Multiple Sclerosis: Understanding Disease Progression, Pain, and Function
A Clinical Primer

Multiple Sclerosis Types and Stages of Disease Progression

Two types of multiple sclerosis can be diagnosed initially: relapsing-remitting & primary progressive. More on MS types and differentiating symptoms.

It is estimated that globally, someone is diagnosed with multiple sclerosis (MS) every 5 minutes.In the United States alone, nearly 1 million people have MS,1,2 a chronic immune-mediated disorder of the central nervous system (CNS). According to the 2020 Atlas of MS (updated from 2013), the current average age of onset is 35 in women and 37 in men in the US.MS is uncommonly diagnosed in pediatric age groups. The disease is diagnosed most frequently in persons that are white and of Northern European descent, although MS occurs in all races and ethnic groups. Because MS can affect multiple areas of the brain and spinal cord, the symptoms at onset can vary between persons, although certain features are more prevalent in specific types of MS.

The diagnostic process involves a thorough history and physical examination, imaging, and other tests (eg, blood work, cerebrospinal fluid [CSF] analyses, and evoked potentials), as well as additional consults and studies to rule out other explanations for the individual’s symptoms (eg, infectious, metabolic, vascular, neoplastic, other autoimmune disorders). It is important to note that the diagnosis of MS is best made by a healthcare provider who has MS-related expertise.

The initial symptoms are often worrisome to individuals and their families and the uncertainty and time to make a diagnosis can be very challenging for those undergoing an evaluation (see also our Scripted sample dialogue on talking to patients about MS and job disability below).

The current McDonald criteria (2017) notes that two types of MS can be diagnosed at initial presentation– relapsing-remitting and primary progressive – although about 3% of all persons with MS are initially diagnosed with an unknown disease type.1


The most common type of multiple sclerosis is relapsing-remitting MS, known as RRMS. Worldwide, 85% of persons with MS are initially diagnosed with RRMS.1

Relapsing-Remitting MS Diagnostic Criteria

To be diagnosed with RRMS, patients must meet the criteria for:3

  • dissemination in time – that is, clinical evidence of two or more demyelinating episodes with two or more lesions; and
  • space – that is, clinical evidence of lesions occurring in different CNS locations.

Lesions can be symptomatic or asymptomatic; they can be periventricular, juxtacortical or cortical, infratentorial, or spinal.3 While the previous versions of the McDonald criteria required a distinction between symptomatic and asymptomatic lesions, this differentiation is no longer required as of the 2017 update.3

An MS diagnosis can also be made if an individual has a typically clinically isolated syndrome (ie, one episode) and if they have evidence of dissemination in space plus CSF-specific oligoclonal bands.3

The time to diagnosis can be shortened through the judicious use of clinical evidence of a classic historical relapse, MRI findings consistent with separate relapses in different areas, or the presence of CSF-specific oligoclonal bands. The 2017 McDonald criteria describe the combinations that meet criteria for dissemination in time and space in the setting of classic symptoms and signs in a person with a high likelihood of having MS, for whom other disorders have been ruled out, by a provider with knowledge of MS.3

Misdiagnosis of RRMS, however, is not uncommon.In cases where there is an atypical presentation or an individual with a lower likelihood of having MS, further diagnostic testing may be warranted to confirm the MS diagnosis or determine that the symptoms are due to another process which requires a different treatment approach.5

Relapsing-Remitting MS Symptoms 

The initial symptoms of RRMS may be monofocal or multifocal, with the presentation dependent on the location of the lesion(s).Certain symptoms, however, are more typical at initial presentation, which can involve the optic nerve, cerebellum or brain stem, cerebral hemispheres, and/or spinal cord. These initial symptoms can include:6

  • unilateral optic neuritis, which can include reductions in visual acuity and color vision as well as mild pain with eye movement
  • bilateral internuclear ophthalmoplegia
  • paroxysmal phenomena that lasts for at least 24 hours
  • incomplete transverse myelitis, in which only part of the spinal cord is affected, can include symptoms such as paresthesia, upper or lower extremity weakness, pain, and urinary and bowel dysfunction (ie, incontinence, urgency, and constipation)
  • Lhermitte’s sign, an electrical-like sensation in the spine brought about by flexing the neck
  • asymmetric limb weakness
  • bladder incontinence or retention
  • hemiparesis

