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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 disorders and 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.

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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.

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• 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 ]

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• Multiple Sclerosis
• Pediatric Multiple Sclerosis
• Neuro-Ophthalmologic Manifestations of Multiple Sclerosis
• Multiple Sclerosis Spine Imaging
• Brain Imaging in Multiple Sclerosis
• The Patient's Journey Through Multiple Sclerosis
• Biomarker Testing in Multiple Sclerosis
• Migraine a Forerunner of Multiple Sclerosis?
• Frexalimab Promising for Relapsing Multiple Sclerosis
• Does Multiple Sclerosis Protect Against Alzheimer's?

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• Multiple sclerosis

Neurological exam

A complete neurological exam and medical history are needed to diagnose MS .

• Multiple sclerosis FAQs

Neurologist Oliver Tobin, M.B., B.Ch., B.A.O., Ph.D., answers the most frequently asked questions about multiple sclerosis.

So people who are overweight have a higher chance of developing MS and people who have MS who are overweight tend to have more active disease and a faster onset of progression. The main diet has been shown to be neuroprotective is the Mediterranean diet. This diet is high in fish, vegetables, and nuts, and low in red meat.

So this question comes up a lot because patients who have multiple sclerosis can sometimes get a transient worsening of their symptoms in heat or if they exercise strenuously. The important thing to note is that heat does not cause an MS attack or MS relapse. And so it's not dangerous. You're not doing any permanent damage if this occurs. Exercise is strongly recommended and is protective to the brain and spinal cord.

Scientists do not yet know which stem cells are beneficial in MS, what route to give them or what dose to give them or what frequency. So at the moment, stem cell treatments are not recommended outside of the context of a clinical trial.

Neuromyelitis optica spectrum disorder or NMOSD and MOG-associated disorder can give features similar to multiple sclerosis. These are more common in people of Asian or African-American ethnicity. And your doctor may recommend blood tests to exclude these disorders.

Well, the first drug approved by the FDA for treatment of multiple sclerosis was in 1993. Since then, over 20 drugs have become available for treatment of MS. And the potency of these drugs has increased over time to the point where we can almost completely suppress the inflammatory component of the disease. This would not be possible if patients like you did not enroll in research studies. There are many different types of research studies, not just drug trials, but also observational studies, as all of these enhance our understanding of the disease, hopefully to lead to even better cures for multiple sclerosis.

Well, the most important thing about having a diagnosis of multiple sclerosis is that you are at the center of your medical team. A comprehensive MS center is the best place for management of multiple sclerosis, and this typically includes physicians with expertise in multiple sclerosis, neurologists, but also urologists, physiatrists or physical medicine and rehabilitation providers, psychologists, and many other providers who have specialty interest in multiple sclerosis. Engaging this team around you and your particular needs will improve your outcomes over time.

There are no specific tests for MS . Instead, a diagnosis of multiple sclerosis often relies on ruling out other conditions that might produce similar signs and symptoms, known as a differential diagnosis.

Your doctor is likely to start with a thorough medical history and examination.

Lumbar puncture, also known as a spinal tap

During a lumbar puncture, also known as a spinal tap, you typically lie on your side with your knees drawn up to your chest. Then a needle is inserted into your spinal canal — in your lower back — to collect cerebrospinal fluid for testing.

• MRI multiple sclerosis lesions

Brain MRI scan showing white lesions associated with multiple sclerosis.

Your doctor may then recommend:

• Blood tests, to help rule out other diseases with symptoms like MS . Tests to check for specific biomarkers associated with MS are currently under development and may also aid in diagnosing the disease.
• Spinal tap (lumbar puncture), in which a small sample of cerebrospinal fluid is removed from your spinal canal for laboratory analysis. This sample can show abnormalities in antibodies that are associated with MS . A spinal tap can also help rule out infections and other conditions with symptoms like MS . A new antibody test (for kappa free light chains) may be faster and less expensive than previous spinal fluid tests for multiple sclerosis.
• MRI, which can reveal areas of MS (lesions) on your brain, cervical and thoracic spinal cord. You may receive an intravenous injection of a contrast material to highlight lesions that indicate your disease is in an active phase.
• Evoked potential tests that record the electrical signals produced by your nervous system in response to stimuli may be done. An evoked potential test may use visual stimuli or electrical stimuli. In these tests, you watch a moving visual pattern, as short electrical impulses are applied to nerves in your legs or arms. Electrodes measure how quickly the information travels down your nerve pathways.

In most people with relapsing-remitting MS , the diagnosis is straightforward and based on a pattern of symptoms consistent with the disease and confirmed by brain imaging scans, such as an MRI.

Diagnosing MS can be more difficult in people with unusual symptoms or progressive disease. In these cases, further testing with spinal fluid analysis, evoked potentials and additional imaging may be needed.

Brain MRI is often used to help diagnose multiple sclerosis.

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• Lumbar puncture (spinal tap)
• Explaining multiple sclerosis

There is no cure for multiple sclerosis. Treatment typically focuses on speeding recovery from attacks, reducing new radiographic and clinical relapses, slowing the progression of the disease, and managing MS symptoms. Some people have such mild symptoms that no treatment is necessary.

Multiple sclerosis research laboratory at Mayo Clinic

Treatments for MS attacks

• Corticosteroids, such as oral prednisone and intravenous methylprednisolone, are prescribed to reduce nerve inflammation. Side effects may include insomnia, increased blood pressure, increased blood glucose levels, mood swings and fluid retention.
• Plasma exchange (plasmapheresis). The liquid portion of part of your blood (plasma) is removed and separated from your blood cells. The blood cells are then mixed with a protein solution (albumin) and put back into your body. Plasma exchange may be used if your symptoms are new, severe and haven't responded to steroids.

Treatments to modify progression

There are several disease modifying therapies (DMTs) for relapsing-remitting MS . Some of these DMTs can be of benefit for secondary progressive MS , and one is available for primary progressive MS .

Much of the immune response associated with MS occurs in the early stages of the disease. Aggressive treatment with these medications as early as possible can lower the relapse rate, slow the formation of new lesions, and potentially reduce risk of brain atrophy and disability accumulation.

Many of the disease-modifying therapies used to treat MS carry significant health risks. Selecting the right therapy for you will depend on careful consideration of many factors, including duration and severity of disease, effectiveness of previous MS treatments, other health issues, cost, and child-bearing status.

Treatment options for relapsing-remitting MS include injectable, oral and infusions medications.

Injectable treatments include:

Interferon beta medications. These drugs used to be the most prescribed medications to treat MS . They work by interfering with diseases that attack the body and may decrease inflammation and increase nerve growth. They are injected under the skin or into muscle and can reduce the frequency and severity of relapses.

Side effects of interferons may include flu-like symptoms and injection-site reactions. You'll need blood tests to monitor your liver enzymes because liver damage is a possible side effect of interferon use. People taking interferons may develop neutralizing antibodies that can reduce drug effectiveness.

• Glatiramer acetate (Copaxone, Glatopa). This medication may help block your immune system's attack on myelin and must be injected beneath the skin. Side effects may include skin irritation at the injection site.
• Monoclonal antibodies. Ofatumumab (Kesimpta, Arzerra) targets cells that damage the nervous system. These cells are called B cells. Ofatumumab is given by an injection under the skin and can decrease multiple sclerosis brain lesions and worsening symptoms. Possible side effects are infections, local reactions to the injection and headaches.

