), and spinal cord lesions on MRI [13]. (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".)

Clinically isolated syndrome — A clinically isolated syndrome (CIS) is the first clinical episode that is suggestive of MS, or it may be the first attack of MS if the evaluation confirms that the patient fulfills diagnostic criteria for MS (table 1), in which case it is reclassified as relapsing-remitting MS.

●Onset – A CIS is characterized by the following features [14-16]:

•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 clinical episodes of demyelination from the patient's history or examination, although such evidence may be found with subsequent imaging or cerebrospinal fluid analysis.

●Typical presentations – A CIS usually presents with one of the following syndromes [15,17]:

•Unilateral optic neuritis, manifesting with monocular visual loss consisting of visual blurring or scotoma as well as reduced color vision, pain with eye movements, and a relative afferent pupillary defect on examination.

•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. CIS is best thought of as a precursor to MS in most patients.

The McDonald diagnostic criteria for MS (table 1) have broadened over the years since they were originally developed in 2001, resulting in fewer patients with a diagnosis of CIS after evaluation. As an example, a patient with a single clinical demyelinating event will be diagnosed with MS if their MRI shows both enhancing and nonenhancing brain or spinal cord lesions, indicative of inflammation separated in space and time. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'For a clinically isolated syndrome'.)

Characteristic multiple sclerosis findings — There are no clinical findings that are unique to MS, but some are highly characteristic of the disease (table 2). Common manifestations (table 3) include sensory loss in limbs or one side of the face, optic neuritis (unilateral visual loss, typically with loss of color vision and pain with eye movements), acute or subacute motor weakness, binocular 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 partial transverse myelitis, and pain. Presenting symptoms and signs may be either monofocal (consistent with a single lesion) or polyfocal (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.

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). 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'.)

MULTIPLE SCLEROSIS PHENOTYPES

Phenotype classification — The core MS phenotypes are those of relapsing-remitting and progressive disease [14]. The pattern and course of MS is further categorized into several clinical subtypes: clinically isolated syndrome (CIS), often representing the first attack of MS; relapsing-remitting MS; secondary progressive MS; and primary progressive MS [14,18].

In addition, these phenotypes are modified by assessments of disease activity and disease progression over time [14,19].

●Disease activity – This is determined by clinical relapses or MRI evidence of contrast-enhancing lesions and/or new or unequivocally enlarging lesions on T2-weighted images.

●Disease progression – While relapses can lead to sustained deficits that are measurable on neurologic examination, MS progression (as defined by gradually 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 they say nothing about which symptoms a patient experiences or the severity of these symptoms.

Relapsing-remitting multiple sclerosis

●Definition – 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 [20]. 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. Relapsing-remitting MS may progress over time to secondary progressive MS, as described below. (See 'Secondary progressive multiple sclerosis' below.)

●Clinical features – Relapsing-remitting MS 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.

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. (See 'Relapses' below and 'Disability progression with neurodegeneration' below.)

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) [21]. However, relapses can emerge from lesions in any part of the central nervous system; when new or worsening symptoms develop that are similar to prior relapses, it may be difficult to determine if there is new inflammatory activity by history or examination [22]. In this situation, MRI can usually reveal whether the symptoms reflect new inflammation.

●Diagnosis – Diagnosing relapsing-remitting MS depends on showing evidence of dysfunction in separate parts of the central nervous system that occurred at different time points. The initial attack is an isolated neurologic problem, a 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 nonenhancing lesions (called dissemination in time) in the requisite number of locations (called dissemination in space). Oligoclonal bands that are present in cerebrospinal fluid but absent in the serum can also be used to meet dissemination in time criteria, though a spinal tap is generally not indicated in patients whose history, examination, and imaging are highly consistent with and otherwise fulfill criteria for MS.

In some cases, clear evidence of a historical MS attack can be elucidated from history and/or examination, such that the symptoms leading to new presentation would not be the CIS. The 2017 revisions to the McDonald criteria are shown in the table (table 1). The diagnosis of MS is reviewed in detail elsewhere. (See "Evaluation and diagnosis of multiple sclerosis in adults".)