While there have been rare cases where persons with MS present with pain syndromes,certain pain symptoms are atypical during the initial episode, such as optic neuritis with very severe pain, isolated trigeminal neuralgia, and localized or radicular spinal pain (more on pain in MS below).6

MS Relapses and Pseudorelapses

One of the hallmarks of RRMS is relapses, which are also referred to as episodes, attacks, flare-up, or exacerbations. A relapse is defined as new or worsening symptoms that last for more than 24 hours.After a relapse, persons with MS may have partial or full recovery followed by periods of neurological stability.To be considered a separate relapse, there needs to be at least 30 days between episodes.Persons with RRMS are considered to have active disease if they are having relapses and/or there is evidence of new lesions on their MRI.3

As noted, the symptom profile for RRMS depends on where in the CNS the lesions occur. Besides the initial symptoms present during the first episode suggestive of MS, other symptoms can develop over the course of the disease, such as:9

  • mobility-related problems
  • neuro-ophthalmologic symptoms
  • cerebellar and brainstem dysfunction (eg, tremors, ataxia, vertigo, and speech and swallowing difficulties)
  • urinary and bowel dysfunction
  • sexual dysfunction
  • cognitive impairment
  • mood changes
  • fatigue
  • sleep disorders

It is important to note that persons with MS can experience “pseudorelapses” or Uhthoff phenomenon. A pseudorelapse refers to a temporary aggravation of neurological symptoms that have occurred previously without new CNS disease activity.A pseudorelapse is commonly associated with:

  • a fever or exposure to heat, such as from exercise, hot weather, or a hot shower or bath (see also, how to talk to patients about elevated temperature)

Other factors that are associated with a pseudorelapse include:10-12

  • upper respiratory or urinary tract infections
  • comorbidities
  • premenstrual symptoms
  • lack of sleep
  • psychological stress

Unlike a true MS relapse, pseudorelapses resolve in less than 24 hours and when the precipitating situation has subsided.

Secondary Progressive Multiple Sclerosis (SPMS)

Over time, persons with RRMS may develop secondary progressive MS (SPMS). Defined as having an initial relapsing-remitting course, persons with SPMS experience a later progressive disease course in which the relapses become less prominent and instead they experience a progression of symptoms and neurological findings with accumulation of disability over time.3,13 While persons with RRMS may experience worsening of their disease due to a partial recovery from a relapse, persons with SPMS can have worsening of their disease without a relapse or MRI activity (ie, progression).

As with RRMS, individuals with SPMS can be categorized as having active disease if they are experiencing relapses and/or there is evidence of new lesions of their MRI. SPMS can also be classified as progressive if there is evidence of accumulation of disability, although some people with MS may be stable with no activity or additional progression. It is recommended that these disease characterizations be re-evaluated regularly and as indicated by disease course, as they can inform pharmacological and non-pharmacological treatment approaches.3

According to the National Multiple Sclerosis Society,14 historically, approximately 50% of persons with RRMS will convert to SPMS within 10 years, with 90% of individuals converted by 25 years, although the development of improved disease-modifying therapies may change this. Men and individuals who were older at the onset of their MS may have a shorter conversion time from RRMS to SPMS.13 Compared to persons with RRMS, persons with SPMS endorse greater disease severity. In addition, certain symptoms may be more prevalent in SPMS. For instance, higher rates of constipation, difficulty with balance or ambulation, muscle spasms, urinary issues, stiffness, tremor, and sexual dysfunction have been reported in persons with SPMS in comparison to persons with RRMS. Clinicians, however, should be aware that disease duration and age-related comorbid conditions may have an influence on symptom presentation. Both patient groups endorsed high rates of fatigue, numbness, and pain.15



Approximately 12% of people living with MS are initially diagnosed with primary progressive MS (PPMS)– the second core type of MS defined by the McDonald criteria. Unlike persons with RRMS, persons with PPMS do not have distinct relapses, and as a result, there is less inflammation. As PPMS has a different initial presentation than RRMS, separate diagnostic criteria are used.

