typical presentation of multiple sclerosis

Multiple Sclerosis Clinical Presentation

• Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
• Sections Multiple Sclerosis
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Clinical Rating Scales
• Criteria for Categorizing MS
• Approach Considerations
• McDonald Criteria for MS Diagnosis
• Blood Studies
• Magnetic Resonance Imaging
• Other Imaging Studies in Multiple Sclerosis
• Evoked Potentials
• Electroencephalography
• Lumbar Puncture
• Emergency Department Management
• Treatment of Acute Relapses
• Immunomodulatory Therapy for Relapsing-Remitting MS
• Treatment of Aggressive MS
• Immunomodulatory Therapy for Progressive MS
• Experimental Agents
• Stem Cell Transplantation
• Treatment of MS in Pregnancy
• Symptom Management
• Rehabilitation
• Surgery for Alleviating Symptoms
• Deterrence and Prevention
• Consultations
• Long-Term Monitoring
• Medication Summary
• Immunomodulators
• Corticosteroids
• Immunosuppressants
• Sphingosine 1-Phosphate Receptor Modulators
• Dopamine Agonists
• Skeletal Muscle Relaxant
• Neuromuscular Blockers, Botulinum Toxins
• Alpha2-Adrenergic Agonists
• Benzodiazepines
• Anticonvulsants, Other
• Anticonvulsants, Hydantoin
• Selective Serotonin/Norepinephrine Reuptake Inhibitors
• Nonsteroidal Anti-Inflammatory Drugs
• Antispasmodic Agents, Urinary
• Acetylcholinesterase Inhibitors, Central
• Antidiarrheals
• Potassium Channel Blockers
• Questions & Answers
• Media Gallery

Attacks or exacerbations of multiple sclerosis (MS) are characterized by symptoms that reflect central nervous system (CNS) involvement. The sine qua non of MS is that symptomatic episodes are “separated in time and space”—that is, episodes occur months or years apart and affect different anatomic locations. As an example, a patient may present with paresthesias of a hand that resolve, followed a few months later by weakness in a leg or visual disturbances (eg, diplopia). In addition, the duration of the attack should be longer than 24 hours.

Presentation of MS often varies among patients. Some patients have a predominance of cognitive changes, while others present with prominent ataxia, hemiparesis or paraparesis, depression, or visual symptoms. Additionally, it is important to recognize that the progression of physical and cognitive disability in MS may occur in the absence of clinical exacerbations.

Classic MS symptoms are as follows:

Sensory loss (ie, paresthesias) - Usually an early complaint

Spinal cord symptoms (motor) - Muscle cramping secondary to spasticity

Spinal cord symptoms (autonomic) - Bladder, bowel, and sexual dysfunction

Cerebellar symptoms - Charcot triad of dysarthria (scanning speech), nystagmus, and intention tremor

Optic neuritis

Trigeminal neuralgia - Bilateral facial weakness or trigeminal neuralgia

Facial myokymia (irregular twitching of the facial muscles) - May also be a presenting symptom

Eye symptoms - Including diplopia on lateral gaze; these occur in 33% of patients

Heat intolerance

Constitutional symptoms - especially fatigue (which occurs in 70% of cases) and dizziness; fatigue must be differentiated from depression (which may, however, coexist), lack of sleep, and exertional exhaustion due to disability

Pain - Occurs in 30–50% of patients at some point in their illness

Subjective cognitive difficulties - With regard to attention span, concentration, memory, and judgment

Depression - A common symptom

Euphoria - Less common than depression

Bipolar disorder or frank dementia - May appear late in the disease course but is sometimes found at the time of initial diagnosis.

Symptoms associated with partial acute transverse myelitis

Patients with MS may present with many other manifestations, including the following:

Aphasia or dysphasia (occurs very rarely)

Seizures (5% of patients with MS)

Other paroxysmal symptoms (eg, ataxia, akinesia, paresthesias, pruritus)

Significant motor complaints without sensory deficits or dysautonomia

Paroxysmal symptoms may occur in bouts and are often triggered by movement or sensory stimuli.

Optic neuritis (ON) can be the first demyelinating event in approximately 20% of patients with MS. ON develops in approximately 40% of MS patients during the course of their disease. [ 57 ]

ON is characterized by loss of vision (or loss of color vision) in the affected eye and pain on movement of the eye. Much less commonly, patients with ON may describe phosphenes (transient flashes of light or black squares) lasting from hours to months. Phosphenes may occur before or during an ON event or even several months following recovery.

Acute transverse myelitis

Partial, rather than total, acute transverse myelitis usually is a manifestation of MS. Acute partial loss of motor, sensory, autonomic, reflex, and sphincter function below the level of the lesion indicates acute transverse myelitis. One should strongly consider mechanical compression of the spinal cord in the differential diagnosis of transverse myelitis.

Fatigue is one of the most common symptom of MS, reported by at least 75% of patients with the disease. [ 58 ] Fatigue is described as an overwhelming feeling of lassitude or lack of physical or mental energy that interferes with activities.

An estimated 50–60% of persons with MS describe fatigue as one of their most bothersome symptoms, and it is a major reason for unemployment among MS patients. One should rule out comorbid medical conditions, such as infections, anemia, vitamin deficiencies (eg, vitamin B 12 , folic acid, vitamin D deficiency) or thyroid disease, before attributing fatigue to MS.

Spasticity in MS is characterized by increased muscle tone and resistance to movement; it occurs most frequently in muscles that function to maintain upright posture. The muscle stiffness greatly increases the energy expended to perform activities of daily living (ADLs), which in turn contributes to fatigue.

Cognitive dysfunction

The estimated prevalence of cognitive dysfunction in MS ranges from 40–70%. No correlation exists with the degree of physical disability, and cognitive dysfunction may occur early in the course of disease. This complication of MS can be a significant problem, affecting family and social relationships, as well as employment. Areas of cognition affected may include any of the following:

Comprehension and use of speech

Visual perception

Problem solving

Executive function (ability to correctly follow sequential steps)

Abstract reasoning

As previously mentioned, pain can be a common occurrence in MS, with 30–50% of patients experiencing it at some time in the course of their illness. Pain typically is not associated with a less favorable prognosis, nor does it necessarily impair function; however, since it can have significant impact on quality of life, it needs to be treated appropriately.

Pain in MS can be classified as primary or secondary. Primary pain is related to the demyelinating process itself. This neuropathic pain is often characterized as having a burning, gnawing, or shooting quality. Secondary pain in MS is primarily musculoskeletal in nature and possibly results from poor posture, poor balance, or abnormal use of muscles or joints as a result of spasticity.

Urinary symptoms

Urinary symptoms are common in MS, with most patients experiencing problems at some point in their disease. Bladder problems are a source of significant morbidity, affecting the person's family, social, and work responsibilities. Bladder dysfunction can be classified as failure to store, failure to empty, or both. Patients with impaired storage have a small, spastic bladder with hypercontractility of the detrusor muscle. Symptoms experienced may include urgency, frequency, incontinence, and nocturia. MS patients with advancing disability and impaired bladder function may experience recurrent urinary tract infections.

Constipation

Constipation is the most frequent bowel complaint in patients with MS and is characterized as the infrequent or difficult passage of stools. Constipation may be the result of a neurogenic bowel or of immobility, which leads to slowed bowel activity. In addition, patients who have limited their fluid intake in an attempt to manage bladder symptoms and those with limited access to fluids due to immobility tend to have dry hard stools.

Persons with MS often experience an increase in symptoms of fatigue or weakness when exposed to high temperatures due to weather (especially hot, humid weather), exercise, hot showers or baths, or fever. Overheating, or heat intolerance , may result in blurring of vision (Uhthoff sign), usually in an eye previously affected by ON. These symptoms result from elevation of core body temperature, which further impairs conduction by demyelinated nerves, and they typically reverse rapidly when exposure to high temperature ends.

A thorough physical examination, including neurologic assessment, is critical to determine deficits in MS. All systems must be addressed, including cognition, mood, motor, sensory, and musculoskeletal, as well as the following:

Coordination

Bulbar function

Bulbar involvement typically refers to dysfunction of lower cranial nerves whose nuclei reside in the lower brainstem. Manifestations include dysphagia, which does not occur often in early MS and so may be attributed to a different disorder.

Patients with MS may demonstrate a variety of abnormal physical findings, and these findings may change from examination to examination, depending on the pattern of disease and whether the patient is having an exacerbation or relapse. Findings may include the following:

Localized weakness

Focal sensory disturbances (with persistent decrease of proprioception and vibration)

Hyperreactive reflexes with clonus in the ankles and upgoing toes

Increased tone or stiffness in the extremities, with velocity-dependent passive range of motion

Additional signs may include poor coordination of upper and lower extremity movements, the Lhermitte sign, and wide-based gait with inability to tandem walk.

Secondary problems may include infections, urinary problems, skin breakdown, and musculoskeletal complaints. The skin should be examined in all nonambulatory patients, and the musculoskeletal system must be addressed as appropriate.

Ophthalmologic examination

Optic neuritis, which involves the afferent visual pathway, typically causes acute to subacute unilateral loss of visual acuity, deficits in color and contrast sensitivity, visual field changes, and pain. Onset of ON typically occurs over minutes or hours, rarely days; however, loss of visual acuity may progress over days to weeks.

The loss of visual acuity in patients with ON may range from minimal to profound. In the Optic Neuritis Treatment Trial (ONTT), 35% of patients had visual acuities of 20/40 or better on entry, 30% of patients had visual acuities of between 20/50 and 20/200, and 35% of patients had visual acuities of 20/200 or worse. [ 59 ] Only 3% of patients had no light perception (NLP). Given the rarity of NLP in ON, other potential etiologies for vision loss (eg, inflammatory, infiltrative, neoplastic) need to be considered in such patients.

Most cases of ON are retrobulbar. In these cases, "the patient sees nothing, and the doctor sees nothing" (ie, the fundus is normal). The disc may show mild hyperemia, however. Severe disc edema, marked hemorrhages, or exudate should prompt reconsideration of a diagnosis of demyelinating ON.

Optic disc pallor (involving a sector or being diffuse) often occurs months after anterior or posterior ON. Uncommon fundus findings include the following:

Anterior uveitis

Vascular sheathing

Disc and papillary hemorrhages

Compromise of the central arterial and venous circulations

The appearance of the disc does not correlate directly with the amount of inflammation, changes in visual field, or loss of visual acuity.

Patients with ON typically have loss of visual acuity in the ipsilateral eye. Contralateral and often asymptomatic visual field loss may also be detected. A relative afferent pupillary defect is present in unilateral cases and in bilateral-but-asymmetrical cases but may be absent in bilateral and symmetrical cases.

In the ONTT, nearly 100% of patients whose visual acuities were 20/50 or worse had a defect in their color sensitivity, and in those patients with visual acuities of 20/20 or better, 51–70% had altered color vision. [ 59 ] Although visual acuity typically recovers after ON, patients may continue to complain of residual deficits in color, contrast sensitivity, brightness, and stereovision.

Patients with ON may describe phosphenes (transient flashes of light or black squares) lasting from hours to months. Movement or sound may induce them. Phosphenes may occur before or during an ON event or even several months following recovery.

Visual field changes (loss of visual field is usually in the ipsilateral eye) are common in patients with ON and typically reflect nerve fiber layer defects. The classic visual field defect of ON is the central scotoma, but any nerve fiber–type defect may occur.

Most patients with ON develop retrobulbar pain that becomes worse with extraocular movement. In the ONTT, mild to severe pain was present in 92.2% of patients. [ 59 ] Pain was constant in 7.3% of patients, was constant and worse upon extraocular motility in 51.3% of patients, and was noted only with eye movement in 35.8% of patients.

Other reported visual changes in patients with ON include the following:

Flickering scotomas

Uhthoff phenomenon - Exacerbation of symptoms induced by exercise, a hot meal, or a hot bath

Pulfrich effect - Latencies between the eyes are unequal, resulting in a sense of disorientation in moving traffic

In addition to ON, visual disorders that may occur in MS include diplopia, oscillopsia, and nystagmus (all of which involve the efferent visual pathway).

Patients with MS may present with diplopia from an internuclear ophthalmoplegia (INO). In an INO, an adduction deficit of the ipsilateral eye is present, with horizontal gaze nystagmus in the contralateral abducting eye. The lesion involves the medial longitudinal fasciculus (MLF).

The finding of bilateral INO is strongly suggestive of MS. Diplopia in MS may also result from an ocular motor cranial neuropathy, with a sixth nerve palsy representing the most common manifestation. Third and fourth cranial neuropathies are uncommon in MS. [ 57 ] Combinations of deficits that may occur in MS include the following:

Horizontal or vertical gaze palsies

Wall-eyed bilateral INO (WEBINO) or wall-eyed monocular INO (WEMINO)

Paralytic pontine exotropia

The one-and-a-half syndrome (ie, unimpaired vertical gaze, ipsilateral eye fixed in horizontal gaze, and contralateral eye able to abduct in the horizontal plane only)

Oscillopsia can occur secondary to various types of nystagmus in MS. A new-onset, acquired pendular nystagmus is relatively common, but upbeat, downbeat, convergence-retraction, and other forms of nystagmus may also develop in MS, depending on the location of the demyelinating lesion.

A patient may be rated according to several clinical disability scales, on the basis of findings on the history and physical examination. The most widely accepted of these is the 10-point Kurtzke Expanded Disability Status Scale (EDSS), which was developed originally in 1955 as the Disability Status Scale and has been revised over the years. [ 60 ]

The EDSS assigns a severity score to the patient's clinical status that ranges from 0–10 in increments of 0.5. The scores from grades 0–4 are determined using functional systems (FS) scales that evaluate dysfunction in the following 8 neurologic systems:

Bladder and bowel

EDSS grades are as follows:

0 - Normal neurologic examination (all grade 0 in FS, cerebral grade 1 acceptable)

1.0 - No disability, minimal signs in 1 FS (ie, grade 1 excluding cerebral grade 1)

1.5 - No disability, minimal signs in more than 1 FS (more than 1 grade 1 excluding cerebral grade 1)

2.0 - Minimal disability in 1 FS (1 FS grade 2, others 0 or 1)

2.5 - Minimal disability in 2 FS (2 FS grade 2, others 0 or 1)

3.0 - Moderate disability in 1 FS (1 FS grade 3, others 0 or 1) or mild disability in 3 or 4 FS (3/4 FS grade 2, others 0 or 1) though fully ambulatory

3.5 - Fully ambulatory but with moderate disability in 1 FS (1 grade 3) and 1 or 2 FS grade 2, or 2 FS grade 3, or 5 FS grade 2 (others 0 or 1)

4.0 - Fully ambulatory without aid; self-sufficient; up and about some 12 hours a day despite relatively severe disability, consisting of 1 FS grade 4 (others 0 or 1) or combinations of lesser grades exceeding limits of previous steps; able to walk approximately 500 m without aid or resting

4.5 - Fully ambulatory without aid; up and about much of the day; able to work a full day; may otherwise have some limitation of full activity or require minimal assistance; characterized by relatively severe disability, usually consisting of 1 FS grade 4 (others 0 or 1) or combinations of lesser grades exceeding limits of previous steps; able to walk approximately 300 m without aid or rest

5.0 - Ambulatory without aid or rest for approximately 200 m; disability severe enough to impair full daily activities (eg, to work full day without special provisions; usual FS equivalents are 1 grade 5 alone, others 0 or 1; or combinations of lesser grades usually exceeding specifications for step 4.0)

5.5 - Ambulatory without aid or rest for approximately 100 m; disability severe enough to preclude full daily activities (usual FS equivalents are 1 grade 5 alone; others 0 or 1; or combinations of lesser grades usually exceeding those for step 4.0)

6.0 - Intermittent or unilateral constant assistance (cane, crutch, or brace) required to walk approximately 100 m with or without resting (usual FS equivalents are combinations with more than 2 FS grade 3+)

6.5 - Constant bilateral assistance (canes, crutches, or braces) required to walk approximately 20 m without resting (usual FS equivalents are combinations with more than 2 FS grade 3+)

7.0 - Unable to walk beyond approximately 5 m even with aid; essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about approximately 12 hr/day (usual FS equivalents are combinations with more than 1 FS grade 4+; very rarely, pyramidal grade 5 alone)

7.5 - Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels self but cannot carry on in standard wheelchair a full day; may require motorized wheelchair (usual FS equivalents are combinations with more than 1 FS grade 4+)

8.0 - Essentially restricted to bed or chair or perambulated in wheelchair but may be out of bed itself much of the day, retains many self-care functions; generally has effective use of arms (usual FS equivalents are combinations, generally grade 4+ in several systems)

8.5 - Essentially restricted to bed much of the day; has some effective use of arms; retains some self-care functions (usual FS equivalents are combinations, generally 4+ in several systems)

9.0 - Helpless bedridden patient; can communicate and eat (usual FS equivalents are combinations, mostly grade 4+)

9.5 - Totally helpless bedridden patient; unable to communicate effectively or eat/swallow (usual FS equivalents are combinations, almost all grade 4+)

10.0 - Death due to MS

Advantages of the EDSS are that it is widely used clinically, is easy to administer, and requires no special equipment. Its limitations are as follows:

It is heavily dependent on mobility

It is somewhat subjective in certain areas (eg, bowel and bladder function)

It is insensitive to small changes

It does not present an accurate picture of the patient's cognitive abilities and functional abilities in performing activities of daily living (ADLs)

It is nonlinear in terms of the time spent at various ranges of the scale

Despite its limitations, the EDSS is often used as a standardization measure for clinical trials.

Other useful scales include the Ambulation Index, which is based solely on the ability to walk 25 feet, and the Multiple Sclerosis Functional Composite (MSFC), which includes the Ambulation Index, the 9-hole peg test, and the PASAT attention test. The MSFC is reported as z scores, which have been difficult to translate into clinical significance. In addition, the Scripps Neurologic Rating Scale, developed by Sipe in 1984, has been used by some investigators. This scale has a finer incremental scale than the Kurtzke scale, but it is not widely accepted and does not consider cognitive involvement.

MS is divided into the following categories, principally on the basis of clinical criteria, including the frequency of clinical relapses, time to disease progression, and lesion development on MRI: [ 61 , 2 , 3 , 4 ]

Relapsing-remitting MS (RRMS)

Secondary progressive MS (SPMS)

Primary progressive MS (PPMS)

Progressive-relapsing MS (PRMS)

RRMS is characterized by recurrent attacks in which neurologic deficits appear in different parts of the nervous system and resolve completely or almost completely over a short period of time, leaving little residual deficit. Patients with a relapsing-remitting pattern account for approximately 85% of MS cases (see the images below).

Two subgroups sometimes included in RRMS are clinically isolated syndrome (CIS) and benign MS. CIS consists of a single episode of neurologic symptoms; it is sometimes labeled possible MS. In benign MS, patients have almost complete remission between relapses, and even 15–20 years after diagnosis they have little if any accumulation of physical disability. Making a diagnosis of benign MS too early during the course of the disease is discouraged, since MS can worsen, sometimes drastically, in patients with a history of mild manifestations at onset.

Global clinical deterioration in RRMS has traditionally been attributed to cumulative deficit due to incomplete recovery from repeated occurrences of individual relapses. However, evidence increasingly suggests an ongoing background neurologic deterioration that is independent of relapses.

Although MS was previously thought to be silent between relapses, magnetic resonance imaging (MRI) studies have demonstrated that inflammatory events are occurring in the brain at 10–20 times the predicted rate indicated by the mean relapse rate. This silent disease activity can occur in both white and gray matter and is associated with cerebral atrophy, which in most patients is evident in volumetric studies even at diagnosis.

Natural history data indicate that approximately 50% of patients with RRMS convert to a secondary progressive pattern within 10–15 years after disease onset. This pattern may or may not include relapses, but it is characterized by continued progression over years, with increasing disability. Treatment with disease-modifying agents is thought to slow the progression of RRMS. Unlike RRMS, SPMS without relapses does not seem to be responsive to currently available disease-modifying agents. [ 62 ]

In PPMS, which accounts for approximately 10% of MS cases, function declines steadily without relapses. In PRMS, which accounts for fewer than 5% of patients with MS, occasional relapses are superimposed on progressive disease.

Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol . 2018 Feb. 17 (2):162-173. [QxMD MEDLINE Link] .

Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol . 1983 Mar. 13(3):227-31. [QxMD MEDLINE Link] .

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology . 1996 Apr. 46(4):907-11. [QxMD MEDLINE Link] .

McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol . 2001 Jul. 50(1):121-7. [QxMD MEDLINE Link] .

Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology . 2011 Jan 18. 76(3):294-300. [QxMD MEDLINE Link] . [Full Text] .

Sanford M, Lyseng-Williamson KA. Subcutaneous recombinant interferon-ß-1a (Rebif®): a review of its use in the treatment of relapsing multiple sclerosis. Drugs . 2011 Oct 1. 71(14):1865-91. [QxMD MEDLINE Link] .

Betaseron [package insert]. Montville, NJ: Bayer Healthcare Pharmaceuticals Inc. May 2010.

Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, et al. Pegylated interferon ß-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol . 2014 Jul. 13(7):657-65. [QxMD MEDLINE Link] .

Gilenya [package insert]. East Hanover, NJ: Novartis. September 2010.

Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet . 2018 Mar 31. 391 (10127):1263-1273. [QxMD MEDLINE Link] .

Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol . 2019 Nov. 18 (11):1009-1020. [QxMD MEDLINE Link] .

Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol . 2019 Nov. 18 (11):1021-1033. [QxMD MEDLINE Link] .

Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev . 2011 Oct 5. CD007621. [QxMD MEDLINE Link] .

Tysabri [package insert]. South San Francisco, CA: Biogen Idec Inc. 2011.

Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet . 2012 Nov 24. 380(9856):1819-28. [QxMD MEDLINE Link] .

Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet . 2012 Nov 24. 380(9856):1829-39. [QxMD MEDLINE Link] .

Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, et al. Alemtuzumab more effective than interferon ß-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology . 2012 Apr 3. 78(14):1069-78. [QxMD MEDLINE Link] .

Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med . 2017 Jan 19. 376 (3):221-234. [QxMD MEDLINE Link] .

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med . 2017 Jan 19. 376 (3):209-220. [QxMD MEDLINE Link] .

Steinman L, Fox E, Hartung HP, Alvarez E, Qian P, Wray S, et al. Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med . 2022 Aug 25. 387 (8):704-714. [QxMD MEDLINE Link] .

Copaxone [package insert] [package insert]. North Wales, PA: Teva Pharmaceuticals USA. February 2009.

Novantrone [package insert]. Rockland, MA: Serono, Inc. May 2012.

Aubagio (teriflunomide) [package insert]. Cambridge, MA: Genentech Corp. September, 2012. Available at [Full Text] .

Jeffrey S. FDA approves third oral agent for MS. March 27, 2013. Medscape Medical News. Available at https://www.medscape.com/viewarticle/781450 . Accessed: April 2, 2013.

US Food and Drug Administration. FDA approves new multiple sclerosis treatment: Tecfidera. March 27, 2013. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345528.htm . Accessed: April 2, 2013.

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med . 2012 Sep 20. 367(12):1098-107. [QxMD MEDLINE Link] . [Full Text] .

Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med . 2012 Sep 20. 367(12):1087-97. [QxMD MEDLINE Link] . [Full Text] .

Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Hartung HP, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol . 2014 Mar. 13 (3):257-67. [QxMD MEDLINE Link] .

Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan K, Rieckmann P, Comi G, et al. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study. Mult Scler . 2018 Oct. 24 (12):1594-1604. [QxMD MEDLINE Link] .

Jeffrey S. FDA Approves Interferon Autoinjector for MS. Available at https://www.medscape.com/viewarticle/777065 . Accessed: February 20, 2013.

Windhagen A, Newcombe J, Dangond F, et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med . 1995 Dec 1. 182(6):1985-96. [QxMD MEDLINE Link] . [Full Text] .

Huan J, Culbertson N, Spencer L, et al. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res . 2005 Jul 1. 81(1):45-52. [QxMD MEDLINE Link] .

Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev . 2008 Jun. 223:87-113. [QxMD MEDLINE Link] . [Full Text] .

Minagar A, Jy W, Jimenez JJ, et al. Elevated plasma endothelial microparticles in multiple sclerosis. Neurology . 2001 May 22. 56(10):1319-24. [QxMD MEDLINE Link] .

Trapp BD, Vignos M, Dudman J, Chang A, Fisher E, Staugaitis SM, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol . 2018 Aug 21. [QxMD MEDLINE Link] .

Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med . 2005 Aug 15. 202(4):473-7. [QxMD MEDLINE Link] . [Full Text] .

Nielsen NM, Westergaard T, Rostgaard K, et al. Familial risk of multiple sclerosis: a nationwide cohort study. Am J Epidemiol . 2005 Oct 15. 162(8):774-8. [QxMD MEDLINE Link] .

Nischwitz S, Muller-Myhsok B, Weber F. Risk conferring genes in multiple sclerosis. FEBS Lett . 2011 Dec 1. 585(23):3789-97. [QxMD MEDLINE Link] .

Yeo TW, De Jager PL, Gregory SG, et al. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol . 2007 Mar. 61(3):228-36. [QxMD MEDLINE Link] . [Full Text] .

Salvetti M, Giovannoni G, Aloisi F. Epstein-Barr virus and multiple sclerosis. Curr Opin Neurol . 2009 Jun. 22(3):201-6. [QxMD MEDLINE Link] .

Kampman MT, Brustad M. Vitamin D: a candidate for the environmental effect in multiple sclerosis - observations from Norway. Neuroepidemiology . 2008. 30(3):140-6. [QxMD MEDLINE Link] .

Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA . 2006 Dec 20. 296(23):2832-8. [QxMD MEDLINE Link] .

Islam T, Gauderman WJ, Cozen W, Mack TM. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology . 2007 Jul 24. 69(4):381-8. [QxMD MEDLINE Link] .

Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry . 2009 Apr. 80(4):392-9. [QxMD MEDLINE Link] . [Full Text] .

Zivadinov R, Schirda C, Dwyer MG, et al. Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control study. Int Angiol . 2010 Apr. 29(2):158-75. [QxMD MEDLINE Link] .

Study To Evaluate Treating Chronic Cerebrospinal Venous Insufficiency (CCSVI) in Multiple Sclerosis Patients. Available at https://clinicaltrials.gov/ct2/show/NCT01089686 . Accessed: 10/4/2010.

Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg . 2009 Dec. 50(6):1348-58.e1-3. [QxMD MEDLINE Link] .

Laupacis A, Lillie E, Dueck A, et al. Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. CMAJ . 2011 Nov 8. 183(16):E1203-12. [QxMD MEDLINE Link] . [Full Text] .

Centers for Disease Control and Prevention. FAQs about Hepatitis B Vaccine (Hep B) and Multiple Sclerosis. [Full Text] .

National Multiple Sclerosis Society. Vaccination. Available at https://www.nationalmssociety.org/living-with-multiple-sclerosis/healthy-living/vaccinations/index.aspx . Accessed: November 17, 2011.

Noonan CW, Williamson DM, Henry JP, et al. The prevalence of multiple sclerosis in 3 US communities. Prev Chronic Dis . 2010 Jan. 7(1):A12. [QxMD MEDLINE Link] . [Full Text] .

National Multiple Sclerosis Society. Who Gets MS?. Available at https://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/index.aspx . Accessed: 10/04/2010.

Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci . 2001 Apr. 22(2):117-39. [QxMD MEDLINE Link] .

Aguirre-Cruz L, Flores-Rivera J, De La Cruz-Aguilera DL, Rangel-Lopez E, Corona T. Multiple sclerosis in Caucasians and Latino Americans. Autoimmunity . 2011 Nov. 44(7):571-5. [QxMD MEDLINE Link] .

Matsuda PN, Shumway-Cook A, Bamer AM, Johnson SL, Amtmann D, Kraft GH. Falls in multiple sclerosis. PM R . 2011 Jul. 3(7):624-32; quiz 632. [QxMD MEDLINE Link] .

Roodhooft JM. Ocular problems in early stages of multiple sclerosis. Bull Soc Belge Ophtalmol . 2009. 65-8. [QxMD MEDLINE Link] .

Braley TJ, Chervin RD. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep . 2010 Aug. 33(8):1061-7. [QxMD MEDLINE Link] .

Optic Neuritis Study Group. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group. Arch Ophthalmol . 1991 Dec. 109(12):1673-8. [QxMD MEDLINE Link] .

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology . 1983 Nov. 33(11):1444-52. [QxMD MEDLINE Link] .

Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol . 2005 Dec. 58(6):840-6. [QxMD MEDLINE Link] .

Lonergan R, Kinsella K, Duggan M, Jordan S, Hutchinson M, Tubridy N. Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started?. Mult Scler . 2009 Dec. 15(12):1528-31. [QxMD MEDLINE Link] .

Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med . 1998 Jan 29. 338(5):278-85. [QxMD MEDLINE Link] .

Prashanth LK, Taly AB, Sinha S, Arunodaya GR, Swamy HS. Wilson's disease: diagnostic errors and clinical implications. J Neurol Neurosurg Psychiatry . 2004 Jun. 75(6):907-9. [QxMD MEDLINE Link] . [Full Text] .

Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain . 1997 Nov. 120 ( Pt 11):2059-69. [QxMD MEDLINE Link] .

Bonhomme GR, Waldman AT, Balcer LJ, et al. Pediatric optic neuritis: brain MRI abnormalities and risk of multiple sclerosis. Neurology . 2009 Mar 10. 72(10):881-5. [QxMD MEDLINE Link] .

Filippi M. Enhanced magnetic resonance imaging in multiple sclerosis. Mult Scler . 2000 Oct. 6(5):320-6. [QxMD MEDLINE Link] .

Filippi M, Bozzali M, Horsfield MA, et al. A conventional and magnetization transfer MRI study of the cervical cord in patients with MS. Neurology . 2000 Jan 11. 54(1):207-13. [QxMD MEDLINE Link] .

Filippi M, Yousry TA, Alkadhi H, Stehling M, Horsfield MA, Voltz R. Spinal cord MRI in multiple sclerosis with multicoil arrays: a comparison between fast spin echo and fast FLAIR. J Neurol Neurosurg Psychiatry . 1996 Dec. 61(6):632-5. [QxMD MEDLINE Link] . [Full Text] .

Grossman RI, Barkhof F, Filippi M. Assessment of spinal cord damage in MS using MRI. J Neurol Sci . 2000 Jan 15. 172 Suppl 1:S36-9. [QxMD MEDLINE Link] .

Neema M, Goldberg-Zimring D, Guss ZD, et al. 3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis. Neuroimage . 2009 Jul 1. 46(3):633-41. [QxMD MEDLINE Link] . [Full Text] .

Poonawalla AH, Hou P, Nelson FA, Wolinsky JS, Narayana PA. Cervical Spinal Cord Lesions in Multiple Sclerosis: T1-weighted Inversion-Recovery MR Imaging with Phase-Sensitive Reconstruction. Radiology . 2008 Jan. 246(1):258-264. [QxMD MEDLINE Link] .

Stankiewicz JM, Glanz BI, Healy BC, et al. Brain MRI lesion load at 1.5T and 3T versus clinical status in multiple sclerosis. J Neuroimaging . 2011 Apr. 21(2):e50-6. [QxMD MEDLINE Link] . [Full Text] .

Vaneckova M, Seidl Z, Krasensky J, et al. Patients' stratification and correlation of brain magnetic resonance imaging parameters with disability progression in multiple sclerosis. Eur Neurol . 2009. 61(5):278-84. [QxMD MEDLINE Link] .

Wattjes MP, Barkhof F. High field MRI in the diagnosis of multiple sclerosis: high field-high yield?. Neuroradiology . 2009 May. 51(5):279-92. [QxMD MEDLINE Link] .

[Guideline] Traboulsee, A. et al. Revised Recommendations of the CMSC Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-up of Multiple Sclerosis. Consortim of Multiple Sclerosis Centers. Available at https://c.ymcdn.com/sites/www.mscare.org/resource/collection/9C5F19B9-3489-48B0-A54B-623A1ECEE07B/MRIprotocol2015.pdf . Accessed: August 13, 2015.

Agosta F, Absinta M, Sormani MP, et al. In vivo assessment of cervical cord damage in MS patients: a longitudinal diffusion tensor MRI study. Brain . 2007 Aug. 130:2211-9. [QxMD MEDLINE Link] .

Fazekas F, Offenbacher H, Fuchs S, et al. Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis. Neurology . 1988 Dec. 38(12):1822-5. [QxMD MEDLINE Link] .

Zivadinov R, Tavazzi E, Bergsland N, Hagemeier J, Lin F, Dwyer MG, et al. Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis. Radiology . 2018 Jul 17. 180136. [QxMD MEDLINE Link] .

Colorado RA, Shukla K, Zhou Y, Wolinsky JS, Narayana PA. Multi-task functional MRI in multiple sclerosis patients without clinical disability. Neuroimage . 2012 Jan 2. 59(1):573-81. [QxMD MEDLINE Link] . [Full Text] .

Wang J, Xiao Y, Luo M, Zhang X, Luo H. Statins for multiple sclerosis. Cochrane Database Syst Rev . 2010 Dec 8. CD008386. [QxMD MEDLINE Link] .

Arnold DL, Matthews PM, Francis G, Antel J. Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis: assessment of the load of disease. Magn Reson Med . 1990 Apr. 14(1):154-9. [QxMD MEDLINE Link] .

Henning A, Schar M, Kollias SS, Boesiger P, Dydak U. Quantitative magnetic resonance spectroscopy in the entire human cervical spinal cord and beyond at 3T. Magn Reson Med . 2008 Jun. 59(6):1250-8. [QxMD MEDLINE Link] .

Marliani AF, Clementi V, Albini-Riccioli L, Agati R, Leonardi M. Quantitative proton magnetic resonance spectroscopy of the human cervical spinal cord at 3 Tesla. Magn Reson Med . 2007 Jan. 57(1):160-3. [QxMD MEDLINE Link] .

Berg D, Maurer M, Warmuth-Metz M, Rieckmann P, Becker G. The correlation between ventricular diameter measured by transcranial sonography and clinical disability and cognitive dysfunction in patients with multiple sclerosis. Arch Neurol . 2000 Sep. 57(9):1289-92. [QxMD MEDLINE Link] .

Walter U, Wagner S, Horowski S, Benecke R, Zettl UK. Transcranial brain sonography findings predict disease progression in multiple sclerosis. Neurology . 2009 Sep 29. 73(13):1010-7. [QxMD MEDLINE Link] .

Vazquez-Marrufo M, Gonzalez-Rosa JJ, Vaquero E, et al. Quantitative electroencephalography reveals different physiological profiles between benign and remitting-relapsing multiple sclerosis patients. BMC Neurol . 2008 Nov 24. 8:44. [QxMD MEDLINE Link] . [Full Text] .

Jeffrey S. TOPIC: Teriflunomide Delays Clinically Definite MS. Medscape Medical News. Available at https://www.medscape.com/viewarticle/803177 . Accessed: May 8, 2013.

Rodriguez M, Karnes WE, Bartleson JD, Pineda AA. Plasmapheresis in acute episodes of fulminant CNS inflammatory demyelination. Neurology . 1993 Jun. 43(6):1100-4. [QxMD MEDLINE Link] .

Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, et al. Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis. Eur J Neurol . 2016 Jan 19. [QxMD MEDLINE Link] .

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology . 1993 Apr. 43(4):655-61. [QxMD MEDLINE Link] .

Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol . 1996 Mar. 39(3):285-94. [QxMD MEDLINE Link] .

Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet . 1998 Nov 7. 352(9139):1498-504. [QxMD MEDLINE Link] .

Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology . 2002 Nov 26. 59(10):1496-506. [QxMD MEDLINE Link] .

Schwid SR, Panitch HS. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clin Ther . 2007 Sep. 29(9):2031-48. [QxMD MEDLINE Link] .

Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology . 1995 Jul. 45(7):1268-76. [QxMD MEDLINE Link] .

Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler . 2000 Aug. 6(4):255-66. [QxMD MEDLINE Link] .

Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol . 2013 Jun. 73(6):705-13. [QxMD MEDLINE Link] .

Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med . 2006 Mar 2. 354(9):899-910. [QxMD MEDLINE Link] .

Cadavid D, Jurgensen S, Lee S. Impact of natalizumab on ambulatory improvement in secondary progressive and disabled relapsing-remitting multiple sclerosis. PLoS One . 2013. 8(1):e53297. [QxMD MEDLINE Link] . [Full Text] .

Chun J, Brinkmann V. A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med . 2011 Sep. 12(64):213-28. [QxMD MEDLINE Link] .

Hughes S. Shorter washout reduces MS relapse switching off natalizumab. Medscape Medical News . October 7, 2013. [Full Text] .

Hughes S. Shorter Washout Better for Natalizumab-to-Fingolimod Switch. Medscape Medical News. Available at https://www.medscape.com/viewarticle/822567 . Accessed: April 1, 2014.

Cohen M, Maillart E, Tourbah A, De Sèze J, Vukusic S, Brassat D, et al. Switching From Natalizumab to Fingolimod in Multiple Sclerosis: A French Prospective Study. JAMA Neurol . 2014 Feb 24. [QxMD MEDLINE Link] .

Weber MS, Kappos L, Hauser SL, et al. The Patient Impact of 10 Years of Ocrelizumab Treatment in Multiple Sclerosis: Long-Term Data from the Phase III OPERA and ORATORIO Studies. Presented at the 9th Joint European Committee for Treatment and Research in MS - Americas Committee for Treatment and Research in MS Meeting in Milan; October 11-13, 2023. ECTRIMS-ACTRIMS Poster #P302. Available at https://medically.gene.com/global/en/unrestricted/neuroscience/ECTRIMS-2023/ectrims-2023-poster-weber-the-patient-impact-of-10-year.html .