●Course – Most patients have relapsing-remitting MS at onset, and the clinical course may evolve to secondary progressive MS [20,23]. Patients with an initial relapsing-remitting MS course who have active disease tend to have incomplete recovery between attacks, and the level of disability begins to increase with time. This accumulation of disability is likely caused in whole or in part by underlying progression, which is thought to be neurodegenerative in nature.

Eventually, patients with relapsing-remitting MS continue to worsen even in the absence of relapses, and the disease is then said to convert to secondary progressive MS. With longer time from diagnosis, the proportion of patients with relapsing-remitting MS falls as patients transition to secondary progressive MS, as discussed in the section that follows.

Secondary progressive multiple sclerosis

●Definition and course – Secondary progressive MS is characterized by an initial relapsing-remitting MS disease course (see 'Relapsing-remitting multiple sclerosis' above) followed by gradual worsening with or without occasional relapses, minor remissions, and plateaus. Secondary progressive MS can be further characterized at different points in time as either active (with relapses and/or evidence of new 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.

●Time to transition – In various studies, the median transition time from relapsing-remitting MS to secondary progressive MS ranges from 10 to 39 years after disease onset [24-28]; these studies also suggest that the median time to transition has risen since the early 2000s because the number of patients converting to the secondary progressive phase has decreased, perhaps due in part to greater use of appropriate disease-modifying therapy (DMT) management [28]. However, among the subset of patients who do convert, the median time to a diagnosis of secondary progressive MS is approximately 10 years from the onset of relapsing-remitting MS [28,29].

●Diagnosis – 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 [14]. Thus, secondary progressive MS may represent a late recognition of silent progression rather than a distinct disease phase. (See 'Disability progression with neurodegeneration' below.)

Primary progressive multiple sclerosis

●Definition and course – Primary progressive MS is characterized by progressive accumulation of disability from disease onset; occasional plateaus, temporary minor improvements, or acute relapses may occur, and all are consistent with the definition. Primary progressive MS represents approximately 10 percent of adult MS cases at disease onset [30].

Primary progressive MS can be further characterized at different points in time as either active (with an occasional relapse and/or evidence of new 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. The term progressive-relapsing MS, previously used to characterize patients who had progressive disease from onset and clear acute relapses [18], is now obsolete [14]. 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 [14].

Based on similarities between primary progressive and secondary progressive MS, some experts suspect that primary progressive MS represents secondary progressive MS where the initial relapsing phase was silent or subclinical.

●Epidemiology – The mean age at onset is approximately 40 years [31,32], 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 [20]. Unlike relapsing-remitting MS, primary progressive MS occurs equally in males and females [33].

●Clinical features – 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 [34]. 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 [35]. These patients have a worse prognosis for ultimate disability in comparison with patients who have relapsing-remitting MS.

●Diagnosis – A diagnosis of primary progressive MS is made exclusively on patient history, and there are no imaging or examination findings that distinguish primary progressive MS from relapsing-remitting MS.

DISEASE SEVERITY AND PROGRESSION

Clinical course is highly variable — Neurologic disability resulting from MS is highly variable (see 'Rate of worsening' below). The impact of MS on any one individual varies according to several 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.

At the extreme ends of the severity spectrum, there are "benign" and "malignant" forms of MS. 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 [14].

●Benign multiple sclerosis – Benign MS refers to disease in which the patient remains fully functional in all neurologic systems 15 years or more after the disease onset. An alternative definition requires an Expanded Disability Status Scale (EDSS) score ≤3.0 at ≥15 years of disease duration (table 4). However, definitions based on EDSS are imperfect; patients with an EDSS of 3 could have moderate disability in one of the functional systems, and symptoms that don’t contribute to the EDSS (eg, fatigue) may cause functional impairment.

Benign MS 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 11,222 patients in a population-based cohort study from Sweden published in 2019 who had MS for 15 or more years, approximately 22 percent had an EDSS score ≤3.0 [36].

Autopsy studies have found a number of cases with central nervous system pathology consistent with MS but no documented clinical evidence of disease [37-40]. MRI studies of asymptomatic relatives of MS patients have discovered lesions consistent with demyelination in up to 15 percent of these relatives [41]. The use of MRI may expand the spectrum of MS by detecting milder cases that previously were not included in prognosis studies.

