Multiple Sclerosis 

Updated: Oct 08, 2019
Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA 

Overview

Practice Essentials

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system, destroying the myelin and the axon in variable degrees and producing significant physical disability within 20–25 years in more than 30% of patients. The hallmark of MS is symptomatic episodes that occur months or years apart and affect different anatomic locations. See the image below.

MRI of the head of a 35-year-old man with relapsin 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.

See Multiple Sclerosis, a Critical Images slideshow, for more information on incidence, presentation, and intervention, as well as additional resources.

Also, see the Autoimmune Disorders: Making Sense of Nonspecific Symptoms slideshow to help identify several diseases that can cause a variety of nonspecific symptoms.

Signs and symptoms

Classic MS signs and 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 (33% of patients)

  • Heat intolerance

  • Constitutional symptoms: Especially fatigue (70% of cases) and dizziness

  • 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 be a late finding but is sometimes found at initial diagnosis

  • Symptoms associated with partial acute transverse myelitis

See Clinical Presentation for more detail.

Diagnosis

MS is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests. Tests include the following:

  • Magnetic resonance imaging: The imaging procedure of choice for confirming MS and monitoring disease progression in the CNS

  • Evoked potentials: Used to identify subclinical lesions; results are not specific for MS

  • Lumbar puncture: May be useful if MRI is unavailable or MRI findings are nondiagnostic; CSF is evaluated for oligoclonal bands and intrathecal immunoglobulin G (IgG) production

Classification

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:[1, 2, 3, 4]

  • Relapsing-remitting MS (RRMS): Approximately 85% of cases

  • Secondary progressive MS (SPMS)

  • Primary progressive MS (PPMS)

  • Progressive-relapsing MS (PRMS)

The following 2 subgroups are sometimes included in RRMS:

  • Clinically isolated syndrome (CIS): A single episode of neurologic symptoms

  • Benign MS: MS with almost complete remission between relapses and little if any accumulation of physical disability over time

See Workup for more detail.

Management

Treatment of MS has 2 aspects: immunomodulatory therapy (IMT) for the underlying immune disorder and therapies to relieve or modify symptoms.

Treatment of acute relapses is as follows:

  • Methylprednisolone (Solu-Medrol) can hasten recovery from an acute exacerbation of MS

  • Plasma exchange (plasmapheresis) can be used short term for severe attacks if steroids are contraindicated or ineffective[5]

  • Dexamethasone is commonly used for acute transverse myelitis and acute disseminated encephalitis

Most of the disease-modifying agents for MS (DMAMS) have been approved for use only in relapsing forms of MS. However, siponimod, ocrelizumab, and cladribine are also approved for active secondary progressive disease. The DMAMS currently approved for use by the US Food and Drug Administration (FDA) include the following:

  • Interferon beta-1a (Avonex, Rebif)[6]

  • Interferon beta-1b (Betaseron, Extavia)[7]

  • Peginterferon beta-1a (Plegridy)[8]

  • Glatiramer acetate (Copaxone)[9]

  • Natalizumab (Tysabri)[10, 11]

  • Mitoxantrone[12]

  • Fingolimod (Gilenya)[13]

  • Siponimod (Mayzent)[14]

  • Teriflunomide (Aubagio)[15]

  • Dimethyl fumarate (Tecfidera)[16, 17, 18, 19]

  • Alemtuzumab (Lemtrada)[20, 21, 22]

  • Ocrelizumab (Ocrevus)[23, 24]

  • Cladribine (Mavenclad)[25, 26]

A single-use autoinjector is also available for self-injection of interferon beta-1a (Rebif) in patients with relapsing forms of MS.[27]

The following agents are used for treatment of aggressive MS:

  • High-dose cyclophosphamide (Cytoxan) has been used for induction therapy

  • Mitoxantrone is approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with SPMS, PRMS, or worsening RRMS

Treatment of the symptoms of MS involves both pharmacologic and nonpharmacologic measures. The following symptoms may be amenable to pharmacologic therapy:

  • Fatigue: Off-label treatments include amantadine, methylphenidate, and fluoxetine

  • Depression: Selective serotonin reuptake inhibitors are preferred

  • Spasticity: Baclofen is effective in most cases

  • Pain: Tricyclic antidepressants are first-line drugs for primary pain

  • Sexual dysfunction: Oral phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil)

  • Optic neuritis: Intravenous methylprednisolone may speed recovery

See Treatment and Medication for more detail.

Background

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system (CNS), destroying the myelin and the axon in variable degrees. In most cases, the disease follows a relapsing-remitting pattern, with short-term episodes of neurologic deficits that resolve completely or almost completely. A minority of patients experience steadily progressive neurologic deterioration.

The cause of MS is not known, but it likely involves a combination of genetic susceptibility and a presumed nongenetic trigger (eg, viral infection, low vitamin D levels) that together result in a self-sustaining autoimmune disorder that leads to recurrent immune attacks on the CNS (see Etiology). Geographic variation in the incidence of MS (see Epidemiology) supports the probability that environmental factors are involved in the etiology.

MS is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests, such as magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid examination. (See Workup.) Traditionally, MS could not be diagnosed after only a single symptomatic episode, as diagnosis required the occurrence of repeat clinical attacks suggesting the appearance of lesions separated in time and space; however, recent guidelines allow diagnosis of MS even with a first clinical episode as long as ancillary tests support separation of lesions in time or space.

A common misconception is that any attack of CNS demyelination means a diagnosis of acute MS. When a patient has a first attack of demyelination, the physician should not rush to diagnose MS, because the differential diagnosis includes a number of other diseases. For example, MS must be distinguished from other neuroinflammatory disorders (see DDx.)

Treatment consists of immunomodulatory therapy for the underlying immune disorder and management of symptoms, as well as nonpharmacologic treatments, such as physical and occupational therapy (see Treatment). In the United States, various disease-modifying agents for MS are currently approved for use in relapsing MS.