O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med . 2011 Oct 6. 365(14):1293-303. [QxMD MEDLINE Link] .

Semedo, D. Aubagio (Teriflunomide) Slows Brain Atrophy in Patients with Relapsing Multiple Sclerosis. Multiple Sclerosis News Today. Available at https://multiplesclerosisnewstoday.com/2015/10/08/aubagio-teriflunomide-slows-brain-atrophy-patients-relapsing-multiple-sclerosis/ . October 8, 2015; Accessed: October 14, 2015.

A study comparing the effectiveness and safety of teriflunomide and interferon beta-1a in patients with relapsing multiple sclerosis (TENERE). 4th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC)/Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). June 2, 2012 (ClinicalTrials.gov identifier: NCT00883337).

A multicenter double-blind parallel-group placebo-controlled study of the efficacy and safety of teriflunomide in patients with relapsing multiple sclerosis who are treated with interferon-beta. (ClinicalTrials.gov identifier: NCT01252355).

Fox EJ, Sullivan HC, Gazda SK, et al. A single-arm, open-label study of alemtuzumab in treatment-refractory patients with multiple sclerosis. Eur J Neurol . 2012 Feb. 19(2):307-11. [QxMD MEDLINE Link] .

Anderson P. Alemtuzumab Benefits Hard-to-Treat MS Patients. Medscape Medical News. Available at https://www.medscape.com/viewarticle/805173 . Accessed: June 12, 2013.

Brauser, D. Ocrelizumab Linked to Improved Visual Outcomes in Relapsing MS. Medscape Medical News. Available at https://www.medscape.com/viewarticle/887722 . October 27, 2017; Accessed: October 27, 2017.

Kesimpta [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. August 2020. Available at [Full Text] .

Harrison DM, Gladstone DE, Hammond E, et al. Treatment of relapsing-remitting multiple sclerosis with high-dose cyclophosphamide induction followed by glatiramer acetate maintenance. Mult Scler . 2012 Feb. 18(2):202-9. [QxMD MEDLINE Link] .

Rojas JI, Romano M, Ciapponi A, Patrucco L, Cristiano E. Interferon beta for primary progressive multiple sclerosis. Cochrane Database Syst Rev . 2009 Jan 21. CD006643. [QxMD MEDLINE Link] .

Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol . 1995 Jan. 37(1):30-40. [QxMD MEDLINE Link] .

Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med . 2010 Feb 4. 362(5):387-401. [QxMD MEDLINE Link] .

Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med . 2010 Feb 4. 362(5):402-15. [QxMD MEDLINE Link] .

Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol . 2011 Jun. 10(6):520-9. [QxMD MEDLINE Link] .

Killestein J, Rudick RA, Polman CH. Oral treatment for multiple sclerosis. Lancet Neurol . 2011 Nov. 10(11):1026-34. [QxMD MEDLINE Link] .

Multiple Sclerosis Association of America (MSAA). MS Research Update. Available at https://mymsaa.org/PDFs/MSAA_Research_Update_2013.pdf . Accessed: March 27, 2013.

Anderson P. Myelin peptide skin patch safe, reduces MS activity. Medscape Medical News . July 29, 2013. [Full Text] .

Walczak A, Siger M, Ciach A, Szczepanik M, Selmaj K. Transdermal application of myelin peptides in multiple sclerosis treatment. JAMA Neurol . 2013 Jul 1. 1-6. [QxMD MEDLINE Link] .

Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol . 2017 Feb 20. [QxMD MEDLINE Link] .

Herman AO. "Unprecedented" Findings for Stem Cell Therapy in MS. NEJM Journal Watch. Available at https://www.jwatch.org/fw113985/2018/03/21/unprecedented-findings-stem-cell-therapy-ms . March 21, 2018; Accessed: March 28, 2018.

Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med . 1998 Jul 30. 339(5):285-91. [QxMD MEDLINE Link] .

Tsui A, Lee MA. Multiple sclerosis and pregnancy. Curr Opin Obstet Gynecol . 2011 Dec. 23(6):435-9. [QxMD MEDLINE Link] .

Krupp LB, Christodoulou C, Melville P, et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology . 2011 Apr 26. 76(17):1500-7. [QxMD MEDLINE Link] . [Full Text] .

Attarian HP, Brown KM, Duntley SP, Carter JD, Cross AH. The relationship of sleep disturbances and fatigue in multiple sclerosis. Arch Neurol . 2004 Apr. 61(4):525-8. [QxMD MEDLINE Link] .

MacAllister WS, Krupp LB. Multiple sclerosis-related fatigue. Phys Med Rehabil Clin N Am . 2005 May. 16(2):483-502. [QxMD MEDLINE Link] .

Solaro C, Uccelli MM. Management of pain in multiple sclerosis: a pharmacological approach. Nat Rev Neurol . 2011 Aug 16. 7(9):519-27. [QxMD MEDLINE Link] .

Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet . 2009 Feb 28. 373(9665):732-8. [QxMD MEDLINE Link] .

Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics, Inc. 2010.

Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev . 2009 Jan 21. CD004193. [QxMD MEDLINE Link] .

US Food and Drug Administration. FDA approves Botox to treat specific form of urinary incontinence. August 25, 2011. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269509.htm . Accessed: November 28, 2011.

Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med . 1992 Feb 27. 326(9):581-8. [QxMD MEDLINE Link] .

Myhr KM. Vitamin D treatment in multiple sclerosis. J Neurol Sci . 2009 Nov 15. 286(1-2):104-8. [QxMD MEDLINE Link] .

Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. November 30, 2010. Available at https://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx . Accessed: December 29, 2011.

Summerday NM, Brown SJ, Allington DR, Rivey MP. Vitamin D and multiple sclerosis: review of a possible association. J Pharm Pract . 2012 Feb. 25(1):75-84. [QxMD MEDLINE Link] .

Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev . 2010 Dec 8. CD008422. [QxMD MEDLINE Link] .

DeStefano F, Verstraeten T, Jackson LA, et al. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol . 2003 Apr. 60(4):504-9. [QxMD MEDLINE Link] .

Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med . 2001 Feb 1. 344(5):319-26. [QxMD MEDLINE Link] .

Farez MF, Correale J. Yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis. Arch Neurol . 2011 Oct. 68(10):1267-71. [QxMD MEDLINE Link] .

Rovira À, Wattjes MP, Tintoré M, Tur C, Yousry TA, Sormani MP, et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process. Nat Rev Neurol . 2015 Aug. 11 (8):471-82. [QxMD MEDLINE Link] .

[Guideline] Filippi M, Rocca A, Arnold DL, Bakshi R, Barkhof F, De Stefano N, et al. Use of Imaging in Multiple Sclerosis. Gilhus NE, Barnes MP, Brainin M. European Handbook of Neurological Management . 2nd ed. Oxford (UK): Wiley-Blackwell; 2011. Vol 1: 35-51.

Wattjes MP, Rovira À, Miller D, Yousry TA, Sormani MP, de Stefano MP, et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis--establishing disease prognosis and monitoring patients. Nat Rev Neurol . 2015 Oct. 11 (10):597-606. [QxMD MEDLINE Link] .

[Guideline] Multiple Sclerosis Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence: A Consensus Paper. The Consortium of Multiple Sclerosis Centers. Available at https://www.mscare.org/?page=dmt . July 2014;

Hughes, S. European MS Treatment Guidelines Released. Medscape Medical News. Available at https://www.medscape.com/viewarticle/887730 . October 27, 2017; Accessed: October 27, 2017.

Jeffrey S. New AAN Guidelines Advocate Early MS Treatment. Medscape Medical News. Available at https://www.medscape.com/viewarticle/895598 . April 23, 2018; Accessed: April 23, 2018.

Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology . 2018 Apr 24. 90 (17):777-788. [QxMD MEDLINE Link] .

Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, et al. Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology . 2018 Apr 24. 90 (17):789-800. [QxMD MEDLINE Link] .

[Guideline] Farez MF, Correale J, Armstrong MJ, Rae-Grant A, Gloss D, Donley D, et al. Practice guideline update summary: Vaccine-preventable infections and immunization in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology . 2019 Sep 24. 93 (13):584-594. [QxMD MEDLINE Link] .

Azasan [package insert] [package insert]. Wilmington, NC: Salix pharmaceuticals Inc. August 2011.

Cyclophosphamide [package insert]. Deerfield, IL: Baxter Healthcare Corporation. June 2004.

Brooks M. New AAN guideline on psychiatric disorders in MS. Medscape Medical News . January 3, 2014. [Full Text] .

Hughes S. New Test to Identify PML Risk With Natalizumab in MS. Medscape Medical News. Available at https://www.medscape.com/viewarticle/832504 . Accessed: October 7, 2014.

Jeffrey S. No Cognitive Disadvantage in Pediatric- vs Adult-Onset MS. Medscape Medical News. Available at https://www.medscape.com/viewarticle/831536 . Accessed: September 15, 2014.

Keller DM. Fingolimod Reduces Annual Brain Volume Loss in MS. Medscape Medical News . Jun 6 2014. [Full Text] .

Minden SL, Feinstein A, Kalb RC, Miller D, Mohr DC, Patten SB, et al. Evidence-based guideline: Assessment and management of psychiatric disorders in individuals with MS: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology . 2013 Dec 27. [QxMD MEDLINE Link] .

• The mechanism of demyelination in multiple sclerosis may be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. Antibodies against myelin also may be generated in the periphery or intrathecally. Ongoing inflammation leads to epitope spread and recruitment of other inflammatory cells (ie, bystander activation). The T cell receptor recognizes antigen in the context of human leukocyte antigen molecule presentation and also requires a second event (ie, co-stimulatory signal via the B7-CD28 pathway, not shown) for T cell activation to occur. Activated microglia may release free radicals, nitric oxide, and proteases that may contribute to tissue damage.
• MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. MRI reveals multiple lesions with high T2 signal intensity and one large white matter lesion. These demyelinating lesions may sometimes mimic brain tumors because of the associated edema and inflammation.
• MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. This MRI, performed 3 months after the one in the related image, shows a dramatic decrease in the size of lesions.
• Inflammation in multiple sclerosis. Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages.
• Demyelination in multiple sclerosis. Luxol fast blue (LFB)/periodic acid-Schiff (PAS) stain confers an intense blue to myelin. Loss of myelin is demonstrated in this chronic plaque. Note that absence of inflammation may be demonstrated at the edge of chronic lesions.
• Gadolinium-enhanced, T1-weighted image showing enhancement of the left optic nerve (arrow).
• Corresponding axial images of the spinal cord showing enhancing plaque (arrow). The combination of optic neuritis and longitudinally extensive spinal cord lesions constitutes Devic neuromyelitis optica.
• Table 1. 2017 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis [ 1 ]

Contributor Information and Disclosures

Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology Disclosure: Nothing to disclose.

Fernando Dangond, MD, FAAN Head of US Medical Affairs, Neurodegenerative Diseases, EMD Serono, Inc Fernando Dangond, MD, FAAN is a member of the following medical societies: American Academy of Neurology , American Medical Association Disclosure: Received salary from EMD Serono, Inc. for employment.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Received salary from Medscape for employment. for: Medscape.

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology , American Association of Neuromuscular and Electrodiagnostic Medicine , American Clinical Neurophysiology Society , American Medical Association Disclosure: Nothing to disclose.

Martin K Childers, DO, PhD Professor, Department of Neurology, Wake Forest University School of Medicine; Professor, Rehabilitation Program, Institute for Regenerative Medicine, Wake Forest Baptist Medical Center

Martin K Childers, DO, PhD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation , American Congress of Rehabilitation Medicine , American Osteopathic Association , Christian Medical & Dental Society , and Federation of American Societies for Experimental Biology

Disclosure: Allergan pharma Consulting fee Consulting

Edmond A Hooker II, MD, DrPH, FAAEM Assistant Professor, Department of Emergency Medicine, University of Cincinnati College of Medicine

Edmond A Hooker II, MD, DrPH, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine , American Public Health Association , Society for Academic Emergency Medicine , and Southern Medical Association

Disclosure: Nothing to disclose.

J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine , American Academy of Neurology , American College of Emergency Physicians , and Society for Academic Emergency Medicine

Marjorie Lazoff, MD Editor-in-Chief, Medical Computing Review

Marjorie Lazoff, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Emergency Physicians , American Medical Informatics Association , and Society for Academic Emergency Medicine

Consuelo T Lorenzo, MD Physiatrist, Department of Physical Medicine and Rehabilitation, Alegent Health, Immanuel Rehabilitation Center

Consuelo T Lorenzo, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation

William J Nowack, MD Associate Professor, Epilepsy Center, Department of Neurology, University of Kansas Medical Center

William J Nowack, MD is a member of the following medical societies: American Academy of Neurology , American Clinical Neurophysiology Society , American Epilepsy Society , American Medical Electroencephalographic Association, American Medical Informatics Association , and Biomedical Engineering Society

Richard Salcido, MD Chairman, Erdman Professor of Rehabilitation, Department of Physical Medicine and Rehabilitation, University of Pennsylvania School of Medicine

Richard Salcido, MD is a member of the following medical societies: American Academy of Pain Medicine , American Academy of Physical Medicine and Rehabilitation , American College of Physician Executives , American Medical Association , and American Paraplegia Society

Daniel D Scott, MD, MA Associate Professor, Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine; Attending Physician, Department of Physical Medicine and Rehabilitation, Denver Veterans Affairs Medical Center, Eastern Colorado Health Care System

Daniel D Scott, MD, MA is a member of the following medical societies: Alpha Omega Alpha , American Academy of Physical Medicine and Rehabilitation , American Association of Neuromuscular and Electrodiagnostic Medicine , American Paraplegia Society , Association of Academic Physiatrists , National Multiple Sclerosis Society , and Physiatric Association of Spine, Sports and Occupational Rehabilitation

Fu-Dong Shi, MD, PhD Director of Neuroimmunology Laboratory, Barrow Neurological Institute, St Joseph's Hospital and Medical Center

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology , American Neurological Association , American Paraplegia Society , Consortium of Multiple Sclerosis Centers , and National Multiple Sclerosis Society

Timothy Vollmer, MD Consulting Staff, Department of Emergency Medicine, Geisinger Medical Center

Sandra F Williamson, MS, ANP-C, CRRN Clinic Coordinator, Department of Rehabilitation Medicine, Denver Veterans Affairs Medical Center

Sandra F Williamson, MS, ANP-C, CRRN is a member of the following medical societies: Phi Beta Kappa , Phi Kappa Phi, and Sigma Theta Tau International

What would you like to print?

• Print this section
• Print the entire contents of
• Print the entire contents of article

• Multiple Sclerosis
• Pediatric Multiple Sclerosis
• Neuro-Ophthalmologic Manifestations of Multiple Sclerosis
• Multiple Sclerosis Spine Imaging
• Brain Imaging in Multiple Sclerosis
• Biomarker Testing in Multiple Sclerosis
• Trending Clinical Topic: Multiple Sclerosis
• Migraine a Forerunner of Multiple Sclerosis?
• Frexalimab Promising for Relapsing Multiple Sclerosis
• US FDA Declines to Approve Viatris's Injection for Multiple Sclerosis

• Drug Interaction Checker
• Pill Identifier
• Calculators

Multiple Sclerosis

What is multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disorder. It is an autoimmune disorder, meaning that in MS the immune system, which normally protects us from viruses, bacteria, and other threats mistakenly attacks healthy cells. MS symptoms usually begin in young adults, between the ages of 20 and 40.  

MS affects people differently. A small number of people with MS will have mild symptoms with little disability, whereas others will experience worsening symptoms that will lead to increased disability over time. Most people with MS have short periods of symptoms that resolve fully or partially after they appear. These periods are followed by long stretches without noticeable symptoms. Most people with MS have a normal life expectancy. 

Myelin and the immune system

In MS, the immune system attacks myelin in the central nervous system, which is made up of the brain, the spinal cord, and the optic nerves, which connect the eyes to the brain. Myelin is a mixture of protein and fatty acids that makes up the protective cover (known as the myelin sheath) that coats nerve fibers (axons). Myelin is what gives the brain’s white matter its whitish appearance. 

In addition to causing damage to the myelin sheath, MS also damages the nerve cell bodies, which are found in the brain's gray matter, as well as the axons themselves. As the disease progresses, the outermost layer of the brain, called the cerebral cortex, shrinks. This process is known as cortical atrophy. The way that cortical atrophy happens in MS may connect it with some neurodegenerative disorders.  

Sclerosis is a medical term for the distinctive areas of scar-like tissue that result from the attack on myelin by the immune system. These areas are visible on an MRI (magnetic resonance imaging). The patches of scar-like tissue (also called plaques or lesions) can be as small as the head of a pin or as large as a golf ball.

The symptoms of MS depend on the severity of the attacks as well as the location and size of the plaques.

Types of multiple sclerosis

The course of MS is different for each person, which makes it difficult to predict how an individual will do with the disease. While many different courses or progressions of MS have been used over the years, these are changing as the scientific and medical community betters understand typical disease progressions. 

Currently, the five courses used to describe MS are:

• Clinically isolated syndrome —Symptoms come from a single attack (also called exacerbation or relapse) followed by complete or near-complete recovery. Magnetic resonance imaging (MRI) and other tests, such as a spinal tap or electrical tests of vision, may show “silent” damage in other places in the central nervous system. If this damage is identified, it could allow a full diagnosis of MS even after a single attack.
• Relapsing-remitting MS —Symptoms come in the form of recurrent attacks with total or partial recovery. The periods of disease inactivity between MS attacks are referred to as remission. Weeks, months, or even years may pass before another attack occurs, followed again by a period of inactivity. Treatment with disease-modifying therapies can reduce the frequency of attacks or eliminate them entirely. Most people with MS are initially diagnosed with this form.
• Secondary-progressive MS —Relapsing-remitting MS can gradually evolve into secondary-progressive MS. Attacks become less and less common but may still occur, and people start to develop gradual and steady symptoms with deterioration in their functioning over time. Secondary-progressive MS with attacks is called “active,” whereas secondary-progressive MS without attacks is called “non-relapsing.” Disease-modifying therapy for relapsing-remitting MS can delay and sometimes prevent secondary progressive MS, but the transition can occur even with treatment.
• Primary-progressive MS —This course of MS is less common and is characterized by progressively worsening symptoms from the beginning, with no noticeable acute attacks, although there may be temporary or minor worsening of, or relief from, symptoms.
• Radiologically isolated syndrome —The rarest course of MS in which a person has abnormal MRI results that look like MS, but doesn’t have MS symptoms. However, symptoms (attacks or progression) may occur in the future.

Symptoms of MS

Early MS symptoms often include:

• Vision problems, such double vision or optic neuritis (inflammation of the optic nerve), which causes pain with eye movement and vision loss
• Muscle weakness, often in the arms and legs, and muscle stiffness accompanied by painful muscle spasms
• Tingling, numbness, or pain in the arms, legs, trunk, or face
• Clumsiness, especially difficulty staying balanced when walking
• Bladder control problems
• Intermittent or constant dizziness

MS may also cause other symptoms, such as:

• Mental or physical fatigue
• Mood changes such as depression or difficulty with emotional expression or control
• Cognitive changes, including problems concentrating, multitasking, thinking, or learning, or difficulties with memory or judgment

Muscle weakness, stiffness, and spasms may be severe enough to affect walking or standing. In some cases, MS leads to partial or complete paralysis. The use of a wheelchair is not uncommon, particularly in individuals who are untreated or have advanced disease. Many people with MS find that their symptoms are worse when they have a fever or are exposed to heat or following common infections.

Pain is rarely the first sign of MS, but pain often occurs with optic neuritis and  trigeminal neuralgia . Painful limb spasms and sharp pain shooting down the legs or around the abdomen can also be symptoms of MS.

Who is more likely to get multiple sclerosis?

Women are more likely to get MS than men. People of all races and ethnicities can get MS, but it is most common in White people.  

Having a parent or sibling with MS also increases the likelihood of a person getting MS, although MS itself is not an inherited disorder. Research suggests that hundreds of genes and gene variants combine to create vulnerability to MS. Some of these genes have been identified, and most are associated with functions of the immune system. Some the known genes are similar to those that have been identified in people with other autoimmune diseases, such as inflammatory bowel disease, celiac disease, type 1 diabetes, rheumatoid arthritis, or lupus.

Several viruses have been found in people with MS, but the virus most consistently linked to the development of MS is the Epstein-Barr virus (EBV) which causes infectious mononucleosis. Almost everyone has been infected by EBV at some point in their lives. Only about 5% of the population has not been infected, and these individuals are at a lower risk for developing MS than those who have been infected. People who got EBV during childhood are at a lower risk of getting MS than people who infected with EBV in adolescence or adulthood. However, the vast majority of people who get infected with EBV are not going to develop MS.

Research indicates that people who spend more time in the sun, and those with relatively higher levels of vitamin D, are less likely to develop MS than those who do not. Additionally, people with MS who spend significant time in the sun and/or have higher vitamin D levels have a less severe course of disease and fewer relapses. Bright sunlight helps human skin produce vitamin D. Researchers believe that vitamin D may help regulate the immune system in ways that reduce the risk of MS or autoimmune disorders in general. People from regions near the equator, where there is a great deal of bright sunlight, generally have a much lower risk of MS than people from temperate areas such as the U.S. and Canada, where sunshine is highly variable throughout the year.

Studies have found that people who smoke are more likely to develop MS and have a more aggressive disease course. They also tend to have more brain lesions and brain shrinkage than non-smokers. 

How is multiple sclerosis diagnosed and treated?

Diagnosing ms.

There is no single test used to diagnose MS. Doctors use different tests to rule out or confirm the diagnosis. In addition to a complete medical history, physical examination, and a  detailed neurological examination , a doctor may recommend MRI scans of the brain and spinal cord to look for the characteristic lesions of MS. A special dye or contrast agent may be injected into a vein to enhance the brain images.

In addition, a doctor may recommend:

• Lumbar puncture (sometimes called a spinal tap) to obtain a sample of cerebrospinal fluid and examine it for proteins and inflammatory cells associated with the disease. This can also test for diseases that may look like MS.
• Evoked potential tests, which use electrodes placed on the skin and painless electric signals to measure how quickly and accurately the nervous system responds to stimulation.
• MRI of the optic nerves, optic coherence tomography (OCT), or visual evoked potentials to detect optic nerve lesions

In most cases, doctors can diagnose MS by assessing symptoms and identifying characteristic MS signs on an MRI. 

Treating MS

There is no cure for MS, but there are treatments that can reduce the number and severity of relapses and delay the long-term progression of the disease.

Corticosteroids, such as methylprednisolone, are prescribed over the course of three to five days and are usually injected into a vein. Corticosteroids quickly and potently suppress the immune system and reduce inflammation. They may be followed by a tapered dose of oral corticosteroids. Clinical trials have shown that these drugs hasten recovery from MS attacks but do not alter the long-term outcome of the disease.

Disease-modifying treatments

Current therapies approved by the U.S. Food and Drug Administration (FDA) for MS are designed to modulate or suppress the inflammatory reactions of the disease. They are most effective for relapsing-remitting MS or secondary-progressive MS with residual attacks. They are also effective in some cases of radiologically isolated syndrome to prevent development of clinical MS. Radiologically isolated syndrome is a condition in which a person has abnormal MRI results that look like MS, but doesn’t have MS symptoms.

Infusion treatments include:

• Natalizumab (brand name: Tysabri®) works by preventing cells of the immune system from entering the central nervous system. It is very effective but is associated with an increased risk of a serious and potentially fatal viral infection of the brain called progressive multifocal leukoencephalopathy (PML). Regular blood tests to test for antibodies to the virus that causes PML can help address this risk. 
• Ocrelizumab (brand name: Ocrevus®) treats adults with relapsing-remitting, or active secondary-progressive, or primary-progressive MS. It is currently the only FDA-approved disease-modifying therapy for primary-progressive MS. The drug targets circulating immune cells (“B cells”) that have many functions, including giving rise to the cells that produce antibodies. Side effects include infusion-related reactions and increased risk of infections. Ocrelizumab may slightly increase the risk of cancer and reduce the effectiveness of some vaccines.
• Alemtuzumab targets proteins on the surface of immune cells. Because this drug increases the risk of autoimmune disorders, it is usually used in those who have not responded sufficiently to two or more MS therapies.

Oral treatments include:

• Fingolimod (brand name: Gilenya®) reduces the MS relapse rate in adults and children. It is the first FDA-approved drug to treat MS in adolescents and children age 10 and older. The drug prevents white blood cells called lymphocytes from leaving the lymph nodes and entering the blood, brain, and spinal cord. Fingolimod may result in a slow heart rate and eye problems when first taken. Fingolimod can also increase the risk of infections, such as herpes virus infections, or in rare cases be associated with PML. Siponimod has a similar mechanism of action to fingolimod. Siponimod has been approved by the FDA to treat secondary-progressive MS.
• Dimethyl fumarate (brand name: Tecfidera®) is used to treat relapsing forms of MS. Its exact mechanism of action is not currently known. Side effects of dimethyl fumarate are flushing (temporary reddening of the skin), diarrhea, nausea, and lowered white blood cell count. Diroximel fumarate (brand name: Vumerity®) is a drug similar to dimethyl fumarate, but with fewer gastrointestinal side effects. 
• Teriflunomide (brand name: Aubagio®) reduces the rate of growth in the number of activated immune cells. Teriflunomide side effects can include nausea, diarrhea, liver damage, and hair loss.
• Cladribine (brand names: Mavenclad® and Leustatin® DSC) targets certain types of white blood cells that drive immune attacks in MS. The drug may increase the person’s risk of developing cancer.

Injectable medications include:

• Beta interferon drugs were once the most commonly used treatments for MS but are much more rarely used now. Potential side effects of these drugs include flu-like symptoms (which usually fade with continued therapy), depression, or elevation of liver enzymes. 
• Glatiramer acetate can also reduce the frequency of attacks in relapsing-remitting MS.  

Clinical trials have shown that cladribine, diroximel fumarate, and dimethyl fumarate decrease the number of relapses, delay the progress of physical disability, and slow the development of brain lesions.

Managing MS symptoms

MS causes a variety of symptoms that can interfere with daily activities. Fortunately, many of the symptoms of MS can usually be treated or managed. Neurologists with advanced training in the treatment of MS can prescribe specific medications to treat these problems.

Eye and vision problems

Eye and vision problems are common in people with MS but rarely result in permanent blindness. Symptoms may include blurred or grayed vision, temporary blindness in one eye, loss of normal color vision, issues with depth perception, or loss of vision in parts of the visual field. Uncontrolled horizontal or vertical eye movements (nystagmus), “jumping vision" (opsoclonus), and double vision (diplopia) are common in people with MS. Vision therapy exercises, special eyeglasses, and resting the eyes may be helpful.

Muscle and mobility problems

Muscle weakness and spasticity are common in MS. It is very important that people with MS stay physically active because physical inactivity can contribute to worsening stiffness, weakness, pain, fatigue, and other symptoms. Mild spasticity can be managed by stretching and exercising muscles through water therapy, yoga, or physical therapy. Medications are available to help reduce spasticity. 

Tremor , or uncontrollable shaking, develops in some people with MS. Assistive devices are sometimes helpful for people with tremor. Deep brain stimulation and medications may also be useful.

Problems with walking and balance occur in many people with MS. The most common walking problem is ataxia —unsteady, uncoordinated movements—due to damage to the areas of the brain that coordinate muscle balance. People with severe ataxia generally benefit from the use of a cane, walker, or other assistive device. Physical therapy also can reduce walking problems. Occupational therapy can help people learn how to walk using an assistive device or in a way that saves physical energy. The FDA has approved the drug dalfampridine to improve walking speed in people with MS. 

Fatigue is a common symptom of MS and may be both physical (tiredness in the arms or legs) and cognitive (slowed processing speed or mental exhaustion). Daily physical activity programs of mild to moderate intensity can significantly reduce fatigue, although people should avoid excessive physical activity and minimize exposure to high temperatures. Physical therapy (PT) and occupational therapy (OT) can help manage fatigue. PT provides personalized treatments, while OT teaches ways to use energy wisely. They also help find the right changes in the person’s environment. Stress management programs or relaxation training may help some people.

Bladder control and constipation issues

Problems with bladder control and constipation may include problems with frequency of urination, urgency, or the loss of bladder control. A small number of individuals retain large amounts of urine. Medical treatments are available for bladder-related problems. Constipation is also common and can be treated with a high-fiber diet, laxatives, and stool softeners.

Sexual dysfunction

Sexual dysfunction can result from damage to nerves running through the spinal cord. Sexual problems may also stem from MS symptoms, including fatigue, muscle symptoms, and psychological factors. Some of these problems can be corrected with medications. Counseling (therapy) may be helpful.

Mental and emotional problems

Clinical depression is frequent among people with MS. MS may cause depression as part of the disease process and chemical imbalance in the brain. Depression can intensify symptoms of fatigue, pain, and sexual dysfunction. It is most often treated with cognitive behavioral therapy and selective serotonin reuptake inhibitor (SSRI) antidepressant medications, which are less likely than other antidepressant medications to cause fatigue.

Inappropriate and involuntary expressions of laughter, crying, or anger—called pseudobulbar symptoms—are sometimes associated with MS, although this is not as common as in some other neurological disorders. These expressions are often incongruent with mood; for example, people with MS may cry when they are actually happy or laugh when they are not especially happy. The combination treatment of the drugs dextromethorphan and quinidine can treat pseudobulbar affect, as can other drugs such as amitriptyline or citalopram.

Cognitive problems

Cognitive impairment—a decline in the ability to think, learn, and remember—affects up to 75% of people with MS. These cognitive changes may appear at the same time as the physical symptoms, or they may develop gradually over time. Sometimes, cognitive impairment in people with MS is caused by depression. It is important to rule out depression, first. If cognitive impairment is caused by depression, it can be treated. Drugs such as donepezil may be helpful in some cases.

Complementary approaches

Some people with MS report improvement in their symptoms from complementary or alternative approaches such as acupuncture, aromatherapy, ayurvedic medicine, touch and energy therapies, physical movement disciplines such as yoga and tai chi, herbal supplements, and biofeedback. Learn more about research on complementary health approaches for MS . 

Because of the risk of interactions between alternative and conventional therapies, people with MS should discuss all the therapies they are using with their doctor, especially herbal supplements. Herbal supplements have biologically active ingredients that could have harmful effects on their own or interact harmfully with other medications.

What are the latest updates on multiple sclerosis?

NINDS , a component of the National Institutes of Health ( NIH ), is the leading federal funder of research on the brain and nervous system, including research on MS. Other components of NIH are funding research on topics relevant to MS, including cognitive impairment, rehabilitation strategies, and telehealth. 

Although researchers have not been able to identify the exact cause(s) of MS, there has been excellent progress in other areas of MS research—especially in the development of new treatments to prevent exacerbations of the disease. New discoveries are improving and expanding MS treatment options and helping to reduce MS-related disability.

NINDS-supported research projects cover a wide range of topics such as co-occurring conditions, mechanisms of cognitive impairment, blood-brain barrier breakdown in MS, the role of sleep and circadian rhythms, rehabilitation strategies, and telehealth. Other topics include:

• Biomarkers to accurately diagnose MS and monitor disease progression and treatment response, including blood and imaging tests 
• Genetic and environmental risk factors for MS
• The role of the gut microbiome and diet in MS
• Mechanisms that underlie gender differences in the incidence and presentation of MS
• MS risk factors and disease course in African American and Hispanic populations
• Social determinants of health that influence disease outcome and disparities in care
• The role of the immune system in MS, including its function in the central nervous system (CNS)
• The role and crosstalk of various cell types in the CNS with relation to MS
• Basic functions of myelination, demyelination, and axonal degeneration, and strategies to overcome axonal and myelin loss

Genetic research funded by  NINDS  is exploring the roles of "susceptibility genes"—genes that are associated with an increased risk for MS. Several candidate genes have been identified and researchers are studying their function in the nervous system to discover how they may lead to the development of MS.

Other studies aim to develop better neuroimaging tools, such as more powerful MRI methods, to diagnose MS, track disease progression, and assess treatments. Investigators are also using MRI to study the natural history of MS and to help define the mechanism of action and cause of side effects of disease modifying therapies.

Intramural research programs on MS

NINDS  and other  NIH  Institutes have a very active MS intramural research program among scientists working at NIH (known as “intramural” research). Together, they have:

• Established and continue to develop MRI as a critical tool for examining the natural course of the disease in humans, monitoring disease progression, assessing effects of treatments in clinical trials, and understanding MS biology.
• Played an important role in understanding why some people develop a rare and potentially fatal brain infection (called progressive multifocal leukoencephalopathy) when taking potent MS drugs. Research teams are they are now developing new treatments for this infection.
• Unraveled mechanisms by which viruses contribute to the development of MS.
• Conducted next-generation treatment trials targeting specific mechanisms of disease progression, using advanced MRI and fluid biomarkers as outcome measures.
• Developed the first MRI method to visualize the lymph vessels surrounding the brain, which play a critical role in neuro-immune communication.

Translational research

NIH  supports translational studies to develop therapies that will stop or reverse the course of the disease, focusing on pathways that modify immune system function in the periphery and CNS, repair damaged myelin, or protect neurons from damage. Researchers are also developing improved disease models of MS in animals to more accurately predict drug response in human disease. 

Progressive MS therapies

While scientists continue to study the biology and mechanisms of relapsing-remitting MS, increased efforts are being placed to stop and arrest or prevent the steady decline in function that occurs in progressive MS. In the MS-SPRINT trial, the  NINDS  NeuroNEXT clinical trials network tested the drug ibudilast as a potential neuroprotective drug for progressive MS and showed that the drug slowed the rate of brain shrinkage as compared to a placebo. NINDS intramural scientists are conducting proof-of-concept clinical trials to address a key driver of clinical progression called the “chronic active lesion.”

Biomarkers for MS

As part of a larger effort to develop and validate effective biomarkers (signs that may indicate risk of a disease or be used to monitor its progression) for neurological disease,  NINDS  is supporting two definitive multicenter MS studies:

• The Central Vein Sign in MS (CAVS-MS) study, which is testing whether a rapid MRI approach designed by NINDS scientists can use the detection of a central vein passing through brain plaques to differentiate MS from other common neurological disorders that can mimic MS. The goal is to develop a reliable imaging test for MS in order to achieve rapid yet accurate diagnosis and reduce misdiagnosis, which may affect up to 20% of people currently diagnosed with MS.
• A study to test whether a simple new blood test that measures small amounts of neuron-derived proteins (neurofilaments) can be used to predict the severity of disease and help determine whether MS drugs are working to protect brain tissues.

In addition to  NINDS , other  NIH  Institutes fund research on multiple sclerosis. Find more information on NIH research efforts through  NIH RePORTER , a searchable database of current and past research projects supported by  NIH  and other federal agencies. RePORTER also includes links to publications and patents citing support from these projects.

Clinical trials are studies that allow us to learn more about disorders and improve care. They can help connect patients with new and upcoming treatment options.

How can I or my loved one help improve care for people with multiple sclerosis?

Consider participating in a clinical trial so clinicians and scientists can learn more about MS and related disorders. Clinical research with human participants helps researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of participants are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You . Learn about clinical trials currently looking for people with MS at Clinicaltrials.gov .

Where can I find more information about multiple sclerosis?

Information may be available from the following organizations and resources:

Accelerated Cure Project for Multiple Sclerosis Phone: 781-487-0008

Autoimmune Association Phone: 586-776-3900 

Multiple Sclerosis Association of America (MSAA) Phone: 856-488-4500 or 800-532-7667

Multiple Sclerosis Foundation (MS Focus) Phone: 954-776-6805 or 888 673-6287

Myelin Repair Foundation (MRF) Phone: 408-871-2410

National Ataxia Foundation (NAF) Phone: 763-553-0020

National Multiple Sclerosis Society Phone: 800-344-4867

National Organization for Rare Disorders (NORD) Phone: 203-744-0100

National Rehabilitation Information Center (NARIC) Phone: 301-459-5900 or 800-346-2742; 301-459-5984

Paralyzed Veterans of America Phone: 202-872-1300 or 800-555-9140

Multiple Sclerosis (MS)

• Pathophysiology |
• Symptoms and Signs |
• Diagnosis |
• Treatment |
• Prognosis |
• Key Points |

Multiple sclerosis (MS) is characterized by disseminated patches of demyelination in the brain and spinal cord. Common symptoms include visual and oculomotor abnormalities, paresthesias, weakness, spasticity, urinary dysfunction, and mild cognitive symptoms. Typically, neurologic deficits are multiple, with remissions and exacerbations gradually producing disability. Diagnosis requires clinical or MRI evidence of ≥ 2 characteristic neurologic lesions that are separated in both time and space (location in the central nervous system). Treatment includes corticosteroids for acute exacerbations, immunomodulatory medications to prevent exacerbations, and supportive measures.

(See also Overview of Demyelinating Disorders .)

Multiple sclerosis is believed to involve an immunologic mechanism. One postulated cause is infection by a latent virus (possibly a human herpesvirus such as Epstein-Barr virus ), which, when activated, triggers a secondary autoimmune response.

An increased incidence among certain families and presence of human leukocyte antigen (HLA) allotypes (HLA-DR2) suggests genetic susceptibility.

Age at onset ranges from 15 to 60 years, typically 20 to 40 years; women are affected somewhat more often.

Neuromyelitis optica spectrum disorder (Devic disease), previously considered a variant of MS, is now recognized as a separate disorder.

Pathophysiology of Multiple Sclerosis

Localized areas of demyelination (plaques) occur, with destruction of oligodendroglia, perivascular inflammation, and chemical changes in lipid and protein constituents of myelin in and around the plaques. Axonal damage is common, and neuronal cell bodies may also die or be damaged.