Oral treatments include:

• Teriflunomide (Aubagio). This once-daily oral medication can reduce relapse rate. Teriflunomide can cause liver damage, hair loss and other side effects. This drug is associated with birth defects when taken by both men and women. Therefore, use contraception when taking this medication and for up to two years afterward. Couples who wish to become pregnant should talk to their doctor about ways to speed elimination of the drug from the body. This drug requires blood test monitoring on a regular basis.
• Dimethyl fumarate (Tecfidera). This twice-daily oral medication can reduce relapses. Side effects may include flushing, diarrhea, nausea and lowered white blood cell count. This drug requires blood test monitoring on a regular basis.
• Diroximel fumarate (Vumerity). This twice-daily capsule is similar to dimethyl fumarate but typically causes fewer side effects. It's approved for the treatment of relapsing forms of MS .
• Monomethyl fumarate (Bafiertam) was approved by the FDA as a delayed release medicine that has a slow and steady action. Because of its time release, it is hoped that side effects will be decreased. Possible side effects are flushing, liver injury, abdominal pain and infections.

Fingolimod (Gilenya). This once-daily oral medication reduces relapse rate.

You'll need to have your heart rate and blood pressure monitored for six hours after the first dose because your heart rate may be slowed. Other side effects include rare serious infections, headaches, high blood pressure and blurred vision.

• Siponimod (Mayzent). Research shows that this once-daily oral medication can reduce relapse rates and help slow progression of MS . It's also approved for secondary-progressive MS . Possible side effects include viral infections, liver problems and low white blood cell count. Other possible side effects include changes in heart rate, headaches and vision problems. Siponimod is harmful to a developing fetus, so women who may become pregnant should use contraception when taking this medication and for 10 days after stopping the medication. Some might need to have the heart rate and blood pressure monitored for six hours after the first dose. This drug requires blood test monitoring on a regular basis.
• Ozanimod (Zeposia). This oral medication decreases the relapse rate of multiple sclerosis and is given once a day. Possible side effects are an elevated blood pressure, infections and liver inflammation.
• Ponesimod (Ponvory). This oral medication is taken once a day with a gradually increasing dosing schedule. This medicine has a low relapse rate and has demonstrated fewer brain lesions than some other medications used to treat multiple sclerosis. The possible side effects are respiratory tract infections, high blood pressure, liver irritation and electrical problems in the heart that affect heart rate and rhythm.
• Cladribine (Mavenclad). This medication is generally prescribed as a second line treatment for those with relapsing-remitting MS . It was also approved for secondary-progressive MS . It is given in two treatment courses, spread over a two-week period, over the course of two years. Side effects include upper respiratory infections, headaches, tumors, serious infections and reduced levels of white blood cells. People who have active chronic infections or cancer should not take this drug, nor should women who are pregnant or breastfeeding. Men and women should use contraception when taking this medication and for the following six months. You may need monitoring with blood tests while taking cladribine.

Infusion treatments include:

Natalizumab (Tysabri). This is a monoclonal antibody that has been shown to decrease relapse rates and slow down the risk of disability.

This medication is designed to block the movement of potentially damaging immune cells from your bloodstream to your brain and spinal cord. It may be considered a first line treatment for some people with severe MS or as a second line treatment in others.

This medication increases the risk of a potentially serious viral infection of the brain called progressive multifocal leukoencephalopathy (PML) in people who are positive for antibodies to the causative agent of PML JC virus. People who don't have the antibodies have extremely low risk of PML .

Ocrelizumab (Ocrevus). This treatment reduces the relapse rate and the risk of disabling progression in relapsing-remitting multiple sclerosis. It also slows the progression of the primary-progressive form of multiple sclerosis.

This humanized monoclonal antibody medication is the only DMT approved by the FDA to treat both the relapse-remitting and primary-progressive forms of MS . Clinical trials showed that it reduced relapse rate in relapsing disease and slowed worsening of disability in both forms of the disease.

Ocrelizumab is given via an intravenous infusion by a medical professional. Infusion-related side effects may include irritation at the injection site, low blood pressure, a fever and nausea, among others. Some people may not be able to take ocrelizumab, including those with a hepatitis B infection. Ocrelizumab may also increase the risk of infections and some types of cancer, particularly breast cancer.

Alemtuzumab (Campath, Lemtrada). This treatment is a monoclonal antibody that decreases annual relapse rates and demonstrates MRI benefits.

This drug helps reduce relapses of MS by targeting a protein on the surface of immune cells and depleting white blood cells. This effect can limit potential nerve damage caused by the white blood cells. But it also increases the risk of infections and autoimmune disorders, including a high risk of thyroid autoimmune diseases and rare immune mediated kidney disease.

Treatment with alemtuzumab involves five consecutive days of drug infusions followed by another three days of infusions a year later. Infusion reactions are common with alemtuzumab.

The drug is only available from registered providers, and people treated with the drug must be registered in a special drug safety monitoring program. Alemtuzumab is usually recommended for those with aggressive MS or as second line treatment for patients who failed another MS medication.

Recent developments or emerging therapies

Bruton's tyrosine kinase (BTK) inhibitor is an emerging therapy being studied in relapsing-remitting multiple sclerosis and secondary-progressive multiple sclerosis. It works by mostly modulating B cells, which are immune cells in the central nervous system.

Stem cell transplantation destroys the immune system of someone with multiple sclerosis and then replaces it with transplanted healthy stem cells. Researchers are still investigating whether this therapy can decrease inflammation in people with multiple sclerosis and help to "reset" the immune system. Possible side effects are fever and infections.

Researchers are learning more about how existing disease modifying therapies work to lessen relapses and reduce multiple sclerosis-related lesions in the brain. Further studies will determine whether treatment can delay disability caused by the disease.

For primary-progressive MS , ocrelizumab (Ocrevus) is the only FDA-approved disease-modifying therapy (DMT). Those who receive this treatment are slightly less likely to progress than those who are untreated.

For secondary progressive MS , some might consider the use of FDA-approved disease modifying therapies such as ozanimod, siponimod and cladribine, which can potentially slow down disabilities.

Treatments for MS signs and symptoms

Physical therapy can build muscle strength and ease some of the symptoms of MS .

Therapy. A physical or occupational therapist can teach you stretching and strengthening exercises and show you how to use devices to make it easier to perform daily tasks.

Physical therapy along with the use of a mobility aid, when necessary, can also help manage leg weakness and other gait problems often associated with MS .

• Muscle relaxants. You may experience painful or uncontrollable muscle stiffness or spasms, particularly in your legs. Muscle relaxants such as baclofen (Lioresal, Gablofen), tizanidine (Zanaflex) and cyclobenzaprine may help. Onabotulinumtoxin A treatment is another option in those with spasticity.
• Medications to reduce fatigue. Amantadine (Gocovri, Osmolex), modafinil (Provigil) and methylphenidate (Ritalin) have been used to reduce MS -related fatigue. However, a recent study did not find amantadine, modafinil or methylphenidate to be superior to a placebo in improving MS -related fatigue and caused more frequent adverse events. Some drugs used to treat depression, including selective serotonin reuptake inhibitors, may be recommended.
• Medication to increase walking speed. Dalfampridine (Ampyra) may help to slightly increase walking speed in some people. Possible side effects are urinary tract infections, vertigo, insomnia and headaches. People with a history of seizures or kidney dysfunction should not take this medication.
• Other medications. Medications also may be prescribed for depression, pain, sexual dysfunction, insomnia, and bladder or bowel control problems that are associated with MS .
• Acetyl-L-carnitine: Can it relieve MS fatigue?
• Emerging treatments for multiple sclerosis

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

To help relieve the signs and symptoms of MS , try to:

• Get plenty of rest. Look at your sleep habits to make sure you're getting the best possible sleep. To make sure you're getting enough sleep, you may need to be evaluated — and possibly treated — for sleep disorders such as obstructive sleep apnea.
• Exercise. If you have mild to moderate MS , regular exercise can help improve your strength, muscle tone, balance and coordination. Swimming or other water exercises are good options if you have intolerance to heat. Other types of mild to moderate exercise recommended for people with MS include walking, stretching, low-impact aerobics, stationary bicycling, yoga and tai chi.
• Cool down. MS symptoms may worsen when the body temperature rises in some people with MS . Avoiding exposure to heat and using devices such as cooling scarves or vests can be helpful.
• Eat a balanced diet. Since there is little evidence to support a particular diet, experts recommend a generally healthy diet. Some research suggests that vitamin D may have potential benefit for people with MS .
• Relieve stress. Stress may trigger or worsen your signs and symptoms. Yoga, tai chi, massage, meditation or deep breathing may help.
• Exercise and multiple sclerosis
• Vitamin D and MS: Any connection?
• Vitamins for MS: Do supplements make a difference?