Pathophysiology

Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. In pathologic specimens, the demyelinating lesions of MS, called plaques (see the image below), appear as indurated areas—hence the term sclerosis.

Demyelination in multiple sclerosis. Luxol fast bl 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.

Examination of the demyelinating lesions in the spinal cord and brain of patients with MS shows myelin loss, destruction of oligodendrocytes, and reactive astrogliosis, often with relative sparing of the axon cylinder.[28] In some MS patients, however, the axon is also aggressively destroyed.

The location of lesions in the CNS usually dictates the type of clinical deficit that results. As neural inflammation resolves in MS, some remyelination occurs, but some recovery of function that takes place in a patient could be due to nervous system plasticity. MS is also characterized by perivenular infiltration of lymphocytes and macrophages, as demonstrated in the image below. Infiltration of inflammatory cells occurs in the parenchyma of the brain, brainstem, optic nerves, and spinal cord.

Inflammation in multiple sclerosis. Hematoxylin an 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.

One of the earliest steps in lesion formation is the breakdown of the blood-brain barrier. Enhanced expression of adhesion molecules on the surface of lymphocytes and macrophages seems to underlie the ability of these inflammatory cells to penetrate the blood-brain barrier.

The elevated immunoglobulin G (IgG) level in the cerebrospinal fluid, which can be demonstrated by an oligoclonal band pattern on electrophoresis, suggests an important humoral (ie, B-cell activation) component to MS. In fact, variable degrees of antibody-producing plasma cell infiltration have been demonstrated in MS lesions. The image below provides an overview of demyelination.

The mechanism of demyelination in multiple scleros 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.

Immune cells in MS

Molecular studies of white matter plaque tissue have shown that interleukin (IL)-12, a potent promoter of inflammation, is expressed at high levels in lesions that form early in MS. B7-1, a molecule required to stimulate lymphocytes to release proinflammatory cytokines, is also expressed at high levels in early MS plaques.[28] Evidence exists of elevated frequencies of activated myelin-reactive T-cell clones in the circulation of patients with relapsing-remitting MS and higher IL-12 production in immune cells of patients with progressive MS.

Decreased function of T-lymphocytes with a regulatory role (Tregs) has been implicated in MS.[29] These Tregs are CD4+ CD25+ T cells that can be identified by their expression of a transcription factor known as Foxp3.

Conversely, the cytokine IL-23 has been shown to drive cells to commit to a pathogenic phenotype in autoimmune diseases, including MS. These pathogenic CD4+ T cells act reciprocally to counteract Treg function and can be identified by their high expression of the proinflammatory cytokine IL-17; they are therefore referred to as TH 17 cells.[30]

Tregs and TH 17 cells are not the only critical immune cells in the pathogenesis of MS. Immune cells such as microglia (resident macrophages of the CNS), dendritic cells, natural killer (NK) cells, and B cells are gaining increased attention by MS researchers. In addition, nonimmune cells (ie, endothelial cells) have also been implicated in mechanisms that lead to CNS inflammation.[31]

Spinal MS

Approximately 55–75% of patients with MS have spinal cord lesions at some point during the course of the disease. Spinal MS is often associated with concomitant brain lesions; however, as many as 20% of patients with spinal lesions do not have intracranial plaques. No strong correlation has been established between the extent of the plaques and the degree of clinical disability.

Spinal MS has a predilection for the cervical spinal cord (67% of cases), with preferential, eccentric involvement of the dorsal and lateral areas of the spinal cord abutting the subarachnoid space around the cord. The gray matter may be involved.

Myelocortical MS

Myelocortical MS (MCMS) is a new subtype of MS identified in 2018. It is marked by demyelination of the spinal cord and cerebral cortex but not of cerebral white matter. Researchers studied the brain and spinal cords from 100 patients with MS who had died between May 1998 and November 2012. Twelve of these individuals (12%) had demyelinated lesions in the spinal cord and cerebral cortex, but not in cerebral white matter. Researchers then compared the demyelinated lesion area in tissue sections of cerebral white matter, spinal cord, and cerebral cortex of individuals with MCMS with those collected from individuals with traditional MS and found that only the typical MS patients had lesions in the cerebral white matter. This suggests that neurodegeneration can be independent of demyelination in MCMS patients.[32]

Optic neuritis in MS

Approximately 20% of patients with MS present with optic neuritis (ON) as a first demyelinating event, and 40% of patients may experience ON during the course of their disease. Sequential episodes of optic nerve involvement and a longitudinally extensive myelopathy suggest a separate disorder, known as neuromyelitis optica [NMO], or Devic disease (see the images below).[33] Although Devic disease is sometimes categorized as an MS variant, typical MS therapies are ineffective in Devic disease, and most experts consider Devic disease to be separate from MS.

Gadolinium-enhanced, T1-weighted image showing enh Gadolinium-enhanced, T1-weighted image showing enhancement of the left optic nerve (arrow).
Corresponding axial images of the spinal cord show 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.

Etiology

The cause of MS is unknown, but it is likely that multiple factors act in concert to trigger or perpetuate the disease. It has been hypothesized that MS results when an environmental agent or event (eg, viral or bacterial infection, exposure to chemicals, lack of sun exposure) acts in concert with a genetic predisposition to immune dysfunction.

Genetic and molecular factors

The concordance rate for MS among monozygotic twins is only 20–35%, suggesting that genetic factors have only a modest effect. The presence of predisposing non-Mendelian factors (ie, epigenetic modification in 1 twin), along with environmental effects, plays an important role. For first-degree family members (children or siblings) of people affected with MS, the risk of developing the disorder is sevenfold higher than in the general population, but familial excess lifetime risk is only 2.5–5%.[34]

Different variants of genes normally found in the general population, commonly referred to as polymorphisms, may lead to different gradations of cellular expression of those genes and therefore of the proteins that they encode. With MS susceptibility, it may be that a polymorphism within the promoter region of a gene involved in immune reactivity generates an exaggerated response (eg, elevated expression of a proinflammatory gene) to a given antigen, leading to uncontrolled immune cell proliferation and autoimmunity.