Fibrous gliosis develops in plaques that are disseminated throughout the central nervous system (CNS), primarily in white matter, particularly in the lateral and posterior columns (especially in the cervical regions), optic nerves, and periventricular areas. Tracts in the midbrain, pons, and cerebellum are also affected. Gray matter in the cerebrum and spinal cord can be affected but to a much lesser degree.

Symptoms and Signs of Multiple Sclerosis

Multiple sclerosis is characterized by varied CNS deficits, with remissions and recurring exacerbations. When MS is not treated with immunomodulating medications, exacerbations average about 1 every 2 years, but frequency varies greatly.

Although MS may progress and regress unpredictably, there are typical patterns of progression:

Relapsing-remitting pattern: Exacerbations alternate with remissions, when partial or full recovery occurs or symptoms are stable. Remissions may last months or years. Exacerbations can occur spontaneously or can be triggered by an infection such as influenza. Relapsing forms of MS include active secondary MS (defined as a clinical relapse or new lesion seen on an MRI scan of the brain or spinal cord).

Primary progressive pattern: The disease progresses gradually with no remissions, although there may be temporary plateaus during which the disease does not progress. Unlike in the relapsing-remitting pattern, there are no clear exacerbations.

Secondary progressive pattern: This pattern begins with relapses alternating with remissions (relapsing-remitting pattern), followed by gradual progression of the disease.

Progressive relapsing pattern: The disease progresses gradually, but progression is interrupted by sudden, clear relapses. This pattern is rare.

The most common initial symptoms of multiple sclerosis are the following:

Paresthesias in one or more extremities, in the trunk, or on one side of the face

Weakness or clumsiness of a leg or hand

Visual disturbances (eg, partial loss of vision and pain in one eye due to retrobulbar optic neuritis, diplopia due to internuclear ophthalmoplegia, scotomas)

Other common early symptoms of MS include slight stiffness or unusual fatigability of a limb, minor gait disturbances, vertigo, and mild affective disturbances; all usually indicate scattered CNS involvement and may be subtle. Most patients with MS have difficulty with bladder control (eg, frequency, urgency, hesitancy, incontinence , retention ). Fatigue is common. Excess heat (eg, warm weather, a hot bath, fever) may temporarily exacerbate symptoms and signs (Uhthoff phenomenon).

Mild cognitive symptoms are common. Apathy, poor judgment, or inattention may occur. Affective disturbances, including emotional lability, euphoria, or, most commonly, depression, are common. Depression may be reactive or partly due to cerebral lesions of MS. A few patients have seizures.

Cranial nerves

Unilateral or asymmetric optic neuritis and bilateral internuclear ophthalmoplegia are typical.

Central vision is affected more than peripheral vision.

Optic neuritis causes loss of vision (ranging from scotomas to blindness), eye pain during eye movement, and sometimes abnormal visual fields, a swollen optic disk, or a partial or complete afferent pupillary defect.

Internuclear ophthalmoplegia results if there is a lesion in the medial longitudinal fasciculus connecting the 3rd, 4th, and 6th nerve nuclei. During horizontal gaze, adduction of one eye is decreased, with nystagmus of the other (abducting) eye; convergence is intact. In MS, internuclear ophthalmoplegia is typically bilateral; unilateral internuclear ophthalmoplegia is often caused by ischemic stroke.

Rapid, small-amplitude eye oscillations in straight-ahead (primary) gaze (pendular nystagmus) are uncommon but characteristic of MS. Vertigo is common. Intermittent unilateral facial numbness or pain (resembling trigeminal neuralgia ), palsy, or spasm may occur. Mild dysarthria may occur, caused by bulbar weakness, cerebellar damage, or disturbance of cortical control. Other cranial nerve deficits are unusual but may occur secondary to brain stem injury.

Weakness is common. It usually reflects corticospinal tract damage in the spinal cord, affects the lower extremities preferentially, and is bilateral and spastic.

Deep tendon reflexes (eg, knee and ankle jerks) are usually increased, and an extensor plantar response ( Babinski sign ) and clonus are often present. Spastic paraparesis produces a stiff, imbalanced gait; in advanced cases, it may confine patients to a wheelchair. Painful flexor spasms in response to sensory stimuli (eg, bedclothes) may occur late. Cerebral or cervical spinal cord lesions may result in hemiparesis, which sometimes is the presenting symptom.

Reduced mobility increases the risk of osteoporosis.

In advanced MS, cerebellar ataxia plus spasticity may be severely disabling; other cerebellar manifestations include slurred speech, scanning speech (slow enunciation with a tendency to hesitate at the beginning of a word or syllable), and Charcot triad (intention tremor, scanning speech, and nystagmus).

Paresthesias and partial loss of any type of sensation are common and often localized (eg, to one or both hands or legs).

Various painful sensory disturbances (eg, burning or electric shocklike pains) can occur spontaneously or in response to touch, especially if the spinal cord is affected. An example is Lhermitte sign, an electric shocklike pain that radiates down the spine or into the legs or arms when the neck is flexed.

Objective sensory changes tend to be transient and difficult to demonstrate early in the disease.

Spinal cord

Involvement commonly causes bladder dysfunction (eg, urinary urgency or hesitancy, partial retention of urine, mild urinary incontinence). Constipation, erectile dysfunction in men, and genital anesthesia in women may occur. Frank urinary and fecal incontinence may occur in advanced MS.

Spinal cord lesions (plaques) are a common source of neuropathic pain.

Progressive myelopathy , a variant of MS, causes spinal cord motor weakness but no other deficits.

Diagnosis of Multiple Sclerosis

Clinical criteria

Brain and spinal MRI

Sometimes cerebrospinal fluid (CSF) IgG levels and evoked potentials

Multiple sclerosis is suspected in patients with optic neuritis , internuclear ophthalmoplegia , or other symptoms that suggest MS, particularly if deficits are multifocal or intermittent. If MS is suspected, brain MRI and spinal MRI are done.

MRI is the most sensitive imaging test for MS and can exclude other treatable disorders that may mimic MS, such as nondemyelinating lesions at the junction of the spinal cord and medulla (eg, subarachnoid cyst, foramen magnum tumors). Gadolinium-contrast enhancement can distinguish actively inflamed from older plaques. Also, higher-field MRI magnets (3 to 7 Tesla) can distinguish perivenular MS plaques from nonspecific white-matter lesions.

© 2017 Elliot K. Fishman, MD.

MS must be distinguished from the following:

Clinically isolated syndromes (consisting of only a single clinical manifestation typical of MS)

Radiologically isolated syndrome (MRI findings typical of MS that are incidentally noted in patients with no clinical manifestations)

MS can be distinguished because diagnosis of MS requires evidence of CNS lesions that are separated in both time and space (location in the CNS). For example, any of the following can indicate separation in time:

A history of exacerbations and remissions

MRI that shows simultaneous enhancing and nonenhancing lesions, even if patients are asymptomatic

A new lesion on a subsequent MRI in patients with a previous lesion

Separation (dissemination) in space can be established by finding lesions in ≥ 2 of the 5 following CNS areas typically affected by MS ( 1 ):

Periventricular: ≥ 3 lesions

Cortical/juxtacortical (white matter next to cortex and/or cortex): ≥ 1 lesions

Infratentorial: ≥ 1 lesions

Spinal cord: ≥ 1 lesions

Optic nerve: ≥ 1 lesions (either by MRI or clinical evaluation)

Additional testing

If MRI plus clinical findings are not diagnostic, additional testing may be necessary to objectively demonstrate separate neurologic abnormalities. Such testing may include evoked potentials and, occasionally, CSF examination or blood tests.

Evoked potentials (delays in electrical responses to sensory stimulation) are often more sensitive for MS than symptoms or signs. Visual evoked responses are sensitive and particularly helpful in patients with no confirmed cranial lesions (eg, those with lesions only in the spinal cord). Somatosensory evoked potentials and brain stem auditory evoked potentials are sometimes also measured.

CSF examination is being done less frequently (because the diagnosis can usually be based on MRI) but can be helpful if MRI plus clinical findings are inconclusive or if infection (eg, CNS Lyme disease <

Blood tests may be necessary. Sometimes systemic disorders (eg, SLE ) and infections (eg, Lyme disease ) can mimic MS and should be excluded with specific blood tests. Blood tests to measure an IgG antibody specific for neuromyelitis optica spectrum disorder (aquaporin-4 antibody [also known as NMO-IgG] and anti-MOG [myelin oligodendrocyte glycoprotein] antibodies) may be done to differentiate that disorder from MS.

Diagnosis reference

1. Filippi M, Rocca MA, Ciccarelli O, et al : MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol 15 (3):292–303, 2016. doi: 10.1016/S1474-4422(15)00393-2

Treatment of Multiple Sclerosis

Corticosteroids

Immunomodulators to prevent exacerbations and delay eventual disability

Supportive care

Goals for treatment of multiple sclerosis include the following:

Shortening acute exacerbations

Decreasing frequency of exacerbations

Relieving symptoms

Delaying disability, particularly maintaining the patient’s ability to walk

Treatment of exacerbations and relapses

Corticosteroids , given in brief courses, are used to treat acute onset of symptoms or exacerbations that cause objective deficits sufficient to impair function (eg, loss of vision, strength, or coordination); regimens include

1 , 2 ). Some evidence indicates that IV corticosteroids shorten acute exacerbations, slow progression, and improve MRI measures of disease.

If corticosteroids are ineffective in reducing the severity of an exacerbation, plasma exchange may be used. Plasma exchange can be used for any relapsing form of MS (relapsing-remitting, progressive relapsing, secondary progressive). It is not used for primary progressive MS.

Plasma exchange and hematopoietic stem cell transplantation may be somewhat useful for severe, intractable disease.

Disease-modifying therapies

For additional information, see Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis .

Common adverse effects of interferons include flu-like symptoms and depression (which tend to decrease over time), development of neutralizing antibodies after months of therapy, and cytopenias.

The following oral immunomodulatory medications can be used to treat relapsing forms of MS, including active secondary MS.

3 , 4 , 5 ).

Because most people are averse to self-injection, oral immunomodulatory medications are being increasingly used as first-line treatments for relapsing forms of MS.

Disease-modifying therapies can be used to treat relapsing forms of MS. There is no consensus regarding choice of disease-modifying immunomodulatory therapy. Many experts recommend patient education and shared decision-making, including when disease-modifying therapies are offered to patients who have > 1 lesion (seen on imaging) and a clinically isolated syndrome. If one medication is ineffective, a different one can be tried.

progressive multifocal leukoencephalopathy (PML).

Medications that increase the risk of PML include the following (in descending order of risk):

If any of these medications are used, consultation with a neurologist with training in MS is highly recommended. Before these medications are started, blood tests should be done to check for antibodies to JC virus (JCV), which causes PML. Based on the results, the following is done:

If results are positive, patients should be counseled about the risk of PML.

If results are negative, antibody tests should be done every 6 months as long as any of these medications is used because seroconversion is common.

If test results become positive, patients should be counseled again about the risk, and clinicians should consider switching to a medication without this risk.

If the high-risk medication is continued, MRI of the brain should be done about every 6 months.

Development of PML symptoms (eg, aphasia, change in mental status, hemianopia, ataxia) requires immediate brain MRI, with and without gadolinium. MRI can often distinguish PML from MS. After MRI, a lumbar puncture plasma exchange can be done to remove the medication quickly, and if immune reconstitution inflammatory syndrome (IRIS) develops, corticosteroids are given.

Pearls & Pitfalls

9 , 10 ). Treatments should be tailored to the patient and managed by MS specialists with expertise in their use.

If immunomodulatory medications are ineffective, monthly IV immune globulin may help.

Symptom control

Other treatments can be used to control specific symptoms:

Problems with gait

Painful paresthesias

Depression is treated with counseling and antidepressants .

Bladder dysfunction is treated based on its underlying mechanism.

Constipation may be treated with stool softeners or laxatives, taken regularly.

Tremor: 11 ).

Encouragement and reassurance help patients with multiple sclerosis.

Regular exercise (eg, stationary biking, treadmill, swimming, stretching, balance exercises), with or without physical therapy, is recommended, even for patients with advanced MS, because exercise conditions the heart and muscles, reduces spasticity, prevents contractures and falls, and has psychologic benefits.

Patients should maintain as normal and active a life as possible but should avoid overwork, fatigue, and exposure to excess heat. Cigarette smoking should be stopped.

Vaccination does not appear to increase risk of exacerbations.

Debilitated patients require measures to prevent pressure ulcers and urinary tract infections ; intermittent urinary self-catheterization may be necessary.

Treatment references

1. Le Page E, Veillard D, Laplaud DA, et al Lancet 386 (9997):974–981, 2015. doi: 10.1016/S0140-6736(15)61137-0

2. Burton JM, O'Connor PW, Hohol M, Beyene J : Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev 12:CD006921, 2012. doi: 10.1002/14651858.CD006921.pub3

3. Freedman MS, Devonshire V, Duquette P, et al : Treatment optimization in multiple sclerosis: Canadian MS working group recommendations. Can J Neurol Sci 47 (4):437–455, 2020. doi: 10.1017/cjn.2020.66 Epub 2020 Apr 6

4. Li H, Hu F, Zhang Y, Li K : Comparative efficacy and acceptability of disease-modifying therapies in patients with relapsing–remitting multiple sclerosis: A systematic review and network meta-analysis.  J Neurol 267(12):3489-3498, 2020. doi: 10.1007/s00415-019-09395-w Epub 2019 May 25

5. Rae-Grant A, Day GS, Ruth Ann Marrie RA, et al : Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 90 (17):777–788, 2018. doi: 10.1212/WNL.0000000000005347

6. Hauser SL, Bar-Or A, Comi G, et al N Engl J Med 376 (3):221–234, 2017. doi: 10.1056/NEJMoa1601277

7. Hauser SL, Bar-Or A, Cohen JA, et al N Engl J Med 383 (6):546–557, 2020. doi: 10.1056/NEJMoa1917246

8. Granqvist M, Boremalm M , Poorghobad A, et al JAMA Neurol 75 (3):320–327, 2018. doi: 10.1001/jamaneurol.2017.4011

9. Casanova B, Quintanilla-Bordás C, Gascón F : Escalation vs. early intense therapy in multiple sclerosis.  J Pers Med 12 (1):119, 2022. doi: 10.3390/jpm12010119

10. Simonsen CS, Flemmen HO, Broch, L, et al : Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in a Norwegian population-based registry. Front Neurol 12:693017, 2021. doi: 10.3389/fneur.2021.693017

11. Makhoul K, Ahdab R, Riachi N, et al : Tremor in multiple sclerosis-An overview and future perspectives. Brain Sci  10 (10):722, 2020. doi: 10.3390/brainsci10100722

12. Multiple Sclerosis Society of Canada Public Health Nutr (23) 7: 1278–1279, 2020.

Prognosis for Multiple Sclerosis

The course of multiple sclerosis is highly varied and unpredictable. In most patients, especially when MS begins with optic neuritis, remissions can last months to > 10 years.

Most patients (60 to 80% [ 1 ]) who initially have a clinically isolated syndrome eventually develop MS, with a second lesion becoming evident or MRI detecting a lesion, usually within 5 years after the initial symptoms begin. Treatment with disease-modifying therapies can delay this progression. If patients have a radiologically isolated syndrome without a history of a clinical episode consistent with demyelination, the risk of developing MS is 19 to 90%, depending on the patient's age and the presence of spinal cord or gadolinium-enhancing lesions ( 2 ).

If the initial brain or spinal MRI shows more extensive disease, patients may be at risk of earlier disability, as may patients who have motor, bowel, and/or bladder symptoms when they present or who have incomplete recovery during relapses. Some patients, such as men with onset in middle age and with frequent exacerbations, can become rapidly incapacitated. Cigarette smoking may accelerate disease progression.

Life span is shortened only in very severe cases.

Prognosis references

1. National Multiple Sclerosis Society : Clinically isolated syndrome (CIS). Accessed 5/1/23.

2. Lebrun-Frénay C, Rollot F, Mondot L, et al : Risk factors and time to clinical symptoms of multiple sclerosis among patients with radiologically isolated syndrome. JAMA Netw Open  4 (10):e2128271, 2021. doi: 10.1001/jamanetworkopen.2021.28271

Multiple sclerosis involves demyelination of the CNS; MS may progress unpredictably but has several typical patterns of progression.

The most common symptoms are paresthesias, weakness or clumsiness, and visual symptoms, but a wide variety of symptoms are possible.

MS is confirmed if MRI and clinical findings establish characteristic lesions that are separate in time and space; however, progression to MS is likely if patients have even a single characteristic clinical deficit or possibly a single radiologic lesion.

Treat patients with corticosteroids (for severe exacerbations) and immunomodulatory medications (to delay or prevent exacerbations).

Treat patients supportively, using medications to treat symptoms (eg, spasticity, painful paresthesias, depression, bladder dysfunction, fatigue, gait problems) when warranted.

Copyright © 2024 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved.

• Cookie Preferences

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• My Bibliography
• Collections
• Citation manager

Save citation to file

Email citation, add to collections.

• Create a new collection
• Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

• Search in PubMed
• Search in NLM Catalog
• Add to Search

Clinical presentation and diagnosis of multiple sclerosis

Affiliation.

• 1 Leeds Centre for Neurosciences, Leeds, UK [email protected].
• PMID: 32675142
• PMCID: PMC7385797
• DOI: 10.7861/clinmed.2020-0292

The diagnosis of multiple sclerosis (MS) is through clinical assessment and supported by investigations. There is no single accurate and reliable diagnostic test. MS is a disease of young adults with a female predominance. There are characteristic clinical presentations based on the areas of the central nervous system involved, for example optic nerve, brainstem and spinal cord. The main pattern of MS at onset is relapsing-remitting with clinical attacks of neurological dysfunction lasting at least 24 hours. The differential diagnosis includes other inflammatory central nervous system disorders. Magnetic resonance imaging of the brain and lumbar puncture are the key investigations. New diagnostic criteria have been developed to allow an earlier diagnosis and thus access to effective disease modifying treatments.

Keywords: MS; Multiple sclerosis; neurology.

© Royal College of Physicians 2020. All rights reserved.

PubMed Disclaimer

Multiple sclerosis disease course.

• Multiple sclerosis. Kausar SA. Kausar SA. Clin Med (Lond). 2020 Sep;20(5):e138-e139. doi: 10.7861/clinmed.Let.20.5.7. Clin Med (Lond). 2020. PMID: 32934059 Free PMC article. No abstract available.

Similar articles

• Brain and spinal cord lesion criteria distinguishes AQP4-positive neuromyelitis optica and MOG-positive disease from multiple sclerosis. Bensi C, Marrodan M, González A, Chertcoff A, Osa Sanz E, Chaves H, Schteinschnaider A, Correale J, Farez MF. Bensi C, et al. Mult Scler Relat Disord. 2018 Oct;25:246-250. doi: 10.1016/j.msard.2018.08.008. Epub 2018 Aug 9. Mult Scler Relat Disord. 2018. PMID: 30144694
• Revised diagnostic criteria of multiple sclerosis. Milo R, Miller A. Milo R, et al. Autoimmun Rev. 2014 Apr-May;13(4-5):518-24. doi: 10.1016/j.autrev.2014.01.012. Epub 2014 Jan 12. Autoimmun Rev. 2014. PMID: 24424194 Review.
• Structured Reporting in Multiple Sclerosis - Consensus-Based Reporting Templates for Magnetic Resonance Imaging of the Brain and Spinal Cord. Riederer I, Mühlau M, Wiestler B, Bender B, Hempel JM, Kowarik M, Huber T, Zimmer C, Andrisan T, Patzig M, Zimmermann H, Havla J, Berlis A, Behrens L, Beer M, Dietrich J, Sollmann N, Kirschke JS. Riederer I, et al. Rofo. 2023 Feb;195(2):135-138. doi: 10.1055/a-1867-3942. Epub 2022 Jul 29. Rofo. 2023. PMID: 35913055 English, German.
• Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Filippi M, Preziosa P, Meani A, Ciccarelli O, Mesaros S, Rovira A, Frederiksen J, Enzinger C, Barkhof F, Gasperini C, Brownlee W, Drulovic J, Montalban X, Cramer SP, Pichler A, Hagens M, Ruggieri S, Martinelli V, Miszkiel K, Tintorè M, Comi G, Dekker I, Uitdehaag B, Dujmovic-Basuroski I, Rocca MA. Filippi M, et al. Lancet Neurol. 2018 Feb;17(2):133-142. doi: 10.1016/S1474-4422(17)30469-6. Epub 2017 Dec 21. Lancet Neurol. 2018. PMID: 29275979
• Disorders of vision in multiple sclerosis. Dhanapalaratnam R, Markoulli M, Krishnan AV. Dhanapalaratnam R, et al. Clin Exp Optom. 2022 Jan;105(1):3-12. doi: 10.1080/08164622.2021.1947745. Epub 2021 Aug 4. Clin Exp Optom. 2022. PMID: 34348598 Review.
• Simultaneous and cumulative effects of tDCS on cerebral metabolic rate of oxygen in multiple sclerosis. Muccio M, Pilloni G, Walton Masters L, He P, Krupp L, Datta A, Bikson M, Charvet L, Ge Y. Muccio M, et al. Front Hum Neurosci. 2024 Jul 16;18:1418647. doi: 10.3389/fnhum.2024.1418647. eCollection 2024. Front Hum Neurosci. 2024. PMID: 39081842 Free PMC article.
• Changes of Target Essential Trace Elements in Multiple Sclerosis: A Systematic Review and Meta-Analysis. Stojsavljević A, Jagodić J, Perović T, Manojlović D, Pavlović S. Stojsavljević A, et al. Biomedicines. 2024 Jul 17;12(7):1589. doi: 10.3390/biomedicines12071589. Biomedicines. 2024. PMID: 39062163 Free PMC article. Review.
• The Evolving Role of Monomethyl Fumarate Treatment as Pharmacotherapy for Relapsing-Remitting Multiple Sclerosis. Kaye AD, Lacey J, Le V, Fazal A, Boggio NA, Askins DH, Anderson L, Robinson CL, Paladini A, Mosieri CN, Kaye AM, Ahmadzadeh S, Shekoohi S, Varrassi G. Kaye AD, et al. Cureus. 2024 Apr 6;16(4):e57714. doi: 10.7759/cureus.57714. eCollection 2024 Apr. Cureus. 2024. PMID: 38711693 Free PMC article. Review.
• Heteromers Formed by GPR55 and Either Cannabinoid CB 1 or CB 2 Receptors Are Upregulated in the Prefrontal Cortex of Multiple Sclerosis Patients. Menéndez-Pérez C, Rivas-Santisteban R, Del Valle E, Tolivia J, Navarro A, Franco R, Martínez-Pinilla E. Menéndez-Pérez C, et al. Int J Mol Sci. 2024 Apr 10;25(8):4176. doi: 10.3390/ijms25084176. Int J Mol Sci. 2024. PMID: 38673761 Free PMC article.
• Data on Ocrelizumab Treatment Collected by MS Patients in Germany Using Brisa App. Papukchieva S, Kahn M, Eberl M, Friedrich B, Joschko N, Ziemssen T. Papukchieva S, et al. J Pers Med. 2024 Apr 12;14(4):409. doi: 10.3390/jpm14040409. J Pers Med. 2024. PMID: 38673036 Free PMC article.
• Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis. Neurology 2014;83:278–86. - PMC - PubMed
• Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol 2016;15:292–303. - PMC - PubMed
• Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018;17:162–173. - PubMed
• Poser CM, Paty DW, Scheinberg LC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–31. - PubMed
• McDonald WI, Compston DA, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001;50:121–7. - PubMed
• Search in MeSH

Related information

Linkout - more resources, full text sources.

• Elsevier Science
• Europe PubMed Central
• Ovid Technologies, Inc.
• PubMed Central
• MedlinePlus Health Information

• Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

• Subscribe to journal Subscribe
• Get new issue alerts Get alerts

Secondary Logo

Journal logo.

Colleague's E-mail is Invalid

Your message has been successfully sent to your colleague.

Save my selection

A current understanding of multiple sclerosis

Shull, Catherine MPAS, PA-C; Hoyle, Brittany MMS, PA-C; Iannotta, Caylin MMS, PA-C; Fletcher, Eden MMS, PA-C; Curan, Megan MMS, PA-C; Cipollone, Victoria MMS, PA-C

Catherine Shull is an assistant professor in the PA program at Wake Forest School of Medicine in Winston-Salem, N.C., and practices at Wake Forest Baptist Health Family Medicine. At the time this article was written, Brittany Hoyle, Caylin Iannotta, Eden Fletcher, Megan Curan , and Victoria Cipollone were students in the PA program at Wake Forest School of Medicine. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org . Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of February 2020.

Multiple sclerosis (MS) is an autoimmune inflammatory disorder that affects more than 900,000 Americans. Patient presentations vary widely; therefore, symptom recognition and an understanding of diagnostic criteria are critical in providing timely patient referrals. This article describes recognition and diagnosis of MS using the updated 2017 criteria, and offers an overview of epidemiology, prognosis, and treatment strategies.

A 59-year-old man with a history of hypertension and vision changes presents to an outpatient family practice clinic with a 2-day history of intermittent dizziness, lightheadedness, and fatigue.

The patient's symptoms are present at rest and worsen with movement. He has difficulty walking in a straight line and his wife has noticed that he walks with a wider, broader-based gait and has problems with balance. Seven months ago, the patient was seen in clinic and by his optometrist; he had experienced 4 weeks of blurred vision while reading. Both physical examination and a formal eye evaluation noted no pathology. A brain MRI was performed and showed multiple lesions in the periventricular white matter. At that time the patient was referred to a neuro-ophthalmologist who believed the vision changes were due to scotoma and unrelated to the MRI findings of possible sarcoidosis or multiple sclerosis (MS). The patient's visual symptoms subsequently resolved without recurrence. However, he and his wife are worried about his new-onset dizziness, gait problems, and unsteadiness. He was referred to a neurologist who felt that a diagnosis of MS could be made based on this second acute neurologic event.

ABOUT MULTIPLE SCLEROSIS

MS is an autoimmune inflammatory disorder characterized by selective demyelination of central nervous system (CNS) axons. Although its exact cause remains unknown, MS likely is due to a combination of environmental, immunologic, and genetic influences. Patients present with various neurologic symptoms based on the location of demyelinated lesions. Therefore, providers must be able to recognize potential MS presentations and provide timely referral to a neurologist specializing in this disorder. Current management strategies focus on treating acute flares and reducing disease progression. Several medications are approved for treatment, though various adverse reaction profiles and patient comorbidities determine their use. A specialist team manages disease-modifying therapies (DMTs) for MS, but providers play a vital role in recognizing initial symptoms or relapses and assisting in management strategies.

EPIDEMIOLOGY AND RISK FACTORS

The predicted prevalence of MS in the United States in 2017 was 913,925, which is more than twice the previous estimate of 400,000 patients. 1,2 Women are two to three times more likely than men to develop MS, though some less common subtypes of the disease have a male predominance. 3 Disease prevalence is highest in patients ages 55 to 64 years. 1 Vitamin D deficiency has been identified as a risk factor for MS development, and patients who live farther from the equator are more susceptible. 2 Current interpretation of this trend is attributed to limited atmospheric absorption of UVB radiation at latitudes of 42° and greater during the winter months. Adequate levels of the active form of vitamin D (75 mmol/L or greater) reduce the likelihood of developing MS by 61%. 4,5 Other important environmental risk factors include cigarette smoking, early-onset obesity, and previous Epstein-Barr viral infections. 6

A positive family history also is a predisposing factor for the disease, as siblings of affected patients have about a 30% higher risk of developing MS compared with the general population. 7 Genetics influence patient susceptibility, as more than 100 genes have been identified in association with MS. 6 Although multiple aspects contribute to the development of MS, modifiable factors such as tobacco use and vitamin D deficiencies can be targeted to reduce risk.

CLINICAL MANIFESTATIONS

Presenting signs and symptoms vary based on lesion location and MS type. Typical presentations can include acute unilateral optic neuritis, diplopia, trigeminal neuralgia, facial sensory loss or motor disturbances, cerebellar ataxia, nystagmus, urinary urge incontinence, constipation, or erectile dysfunction. 8,9 Fatigue, which affects up to 80% of patients, is one of the most common and overwhelming symptoms. 9 Other common manifestations involve visual disturbances such as diplopia, unilateral vision loss or reduced vision, and painful eye movements. 9 Many patients experience ascending sensory disturbances and asymmetric limb weakness, which contribute to problems with mobility and balance and cause frequent falls. 9 Some may develop Lhermitte syndrome, which presents as a shooting, electric-like sensation down the spine with occasional radiation into the limbs following cervical flexion. 9 Patients also may experience Uhthoff phenomenon, in which exposure to high temperatures such as hot showers or baths can reduce visual acuity and cause other optic abnormalities. 10 Have a high suspicion for MS in any patient younger than age 50 years who presents with a history of neurologic symptoms occurring for several days to weeks with subsequent improvement. 9

CLASSIFICATION

Classic MS can be categorized into four types:

• Relapsing-remitting , the most common type, accounts for about 85% of patients with MS. 8 This type of MS is characterized by periods of stable neurologic disability with intermittent acute exacerbations. 11
• Primary progressive is characterized by subsequently worsening neurologic function without relapse. 11
• Secondary progressive is associated with an initial relapsing-remitting course that becomes a steady neurologic decline. 11
• Clinically isolated syndrome (CIS) is a more recent classification, and represents a first clinical presentation that may demonstrate focal or multifocal inflammatory demyelination, but does not meet diagnostic criteria for MS. 11 Patients who have a single neurologic episode that meets criteria for CIS are at increased risk for a subsequent flare leading to an MS diagnosis. 11

Myelocortical MS was identified in 2018. 3 In this new subtype, demyelinated lesions are isolated to the spinal cord and cerebral cortex; typically, they are not present in the white matter of the brain. 3 This variance in distribution results in a symptomatic presentation and diagnostic workup that is different from the more classically occurring subtypes. 3 One study found that 12% of patients previously diagnosed with other MS variants could be posthumously reclassified as having the myelocortical subtype. 3 Because researchers are still attempting to elucidate the differences between myelocortical MS and other classifications, this subtype will not be the focus of this article.

Diagnoses that present similarly to MS include varying types of vasculitis, HIV infection, Lyme disease, thyroid dysfunction, and several nutritional deficiencies. 12 Many of these require less invasive testing for diagnosis and should be performed before imaging for MS. Eliminating these disorders from the differential diagnosis can be accomplished by evaluating thyroid, liver, and renal function; HIV serology; vitamin B12 levels; inflammatory markers; comprehensive metabolic panel (CMP); and complete blood cell (CBC) count. 9

If preliminary test results lead the clinician to suspect a MS diagnosis, a neurology consult is warranted in case a more thorough workup or long-term management is required. Gadolinium-enhancing T2 MRI of the brain and spinal cord remains the most sensitive diagnostic test for relapsing-remitting MS. New advances in MRI technology are leading to higher-resolution imaging that may be tailored to the assessment of individual patients. Depending on the location of a suspected demyelination, variations in the type and orientation of MRI can enhance visualization of lesions. These improvements are being successfully implemented in clinical practice. 13 When following an initial CIS presentation, an MRI can be used to achieve the most rapid MS diagnosis and treatment initiation. 12 The 2017 McDonald diagnostic criteria enable clinicians to identify relapsing-remitting MS more rapidly than previous protocols allowed ( Table 1 ). Similar to the 2010 McDonald criteria, the 2017 update requires the presence of lesions identified via MRI that are separated in both space and time for a diagnosis of relapsing-remitting MS. However, inclusion of cerebrospinal fluid (CSF) findings and more broadly localized lesions now satisfy new diagnostic parameters. 14 In one study, diagnosis was achieved more quickly in 63.5% of patients using the 2017 McDonald criteria, with a reduction time of 7.2 months compared with the 2010 criteria. 12

Demyelinating lesions found on MRI must satisfy several basic diagnostic parameters, the most fundamental of which is the presence of lesions disseminated in space and time.

Dissemination in space refers to evidence of demyelination in multiple distinct CNS regions, such as the spinal cord and cortical, juxtacortical, supratentorial, or periventricular brain regions. 14

Dissemination in time correlates with the development of new demyelinating lesions in the CNS at different points in time. 14 With the 2010 criteria, these parameters were only satisfied by lesions found on MRI that were not directly related to symptomatic presentation. 14

With the exception of lesions in the optic nerve and associated optic neuritis, both symptomatic and nonsymptomatic lesions now meet diagnostic criteria. 14

Dispersal of brain lesions also has been expanded with the 2017 criteria, and allows inclusion of juxtacortical and cortical lesions, as well as those in the spinal cord, to satisfy the requirement for dissemination in space ( Table 1 ). 14 Cortical and juxtacortical lesions are considered equivalent, however, and the presence of both in the absence of an additional lesion outside this domain is insufficient to satisfy dissemination in space. 12 The 2017 criteria still require the presence of at least one periventricular lesion, and the identification of more is recommended in patients who have other potentially causative factors such as vascular disease, migraines, or advanced age. 14 In addition to brain MRI, the Consortium of MS Centers strongly recommends cervical cord imaging if MS is suspected. Symptomatically silent lesions most commonly are found in this region, and may be used to expedite diagnosis if discovered on MRI. These lesions also have a high specificity for progression to true MS when identified in patients presenting with CIS. 13,15

The most drastic change to the diagnostic criteria for relapsing-remitting MS is that the presence of oligoclonal banding in CSF may now be used to satisfy dissemination in time. 14 The banding manifests as a result of intrathecal antibody development due to demyelinating lesions and now fulfills this criterion, even in the absence of new lesions on MRI. 12 Furthermore, the presence of banding is a proven indicator of increased patient risk for subsequent symptomatic flares. 12 Under the 2010 criteria, dissemination in time was only confirmed with new lesions developing over weeks to months. 14 The use of oligoclonal banding in the diagnosis now enables earlier administration of DMTs and improved outcomes. 12

PHARMACOLOGIC TREATMENT

Although MS has no definitive cure, treatment can manage relapses and delay long-term disease progression. A relapse is defined as acute or subacute symptoms and neurologic findings that last at least 24 hours in the absence of fever or infectious signs. 14 Patients presenting with these exacerbations should be treated with a short course of high-dose corticosteroids such as oral methylprednisolone 0.5 g daily for 5 days. 9 Patients who cannot tolerate oral corticosteroids or whose symptoms are unresponsive can be given 1 g IV methylprednisolone daily. 9 Oral and IV methylprednisolone have similar efficacy and safety profiles. 16

Early and accurate diagnosis is essential, and newly diagnosed patients should be referred to a specialist for initiation of DMT, which can reduce relapse frequency and disease progression. Several DMTs are approved for treatment of relapsing-remitting MS, but only one has been shown to reduce disease progression in patients with primary progressive MS. 17 In 2018, the American Academy of Neurology (AAN) released guidelines advising clinicians on initiation, continuation, and cessation of various DMTs. 17 AAN recommends that the specialist team discuss switching medications if the patient continues to experience exacerbations after 1 year of using a given DMT, or if two or more new lesions have been found on MRI. 17 The guidelines also recommend offering DMTs to patients with CIS. For patients with neurologic symptoms that do not meet diagnostic criteria, treatment with certain DMTs can reduce the risk of conversion to MS. 17,18 With numerous new DMTs added to the market over the past several years, clinicians can choose from many options that have varying efficacies, safety profiles, routes of administration, and monitoring requirements.

NONPHARMACOLOGIC TREATMENT

Much like the multifactorial decision for DMT therapy, an individualized approach toward nonpharmacologic treatments can reduce relapse rates and improve patient quality of life. Both pharmacologic and nonpharmacologic treatment regimens must be quickly optimized to prevent cognitive and neurologic decline. 19 Therapy optimization includes addressing specific deficits such as energy, cognitive function, physical ability, motor strength, and mental resilience. 20 Individualization of nonpharmacologic therapy requires a comprehensive team of neuropsychologists, clinical psychologists, occupational and physical therapists, nutritionists, nurses, speech and language therapists, social workers, and continence specialists. 9,20 Due to symptom variability and the progressive nature of MS, all care aspects should be thoroughly reviewed annually. 9

Exercise and mindfulness training have emerged as effective nonpharmacologic treatments. Moderate progressive resistance training, aerobic exercise, balance, and stretching such as yoga can improve mobility and reduce fatigue. 9 Exercise is a safe intervention and patients are at no greater risk for adverse reactions than patients without MS. 21 Physical activity shows no detrimental effects during wellness intervention studies and may be associated with fewer relapses. 21

Cognitive behavioral therapy, fatigue management, and mindfulness training address psychologic stressors and improve MS-related fatigue. 9 Mindfulness training encourages the practice of nonjudgmentally acknowledging one's thoughts and focusing awareness on the present moment. This can help to improve patient quality of life by minimizing symptoms of worsening anxiety, depression, and other manifestations of psychologic distress that often develop after an MS diagnosis. 22 Tailor interventions to patient interest, symptom profiles, and pharmacologic DMTs for true optimization of MS management and quality of life.