Alternative medicine

Many people with MS use a variety of alternative or complementary treatments or both to help manage their symptoms, such as fatigue and muscle pain.

Activities such as exercise, meditation, yoga, massage, eating a healthier diet, acupuncture and relaxation techniques may help boost overall mental and physical well-being in patients with MS .

According to guidelines from the American Academy of Neurology, research strongly indicates that oral cannabis extract (OCE) may improve symptoms of muscle spasticity and pain. There is a lack of evidence that cannabis in any other form is effective in managing other MS symptoms.

Daily intake of vitamin D3 of 2,000 to 5,000 international units daily is recommended in those with MS . The connection between vitamin D and MS is supported by the association with exposure to sunlight and the risk of MS .

Coping and support

Living with any chronic illness can be difficult. To manage the stress of living with MS , consider these suggestions:

• Maintain normal daily activities as best you can.
• Stay connected to friends and family.
• Continue to pursue hobbies that you enjoy and are able to do.
• Contact a support group, for yourself or for family members.
• Discuss your feelings and concerns about living with MS with your doctor or a counselor.

Preparing for your appointment

You may be referred to a doctor who specializes in disorders of the brain and nervous system (neurologist).

What you can do

• Write down your symptoms, including any that may seem unrelated to the reason why you scheduled the appointment.
• Make a list of all your medications, vitamins and supplements.
• Bring any clinical notes , scans, laboratory test results or other information from your primary care provider to your neurologist.
• Write down your key medical information, including other conditions.
• Write down key personal information, including any recent changes or stressors in your life.
• Write down questions to ask your doctor.
• Ask a relative or friend to accompany you, to help you remember what the doctor says.

What to expect from your doctor

Your doctor is likely to ask you questions. Being ready to answer them may reserve time to go over points you want to spend more time on. You may be asked:

• When did you begin experiencing symptoms?
• Have your symptoms been continuous or occasional?
• How severe are your symptoms?
• What, if anything, seems to improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Does anyone in your family have multiple sclerosis?

Questions to ask your doctor

• What's the most likely cause of my symptoms?
• What kinds of tests do I need? Do they require any special preparation?
• Is my condition likely temporary or chronic?
• Will my condition progress?
• What treatments are available?
• I have these other health conditions. How can I best manage them together?

In addition to the questions that you've prepared to ask your doctor, don't hesitate to ask other questions during your appointment.

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Multiple sclerosis

• Multiple sclerosis (MS) affects function in cognitive, emotional, motor, sensory, or visual areas and occurs as a result of a person’s immune system attacking their brain and spinal cord.
• It is estimated that over 1.8 million people have MS worldwide.
• People of all ages can be affected, but it is more common in young adults and in females.
• MS can improve or stabilize by being treated with medicines early in the course of the disease and treatments will be different for each person depending on the severity of the disease and symptoms.

Multiple sclerosis (MS) is a condition that happens when the immune system attacks the brain and spinal cord.

Symptoms of MS vary from person to person and depend on the location and severity of nerve fibre damage. These often include vision problems, tiredness, trouble walking and keeping balance, and numbness or weakness in the arms and legs. Symptoms can come and go or last for a long time.

The causes of MS are not known but a family history of the disease may increase the risk.

While there is no cure for MS, treatment can reduce symptoms, prevent further relapses and improve quality of life.

MS can present in a variety of ways including:

• clinically isolated syndrome (CIS): describes an episode of neurologic symptoms that are the first clinical sign of possible MS;
• relapsing remitting (RRMS): the most common form of MS characterized by intermittent attacks of symptoms (relapses), followed by a short or long period of no clinical attacks (remissions);
• secondary progressive (SPMS): after living with RRMS for a long period of time, relapses decrease and symptoms continue progressively without relapses or remissions; and  
• primary progressive (PPMS): starting from the initial symptoms, the disease gradually progresses and gets worse without any clear relapses or remissions.  

MS is not always easy to diagnose in its early stages. Typically, people who have been diagnosed with MS will have been through several diagnostic stages, which can be an unsettling and frightening experience.

Symptoms of multiple sclerosis can be different from person to person. They can come and go or get worse over time. MS can affect any part of the central nervous system.

MS symptoms can worsen with heat or during other infections such as urinary tract or respiratory infections. 

Symptoms can include:

• vision problems
• difficulty walking or keeping balance
• difficulty thinking clearly
• numbness or weakness especially in the arms and legs
• muscle stiffness
• problems with sexual function or urination
• feeling very tired.

MS is an inflammatory demyelinating condition that results from an autoimmune attack on myelin, the fatty insulation that surrounds the nerves in the brain and spinal cord. This disrupts the electrical impulses that are sent through the nerves to the rest of the body and results in scars (plaques or sclerosis).

It is not known what triggers the immune system to attack myelin, but genetic and environmental factors are thought to play a role. MS happens most commonly in young to middle-aged adults, more in females than males, and is more common in higher latitudes, possibly due to sun exposure and vitamin D.

MS is a diagnosis of exclusion and there are no definitive diagnostic tests. Magnetic resonance imaging (MRI) can help with diagnosis by showing plaques or sclerosis on the brain and spinal cord. Other tests such as lumbar puncture, optical coherence tomography (OCT) and visual evoked potentials can also help support the diagnosis.

Treatment and care

Treatments for MS will be different for each person. They depend on the stage of the disease and symptoms.

The goals of MS treatment are to reduce the frequency and severity of relapses, slow disease progression, manage symptoms, and improve quality of life.

Specific MS disease modifying therapies (DMTs) are started as early as possible to slow disease progression and prevent relapses.

Steroids are sometimes used in the short term to treat relapses. Other medicines can be used to reduce the symptoms of MS such as fatigue, muscle tightening, depression and urinary or sexual problems. These medicines do not change the course of the disease but help manage the symptoms.

Rehabilitation specialists can help improve functioning, quality of life and reduce muscle stiffness and spasms.

Many people feel fatigue with multiple sclerosis. Ways to manage fatigue include:

• regular exercise
• healthy sleep patterns
• avoiding medicines that make fatigue worse.

In the past twenty years treatment options for MS have improved dramatically. In high income countries many oral, intravenous and injectable options exist to treat MS. However, most of these medications are not available in low- and middle-income countries and there is still a lack of treatment options for progressive types of MS.

People with MS and their families should be encouraged to seek services and guidance from local and national Organizations of Disabled People (ODPs) and other disability focused organizations, which can provide vital advice about legal rights, economic opportunities and social engagement to ensure that people disabled by MS or other neurological disorders are able to live full and rewarding lives.

WHO Response

In May 2022, the World Health Assembly endorsed the Intersectoral global action plan on epilepsy and other neurological disorders 2022–2031. The action plan addresses the challenges and gaps in providing care and services for people with epilepsy and other neurological disorders such as MS that exist worldwide and ensure a comprehensive, coordinated response across sectors. This includes raising policy prioritization and strengthening governance, providing effective, timely and responsive diagnosis, treatment and care, implementing strategies for promotion and prevention, fostering research and innovation and strengthening information systems.