Research on single-nucleotide polymorphisms (SNPs) that confer risk of more severe disease or of developing particular forms of MS will be of great interest to the clinicians treating this complex disorder in the early stages. To date, however, HLA-DRB1 is the only chromosomal locus that has been consistently associated with MS susceptibility. Multiple other polymorphisms that may act in concert to predispose to MS have been described with genome-wide approaches, but their individual contribution to risk is not nearly as high as the risk conferred by the HLA locus.[35]

Genes that instead of conferring susceptibility to MS confer relative protection against it are also being investigated, and clues are emerging from within the major histocompatibility complex (MHC) region. For example, it has been suggested that the HLA-C*05 allele confers protection against MS.[36]

Molecular mimicry has been proposed as an etiologic process in MS. The molecular mimicry hypothesis refers to the possibility that T cells in the peripheral blood may become activated to attack a foreign antigen and then erroneously direct their attack toward brain proteins that share similar epitopes.

Viral infection

Another hypothesis is that a virus may infect the immune system, activating self-reactive T cells (myelin reactive) that would otherwise remain quiescent. A virus that infects cells of the immune and nervous systems can possibly be reactivated periodically and thus lead to acute exacerbations in MS.

Epstein-Barr virus (EBV) infection has been found to become periodically reactivated, but a possible causative role in MS has been difficult to prove. Evidence supporting EBV infection as an etiologic factor includes (1) long-term studies showing a higher association with MS in individuals with early presence of serum antibodies against specific EBV antigens and (2) high expression of EBV antigens within MS plaques.[37]

Evidence that argues against an etiologic role for EBV infection includes the fact that MS is a highly heterogeneous disease; EBV might help trigger some cases but not others, making associations in populations difficult. In addition, it is possible that EBV reactivation is an effect rather than a cause (ie, instead of viral reactivation being the trigger for MS, reactivation might be an epiphenomenon of a dysregulated immune system).

Environmental factors

Geography is clearly an important factor in the etiology of MS. The incidence of the disease is lower in the equatorial regions of the world than in the southernmost and northernmost regions. However, a systematic review by Alonso and Hernán found that this latitude gradient became attenuated after 1980, apparently due to an increased incidence of MS in lower latitudes.[38]

Apparently, whatever environmental factor is involved must exert its effect in early childhood. If an individual lives in an area with low incidence of MS until age 15 years, that person's risk remains low even if the individual subsequently moves to an area of high incidence.

On the other hand, certain ethnic groups (eg, Eskimos), despite living in areas of higher incidence, do not have a high frequency of MS. Therefore, the exact role played by geography versus genetics is not clear.

Vitamin D levels

Low levels of vitamin D have been proposed as one environmental factor contributing to the development of MS. Vitamin D has a role in regulating immune response, by decreasing production of proinflammatory cytokines and increasing production of anti-inflammatory cytokines; also, high circulating levels of vitamin D appear to be associated with a reduced risk of MS.[39]

Thus, lower vitamin D levels due to lower sunlight exposure at higher latitudes may be one reason for the geographic variations in MS incidence, and the protective effect of traditional diets high in vitamin D could help explain why certain areas (eg, Norway) have a lower incidence of MS despite having limited sunlight.[40] This hypothesis would also provide an explanation for the correlation between childhood sun exposure and MS in monozygotic twins discordant for MS.[41]

Chronic cerebrospinal venous insufficiency

A controversial hypothesis proposes a vascular rather than an immunologic cause for some cases of MS. In 2008, Paolo Zamboni described an association between MS and chronic cerebrospinal venous insufficiency (CCSVI).[42]

The CCSVI hypothesis posits that stenosis of the main extracranial venous outflow pathways results in compromised drainage and a high rate of cerebral venous reflux. The CCSVI hypothesis has been linked with the potential effects of iron deposition in the brain parenchyma, which some authors suggest is modestly to strongly predictive of disability progression, lesion volume accumulation, and atrophy in some patients with MS.[43, 44]

A small, open-label study suggested that internal jugular vein and azygous vein angioplasty had a positive effect on MS symptoms in patients with CCSVI.[45] A meta-analysis found a positive association between CCSVI and MS, but poor reporting of the success of blinding and marked heterogeneity among studies of CCSVI precluded definitive conclusions.[46]

Because of the potential danger of such experimental procedures in treating this unproven vascular condition, the US Food and Drug Administration (FDA) has issued a warning. See FDA issues alert on potential dangers of unproven treatment for multiple sclerosis.

Given the paucity of supporting evidence, most MS experts also question the CCSVI hypothesis and do not recommend this therapy. Nevertheless, CCSVI has received widespread attention in the lay press and MS support groups, so physicians should be prepared for inquiries from patients on this highly controversial subject.

Hepatitis B vaccine

Worldwide anecdotal reports suggesting a connection between hepatitis B vaccination and MS prompted the US Centers for Disease Control and Prevention (CDC) to investigate this possibility. The CDC concluded that the weight of the available scientific evidence does not support the suggestion that hepatitis B vaccine causes or worsens MS.[47]

On the basis of the CDC findings, a National Multiple Sclerosis Society expert panel concluded as follows: “People with MS should not be denied access to health-preserving and potentially-life saving vaccines because of their MS, and should follow the CDC guidelines for any given vaccine.”[48]

Epidemiology

United States statistics

Prevalence estimates for MS in the United States vary from 58 to 95 per 100,000 population.[49] According to the National Multiple Sclerosis Society, 400,000 individuals in the United States are affected by MS.[50] Misdiagnosis is common, however.

As is true of autoimmune diseases in general, MS is more common in women. The female-to-male ratio of MS incidence has increased since the mid-20th century, from an estimated 1.4 in 1955 to 2.3 in 2000.[38] MS is usually diagnosed in persons aged 15–45 years; however, it can occur in persons of any age. The average age at diagnosis is 29 years in women and 31 years in men.