In our experience and that of others, patients who have had a known benign course for 15 years will only rarely develop a more severe course [42]. 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 [43]. 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 [43]. The EDSS score at 10 years was the only independent predictor of score at 20 years.

●Aggressive multiple sclerosis – 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 [44]. 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 [45]. Another report, which defined aggressive MS by an EDSS score ≥6 reached within 10 years of symptom onset and analyzed data from a registry of over 58,000 patients with MS [46], also found that aggressive MS developed in 6 percent [47].

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 [44,45,47]. However, these studies may have some degree of incorporation bias, since progressive MS itself is associated with a more aggressive course. (See 'Disability progression with neurodegeneration' below.)

Disability measures — Several instruments are available for measuring disability and functional status in patients with MS; all require a trained examiner to administer and score. The following are among the more commonly used scales:

●Based on the classic neurologic examination, the Kurtzke disability status scale (table 5) and the expanded version known as the EDSS (table 4) are commonly used indices of clinical disability in MS [48,49]. 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.

●The Patient-Determined Disease Steps (PDDS) scale (table 6) utilizes patient-reported outcomes to derive a disability score [50].

●The Multiple Sclerosis Functional Composite (MSFC) is a three-part assessment that measures arm, leg, and cognitive function [51]. The MSFC administration and scoring manual is available online.

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 EDSS score of 4 or 5 is 1.2 years, while the median time spent at EDSS 1 is four years and at EDSS 6 is three years [20].

The EDSS is universally used in clinical trials, often with additional measures, but it has several 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 nonlinear, 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 cane (EDSS 6) to using a wheelchair (EDSS 7). Thus, other outcome measures such as the PDDS and/or the MSFC may be helpful; minor changes in the EDSS alone should not be over-interpreted.

Rate of worsening — The rate of worsening of neurologic function due to MS is variable [25,42,52-55] but may be slowing since the advent of disease-modifying therapies (DMTs).

●Rate of disability – In one prospective report published in 2016 of 517 patients with MS who were managed at a single MS center, 11 percent of patients had reached an EDSS ≥6 (unilateral assistance necessary for ambulation) at a median of approximately 17 years after disease onset [26].

This contrasts with earlier studies that suggested a faster rate of progression. 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 [56]. By contrast, a 2006 publication reported on a longitudinal study in British Columbia that followed 2319 patients with symptom onset prior to July 1988 [54]. At 15 years after onset, 21 percent required a cane (EDSS >6). The median time from disease onset to EDSS 6 was 27.9 years. The median age from birth to EDSS 6 was 59 years. 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 2006 large epidemiology study from France [57].

●Impact of disease-modifying therapy – The main driver of long-term worsening in MS is thought to be silent progression that is independent of relapse activity. Thus, while DMTs (first introduced in the 1990s) are effective for reducing the frequency of relapses in patients with relapsing-remitting MS, it has been unclear whether they reduce the progression of disability. However, mounting evidence suggests that they do improve short-term (two to three years) disability progression [58,59].

Long-term data are limited; an analysis utilizing the Novartis-Oxford multiple sclerosis (NO.MS) cohort evaluated data from 4970 patients enrolled in double-blind placebo-controlled randomized trials and found that the use of DMT delayed disability progression by several years; 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) [60].

Relapses

●Frequency – The frequency of MS relapses (ie, attacks, exacerbations) is highly variable. Summaries of many older studies, largely from the pre-DMT era, provided 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 [61]. 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 [24,62,63]. However, other data suggest that relapse frequency is not associated with long-term disability progression [52]. Rather, most disability is thought to accrue from silent progression. (See 'Disability progression with neurodegeneration' below.)

Relapses may be more common after stressful life events [64-66]. A meta-analysis of 14 observational studies found a significant association between stress and MS exacerbations [64]. However, patients may suffer from a recall bias, and the authors cautioned that the study does not offer proof of a causal association.