WHO also supports countries to manage MS by:

• working to include MS medications in WHO Essential Medicines Lists (EML);
• collaboration with civil society such as Multiple Sclerosis International Federation (MSIF) on broad issues and advocacy including through World MS Day (May 30);
• creation of the Atlas of Multiple Sclerosis for use by people with MS, health professionals and MS groups and organizations to stimulate and inform campaigns for improvements in the services and support provided to people with MS and those with an interest in their well-being and quality of life; and
• supporting countries to implement guidelines and strengthen health systems to improve the rehabilitation services for people with neurological disorders.
• Intersectoral global action plan on epilepsy and other neurological disorders 2022–2031
• WHO Global disability action plan
• Atlas: Multiple Sclerosis Resources in the World 2008
• WHO's work on brain health

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

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.

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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.

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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.

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Multiple Sclerosis

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Introduction

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) which is characterised by demyelination . It is the most common progressive neurological disorder in high-income countries, and in young adults. 1,2

Pathophysiology

MS is an autoimmune inflammatory process in the central nervous system thought to likely be mediated by aberrant T-cell activation . 3

The underlying cause of this process, however, remains unclear. 2-5

It is thought to be a complex relationship between a genetic predisposition and exposure to environmental triggers . 2,4

Classification

It is helpful to think of MS as a continuous spectrum of disease , where the rate of progression and severity worsens over time.

However, for management and research purposes it is simpler to categorise patients into four main groups .

Clinically/radiologically isolated syndrome (CIS/RIS)

Clinically isolated syndrome (CIS) is an otherwise unexplained clinical episode of neurologic dysfunction, and radiologically isolated syndrome (RIS) is evidence of white matter pathology on neuroimaging not attributable to any other pathology in the absence of clinical symptoms. 4

Both syndromes have features suggestive of MS, however, neither CIS nor RIS satisfies the diagnostic criteria that must be met to make a diagnosis of MS (see McDonald’s criteria in investigations section). 3-7

Patients who present with a CIS/RIS are much more likely than the general population to develop MS. Some 34% of patients with RIS develop acute neuropathic symptoms consistent with multiple sclerosis within 5 years. 4

Relapsing-remitting MS (RRMS)

Relapsing-remitting MS (RRMS) is by far the most common form of disease at presentation, encompassing approximately 85% of patients. 3,5,6

RRMS constitutes unpredictable attacks of neurological dysfunction (lasting >24 hours in the absence of fever), followed by relief of symptoms though patients may not return fully to baseline function. 3-7

Secondary progressive MS

Secondary progressive MS initially presents as RRMS, then later declines steadily and progressively without remission. 3-7

Primary progressive MS

Primary progressive MS is a steady, progressive worsening of disease severity from the onset without remission. 3-7

Risk factors

Risk factors for MS include: 1-4

• Family history
• Sex (F>M) 
• Age between 25-35
• Other co-existing autoimmune diseases, such as type 1 diabetes mellitus
• Previous EBV infection; infectious mononucleosis / raised anti-EBV nuclear antigen 1 (EBNA1) antibody titres
• Latitude of habitat
• Vitamin D deficiency

Clinical features

While there are no clinical findings that are unique to MS, there is a range of recognised characteristic symptoms (table 1).

The most common symptoms on initial presentation are: 5

• Limb numbness/tingling
• Limb weakness (subacute onset)
• Cerebellar symptoms

Certain phenomena are also considered characteristic of MS: 5

• Uhthoff’s phenomenon : worsening of symptoms on exercise/in warm environments (e.g. in a bath).
• Lhermitte ’ s phenomenon : lightning-shock pain down the spine on flexion of the neck secondary to cervical cord plaque formation.

Table 1. An overview of the clinical features of MS.

Other important areas to cover in the history include:

• Past medical history (such as any history of focal neurologic deficit, or other autoimmune diseases)
• Family history of MS/other autoimmune diseases
• Smoking status
• Impact on activities of daily living
• Driving status
• Falls risk assessment

Clinical examination

MS has the potential to involve multiple different systems. As such, it is important to carry out a thorough neurological examination including a cranial nerve examination and cerebellar examination .

Patients with MS may have a wide range of clinical signs on cranial nerve examination. 

Optic nerve (CN II)

Optic neuritis , which is usually monocular, can be the first sign of MS. Fundoscopy may reveal blurring of the optic disc in the acute setting, though often no changes are apparent. A previous episode of optic neuritis is often characterised by disc pallor, which is often far more helpful.

Relative afferent pupillary defect (RAPD) is another manifestation MS which may be revealed by the pendular swinging light test.

The pupil of the healthy eye will constrict as light is shone on it, exhibiting a normal direct light reflex. The contralateral pupil will also constrict as there is a normal consensual light reflex. 

When the light is then swung to the affected eye, the previously constricted pupil will dilate as there is no afferent (outgoing) signal being transmitted by the inflamed optic nerve , impairing the direct light reflex . 

See the Geeky Medics visual assessment guide for more information on pupillary reflexes. 

Oculomotor (CN III), trochlear (CN IV) and abducens (CNVI) nerve

Ophthalmoplegia arises from involvement of the cranial nerve nuclei, resulting in symptoms of a cranial nerve palsy, or involvement of the medial longitudinal fasciculus (MLF) resulting in internuclear ophthalmoplegia (INO).

INO is a conjugate lateral gaze palsy , where there is a failure of adduction of the affected eye during horizontal eye movement (figure 1). 

Nystagmus is usually observed with the abduction of the contralateral eye, as it tries to normalise the two discordant images being sent to the brain simultaneously (figure 1).

Trigeminal nerve (CN V)

Involvement of CN V nucleus may result in facial paraesthesia , and/or weakness of the muscles of mastication.

Facial nerve (CN VII)

CN VII lesions will result in weakness of facial muscles of expression. This can mimic the signs of an acute stroke. MS is an upper motor neuron lesion, and as such there will be sparing of frontalis controlling expression of the forehead.

Vestibulocochlear nerve (CN VIII)

Loss of balance, and/or sensorineural deafness.

Glossopharyngeal  (CN IX), vagus (CN X) and hypoglossal nerve (CN XII)

Loss of motor function to tongue/pharynx resulting in speech and swallowing problems. 

Accessory nerve (CN XI)

Loss of motor function to sternocleidomastoid and trapezius resulting in neck weakness and hypertonia.

Cerebellar signs

MS has the potential to affect any part of the CNS. As such, sometimes patients may present with symptoms of cerebellar dysfunction including:

• Nystagmus : slow, large-amplitude nystagmus while eyes are resting at the midline, flickering towards the side of the lesion.
• Intention tremor : a slow, coarse tremor that gets worse on the extension of a limb towards an intended object/target, often associated with dysmetria.
• Scanning dysarthria : sentences or even words are broken up into a number of separate syllables that can be expressed at varying volume. It may appear as though the patient is searching for (or scanning for) the correct next word/sound.

Peripheral nervous system signs

Sensory signs :

• Abnormal sensation
• Romberg’s test positive: this suggests the involvement of the dorsal column of the spinal cord, affecting proprioception.

Motor signs :

• Decreased power
• Hyperreflexia

Differential diagnoses

The presentation of multiple sclerosis can be varied . MS can resemble a broad number of other disorders which should be considered/ruled out ahead of making a diagnosis: 8

• Migraine with aura
• Hypoglycaemia
• Hypothyroidism
• Electrolyte abnormalities (e.g. hyponatraemia)
• Peripheral neuropathy (e.g. B12 deficiency, diabetic neuropathy, radiculopathy, motor neuron disease)
• Space occupying lesion (e.g. glioblastoma/meningioma/lymphoma or cerebral abscess)
• Compression of brainstem or spinal cord (e.g. Chiari malformation, cervical spondylosis, disc herniation)
• Infection (e.g. Lyme disease, syphilis, HIV)
• Inflammatory/autoimmune (e.g. sarcoidosis, systemic lupus erythematosus, CNS vasculitis)

Investigations

Laboratory investigations.