International statistics

Worldwide, approximately 2.1 million people are affected by MS. The disease is seen in all parts of the world and in all races, but rates vary widely.[50] In general, the prevalence of MS tends to increase with latitude (eg, lower rates in the tropics, higher rates in northern Europe), but there are many exceptions to this gradient (eg, low rates among Chinese, Japanese, and African blacks; high rates among Sardinians, Parsis, and Palestinians).

The presence of these exceptions implies that racial and ethnic differences affect risk. In addition, a substantial increase in MS incidence has been reported from different regions, suggesting that environmental factors, as well as geographic and genetic ones, play an important role in MS.[51] (See Etiology.)

Epidemiologic studies indicate an increase in MS prevalence in Latin America. Susceptibility to MS and clinical behavior of the disease varies genetically in Latin America; for example, MS apparently does not occur in Amerindians with Mongoloid genes.[52]

Prognosis

If left untreated, more than 30% of patients with MS will develop significant physical disability within 20–25 years after onset. Several of the disease-modifying agents used in MS have slowed disability progression within the duration of research trials; whether these effects will be maintained over longer periods is not known.

Less than 5–10% of patients have a clinically milder MS phenotype, in which no significant physical disability accumulates despite the passage of several decades after onset (sometimes in spite of multiple new lesions seen on MRI). Detailed examination of these patients in many instances reveals some degree of cognitive deterioration.

Male patients with primary progressive MS have the worst prognosis, with less favorable response to treatment and rapidly accumulating disability. The higher incidence of spinal cord lesions in primary progressive MS is also a factor in the rapid development of disability.

Life expectancy is shortened only slightly in persons with MS, and the survival rate is linked to disability. Death usually results from secondary complications (50–66%), such as pulmonary or renal causes, but can also be due to primary complications, suicide, and causes unrelated to MS. The Marburg variant of MS is an acute and clinically fulminant form of the disease that can lead to coma or death within days.

Patient Education

Patients should be educated on the purposes of medications, doses, and the management of adverse effects. Patients and caregivers need education on appropriate management of problems related to pain, fatigue, and spasticity, as well as on issues related to bowel, bladder, and sexual function. For patients with advanced disease, caregivers need hands-on training in transfer techniques, as well as in management of skin integrity, bowel programs, and urinary collection devices.

Patients with MS report a high incidence of falling. Contributing factors are similar to those in other populations with neurologic diseases. Patients with MS can benefit from receiving information about preventing falls from their healthcare practitioner.[53]

To ensure a successful outcome, family members and caregivers should be included in any education provided. Community agencies, such as the state chapters of the National Multiple Sclerosis Society, can provide valuable information concerning community resources, as well as social support and education.

Patients may benefit from referral to comprehensive and professional organizations and Web sites that are dedicated to MS. Among these, the National Multiple Sclerosis Society is highly recommended for information on current hypotheses, ongoing research, general resources, and educational programs. Other highly recommended MS-related Web sites include MultipleSclerosis.com and The Consortium of Multiple Sclerosis Centers.

For patient education information, see the Brain & Nervous System Center.

 

Presentation

History

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

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.[54]

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

Fatigue is one of the most common symptom of MS, reported by at least 75% of patients with the disease.[55] 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 B12, folic acid, vitamin D deficiency) or thyroid disease, before attributing fatigue to MS.

Spasticity

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

  • Attention

  • Memory

  • Visual perception

  • Planning

  • Problem solving

  • Executive function (ability to correctly follow sequential steps)

  • Abstract reasoning

Pain

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.

Heat intolerance

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.

Physical Examination

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:

  • Reflexes

  • Coordination

  • Bulbar function

  • Vision

  • Gait

  • Skin

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.[56] 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

  • Vitreitis

  • 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.[56] 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.[56] 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.[54] 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.

Clinical Rating Scales

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.[57]

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:

  • Pyramidal

  • Cerebellar

  • Brainstem

  • Sensory

  • Bladder and bowel

  • Vision

  • Cerebral

  • Other

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.

Criteria for Categorizing MS

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:[58, 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).

MRI of the head of a 35-year-old man with relapsin 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 relapsin 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.

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.[59]

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.

 

DDx

Diagnostic Considerations

A common misconception is that any attack of CNS demyelination means a diagnosis of acute multiple sclerosis (MS). When a patient has a first attack of demyelination, the physician should not rush to diagnose MS, because the differential diagnosis includes a number of other diseases.

Clinicians who specialize in MS commonly see patients referred for multiple, ill-defined, vague complaints and T2 hyperintense lesions on recent head or spinal magnetic resonance imaging (MRI) scans. Careful questioning in these cases reveals that symptoms have been stereotyped and vague or are consistent with other disorders (eg, scintillating scotomas in a patient with concomitant migraines, or hand symptoms consistent with carpal tunnel syndrome). A history of meningoencephalitis during childhood occasionally emerges.

Another common problem is the presence of small T2 hyperintensities on MRI studies of the CNS, typically referred to as unidentified bright objects (UBOs) by neuroradiologists. These nonspecific lesions are relatively common in the general adult population, and clinical correlation (ie, a high degree of suspicion based on clinical evidence) becomes important in the diagnosis. To confirm MS in these cases, the physician should look for sites of involvement that are rare for UBOs but frequent for MS (eg, the corpus callosum or throughout the spinal cord).

The main differential diagnoses for MS include, but are not limited to, the following:

  • Spinal cord neoplasms (eg, astrocytomas, ependymomas)

  • Acute disseminated encephalomyelitis (ADEM)

  • Schilder disease

  • Baló concentric sclerosis

  • Sarcoidosis

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

  • Transverse myelitis

  • Infarction of the spinal cord

  • Vasculitis

  • Radiation myelitis

  • Arteriovenous fistula

  • Progressive multifocal leukoencephalitis

  • Subacute combined degeneration of the spinal cord (vitamin B12 deficiency)

  • Small-vessel ischemic disease (affecting the brain primarily, and caused by diseases with vascular risk factors, such as diabetes, hypertension, hyperlipidemia, old age)

Spinal cord neoplasms

Both primary and metastatic spinal cord neoplasms must be considered in the differential diagnosis of MS. On imaging studies, the presence of cysts and hemorrhage support the diagnosis of neoplasm.