Newly diagnosed MS patients may find it helpful to understand disease progression and prognosis. Clinicians benefit from recognizing diagnostic factors that put patients at increased risk for more debilitating disease or, in those presenting with a CIS, progression to true MS. The Expanded Disability Status Scale (EDSS) is routinely used to assess disability related to disease progression. 23 Although the EDSS has been criticized for its reliance on walking as the primary means of determining debility, it remains the most widely used screening tool. The disability severity scale ranges from 1 (no disability) to 10 (death related to disease progression), with a score of 3 or greater corresponding with significant disability. 23

The number of presenting lesions on initial MRI and the presence of oligoclonal bands are the most critical factors for determining recurrence and debility of diagnosable MS. The best predictive factor for MS development and related disability with a CIS is the initial number of demyelinating lesions identified on T2 MRI; the presence of oligoclonal banding correlates with increased recurrence of symptomatic flares. 12,23 One study found that for patients with a larger number of presenting lesions (10 or more found on MRI), the likelihood of developing significant disability within 5 years of diagnosis was about 11%, and up to 30% within 10 years. 23

Gender does not appear to play a statistically significant role in MS recurrence or progression, despite an overall greater risk of initial CIS presentation in females. 23 Younger patients with CIS onset have an increased risk of progression to diagnosable MS, but a lower risk of developing significant disability, though the statistical significance is marginal. 23 Interestingly, CIS presentation associated with optic neuritis appears to be a protective factor, reducing the likelihood of significant future disability and an eventual diagnosis of MS. 23

Mortality associated with disease progression has been difficult to quantify, as the most common causes of death are complications related to longstanding MS and resulting immobility, including cardiac and respiratory failure, malnutrition, aspiration, uremia, and septic shock. 24 Survivability therefore is not typically used as an outcome measurement for determining treatment efficacy. 16 Patient mortality is influenced by MS classification, age at diagnosis, presence and severity of systemic complications, and delays in initiation of DMTs. 23 Regardless of the underlying cause of death, patients with MS have a predicted 7- to 14-year reduction in their total life expectancy. 24

Although clinical research is rapidly expanding our understanding of MS, it remains a complex disorder with variable presentations. Clinicians must be able to recognize risk factors, signs, and symptoms suggestive of MS in order to make appropriate and timely neurologic referrals. These referrals can now be made to MS centers across the United States that have multidisciplinary teams providing a comprehensive approach to care. The 2017 updates to the McDonald criteria can bring about expedited diagnosis and treatment, with a focus on managing acute flares, preventing relapse, and slowing long-term progression using corticosteroids and DMTs. Nonpharmacologic treatments aim to maintain motor function, manage psychologic stress, and improve quality of life. Further research into disease processes, risk factors, and comparative efficacy of DMTs and their long-term effects will continue to increase our knowledge of MS and improve patient care. In order to be integral members of the comprehensive care team as research evolves, clinicians should remain current in their understanding of MS presentation, diagnosis, and treatment.

• Cited Here |
• View Full Text | PubMed | CrossRef
• PubMed | CrossRef

multiple sclerosis; epidemiology; risk factors; 2017 McDonald criteria; clinical manifestations; treatment strategies

• + Favorites
• View in Gallery

Readers Of this Article Also Read

A review of organizing pneumonia, recognizing and treating five common dermatologic conditions seen in primary..., peripheral neuropathy: clinical pearls for making the diagnosis, a young man with visual disturbances and a mild headache, huntington disease.

Masks Strongly Recommended but Not Required in Maryland

Respiratory viruses continue to circulate in Maryland, so masking remains strongly recommended when you visit Johns Hopkins Medicine clinical locations in Maryland. To protect your loved one, please do not visit if you are sick or have a COVID-19 positive test result. Get more resources on masking and COVID-19 precautions .

• Vaccines  
• Masking Guidelines
• Visitor Guidelines  

Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a long-lasting (chronic) disease of the central nervous system. It is thought to be an autoimmune disorder, a condition in which the body attacks itself by mistake. MS is an unpredictable disease that affects people differently. Some people with MS may have only mild symptoms. Others may lose their ability to see clearly, write, speak, or walk when communication between the brain and other parts of the body becomes disrupted.

Myelin is a protein and fatty substance that surrounds and protects nerve fibers. In MS, the immune system attacks the myelin, which becomes destroyed in many areas. This loss of myelin forms scar tissue called sclerosis. These areas are also called plaques or lesions. When the nerves are damaged in this way, they can’t conduct electrical impulses normally to and from the brain.

When MS causes repeated attacks, it's called relapsing remitting MS. When the symptoms progress over time without clear attacks, it's called primary progressive MS.

What causes multiple sclerosis?

There are many possible causes of MS, such as:

Autoimmune disorders

Infectious agents, such as viruses

Environmental factors

Genetic factors

What are the symptoms of multiple sclerosis?

The symptoms of MS are often unpredictable. They may be mild or severe, short-term or long-lasting. They may appear in different combinations, depending on the area of the nervous system affected. The following are the most common symptoms of MS. But each person may have different symptoms.

First symptoms of MS

Blurred or double vision

Red-green color distortion

Pain and loss of vision because of swelling of the optic nerve (optic neuritis)

Trouble walking and difficulty with balance

An abnormal feeling, such as numbness, prickling, or pins and needles (paresthesia)

Other symptoms of multiple sclerosis

Muscle weakness in the arms and legs

Trouble with coordination. You may have problems walking or standing. You may also be partly or completely paralyzed.

Spasticity. This is the involuntary increased tone of muscles leading to stiffness and spasms.

Fatigue. This may be brought on by physical activity. But it may ease with rest. You may have constant tiredness that doesn't go away.

Loss of feeling

Speech problems

Hearing loss

Bowel and bladder problems

Changes in sexual function

About half of all people with MS have thinking (cognitive) problems linked to the disease. The effects of these problems may be mild. Your healthcare provider may only find them after much testing. The problems may be with:

Focusing (concentration)

Poor judgment

Symptoms of MS are grouped as primary, secondary, or tertiary as described below:

The symptoms of MS may look like other health problems. Always talk with your healthcare provider for a diagnosis.

How is multiple sclerosis diagnosed?

Not one specific test is used to diagnose MS. Diagnosis is based on symptoms and signs, imaging tests, and lab tests. A healthcare provider can make a diagnosis by following a careful process to rule out other causes and diseases. Two things must be true to make a diagnosis of relapsing remitting MS:

You must have had 2 attacks at least 1 month apart. An attack is when any MS symptoms show up suddenly. Or when any MS symptoms get worse for at least 24 hours.

You must have more than 1 area of damage to the central nervous system myelin. Myelin is the sheath that surrounds and protects nerve fibers. This damage must have occurred at more than 1 point in time and not have been caused by any other disease.

Your healthcare provider will ask about your health history and do a neurological exam. This includes:

Mental functions

Emotional functions

Language functions

Movement and coordination

Functions of the 5 senses

You may also need:

MRI.  This diagnostic test uses a combination of large magnets and a computer to make detailed pictures of organs and structures within the body without the use of X-rays. It can find plaques or scarring caused by MS. Generally, a single attack along with certain patterns of changes in brain tissue seen on an MRI scan of the brain done with contrast can mean that you have MS.

Evoked potentials.  These tests record the brain's electrical response to visual, auditory, and sensory stimuli. These tests show if you have a slowing of messages in the different parts of the brain.

Cerebrospinal fluid analysis.  This is also called a spinal tap or lumbar puncture. It looks at the fluid taken from the spinal column to make an evaluation or diagnosis. This test checks for cellular and chemical abnormalities seen with MS.

Blood tests.  These are done to rule out other causes for various neurological symptoms.

Eye exam  and visual fields measurements.

How is multiple sclerosis treated?

Treatment will depend on your symptoms, age, and general health. It will also depend on how bad the condition is.

Currently, treatments are divided into:

Disease-modifying treatments.  These directly target inflammation in the central nervous system. They help slow its deterioration.

Treatment of acute relapses.  The use of steroids and plasma exchange (PLEX) can speed up your recovery when you have an MS attack.

There is no known cure for MS. But you can do things to help change the course of the disease, treat flare-ups, manage symptoms, and improve your function and mobility.

Treatments for the conditions seen with MS may include:

Medicines (talk with your provider to see what medicines may be an option for you)

Equipment, such as canes, braces, or walkers

Rehabilitation activities

Rehab varies depending on your symptoms and how bad they are. MS rehab may help you to:

Get back functions that are important for daily living

Be as independent as you can

Involve your family

Make the right decisions relating to your care

Learn about equipment like canes, braces, or walkers that can make is easier to move around

Set up an exercise program that builds muscle strength, endurance, and control

Get back motor skills

Speak more easily if you have weakness or a lack of coordination of face and tongue muscles

Manage bowel or bladder incontinence

Relearn thinking skills

Change the way your home is set up to keep you safe but allow you to move about as easily as possible

What are possible complications of multiple sclerosis?

The complications of MS range from mild to severe. They can range from fatigue to the inability to walk. Other problems include loss of vision, balance, and bowel or bladder control. Depression can result from the difficulty of living with a chronic condition.

Living with multiple sclerosis

It's important to take your medicines as directed. You may get help by taking part in a clinical trial. Using equipment like canes or walkers can help you get around as walking becomes harder to do. Rehab activities can also help you keep or get back functioning. Changing the way your home is set up can help you stay independent. Talk with your family and healthcare providers about what you need.

Key points about multiple sclerosis

Multiple sclerosis (MS) is a chronic disease of the central nervous system.

MS is unpredictable. Some people may be only mildly affected. Others may lose the ability to see clearly, write, speak, or walk.

Early symptoms can include vision problems, trouble walking, and tingling feelings.

MS affects people differently. But common problems are trouble with movement and thinking, and bowel and bladder incontinence.

Medicines and rehabilitation can help to keep or restore functioning.

• Primary Progressive Multiple Sclerosis
• Relapsing-Remitting Multiple Sclerosis
• Multiple Sclerosis and Pregnancy
• Multiple Sclerosis: Why Are Women More at Risk?

Wellness and Prevention

• 5 Myths About Multiple Sclerosis and Depression
• 5 Tips for Living Better with MS: Patients and Caregivers
• Multiple Sclerosis and Mental Health 3 Common Challenges

Find a Doctor

Specializing In:

• Neuromuscular Disease
• CNS Autoimmune/Inflammatory Disorders
• Multiple Sclerosis
• Multiple Sclerosis Rehabilitation

Request an Appointment

Specializing In

At Another Johns Hopkins Member Hospital:

• Howard County Medical Center
• Sibley Memorial Hospital
• Suburban Hospital

Related Topics

Website maintenance is scheduled for Saturday, September 7, and Sunday, September 8. Short disruptions may occur during these days.

AARON SAGUIL, MD, MPH, EDWIN A. FARNELL, IV, MD, AND TENEISHA S. JORDAN, MD

Am Fam Physician. 2022;106(2):173-183

Author disclosure: No relevant financial relationships.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system and the most common cause of nontraumatic neurologic disability in young adults. Types of MS include relapsing-remitting (most common), secondary progressive, and primary progressive. Clinically isolated syndrome and radiologically isolated syndrome are additional categories for patients with findings concerning for MS who do not yet meet the diagnostic criteria for the disease. Symptoms of MS depend on the areas of neuronal involvement. Common symptoms include sensory disturbances, motor weakness, impaired gait, incoordination, optic neuritis, and Lhermitte sign. A patient history, neurologic examination, and application of the 2017 McDonald Criteria are needed to diagnose MS accurately. Patients with MS should be treated by a multidisciplinary team that may include physical and occupational therapists, speech and language therapists, mental health professionals, pharmacists, dietitians, neurologists, and family physicians. Steroids are the mainstay of treatment for the initial presentation of MS and relapses. Patients who do not adequately respond to steroids may benefit from plasmapheresis. Patients with MS who smoke tobacco should be strongly encouraged to quit. Disease-modifying therapy has been shown to slow disease progression and disability; options include injectable agents, infusions, and oral medications targeting different sites in the inflammatory pathway. Symptom-based care is important to address the bowel and bladder dysfunction, depression, fatigue, movement disorders, and pain that often complicate MS.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system and the most common cause of nontraumatic neurologic disability in young adults. 1 Prevalence differs by latitude, with higher rates among those living further from the equator. The prevalence of MS is 40 per 100,000 people in Lubbock, Tex., compared with 191 per 100,000 people in Olmstead County, Minn. 2 An estimated 1 million people in the United States live with MS. 1 Risk factors include smoking and a history of infectious mononucleosis. Women are twice as likely as men to have MS, and there is a modest genetic influence. 3 , 4

A woman with MS diagnosed at 35 years of age has an average life expectancy of seven to eight years less than that of the general population. Because MS has a relatively high prevalence and patients have a long life span after diagnosis, many family physicians care for patients with the disease. 5

Pathophysiology

Types of MS include relapsing-remitting (RRMS; most common), secondary progressive, and primary progressive ( Table 1 6 – 13 ) . There are also classifications for people with first episodes concerning for MS who do not meet the diagnostic criteria for MS (clinically isolated syndrome) and those with incidental radiologic findings concerning for MS in the absence of clinical symptoms (radiologically isolated syndrome). 13

MS is characterized by focal areas of inflammation, demyelination, gliosis (proliferation and activation of glial cells), and degeneration (axonal loss) secondary to immune-mediated attacks. 10 There is debate about whether the inflammation leading to MS is initiated within or outside the central nervous system; however, T cells, B cells, macrophages (including central nervous system microglia), astrocytes, inflammatory mediators, and blood-brain barrier permeability are all involved in a response that is associated with myelin sheath destruction, axonal injury, and clinical symptoms. 4 , 10 , 14 – 16 In RRMS, clinical lesions may resolve through mechanisms such as axonal changes, neuroplasticity, and remyelination. 13 Progressive forms of MS are associated with cumulative axonal loss and increasing neurologic deficits. 10

Clinical Presentation

Symptoms and signs of MS depend on the areas of neuronal involvement 17 ( Table 2 1 , 18 – 22 ) . Common presenting symptoms include sensory disturbances, motor weakness, impaired gait, incoordination, optic neuritis (unilateral vision loss with pain worsened by extraocular movements), and Lhermitte sign (an electric shock–like sensation down the spine on neck flexion). 18 – 20 Other symptoms include urinary, bowel, and sexual dysfunction.

In RRMS, relapse symptoms evolve over days before partially or fully resolving, and patients are typically stable between acute exacerbations. Some symptoms, such as fatigue, can be persistent. 20 , 23

Multiple diseases may mimic MS clinically and radiologically ( Table 3 ) . 13 , 18 , 23 , 24 The differential diagnosis includes genetic, infectious, inflammatory, metabolic, and neoplastic processes. Psychiatric diseases, ingestions, and nutritional deficiencies may also be mistaken for MS. 13 , 18 , 23 , 24 Table 4 lists tests that may help differentiate MS from other diseases. 18

A patient history, neurologic examination, and application of the 2017 McDonald Criteria are needed to accurately diagnose MS ( Table 5 ) . 25 Diagnosis relies on the acute exacerbations of MS being disseminated in space and time ( Figure 1 18 ) . In cases where only part of the diagnostic criteria are met, magnetic resonance imaging (MRI) of the brain and spine may be used to confirm the presence of lesions consistent with MS ( Figure 2 , Figure 3 , and  Figure 4 ) . 18 Cerebrospinal fluid assays demonstrating oligoclonal bands may also aid in meeting diagnostic criteria. 25

The diagnosis should be questioned if the patient has a family history of neurologic disorders other than MS, an abrupt or transient (less than 24 hours) presentation, progressive ataxia, cognitive dysfunction, other organ involvement, or nonspecific neurologic symptoms that are difficult to localize. 13 , 20 , 26

Patients with MS should be treated by a multidisciplinary team that may include physical and occupational therapists, speech and language therapists, mental health professionals, pharmacists, dietitians, neurologists, and family physicians. 27

INITIAL PRESENTATION AND ACUTE RELAPSES

Steroids are the mainstay of treatment for the initial presentation of MS and MS relapses. A Cochrane review and another systematic review and meta-analysis found no difference in effectiveness between intravenous and oral steroids for relapse recovery or MRI activity. 28 , 29 A higher dosage of steroids, such as 1,000 mg per day of methylprednisolone (intravenously or orally) for three days, is recommended. 30 , 31 Patients who do not have an adequate response to treatment with steroids may benefit from plasmapheresis. 30 , 32 A randomized controlled trial involving six plasmapheresis treatments in patients unresponsive to steroids found higher rates of complete recovery at one month than in those treated with placebo. 33

SMOKING CESSATION

Patients with MS who smoke tobacco should be strongly encouraged to quit. A cohort study found that each smoke-free year was associated with a decrease in disability progression. 34 A cross-sectional study found that each additional year of smoking accelerated the development of secondary progressive MS by 4.7% (95% CI, 2.3 to 7.2). 35

DISEASE-MODIFYING THERAPY

In patients with active MS, long-term disease-modifying therapy should be initiated to decrease new clinical attacks and radiographic lesions and delay disability progression. 36 , 37 There is disagreement about whether to use disease-modifying therapy in patients with clinically isolated syndrome. 36 – 38

Interferon beta-1b (Betaseron, Extavia) was the first disease-modifying therapy approved for use in 1993. Since then, multiple injectable agents, infusions, and oral medications such as monoclonal antibodies and other immunomodulatory medications targeting multiple steps in the MS inflammatory pathway have been approved by the U.S. Food and Drug Administration ( Table 6 ) . 13 , 37 – 39

The choice of initial disease-modifying therapy is dependent on patient preference, disease activity, potential adverse effects, and specialist input. All approved agents help prevent disease progression, with a relative risk of progression from 0.47 for mitoxantrone to 0.87 for interferon beta-1a (Avonex, Rebif). 40 For patients with less active disease, agents with a lower risk of adverse effects (e.g., cardiac arrhythmia, increased risk of malignancy, progressive multifocal leukoencephalopathy) are preferred at the cost of effectiveness. For patients with more active disease, effectiveness may be considered more important than avoiding adverse effects. Shared decision-making conversations should consider the availability of the medication options, route and frequency of administration, patient preferences regarding effectiveness vs. adverse effects, and the patient's ability to tolerate and comply with monitoring regimens. 36 , 37

For patients who have newly diagnosed RRMS with minimal symptoms and MRI burden of disease, an appropriate regimen may include a moderately effective agent such as interferon or glatiramer (Copaxone, Glatopa) to control disease activity while minimizing adverse effects. In patients with newly diagnosed, rapidly evolving RRMS, a highly effective agent such as alemtuzumab (Lemtrada), cladribine (Mavenclad), natalizumab (Tysabri), or ocrelizumab (Ocrevus) may be considered. A greater risk of debilitating adverse effects is weighed against a greater chance of controlling disease activity in this strategy. 38 Ocrelizumab is the only disease-modifying therapy currently approved by the U.S. Food and Drug Administration for primary progressive MS. 39

Medications should be continued for at least six months to allow time for benefits to occur. If the disease is not controlled by initial therapy, the patient should be offered a more effective medication, recognizing the increased potential for adverse effects. 37 , 38 It is appropriate to consider switching medications if adverse effects develop. 37

Once started, disease-modifying therapy is generally continued for the patient's lifetime; however, guidelines allow for exceptions. Discontinuation can be considered for patients with secondar y progressive MS who have a higher level of disability, are nonambulatory, and have not had a relapse in two years. Discontinuation can also be considered before conception for patients who want to become pregnant and have well-controlled MS. 37 , 38 During pregnancy, patients tend to have a lower risk of flare-ups, with overall better-controlled disease. 41

In addition to disease-modifying therapy, preliminary research suggests that hematopoietic stem cell transplantation may be a more effective alternative in preventing relapses and disability accumulation. 42

SYMPTOM-BASED CARE

In addition to treatment directed at acute relapses and disease progression, patients with MS require a comprehensive program that addresses overall wellness, symptom management, and comorbid mental health and physical conditions ( Table 7 ) . 13 , 22 , 38 , 43 – 85 A multidisciplinary approach is most effective for many symptoms. Physical activity has good evidence for improving walking ability (increased distance on six-minute walking test, faster times on 10-minute walking test), balance (as measured by the Berg Balance Scale), and depression (decreased scores on depression scales). 43 – 45 Pharmacotherapy used for symptoms associated with MS is often off-label and supported by low-quality evidence. A notable exception is dalfampridine extended-release (Ampyra), which has been approved by the U.S. Food and Drug Administration to improve walking in patients with MS. 86 Pain is treated with analgesics, neuromodulators, hydrotherapy, and sometimes cannabinoids. 49 , 82 , 84

More than one-half of patients with untreated RRMS transition to secondary progressive disease. 36 Greater disability and brain atrophy at the time of diagnosis, male sex, and older age are risk factors for progression to more significant functional limitations. 13 Disease-modifying therapy has been shown to alter the course of MS, decreasing the rate at which disability progresses, and is also associated with a lower likelihood of transitioning to progressive disease. 37 , 87

Many governments, nonprofit organizations, and websites provide information and support for individuals and families affected by MS ( eTable A ) .

This article updates previous articles on this topic by Saguil, et al. , 18  and Calabresi . 88

Data Sources: PubMed, the Cochrane Database of Systematic Reviews, Essential Evidence Plus, the National Institute for Health and Care Excellence (UK), and the European Committee for Treatment and Research in Multiple Sclerosis were searched for relevant articles and clinical practice guidelines. Key words included multiple sclerosis, demyelinating disorders, disease-modifying treatment, and others as directed by the search. Search dates: August 2021 and May 2022.

Editor's Note: Dr. Saguil is a contributing editor for AFP .

The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Army or the Uniformed Services University of the Health Sciences.

Hauser SL, Cree BAC. Treatment of multiple sclerosis: a review. Am J Med. 2020;133(12):1380-1390.e2.

Howard J, Trevick S, Younger DS. Epidemiology of multiple sclerosis. Neurol Clin. 2016;34(4):919-939.

Belbasis L, Bellou V, Evangelou E, et al. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol. 2015;14(3):263-273.

Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018;378(2):169-180.

Palmer AJ, van der Mei I, Taylor BV, et al. Modelling the impact of multiple sclerosis on life expectancy, quality-adjusted life years and total lifetime costs: evidence from Australia. Mult Scler. 2020;26(4):411-420.

Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286.

Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8(11):647-656.

Antel J, Antel S, Caramanos Z, et al. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity?. Acta Neuropathol. 2012;123(5):627-638.

Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol. 2012;11(2):157-169.

Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545-558.

Lublin FD, Reingold SC National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46(4):907-911.

Koch-Henriksen N, Magyari M. Apparent changes in the epidemiology and severity of multiple sclerosis. Nat Rev Neurol. 2021;17(11):676-688.

Thompson AJ, Baranzini SE, Geurts J, et al. Multiple sclerosis. Lancet. 2018;391(10130):1622-1636.

Kutzelnigg A, Lassmann H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb Clin Neurol. 2014;122:15-58.

Bø L, Vedeler CA, Nyland HI, et al. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol. 2003;62(7):723-732.

Gilmore CP, Geurts JJ, Evangelou N, et al. Spinal cord grey matter lesions in multiple sclerosis detected by post-mortem high field MR imaging. Mult Scler. 2009;15(2):180-188.

Ledesma J, Puttagunta PP, Torabi S, et al. Presenting symptoms and disease severity in multiple sclerosis patients. Neurol Int. 2021;13(1):18-24.

Saguil A, Kane S, Farnell E. Multiple sclerosis: a primary care perspective. Am Fam Physician. 2014;90(9):644-652.

Colombo B, Martinelli Boneschi F, Rossi P, et al. MRI and motor evoked potential findings in nondisabled multiple sclerosis patients with and without symptoms of fatigue. J Neurol. 2000;247(7):506-509.

Brownlee WJ, Hardy TA, Fazekas F, et al. Diagnosis of multiple sclerosis: progress and challenges. Lancet. 2017;389(10076):1336-1346.

Nazari F, Shaygannejad V, Mohammadi Sichani M, et al. Sexual dysfunction in women with multiple sclerosis: prevalence and impact on quality of life. BMC Urol. 2020;20(1):15.

Amato MP, Langdon D, Montalban X, et al. Treatment of cognitive impairment in multiple sclerosis: position paper. J Neurol. 2013;260(6):1452-1468.

Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269-290.

Ömerhoca S, Akkaş SY, İçen NK. Multiple sclerosis: diagnosis and differential diagnosis. Noro Psikiyatr Ars. 2018;55(suppl 1):S1-S9.

Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173.

Toledano M, Weinshenker BG, Solomon AJ. A clinical approach to the differential diagnosis of multiple sclerosis. Curr Neurol Neurosci Rep. 2015;15(8):57.

Kraft AK, Berger K. Quality of care for patients with multiple sclerosis—a review of existing quality indicators. Front Neurol. 2021;12:708723.

Burton JM, O'Connor PW, Hohol M, et al. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2012(12):CD006921.

Lattanzi S, Cagnetti C, Danni M, et al. Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017;264(8):1697-1704.

Le Page E, Veillard D, Laplaud DA, et al.; COPOUSEP investigators; West Network for Excellence in Neuroscience. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomized, controlled, double-blind, non-inferiority trial [published correction appears in Lancet . 2016; 387(10016): 340]. Lancet. 2015;386(9997):974-981.

Smets I, Van Deun L, Bohyn C, et al.; Belgian Study Group for Multiple Sclerosis. Corticosteroids in the management of acute multiple sclerosis exacerbations. Acta Neurol Belg. 2017;117(3):623-633.

Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):294-300.

Brochet B, Deloire M, Germain C, et al. Double-blind, randomized controlled trial of therapeutic plasma exchanges vs. sham exchanges in moderate-to-severe relapses of multiple sclerosis. J Clin Apher. 2020;35(4):281-289.

Tanasescu R, Constantinescu CS, Tench CR, et al. Smoking cessation and the reduction of disability progression in multiple sclerosis: a cohort study. Nicotine Tob Res. 2018;20(5):589-595.

Ramanujam R, Hedström AK, Manouchehrinia A, et al. Effect of smoking cessation on multiple sclerosis prognosis. JAMA Neurol. 2015;72(10):1117-1123.

Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis [published correction appears in Mult Scler . 2020; 26(4): 517]. Mult Scler. 2018;24(2):96-120.

Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology [published correction appears in Neurology . 2019; 92(2): 112]. Neurology. 2018;90(17):777-788.

National Health Service England. Treatment algorithm for multiple sclerosis disease-modifying therapies. Updated March 8, 2019. Accessed November 23, 2021. https://www.england.nhs.uk/commissioning/wp-content/uploads/sites/12/2019/03/Treatment-Algorithm-for-Multiple-Sclerosis-Disease-Modifying-Therapies-08-03-2019-1.pdf

U.S. Food and Drug Administration. Drugs@FDA: FDA-approved drugs. Accessed November 23, 2021. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm

Li H, Hu F, Zhang Y, et al. Comparative efficacy and acceptability of disease-modifying therapies in patients with relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis. J Neurol. 2020;267(12):3489-3498.

Vukusic S, Michel L, Leguy S, et al. Pregnancy with multiple sclerosis. Rev Neurol (Paris). 2021;177(3):180-194.

Burt RK, Balabanov R, Burman J, et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs. continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA. 2019;321(2):165-174.

National Institute for Health and Care Excellence. Multiple sclerosis in adults: management. Updated November 11, 2019. Accessed November 30, 2021. https://www.nice.org.uk/guidance/cg186/chapter/Recommendations#ms-symptom-management-and-rehabilitation

Haselkorn JK, Hughes C, Rae-Grant A, et al. Summary of comprehensive systematic review: rehabilitation in multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2015;85(21):1896-1903.

Selph SS, Skelly AC, Wasson N, et al. Physical activity and the health of wheelchair users: a systematic review in multiple sclerosis, cerebral palsy, and spinal cord injury. Arch Phys Med Rehabil. 2021;102(12):2464-2481.e33.

Frohman TC, Castro W, Shah A, et al. Symptomatic therapy in multiple sclerosis. Ther Adv Neurol Disord. 2011;4(2):83-98.

Samkoff LM, Goodman AD. Symptomatic management in multiple sclerosis. Neurol Clin. 2011;29(2):449-463.

Filli L, Zörner B, Kapitza S, et al. Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis. Neurology. 2017;88(9):832-841.

Koppel BS, Brust JC, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(17):1556-1563.

Herring MP, Puetz TW, O'Connor PJ, et al. Effect of exercise training on depressive symptoms among patients with a chronic illness: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(2):101-111.

Rietberg MB, Brooks D, Uitdehaag BM, et al. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2005(1):CD003980.

Nicholas RS, Friede T, Hollis S, et al. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev. 2009(1):CD004193.

Rosti-Otajärvi EM, Hämäläinen PI. Neuropsychological rehabilitation for multiple sclerosis. Cochrane Database Syst Rev. 2014(2):CD009131.

Coggrave M, Norton C, Cody JD. Management of faecal incontinence and constipation in adults with central neurological diseases. Cochrane Database Syst Rev. 2014(1):CD002115.

He D, Zhang Y, Dong S, et al. Pharmacological treatment for memory disorder in multiple sclerosis. Cochrane Database Syst Rev. 2013(12):CD008876.

Xiao Y, Wang J, Luo H. Sildenafil citrate for erectile dysfunction in patients with multiple sclerosis. Cochrane Database Syst Rev. 2012(4):CD009427.

Khan F, Turner-Stokes L, Ng L, et al. Multidisciplinary rehabilitation for adults with multiple sclerosis. Cochrane Database Syst Rev. 2007(2):CD006036.

Khan F, Ng L, Turner-Stokes L. Effectiveness of vocational rehabilitation intervention on the return to work and employment of persons with multiple sclerosis. Cochrane Database Syst Rev. 2009(1):CD007256.

Koch MW, Glazenborg A, Uyttenboogaart M, et al. Pharmacologic treatment of depression in multiple sclerosis. Cochrane Database Syst Rev. 2011(2):CD007295.

Mills RJ, Yap L, Young CA. Treatment for ataxia in multiple sclerosis. Cochrane Database Syst Rev. 2007(1):CD005029.

Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst Rev. 2001(4):CD001332.

Thomas PW, Thomas S, Hillier C, et al. Psychological interventions for multiple sclerosis. Cochrane Database Syst Rev. 2006(1):CD004431.

Silveira SL, Huynh T, Kidwell A, et al. Behavior change techniques in physical activity interventions for multiple sclerosis. Arch Phys Med Rehabil. 2021;102(9):1788-1800.

Molhemi F, Monjezi S, Mehravar M, et al. Effects of virtual reality vs. conventional balance training on balance and falls in people with multiple sclerosis: a randomized controlled trial. Arch Phys Med Rehabil. 2021;102(2):290-299.

Kim Y, Mehta T, Lai B, et al. Immediate and sustained effects of interventions for changing physical activity in people with multiple sclerosis: meta-analysis of randomized controlled trials. Arch Phys Med Rehabil. 2020;101(8):1414-1436.

Lincoln NB, Bradshaw LE, Constantinescu CS, et al. Group cognitive rehabilitation to reduce the psychological impact of multiple sclerosis on quality of life: the CRAMMS RCT. Health Technol Assess. 2020;24(4):1-182.

Khan F, Amatya B. Rehabilitation in multiple sclerosis: a systematic review of systematic reviews. Arch Phys Med Rehabil. 2017;98(2):353-367.

Andreu-Caravaca L, Ramos-Campo DJ, Chung LH, et al. Dosage and effectiveness of aerobic training on cardiorespiratory fitness, functional capacity, balance, and fatigue in people with multiple sclerosis: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2021;102(9):1826-1839.

Tramontano M, Russo V, Spitoni GF, et al. Efficacy of vestibular rehabilitation in patients with neurologic disorders: a systematic review. Arch Phys Med Rehabil. 2021;102(7):1379-1389.

Abou L, Alluri A, Fliflet A, et al. Effectiveness of physical therapy interventions in reducing fear of falling among individuals with neurologic diseases: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2021;102(1):132-154.

Minden SL, Feinstein A, Kalb RC, et al.; Guideline Development Subcommittee of the American Academy of Neurology. Evidence-based guideline: assessment and management of psychiatric disorders in individuals with MS. Neurology. 2014;82(2):174-181.

Latimer-Cheung AE, Pilutti LA, Hicks AL, et al. Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. Arch Phys Med Rehabil. 2013;94(9):1800-1828.e3.

Amatya B, Khan F, La Mantia L, et al. Non pharmacological interventions for spasticity in multiple sclerosis. Cochrane Database Syst Rev. 2013(2):CD009974.

Phé V, Chartier-Kastler E, Panicker JN. Management of neurogenic bladder in patients with multiple sclerosis. Nat Rev Urol. 2016;13(5):275-288.

Van Der Walt A, Sung S, Spelman T, et al. A double-blind, randomized, controlled study of botulinum toxin type A in MS-related tremor. Neurology. 2012;79(1):92-99.

Oliveria SF, Rodriguez RL, Bowers D, et al. Safety and efficacy of dual-lead thalamic deep brain stimulation for patients with treatment-refractory multiple sclerosis tremor: a single-centre, randomised, single-blind, pilot trial. Lancet Neurol. 2017;16(9):691-700.

Motl RW, Sandroff BM, Kwakkel G, et al. Exercise in patients with multiple sclerosis. Lancet Neurol. 2017;16(10):848-856.

Hempel S, Graham GD, Fu N, et al. A systematic review of the effects of modifiable risk factor interventions on the progression of multiple sclerosis. Mult Scler. 2017;23(4):513-524.

Ploughman M. A new era of multiple sclerosis rehabilitation: lessons from stroke. Lancet Neurol. 2017;16(10):768-769.

Boesen F, Nørgaard M, Trénel P, et al. Longer term effectiveness of inpatient multidisciplinary rehabilitation on health-related quality of life in MS patients: a pragmatic randomized controlled trial – The Danish MS Hospitals Rehabilitation Study. Mult Scler. 2018;24(3):340-349.

Abo Youssef N, Schneider MP, Mordasini L, et al. Cannabinoids for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: a systematic review and meta-analysis. BJU Int. 2017;119(4):515-521.

Thompson AJ, Toosy AT, Ciccarelli O. Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions. Lancet Neurol. 2010;9(12):1182-1199.

Goverover Y, Chiaravalloti ND, O'Brien AR, et al. Evidenced-based cognitive rehabilitation for persons with multiple sclerosis: an updated review of the literature from 2007 to 2016. Arch Phys Med Rehabil. 2018;99(2):390-407.

Castro-Sánchez AM, Matarán-Peñarrocha GA, Lara-Palomo I, et al. Hydrotherapy for the treatment of pain in people with multiple sclerosis: a randomized controlled trial. Evid Based Complement Alternat Med. 2012;2012:473963.

Yadav V, Bever C, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82(12):1083-1092.

Zhang E, Tian X, Li R, et al. Dalfampridine in the treatment of multiple sclerosis: a meta-analysis of randomised controlled trials. Orphanet J Rare Dis. 2021;16(1):87.

Iaffaldano P, Lucisano G, Patti F, et al.; Italian MS Register. Transition to secondary progression in relapsing-onset multiple sclerosis: definitions and risk factors. Mult Scler. 2021;27(3):430-438.

Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician. 2004;70(10):1935-1944.

Continue Reading

More in AFP

More in pubmed.

Copyright © 2022 by the American Academy of Family Physicians.

This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.  See permissions  for copyright questions and/or permission requests.

Copyright © 2024 American Academy of Family Physicians. All Rights Reserved.

• myCME Login
• Monthly CME eNewsletter

Live Events

Text-based cme, journal cme, self-study cme, multiple sclerosis, carrie m. hersh, do, msc, robert j. fox, md.

Published: April 2018 Expire: April 2021

Introduction

Definition and disease course, pathophysiology, signs and symptoms, treatment strategies, considerations in special populations.

Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disorder of the central nervous system (CNS) that affects the white and grey matter of the brain, spinal cord, and optic nerve. MS is one of the most common causes of non-traumatic disability among young and middle-aged adults. Direct MS-related healthcare costs are estimated to be more than $10 billion annually in the United States. 1 As symptoms of MS are extremely variable and often quite subtle, diagnosis and management have been greatly enhanced by the use of magnetic resonance imaging (MRI). Therapies that target inflammation and slow progression of disease are available; therefore, early diagnosis and treatment are important in limiting the impact of this potentially devastating disease. Complementary approaches such as symptom management and healthy lifestyle practices also have an important role in MS care.

There are several different forms of MS. Since these classifications were based upon clinical characteristics, they are empiric and do not reflect specific biologic pathophysiology. Nonetheless, they provide an organized framework for diagnosis and long-term management. Approximately 85% of patients present with a relapsing-remitting MS (RRMS) disease course at onset, where symptoms appear for several days to weeks, after which they usually resolve spontaneously. 2 After tissue damage accumulates over many years and reaches a critical threshold, about two-thirds of the patients transition to secondary progressive MS (SPMS), where pre-existing neurologic deficits gradually worsen over time. Relapses can be seen during the early stages of SPMS, but are uncommon as the disease further progresses. About 10% to 15% of patients have gradually worsening manifestations from the onset without clinical relapses, known as primary progressive MS (PPMS). 3 Patients with PPMS tend to be older, have fewer abnormalities on brain MRI, and generally respond less effectively to standard MS therapies. 4

Back to Top

MS affects approximately 1 million individuals in the US and 2.5 million worldwide. 5,6 Initial symptoms typically occur between 20 and 50 years of age, and women have about 3 times increased likelihood of developing MS compared with men. 1 Although MS is more frequently seen in white than African American and Hispanic populations, the latter groups overall have poorer disease outcomes in that they accumulate disability more quickly, suggesting more destructive tissue injury in these groups. The prevalence of MS varies by location and generally increases the further one travels from the equator in either hemisphere. It remains unclear whether this altered incidence represents an environmental influence (eg, vitamin D deficiency), genetic difference, variable surveillance, or other, as yet unidentified, differences.

Early in the disease course, MS involves recurrent bouts of CNS inflammation that results in damage to both the myelin sheath surrounding axons as well as the axons themselves. Histologic examination reveals foci of severe demyelination, decreased axonal and oligodendrocyte numbers, and glial scarring. The exact cause of inflammation remains unclear, but an autoimmune response directed against CNS antigens is suspected.