●Pseudorelapses – In the absence of a new demyelinating event, previous clinical deficits may temporarily worsen in the setting of any elevated physiologic 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. Psychologic stress and poor sleep have also been associated with recrudescence of previous symptoms.

Disability progression with neurodegeneration — Mounting evidence suggests that disability progression occurs primarily because of neurodegeneration of brain and spinal cord that is independent of relapse activity [52,67-70].

●Disability progression is more common in progressive versus relapsing multiple sclerosis – Most untreated and many treated patients with relapsing MS will eventually enter a secondary progressive phase of disease where neurologic function gradually worsens regardless of relapses [20,23]. The development of a progressive course may be the single most adverse factor that influences prognosis [23,56,71-76]. An observational natural history study found that irreversible disability occurred sooner in patients in whom the disease was progressive from the onset compared with those in whom the onset was relapsing-remitting [53]. Once irreversible disability occurred, however, the time course of progressive disability was similar in the two groups.

●Relapses are not a major driver of disability – Relapses that lead to permanent disability are rare. 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 [23]. Similarly, an analysis of the NO.MS clinical trial data set found that 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, was present early in the course of MS in all phenotypes and became the main driver of disability in the later stages of MS [60]. By contrast, relapse-associated worsening contributed to disability primarily in the early stages of MS. Note that PIRA is a controversial term since it describes a course that is similar if not identical to progressive MS.

In a single-center study that analyzed data from 2587 relapses occurring in 1078 patients during an average follow-up of 7.4 years, only seven patients had relapses that resulted in permanent need for a cane, crutch, or brace to walk 100 meters with or without resting [77].

●Neurodegeneration is associated with progressive disability – Longitudinal neuroimaging studies have associated evidence of neurodegeneration (atrophy) with subsequent risk of clinical progression. In a 10-year prospective cohort study of 372 patients with or at risk for relapsing-remitting MS, relapses were associated with a temporary increase in disability but not with confirmed disability progression [67]. Rather, disability progression correlated with declines in relative brain volume measured by MRI, suggesting that underlying neurodegeneration with brain atrophy is an important mechanism. The authors proposed the term "silent progression" to characterize the neurodegeneration that develops in many patients with relapsing-remitting MS. In a subsequent case-control study from the same investigators, progressive cervical spinal cord atrophy was associated with a shorter time to silent progression and a shorter time to secondary progressive MS conversion [68]. 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. These findings suggest that secondary progressive MS represents a late recognition of silent progression rather than a distinct disease phase.

Mortality — Several reports suggest that mortality is increased in patients with MS [78-80]. A review of large MS cohort registries assessing mortality and published from 2004 to 2012 found that life expectancy in patients with MS was reduced by 7 to 14 years [78]. One-half or more of the deaths among patients with MS were directly related to complications of MS. A meta-analysis of 12 studies, covering the period 1949 to 2012 and 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) [79]. Compared with the general population, patients with MS had increased rates of death from infection and respiratory diseases, suicide, and cardiovascular disease.

Using excess death rates (EDRs) rather than SMR, a retrospective study of data from 18 French MS centers with over 37,500 patients having clinical onset between 1960 and 2014 found no excess mortality caused by MS during the first 10 years after MS onset [80]. 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.

Future mortality estimates are likely to show that MS-related mortality is declining; only patients diagnosed since approximately 2015 are beneficiaries of full access to the spectrum of moderate to highly efficacious DMTs and a clearer strategy of eradicating inflammatory activity.

PROGNOSTIC FACTORS — A variety of factors have been identified as possible prognostic indicators in MS that may modify the disease course or predict exacerbations (figure 2) [81]. However, none are established as reliable, and our ability to accurately predict outcome for individual patients with MS is quite limited [82].

MRI markers — The main MRI markers of MS disease activity and pathology are lesion load and cerebral atrophy [83,84].

●Atrophy – The degree of atrophy affecting the brain, particularly the gray 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 associate better with clinical disability than lesion volume on T2-weighted MRI [85]. Although not routinely assessed in clinical practice, spinal cord atrophy is also associated with disability [86-88].