Diagnostic Criteria for  Primarily Progressive Multiple Sclerosis

According to the 2017 McDonald criteria,PPMS can be diagnosed with evidence of 1 year of disability progression, either from prospective or retrospective report, and two of the following:

  • one of more symptomatic or asymptomatic T2-hyperintense lesion, which can be periventricular, juxtacortical or cortical, or infratentorial
  • two or more T2-hyperintense spinal cord lesions


  • CSF-specific oligoclonal bands.

As with SPMS, PPMS can be characterized as active (ie, evidence of new lesions on MRI) or not active, as well as with progression (ie, further disability over time, which may or may not occur with new MRI activity) or without progression.3


Differentiating Symptoms of RRMS to PPMS

Compared to RRMS, functional impairments develop more slowly in PPMS.16 In addition, the initial symptoms typically seen at onset can differ between relapsing-remitting and primary progressive MS. While optic neuritis and sensory symptoms are more common in RRMS, motor and cerebellar symptoms, brainstem symptoms, and ataxia are more common at the time of diagnosis of PPMS.17 Certain symptoms are also more prevalent in the course of PPMS. These PPMS symptoms include:16

  • progressive spastic paraparesis
  • impaired mobility
  • exercise-related fatigable weakness
  • incontinence
  • constipation
  • sexual dysfunction

Sensory symptoms can occur in PPMS as well, however, motor symptoms are more common.16



Pain is a prevalent issue in individuals diagnosed with multiple sclerosis, with about 50% of persons with RRMS, nearly 70% of persons with SPMS, and more than 70% of persons with PPMS experiencing pain.18 In a non-clinical sample of persons with MS, where over 56% had RRMS, individuals experienced pain in 6.62 locations, on average, with the most common locations being their legs, lower back, neck, and shoulders.19

MS-related pain can be acute, such as with trigeminal neuralgia, Lhermitte’s sign, and optic neuritis, or chronic, such as with leg spasms and girdle-band pain, also referred to as the “MS hug.”20 Dysesthesias can be both acute and chronic as well.20

Compared to the US population, persons with MS (all types) have significantly higher pain severity, even after adjusting for age and sex.19 In addition, compared to the general US population, persons with PPMS have higher pain interference.16 That said, the level of pain severity and pain interference has not been shown to be significantly different between RRMS and PPMS.21

Further, pain can have negative effects on daily function, impacting sleep and engagement in recreational activities.19 One study, in which over 53% of participants had RRMS, found that pain-related illness intrusiveness was negatively associated with activity engagement, such as activities away from home (eg, going out to a movie).22

Clinicians should be aware that, in addition to pain resulting from the disease process, persons with MS can experience pain secondary to their MS treatments (eg, injection-related pain) or unrelated to their MS (eg, a co-occurring pain disorder such as musculoskeletal pain due to overuse or peripheral nerve conditions due to entrapments).20



How to talk to patients about an MS diagnosis and what it may mean for their career, including job disability and accommodations:





Overall, while relapsing-remitting MS is defined by relapses, from which there may be partial or full recovery, with periods of stability, both secondary progressive and primary progressive MS are characterized by progression of the disease, which may or may not occur alongside new MRI activity. While the symptoms seen in each type of MS is dependent on the location of the lesions in the CNS, persons with SPMS and PPMS can exhibit more issues with mobility, bowel and bladder functioning, and sexual dysfunction compared to persons with RRMS.

Pain is a significant concern across all three types of MS. While pain may be acute and seen early in the disease process, such as with optic neuritis and Lhermitte’s sign, clinicians should be aware of chronic problems, such as spasms, that can have implications in other areas of functioning.


Part II of this Clinical Primer discusses MS diagnosis and assessment protocols, including differential diagnoses and comorbidities.

Last updated on: September 13, 2021
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Multiple Sclerosis: Symptoms, Types, Risk Factors
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