In progressive MS, inflammation is a less defining pathological hallmark. Instead, progressive MS is characterized by neurodegeneration of the white and grey matter resulting in brain and spinal cord atrophy on a background of mild-moderate inflammation. 7 Predominant factors driving neurodegeneration include mitochondrial dysfunction due to defective oxidative phosphorylation and nitric oxide production, resulting in a chronic state of virtual hypoxia due to unmet energy demands, 8 and age-dependent iron accumulation in myelin and oligodendrocytes leading to oxidative tissue damage. 9 Further research is needed to understand how these different pathologic subtypes affect prognosis and response to treatments. Currently, brain biopsy is the only method to definitively determine pathologic subtypes, but studies are underway to find blood, cerebrospinal fluid, and MRI biomarkers.

Historically, MS was classified as an inflammatory disease targeting white matter, with diagnostics and therapeutics focused on this mechanism of pathology. However, more recent imaging and histopathological studies suggest that cortical demyelination plays a crucial role in MS pathogenesis and cognitive dysfunction. Cortical demyelination is now recognized in early MS. 10 Although some investigative MRI modalities capture some cortical involvement, including double inversion recovery sequences at 3 tesla and ultra-high field MRI, conventional MRI metrics used in clinical practice do not show these changes well. Likewise, extensive cortical demyelination that is seen in histopathological studies is not clearly demonstrated on any current MRI modality. This pathology/imaging discordance demonstrates that we are still technologically disadvantaged in accurately assessing cortical lesion pathology in the live patient.

In the past, inflammation was thought to involve only demyelination, but pathologic studies have found significant axonal pathology as well. In actively demyelinating MS lesions, an average of more than 11,000 transected axons/mm 3 were observed, while control brain tissue had less than one transected axon/mm. 11 Significant axonal injury is also observed in cortical demyelinating lesions. Clearly, axonal injury is significant in the early stages of disease.

Later in the disease course, gradual progression of disability is observed. However, there is significantly less active inflammation during this period, so clinical progression may arise instead from degenerative changes. Nonetheless, oligodendrocyte progenitor cells capable of remyelinating axons have been observed even in white matter plaques from patients with chronic MS ( Figure 1 ). 12 This observation suggests that the potential for remyelination persists even very late in the disease course, which is an encouraging indicator for possible therapeutic targets at this late stage of disease.

Current concepts of the pathophysiology of MS are illustrated in Figure 2 . 13 In the preclinical phase, patients may develop lesions characteristic of MS visible on MRI before they phenotypically manifest symptoms, known as radiologically isolated syndrome. In a different scenario, patients may develop MS symptoms compatible with inflammatory demyelination without other characteristic lesions on MRI. This phenomenon is called clinically isolated syndrome.

On average, patients with RRMS experience clinical relapses every 1 to 2 years. Serial MRI studies show that lesions develop up to 10 to 20 times more frequently than clinical relapses Thus, although RRMS appears to have clinically active and quiescent periods, inflammatory lesions are developing and evolving almost continuously. A current hypothesis states that overt progression of disability, which marks the transition from RRMS to SPMS, occurs when ongoing irreversible tissue injury exceeds a critical threshold beyond which the nervous system can no longer compensate. It is thought that at this point the disease has primarily transitioned to a neurodegenerative condition with neurologic deterioration independent of ongoing inflammation, although superimposed inflammation can continue to cause additional injury. An important implication of this hypothesis is that the accumulation of irreversible tissue damage limits the potential for anti-inflammatory disease modifying therapies (DMTs) when used in the progressive stage of the disease. To be maximally effective, DMTs should be started early in patients with RRMS before permanent disability develops. Overall, an incomplete understanding of progressive MS pathogenesis has slowed the development of effective therapies and requires further inquiry.

MS can cause a wide variety of neurologic symptoms since it can affect numerous areas of the brain, optic nerve, and spinal cord ( Figure 3 ). Characteristic lesions are located in the periventricular and juxtacortical regions, in addition to the brainstem, cerebellum, spinal cord, and optic nerve. Disease localized to the spinal cord may cause partial or complete transverse myelitis, involving sensory or motor changes involving 1 or both sides of the body. Lhermitte’s phenomenon is a nonspecific symptom whereby flexion of the neck causes an electrical-like shooting sensation that extends into the arms or down the back. It is thought to arise from partially demyelinated tissue, whereby mechanical stimulation leads to axonal activation. Other common symptoms of MS often stemming from spinal cord lesions include bladder and bowel dysfunction. Posterior fossa (eg, brainstem and cerebellum) involvement may present as diplopia, dysphagia, altered sensation or weakness of the face, or ataxia. Inflammation of the optic nerve (optic neuritis) usually presents as blurry vision with painful eye movements, and is often an early clinical manifestation of RRMS.

Of all the lesions in MS, cerebral lesions are the most common but cause the fewest symptoms early in MS. Most cerebral lesions are not located in eloquent regions and so are thus clinically silent and identified only by brain MRI. Very large cerebral lesions may present with weakness or numbness and rarely may cause aphasia or other cortical dysfunction. Cerebral and cortical lesions may also cause subtle symptoms, such as cognitive impairment, fatigue, and affective disorders like depression. Although these symptoms are not uncommon in patients with MS, they are also nonspecific and can be seen in a multitude of disorders.

Symptoms of a clinical relapse typically arise over hours to days, worsen over several weeks, and then gradually subside over several weeks or months. Residual enduring neurologic symptoms are common. The gradual progression of progressive MS can manifest as worsening myelopathy causing asymmetric limb weakness, ataxia, spasticity, and bladder/bowel and sexual dysfunction; impaired mobility; impaired motor dexterity; and cognitive impairment.

There are no pathognomonic clinical, laboratory, or imaging findings in MS. The diagnosis ultimately is a clinical decision based on weighing the factors that support the diagnosis against those that fail to support it or point to the possibility of an alternative diagnosis.

The Schumacher criteria from 1965 capture the essence of the diagnosis of MS: CNS lesions disseminated in space and time and the elimination of alternative diagnoses. 14 These core diagnostic characteristics remain relevant today.

The International Panel on MS Diagnosis criteria, also called the McDonald criteria, are diagnostic criteria for MS that incorporate the clinical characteristics and MRI features. 15 Revisions were made in 2005, 2010, and most recently in 2017 as a reflection of an increased understanding of the natural history of MS and improved MRI techniques.

The latest version of the McDonald criteria (2017) simplifies the diagnostic process and allows earlier diagnosis ( Table 1 ). 16 A diagnosis of clinically definite multiple sclerosis requires fulfillment of dissemination in space and time. Dissemination in space is defined as 1 or more T2-hyperintense lesions in more than 1 characteristic location of MS, which includes the periventricular, juxtacortical, and infrantentorial regions (eg, brainstem and cerebellum), and spinal cord. Cerebrospinal-fluid restricted oligoclonal bands can be used as paraclinical support for an early diagnosis of MS ( see Table 1 ). The 2016 magnetic resonance imaging in multiple sclerosis (MAGNIMS) criteria now include the optic nerve as 1 of the characteristic locations fulfilling an MS diagnosis, 17 though it still remains separate from the McDonald criteria. Dissemination in time is defined as 1) the simultaneous presence of a gadolinium-enhancing (GdE) and non-enhancing lesion at any time on initial MRI or 2) a new T2-hyperintense or GdE lesion on follow-up MRI with reference to a baseline scan, irrespective of the timing of the baseline MRI.

Table 1: Summary of the 2017 McDonald Criteria

a DIS and DIT can be made by clinical features alone or by a combination of clinical and MRI features. b DIS principle requires that there are asymptomatic lesions typical of MS present in 2 or more sites within the central nervous system: periventricular, subcortical, infrantentorial, and spinal cord. c DIT principle requires that 2 attacks separated by more than 30 days have occurred in different parts of the central nervous system. MRI criteria for DIT stipulate either an asymptomatic enhancing T2 lesion along with a non-enhancing T2 lesion on any one scan, or a new T2 or gadolinium-enhancing lesion on a follow-up scan. d In a patient with a typical clinically isolated syndrome and fulfillment of clinical or MRI criteria for DIS with no better explanation for the clinical presentation, demonstration of cerebrospinal fluid-specific oligoclonal bands allows an MS diagnosis to be made (change from the 2010 McDonald Criteria).

Adapted from AJ Thompson, et al. 16

In all cases, the practitioner must rule out better explanations for the clinical presentation other than multiple sclerosis. In the context of the MacDonald criteria, a single episode of demyelination and certain findings on a single MRI can fulfill the diagnostic criteria for MS, even before a second clinical episode or new MRI lesion. The revisions also preserve diagnostic sensitivity and specificity and address their applicability across different populations, allowing for more uniform and widespread use across groups.

In 2013, an international panel of MS experts proposed changes to the classification of MS to more effectively characterize the disease course. 18 One of the changes included the categorization of disease as either manifesting active inflammation (‘active’) or no active inflammation (‘non-active’) based on new clinical relapses or new T2 or GdE MRI lesions or in combination within the past year. Another change was the categorization of disease based on the presence or absence of continued gradual clinical decline (with progression or without progression) ( Figure 4 ). 18 These disease classifications were intended to provide a clearer conceptualization of progressive MS and its differentiation from active inflammation.

Although the diagnosis of MS cannot be based on MRI alone, typical MRI lesions in the periventricular and juxtacortical regions, as well as the brainstem, cerebellum, and spinal cord can raise the suspicion of MS, warranting further diagnostic workup or monitoring. MRI is typically obtained at the time of diagnosis to both exclude other diagnoses and stage the severity of disease. Patients with a typical history of MS without typical MRI findings are highly unusual and should prompt consideration of an alternative diagnosis.

Management of MS requires multiple therapeutic approaches. The current goals of MS management involve the treatment of acute relapses, prevention of new disease activity and disability progression, management of symptoms that affect quality of life, and adherence to a healthy lifestyle.

Acute Relapse

Several studies have found that treatment with corticosteroids can shorten the length of relapses and may even improve long-term outcomes. 19,20 A typical regimen is 500 mg to 1,000 mg of intravenous methylprednisolone with or without a tapering dose of oral prednisone over several weeks. The standard protocol at the Cleveland Clinic is intravenous methylprednisolone 1,000 mg daily for 3 to 5 days, followed by a 12-day prednisone taper (60 mg daily, decreasing by 20 mg every 4 days). Evaluation of a relapse should include a search for precipitating factors such as fever, upper respiratory illness, or bladder infection. For patients who do not respond sufficiently to corticosteroids or who do not tolerate corticosteroids, adrenocorticotropic hormone or plasma exchange can be considered.

Disease-Modifying Therapies for Relapsing MS: Treatment Targets and Therapeutic Strategies

After the acute relapse is treated, consideration should be given to use of DMTs, which primarily target the inflammatory, demyelinating aspects of the disease. A list of DMTs for MS approved by the U.S. Food & Drug Administration (FDA) is presented in Table 2 .

Table 2: Disease-Modifying Therapies (Brand Name) for MS

ª Voluntarily withdrawn from the market in March 2018 due to concern about the benefit/risk profile, see https://www.fda.gov/Drugs/DrugSafety/ucm600999.htm

Current therapies target the immune dysfunction in MS and resultant neural tissue damage with the goal of preventing or at least reducing the long-term risk of clinically significant disability. Early treatment is key since it offers the greatest chance of preventing or delaying tissue injury and long-term disability. Although the underlying pathogenesis of MS still remains poorly understood, remarkable progress has been made in the development of drug therapies that inhibit disease activity. Using available options, including the advent of newer more effective drugs, there is the potential to achieve a disease-free status, characterized by the prevention of clinical relapses and disability progression and absence of new lesions on MRI. This widely accepted treat-to-target approach is known as “No Evidence of Disease Activity” (NEDA). Patients who achieve NEDA may have better long-term outcomes, although maintaining NEDA over the course of years or decades is challenging.

Escalation therapy and high-efficacy early therapy (HET) are 2 general management strategies to achieve NEDA in RRMS. In escalation therapy, the patient is initially started on a lower efficacy agent, such as one of the standard injectable DMTs. The rationale for using lower efficacy treatment is that such agents typically have a more desirable safety profile for better long-term safety overall. In the presence of disease activity, the patient is subsequently switched to higher efficacy treatment, often in a step-wise approach (eg, injectable → oral → infusion). HET is an alternative approach in which patients are started on high-efficacy therapy (eg, natalizumab and ocrelizumab) early in the course of their disease, and even as first-line agents. This approach may carry more risk in certain circumstances, especially given that patients will have more long-term exposure to drugs with significant immune-altering effects. However, the rationale behind this treatment strategy is that the benefits of early disease control outweigh the risks and may have longer-term benefit compared with escalation therapy. There are middle-ground approaches, too, that utilize oral therapies such as fingolimod and dimethyl fumarate as first-line treatments. Multicenter, prospective, pragmatic clinical trials are needed to address these important clinical questions.

It is important to note that all current MS therapies are preventative and not restorative. As the disease progresses, response to DMT typically declines. The key to successful treatment of MS is to slow the inflammatory process early in the disease. The therapeutic nihilism of the past should be replaced by aggressive treatment and monitoring, while carefully balancing the potential risks and benefits. Monitoring patients clinically and with surveillance MRI scans during treatment is important to detect non-responders and modify therapy accordingly.

It is likely that the accumulation of irreversible tissue damage limits the potential for benefit from DMT as the disease progresses. However, with better understanding of MS pathogenesis and identification of appropriate outcomes measures for progressive MS in clinical trials, the therapeutic landscape of DMT strategies for this disabling and neurodegenerative disease state is rapidly evolving and holds great promise for the future.

Injectable Platform Therapies

Four first-line injectable therapies, otherwise known as platform agents, are currently available in the US: intramuscular interferon (IFN) beta-1a (Avonex), subcutaneous IFN beta-1a (Rebif; Plegridy), subcutaneous IFN beta-1b (Betaseron, Extavia), and glatiramer acetate (Copaxone, Glatopa) ( Table 3 ). The IFN medications are recombinant products with an amino acid sequence that is identical or nearly identical to that of human IFN beta-1. Glatiramer acetate is a random polypeptide based on the amino acid sequence of a myelin protein. All of these medications appear to modulate the immune response in MS, although glatiramer acetate and IFN beta medications probably work through different mechanisms.

Table 3: Injectable Platform Therapies

Based on data from Oh J, et al. 21

In randomized, placebo-controlled trials, all of these medications decreased the rate of clinical relapses by about 30%, decreased the severity of the relapses, and had beneficial effects on measures of disease activity on MRI. 22-25 All of the platform medications are reasonably well tolerated, and 15 to 20 years of accumulated data and clinical experience suggest strong long-term safety. The platform therapies are similar in efficacy, and selection is generally based on physician and patient preferences and side-effect profile. Potential adverse effects of the IFN medications include hepatic and hematological toxicities, flu-like side effects, and worsening of headaches, depression, and spasticity. Glatiramer acetate may have the potential for more bothersome injection site reactions, particularly in thin patients. All 4 injectable platform therapies are appropriate first-line therapies in RRMS.

Daclizumab (Zinbryta, 150 mg once monthly subcutaneous injection) was voluntarily withdrawn from the market in March 2018 due to concern about the drug’s benefit/risk profile( https://www.fda.gov/Drugs/DrugSafety/ucm600999.htm ). Approved by the FDA for relapsing forms of MS in May 2016, daclizumab is a humanized monoclonal antibody that binds to and blocks the high-affinity interleukin-2 receptor alpha chain, which inhibits T-cell activation and proliferation. Its clinical benefit is also thought to result from the expansion of a subset of regulatory natural killer cells. 26

• Liver function tests: baseline before initiations, monthly prior to next dose, and monthly for 6 months after discontinuation
• Purified protein derivative skin or blood tuberculosis test: before initiation
• Hepatitis serology: before initiation
• Pregnancy test: before initiation
• Cutaneous reactions: after initiation.

Randomized controlled trials (RCTs) of daclizumab found that it reduces the annualized relapse rate (ARR) by 54% compared with placebo 27 and by 45% compared with active comparator intramuscular IFN beta-1a. 28 The number of new or newly enlarging T2-hyperintense lesions was 54% lower with daclizumab than with intramuscular IFN beta-1a over a period of 96 weeks. 28

Overall, the incidence of adverse effects was comparable between daclizumab and comparator treatments in phase 3 clinical trials. 27,28 However, daclizumab is associated with a higher proportion of serious infections. Of these, urinary tract infections, upper respiratory tract infections, pharyngitis, and sinusitis are the most common adverse effects. Most resolve with standard treatments without subsequent complications. There was 1 patient treated with daclizumab who died from complications of a local psoas abscess. Other side effects include cutaneous reactions, 1 case of autoimmune hepatitis, 29 and hepatotoxicity including 1 case of fatal fulminant hepatic failure. 30

Oral Therapies

There are currently 3 oral DMTs approved by the FDA. These therapies include fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) ( Table 4 ).

Table 4: Oral Therapies

CBC = complete blood count; ECG = electrocardiogram; LFTs = liver function tests.

Fingolimod was approved in September 2010 as the first oral disease therapy for MS. Fingolimod acts by binding to the sphingosine-1-phosphate receptor on lymphocytes, which prevents egress of lymphocytes from lymph nodes. The sequestration of autoreactive lymphocytes prevents their recirculation to the CNS, thus inhibiting one of the primary steps in MS pathogenesis. Fingolimod crosses into the CNS and may have direct effects within the CNS, as well.

Most fingolimod-associated side effects are mild to moderate in severity and include upper respiratory tract infections, headache, diarrhea, and back pain. The most concerning adverse effects include cardiac events (bradycardia and atrioventricular block at treatment initiation), elevated liver enzymes, rare serious infections (eg, herpes virus infections), and macular edema. The development of these serious side effects during clinical trials led to strict FDA recommendations for close monitoring during first dose administration and risk factor mitigation strategies to reduce potential serious complications. These parameters include baseline complete blood count (CBC), liver function tests (LFTs), electrocardiogram, ophthalmological evaluation, and serum varicella virus immunoglobulin G titer prior to fingolimod initiation. First-dose administration is conducted under the supervision of a healthcare provider (either at home or in a medical center) where patients are monitored for 6 hours with hourly vital sign checks and a repeat electrocardiogram after 6 hours. Extended monitoring for a total of 24 hours is needed if bradycardia or QT prolongation is observed, and with other cardiac risk factors. Periodic labs including CBC and LFTs and ophthalmological reassessment are used for continued safety surveillance.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in association with fingolimod. PML is a serious viral infection of the brain, arising from the ubiquitous John Cunningham virus (JCV), which resides in the kidneys and bone marrow in about half of adults. The estimated rate of PML with fingolimod is about 1:10,000 overall, with a higher rate in those treated for more than 2 years. 33

Teriflunomide

Teriflunomide was the second oral DMT approved by the FDA in September 2012. It is an active metabolite of leflunomide and acts by inhibiting the de novo synthesis of pyrimidine nucleotides through the inhibition of dihydroorotate dehydrogenase. 34 It also inhibits T-lymphocyte activation and cytokine production in addition to cytostatic effects on proliferating B- and T-lymphocytes. 35 Phase 3 trials of teriflunomide showed that it reduces the ARR by 35 compared with placebo. 36,37 However, a phase 3 trial comparing teriflunomide and subcutaneous IFN beta-1a showed them to have relatively similar efficacy. 38

Teriflunomide is relatively safe and generally well-tolerated. There is no increased risk of opportunistic infections, and most of the adverse effects related to the medication are transitory. The most common adverse effects observed in RCTs and in clinical practice are mild to moderate in severity and include nasopharyngitis, gastrointestinal symptoms, decrease in hair density, mildly elevated LFTs, rash, and fatigue. Patients should be screened for tuberculosis before initiating therapy. Risk mitigation strategies include LFTs at baseline and every 6 months while on the medication and a baseline and 6-month CBC. 39

Although teriflunomide was not carcinogenic in mice and rats, it was found to be mutagenic and resulted in embryo lethality in rats. Thus, it has a pregnancy category X designation. In this context, pregnancy must be excluded in all women of childbearing potential prior to treatment, and effective contraceptive methods must be employed for both women and men. An accelerated removal process is available for patients who become pregnant or desire to become pregnant (or father a child) while taking teriflunomide.

Dimethyl Fumarate

The most frequent adverse effects associated with DMF are gastrointestinal symptoms, including stomach pain, nausea, vomiting, and diarrhea. Gastrointestinal symptoms are generally more prominent during the first several weeks of treatment and usually improve significantly thereafter. Taking DMF with food and slower initial dose titration may offset potential gastrointestinal side effects. Transient skin flushing is also observed intermittently. Concomitant use of low-dose aspirin substantially reduces associated skin flushing.

Lymphopenia is a possible side effect without associated increased risk of serious infections. Cases of PML have been reported in association with dimethyl fumarate. The estimated rate of PML with dimethyl fumarate is less than 1:15,000 overall, with a higher rate in those with sustained lymphopenia (ie, 6 months). In this context, baseline and periodic CBC monitoring every 6 months is recommended surveillance measures while on DMF.

Infusion Therapies

There are currently 3 infusion DMTs approved by the FDA to reduce disease activity in relapsing forms of MS and are considered highly effective therapies. These DMTs include natalizumab (Tysabri), alemtuzumab (Lemtrada,), and ocrelizumab (Ocrevus) ( Table 5 ). Ocrelizumab is also the first DMT for treating patient with PPMS approved by the FDA.

Table 5: Common Symptoms in MS and Potential Treatments

Ab = antibody; bid = twice daily; CBC = complete blood count; CMP = complete metabolic profile; CSP = cerebrospinal fluid; HIV = human immunodeficiency virus; JCV = John Cunningham Virus; LFTs = liver function tests; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PO = oral; SCr = serum creatinine; TB = tuberculosis; TSH = thyroid stimulating hormone; VZV = varicella zoster.

Based on data from Oh J, et al. 21 and Ontaneda D, et al. 44

Natalizumab

Natalizumab, approved by the FDA in November 2004, is a monoclonal antibody targeting the cellular adhesion molecule very late antigen-4. By blocking very late antigen-4, fewer inflammatory cells enter the brain and thereby blunt CNS inflammation typical of MS. Clinical trials of natalizumab showed that it reduces clinical relapses by 67% and new brain lesions by 83% in pivotal RCTs. 45,46 Thus natalizumab is considered one of the most clinically effective DMTs for relapsing MS to date.

Natalizumab is relatively well-tolerated with mild headache, fatigue, anxiety, menstrual irregularities, peripheral edema, and routine infections (eg, upper respiratory infection and pharyngitis) occasionally observed. Infusion-related hypersensitivity reactions (eg, hives and pruritus) occur in 2% to 4% of patients and are thought to represent immune-mediated hypersensitivity reactions. 47 Anaphylactic reactions are very rarely observed, but when observed, are typically during the second infusion. Patients who demonstrate a serious infusion reaction should discontinue natalizumab immediately and not be retreated.

The most concerning serious adverse effect of natalizumab is PML, which occurs at an overall incidence of 2.1 per 1,000 population. 48-50 Three identified risk factors that substantially alter an individual’s risk of PML include duration of natalizumab treatment, prior history of immunosuppressive therapy, and serum anti-JCV antibody status. Patients with natalizumab treatment exceeding 60 months, prior use of immunosuppressant drugs, and positive serum anti-JCV antibody testing, carry the highest estimated risk for PML at 1:119 persons. Patients who are negative for JCV antibody have a low risk of PML, estimated at 1:14,285 persons. 51

Because of PML, natalizumab was withdrawn from clinical use in February 2005 but received a second FDA approval in June 2006. Due to the serious potential for PML, natalizumab is generally reserved for patients with worrisome baseline disease activity or negative prognosticators or both, or patients who respond sub-optimally or do not tolerate other MS therapies. However, the growing experience of PML risk stratification suggests that in subjects with persistently negative JCV serology, natalizumab can be considered as first-line therapy. Like with all medications, discussions with potential natalizumab recipients should review the risks and potential benefits of this medication.

In the context of natalizumab’s risk of PML, careful risk stratification prior to treatment initiation is recommended, which enables more informed clinical decision making. It appears that natalizumab-related PML has a better prognosis than PML in other settings, although fatalities or persistent deficits are common. Accelerated removal of natalizumab from the blood (ie, through plasmapheresis or leukopheresis) likely accelerates immune reconstitution and is recommended in patients with natalizumab-related PML.

Alemtuzumab

Alemtuzumab, approved by the FDA in November 2014 for relapsing MS, is a humanized antibody that targets CD52, a cell surface protein expressed on T-lymphocytes, B-lymphocytes, natural killer cells, monocytes, and dendritic cells. 52 Alemtuzumab induces rapid depletion of circulating T- and B-lymphocytes followed by repopulation that leads to a distinctive lymphocyte profile, including an increased proportion of regulatory T-lymphocytes and memory B- and T-lymphocytes. In contrast to the slow recovery of T-lymphocytes, B-lymphocytes return to baseline levels by 3 months, which may explain the occasional development of secondary humoral autoimmune disorders. 53

RCTs of alemtuzumab showed that it reduces the number of clinical relapses versus active comparator, subcutaneous IFN beta-1a, by about 49% to 55%, in both treatment-naïve 54,55 and treatment-experienced patients. 56 Two of these trials showed reduction in the risk of confirmed worsening of disability, and all 3 showed slowing in progression of cerebral atrophy.

The most common adverse effect is infusion-related reactions (IRRs), which occurs in over 90% of patients treated with alemtuzumab without pre-medications. 54,55 The most common symptoms are headache, rash, and pyrexia; which are mostly mild-moderate in severity. IRRs are mitigated by a pretreatment protocol with intravenous methylprednisolone and symptom management with antihistamine and antipyretics.

The principal adverse effect of alemtuzumab is secondary autoimmune disorders, which is theorized to be related to the distinct lymphocyte repertoire that develops following alemtuzumab exposure. Thyroid disease is the most common, occurring in up to 34% in patients followed over 7 years. 57 Other rare secondary autoimmune adverse effects include immune thrombocytopenic purpura and antiglomerular basement membrane disease that led to renal transplant in a patient outside of clinical trials. 58 In the extension phases of clinical trials through year 6, the peak of thyroid disease occurred during year 3, nephropathy during years 1 to 2, and immune thrombocytopenic purpura throughout the study period. 59,60

The subsequent period of rapid lymphocyte depletion immediately following alemtuzumab exposure is associated with a mild increase in infections. Most of these infections are mild to moderate nasopharyngitis, urinary tract infections, and upper respiratory tract infections, although serious listeria and herpes viral infections can occur. Due to the risk of listeria and herpes viral infections, it is recommended that patients be treated with twice daily trimethoprim/sulfamethoxazole for 2 months and daily oral acyclovir for 1 year following each treatment course of alemtuzumab. 61

Ocrelizumab

Ocrelizumab, approved by the FDA in March 2017, is a humanized anti-CD20 monoclonal antibody that binds to an epitope that overlaps with that of rituximab. It is hypothesized that ocrelizumab has comparable efficacy of B-cell depletion to rituximab. In contrast, ocrelizumab is purported to have fewer side effects than rituximab because it is a more humanized antibody and thus produces greater antibody-dependent cellular toxicity and less complement-dependent cytotoxicity. 62 Pivotal phase 3 trials (OPERA I and OPERA II) demonstrated a significant ARR reduction for ocrelizumab compared with subcutaneous IFN beta-1a by 46% to 47%. 63 In a pooled analysis, there was a 40% risk reduction in time to 12-week confirmed disability worsening and a 40% risk reduction in time to 24-week confirmed disability worsening between ocrelizumab and subcutaneous IFN beta-1a.

The most common adverse effects associated with ocrelizumab are IRRs. They typically are mild in degree and managed by symptomatic therapy or slowing the infusion rate. There are no increased rates of serious adverse effects or serious infections.

Malignancy occurred in 0.5% of patients treated with ocrelizumab compared with 0.2% of subcutaneous IFN beta-1a treated patients in clinical trials. 63 Two cases of breast cancer emerged in patients receiving ocrelizumab in 1 of the pivotal RCTs versus none in patients treated with subcutaneous IFNβ-1a. 63 An additional 2 cases of breast cancer occurred during the open-label extension study, during which all patients received ocrelizumab. Given these small numbers, it remains unclear whether ocrelizumab treatment increases the risk of cancer.

Ocrelizumab may increase the risk of PML, but to date there have been no cases of PML directly attributable to ocrelizumab.

Role of Immunosuppressant Drugs in MS

Cyclophosphamide, methotrexate, azathioprine, and cyclosporine have all been studied in small- to medium-sized trials. The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and MS Council for Clinical Practice Guidelines have made recommendations regarding these therapies. 64 Methotrexate, azathioprine, and cyclosporine were each found to be possibly effective (type C recommendation) in altering the course of disease, but cyclosporine was found to have an unacceptable risk/benefit ratio. In their review, pulse cyclophosphamide treatment did not alter the course of MS (type B recommendation), although a more recent clinical trial showed reduced relapses and MRI lesions in patients treated with cyclophosphamide. 65 Given that there are more than a dozen therapies approved by the FDA for relapsing MS and relatively weak evidence supporting the efficacy of immunosuppressant therapies, they are infrequently used in the treatment of MS.

Mitoxantrone (Novantrone, 12 mg/m 2 every 3 months; maximum lifetime dose of 140 mg/m 2 ) is a chemotherapy medication with demonstrated efficacy in very active relapsing and progressive MS. 66 Administration is via intravenous infusion every 3 months, although a monthly induction course is sometimes used in patients with very active disease. Infusion side effects include nausea and alopecia. Adverse effects include cardiotoxicity, acute myeloid leukemia, bone marrow suppression, and gonadal dysfunction. Because of the potential for long-term toxicities including cardiac injury and lymphoproliferative disorders, mitoxantrone is now rarely used in treating MS. Cardiac injury can occur years after completing therapy, which warrants surveillance echocardiogram or multigated acquisition scans prior to each infusion and after the medication has been discontinued.

Disease Modifying Therapy for Progressive MS

Treatment of progressive MS is more challenging than relapsing MS. Previously, certain DMTs (eg, subcutaneous IFN beta-1a and mitoxantrone) approved for RRMS were also found in some trials to slow progression of disability in SPMS, though the effect was modest and seen primarily in those subjects with superimposed active inflammation. It is likely worthwhile to use the DMTs in progressive MS if there is evidence of persistent active inflammation (eg, clinical relapses or active lesions on MRI) and side effects are tolerated, but patients should be informed that these therapies have limited efficacy in slowing the gradual progression of disability seen in progressive MS.

An encouraging advancement in the treatment of progressive MS was seen with ocrelizumab in PPMS, where ocrelizumab treatment was associated with a 24% relative risk reduction of progression of disability compared with placebo at 12 weeks. However, this trial enriched patients with active inflammation by limiting enrollment to those under 56 years of age and disease duration less than 10 to 15 years. 67 The benefit of ocrelizumab was markedly diminished in those without GdE lesions at baseline and those aged over 50 years. 68 The efficacy of ocrelizumab in PPMS patients over age 55 is unknown. Accordingly, the benefit of ocrelizumab on the underlying progressive aspects of PPMS appears to be limited.

Positive phase 2 and 3 clinical trial findings for high dose biotin 69,70 and siponimod 71,72 for progressive MS have been reported. These advances are encouraging for the future development of neuroprotective and neurorestorative agents.

Changing Disease Modifying Therapy and Monitoring Treatment

Broadly speaking, it is appropriate to consider changing DMT for 3 reasons: intolerable adverse effects, safety concerns, and breakthrough disease. With respect to adverse effects, every attempt should be made to manage them symptomatically. Of paramount importance is the patient’s tolerance of and adherence to DMT. It is important to address poor adherence, as it can lead to higher relapse rates and disease progression. If the patient remains intolerant of adverse effects, switching to an alternative agent is advisable.

With the emergence of newer therapeutics with various mechanisms of action and risk profiles, it is imperative that safety is monitored over the course of treatment. If at some point during treatment, the perceived benefits of the DMT no longer outweigh potential risks, then switching to a different agent should be considered. For example, in a patient treated with natalizumab who seroconverts to a highly positive JCV antibody titer, an alternative strategy without similar safety concerns, such as ocrelizumab, should be considered.

Despite its frequency in routine clinical practice, there is no consensus on the optimal approach to either defining or managing breakthrough disease. Breakthrough disease is generally defined as continued clinical or radiographic evidence of inflammatory disease activity despite treatment with an established DMT. Continued clinical relapses or new MRI lesions, particularly after 6 months of treatment with an established DMT, typically constitutes breakthrough disease. The severity of relapses, their subsequent recovery, and the number and size of new or active MRI lesions all contribute to defining when patients are considered to have sufficient breakthrough disease activity to merit changing therapies. Continued surveillance of clinical and radiographic measures of disease activity is important throughout treatment. In general, patients are seen clinically every 3 to 12 months, with repeat brain MRI every 6 to 12 months, depending on the patient’s baseline disease status and DMT.

Novel methods for longitudinal assessment of neurological performance and quality of life metrics for patients with MS are available for clinical use. At Cleveland Clinic, the Multiple Sclerosis Performance Test is used prior to each visit with the healthcare provider. 73 Completed by patients using an iPad, it includes neuro-performance testing that objectively measures walking speed, manual dexterity, low contrast visual acuity, and cognitive processing speed. Patients also complete questionnaires that screen for depression and evaluate patients’ impression of his or her overall health. These longitudinal data are used to carefully monitor patient function and may detect changes that would otherwise escape notice during traditional neurological assessments.

Symptomatic Therapies

Besides neurologic disability, MS can produce a variety of other symptoms that can interfere with daily activities. Identification and treatment of these symptoms should be considered throughout the disease course ( Table 6 ). Specific recommendations for management of fatigue and urinary dysfunction have been outlined by the Multiple Sclerosis Council for Clinical Practice Guidelines. Aggressive evaluation and treatment for these and other symptoms of MS can significantly improve quality of life and are an important component of long-term management of patients with MS.

Table 6: Common Symptoms in MS and Potential Treatments

α The sacral neurostimulation device precludes the ability to undergo MRI studies, limiting its use in patients with MS where monitoring MRIs are often an integral part of patient management.

β Evidence for efficacy for sexual dysfunction in women with MS has been negative.

Healthy Lifestyle and Wellness

In addition to conventional pharmacologic therapy, there is growing interest in the use of lifestyle strategies to support wellness and mitigate disease-related outcomes in MS. This interest is based on a growing appreciation of the role of certain comorbidities and lifestyle factors on disease activity, disability, mortality, and overall quality of life. For example, key observational studies suggest an association between vascular comorbidities (eg, hypertension, hyperlipidemia, and type 2 diabetes) and an increased risk of disability and mortality. 74 While evidence from randomized clinical trials is limited, there is evidence to suggest benefit from vitamin D supplementation, tobacco smoking cessation, routine exercise, and maintenance of emotional well-being as adjunct therapies to DMTs.

MS is a heterogeneous disease with a variable clinical course. Patients can progress rapidly over several years to significant disability or may have a few relapses and then remain clinically stable for many decades. The accumulation of disability in MS is slower than previously thought and varies widely between individuals. Early studies reported a relatively quick progression from disease onset to walking with a cane, with a median time of about 15 years. 75 However, more recent natural history studies reported a longer time to reaching this disability milestone, with a median time from onset to cane of about 30 years. Likewise, in PPMS, early studies reported short median time from disease onset to cane of less than 10 years, whereas more current studies showed that median time is closer to 15 years. 75 The advent of effective immunomodulating therapy for relapsing MS may in part explain a better long-term prognosis, but newer diagnostic criteria may have increased inclusion of MS patients with mild disease as well.

It is difficult to predict which patients will progress and which patients will remain relatively stable over time. Although there are clearly patients in whom the disease remains relatively mild, it is very difficult to predict which patients will eventually follow this course. There are several prognostic factors for unfavorable clinical outcomes. Older age at onset, Black race, Hispanic ethnicity, and initial symptoms involving cerebellar, spinal cord or pyramidal systems, and higher initial clinical activity (eg, high attack frequency and increased disability progression in the first 5 years) are all unfavorable prognostic factors. 76 Smoking and low serum vitamin D levels have also emerged as additional predictors of poor long-term outcome. Prognostic radiologic measures include brain and spinal cord atrophy and number of GdE lesions. MRI measures are also useful tools when evaluating the effect of MS therapies and should be used routinely for DMT monitoring. 76

Pregnancy and MS

Pregnancy does not seem to have a detrimental effect on the overall disease course of MS. In general, DMTs are not recommended during pregnancy, so efficient family planning with the help of the obstetrician can help minimize the amount of time the patient is off DMT. Pregnancy during MS is associated with a decreased incidence of relapses, but there is a rebound in relapse frequency in the postpartum period. 78 Relapses during pregnancy can be treated with short courses of high-dose corticosteroids if needed, though it is preferable to not treat mild relapses since adverse effects to glucocorticoids can be seen. A mid-pregnancy visit with the treating neurologist is recommended for postpartum planning. It is also generally recommended that patients who were previously treated with DMT prior to pregnancy resume treatment immediately postpartum unless they plan to breastfeed. If breastfeeding is pursued, cranial MRI 2 months after delivery for disease surveillance is appropriate. If there is evidence of active disease, the benefits of breastfeeding should be balanced with the need to resume DMT.

Unfortunately, no DMT is proven to be safe during pregnancy or while breastfeeding, and so they are generally not recommended. 79 Most of the available DMTs, including interferon beta, daclizumab, fingolimod, natalizumab, and alemtuzumab are pregnancy category C. Glatiramer acetate is pregnancy category B and is the safest DMT to use in women who need to continue DMT. The potential impact of brief exposures to DMTs (ie, during the first few weeks of pregnancy, before pregnancy is recognized) is relatively unknown, but appears to be minimal. Accordingly, although women who become pregnant while taking DMTs are generally recommended to discontinue DMTs, they can be reassured that the potential impact on their pregnancy is very low. As stated above, teriflunomide is pregnancy category X and should not be used in women of childbearing potential without effective contraception and counseling.