●Lesion load – The lesion load is assessed on conventional T2-weighted, fluid-attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted MRI sequences. The lesion load on T2-weighted MRI scan has been associated with an increased risk of disability in some studies but not others [82]. As an example, a serial MRI study in 71 patients followed for a mean of 14 years found that lesion volume at five years and the change in volume during the first five 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 [89].

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 [90]. 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 [91].

In a longitudinal study of 166 patients who presented with a clinically isolated syndrome (CIS), as defined some years ago, and who 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 [92]. 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.

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 CIS [93,94]. Thus, the thinning is likely a marker of neurodegeneration due to MS rather than a reflection of focal nerve injury related to optic neuritis.

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 [95].

Neurofilament light chain — Several 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 [96-98]. However, sNFL is not specific for MS, and further study is needed to establish its clinical utility as an MS biomarker [98].

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 [99].

Breastfeeding is safe in MS, and women who breastfeed their baby may even have a lower risk of MS relapse [100].

These issues are discussed in greater detail separately. (See "Multiple sclerosis: Pregnancy planning" and "Multiple sclerosis: Pregnancy and postpartum care".)

Demographics

●Racial differences – 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 [101]. 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, although systemic inequities likely still drive the worsened prognosis.

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 disorder [NMOSD] by modern criteria), and were more likely to develop transverse myelitis compared with White Americans with MS [101]. 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 [102]. 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'.)

●Sex differences – Data regarding the effect of biologic sex in MS activity and progression are inconsistent. In a longitudinal study that followed 2319 patients prospectively for 22,723 patient-years, sex and age of onset were not independent prognostic factors [54]. Adult males progressed more quickly than adult females from onset, but 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. 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 [25,103].

●Older age – 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 [104]. In addition, disability in MS may be more dependent on patient age than on the initial course, whether relapsing or progressive from onset [57,105]. 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. Even in otherwise healthy adults without MS, older age is associated with significant disability that can increase Expanded Disability Status Scale (EDSS) scores and thereby skew the apparent relationship of MS-related disability with aging [106].

Others

●Cigarette smoking – Cigarette smoking has been associated with an increased rate of transition from relapsing-remitting MS to secondary progressive MS, increased disease activity, higher rates of brain atrophy, and faster disability progression [107-109].

●Obesity – Obesity is associated with increased MS severity and worse outcomes [110-113].

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

●Multiple sclerosis (MS) onset – The typical patient presents as a young adult with one or more clinically distinct episodes of central nervous system dysfunction (ie, a clinically isolated syndrome [CIS] with at least partial resolution).

•Clinically isolated syndrome – A CIS is the first clinical episode that is suggestive of MS, or it may be the first attack of MS if the evaluation confirms that the patient fulfills diagnostic criteria for MS (table 1). Typical presentations include unilateral optic neuritis, painless diplopia, a brainstem or cerebellar syndrome, or partial transverse myelitis. (See 'Clinically isolated syndrome' above.)

•Prodromal multiple sclerosis – Prodromal MS is a relatively novel concept that is not fully defined or characterized, but there is evidence that early nonspecific clinical symptoms and signs precede the typical symptoms and signs of MS. (See 'Radiologically isolated syndrome' above.)

•Radiologically isolated syndrome (RIS) – Some MS cases may be presaged by an RIS, 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. (See 'Radiologically isolated syndrome' above.)

●Core multiple sclerosis phenotypes – The core 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' above):

•Relapsing-remitting multiple sclerosis – 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, many patients with relapsing-remitting MS will eventually enter a secondary progressive phase. (See 'Relapsing-remitting multiple sclerosis' above.)

•Secondary progressive multiple sclerosis – 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 multiple sclerosis' above.)

•Primary progressive multiple sclerosis – 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 multiple sclerosis' above.)

●Disability progression – Progression of disability due to MS is highly variable. Mounting evidence suggests that disability progression occurs primarily because of clinically silent neurodegeneration that is independent of relapse activity. 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 and progression' above.)

●Predicting outcome – There are a variety of possible prognostic indicators in MS (figure 2). However, none is established as completely reliable, and our ability to accurately predict outcomes for individual patients with MS is limited. The development of a progressive course of MS may be the single most adverse factor influencing prognosis. (See 'Prognostic factors' above.)