ADEM

ADEM is considered an isolated postinfectious or postvaccination autoimmune attack on the CNS that leads to diffuse demyelination. ADEM is characterized by acute onset of motor, sensory, cerebellar, and cranial nerve dysfunction with encephalopathy, progressing to coma and eventual death in 30% of cases. Occasionally, ADEM has a fulminant hemorrhagic component, in which case it is termed acute hemorrhagic encephalomyelitis or leukoencephalitis of Weston Hurst.

MRI of the brain may be helpful for showing additional lesions in cases of MS or ADEM. This condition usually responds to steroid therapy; therefore, a treatment trial is often considered before proceeding with biopsy. This process is typically monophasic.

Schilder disease

Schilder disease is characterized in children and young adolescents by massive demyelination, presenting often as asymmetrical foci (often the size of an entire lobe) in the white matter on MRI and with a malignant course (ie, deterioration over months or a few years, with cortical blindness, hemiplegia, or paraplegia). Some patients, however, may respond to steroids and immunosuppressive therapy.

Baló concentric sclerosis

Baló concentric sclerosis is considered by some authors to be a variant of Schilder disease, with MRI lesions showing a characteristic alternating pattern of spared and damaged white matter that suggests progression of the disease process from the ventricles outward. Baló concentric sclerosis is often associated with more inflammatory cerebrospinal fluid (CSF) findings and a more fulminant progression than typical MS.

Sarcoidosis

Sarcoidosis involves the CNS in approximately 5% of cases. Concomitant pial involvement is frequently encountered. Gadolinium enhancement of the pia and white matter lesions on MRI is usually the rule.

CADASIL

CADASIL is an autosomal dominant disease affecting small and middle-sized brain blood vessels and characterized by recurrent headaches and strokes or transient ischemic attacks. Mutations in the Notch 3 gene can be demonstrated with current laboratory techniques. In young people with CADASIL who have multiple white matter lesions, CADASIL may be misdiagnosed as MS. Classical CADASIL hyperintense lesion localizations by MRI include frontal and temporal lobes, and deep gray matter (basal ganglia and thalamus). A family history of headaches and strokes should prompt a diagnostic workup for CADASIL.

Transverse myelitis

Transverse myelitis is the term usually used for idiopathic inflammatory myelopathy. Swelling and enhancement of the spinal cord may be evident on MRI, often affecting a longer segment than the typical involvement seen with partial myelitis in MS. This also needs to be distinguished from the longitudinally extensive transverse myelitis seen in Devic disease, classically involving multiple spinal cord levels with a linear trajectory.

Infarction of the spinal cord

Infarction of the spinal cord is more common at the thoracic level. Usually, only a single lesion is present. Contrast may be present, although this is not the dominant feature. Signal alteration usually and initially involves the anterior gray matter (anterior spinal artery distribution). The patient's clinical presentation will be acute. Particularly consider this entity if the patient is older and/or has a history of aortic/vascular surgery.

Vasculitic processes

Vasculitic processes such as systemic lupus erythematosus can result in spinal lesions that mimic MS. Often, multiple lesions are present. However, the clinical history is often known and helps to establish the correct diagnosis.

Radiation myelitis

Radiation myelitis generally occurs only in patients who have received doses higher than 4000 cGy. However, chemotherapy may be synergistic (ie, may lead to radiosensitization, triggering myelitis at lower radiation doses). The latency period is 1-3 years. Images may show some peripheral enhancement.

Arteriovenous fistula

Arteriovenous fistula usually occurs at the thoracolumbar level, and patients are usually older than 50 years, with a long history of back pain. The cord signal abnormality can involve a very long segment. Look for a serpiginous flow void along the cord surface.

Differential Diagnoses

 

Workup

Approach Considerations

Multiple sclerosis (MS) is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests, such as magnetic resonance imaging (MRI) of the brain and spinal cord and cerebrospinal fluid examination. Clinically, the attack must be compatible with the pattern of neurologic deficits seen in MS, which typically means that the duration of deficit is days to weeks.

Traditionally, MS could not be diagnosed after only a single symptomatic episode, as diagnosis required repeat attacks suggesting the appearance of lesions separated in time and space. In the past, treating physicians were content to "sit back and watch" after a single episode, as it was assumed the disease would "declare" itself. The 2017 McDonald criteria (see Table 1, below) allow diagnosis of MS even with a first clinical episode.[1]

Early diagnosis is important because there is growing evidence that early intervention is useful. It is known through the work of Trapp et al. that axonal loss can be present, even in asymptomatic patients, early in the disease process.[60] In addition, studies in patients with a first attack of neurologic symptoms suggestive of MS have demonstrated decreased disability and lower secondary relapse rates with interferon treatment.

McDonald Criteria for MS Diagnosis

The McDonald criteria, which were developed in 2001 by an international expert panel and revised several times, most recently in 2017, provide recommendations on the diagnosis of MS, including diagnosis after a single attack.[1] The criteria consist of a combination of clinical, imaging, and paraclinical tests (ie, CSF, evoked potentials).[4] (See Table 1, below.) 