Vaccines and MS

The effect of vaccines on MS has been studied very carefully and there appears to be no adverse effect of vaccines on the course of disease. 80 Vaccines can be given safely in patients with MS and should be administered when clinically indicated, unless patients are on specific medications with an impact on response to vaccination. Inactivated vaccines are generally preferred, including in patients taking DMTs. Live attenuated vaccines are generally not recommended for a person with MS because of their theoretical ability to stimulate MS inflammation, although there is no compelling evidence showing an increased risk in the MS population of live attenuated vaccines at this time.

• Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disorder affecting the brain, optic nerve, and spinal cord.
• Symptoms of MS can involve almost any neurologic function; therefore, accurate diagnosis relies on a combination of clinical history, neurological examination, and paraclinical testing such as magnetic resonance imaging (MRI) and sometimes cerebrospinal fluid analysis.
• The 2017 McDonald Criteria simplify the diagnostic process, while preserving high sensitivity and specificity, and allowing early diagnosis of MS and prompt treatment.
• Many disease modifying therapies (DMTs) are available for relapsing forms of MS. They decrease the clinical episodes of inflammation, new MRI lesions, and slow the progression of disability.
• Available DMTs, including newer, more effective agents, allow for the increasingly accepted treat-to-target approach of “No Evidence of Disease Activity” (NEDA), which is defined as freedom from clinical and radiographic disease.
• The first DMT indicated for primary progressive MS (PPMS), ocrelizumab, suggests a potential role for B-cell therapy for progressive MS in younger patients with more active disease. However, the benefit of ocrelizumab on the underlying progressive aspects of PPMS appears to be limited.
• Despite emerging neurotherapeutics for progressive MS, early diagnosis and treatment are still key in preventing central nervous system inflammation and forestalling progressive disability related to neurodegeneration.
• Symptom management and healthy lifestyle strategies are important complementary approaches for better outcomes and quality of life for patients with MS.
• Gooch CL, Pracht E, Borenstein AR. The burden of neurological disease in the United States: A summary report and call to action. Ann Neurol 2017; 81:479–484.
• Weinshenker BD. Natural history of multiple sclerosis. Ann Neurol 1994; 36(Suppl):S6–S11.
• Koch M, Kingwell E, Rieckmann P, Tremlett H. The natural history of primary progressive multiple sclerosis. Neurology 2009; 73:1996–2002.
• Cottrell DA, Kremenchutzky M, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis. Brain 1999; 122:625–639.
• Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD. Multiple sclerosis prevalence in the United States commercially insured population. Neurology 2016; 86:1014–1021
• Atlas of MS FAQs. MS International Federation website. https://www.msif.org/about-us/who-we-are-and-what-we-do/advocacy/atlas/atlas-of-ms-faqs/. Updated March 14 2017. Accessed April 2, 2018.
• Lucchinetti CF, Brueck W, Rodriguez M, Lassmann H. Multiple sclerosis: lessons from neuropathology. Semin Neurol 1998; 18:337–349.
• Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 2015; 14:183–193.
• Hametner S, Wimmer I, Haider L, Pfeifenbring S, Brück W, Lassmann H. Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 2013; 74:848–861.
• Lucchinetti CF, Popescu BFG, Bunyan RF, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Eng J Med 2011; 365:2188–2197.
• Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338:278–285.
• Chang A, Tourtellotte WW, Rudick RA, Trapp BD. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 2002; 346:165–173.
• Fox RJ, Cohen JA: Multiple sclerosis: the importance of early recognition and treatment. Cleve Clin J of Med, 2001; 68:157–70.
• Schumacher GA, Beebe G, Kibler RF, et al. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci 1965; 122:552–568.
• McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001; 50:121–127.
• Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald Criteria. Lancet Neurol 2018; 17:162–173.
• Filippi M, Rocca MA, Ciccarelli O, et al; on behalf of the MAGNIMS Study Group. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS concensus guidelines. Lancet Neurol 2016; 15:292–303.
• Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83:278–286.
• Milligan NM, Newcombe R, Compston DA. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatry 1987; 50:511–516.
• Sellebjerg F, Frederiksen JL, Nielsen PM, Olesen J. Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology 1998; 51:529–534.
• Oh J, Calabresi PA. Disease-modifying therapies in relapsing multiple sclerosis. In: Rae-Grant A, Fox RJ, Bethoux F. Multiple Sclerosis and Related Disorders: Clinical Guide to Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos Medical ; 2013:104.
• Jacobs LD, Cookfair DL, Rudick RA, et al; The Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39:285–294.
• Johnson KP, Brooks BR, Cohen JA, et al; Copolymer 1 Multiple Sclerosis Study Group. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurolog y 1995; 45:1268–1276.
• Ebers GC, Rice G, Lesaux J; on behalf of the PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352:1498–1504.
• IFNB Multiple Sclerosis Study Group, University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized, controlled trial. Neurology 1995; 45:1277–1285.
• Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 2006; 103:5941–5946.
• Gold R, Giovannoni G, Selmaj K, et al; for the SELECT study investigators. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013; 381:2167–2175.
• Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2015; 373:1418–1428.
• Giovannoni G, Gold R, Selmaj K, et al; for the SELECTION Study Investigators. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol 2014; 13:472–481.
• Restrictions of use of Zinbryta (daclizumab) in view of fatal fulminant liver failure. Biogen Health Products Regulatory Authority website. https://www.hpra.ie/docs/default-source/Safety-Notices/important-safety-information---zinbryta-(daclizumab).pdf?sfvrsn=0). Published July 11, 2017. Accessed March 9, 2018.
• Kappos L, Radue E-W, O'Connor P, et al; for the FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362:387–401.
• Cohen JA, Barkhof F, Comi G, et al; for the TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362:402–415.
• Berger JR. Classifying PML risk with disease modifying therpaties. Mult Scler Relat Disord 2017; 12:59–63.
• Greene S, Watanabe K, Braatz-Trulson J, Lou L. Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol 1995; 50:861–867.
• Xu X, Blinder L, Shen J, et al. In vivo mechanism by which leflunomide controls lymphoproliferative and autoimmune disease in MRL/MpJ-lpr/lpr mice. J Immunol 1997; 159:167–174.
• O'Connor P, Wolinsky JS, Confavreux C, et al; for the TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365:1293–1303.
• Confavreux C, O'Connor P, Comi G, et al; for the TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13:247–256.
• Vermersch P, Czlonkowska A, Grimaldi LME, et al; for the TENERE Trial Group. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler 2014; 20:705–716.
• Aubagio [package insert]. Cambridge, MA: Genzyme Corporation; 2012.
• Linker RA, Lee D-H, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011; 134:678–692.
• Reich K, Thaci D, Mrowietz U, Kamps A, Neureither M, Luger T. Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis—a retrospective study (FUTURE). J Dtsch Dermatol Ges 2009; 7:603–611.
• Gold R, Kappos L, Arnold DL, et al; for the DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367:1098-1107.
• Fox RJ, Miller DH, Phillips JT, et al; for the CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367:1087–1097.
• Ontaneda D, Fox RJ. Emerging therapies for relapsing multiple sclerosis. In: Rae-Grant A, Fox RJ, Bethoux F. Multiple Sclerosis and Related Disorders: Clinical Guide to Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos Medical; 2013:133.
• Rudick RA, Stuart WH, Calabresi PA, et al; for the SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354:911–923.
• Polman CH, O'Connor PW, Havrdova E, et al; for the AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899–910.
• Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc.; 2012.
• Sørensen PS, Bertolotto A, Edan G, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 2012; 18:143–152.
• Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366:1870–1880.
• Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354:924–933.
• Berger JR, Fox RJ. Reassessing the risk of natalizumab-associated PML. J Neurovirol 2016; 22:533–535. doi:10.1007/s13365-016-0427-6.
• Bielekova B, Becker BL. Monoclonal antibodies in MS: mechanisms of action. Neurology 2010; 74(suppl 1):S31–S40.
• Thompson SAJ, Jones JL, Cox AL, Compston DAS, Coles AJ. B-cell reconstitution and BAFF after alemtuzumab (campath-1H) treatment of multiple sclerosis. J Clin Immunol 2010; 30:99–105.
• Coles AJ, Compston DAS, Selmaj KW, et al; CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008; 359:1786–1801.
• Cohen JA, Coles AJ, Arnold DL, et al; for the CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380:1819–1828.
• Coles AJ, Twyman CL, Arnold DL, et al; for the CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380:1829–1839.
• Lemtrada [package insert]. Cambridge, MA: Genzyme Corporation; 2017.
• Clatworthy MR, Wallin EF, Jayne DR. Anti-glomerular basement membrane disease after alemtuzumab. N Engl J Med 2008; 359:768–769.
• Fox EJ, Alroughani R, Brassat D, et al; on behalf of the CARE-MS II Investigators. Efficacy of alemtuzumab is durable over 6 years with active relapsing-remitting multiple sclerosis and an inadequate response to prior therapy in the absence of continuous treatment (CARE-MS II). Abstract presented at the 32nd Congress of ECTRIMS; September 16, 2016; London, UK. Abstract P1150.
• Singer B, Dunn J, Izquierdo G, et al; on behalf of the CARE-MS II Investigators. Alemtuzumab significantly improves disability in patients with active relapsing-remitting MS and an inadequate response to prior therapy as assessed using a novel, composite measure: confirmed disability improvement-plus: results of CARE-MS II. Abstract presented at the 32nd Congress of ECTRIMS; September 15, 2016; London, UK. Abstract P610.
• Coles A, Robertson N, Al-Araji A, et al; MS Advisory group. Guidance on the prevention of Listeria infection after alemtuzumab treatment of multiple sclerosis. Website: https://www.theabn.org/media/Guidance%20on%20the%20prevention%20of%20Listeria%20infection%20after%20alemtuzumab%20treatment% 20of%20multiple%20sclerosis.pdf. Published May 15, 2017. Accessed March 12, 2018.
• Morschhauser F, Marlton P, Vitolo U, et al. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol 2010; 21:1870–1876.
• Hauser SL, Bar-Or A, Comi G, et al; for the OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376:221–234.
• Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58:169–178.
• Smith DR, Weinstock-Guttman B, Cohen JA, et al. A randomized blinded trial of combination therapy with cyclophosphamide in patients with active multiple sclerosis on interferon beta. Mult Scler 2005; 11:573–582.
• Hartung H-P, Gonsette R, König N, et al; Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360:2018–2025.
• Montalban X, Hauser SL, Kappos L, et al; for the ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376:209–220.
• Ocrelizumab Summary of Product Characteristics. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004043/WC500241124.pdf. Accessed March 12, 2018.
• Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord 2015; 4:159–169.
• Tourbah A, Lebrun-Frenay C, Edan G, et al; on behalf of the MS-SPI study group. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomized, double-blind, placebo-controlled study. Mult Scler 2016; 22:1719–1731.
• Selmaj K, Li DKB, Hartung H-P, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 2013; 12:756–767.
• Kappos L, Bar-Or A, Cree B, et al. Efficacy and safety of siponimod in secondary progressive multiple sclerosis: results of the placebo controlled, double-blind, phase III EXPAND study. Abstract presented at the 32nd Congress of ECTRIMS; September 16, 2016; London, UK. Abstract 250.
• Rudick RA, Miller D, Bethoux F, et al. The multiple sclerosis performance test (MSPT): an iPad-based disability assessment tool. J Vis Exp 2014; 88:e51318.
• Marrie RA, Rudick R, Horwitz R, et al. Vascular comorbitity is associated with more rapid disability progression in multple sclerosis. Neurology 2010; 74:1041–1047.
• Tremlett H, Zhao Y, Rieckmann P, Hutchinson M. New perspectives in the natural history of multiple sclerosis. Neurology 2010; 74:2004–2015.
• Renoux C. Natural history of multiple sclerosis: long-term prognostic factors. Neurol Clin 2011; 29:293–308.
• Kaunzner UW, Gauthier SA. MRI in the assessment and monitoring of multiple sclerosis: an update on best practice. Ther Adv Neurol Discord 2017; 10:247–261.
• Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T; Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998; 339:285–291.
• Cree BAC. Update on reproductive safety of current and emerging disease-modifying therapies for multiple sclerosis. Mult Scler 2013:19:835–843.
• Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S; Vaccines in Multiple Sclerosis Study Group. Vaccinations and the risk of relapse in multiple sclerosis. N Engl JMed 2001; 344:319–326.

• Site Disclaimer
• Privacy Policy
• Editorial Policy
• Editorial Board

Lectures:   Clinical Presentation Introduction Initial Symptoms Ongoing Symptoms Clinical Cases   Introduction It is important to note that patients with MS have subjective complaints and objective signs that frequently are not attributable to one specific lesion in the CNS. It is usually possible to distinguish at least two or more separate foci of involvement based on the clinical assessment of the patient. Multiple Sclerosis most often is characterized by episodes of neurological dysfunction followed by periods of stabilization or partial to complete remission of symptoms. These symptoms (relapses or exacerbations) can appear over a few hours or days, can be gradually worsening over a period of a few weeks, or sometimes can present themselves acutely. Depending on a course and a subtype of the disease, these symptoms will either persist or slowly resolve over weeks or months and may even culminate as a complete remissions. A relapsing-remitting pattern is the most common and is characteristic for this disease .   Initial Symptoms Certain signs and symptoms are more common in the early stages of the disease. Patients may be complaining of double or blurred vision, numbness, weakness in one or two extremities, instability in walking, tremors and problems with bladder control, heat intolerance. As is well known, sensory exam is the most difficult one to perform reliably and accurately in evaluation of patients with neurologic complaints. However, certain distributions of sensory problems can be suspicious for early MS. Among those are: - ascending numbness starting in the feet; - bilateral hand numbness; - hemiparesthesia; - dysesthesia in one of the above distributions; - generalized heat intolerance Objectively the most common sensory findings in the"numb" areas are dorsal column signs, such as reduction of vibration, proprioception and stereognosis, rather than problems with spinothalamic tract. Usually double vision in MS patients results from a unilateral or bilateral partial of complete internuclear ophthalmoplegia . VI nerve paresis and palsy also have been described as presenting symptoms of MS. III and IV nerves palsy are rather uncommon. Optic Neuritis is a frequent presenting symptom of MS. It is characterized by blurred vision, a change in color perception, visual field defect i.e.,. Central scotoma, and possible headaches and retro-orbital pain precipitated by eye movements. These symptoms may require neuro-ophthalmologic evaluation, MRI imaging and Visual Evoked Potential studies to establish a degree of optic nerve function. Motor weakness often is accompanied by upper motor neuron signs, such as mild spasticity, hyperreflexia, and pathologic signs. The most common initial presentation is paraparesis, but weakness can be also found in just one extremity (monoparesis) or all four extremities (quadriparesis).   Ongoing Symptoms and Signs As the disease progresses, the original signs and symptoms may worsen, and the new ones may appear. The most common symptoms and signs include: Motor system: -weakness (variable severity mono- and paraparesis, hemiparesis, quadriparesis) -increased spasticity resulting in spastic gait -pathologic signs (Babinski's, Chaddock's, Hoffmann, Oppenheim's, etc.) -dysarthria Cerebellar signs: -incoordination (dysdiadochokinesia, problems with heel-to-shin test) -slowing of rapid repeating movements -cerebellar ataxia (ataxic gait) -scanning speech -loss of balance Sensory systems: -Lhermitte's sign -dysesthetic pain -paresthesia -numbness -dorsal column signs (i.e.,. severe decrease or loss of vibratory sense and proprioception, positive Romberg's test) Urinary incontinence, incomplete emptying, increased frequency of urination. All of these problems may result in urinary tract infections. Optic disc pallor, atrophy, blurred vision, diplopia, nystagmus, oscillopsia, intranuclear ophthalmoplegia, central scotomas or other visual field defects Cognitive and emotional abnormalities (emotional lability, depression, anxiety) Fatigue Sexual dysfunction At this stage in the disease, uncommon but important problems may include bowel incontinence, difficulty swallowing, seizures, trigeminal neuralgia, dystonia, hearing loss, and facial nerve (Bell's) palsy. All of the above-mentioned symptoms can be precipitated by heat, i.e.,. being in a hot, humid environment, or taking a hot bath.   Clinical Cases Case 1   History Case 1   Questions Case 2:   History Case 2:   Questions Case 3   History Case 3   Questions   ©   John W.Rose, M.D.,   Maria Houtchens, MSIII,   Sharon G. Lynch, M.D.

CKS is only available in the UK

The NICE Clinical Knowledge Summaries (CKS) site is only available to users in the UK, Crown Dependencies and British Overseas Territories.

CKS content is produced by Clarity Informatics Ltd (trading as Agilio Software | Primary Care). It is available to users outside the UK via subscription from the Agilio | Prodigy website .

If you believe you are seeing this page in error please  contact us .

• Multiple Sclerosis
• What Is Multiple Sclerosis?
• MS in Women
• MS in Children
• What Are the Different Types of MS?
• Relapsing-Remitting
• Secondary Progressive
• Other Types of Multiple Sclerosis
• MS Symptoms & Early Warning Signs
• Causes & Risks
• Tests & Diagnosis
• Treatments for MS
• Disease-Modifying Therapy
• Acute Flareups
• Symptom Management
• Complementary & Alternative Medicine
• Daily Living
• Seasonal Changes
• Diet & Exercise
• Emotional & Mental Health
• Work, Family & Relationships
• Mobility & Assistive Devices
• Complications From MS
• Brain & Nervous System
• Bladder & Gastrointestinal
• Other Complications
• Caregiving & Support
• Appointment Prep
• View Full Guide

What Are the Different Types of Multiple Sclerosis?

In some ways, each person with multiple sclerosis lives with a different illness. Although nerve damage is always a part of the disease, the pattern is unique for everyone.

Doctors have identified a few major types of MS. The categories are important, because they help predict how severe the disease can be and how well treatment will work.

Relapsing-Remitting Multiple Sclerosis

Most people with multiple sclerosis -- around 85% -- have this type. They usually have their first signs of the disease in their early 20s. After that, they have attacks of symptoms (called relapses) from time to time, followed by weeks, months, or years of recovery (called remissions).

The nerves that are affected, how severe attacks are, the degree of recovery, and the time between relapses all vary widely from person to person.

Eventually, most people with relapsing-remitting MS will move on to a secondary progressive phase of MS. Learn more about the symptoms of relapsing-remitting MS.

Secondary Progressive Multiple Sclerosis

After living with relapsing-remitting MS for many years, most people will get secondary progressive MS . In this type, symptoms begin a steady march without relapses or remissions. (In this way, it’s like primary progressive MS.) The change typically happens between 10 and 20 years after you’re diagnosed with relapsing-remitting MS.

It's unclear why the disease makes the shift. But scientists know a few things about the process:

• The older a person is when they are first diagnosed, the shorter the time they have before the disease becomes secondary progressive.
• People who don’t fully recover from relapses generally move to secondary progressive MS sooner than those who do.
• The process of ongoing nerve damage changes. After the transformation, there's less inflammation and more of a slow decline in how well the nerves work.

Secondary progressive MS is tough to treat, and the disease can be hard to handle day to day. Symptoms get worse at a different rate for each person. Treatments work moderately well, but most people will have some trouble using their body like they used to. Get more information on treatments for secondary progressive MS.

Primary Progressive Multiple Sclerosis

In primary progressive multiple sclerosis , the disease gradually gets worse over time. There are no well-defined attacks of symptoms, and there is little or no recmissions. In addition, MS treatments don't work as well with this type of MS. About 10% of people with MS have this type.

A few things make it different from other types of MS:

• People with primary progressive MS are usually older when they’re diagnosed -- an average age of 40.
• Roughly equal numbers of men and women get it. In other types of the disease, women outnumber men 3 to 1.
• It usually leads to disability earlier than the most common type, relapsing-remitting MS.

You may have heard PPMS referred to as progressive relapsing multiple sclerosis ( PRMS ), but this terminology is no longer used. Find out more on how multiple sclerosis changes over time.

What Causes Multiple Sclerosis?

No one knows. Tantalizing clues have sparked research in many areas, but there are no definite answers. Some theories include:

• Geography. People in colder parts of the world get MS more often than those in the warmer parts. Researchers are looking into how vitamin D and sunlight might protect against the disease.
• Smoking . Tobacco may raise the risk slightly. But it's not the whole story.
• Genetics. Genes do play a role. If an identical twin has MS, the other twin has a 20% to 40% chance of getting it. Siblings have a 3% to 5% chance if a brother or sister has it.
• Vaccines. Extensive research has essentially ruled out vaccines as a cause of MS.
• Epstein-Barr virus exposure . Some research has shown that people who develop MS have antibodies to the EBV in their bodies. That means they have been exposed to the virus. It has also shown that the risk of developing MS is much higher in people who have been ill with EBV.

Multiple sclerosis is probably an autoimmune disease. Like lupus or rheumatoid arthritis , the body creates antibodies against itself, causing damage. In MS, the damage occurs in the covering, or myelin, of nerves. Read more on the possible causes of multiple sclerosis.

Top doctors in ,

Find more top doctors on, related links.

• Multiple Sclerosis Center Blogs
• MS Community
• MS Medications
• Find a Neurologist
• Living Better With MS
• Brain Lesions
• Essential Tremor
• Sleep Problems
• Multiple Sclerosis Overview
• Multiple Sclerosis Symptoms
• Multiple Sclerosis Causes
• Multiple Sclerosis Diagnosis
• Multiple Sclerosis Treatment
• Risks and Complications

• Type 2 Diabetes
• Heart Disease
• Digestive Health
• Multiple Sclerosis
• Diet & Nutrition
• Health Insurance
• Public Health
• Patient Rights
• Caregivers & Loved Ones
• End of Life Concerns
• Health News
• Thyroid Test Analyzer
• Doctor Discussion Guides
• Hemoglobin A1c Test Analyzer
• Lipid Test Analyzer
• Complete Blood Count (CBC) Analyzer
• What to Buy
• Editorial Process
• Meet Our Medical Expert Board

Early Warning Signs of Multiple Sclerosis (MS)

Early warning signs, most common symptoms.

• Males vs. Females

Frequently Asked Questions

While no two people experience multiple sclerosis (MS) the same way, some symptoms tend to crop up earlier in the disease course than others. These symptoms may serve as warning signs of the disease, potentially allowing you or a loved one to receive a diagnosis of MS sooner than later.

In multiple sclerosis, your immune system goes awry and damages the fatty covering ( myelin ) that insulates nerve fibers within your central  nervous system  (CNS). Your CNS consists of your brain, spinal cord, and the  optic nerves  of your eyes.

As a result of myelin damage, nerve signals cannot be transmitted rapidly or efficiently between the CNS and the rest of your body. This can lead to various symptoms like blurry vision, pain, abnormal sensations, and muscle weakness, among many others.

This article reviews some of the common early symptoms and signs of MS. It also gives a brief overview of differences of MS between males and females and how MS is diagnosed.

peakSTOCK / Getty Images

Two phenomena—clinically isolated syndrome and optic neuritis—may serve as early warning signs of MS. People who experience one (or both) of these may or may not go on to develop MS.

Clinically Isolated Syndrome

Clinically isolated syndrome (CIS) refers to a person's first-time episode of neurological symptoms caused by inflammation and damaged myelin in the CNS.

As an example, a patient diagnosed with CIS may experience numbness and tingling in their legs. This would be accompanied by magnetic resonance imaging (MRI) findings that reveal damage to the CNS.

CIS is followed by a recovery period where the symptoms improve or completely go away.

Difference Between CIS and MS

The key difference between CIS and MS is that CIS is diagnosed after a person experiences one episode of neurological symptoms. MS can only be diagnosed when a person has experienced more than one episode of neurological symptoms.

Optic Neuritis

Optic neuritis —inflammation of one of your two optic nerves—is a common first presentation of MS. In fact, CIS may be diagnosed from an attack of optic neuritis.

Your optic nerve delivers messages to your brain about what your eye sees. When the myelin covering the optic nerve is damaged, signals related to sight are interrupted.

The common symptoms of optic neuritis include pain with eye movements, blurry or "foggy" vision, and seeing colors less vividly. Vision symptoms usually improve and fully recover within three to five weeks. That said, up to 10% of patients may experience long-term vision problems.

Even though the symptoms of MS vary in type, severity, and duration, there are some that are more common than others. The following is a brief snapshot of such symptoms:

Vision Problems

Besides optic neuritis, other common vision problems seen in MS are:

• Nystagmus is uncontrolled, jerking movement of the eyes, sometimes referred to as "dancing eyes." This symptom is caused by damage to the area of the brainstem that controls eye movements.
• Diplopia (double vision) is uncoordinated eye movements that cause you to see double. This symptom results from damage to the nerves that control your eye muscles.

Muscle Spasms

Muscle spasms are common in MS and are primarily caused by damaged myelin in the nerves that innervate or connect to your muscles. As a result of disrupted nerve signals, your muscles cannot relax properly. This causes muscle stiffness and/or a tightening, cramping, or heavy sensation in the affected muscle(s).

The legs are most commonly affected by spasms, but they can occur anywhere in the body. Muscle spasms also tend to be asymmetric, meaning they are more likely to happen on one side of the body versus both sides.

Nerve fiber damage in MS causes neuropathic pain , which is associated with burning, stabbing, sharp, itching, or squeezing sensations. This type of pain is associated with disability, depression, and fatigue in MS.

Specific types of neuropathic pain that may be early signs of MS include:

• Lhermitte's sign is a sensation of electricity that runs down your spine when you touch your chin to your chest. In MS, it's caused by damage to nerve fibers in your upper spine.
• MS hug is a tightening sensation around the chest and ribs caused by damage to the nerve fibers in your spine.
• Trigeminal neuralgia is an electric-shock-like or stabbing pain in the face or jaw area that is caused by damage to the trigeminal nerve (the fifth  cranial nerve ).

Fatigue and Weakness

MS fatigue is often felt both physically and mentally. Described by many as "having the flu," MS fatigue is not eased by sleep and tends to come on suddenly and worsen with heat and humidity.

The overwhelming exhaustion and depletion of energy seen with MS fatigue may arise from the disease itself and/or other factors like medications, sleep disorders, or depression.

Timeline of MS Fatigue

Fatigue can occur at any time during the course of MS, and its development is not necessarily related to the progression of more objective neurological symptoms (e.g., walking problems).

Weakness is also common in MS and may arise from damage to the nerve fibers in the CNS that normally control muscle movements. Lack of activity due to MS-related pain, fatigue, or other symptoms can also contribute to MS weakness.

Bladder and Bowel Problems

Bladder dysfunction   is common in MS, affecting the majority of patients at some point in the course of their disease. Urinary symptoms as the first presentation of MS occur in around 3% to 10% of people.

Symptoms and signs of bladder dysfunction in MS vary from mild to severe. They may include:

• Urgency : Feeling like you have to urinate right away
• Hesitancy : Having trouble initiating urination or you cannot maintain a steady stream
• Nocturia : Having to urinate often at night
• Incontinence : Having an involuntary loss of urine control

Recurrent urinary tract infections may also be a sign of bladder dysfunction in MS.

Bowel problems are common in MS, with  constipation being the most frequent complaint. Constipation can aggravate other MS symptoms including muscle spasms, pain, bladder dysfunction, and walking problems. It can also contribute to fecal incontinence , which is the loss of control of your bowels.

Depression and Emotional Changes

Depression is associated with constant sadness and a lack of interest in activities you once enjoyed. In MS, depression can occur at any time in the course of the disease, including early or later on.

Depression in MS may stem from a number of different factors, including:

• MS itself : Damage to the areas of the brain that regulate emotion
• Side effects of MS medications : For example, corticosteroids (used to treat MS relapses ) and interferon drugs (used as disease-modifying therapies )
• Stress associated with living with MS : Undergoing a new diagnosis, relapse, or major change in function.

Other common emotional symptoms in MS include grief, anxiety , irritability, and anger. Many of these emotions stem from the unpredictable nature of MS, and the physical and emotional impact the disease has on a person's life.

Presentation in Males vs. Females

Differences exist in MS in males and females. For instance, research has found that females are twice as likely to live with MS as males. Moreover, those diagnosed with primary progressive MS (PPMS) are more likely to be male.

What Is PPMS?

PPMS is characterized by worsening symptoms from the onset of the disease. People with PPMS do not experience relapses or periods of symptom improvement ("remission").

Experts haven't yet teased out fully why these differences between sexes exist. Sex hormones, pregnancy, social factors (delayed care-seeking behavior), and/or differences in genes or environmental exposures may be involved.

How MS Is Diagnosed

The diagnosis of MS is often challenging, considering the symptoms are so variable. In addition, symptoms early on can often be vague or mimic those of other conditions, such as systemic lupus erythematosus (SLE) (an autoimmune disease that can affect many body systems) or vitamin B12 deficiency .

A neurologist —a doctor who specializes in diseases of the nervous system—will use the following tools to confirm a diagnosis of MS:

• Your medical history and neurological exam
• The McDonald criteria (a set of guidelines that focuses on diagnosing MS by showing evidence of damage to the CNS at different dates and to different parts)
• Magnetic resonance imaging (MRI) of the brain and spinal cord (which uses strong magnets to produce detailed images)
• Laboratory tests, mostly to rule out other conditions
• Other tests, including a spinal tap (lumbar puncture) and evoked potential tests (which measure electrical activity of the nerves of the eye)

Even though no two people experience MS in the same way, there are some symptoms, including vision problems and sensory disturbances, that may serve as early warning signs of the disease. Other common symptoms of MS include fatigue, muscle spasms, pain, bladder problems, and constipation.

A Word From Verywell

If you are concerned that you may be experiencing possible symptoms of MS, schedule an appointment with your healthcare provider or a neurologist. Diagnosing and treating MS as early as possible is associated with better long-term outcomes .

Keep in mind that many symptoms of MS overlap with other common medical conditions. Be proactive and get checked out, but try not to worry yourself until you know more information.

Most people are diagnosed with MS between the ages of 20 and 50 years old. That said, MS can develop at any age, and symptoms may predate a diagnosis by years.

Yes. In fact, research suggests MS may have a prodromal ("very early") phase. This phase includes various nonspecific symptoms, like fatigue, depression, pain, and headache. These symptoms may precede an MS diagnosis by several years.

There is no blood test that can diagnose MS. If you or a loved one are being evaluated for MS, your neurologist will use a variety of diagnostic tools, including your medical history, neurological exam, an MRI, and various blood or spinal fluid tests.

MS occurs when your immune system mistakingly attacks myelin, a protective coating on your nerves. These attacks lead to inflammation in the brain and spinal cord. The inflammation shows up as "lesions" or "plaques" on an MRI .

National MS Society. Clinically isolated syndrome .

Kale N.  Optic neuritis as an early sign of multiple sclerosis .  Eye Brain.  2016;8:195–202. doi:10.2147/EB.S54131

Cavenaghi VB, Dobrianskyj FM, Sciascia do Olival G, Castello Dias Carneiro RP, Tilbery CP.  Characterization of the first symptoms of multiple sclerosis in a Brazilian center: cross-sectional study .  Sao Paulo Med J. 2 017;135(3):222-225. doi:10.1590/1516-3180.2016.0200270117

National MS Society. Vision problems in multiple sclerosis .

Heitmann H, Biberacher V, Tiemann L et al. Prevalence of neuropathic pain in early multiple sclerosis . Mult Scler. 2016;22(9):1224-30. doi:10.1177/1352458515613643

Tur C. Fatigue management in multiple sclerosis . Curr Treat Options Neurol.  2016;18:26. doi:10.1007/s11940-016-0411-8

Aharony SM, Lam O, Corcos J. Evaluation of lower urinary tract symptoms in multiple sclerosis patients: Review of the literature and current guidelines . Can Urol Assoc J.  2017;11(1-2):61–64. doi:10.5489/cuaj.4058

Walton C, Rechtman L. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition . Mult Scler.  2020 Dec; 26(14): 1816–1821. doi:10.1177/1352458520970841

Eccles A. Delayed diagnosis of multiple sclerosis in males: may account for and dispel common understandings of different MS 'types .' Br J Gen Pract.  2019;69(680):148–149. doi:10.3399/bjgp19X701729

Brownlee WJ, Hardy TA, Fazekas F, Miller DH.  Diagnosis of multiple sclerosis: progress and challenges .  Lancet . 2017;389(10076):1336-1346. doi:10.1016/S0140-6736(16)30959-X

DiSanto G, Zecca C, MacLachlan S et al. Prodromal symptoms of multiple sclerosis in primary care . Ann Neurol 2018;83(6):1162-1173. doi:10.1002/ana.25247

By Colleen Doherty, MD Dr. Doherty is a board-certified internist and writer living with multiple sclerosis. She is based in Chicago.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Acad Pathol
• v.9(1); 2022

Educational Case: Multiple sclerosis

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see https://www.journals.elsevier.com/academic-pathology/news/pathology-competencies-for-medical-education-pcme . 1

Primary objective

Objective NSC3.3: Multiple sclerosis. Describe the pathogenesis, clinical presentation, and gross and microscopic pathologic features of multiple sclerosis.

Competency 2: Organ System Pathology; Topic NSC: Nervous System – Central Nervous System; Learning Goal 3: Spinal Cord Disorders.

Secondary objective

Objective NSC6.1: Autoimmune mechanisms in multiple sclerosis. Describe the autoimmune mechanism mediated by CD4 + T cells that react against self-myelin antigens in multiple sclerosis and outline the clinicopathologic features of the disease.

Competency 2: Organ System Pathology; Topic NSC: Nervous System – Central Nervous System; Learning Goal 6: Demyelinating Disorders.

Patient presentation

A 32-year-old woman with no past medical history presents to the emergency room with a 6-month history of waxing and waning unilateral visual impairment and facial numbness. She was well until 6 months ago when she noticed the onset of right-sided facial numbness and blurred vision lasting several weeks. She states that three episodes have occurred during the past 6-month time period. There was no associated muscle weakness of the facial muscles. Earlier today, upon waking up, the patient noted a sudden onset of blurry vision in her right eye and numbness on the right side of her face. She states she has not observed any muscle weakness, gait disturbance, fever, or urinary incontinence.

Diagnostic findings, Part 1

Physical examination reveals a well appearing, anxious woman. Vital signs are temperature: 98.6 °F, heart rate: 82 beats per minute, blood pressure: 116/84 mmHg, respiratory rate: 16 breaths per minute. Neurologic exam reveals 20/20 vision in the left eye and 20/100 vision in the right eye. Muscle strength is 5/5 in all extremities. There is unilateral loss of sensation on the entire right half of the face; otherwise, all other cranial nerves are intact. Romberg sign is negative, and no gait disturbances are noted. Cardiac, pulmonary, and abdominal examinations are unremarkable.

Questions/discussion points, Part 1

What is the differential diagnosis based on the clinical findings.

Relapsing-remitting visual deficits are suggestive of optic neuritis which, along with new-onset facial neuropathy manifesting as numbness, are most suggestive of a central nervous system (CNS) demyelinating disease. Demyelinating disorders that affect the CNS can be grouped by their etiologies, which includes inflammatory, infectious, and toxic-metabolic-nutritional ( Table 1 ). Among inflammatory disease processes, the relapsing-remitting nature of vision deficits in a woman in her 30s raises multiple sclerosis (MS) highest in the differential diagnosis, discussed below. In addition to MS, other demyelinating disorders in the differential include neuromyelitis optica spectrum disorder (NMOSD) and acute disseminated encephalomyelitis (ADEM). NMOSD present with relapsing-remitting neurological symptoms and lesions on magnetic resonance imaging (MRI) studies are similar to those in MS. However, lesions in NMOSD are characteristically limited to the spinal cord and optic nerves, whereas MS characteristically has cranial involvement in addition to the spinal cord and optic nerves. ADEM is rarely confused with MS as it is usually a monophasic, self-limiting, post-viral, or rarely post-vaccination disease of childhood. It typically presents with acutely evolving, multifocal CNS disease, whereas in MS, the neurological deficits during initial presentation or a relapse are usually limited to a single site or a few sites. ADEM can rarely manifest with relapses, although, in this setting, MRI lesions are typically more extensive and symmetric than MS.

Table 1

Disorders that may present with myelin loss in the central nervous system, peripheral nervous system, or both.

Abbreviations: CNS, central nervous system; PNS, peripheral nervous system.

Infectious etiologies of CNS demyelination include progressive multifocal leukoencephalopathy, Lyme disease, and neurosyphilis. Progressive multifocal leukoencephalopathy is an infection of oligodendroglial cells by the JC virus leading to demyelination in the setting of immunodeficiency (e.g., acquired immunodeficiency disease or iatrogenic immunosuppression). The optic nerve is myelinated by oligodendroglial cells; therefore, the optic nerve is affected in progressive multifocal leukoencephalopathy and not in peripheral nervous system (PNS) demyelinating diseases like Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy. Early disseminated stage 2 lyme disease can present with recurrent cranial neuropathies in the context of meningitis.

Inherited toxic-metabolic-nutritional disorders that lead to loss of myelin (leukodystrophy) include the lysosomal storage diseases Krabbe disease and metachromic leukodystrophy, as well as the peroxisomal disease adrenoleukodystrophy. These disorders typically present in childhood with a slow, progressive course, eventually leading to symptoms in both the CNS and PNS due to loss of myelin. Adrenoleukodystrophy also leads to adrenal cortex dysfunction due to steroid hormone production deficits, manifesting clinically as Addison disease. The leukodystrophies are inherited, with an autosomal recessive inheritance in Krabbe disease and metachromic leukodystrophy and an X-linked pattern of inheritance in adrenoleukodystrophy.