Laboratory investigations are important for ruling out other causes of neurological dysfunction: 8,9

• Full blood count: white cell count for infection.
• C‑reactive protein: a marker of an inflammatory process (e.g. infective/autoimmune).
• Liver function tests: for basic baseline biochemistry and to rule out hepatic pathology associated with MS mimics.
• Urea and electrolytes: to rule out electrolyte disturbance, which might mimic MS.
• Calcium and angiotensin-converting enzyme: to rule out sarcoidosis.
• Thyroid function tests: to rule out hypothyroidism.
• Vitamin B12: to rule out B12 peripheral neuropathy.
• HIV serology: to rule out HIV.

Radiological investigations

The main investigation for MS is MRI of the brain and spinal cord with gadolinium contrast. MS lesions will be apparent as T2-hyperintense white matter plaques (figure 2).

Other investigations

Lumbar puncture for CSF analysis is useful, especially when there is no clear radiological evidence of white matter pathology consistent with MS on MRI (see McDonald’s criteria below).

Typical findings in the CSF of an MS patient include a high protein content and oligoclonal bands of immunoglobulin aggregates on CSF electrophoresis. 9

CSF electrophoresis must be accompanied by serum protein electrophoresis (SPEP) concurrently for results to have any meaning. Oligoclonal bands should not appear on SPEP.

Evoked potentials are also a supportive investigation that historically would have been considered useful in the workup of MS, visual evoked potentials being the most useful. In clinical practice today it is considered solely supportive and not diagnostic in isolation. 10

McDonald diagnostic criteria

The McDonald criteria outline the clinical, radiological and biochemical findings which must be met to make a diagnosis of MS. 6

It is centred around the principle that MS is a disease which demonstrates pathology that is disseminated in time (i.e. events occur at >1 distinct time periods) and disseminated in space (i.e. ≥2 lesions affecting distinctly different locations in the CNS).

Table 2 describes further what dissemination in time and space means in a clinical and radiological context, and table 3 describes how the McDonald criteria apply this information to make a diagnosis of MS.

Table 2a : Description of the clinical findings required to satisfy the McDonald criteria, focussing on the necessity to demonstrate dissemination in time and dissemination in space.

Table 2b : Description of the radiological findings required to satisfy the McDonald criteria, focussing on the necessity to demonstrate dissemination in time and dissemination in space.

*periventricular, cortical, juxtacortical, infratentorial and the spinal cord **active lesions will enhance with gadolinium, old/inactive lesions will not

Table 3: The McDonald diagnostic criteria for the diagnosis of MS, adapted from Thompson et al., 2018. 6

Management of an acute episode

NICE guidelines state that a relapse/attack can be diagnosed if a patient presents with: 9

• New symptoms or worsening of existing symptoms
• Subacute onset (>24hrs)
• Absence of fever/signs of active infection

Not all relapses require medical intervention. If left alone, some symptoms may remit on their own.

If symptoms are severe, however, or interfere with activities of daily living then you should consider medical intervention. Treatment of an acute attack/relapse requires high dose steroid therapy with methylprednisolone (500mg by mouth for five days, or 1g by mouth for three to five days). 4,9

Patients can be managed in the community by their GP or may require admission to hospital for specialist input, depending on the severity of their symptoms and the impact of symptoms on their activities of daily living. 9

Plasmapheresis is also an option if the exacerbation is refractory to steroids. 4,5

Flares of MS symptoms may also often be caused by something other than an attack, such as an infection . In such an event, treatment of the underlying cause should be the primary concern.

Long-term management

There are currently no curative therapies for MS. Management of the disease focuses on curtailing the demyelination process and managing side-effects of the disease process.

Management of the demyelinating process

Beta-interferon (beta-IFN) and glatiramer acetate are injectable disease-modifying agents regularly used in the management of MS, which have both been shown to be similarly effective in decreasing relapses in RRMS. These medications do not, however, alter disease progression. 4,9,11,12

Additionally, there are a number of approved oral disease-modifying therapies for RRMS, including dimethyl fumarate , fingolimod and cladribine . 11,12

Monoclonal antibody therapies such as alemtuzumab and natalizumab are effective therapies in the treatment of RRMS. These drugs carry more dangerous side effect profiles. Most notably, natalizumab can rarely cause progressive multifocal leukoencephalopathy via reactivation of the JC virus , a very common virus often otherwise found dormant in glial cells. 4,9,11

In addition, alemtuzumab also has had an FDA black box warning for strokes and arterial dissections and thus should be used extremely cautiously. 13,14

With regard to PPMS, ocrelizumab is the only medication to date that has been shown to be effective in slowing the progression of symptoms in patients. 4,15

It is also worth mentioning the emerging role of autologous haematopoietic stem cell transplantation in patients with MS refractory to disease-modifying drug therapy, which has shown great promise to date. 4

The symptoms secondary to the demyelinating process in MS can have marked and severe impacts on a patient’s quality of life. As such, it is paramount that these be treated effectively and in a timely manner. These symptoms are outlined in table 3, along with multidisciplinary management options that should be considered. 4,5,9

Other management strategies

Other important management strategies for MS include:

• Amelioration of modifiable risk factors (e.g. smoking cessation, obesity, vitamin D) 4,5
• Ensuring immunisations are up to date

A multidisciplinary approach is important, other professionals who may be involved include: 

• Nurse specialist involvement for assistance in managing the complex needs individuals with MS, their families and carers experience on a day-to-day basis.
• Physiotherapy for assistance and rehabilitation of balance, strength and mobility difficulties.
• Occupational therapy for management around the home and any modifications/aids required.
• Speech and language therapy for the assessment, diagnosis and rehabilitation of speech and/or swallowing difficulties.
• Social care worker for the management of emotional, social and economic need of patients with MS (e.g. social welfare entitlements).
• Psychologist involvement for any mood disturbance. Conversion disorder and depression are common complications of MS.
• GP involvement in the co-ordination of community care.

Complications

MS is a chronic, progressive disease, with a variable clinical course . 3-5

Not much is understood of its aetiology, and as such, there is difficulty identifying reliable biomarkers of disease severity/rate of disability onset. 5

Morbidity 5

The majority of people diagnosed with MS become unemployed within the following 15 years.

50% of patients require some form of mobility aid within 20 years of diagnosis.

Approximately half of patients eventually develop substantial cognitive deficits.

Mortality 5

Patients with multiple sclerosis have a reduction in life expectancy of 7 to 14 years compared with the general population.

At least half die from causes directly related to multiple sclerosis.

Primary progressive disease and older age at onset are associated with shorter survival.

There are numerous recognised complications of MS in addition to the classical motor/sensory symptoms associated with the disease (table 4).

Table 4.  An overview of the complications of MS.

• Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) which is characterised by demyelination .
• Risk factors include being young, having a family/personal history of autoimmune disease and previous infection with EBV. There are also a number of recognised preventable risk factors such as vitamin D deficiency, the latitude of habitat and smoking.
• The presentation of MS can be quite varied, and may potentially involve quite a number of systems.
• Diagnosis is made using the McDonald criteria , which encompasses clinical and radiological findings consistent with MS, disseminated in time and space .
• Examination of MS patients includes the full examination of the peripheral nervous system, along with a cerebellar exam and a cranial nerve exam.
• The mainstay for management of an acute attack is high-dose steroid therapy to reduce inflammation, along with the management of any specific complications.
• Long term management requires multidisciplinary input. Treatment focuses on the disease itself (beta-IFN/Glatiramer acetate + monoclonal antibodies) along with the long-term management of side effects.

Neurology Registrar

Dr chris jefferies.

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Remembering My First MS Symptom

by Ed Tobias | April 29, 2022

Share this article:

What was your first MS symptom ?

Mine — the one that made me realize something was really wrong — was my inability to squeeze the toothpaste tube with my left hand one morning. Of course, there were earlier hints of trouble. I was unusually tired while attending a business conference. On the flight home from that conference, I felt spacey — there’s no other way to describe it. Another time, I accidentally drove through a red light because my peripheral vision suddenly narrowed and I failed to see the traffic signal to my right.