Table 1. 2017 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis [1] (Open Table in a new window)

Clinical Presentation

Additional Data Needed for MS Diagnosis

  • Two or more attacks

  • Objective clinical evidence of 2 or more lesions with reasonable historical evidence of a prior attack

None; clinical evidence will suffice. Additional evidence (eg, brain MRI) desirable,

but must be consistent with MS

  • Two or more attacks

  • Objective clinical evidence of 1 lesion

Dissemination in space demonstrated by MRI or

Await further clinical attack implicating a different site

  • One attack

  • Objective clinical evidence of 2 or more lesions

Dissemination in time demonstrated by

MRI or second clinical attack or demonstration of CSF-specific oligoclonal bands

  • One attack

  • Objective clinical evidence of 1 lesion (clinically isolated syndrome)

Dissemination in space demonstrated by

MRI or await a second clinical attack implicating a different CNS site

and

Dissemination in time, demonstrated by MRI or second clinical attack

· Insidious neurologic progression suggestive of MS

One year of disease progression and dissemination in space, demonstrated by 2 of the following:

  • One or more T2 lesions in brain, in regions characteristic of MS

  • Two or more T2 focal lesions in spinal cord

  • Positive CSF

Notes: An attack is defined as a neurologic disturbance of the kind seen in MS. It can be documented by subjective report or by objective observation, but it must last for at least 24 hours. Pseudoattacks and single paroxysmal episodes must be excluded. To be considered separate attacks, at least 30 days must elapse between onset of one event and onset of another event.

Key changes made to the McDonald Criteria in 2017 include the following:

  • Brain stem and cord lesions can now be counted among the 2 lesions disseminated in space and time.
  • CSF oligoclonal bands can now be used to substitute for demonstration of dissemination in time in some settings.
  • Both asymptomatic and now symptomatic MRI lesions can be considered in determining dissemination in space (optic nerve lesions are still excluded).
  • Cortical lesions have been added to juxtacortical lesions as determinant for dissemination in space.

Blood Studies

Results of blood studies are usually normal in MS patients. Perform blood work to help exclude conditions such as the following:

  • Collagen vascular disease and other rheumatologic conditions

  • Infections (ie, Lyme disease, syphilis)

  • Endocrine abnormalities (eg, thyroid disease)

  • Vitamin B12 deficiency

  • Sarcoidosis

  • Vasculitis

Neuromyelitis optica (NMO, or Devic disease) can be confirmed by the presence of serum antibodies against aquaporin 4, a water channel expressed at major fluid-tissue barriers across the CNS.[33]

In patients with movement disorders and ocular manifestations, copper studies may be useful. Wilson disease has been misdiagnosed as MS.[61]

Magnetic Resonance Imaging

Although MRI alone cannot be used to diagnose MS, it remains the imaging procedure of choice for confirming MS and monitoring disease progression in the brain and spinal cord. MRI is not specific, but it is considered the most sensitive imaging modality for diagnosing spinal cord MS, for evaluating its extent, and for following up the response to treatment.[62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72]

The Consortium of Multiple Sclerosis Centers (CMSC) revised its MRI protocol and guidelines in 2015. The revised guidelines recommend using higher-resolution three-dimensional (3D) imaging over two-dimensional (2D) imaging whenever possible. More frequent scanning is recommended to monitor for progressive multifocal leukoencephalopathy in patients taking natalizumab.[73]

MRI is more sensitive for identifying active plaques than is double-dose computed tomography (CT) scanning or clinical examination. MRI far exceeds CT scanning in the ability to demonstrate intramedullary pathology.[74]

MRI shows brain abnormalities in 90-95% of MS patients and spinal cord lesions in up to 75%, especially in elderly patients.[75] T2-weighted images show edema and more chronic lesions, whereas T1-weighted images demonstrate cerebral atrophy and "black holes." These black holes represent areas of axonal death.

According to new research, monitoring levels of iron in specific areas of the brain in patients with MS by using novel MRI may track disease progression and assess treatment efficacy in clinical trials. In the study, a new technique known as quantitative susceptibility mapping (QSM) identified different iron patterns in the brains of patients with MS (N=600) compared with healthy controls (N=250). Patients with MS had lower iron content in the thalamus and higher iron content in other deep gray-matter structures compared with controls.[76]

One of the limitations of using MRI in patients with MS is the discordance between lesion location and the clinical presentation. In addition, depending on the number and location of findings, MRI can vary greatly in terms of sensitivity and specificity in the diagnosis of MS.

A subset of patients with MS experiences minimal clinical impairment despite significant lesions on MRI. Functional MRI (fMRI) studies detects changes in blood flow related to energy use by brain cells; fMRI studies suggest that increased cognitive control recruitment in the motor system may limit the clinical manifestations of the disease in such cases.[77]

MR spectroscopy is another MRI-based technique that detects a “spectrum” of chemical shifts; this technique appears capable of depicting changes in white matter that are not detected with routine pulse sequences. Because the findings could be correlated with disability scores, the use of MR spectroscopy may prove valuable in monitoring patients after treatment and in formulating their prognosis.[78, 79, 80, 81]

For more information, see Brain Imaging in Multiple Sclerosis and Spine Imaging in Multiple Sclerosis.

Other Imaging Studies in Multiple Sclerosis

The advent of MRI has limited the role of CT and radiography in the diagnosis and treatment of MS. Occasionally, plain radiographs may be used to exclude mechanical bony lesions.

Angiography also has a limited role, but may occasionally be considered when CNS vasculitis is part of the differential diagnosis in a patient with undifferentiated findings. No positive angiographic findings are specific to MS.

Ultrasonography is not currently used in the investigation of MS. However, Berg et al used transcranial ultrasonography to determine the size of the ventricles in patients with MS and found that increasing ventricular size is correlated with the MRI-determined brain volume, as well as with cognitive dysfunction and clinical disability.[82] Further studies may establish a role for ultrasonography in determining the prognosis and guiding treatment of patients with MS.[83]

Evoked Potentials

Evoked potentials (ie, recording of the timing of CNS responses to specific stimuli) can be useful neurophysiologic studies for evaluation of MS. These tests, which are used to identify subclinical lesions but which are nonspecific for MS, include the following:

  • Visual evoked potentials (VEPs)

  • Somatosensory evoked potentials (SSEPs)

  • Brainstem auditory evoked potentials (BAEPs)

VEPs are performed by having a patient focus on a reversing black-and-white checkerboard pattern. Delays in latencies indicate demyelination in the anterior visual pathways. VEPs are not typically necessary for patients with clear clinical evidence of optic neuritis (ON).