Inflammatory disorders that can mimic MS include cerebral vasculitis, systemic lupus erythematosus, Sjogren syndrome, and neurosarcoidosis. These disorders only rarely present initially with neurological symptoms, and systemic signs and symptom characteristics of these disorders are usually present. MRI studies and laboratory testing performed on blood and cerebrospinal fluid (CSF) can help differentiate between an inflammatory demyelinating disorder and infectious and inflammatory disease processes. Arteriovenous malformations can result in relapsing-remitting, single-site neurological symptoms similar to MS, but MRI and computed tomography angiography can distinguish vascular malformation from other disorders. Similarly, tumors in certain locations can mimic MS symptoms. Pituitary adenomas, craniopharyngiomas, and meningiomas can occur in the sella turcica region and compress on the optic chiasm and optic nerves resulting in visual deficits, although characteristically with a progressive loss of vision rather than with relapsing and remitting symptoms. 2 , 3

Define the different clinical subtypes (phenotypes) of multiple sclerosis

In 1996, the US National MS Society defined three phenotypes of MS, which were later refined by Lublin et al., in 2013: relapsing-remitting (RRMS), secondary-progressive (SPMS), and primary-progressive (PPMS). 4 RRMS is defined as having relapses that last at least 24h and have complete or partial remission of symptoms between attacks. RRMS can transform into SPMS, which is where symptoms are no longer stable between relapses and instead there is progressive accumulation of disability. PPMS is when a patient initially presents with a progressive accumulation of disability, without a period of RRMS beforehand.

In addition to refining the definitions of the MS phenotypes, Lublin et al. introduced a new category: the clinically isolated syndrome (CIS). A CIS is defined as the first clinical presentation of a disease that could be MS but has yet to fulfill the dissemination in time (DIT) criteria required to diagnose MS. DIT will be described in more detail below, but as it requires at least two attacks to have occurred, MS cannot be diagnosed at the initial presentation. The inclusion of CIS as a subgroup of MS allows patients with probable MS to begin treatment earlier than before its inclusion. Another concept the Lublin group added was active vs. not active MS. Active MS is defined as a patient with clinical evidence of a relapse or a new gadolinium-enhancing lesion on a current MRI. Conversely, not active MS is a patient without clinical evidence of a relapse or a new lesion on MRI. “Active” and “not active” are used as modifiers to the MS phenotype; thus, a patient can have RRMS – active, or SPMS – not active. Lublin et al. used 1 year as the minimum time frame to assess for activity; thus, if the annual MRI for MS activity showed no new lesions, and there were no clinical relapses in the past year, the patient would have “not active” MS. However, no recommendation for what time frame to use was given in this article, and in 2020, Lublin et al. published an article to clarify the necessity of defining a time frame in which to define activity or else this modifier would have little meaning. 5

What are the diagnostic criteria for multiple sclerosis?

The diagnosis of MS incorporates a combination of clinical, imaging, and laboratory criteria, which are compiled by an expert panel and then revised periodically, most recently in 2010 and 2017. 6 , 7 These criteria are termed the McDonald criteria, after the lead author on the paper detailing the criteria that were originally composed in 2001. 8 Due to the reliance on the combination of information, as there is no single laboratory test that can diagnose MS, consideration and exclusion of alternative disease processes is critical to the diagnostic workup. To diagnose MS, you must demonstrate dissemination of lesions in the CNS in space and time (DIS/DIT). DIS and DIT are defined as either clinical or radiologic evidence of greater than one lesion at different anatomical locations, separated in time by a period of complete or partial remission. The McDonald criteria define different ways DIS and DIT can be demonstrated to make the diagnosis. In a patient with a relapsing-remitting presentation of MS, DIS can be demonstrated through either:

• - Objective, clinical evidence of ≥2 lesions or
• - ≥ 1 symptomatic or asymptomatic MS-typical T2 lesions in 2 or more areas of the CNS: periventricular, juxtacortical/cortical, infratentorial, or the spinal cord.

DIT can be demonstrated through either:

• - ≥ 2 typical MS attacks separated by a period of remission,
• - The simultaneous presence of both enhancing and non-enhancing symptomatic or asymptomatic MS-typical MRI lesions,
• - A new T2-enhancing MRI lesion compared to a baseline scan, or
• - The presence of CSF-specific oligoclonal bands.

If, however, a patient initially presents with a continual progression of disability, MS can still be diagnosed if they have had at least 1 year of disability progression and two of the following:

• - ≥ 1 symptomatic or asymptomatic MS typical T2 lesions (periventricular, juxtacortical/cortical, or infratentorial),
• - ≥ 2 T2 spinal cord lesions, or
• - The presence of CSF-specific oligoclonal bands. 6

What imaging is indicated and what results would support a diagnosis of MS?

An MRI of the brain and spinal cord is extremely important in the diagnosis of MS as it is very sensitive in detecting white matter abnormalities. To diagnose MS there should be at least one typical MS lesion in at least two areas that are characteristic of MS. A typical MS lesion is a focal hyperintensity on a T2 weighted sequence, round/ovoid in shape, ranges from a few millimeters to 1–2 cm in size, and is at least 3 mm in its long axis. Characteristic locations include periventricular (in direct contact with the lateral ventricles, without intervening normal white matter), juxtacortical/cortical (in direct contact with the cortex, without intervening normal white matter), infratentorial (in the brainstem, cerebellar peduncles, or cerebellum), or anywhere in the spinal cord (the cervical cord is the most frequently involved). Another feature characteristic of MS lesions is gadolinium enhancement. Gadolinium enhancement is seen in acute MS lesions and is transient, usually lasting 4 weeks or less. This feature can help support the DIT criteria of diagnosis, as the presence of gadolinium-enhancing and nonenhancing lesions confirms the presence of new and chronic lesions. 9

What laboratory testing is indicated and what results would support a diagnosis of MS?

CSF analysis and serum antibody testing can be useful, especially when the clinical picture is not “classic” for MS to support or cast doubt on the diagnosis of MS. In the workup of MS, CSF analysis should include white blood cell count, red blood cell count, protein concentration, glucose level, immunoglobulin G (IgG) index, and oligoclonal band testing. The white blood cell count, protein concentration, and glucose levels are helpful in ruling out MS; white blood cell counts can be mildly elevated in MS, but very high counts (>50/mm 3 ), low glucose level, and high total protein are more indicative of infection than MS. A high red blood cell count likely indicates a traumatic tap, which may make the other tests uninterpretable, so a CSF analysis with high red blood cells should be interpreted with caution. An IgG index (IgG CSF /IgG Serum )/(Albumin CSF /Albumin Serum ) is indicative of how much IgG is being produced in the CSF and is used instead of just measuring the level of IgG in the CSF because peripherally produced IgG can cross the blood–brain barrier and be measured in the CSF. Another method to detect CSF-specific IgG is oligoclonal bands. Through isoelectric focusing and immunoblotting, antibodies can be visualized as dark bands. Oligoclonal bands are antibodies seen only in the CSF and not in the patient's serum. Two or more oligoclonal bands in the CSF suggest intrathecal production of IgG (as seen in MS) rather than a systemic production of IgG that is being leaked into the CSF. In the latter case, the bands of IgG antibodies being detected in the serum would be observed in the CSF as well. 10 Another laboratory test that is sometimes used in the workup of MS is testing the serum for the presence of antibodies. There is no specific antibody associated with MS, but detection of specific antibodies can help rule out MS. Antibodies against an aquaporin-4 water channel in astrocytes is seen in NMOSD and can help rule out MS if present. Anti-myelin oligodendrocyte glycoprotein (anti-MOG) targets one of the proteins found in myelin, and though once thought to be indicative of MS, it has been discovered to be a separate entity, termed anti-MOG syndrome. The clinical course of anti-MOG syndrome is like ADEM in pediatric patients, whereas adults typically show optic neuritis and brainstem encephalitis. Importantly though, pediatric and adult patients with seropositive anti-MOG titers don't ever fulfill diagnostic criteria for MS, further solidifying anti-MOG syndrome as a separate entity from MS. 11

What electrophysiologic testing could be performed and what results would support a diagnosis of MS?

Evoked potentials (EPs) are used to measure electrical activity in areas of the brain and spinal cord. There are different types of EPs, and the ones most used in MS are visual (testing the optic nerve) and motor EPs. There are certain situations EPs can be helpful: when the MRI is equivocal or to predict the aggressiveness of the disease. MRI is more sensitive than an EP and is better at diagnosing MS, but if the MRI is equivocal, an EP can be used to help support or rule out the diagnosis. Second, EPs are better at predicting the clinical course of MS as it can detect early or even subclinical demyelination prior to its visualization on MRI. EPs can be used to monitor a patient, and if an EP is positive, more aggressive treatment can be initiated. 12

Diagnostic findings, Part 2

Lumbar puncture and blood draw are performed, and CSF and serum obtained for additional studies. The results are listed in Table 2 , Table 3 . T2 FLAIR MRI images of the brain, optic nerves, and spinal cord are also obtained ( Fig. 1 ). Focal hyperintensities are seen in the brain, right optic nerve, and spinal cord. The clinical presentation, imaging, and lab data are consistent with MS as the diagnosis.

Table 2

Cerebrospinal fluid (CSF) values.

Table 3

Additional results.

Abbreviation: CSF, cerebrospinal fluid.

Parasagittal MRI image demonstrates several periventricular demyelinating plaques (red arrowheads) referred to as Dawson fingers in multiple sclerosis. Reproduced with permission from Harrison Klause, MD, EVMS, Norfolk, VA. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Questions/discussion points, Part 2

Describe the epidemiologic features of ms.

MS is a disorder that leads to disability in young adults. Patients are usually between 15 and 45 years of age when symptoms present. The mean age of onset is from 28 to 31 years. The age of onset varies among the clinical subtypes (phenotypes). RRMS has an earlier onset, averaging between 25 and 29 years, with SPMS presenting at a mean age between 40 and 49 years of age. The estimated male to female ratio is 1.4–2.3 to 1. Geographic variation exists with MS more common in northern latitudes. In the US, the estimated prevalence is 1–1.5 per 1000 individuals. 2 , 13

How does autoimmunity play a role in the mechanism of MS?

Normally, when a dendritic cell detects a foreign antigen, it presents the antigen to CD4 + T cells and releases cytokines that induce inflammation and helps shape the adaptive immune system. In MS, dendritic cells are overactivated and migrate through the blood–brain barrier to induce Th1 and Th17 differentiation in the CNS. The proportion of Th17 to Th1 cells is also increased in the peripheral blood of MS patients during acute relapses. Th17 releases matrix metalloproteinase and granulocyte macrophage colony-stimulating factor, which increases blood–brain barrier permeability and recruits bone marrow-derived monocytes, respectively. Th1 and Th17 are both involved in ectopic lymphoid follicle formation and play a role in activating B-cells. In MS patients, B-cells produce autoantibodies that mediate demyelination and axonal disruption. Also, memory B-cells differentiate into CSF plasma cells, which produce antibodies that manifest as oligoclonal bands on protein electrophoresis. B-cells are important regulators of the immune system, and this regulatory function is defective in MS patients, leading to autoreactive B-cells and an overactive immune system. In addition to B-cells and T-cells, astrocytes, the gut microbiome, and dieting patterns are also thought to play a role in the immune response in MS patients. Astrocytes play an important role in maintaining the blood–brain barrier and regulate the activity of microglia and oligodendrocytes. Dysfunction in these processes is thought to contribute to demyelination, axonal damage, and infiltration of pro-inflammatory leukocytes into the CNS. 2 , 14

Describe the gross and histological findings observed in the brain from a patient with multiple sclerosis

Fig. 2 is a picture from an autopsy patient with MS who died of an unrelated cause. There are several well-circumscribed, gray-tan, irregularly shaped paraventricular and juxtacortical plaques (arrows), representing chronic MS plaques that are demyelinated. On histology, active plaques can be recognized by the presence of foamy macrophages, which are stripping myelin from axons and digesting it in lysosomes ( Fig. 3 , Fig. 4 ). In chronic plaques, there is little to no myelin left, which is highlighted with the Luxol fast blue stain which stains myelin blue ( Fig. 5 , Fig. 6 , Fig. 7 ). 2

Multiple sclerosis. In a coronal section of brain, multiple sharply defined, tan-gray plaques are identified in the white matter, adjacent to the right ventricle (paraventricular), involving the cortex at the gray matter-white interface (juxtacortical), and in other locations (arrows).

Active MS plaque shows abundant foamy macrophages, which are ingesting the myelin breakdown products, accompanied by an intense lymphocytic perivascular infiltrate (perivascular cuffing) (H&E stain, intermediate magnification).

Foamy macrophages (arrowheads) are distended with myelin breakdown product (Luxol fast blue stain, high magnification). Reproduced with permission from Suzanne Zein-Powell, MD, Methodist Hospital, Houston, TX. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

A c oronal section of midbrain at the interface between the pons and midbrain shows several areas of demyelination, most notably centrally within the cerebral peduncle, within the corticospinal fiber tract (arrowhead) (Luxol fast blue stain, no magnification). Reproduced with permission from the College of American Pathologists. AUB, 1996 Education Programs. Northfield, IL: College of American Pathologists; 1996. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

On histological examination, the brain shows an area of demyelination with axonal preservation (arrowhead) seen as the tan-gray plaque on gross examination. (Luxol fast blue stain, intermediate magnification). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Chronic plaque at interface with normal white matter. The axons are retained within the plaque; however, many have not been remyelinated. In addition, macrophages and lymphocytes are decreased in number in a chronic plaque, so the cellularity within a chronic plaque is less than in an active/acute plaque ( Fig. 3 , Fig. 4 ). (Luxol fast blue stain, intermediate magnification). Courtesy of Philip Boyer, MD, PhD, Brody School of Medicine, Greenville, NC. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Do a patient's acute exacerbation symptoms correlate with pathologic findings?

Clinical symptoms of acute exacerbations are correlated histopathologically with focal inflammatory demyelinating white matter lesions. Inflammatory cells recruited from the circulation, mostly T-cells and macrophages, accumulate in the lesions and eventually lead to partial/complete demyelination. Overall, white matter demyelination and peripheral immune cell accumulation are pathological hallmarks of an acute plaque and correlate with clinical symptoms. Additionally, edema associated with the inflammatory lesion likely contributes to the observed functional deficits, especially in regions with low swelling capacity, such as the spinal cord. Both demyelination and compression of nerve fibers lead to reduced conduction velocity and sometimes complete conduction block. 15

Describe the pathological hallmarks of progressive disease

Although there is likely some crossover, disease progression is characterized more by neurodegeneration than focal, autoimmune-driven inflammation like that of acute relapses. In the later chronic stages of MS, all aspects of the neuron undergo degenerative changes including axons, cell bodies, dendrites, spines, and neurotransmitter metabolism. The direct mechanism leading to neurodegeneration is unknown, but possible mechanisms include microglia activation, reactive oxygen species, and mitochondrial dysfunction. The triggers of neurodegeneration seen in chronic, progressive MS are the “normal appearing” white matter (NAWM) lesions and tissue damage in the gray matter. NAWM appears normal in routine stains and imaging; however, detailed histological studies reveal diffuse gliosis, microglial activation, vascular fibrosis, perivascular cuffing by inflammatory cells, perivascular lipofuscin, abnormal endothelial tight junctions, blood–brain barrier breakdown, and/or vessels containing proliferating endothelial cells. Axonal loss has also been observed in NAWM. Notably, NAWM lesions correlate better with clinical disability than focal inflammatory white matter lesions. In addition to white matter, gray matter is damaged in progressive MS. Damage can extend throughout the cortex and subcortical regions. An important element of gray matter damage is meningeal inflammation. Lymphoid structures resembling B-cell follicles form in the meninges. They are found extensively in patients with primary progressive MS who exhibit a more severe clinical course. 16 , 17

Describe remyelination in MS

Remyelination in the CNS is accomplished by oligodendrocytes, and in MS patients, they contribute to the complete or partial resolution of clinical symptoms in RRMS. Remyelination is dependent on adult oligodendrocyte progenitor cells (OPC) as preexisting, mature oligodendrocytes cannot add to the pool of myelinogenic oligodendrocytes. It is thought that the main reason remyelination fails in MS is because OPC become quiescent and unable to differentiate, but there are likely other factors that contribute to the failure to remyelinate. For example, reactive astrocytes secrete inhibitors of remyelination at the site of demyelination. Similarly, clearance of myelin debris is an important step in remyelination since it contains remyelination inhibitors. The macrophages and activated microglia that are responsible for phagocytosis of debris also secrete various neutrophilic factors. There is also an age dependent decline in remyelination, and this is more clearly due to decreased differentiation of OPC. Mechanistically, it is thought that aged OPC become less responsive to factors that induce differentiation through dysfunction of the mTOR pathway. Finally, remyelination also depends on the location in the CNS. For example, periventricular lesions are less amenable to remyelination than subcortical lesions. Overall, as patients age and the disease progresses, there is less remyelination of lesions, correlating with progressive clinical dysfunction. 18

How is MS treated?

Treatment is multifactorial including counseling, physical therapy, exercise and pharmacotherapy. Pharmacotherapy consists of medications directed at immunosuppression or immunomodulation. 2 Although not curative, pharmacotherapy may ameliorate symptoms. Disease modifying therapeutic agents depends on which clinical subtype (phenotype) (CIS, RRMS, SPMS, and PPMS) the patient presents with. Monoclonal antibodies (natalizumab, ocrelizumab, rituximab, ofatumumab, and alemtuzumab) may be indicated for active disease. Fumarates (e.g. dimethyl fumarate) and sphingosine 1-phosphate receptor modulators (e.g. fingolimod) are other considerations along with injectable agents, such as recombinant human interferon beta-1b, recombinant human interferon beta-1a, and glatiramer acetate. Healthcare workers need to consider the risk benefit of selected agents, given the potential adverse effects including infection. 2 , 19 , 20 , 21

Teaching Points

• • Multiple sclerosis (MS) is a chronic demyelinating disorder of autoimmune etiology in which the clinical findings are separated in both time and space.
• • MS presents with symptoms usually between 15 and 45 years of age. It is twice as common in women and has a prevalence between 1/1000 persons in the US.
• • The diagnosis of MS incorporates a combination of clinical, imaging, and laboratory data to show dissemination of lesions in space and time, along with the consideration and exclusion of alternative diagnoses.
• • Laboratory testing contributes to the diagnostic workup of a patient with MS in the differential diagnosis; however, no single laboratory test, in isolation, is diagnostic of MS.
• • The most characteristic finding seen on MRI are T2-hyperintense and/or gadolinium contrast-enhancing T1 cerebral hemisphere periventricular, juxtacortical, infratentorial, and spinal cord white matter lesions.
• • The presence of CSF-specific oligoclonal bands can substitute for MRI data demonstrating dissemination in time.
• • Autoimmunity is thought to play an important role in the pathogenesis of MS, involving T and B cell dysfunction.
• • Acute exacerbations are characterized by demyelination, inflammation, and edema.
• • Chronic, progressive disease is characterized by neurodegeneration, axonal damage, normal appearing white matter lesions, and gray matter abnormalities.
• • Remyelination is thought to play a role in the partial or complete recovery of neurological function in relapsing-remitting MS.
• • As MS progresses and patients age, remyelination lessens and neurological dysfunction becomes permanent.
• • Treatment of MS is multifactorial including counseling, physical therapy, exercise, and pharmacotherapy.

Conflict of interest

The author(s) declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Acknowledgments

Fig. 2 , Fig. 3 , Fig. 6 were obtained during the scope of US government employment for Dr. Conran.

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Expert Recommendation
• Published: 03 September 2024

The influence of MOGAD on diagnosis of multiple sclerosis using MRI

• Ruth Geraldes   ORCID: orcid.org/0000-0001-5829-808X 1 , 2 , 3 ,
• Georgina Arrambide   ORCID: orcid.org/0000-0002-2657-5510 4 ,
• Brenda Banwell 5 , 6 , 7 ,
• Àlex Rovira   ORCID: orcid.org/0000-0002-2132-6750 8 ,
• Rosa Cortese 9 ,
• Hans Lassmann   ORCID: orcid.org/0000-0001-8617-5052 10 ,
• Silvia Messina 2 , 3 ,
• Mara Assunta Rocca   ORCID: orcid.org/0000-0003-2358-4320 11 , 12 , 13 ,
• Patrick Waters   ORCID: orcid.org/0000-0003-4142-2667 2 ,
• Declan Chard   ORCID: orcid.org/0000-0003-3076-2682 14 , 15 ,
• Claudio Gasperini 16 ,
• Yael Hacohen 17 ,
• Romina Mariano 2 ,
• Friedemann Paul 18 ,
• Gabriele C. DeLuca   ORCID: orcid.org/0000-0003-0342-5197 2 ,
• Christian Enzinger 19 , 20 ,
• Ludwig Kappos   ORCID: orcid.org/0000-0003-4175-5509 21 ,
• M. Isabel Leite   ORCID: orcid.org/0000-0002-4277-9855 1 , 2 ,
• Jaume Sastre-Garriga 4 ,
• Tarek Yousry 14 ,
• Olga Ciccarelli 22 , 23 ,
• Massimo Filippi   ORCID: orcid.org/0000-0002-5485-0479 11 , 12 , 13 ,
• Frederik Barkhof   ORCID: orcid.org/0000-0003-3543-3706 24 , 25 ,
• Jacqueline Palace   ORCID: orcid.org/0000-0003-4779-6133 1 , 2 &

MAGNIMS Study Group

Nature Reviews Neurology ( 2024 ) Cite this article

9 Altmetric

Metrics details

• Medical imaging
• Multiple sclerosis

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an immune-mediated demyelinating disease that is challenging to differentiate from multiple sclerosis (MS), as the clinical phenotypes overlap, and people with MOGAD can fulfil the current MRI-based diagnostic criteria for MS. In addition, the MOG antibody assays that are an essential component of MOGAD diagnosis are not standardized. Accurate diagnosis of MOGAD is crucial because the treatments and long-term prognosis differ from those for MS. This Expert Recommendation summarizes the outcomes from a Magnetic Resonance Imaging in MS workshop held in Oxford, UK in May 2022, in which MS and MOGAD experts reflected on the pathology and clinical features of these disorders, the contributions of MRI to their diagnosis and the clinical use of the MOG antibody assay. We also critically reviewed the literature to assess the validity of distinctive imaging features in the current MS and MOGAD criteria. We conclude that dedicated orbital and spinal cord imaging (with axial slices) can inform MOGAD diagnosis and also illuminate differential diagnoses. We provide practical guidance to neurologists and neuroradiologists on how to navigate the current MOGAD and MS criteria. We suggest a strategy that includes useful imaging discriminators on standard clinical MRI and discuss imaging features detected by non-conventional MRI sequences that demonstrate promise in differentiating these two disorders.

This is a preview of subscription content, access via your institution

Access options

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

24,99 € / 30 days

cancel any time

Subscribe to this journal

Receive 12 print issues and online access

195,33 € per year

only 16,28 € per issue

Buy this article

• Purchase on SpringerLink
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Advanced MRI features in relapsing multiple sclerosis patients with and without CSF oligoclonal IgG bands

MAGNIMS consensus recommendations on the use of brain and spinal cord atrophy measures in clinical practice

A real-world clinical validation for AI-based MRI monitoring in multiple sclerosis

Thompson, A. J. et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 17 , 162–173 (2018).

Article   PubMed   Google Scholar  

Geraldes, R. et al. The current role of MRI in differentiating multiple sclerosis from its imaging mimics. Nat. Rev. Neurol. 14 , 199–213 (2018).

Marignier, R. et al. Myelin-oligodendrocyte glycoprotein antibody-associated disease. Lancet Neurol. 20 , 762–772 (2021).

Article   CAS   PubMed   Google Scholar  

Walton, C. et al. Rising prevalence of multiple sclerosis worldwide: insights from the atlas of MS, third edition. Mult. Scler. J. 26 , 1816–1821 (2020).

Article   Google Scholar  

Filippi, M. et al. Multiple sclerosis. Nat. Rev. Dis. Prim. 4 , 43 (2018).

Thompson, A. J., Baranzini, S. E., Geurts, J., Hemmer, B. & Ciccarelli, O. Multiple sclerosis. Lancet 391 , 1622–1636 (2018).

Hohlfeld, R., Dornmair, K., Meinl, E. & Wekerle, H. The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol. 15 , 198–209 (2016).

Reindl, M. & Waters, P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat. Rev. Neurol. 15 , 89–102 (2019).

O’Connell, K. et al. Prevalence and incidence of neuromyelitis optica spectrum disorder, aquaporin-4 antibody-positive NMOSD and MOG antibody-positive disease in Oxfordshire, UK. J. Neurol. Neurosurg. Psychiatry 91 , 1126–1128 (2020).

Papp, V. et al. Worldwide incidence and prevalence of neuromyelitis optica: a systematic review. Neurology 96 , 59–77 (2021).

Article   PubMed   PubMed Central   Google Scholar  

Hor, J. Y. et al. Epidemiology of neuromyelitis optica spectrum disorder and its prevalence and incidence worldwide. Front. Neurol. 11 , 543047 (2020).

Cobo-Calvo, A. et al. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the MOGADOR study. Neurology 90 , e1858–e1869 (2018).

Jurynczyk, M. et al. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain 140 , 3128–3138 (2017).

Molazadeh, N. et al. Progression independent of relapses in aquaporin4-IgG-seropositive neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and multiple sclerosis. Mult. Scler. Relat. Disord. 80 , 105093 (2023).

Chen, B. et al. Do early relapses predict the risk of long-term relapsing disease in an adult and paediatric cohort with MOGAD? Ann. Neurol. 94 , 508–517 (2023).

Cobo-Calvo, A. et al. Clinical features and risk of relapse in children and adults with myelin oligodendrocyte glycoprotein antibody-associated disease. Ann. Neurol. 89 , 30–41 (2021).

Satukijchai, C. et al. Factors associated with relapse and treatment of myelin oligodendrocyte glycoprotein antibody-associated disease in the United Kingdom. JAMA Netw. Open 5 , e2142780 (2022).

Shahriari, M., Sotirchos, E. S., Newsome, S. D. & Yousem, D. M. MOGAD: how it differs from and resembles other neuroinflammatory disorders. Am. J. Roentgenol. 216 , 1031–1039 (2021).

Fadda, G., Armangue, T., Hacohen, Y., Chitnis, T. & Banwell, B. Paediatric multiple sclerosis and antibody-associated demyelination: clinical, imaging, and biological considerations for diagnosis and care. Lancet Neurol. 20 , 136–149 (2021).

Ciccone, A. et al. Corticosteroids for the long-term treatment in multiple sclerosis. Cochrane Database Syst. Rev. 23 , CD006264 (2008).

Google Scholar  

Hauser, S. L. & Cree, B. A. C. Treatment of multiple sclerosis: a review. Am. J. Med. 133 , 1380–1390.e2 (2020).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Hacohen, Y. et al. Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease. JAMA Neurol. 75 , 478–487 (2018).

Wang, X. et al. Effectiveness and tolerability of different therapies in preventive treatment of MOG-IgG-associated disorder: a network meta-analysis. Front. Immunol. 13 , 953993 (2022).

Jarius, S. et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J. Neuroinflamm. 13 , 280 (2016).

Corbali, O. & Chitnis, T. Pathophysiology of myelin oligodendrocyte glycoprotein antibody disease. Front. Neurol. 14 , 1137998 (2023).

Dendrou, C. A., Fugger, L. & Friese, M. A. Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 15 , 545–558 (2015).

Yandamuri, S. S. et al. MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity. JCI Insight 8 , e165373 (2023).

Prüss, H. Autoantibodies in neurological disease. Nat. Rev. Immunol. 21 , 798–813 (2021).

Sun, B., Ramberger, M., O’Connor, K. C., Bashford-Rogers, R. J. M. & Irani, S. R. The B cell immunobiology that underlies CNS autoantibody-mediated diseases. Nat. Rev. Neurol. 16 , 481–492 (2020).

Kwon, Y. N. et al. Peripherally derived macrophages as major phagocytes in MOG encephalomyelitis. Neurol. Neuroimmunol. NeuroInflamm. 6 , e60 (2019).

Saadoun, S. et al. Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain. Acta Neuropathol. Commun. 2 , 35 (2014).

Höftberger, R. et al. The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody. Acta Neuropathol. 139 , 875–892 (2020).

Lassmann, H. Multiple sclerosis: lessons from molecular neuropathology. Exp. Neurol. 262 , 2–7 (2014).

Calahorra, L., Camacho-Toledano, C., Serrano-Regal, M. P., Ortega, M. C. & Clemente, D. Regulatory cells in multiple sclerosis: from blood to brain. Biomedicines 10 , 335 (2022).

Banwell, B. et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 22 , 268–282 (2023).

Villacieros‐Álvarez, J. et al. MOG antibodies in adults with a first demyelinating event suggestive of multiple sclerosis. Ann. Neurol . https://doi.org/10.1002/ana.26793 (2023).

Waters, P. J. et al. A multicenter comparison of MOG-IgG cell-based assays. Neurology 92 , e1250–e1255 (2019).

Hyun, J.-W. et al. Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases. J. Neurol. Neurosurg. Psychiatry 88 , 811–817 (2017).

Gastaldi, M. et al. Prognostic relevance of quantitative and longitudinal MOG antibody testing in patients with MOGAD: a multicentre retrospective study. J. Neurol. Neurosurg. Psychiatry 94 , 201–210 (2023).

Waters, P. et al. Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes. JAMA Neurol. 77 , 82–93 (2020).

Carta, S. et al. Significance of myelin oligodendrocyte glycoprotein antibodies in CSF: a retrospective multicenter study. Neurology 100 , e1095–e1108 (2023).

Kim, H. J. & Palace, J. Should we test for IgG antibodies against MOG in both serum and CSF in patients with suspected MOGAD? Neurology 100 , 497–498 (2023).

Kwon, Y. N. et al. Myelin oligodendrocyte glycoprotein-immunoglobulin G in the CSF: clinical implication of testing and association with disability. Neurol. Neuroimmunol. Neuroinflamm. 9 , e1095 (2022).

Armangue, T. et al. Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study. Lancet Neurol. 19 , 234–246 (2020).

de Mol, C. L. et al. The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults. Mult. Scler. 26 , 806–814 (2020).

Wendel, E.-M. et al. High association of MOG-IgG antibodies in children with bilateral optic neuritis. Eur. J. Paediatr. Neurol. 27 , 86–93 (2020).

Yang, M. et al. Clinical predictive factors for diagnosis of MOG-IgG and AQP4-IgG related paediatric optic neuritis: a Chinese cohort study. Br. J. Ophthalmol. 106 , 262–266 (2022).

Chen, J. J. et al. MOG-IgG among participants in the pediatric optic neuritis prospective outcomes study. JAMA Ophthalmol. 139 , 583–585 (2021).

Jurynczyk, M. et al. Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis. Brain 140 , 617–627 (2017).

Cortese, R. et al. Clinical and MRI measures to identify non-acute MOG-antibody disease in adults. Brain 146 , 2489–2501 (2022).

Carandini, T. et al. Distinct patterns of MRI lesions in MOG antibody disease and AQP4 NMOSD: a systematic review and meta-analysis. Mult. Scler. Relat. Disord. 54 , 103118 (2021).

Carnero Contentti, E. et al. MRI to differentiate multiple sclerosis, neuromyelitis optica, and myelin oligodendrocyte glycoprotein antibody disease. J. Neuroimaging 33 , 688–702 (2023).

Varley, J. A. et al. Validation of the 2023 International Diagnostic criteria for MOGAD in a selected cohort of adults and children. Neurology 103 , e209321 (2024).

Kim, K. H., Kim, S.-H., Park, N. Y., Hyun, J.-W. & Kim, H. J. Validation of the International MOGAD Panel proposed criteria. Mult. Scler. J. 29 , 1680–1683 (2023).

Forcadela, M. et al. Timing of MOG-IgG testing is key to 2023 MOGAD diagnostic criteria. Neurol. Neuroimmunol. Neuroinflamm. 11 , e200183 (2024).

Lipps, P. et al. Ongoing challenges in the diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease. JAMA Neurol. 80 , 1377–1379 (2023).

Ciccarelli, O., Toosy, A. T., Thompson, A. & Hacohen, Y. Navigating through the recent diagnostic criteria for MOGAD: challenges and practicalities. Neurology 100 , 689–690 (2023).

Lassmann, H. & Bradl, M. Multiple sclerosis: experimental models and reality. Acta Neuropathol. 133 , 223–244 (2017).

Takai, Y. et al. Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study. Brain 143 , 1431–1446 (2020).

Gilli, F. & Ceccarelli, A. Magnetic resonance imaging approaches for studying mouse models of multiple sclerosis: a mini review. J. Neurosci. Res. 101 , 1259–1274 (2023).

Sechi, E. et al. Comparison of MRI lesion evolution in different central nervous system demyelinating disorders. Neurology 97 , e1097–e1109 (2021).

Beltrán, E. et al. Archeological neuroimmunology: resurrection of a pathogenic immune response from a historical case sheds light on human autoimmune encephalomyelitis and multiple sclerosis. Acta Neuropathol. 141 , 67–83 (2021).

Carta, S. et al. Antibodies to MOG in CSF only: pathological findings support the diagnostic value. Acta Neuropathol. 141 , 801–804 (2021).

Nicaise, A. M. et al. Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proc. Natl Acad. Sci. USA 116 , 9030–9039 (2019).

Junker, A. et al. Extensive subpial cortical demyelination is specific to multiple sclerosis. Brain Pathol. 30 , 641–652 (2020).

Ciotti, J. R. et al. Central vein sign and other radiographic features distinguishing myelin oligodendrocyte glycoprotein antibody disease from multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica. Mult. Scler. 28 , 49–60 (2022).

Lassmann, H. Neuroinflammation: 2021 update. Free Neuropathol. 2 , 1 (2021).

Wattjes, M. P. et al. 2021 MAGNIMS–CMSC–NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol. 20 , 653–670 (2021).

Soelberg, K. et al. A population-based prospective study of optic neuritis. Mult. Scler. J. 23 , 1893–1901 (2017).

Article   CAS   Google Scholar  

Asseyer, S. et al. Prodromal headache in MOG-antibody positive optic neuritis. Mult. Scler. Relat. Disord. 40 , 101965 (2020).

Hassan, M. B. et al. Population-based incidence of optic neuritis in the era of aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies. Am. J. Ophthalmol. 220 , 110–114 (2020).

Winter, A. & Chwalisz, B. MRI characteristics of NMO, MOG and MS related optic neuritis. Semin. Ophthalmol. 35 , 333–342 (2020).

Vicini, R., Brügger, D., Abegg, M., Salmen, A. & Grabe, H. M. Differences in morphology and visual function of myelin oligodendrocyte glycoprotein antibody and multiple sclerosis associated optic neuritis. J. Neurol. 268 , 276–284 (2021).

Falcão-Gonçalves, A. B., Bichuetti, D. B. & de Oliveira, E. M. L. Recurrent optic neuritis as the initial symptom in demyelinating diseases. J. Clin. Neurol. 14 , 351–358 (2018).

Kraker, J. A. & Chen, J. J. An update on optic neuritis. J. Neurol. 270 , 5113–5126 (2023).

Chen, J. J. et al. Myelin oligodendrocyte glycoprotein antibody-positive optic neuritis: clinical characteristics, radiologic clues, and outcome. Am. J. Ophthalmol. 195 , 8–15 (2018).

Oertel, F. C. et al. Longitudinal retinal changes in MOGAD. Ann. Neurol. 92 , 476–485 (2022).

Roca-Fernández, A. et al. The use of OCT in good visual acuity MOGAD and AQP4-NMOSD patients; with and without optic neuritis. Mult. Scler. J. Exp. Transl. Clin. 7 , 20552173211066446 (2021).

PubMed   PubMed Central   Google Scholar  

Petzold, A. et al. Diagnosis and classification of optic neuritis. Lancet Neurol. 21 , 1120–1134 (2022).

Schroeder, A. et al. Detection of optic neuritis on routine brain MRI without and with the assistance of an image postprocessing algorithm. Am. J. Neuroradiol. 42 , 1130–1135 (2021).

Petzold, A. et al. The investigation of acute optic neuritis: a review and proposed protocol. Nat. Rev. Neurol. 10 , 447–458 (2014).

Riederer, I., Mühlau, M., Hoshi, M.-M., Zimmer, C. & Kleine, J. F. Detecting optic nerve lesions in clinically isolated syndrome and multiple sclerosis: double-inversion recovery magnetic resonance imaging in comparison with visually evoked potentials. J. Neurol. 266 , 148–156 (2019).

Hodel, J. et al. Comparison of 3D double inversion recovery and 2D STIR FLAIR MR sequences for the imaging of optic neuritis: pilot study. Eur. Radiol. 24 , 3069–3075 (2014).

Fadda, G. et al. Myelitis features and outcomes in CNS demyelinating disorders: comparison between multiple sclerosis, MOGAD, and AQP4-IgG-positive NMOSD. Front. Neurol. 13 , 1011579 (2022).

Mariano, R. et al. Comparison of clinical outcomes of transverse myelitis among adults with myelin oligodendrocyte glycoprotein antibody vs aquaporin-4 antibody disease. JAMA Netw. Open 2 , e1912732 (2019).

Sechi, E. et al. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): a review of clinical and MRI features, diagnosis, and management. Front. Neurol. 13 , 885218 (2022).

Budhram, A. et al. Unilateral cortical FLAIR-hyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome. J. Neurol. 266 , 2481–2487 (2019).

Budhram, A., Sechi, E., Nguyen, A., Lopez-Chiriboga, A. S. & Flanagan, E. P. FLAIR-hyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES): is immunotherapy always needed to put out the fire? Mult. Scler. Relat. Disord. 44 , 102283 (2020).