My wife made fun of me for complaining my legs were getting tired after only a couple of runs down an easy ski slope. One day she accidentally tapped my left foot and it began to shake. It was clonus , another MS symptom. I didn’t know that, but my wife, a physical therapist, did.

Gray Matter Loss in Spine Crucial, But Difficult, Marker of MS Disability

I saw a doctor, and when she tapped my left knee with a rubber reflex hammer, my leg shot out so fast and far that I kicked her in the stomach. But it was my weak left hand that bothered me the most. I knew, after trying to ignore things, that I wouldn’t be able to squeeze this toothpaste back into the tube. That was in 1979. I was diagnosed in August 1980.

A lot of symptoms on my chart

Since my diagnosis, I’ve lived with a medical chart full of symptoms, as most of us do. The most debilitating has been my left foot drop and my general leg weakness. It’s hard to walk more than about 100 steps, even using two canes and a Bioness L300 Go functional electronic stimulator. Other symptoms include fatigue, heat sensitivity, spasticity, restless legs in bed, and bowel and bladder problems. Oh, of course, there’s also “cog fog.” I almost forgot.

My bladder and bowels have improved over the past few years, as has my fatigue. My vision problem only occurred that one time, and my weak left hand returned to normal after my first infusion of the steroid Solu-Medrol (methylprednisolone sodium succinate).

Your symptoms may vary

I’m revisiting these symptoms because of a project recently started by my friend and former MS News Today columnist Laura Kolaczkowski . Laura has begun producing the podcast “ MS Diagnosis Journey .” It’s a series of short chats with people with MS about how they discovered their illness, the diagnostic tests they took, their experience with neurologists, and the like. It’s all information that’s likely to be especially interesting and useful to MS “newbies.” The podcast can be found on all the major podcast platforms, or you can search “MS Diagnosis Journey podcast” to listen via a website. I expect my interview to be available on May 12.

I also just discovered an A to Z listing of MS symptoms in the latest issue of Momentum , the National MS Society’s magazine and blog. The story includes 23 symptoms, such as fatigue, the “MS hug,” and kissing issues. (The letters X, Y, and Z are rolled into a “ways to live well” lump.) It’s an interesting read.

What were your first MS symptoms and when did you notice them? Please share in the comments below. You’re also invited to visit my personal blog at www.themswire.com .

Note:  Multiple Sclerosis News Today  is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of  Multiple Sclerosis News Today  or its parent company, Bionews, and are intended to spark discussion about issues pertaining to multiple sclerosis.

About the Author

Yvonne Ashman

For years I suffered with overwhelming fatigue which I put down to being lazy, and spells of vertigo that put a stop to my motorcycle riding and made me a pedestrian. Symptoms were so vague, so I kept them to myself for years. I'd always been slapped down by the medical profession as I was obese, and, as far as they were concerned, all I needed to do was exercise more and eat less - et voila! - I'd be miraculously cured of everything from a broken toe to migraine. (Despite spending 4 hours a day speed walking and crunching numbers at the local gym...plus eating less than 800 calories a day. Go figure...)

In 2012 I lost the vision in my left eye...a quick visit to my optometrist, a few eye tests, and I was rushed to the Eye and Ear Hospital in Melbourne. Twelve months of testing later and an MRI showed what the problem had been all along...

I don't beat myself up anymore about 'being lazy'...and, I've lost weight to help with mobility. Strange what the right advice can do for you...It's not all plain sailing with the medical professionals I see, but I now have a focus and an understanding that sometimes I need to adjust my expectations, compromise and develop new ways of achieving my goals.

Thanks for sharing all of that. I've heard so many stories over the years of docs who think all that's needed is more exercise and less food that I could write a book. (Gee, actually I have written a book. It's called "The Multiple Sclerosis Toolbox." Shameless plug.) It sounds as if you've managed to turn things around a bit since your diagnosis by following my favorite advice: Life isn't about hiding from the storm, it's about learning to dance in the rain. Bravo to you!

Karen Bates

My first symptom appeared on the 6th Feb 2012 (quite precise I know, but it was my partners birthday on the 10th Feb and it was the following day (the 11th Feb) when I had my second symptom - waking up very very tired). My original symptom was my hands felt ‘funny’. I couldn’t even wash my hair as my hands didn’t feel ‘right’. I needed help doing this. Despite this, I still went in to office (I was a very conscientious PA and constantly busy), so after I really couldn’t function properly on the 11th Feb, I never made it back in to the office, which I was sad about as I genuinely loved my job. I was 34 when it happened, and had to retire at 36 ☹️.

I'm really sorry that you had to retire so young. It makes me even more appreciative of being able to work, full-time, until I was 64. Have you been able to do something else to keep you involved in things since you retired?

I can’t remember a “first” symptom. I was aware of frequent fatigue, but like Yvonne assumed I was just lacking initiative! Interestingly, it was usually associated with stressful situations, of which there many with my narcissistic mother (RIP) and ex-husband. Wish I had known what was going on at the time. Would have improved my self esteem to know I was not “to blame” for the lack of energy. SIGH….

I have no doubt that stress also played a role for me, working in the broadcast news media for a boss who I didn't get along with, when I was diagnosed. It'll be interesting to read the experiences of others. Thanks for sharing yours.

Deidre Squairs

My first symptom appeared in the fall of 2017, I was a struggling first time mom with a 5 month old trying to balance work, home and myself. I was doing an Alzheimer's walk with my son and husband when it started to feel like I was walking through knee high water. I couldn't even make it one lap around the race area. The leg weakness had been occurring on and off over the past week, but this was the worst. At the time I thought that it was just stress, I had been struggling with breast feeding and decided that it was time to call it quits, I had done my best and that was ok. The leg weakness went away. Turns out I was right, that it was stress, just not stress as I knew it. In December 2020, I had my annual physical with my PCP and I noted having a lot of anxiety, I am a health care worker and COVID was taking over our lives. My PCP didn't seem too concerned because my symptoms weren't alarming. I worked on non medicinal treatments which did help for a time. Labor Day weekend 2021 I started having eye pain, my facility had just started using a full electronic medical record, and I was in front of a computer more then ever. At the same time my family was getting ready for my son, who is special needs, to start Pre-K, which was very stressful. Over the course of the weekend I lost vision in my right eye. After seeing my PCP, an ophthalmologist, going to the ER to be admitted to the hospital, 2.5 hours of MRI and a lumbar puncture I was diagnosed with MS. I was 33 year old.

I feel very lucky that I have not had any long term effects from my symptoms. My legs haven't had any weakness since 2017. My increased anxiety that I experienced has been helped by stress management. I am now rocking a pair of black framed glasses, that I actually love. My husband is very supportive, and continues to remind me that MS is manageable, and manage we will.

Thanks for sharing all of that. I'm sure that many of us can associate with your story. (Well, maybe not the breast feeding for me.) Stress seems to be the common denominator here. It certainly played roll for me, when I was DXed at 32. I'm glad that things are going well for you and I think your overall attitude has something to do with that. Also, THANK YOU for whatever roll you played in working with COVID-19 patients. We're still not out of the woods but I think we know the path we need to follow to get us there.

Nancy Starks

My first symptom was double vision at the onset of my MS (in 2004); which I understand is the lessor of the two vision symptoms that can occur when diagnosed with MS. My first bout of this was when I had the flu and my eyes went back to normal after I recovered from the flu. Two months later it came back with a vengeance and lasted six to eight weeks. It was during this time that I received my MS diagnosis. Eventually my vision came back to normal. The medical term for the double vision I experienced is Internuclear ophthalmoplegia.