SSEPs evaluate the posterior column of the spinal cord, the brainstem, and the cerebral cortex. Delays in latencies of various peaks indicate demyelination in the correlated pathway of the spinal cord or brain.

BAEPs are performed to evaluate ipsilateral asymptomatic MS lesions in the auditory pathways. They are less sensitive than VEPs and SSEPs.

Electroencephalography

Electroencephalographic results have been found to be outside the reference range in some patients with MS, but the findings are nonspecific. Nonspecific electroencephalographic abnormalities can also be seen in normal individuals in the general population. A small study by Vazquez-Marrufo et al found that on quantitative electroencephalography, benign MS and relapsing-remitting MS produce different physiologic profiles.[84]

Lumbar Puncture

Lumbar puncture with CSF analysis is no longer routine in the investigation of MS, but this test may be of use when MRI is unavailable or MRI findings are nondiagnostic. CSF is evaluated for oligoclonal bands (OCBs) and intrathecal immunoglobulin G (IgG) production, as well as for signs of infection.

OCBs are found in 90-95% of patients with MS, and intrathecal IgG production is found in 70–90% of patients. Although these findings are not specific for MS, CSF analysis is the only direct test capable of proving that the patient has a chronic inflammatory CNS condition.

 

Treatment

Approach Considerations

Treatment of multiple sclerosis (MS) has 2 aspects: immunomodulatory therapy (IMT) for the underlying immune disorder and therapies to relieve or modify symptoms. IMT is directed toward reducing the frequency of relapses and slowing progression. Currently, most disease-modifying agents have been approved for use only in relapsing forms of MS. Mitoxantrone (see below) is also approved for the treatment of secondary (long-term) progressive and progressive relapsing MS.

Although therapy for clinically isolated syndrome (CIS) (a single episode of neurologic symptoms) with immunomodulatory medications has not yet become standard practice throughout the world, trials such as the TOPIC trial suggest that early intervention may be appropriate. Decisions regarding early treatment of relapsing MS can be guided by using the McDonald diagnostic criteria.

Results from the multicenter TOPIC trial provide evidence that treatment of clinically CIS with the drug teriflunomide delays conversion to MS.[85] Patients with CIS have a high likelihood of developing MS.

In the study, 618 patients were treated either with teriflunomide in doses of 14 mg or 7 mg per day or placebo.[85] Patients were included if they experienced a first acute or subacute well-defined neurologic event consistent with demyelination, onset of MS symptoms within 90 days of randomization, and MRI showing 2 or more characteristics of MS. During 2 years of treatment, patients receiving 14 mg of teriflunomide experienced a 43% reduction in the risk for conversion to clinically definite MS compared with placebo. Patients who received 7 mg of the drug per day had a 37% reduction in the risk for conversion vs placebo.[85]

Given the wide spectrum of clinical manifestations that MS can produce, patients may require consultations with a variety of specialists. Indeed, patients with MS are often best served by a multidisciplinary approach.

Emergency Department Management

Medical management goals that are sometimes achievable in the emergency department are to relieve symptoms and to ameliorate risk factors associated with an acute exacerbation. In patients with fulminant MS or disseminating acute encephalitis, management involves the following:

  • Stabilize acute life-threatening conditions

  • Initiate supportive care and seizure precautions

  • Monitor for increasing intracranial pressure

Consider intravenous steroids, IV immunoglobulin (IVIG), or emergent plasmapheresis. One study suggested that plasmapheresis may be superior to IV steroids in patients with acute fulminant MS.[86] The 2011 American Academy of Neurology (AAN) plasmapheresis guideline update states that plasmapheresis is possibly effective and may be considered in acute fulminant demyelinating CNS disease.[5]

Identification and control of known precipitants of MS exacerbation include the following:

  • Aggressively treat infections with antibiotics

  • In patients with a fever, normalize the body temperature with antipyretics, as even small increases in temperature can strongly affect conduction through partially demyelinated fibers

  • Provide urinary drainage and skin care, as appropriate

Preoperative considerations for emergency surgery in patients with fulminant MS are as follows:

  • Gastric emptying may be delayed secondary to autonomic GI dysfunction

  • Lability of the autonomic nervous system may precipitate hypotension during anesthesia and surgery

  • Spontaneous ventilation may be disrupted

Treatment of Acute Relapses

Methylprednisolone (Solu-Medrol) can hasten recovery from an acute exacerbation of MS. There is no clear evidence that it changes the overall disease progression.

Plasma exchange (plasmapheresis) can be used short term for severe attacks if steroids are contraindicated or ineffective. The 2011 AAN guideline for plasmapheresis in neurological diseases categorizes plasmapheresis as “probably effective” as second-line treatment for relapsing MS exacerbations that do not respond to steroids.[5]

Texts commonly describe anti-inflammatory treatment as an option for acute transverse myelitis and acute disseminated encephalitis; however, not many supporting data are given. Dexamethasone is commonly used. Anti-inflammatory treatment for ON is very controversial.