Wang, Y.-F. et al. The clinical features of FLAIR-hyperintense lesions in anti-MOG antibody associated cerebral cortical encephalitis with seizures: case reports and literature review. Front. Immunol. 12 , 582768 (2021).

Banks, S. A. et al. Brainstem and cerebellar involvement in MOG-IgG-associated disorder versus aquaporin-4-IgG and MS. J. Neurol. Neurosurg. Psychiatry 92 , 384–390 (2020).

Jarius, S. et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: brainstem involvement — frequency, presentation and outcome. J. Neuroinflamm. 13 , 281 (2016).

Kunchok, A. et al. Does area postrema syndrome occur in myelin oligodendrocyte glycoprotein-IgG-associated disorders (MOGAD)? Neurology 94 , 85–88 (2020).

Zhao-Fleming, H. H. et al. CNS demyelinating attacks requiring ventilatory support with myelin oligodendrocyte glycoprotein or aquaporin-4 antibodies. Neurology 97 , e1351–e1358 (2021).

Sinha, S. et al. Hemicraniectomy and externalized ventricular drain placement in a pediatric patient with myelin oligodendrocyte glycoprotein-associated tumefactive demyelinating disease. Childs Nerv. Syst. 38 , 185–189 (2022).

McLendon, L. A. et al. Dramatic response to anti-IL-6 receptor therapy in children with life-threatening myelin oligodendrocyte glycoprotein-associated disease. Neurol. Neuroimmunol. Neuroinflamm. 10 , e200150 (2023).

Hümmert, M. W. et al. Cognition in patients with neuromyelitis optica spectrum disorders: a prospective multicentre study of 217 patients (CogniNMO-Study). Mult. Scler. 29 , 819–831 (2023).

Juryńczyk, M., Jacob, A., Fujihara, K. & Palace, J. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease: practical considerations. Pract. Neurol. 19 , 187–195 (2019).

Yılmaz, Ü., Edizer, S., Songür, Ç. Y., Güzin, Y. & Durak, F. S. Atypical presentation of MOG-related disease: slowly progressive behavioral and personality changes following a seizure. Mult. Scler. Relat. Disord. 36 , 101394 (2019).

Jarius, S. et al. Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 1: results from 163 lumbar punctures in 100 adult patients. J. Neuroinflamm. 17 , 261 (2020).

Sechi, E. et al. Variability of cerebrospinal fluid findings by attack phenotype in myelin oligodendrocyte glycoprotein-IgG-associated disorder. Mult. Scler. Relat. Disord. 47 , 102638 (2021).

Tintoré, M. et al. Isolated demyelinating syndromes: comparison of CSF oligoclonal bands and different MR imaging criteria to predict conversion to CDMS. Mult. Scler. J. 7 , 359–363 (2001).

Dobson, R., Ramagopalan, S., Davis, A. & Giovannoni, G. Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude. J. Neurol. Neurosurg. Psychiatry 84 , 909–914 (2013).

Ramanathan, S. et al. Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis. Mult. Scler. 22 , 470–482 (2016).

Dubey, D. et al. Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody. JAMA Neurol. 76 , 301–309 (2019).

Tzanetakos, D. et al. Cortical involvement and leptomeningeal inflammation in myelin oligodendrocyte glycoprotein antibody disease: a three-dimensional fluid-attenuated inversion recovery MRI study. Mult. Scler. 28 , 718–729 (2022).

Ogawa, R. et al. MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy. Neurol. Neuroimmunol. Neuroinflamm. 4 , e322 (2017).

Budhram, A., Kunchok, A. C. & Flanagan, E. P. Unilateral leptomeningeal enhancement in myelin oligodendrocyte glycoprotein immunoglobulin G-associated disease. JAMA Neurol. 77 , 648 (2020).

Salama, S., Khan, M., Pardo, S., Izbudak, I. & Levy, M. MOG antibody-associated encephalomyelitis/encephalitis. Mult. Scler. J. 25 , 1427–1433 (2019).

Elsbernd, P. et al. Cerebral enhancement in MOG antibody-associated disease. J. Neurol. Neurosurg. Psychiatry 95 , 14–18 (2023).

Salama, S., Khan, M., Levy, M. & Izbudak, I. Radiological characteristics of myelin oligodendrocyte glycoprotein antibody disease. Mult. Scler. Relat. Disord. 29 , 15–22 (2019).

Chia, N. H., Redenbaugh, V., Chen, J. J., Pittock, S. J. & Flanagan, E. P. Corpus callosum involvement in MOG antibody-associated disease in comparison to AQP4-IgG-seropositive neuromyelitis optica spectrum disorder and multiple sclerosis. Mult. Scler. 29 , 748–752 (2023).

Cai, M.-T., Zhang, Y.-X., Zheng, Y., Fang, W. & Ding, M.-P. Callosal lesions on magnetic resonance imaging with multiple sclerosis, neuromyelitis optica spectrum disorder and acute disseminated encephalomyelitis. Mult. Scler. Relat. Disord. 32 , 41–45 (2019).

Mastrangelo, V. et al. Bilateral extensive corticospinal tract lesions in MOG antibody-associated disease. Neurology 95 , 648–649 (2020).

Hacohen, Y. et al. ‘Leukodystrophy-like’ phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease. Dev. Med. Child Neurol. 60 , 417–423 (2018).

Baumann, M. et al. MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein. J. Neurol. 265 , 845–855 (2018).

Maranzano, J. et al. MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis. Neurology 89 , 714–721 (2017).

Cortese, R. et al. Differentiating multiple sclerosis from AQP4-neuromyelitis optica spectrum disorder and MOG-antibody disease with imaging. Neurology 100 , e308–e323 (2023).

Messina, S. et al. Contrasting the brain imaging features of MOG-antibody disease, with AQP4-antibody NMOSD and multiple sclerosis. Mult. Scler. 28 , 217–227 (2022).

Biotti, D. et al. Optic neuritis in patients with anti-MOG antibodies spectrum disorder: MRI and clinical features from a large multicentric cohort in France. J. Neurol. 264 , 2173–2175 (2017).

Carnero Contentti, E. et al. Chiasmatic lesions on conventional magnetic resonance imaging during the first event of optic neuritis in patients with neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein‐associated disease in a Latin American cohort. Eur. J. Neurol. 29 , 802–809 (2022).

Fadda, G. et al. MRI and laboratory features and the performance of international criteria in the diagnosis of multiple sclerosis in children and adolescents: a prospective cohort study. Lancet Child. Adolesc. Health 2 , 191–204 (2018).

Cobo-Calvo, A. et al. Cranial nerve involvement in patients with MOG antibody-associated disease. Neurol. Neuroimmunol. Neuroinflamm. 6 , e543 (2019).

Haider, L. et al. Cranial nerve enhancement in multiple sclerosis is associated with younger age at onset and more severe disease. Front. Neurol. 10 , 1085 (2019).

Denève, M. et al. MRI features of demyelinating disease associated with anti-MOG antibodies in adults. J. Neuroradiol. 46 , 312–318 (2019).

Pekcevik, Y. et al. Differentiating neuromyelitis optica from other causes of longitudinally extensive transverse myelitis on spinal magnetic resonance imaging. Mult. Scler. 22 , 302–311 (2016).

Mariano, R. et al. Quantitative spinal cord MRI in MOG-antibody disease, neuromyelitis optica and multiple sclerosis. Brain 144 , 198–212 (2021).

Webb, L. M. et al. Marked central canal T2-hyperintensity in MOGAD myelitis and comparison to NMOSD and MS. J. Neurol. Sci. 450 , 120687 (2023).

Mohseni, S. H. et al. Leptomeningeal and intraparenchymal blood barrier disruption in a MOG-IgG-positive patient. Case Rep. Neurol. Med. 2018 , 1365175 (2018).

El Naggar, I. et al. MR imaging in children with transverse myelitis and acquired demyelinating syndromes. Mult. Scler. Relat. Disord. 67 , 104068 (2022).

Fadda, G. et al. Comparison of spinal cord magnetic resonance imaging features among children with acquired demyelinating syndromes. JAMA Netw. Open 4 , e2128871 (2021).

Cacciaguerra, L. et al. Timing and predictors of T2-lesion resolution in patients with myelin-oligodendrocyte-glycoprotein-antibody-associated disease. Neurology 101 , e1376–e1381 (2023).

Abdel-Mannan, O. et al. Evolution of brain MRI lesions in paediatric myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and its relevance to disease course. J. Neurol. Neurosurg. Psychiatry 95 , 426–433 (2023).

Kitley, J. et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies. JAMA Neurol. 71 , 276 (2014).

Fadda, G. et al. Silent new brain MRI lesions in children with MOG-antibody associated disease. Ann. Neurol. 89 , 408–413 (2021).

Verhey, L. H. et al. Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials. Neurology 81 , 1215–1221 (2013).

Camera, V. et al. Frequency of new silent MRI lesions in myelin oligodendrocyte glycoprotein antibody disease and aquaporin-4 antibody neuromyelitis optica spectrum disorder. JAMA Netw. Open 4 , e2137833 (2021).

Syc-Mazurek, S. B. et al. Frequency of new or enlarging lesions on MRI outside of clinical attacks in patients with MOG-antibody-associated disease. Neurology 99 , 795–799 (2022).

Schmidt, F. A. et al. Differences in advanced magnetic resonance imaging in MOG-IgG and AQP4-IgG seropositive neuromyelitis optica spectrum disorders: a comparative study. Front. Neurol. 11 , 499910 (2020).

Chien, C. et al. Spinal cord lesions and atrophy in NMOSD with AQP4-IgG and MOG-IgG associated autoimmunity. Mult. Scler. J. 25 , 1926–1936 (2019).

Duan, Y. et al. Brain structural alterations in MOG antibody diseases: a comparative study with AQP4 seropositive NMOSD and MS. J. Neurol. Neurosurg. Psychiatry 92 , 709–716 (2021).

Lotan, I. et al. Volumetric brain changes in MOGAD: a cross-sectional and longitudinal comparative analysis. Mult. Scler. Relat. Disord. 69 , 104436 (2023).

Rechtman, A. et al. Volumetric brain loss correlates with a relapsing MOGAD disease course. Front. Neurol. 13 , 867190 (2022).

Zhuo, Z. et al. Brain structural and functional alterations in MOG antibody disease. Mult. Scler. J. 27 , 1350–1363 (2021).

Fadda, G. et al. Deviation from normative whole brain and deep gray matter growth in children with MOGAD, MS, and monophasic seronegative demyelination. Neurology 101 , e425–e437 (2023).

Gao, C. et al. Structural and functional alterations in visual pathway after optic neuritis in MOG antibody disease: a comparative study with AQP4 seropositive NMOSD. Front. Neurol. 12 , 673472 (2021).

Brier, M. R. et al. Quantitative MRI identifies lesional and non-lesional abnormalities in MOGAD. Mult. Scler. Relat. Disord. 73 , 104659 (2023).

Castellaro, M. et al. The use of the central vein sign in the diagnosis of multiple sclerosis: a systematic review and meta-analysis. Diagnostics 10 , 1025 (2020).

Cagol, A. et al. Diagnostic performance of cortical lesions and the central vein sign in multiple sclerosis. JAMA Neurol. 81 , 143–153 (2024).

Clarke, M. A. et al. Paramagnetic rim lesions and the central vein sign: characterizing multiple sclerosis imaging markers. J. Neuroimaging 34 , 86–94 (2024).

Sinnecker, T. et al. MRI phase changes in multiple sclerosis vs neuromyelitis optica lesions at 7 T. Neurol. Neuroimmunol. Neuroinflamm. 3 , e259 (2016).

Juryńczyk, M., Jakuszyk, P., Kurkowska-Jastrzębska, I. & Palace, J. Increasing role of imaging in differentiating MS from non-MS and defining indeterminate borderline cases. Neurol. Neurochir. Pol. 56 , 210–219 (2021).

Sacco, S. et al. Susceptibility-based imaging aids accurate distinction of pediatric-onset MS from myelin oligodendrocyte glycoprotein antibody-associated disease. Mult. Scler. 29 , 1736–1747 (2023).

Harrison, K. L. et al. Central vein sign in pediatric multiple sclerosis and myelin oligodendrocyte glycoprotein antibody-associated disease. Pediatr. Neurol. 146 , 21–25 (2023).

Clarke, L. et al. Magnetic resonance imaging in neuromyelitis optica spectrum disorder. Clin. Exp. Immunol. 206 , 251–265 (2021).

Matthews, L. et al. Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution. Neurology 80 , 1330–1337 (2013).

Juryńczyk, M. et al. Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease. J. Neurol. Neurosurg. Psychiatry 88 , 132–136 (2017).

Huh, S.-Y. et al. The usefulness of brain MRI at onset in the differentiation of multiple sclerosis and seropositive neuromyelitis optica spectrum disorders. Mult. Scler. 20 , 695–704 (2014).

Carnero Contentti, E. et al. Towards imaging criteria that best differentiate MS from NMOSD and MOGAD: large multi-ethnic population and different clinical scenarios. Mult. Scler. Relat. Disord. 61 , 103778 (2022).

Bensi, C. et al. Brain and spinal cord lesion criteria distinguishes AQP4-positive neuromyelitis optica and MOG-positive disease from multiple sclerosis. Mult. Scler. Relat. Disord. 25 , 246–250 (2018).

Cacciaguerra, L. et al. Brain and cord imaging features in neuromyelitis optica spectrum disorders. Ann. Neurol. 85 , 371–384 (2019).

Solomon, A. J. et al. Differential diagnosis of suspected multiple sclerosis: an updated consensus approach. Lancet Neurol. 22 , 750–768 (2023).

Abdel‐Mannan, O. et al. Incidence of paediatric multiple sclerosis and other acquired demyelinating syndromes: 10‐year follow‐up surveillance study. Dev. Med. Child Neurol. 64 , 502–508 (2022).

Hacohen, Y. et al. Diagnostic algorithm for relapsing acquired demyelinating syndromes in children. Neurology 89 , 269–278 (2017).

Download references

Acknowledgements

The authors thank M. L. Rato for the design of Figs.  1 and 4 , R. França for helping with the design of Fig.  8 and V. Camera and M. Pisa for their help in testing some of the versions of the Fig.  8 flowchart.

Author information

Authors and affiliations.

NMO Service, Department of Neurology, Oxford University Hospitals, Oxford, UK

Ruth Geraldes, M. Isabel Leite & Jacqueline Palace

Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK

Ruth Geraldes, Silvia Messina, Patrick Waters, Romina Mariano, Gabriele C. DeLuca, M. Isabel Leite & Jacqueline Palace

Wexham Park Hospital, Frimley Health Foundation Trust, Slough, UK

Ruth Geraldes & Silvia Messina

Neurology–Neuroimmunology Department, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

Georgina Arrambide & Jaume Sastre-Garriga

Division of Child Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Brenda Banwell

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d’Hebron, Barcelona, Spain

• Àlex Rovira

Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy

Rosa Cortese

Center for Brain Research, Medical University of Vienna, Vienna, Austria

Hans Lassmann

Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

Mara Assunta Rocca & Massimo Filippi

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Vita-Salute San Raffaele University, Milan, Italy

NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK

Declan Chard & Tarek Yousry

National Institute for Health Research (NIHR) University College London Hospitals (CLH) Biomedical Research Centre, London, UK

Declan Chard

Multiple Sclerosis Centre, Department of Neurosciences, San Camillo-Forlanini Hospital, Rome, Italy

Claudio Gasperini

Department of Paediatric Neurology, Great Ormond Street Hospital for Children, London, UK

Yael Hacohen

Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité — Universitätsmedizin Berlin, Berlin, Germany

Friedemann Paul

Department of Neurology, Medical University of Graz, Graz, Austria

Christian Enzinger

Division of Neuroradiology, Vascular and Interventional Radiology, Medical University of Graz, Graz, Austria

Research Center for Clinical Neuroimmunology and Neuroscience, University Hospital and University, Basel, Switzerland

Ludwig Kappos

Department of Neuroinflammation, Queen Square MS Centre, UCL Queen Square Institute of Neurology, London, UK

Olga Ciccarelli

University College London Hospitals (UCLH) National Institute for Health and Research (NIHR) Biomedical Research Centre (BRC), London, UK

Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands

Frederik Barkhof

Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK

You can also search for this author in PubMed   Google Scholar

• , Mara Assunta Rocca
• , Claudio Gasperini
• , Christian Enzinger
• , Ludwig Kappos
• , Jaume Sastre-Garriga
• , Tarek Yousry
• , Olga Ciccarelli
• , Massimo Filippi
• , Frederik Barkhof
•  & Jacqueline Palace

Contributions

R.G., G.A., B.B., A.R., R.C., H.L., S.M., M.A.R. and P.W. researched data for the article. R.G., B.B., A.R., H.L., P.W. and J.P. contributed substantially to discussion of the content. R.G., G.A. and J.P. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Ruth Geraldes or Jacqueline Palace .

Ethics declarations

Competing interests.

R.G. has received support for scientific meetings and courses from Bayer, Biogen, Merck, Novartis and Janssen and honoraria for advisory work or talks from Biogen, Novartis, UCB and MIAC. G.A. has received compensation for consulting services, speaking honoraria or participation in advisory boards from Roche and Horizon Therapeutics; and travel support for scientific meetings from Novartis, Roche, Horizon Therapeutics, ECTRIMS and EAN. She serves as an editor for Europe for Multiple Sclerosis Journal — Experimental , Translational and Clinical and as a member of the editorial and scientific committee of Acta Neurológica Colombiana . She is a member of the International Women in Multiple Sclerosis (iWiMS) network executive committee, the European Biomarkers in Multiple Sclerosis (BioMS-eu) steering committee and the MOGAD Eugene Devic European Network (MEDEN) steering group. B.B. has received or will potentially receive financial compensation for consultancy for Novartis, Roche, UCB, Horizon Therapeutics, Biogen and Immunic Therapeutics for advice on clinical trial design. B.B. is funded by the National Multiple Sclerosis Society and NIH and was previously funded by the Canadian Multiple Sclerosis Society. A.R. serves or has served on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche and Biogen and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries, Novartis, Roche, Bristol-Myers and Biogen, is Chief Marketing Officer and co-founder of TensorMedical and receives research support from Fondo de Investigación en Salud (PI19/00950 and PI22/01589) from Instituto de Salud Carlos III, Spain. R.C. has received speaker honoraria and/or travel support from Roche, Merck, Sanofi-Genzyme, Novartis, Janssen and UCB. H.L. has received honoraria from Novartis, Sanofi, Genzyme, BMS and UCB Biopharma for lectures, unrelated to the topic of this manuscript. S.M. has received travel grants from Roche, Merck and Sanofi and has received speaking honoraria from UCB. M.A.R. has received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen and Roche and speaker honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders . P.W. has received research grants from Euroimmun, CSL Behring and patent royalties for antibody testing (W02010046716A1). He is the Co-Director of the Oxford Autoimmune Neurology Diagnostic Laboratory (Oxford University, Oxford, UK) where MOG-IgG1 autoantibodies are tested, and both he and the University of Oxford receive royalties for antibody tests for LGI1 and CASPR2 (W02010046716A1). He has received honoraria or consulting fees from Biogen Idec, F Hoffmann La-Roche, Mereo BioPharma, Retrogenix, UBC, Euroimmun, University of British Columbia and Alexion; and travel grants from the Guthy-Jackson Charitable Foundation. Work in the Oxford Autoimmune Neurology Diagnostic Laboratory is supported by the UK National Health Service Commissioning service for NMOSD. D.C. is a consultant for Hoffmann-La Roche. In the past 3 years, he has been a consultant for Biogen and has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, the Medical Research Council and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre and a speaker’s honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. C.G. reports personal fees from Biogen, Merck Serono, Teva Pharmaceuticals, Sanofi Genzyme, Almirall, Novartis, Roche and Bayer, outside the submitted work. R.M. undertook graduate studies funded by the Rhodes Trust and the Oppenheimer Memorial Trust. F.P. has received honoraria and research support from Alexion, Bayer, Biogen, Chugai, Merck Serono, Novartis, Genyzme, MedImmune, Shire and Teva Pharmaceuticals and serves on scientific advisory boards for Alexion, MedImmune, Novartis and UCB. He has received funding from Deutsche Forschungsgemeinschaft (DFG Exc 257), Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis), Guthy-Jackson Charitable Foundation, EU Framework Program 7 and National Multiple Sclerosis Society of the USA. He serves on the steering committee of the N-Momentum study of inebilizumab (Horizon Therapeutics) and the OCTiMS Study (Novartis). He is an associate editor for Neurology , Neuroimmunology , and Neuroinflammation and academic editor with PLoS ONE . G.C.D. has received support from the NIHR Biomedical Research Centre (BRC), Oxford; and research funding from the Oxford BRC, MRC(UK), UK MS Society, National Health and Medical Research (Australia), Department of Defense (USA), European Charcot Foundation, American Academy of Neurology (AAN), Merck-Serono and Oxford-Quinnipiac Partnership. G.C.D. has also received travel expenses from Genzyme, Merck Serono, Novartis, Roche, the MS Academy and AAN and honoraria as an invited speaker or faculty for Novartis, Roche, the MS Academy and AAN. C.E. reports personal fees from Biogen, Bayer HealthCare Pharmaceuticals, Merck Serono, Novartis, Shire, Genzyme, Teva Pharmaceuticals, Sanofi, Celgene and Roche, outside the submitted work. L.K. received no personal compensation. His institutions (University Hospital Basel/Stiftung Neuroimmunology and Neuroscience Basel) have received and used exclusively for research support payments for steering committee and advisory board participation, consultancy services and participation in educational activities from Bayer, BMS, Celgene, Dörries-Frank Molnia & Pohlmann, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Japan Tobacco, Merck, MH Consulting, Minoryx, Novartis, F. Hoffmann-La Roche, Senda Biosciences, Sanofi, Santhera, Shionogi, TG Therapeutics and Wellmera; licence fees for Neurostatus-UHB products; and grants from Novartis, Innosuisse and Roche. M.I.L. is funded by the NHS (Myasthenia and Related Disorders Service and National Specialized Commissioning Group for Neuromyelitis Optica, UK) and by the University of Oxford, UK. She has been awarded research grants from the UK Association for Patients with Myasthenia (Myaware), Muscular Dystrophy Campaign (MDUK) and the University of Oxford. She has received speaker honoraria and travel grants from UCB Pharma and Horizon Therapeutics and consultancy fees from UCB Pharma. She serves on scientific or educational advisory boards for UCB Pharma, Argenx and Horizon Therapeutics and on the Steering Committee for Horizon Therapeutics. J.S.-G. reports grants and personal fees from Sanofi Genzyme and personal fees from Almirall, Biogen, Celgene, Merck Serono, Novartis, Roche and Teva Pharmaceuticals, outside the submitted work, and is a member of the Editorial Committee of Multiple Sclerosis Journal and Director of the Scientific Committee of Revista de Neurologia. T.Y. reports personal fees from Biogen, Novartis, Bayer HealthCare Pharmaceuticals and Hikma, outside the submitted work, and has received research support from Biogen, GlaxoSmithKline, Novartis and Schering. O.C. is an NIHR Research Professor (RP-2017-08-ST2-004); over the past 2 years, she has been a member of an independent data and safety monitoring board for Novartis; she gave a teaching talk in a Merck local symposium and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology , for which she receives an honorarium; she has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society and the NIHR-HTA. M.F. is Editor-in-Chief of the Journal of Neurology , Associate Editor of Human Brain Mapping , Neurological Sciences and Radiology ; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda and TEVA; participation in advisory boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme and Takeda; and scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis and Sanofi-Genzyme. He receives research support from Biogen Idec, Merck Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research and Fondazione Italiana Sclerosi Multipla. F.B. is supported by the NIHR biomedical research centre at University College London Hospitals. F.B. is part of the steering committee or a data safety monitoring board member for Biogen, Merck, ATRI/ACTC and Prothena, is a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen and Combinostics, has research agreements with Merck, Biogen, GE Healthcare and Roche and is a co-founder and shareholder of Queen Square Analytics. J.P. has received support for scientific meetings and honoraria for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, Vitaccess, UCB, Mitsubishi, Amplo and Janssen, and grants from Alexion, Argenx, Clene, Roche, Medimmune and Amplo Biotechnology. She holds patent ref. P37347WO, a licence agreement with Numares multimarker MS diagnostics and shares in AstraZeneca. Her group has been awarded an ECTRIMS fellowship and a Sumaira Foundation grant to start later this year. A Charcot fellow worked in Oxford 2019–2021. She acknowledges partial funding to the Oxford University Hospitals Trust by Highly Specialized Services NHS England. She is on the medical advisory boards of the Sumaira Foundation and MOG project charities, is a member of the Guthy Jackon Foundation Charity and is on the Board of the European Charcot Foundation, the steering committee of MAGNIMS and the UK NHSE IVIG Committee. She is Chair of the NHSE neuroimmunology patient pathway and has been an ECTRIMS Council member on the educational committee since June 2023. She is also on the Association of British Neurologists advisory groups for MS and neuroinflammation and neuromuscular diseases. Y.H. declares no competing interests.

Peer review

Peer review information.

Nature Reviews Neurology thanks I. Nakashima, E. Flanagan, R. Dale and E. Sechi for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

MAGNIMS: https://www.magnims.eu/

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Cite this article.

Geraldes, R., Arrambide, G., Banwell, B. et al. The influence of MOGAD on diagnosis of multiple sclerosis using MRI. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-01005-2

Download citation

Accepted : 26 July 2024

Published : 03 September 2024

DOI : https://doi.org/10.1038/s41582-024-01005-2

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

TG Therapeutics Announces Schedule of Data Presentations for BRIUMVI at the 2024 European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting

NEW YORK, Sept. 05, 2024 (GLOBE NEWSWIRE) -- TG Therapeutics, Inc. (NASDAQ: TGTX), today announced the schedule of upcoming data presentations, highlighting data from both the ULTIMATE I & II Phase 3 trials and the ENHANCE Phase 3b trial evaluating BRIUMVI ® (ublituximab-xiiy) in patients with relapsing forms of multiple sclerosis (RMS), at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting, being held September 18 – 20, 2024, in Copenhagen, Denmark. Abstracts are now available online and can be accessed on the ECTRIMS meeting website or at the following link: ECTRIMS 2024 Programme . Details of the presentations are outlined below.

PRESENTATIONS: Poster Presentation Title: Five years of Ublituximab in relapsing multiple sclerosis: additional results from open-label extension of ULTIMATE I and II studies

• Presentation Date/Time: Wednesday, September 18 th at 16.15 – 18.15 CEST (10:15am – 12:15pm ET)
• Session: Poster Session 1 – Room D3
• Abstract Number/Poster Number: Abstract 2102/P324
• Lead Author: Dr. Bruce Cree - Weill Institute for Neurosciences, University of California, San Francisco, CA, United States

Poster Presentation Title: Efficacy and tolerability of ublituximab after transitioning from a different disease modifying therapy: Updates from the ENHANCE study

• Abstract Number/Poster Number: Abstract 2259/P329
• Lead Author: Dr. John Foley - Rocky Mountain Multiple Sclerosis, Salt Lake City, UT, United States

Poster Presentation Title: Comparison of Multiple Sclerosis Disease Activity (MSDA) Test Results Between Patients Treated with Ublituximab and Teriflunomide in the Phase 3 ULTIMATE I and II Studies

• Presentation Date/Time: Wednesday, September 18 th at 08:00 CEST (2:00am ET)
• Session: ePoster (will remain available 3 months after the congress)
• Abstract Number/ePoster Number: Abstract 1382/eP1516

Following the presentation, the data will be available on the Publications page, located within the Pipeline section, of the Company’s website at www.tgtherapeutics.com/publications.cfm.

ABOUT THE ULTIMATE I & II PHASE 3 TRIALS ULTIMATE I & II are two randomized, double-blind, double-dummy, parallel group, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks. Patients were randomized to receive either BRIUMVI, given as an IV infusion of 150 mg administered in four hours, 450 mg two weeks after the first infusion administered in one hour, and 450 mg every 24 weeks administered in one hour, with oral placebo administered daily; or teriflunomide, the active comparator, given orally as a 14 mg daily dose with IV placebo administered on the same schedule as BRIUMVI. Both studies enrolled patients who had experienced at least one relapse in the previous year, two relapses in the previous two years, or had the presence of a T1 gadolinium (Gd)-enhancing lesion in the previous year. Patients were also required to have an Expanded Disability Status Scale (EDSS) score from 0 to 5.5 at baseline. The ULTIMATE I & II trials enrolled a total of 1,094 patients with RMS across 10 countries. These trials were led by Lawrence Steinman, MD, Zimmermann Professor of Neurology & Neurological Sciences, and Pediatrics at Stanford University. Additional information on these clinical trials can be found at www.clinicaltrials.gov (NCT03277261; NCT03277248).

ABOUT BRIUMVI ® (ublituximab-xiiy) 150 mg/6 mL Injection for IV BRIUMVI is a novel monoclonal antibody that targets a unique epitope on CD20-expressing B-cells. Targeting CD20 using monoclonal antibodies has proven to be an important therapeutic approach for the management of autoimmune disorders, such as RMS. BRIUMVI is uniquely designed to lack certain sugar molecules normally expressed on the antibody. Removal of these sugar molecules, a process called glycoengineering, allows for efficient B-cell depletion at low doses.

BRIUMVI is indicated for the treatment of adults with relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

A list of authorized specialty distributors can be found at www.briumvi.com .

IMPORTANT SAFETY INFORMATION Contraindications: BRIUMVI is contraindicated in patients with:

• Active Hepatitis B Virus infection
• A history of life-threatening infusion reaction to BRIUMVI

WARNINGS AND PRECAUTIONS

Infusion Reactions: BRIUMVI can cause infusion reactions, which can include pyrexia, chills, headache, influenza-like illness, tachycardia, nausea, throat irritation, erythema, and an anaphylactic reaction. In MS clinical trials, the incidence of infusion reactions in BRIUMVI-treated patients who received infusion reaction-limiting premedication prior to each infusion was 48%, with the highest incidence within 24 hours of the first infusion. 0.6% of BRIUMVI-treated patients experienced infusion reactions that were serious, some requiring hospitalization.

Observe treated patients for infusion reactions during the infusion and for at least one hour after the completion of the first two infusions unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion. Administer the recommended pre-medication to reduce the frequency and severity of infusion reactions. If life-threatening, stop the infusion immediately, permanently discontinue BRIUMVI, and administer appropriate supportive treatment. Less severe infusion reactions may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.

Infections: Serious, life-threatening or fatal, bacterial and viral infections have been reported in BRIUMVI-treated patients. In MS clinical trials, the overall rate of infections in BRIUMVI-treated patients was 56% compared to 54% in teriflunomide-treated patients. The rate of serious infections was 5% compared to 3% respectively. There were 3 infection-related deaths in BRIUMVI-treated patients. The most common infections in BRIUMVI-treated patients included upper respiratory tract infection (45%) and urinary tract infection (10%). Delay BRIUMVI administration in patients with an active infection until the infection is resolved.

Consider the potential for increased immunosuppressive effects when initiating BRIUMVI after immunosuppressive therapy or initiating an immunosuppressive therapy after BRIUMVI.

Hepatitis B Virus (HBV) Reactivation: HBV reactivation occurred in an MS patient treated with BRIUMVI in clinical trials. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with BRIUMVI. Do not start treatment with BRIUMVI in patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface premedantigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult a liver disease expert before starting and during treatment.

Progressive Multifocal Leukoencephalopathy (PML): Although no cases of PML have occurred in BRIUMVI-treated MS patients, JCV infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies.

If PML is suspected, withhold BRIUMVI and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

MRI findings may be apparent before clinical signs or symptoms; monitoring for signs consistent with PML may be useful. Further investigate suspicious findings to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis.

If PML is confirmed, treatment with BRIUMVI should be discontinued.

Vaccinations: Administer all immunizations according to immunization guidelines: for live or live-attenuated vaccines at least 4 weeks and, whenever possible at least 2 weeks prior to initiation of BRIUMVI for non-live vaccines. BRIUMVI may interfere with the effectiveness of non-live vaccines. The safety of immunization with live or live-attenuated vaccines during or following administration of BRIUMVI has not been studied. Vaccination with live virus vaccines is not recommended during treatment and until B-cell repletion.

Vaccination of Infants Born to Mothers Treated with BRIUMVI During Pregnancy: In infants of mothers exposed to BRIUMVI during pregnancy, assess B-cell counts prior to administration of live or live-attenuated vaccines as measured by CD19 + B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines. Inactivated or non-live vaccines may be administered prior to B-cell recovery. Assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted.

Fetal Risk: Based on data from animal studies, BRIUMVI may cause fetal harm when administered to a pregnant woman. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. A pregnancy test is recommended in females of reproductive potential prior to each infusion. Advise females of reproductive potential to use effective contraception during BRIUMVI treatment and for 6 months after the last dose.

Reduction in Immunoglobulins: As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Decrease in immunoglobulin M (IgM) was reported in 0.6% of BRIUMVI-treated patients compared to none of the patients treated with teriflunomide in RMS clinical trials. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing BRIUMVI therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

Most Common Adverse Reactions: The most common adverse reactions in RMS trials (incidence of at least 10%) were infusion reactions and upper respiratory tract infections.

Physicians, pharmacists, or other healthcare professionals with questions about BRIUMVI should visit www.briumvi.com .

ABOUT BRIUMVI PATIENT SUPPORT BRIUMVI Patient Support is a flexible program designed by TG Therapeutics to support U.S. patients through their treatment journey in a way that works best for them. More information about the BRIUMVI Patient Support program can be accessed at www.briumvipatientsupport.com .

ABOUT MULTIPLE SCLEROSIS Relapsing multiple sclerosis (RMS) is a chronic demyelinating disease of the central nervous system (CNS) and includes people with relapsing-remitting multiple sclerosis (RRMS) and people with secondary progressive multiple sclerosis (SPMS) who continue to experience relapses. RRMS is the most common form of multiple sclerosis (MS) and is characterized by episodes of new or worsening signs or symptoms (relapses) followed by periods of recovery. It is estimated that nearly 1 million people are living with MS in the United States and approximately 85% are initially diagnosed with RRMS. 1,2 The majority of people who are diagnosed with RRMS will eventually transition to SPMS, in which they experience steadily worsening disability over time. Worldwide, more than 2.3 million people have a diagnosis of MS. 1

ABOUT TG THERAPEUTICS TG Therapeutics is a fully integrated, commercial stage, biopharmaceutical company focused on the acquisition, development and commercialization of novel treatments for B-cell diseases. In addition to a research pipeline including several investigational medicines, TG has received U.S. Food and Drug Administration (FDA) approval for BRIUMVI ® (ublituximab-xiiy), for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, as well as approval by the European Commission (EC) and the Medicines and Healthcare Products Regulatory Agency (MHRA) for BRIUMVI to treat adult patients with RMS who have active disease defined by clinical or imaging features in Europe and the United Kingdom, respectively. For more information, visit www.tgtherapeutics.com , and follow us on X (formerly Twitter) @TGTherapeutics and on LinkedIn .

BRIUMVI ® is a registered trademark of TG Therapeutics, Inc.

Cautionary Statement This press release contains forward-looking statements that involve a number of risks and uncertainties. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995.

Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release. In addition to the risk factors identified from time to time in our reports filed with the U.S. Securities and Exchange Commission (SEC), factors that could cause our actual results to differ materially include the below.

Such forward looking statements include but are not limited to statements regarding the results of the ULTIMATE I & II Phase 3 studies, the ENHANCE Phase 3b study, and BRIUMVI as a treatment for relapsing forms of multiple sclerosis (RMS). Additional factors that could cause our actual results to differ materially include the following: the risk that the data from the ULTIMATE I & II or ENHANCE trials that we announce or publish may change, or the product profile of BRIUMVI may be impacted, as more data or additional endpoints are analyzed; the risk that data may emerge from future clinical studies or from adverse event reporting that may affect the safety and tolerability profile and commercial potential of BRIUMVI; the risk that any individual patient’s clinical experience in the post-marketing setting, or the aggregate patient experience in the post-marketing setting, may differ from that demonstrated in controlled clinical trials such as ULTIMATE I and II; the risk that BRIUMVI will not be commercially successful; our ability to expand our commercial infrastructure, and successfully market and sell BRIUMVI in RMS; the Company’s reliance on third parties for manufacturing, distribution and supply, and a range of other support functions for our commercial and clinical products, including BRIUMVI, and the ability of the Company and its manufacturers and suppliers to produce and deliver BRIUMVI to meet the market demand for BRIUMVI; the failure to obtain and maintain requisite regulatory approvals, including the risk that the Company fails to satisfy post-approval regulatory requirements; the uncertainties inherent in research and development; and general political, economic and business conditions, including the risk that the ongoing COVID-19 pandemic could have on the safety profile of BRIUMVI and any of our other drug candidates as well as any government control measures associated with COVID-19 that could have an adverse impact on our research and development plans or commercialization efforts. Further discussion about these and other risks and uncertainties can be found in our Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in our other filings with the U.S. Securities and Exchange Commission.

Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. This press release and prior releases are available at www.tgtherapeutics.com . The information found on our website is not incorporated by reference into this press release and is included for reference purposes only.

Investor Relations Email: [email protected] Telephone: 1.877.575.TGTX (8489), Option 4

Media Relations: Email: [email protected] Telephone: 1.877.575.TGTX (8489), Option 6

1. MS Prevalence. National Multiple Sclerosis Society website. https://www.nationalmssociety.org/About-the-Society/MS-Prevalence . Accessed October 26, 2020. 2. Multiple Sclerosis International Federation, 2013 via Datamonitor p. 236.