I was 57 and the major symptom happened overnight when I woke up with transverse myelitis. I knew right away what it was because I have a daughter who also had TM and was diagnosed with MS when she was almost 20. I had a brain MRI showing brain lesions were inactive so I probably had MS before that time but did not know it. I did have before the TM symptom occasional mild MS hugs but at the time had no idea what they were and my internist did not think much about them either. After my MS diagnosis, I found out what MS hugs were online. Other than that I had no clue anything was wrong. I have not had anyactive lesions since although there was a period of time after diagnosis and after starting Copaxone that I had no MRI's done (-I changed neurologists since.) After age 70, four yrs ago, I stopped with the MS DMT. I am glad that so far I have no major disabilities. My last 3 annual MRIs have been negative and I have another in two days.

Cathy Chester

Numbness, weakness, and fatigue.

I was walking through the Manhattan bus terminal (Port Authority) on my way home from work when one of my high heels came off my foot. I only noticed it when I realized I was walking "crooked" and glanced back 10 feet to see my lovely high heel being kicked around by busy travelers! My feet were so numb I never felt the shoe slip off.

That's when I realized I better call the doctor!

Thanks for sharing that. Growing up in Manhattan I know the Port Authority terminal well and have heard many tales about it, but yours is unique! But you've only told us half...how were you able to hobble home?

It was 1984 I was 28. High stress demanding job (Both conditions I thrived on.) Double vision and an astute and awesome ophthalmologist who suspected MS. An appt with a neurologist and MRI followed. MS (which I had never heard of) was confirmed. No DMTs at the time and neuro basically said "good luck". Stuck w/ the ophthalmologist and dumped the neurologist. Kept working at the same job (which I loved) and disguising my MS for the next 28 years (through some at times elaborate schemes a/k/a cover lies). My MS progressed and physical limitations increased. When I felt I could no longer do my job at the level (I) expected of myself, I "retired" and let out the truth. Two wonderful kids (now adults) and a fulfilling career later I realize I was/am a lucky one. My physical decline was slow. Last 5 years sees me able to walk in the house w/ two canes or a walker, but use an electric scooter for anything else. Would love to do stem cell transplant but age 65 and having had MS now for 38 years is not the target patient profile.

Thanks for sharing that. It looks like we've traveled similar paths. DXed in 1980 at age 32, stressful job, minimal visible symptoms for about 20 years, now two canes and a scooter. And yes, we are lucky.

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Multiple sclerosis: Pathology, diagnosis and treatments

Wen-juan huang.

Department of Neurology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China

Wei-Wei Chen

Multiple sclerosis (MS) is a complex neurodegenerative disease affecting the central nervous system (CNS). The onset of MS has been typically observed in individuals aged from 20 to 40-years, with the female to male ratio of 1:2. MS appears as abrupt onset of focal sensory disturbances that is accompanied by unilateral painless damage of vision, double vision, limb weakness, unsteadiness of gait, and bowel or bladder symptoms. Whereas the exact etiology of the disease is unknown, observational research has suggested genetic and environment influences through an underlined pathophysiology widely believed to be autoimmune in nature. Indeed, plaque of demyelination inside of the CNS with relative conservation of axons remains the clinical symptoms of MS. However, considerable advances in understanding the pathology have contributed to an early diagnosis, particularly the exact neuroanatomical setting of plaques. Accordingly, magnetic resonance imaging has been considered as the primarily adjunctive modality for the constant detection of abnormal white matter. In addition, the analysis of cerebrospinal fluid contents has also been of interest for the diagnosis to discriminate other affections such infection or vasculitis. These resulted in a broad variety of therapies that considerably control the activity and change the course and prognosis of the disease. In the present review, we evaluate the current state of knowledge on MS with emphasis on the pathology itself, the diagnosis and common therapeutical approaches accurately used.

1. Introduction

Multiple sclerosis (MS) is a chronic complex neurodegenerative disease, targeting the central nervous system (CNS) and widely believed to be autoimmune in nature. it is mediated by autoreactive lymphocytes that cross the blood-brain barrier (BBB) and enter the CNS where they cause local inflammation that results in demyelination, gliotic scarring, and axonal loss ( 1 ).

Approximately, 2.5 million individuals are affected worldwide, and young individuals aged between 20- and 40-years are mainly affected ( 2 ). The higher frequency of MS is seen in women who are affected twice as often as men ( 3 ).

However, advances in the understanding of genetics of MS have been relatively slow up until the last decade, since the discovery of the importance of variants in HLA genes of the major histocompatibility complex (MHC) in the 1970s ( 4 ). Accordingly, genome-wide association studies ( 5 ) and the International MS Genetics Consortium (IMSGC) ( 6 ) have opened up an entire new field of research into genetic and subtle epigenetic influences.

However, MS is likely influenced by B cells through a variety of mechanisms, including the establishment of ectopic lymphoid follicles within the CNS, antigen presentation, cytokine production and antibody production ( 7 ). In general, the affected individuals initially present a relapsing-remitting disease course that is followed by a progressive phase several years later ( 8 ). The underlying pathophysiology hallmarks are inflammatory lesions that result in neuronal demyelination, axonal damage and subsequent neurological dysfunctions following the formation of multiple plaques in the grey and white matter of the brain and spinal cord ( 9 ). Accordingly, MS is considered the most common cause of neurological disability since inflammatory lesions associated with MS can affect a large range of systems to a variable degree and cause a myriad of neurological symptoms and comorbidities. These include sensory loss, visual disturbance, double vision, muscle weakness, ataxia and impaired balance, which may considerably reduce the quality of life in affected individuals ( 10 , 11 ). The exact clinical symptoms are the result of plaques of demyelination within the CNS with relative preservation of the axons. Indeed, the myelin sheath around axons is crucial for the transmission of information between regions within the CNS.

Thus, the clinical symptoms of MS are determined by the exact neuroanatomical location of the plaque; the disease being essentially diagnosed by the manifestation of symptoms and signs attributable to lesions of white matter, and the diagnosis is supported by laboratory tests combined with the exclusion of conditions that mimic MS. A poor prognosis of diagnosed patients is generally associated with factors such as older age at onset and a greater number of relapses during the first few years. Although the disease remains incurable, several therapies currently approved are able of modify disease course and improving the quality of life for patients. These therapies are discussed in the current review. We first briefly present the clinical course of MS, giving an overview of the status of knowledge regarding the pathology and diagnosis of this disabling disease to better understand the rational design of therapeutic strategies.

2. Pathology and diagnosis

Clinical course of MS. Patients suffering from MS show a wide variety of neurological symptoms that originate from different parts of the CNS. They can occur alone or combined. According to the spatial distribution of the lesions in the CNS, the symptoms are quite variable from patient to patient, but commonly involve sensory disturbance, bladder dysfunction, cognitive deficits, unilateral painless loss of vision, double vision, limb weakness, ataxia, fatigue, and bowel troubles ( 12 ). Although MS is associated with change in average life expectancy, it is not considered a fatal condition and clinical course, which appears highly variable, is unpredictable for the individual patient. Typically, the disease starts with the sudden onset of neurological deficits. In the majority of cases, the disease shows a purely relapsing remitting course with the absence of symptoms except for the relapses. Specifically, the recurrent periods are followed by remission phases after complete or partial recovery ( 13 ). Over time, most cases evolve into a secondary progressive form of disease, which is characterized by continuous irreversible neurological impairment between relapses. Only a small percentage of patients experience a gradually progressive clinical course from the onset of the disease ( 14 ). Such a clinical course refers to the principal progressive form of MS, in which symptoms start and worsen insidiously with no periods of remission. Therefore, the steady progression of symptoms associated with primary progressive MS leads to disability from the beginning. Patients suffering from this form of MS do not show a female prevalence, and begin the disease later than those with the relapsing remitting form ( 15 ).

MS refers to the plaques that form in the CNS combined with inflammation, demyelination, axonal injury and axonal loss. These plaques are found in the brain and spinal cord, essentially in the white matter around the ventricles, optic nerves and tracts, corpus callosum, cerebellar peduncles, long tracts and subpial region of the spinal cord and brainstem, but also in the gray matter ( 16 ). They are expressed in all forms of MS, but vary over time quantitatively and qualitatively showing a profound heterogeneity in the structure and immunopathological patterns of demyelination and oligodendrocyte pathology between relapsing remitting course and progressive forms of disease ( 17 ).

During the early stages of the relapsing remitting course, the pathology is marked by important demyelination and a variable degree of axonal loss and reactive gliosis ( 18 ). Patients in general, present with focal inflammatory plaques that contain demyelinated axons, reduced number of oligodendrocytes, astrocyte proliferation with subsequent gliosis, transected axons, and perivenular as well as parenchymal infiltrates of lymphocytes and macrophages. In the progressive course, MS is dominated by diffuse gray and white matter atrophy and characterized by low-grade inflammation and microglial activation at the plaque borders combined with diffuse injury of the normal-appearing white matter outside the plaque ( 19 ). Inflammation, microglial activation, axonal and myelin injury occurring during this course are followed by secondary demyelination ( 20 ). In general, the patterns of tissue injured in patients presented with primary or secondary progressive course of MS are homogeneous. They showed oligodendrocyte loss, preferential destruction of small-caliber axons, astrocytic gliosis, and demyelination that consists of the essential criteria ( 21 ). Demyelination and subsequent neurodegeneration associated with different forms of MS involved various components of adaptive and innate immunity ( 22 ). Myelin sheaths are particularly vulnerable to non-specific products, such as cytotoxic cytokines, excitotoxins, reactive oxygen or nitric oxide species, which are released by activated macrophages and microglia ( 23 ). However, the most commonly observed patterns of demyelination are antibody and complement-associated changes, as well as hypoxia-like tissue injury, in which the initiation of demyelination is attributed to the degeneration of distal oligodendrocyte processes and apoptosis of oligocytes, while the loss of polarity by astrocytes leads to the disturbance of the structural organizational of the perivascular glia limitans ( 24 ).

Classically, MS is regarded as a T cell-mediated autoimmune disorder with a predominance of CD8 + cells compared with other T-cell subsets, B cells or plasma cells. It is believed that this disease begins in inflammatory-induced lesions consisting mainly of CD8 + T cells, and CD4 + T cells, and activate microglia/macrophages ( 25 , 26 ).

Evidence of the suppression of function that restricts CD4 + T-cell responses and the tissue-damaging role of CD8 + T cells reported to co-localize with axonal pathology have been observed ( 27 , 28 ). Indeed, the specific interaction of CD8 + T cells with target cells requires MHC-I expression which is tightly regulated in neurons and MHC-I molecules only in response to strong danger signals such as proinflammatory cytokines IFN-γ or TNF-α ( 29 ).

The diagnosis of MS is primary clinical and is dependent on the demonstration of neurologic signs and symptoms subsequent to white matter lesions. To distinguish MS from other conditions with similar neurologic manifestations, several criteria ( 30 , 31 ) including McDonald criteria ( 21 ) have been proposed. These criteria depend on the demonstration of lesions disseminated in time and space to exclude alternative diagnoses. The requirement for such dissemination of lesions is achieved with adjuvant laboratory tests and imaging, including magnetic resonance imaging (MRI) of brain and spinal cord, cerebrospinal fluid analysis, and functional assays of the nervous system. The McDonald criteria, which combine these paraclinical assessments with clinical examination, are the most commonly used diagnostic approach. Currently, the diagnosis of MS depends largely on the results of MRI examination. Using gadolinium as a contrast agent to highlight active plaques, MRI allows detecting plaques that are ongoing to destruction of the BBB, and also those not associated with neurological symptoms at the time of the assessment. Therefore, relapsing remitting MS can be diagnosed earliest after a single relapse with an MRI scan showing gadolinium-enhancing and non-enhancing lesions disseminated in space. Indeed, since 2014 a published classification of the clinically subtypes of MS ( 32 ) has been established by the International Advisory Committee on Clinical Trials. In this new classification, MRI activity (gadolinium-enhancing lesions and new or unequivocally enlarging T2 lesions) and clinical relapses have been taken into account. Nowadays, MS patients are classified as either progressive MS that is divided into either primary progressive or secondary progressive with phenotype defined as either active (clinically or radiologically) or inactive. According to committee recommendations, patients with relapsing MS must share a clinical assessment and MRI brain at least annually, although this may be a significant burden for some radiology departments.

3. Treatments

Treatment of MS is challenging and involves several drugs acting via different mechanisms. The indication essentially depends on the clinical course and form of the disease. Although there is no proven therapy for the primary progressive form, several drugs are available to occasionally ameliorate the secondary progressive form and beneficially modify the activity of disease when dominated by the relapsing-remitting course. Indeed, since the introduction of disease-modifying therapies in the 1990s, the number of agents used in the relapsing form of MS has considerably grown. Over 10 products, varying in their efficiency, side-effect profile and safety security requirements, have been approved, and several more are anticipated.

There are actually 12 products licenced by The European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA). Among them dimethyl fumarate (Tecfidera), alemtuzumab (Lemtrada), pegylated interferon-β (Plegridy) and glatiramer acetate (Copaxone) 40 mg have been produced and licenced since 2013.

Among drugs currently available, Interferon-β-1a (Avonex) variants and Glatiramer acetate have been utilized for more than two decades, and are used as first-line therapies for the relapsing-remitting form of MS ( 33 ). They efficiently reduce the relapse rate, ameliorate relapse severity and delay the progression of neurological disability.

Dimethyl fumarate (Tecfidera), originally used in the treatment of psoriasis, has shown proven effects in clinical trials. It reduces the MS annualised relapse rate by approximately 50% ( 34 , 35 ).

However, vitamin D has provided beneficial therapeutic effects in small studies ( 36 – 41 ).

Another compound that may be comsidered beneficial for MS is Simvastatin.

Indeed, in a primary outcome measure of the rate of whole brain atrophy, with additional secondary outcomes both MRI (new or enlarging T2 lesions) and clinical, expanded disability status scale (EDSS), MS functional composite scale (MSFC), MS impact scale-29 (MSIS-29) and relapse frequency were measured in a phase 2-clinical trial ( 42 ). The study emphasized beneficial effects of EDSS and MSIS-29, but not MSFC. In the MS-SMART study, the Simvastatin trial methodology currently being further tested in exploratory studies repurposing other agents (fluoxetine, amiloride and riluzole) that may have neuroprotective properties ( 43 ).

Of note, Daclizumab, a humanized antibody against IL2Rα chain has been shown to strongly reduce the brain inflammation in MS patients thereby leading to only a mild functional blockade of CD4 T cells, which is known as the major candidate in MS pathogenesis ( 44 ). Another compound that may have a promising future is Ocrelizumab, and anti-CD20 monoclonal antibody targeting B cells that appears to be efficacious and well tolerated. Ocrelizumab reduces relapses by nearly 50% compared to interferon-β in two phase 3 trials (OPERA I and II) ( 45 ). The development of famciclovir, a vaccine to prevent Epstein-Barr virus infection is a key research interest in MS patients ( 46 ).

4. Conclusion

Although MS remains an untreatable disease, the currently used active treatments of the relapsing-remitting phase, not only provide higher choice to physicians and patients, but also offer greater efficacy and tolerability than treatments of the 1990's. These new therapies, particularly the newer immunotherapies including fingolimod, natalizumab, dimethyl fumarate, teriflunomide, alemtuzuma can yield long-lasting benefits, although greater risks. As well, Daclizumab and Ocrelizumab emerge as compounds for further treatments. Further research is needed and physicians and patients need to be carefully vigilant for signs of disease progression or side effects caused by the therapy.

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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.

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Multiple Sclerosis (MS)

• Pathophysiology |
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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.

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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.

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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.

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