Immunomodulatory Therapy for Relapsing-Remitting MS

Disease-modifying therapies have shown beneficial effects in patients with relapsing MS, including reduced frequency and severity of clinical attacks. These agents appear to slow the progression of disability and the reduce accumulation of lesions within the brain and spinal cord. The disease-modifying agents for MS (DMAMS) currently approved for use by the US Food and Drug Administration (FDA) include the following:

  • Interferon beta-1a (Avonex, Rebif)[6]

  • Interferon beta-1b (Betaseron, Extavia)[7]

  • Peginterferon beta-1a (Plegridy)[8]

  • Glatiramer acetate (Copaxone)[9]

  • Natalizumab (Tysabri)[10, 11]

  • Mitoxantrone[12]

  • Fingolimod (Gilenya)[13]

  • Siponimod (Mayzent)[14]

  • Teriflunomide (Aubagio)[15]

  • Dimethyl fumarate (Tecfidera)[16, 17, 18, 19]

  • Alemtuzumab (Lemtrada)[20, 21, 22]

  • Ocrelizumab (Ocrevus)[23, 24]

  • Cladribine (Mavenclad)[25, 26]

Fingolimod, siponimod, cladribine, teriflunomide, and dimethyl fumarate are administered orally; natalizumab, ocrelizumab, and mitoxantrone are administered by intravenous infusion; interferon beta-1a (Avonex) is administered intramuscularly; and interferon beta-1a (Rebif), interferon beta-1b, and glatiramer acetate are administered by subcutaneous injection. 

Note that in January 2013, the FDA approved a single-use autoinjector (Rebidose, EMD Serono Inc./Pfizer Inc) for self-injection of interferon beta-1a (Rebif) in patients with relapsing forms of MS.[27] The ease of use, patient satisfaction and acceptability, and functional reliability of the Rebidose are supported by data from a 12-week open-label, single-group study in 109 patients. The autoinjector is available in a monthly pack in 22 and 44 μg doses and in a titration pack.[27]

Patient lifestyle, patient tolerance, and adverse effects of injections should be considered in the choice of DMAMS. To a certain extent, health-care-provider preference and experience with the medications also play a role in determining which drug is appropriate in a particular situation.

A case-control study from the MSBase longitudinal cohort found that MS patients who are well controlled on injectable drugs but switch to oral therapies aren't at greater risk of early relapse. This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. Results showed there were no differences in the rate of first relapse or disability progression over the first 6 months.[87]

Interferon beta-1b therapy

The first medication approved by the FDA for MS, in 1993, was interferon beta-1b (Betaseron, Extavia). It is indicated for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. It has shown efficacy in patients who have experienced a first clinical episode of MS and have MRI features consistent with MS.[7]

In a double-blind, placebo-controlled trial of 372 patients with relapsing-remitting MS, interferon beta-1b (8 million IU every other day) decreased the frequency of relapses by 34% after 2 years. In treated patients, the MRI T2 lesion burden increased 3.6% over 5 years, compared with 30.2% in the placebo group. At 5 year follow-up, the incidence of disease progression was lower in the interferon beta-1b group compared with the placebo group (35% versus 45%).[88]

Interferon beta-1b is administered every other day subcutaneously by self-injection. The most frequently reported adverse reactions include asthenia, depression, flu-like symptoms, hypertonia, increased liver enzymes, injection site reactions, leukopenia, and myasthenia. Interferon beta-1b can be coadministered with analgesics or antipyretics to help with the occurrence of flu-like symptoms.[7]

Interferon beta-1a (Avonex or Rebif) therapy

In a study of 301 patients with relapsing-remitting disease who were given weekly intramuscular injections (6 million U [30 µg]) of interferon beta-1a (Avonex), the annual exacerbation rate decreased 29%.[89] Over 2 years, disease progression occurred in 21.9% of patients in the interferon beta-1a group and 34.9% of those in the placebo group. In addition, MRI data showed a decrease in the mean lesion volume and number of enhancing lesions in the interferon beta-1a group.

In Europe and Canada, higher doses of subcutaneous interferon beta-1a (Rebif) were studied in the Prevention of Relapse and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) Study.[90] The dose-comparison study of interferon beta-1a reported a 27% reduction in the relapse rate in patients receiving 66 µg/wk and a 33% reduction in those receiving 132 µg/wk. This study, of 560 patients with relapsing-remitting disease, also demonstrated a significant reduction in accrual of disability and MRI lesion burden with the higher dose.[90]

In 2002, the FDA approved interferon beta-1a (Rebif) in 22 µg and 44 µg formulations given 3 times per week.

In the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial, which compared 2 preparations of interferon beta-1a (Rebif and Avonex), relapse occurred less frequently with 44 µg 3 times weekly (Rebif) than with 30 µg once weekly (Avonex) (25% vs 37%).[91] In addition, the mean number of active unique MRI lesions per patient per scan was lower in the Rebif than in the Avonex group (0.17 vs 0.33). Patients on Rebif experienced fewer flulike symptoms, but more injection site reactions, hepatic function disorders, and white blood cell disorders. Rebif-treated patients had a higher incidence of neutralizing antibodies (Nabs). A reduced MRI effect was noted for Nab-positive patients on Rebif compared with Nab-negative patients on Rebif. However, Nab-positive Rebif patients had better clinical and comparable MRI results to Avonex patients.[91]

In a subsequent crossover phase of the EVIDENCE trial, patients who were originally randomized to low-dose weekly treatment were switched to the high-dose 3-times-weekly regimen for an additional 8 months. These patients demonstrated significant reductions in mean relapse rates compared with the last 6 months on Avonex (P< .001).[92]

In patients with uncontrolled depression, interferons should be used with caution. Glatiramer may be an appropriate choice in such cases.

Peginterferon beta-1a

Peginterferon beta-1a (Plegridy) was approved by the FDA in August 2014 for treatment of relapsing forms of MS. It is the first pegylated interferon approved for MS and can be self-administered by SC injection every 2 weeks.[8]

Approval was based on results from the ADVANCE trial of >1,500 patients with MS over a 2-year period. In the first year of the trial, peginterferon beta-1a dosed every 2 weeks significantly reduced annualized relapse rate (ARR) at 1 year by 36% compared with placebo (P = 0.0007). Risk of 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale, was also reduced with peginterferon beta-1a by 38% (P = 0.0383) compared with placebo. Peginterferon beta-1a also significantly reduced the number of new gadolinium-enhanced [Gd+] lesions by 86% (P< 0.0001) and reduced new or newly enlarging T2-hyperintense lesions by 67% (P< 0.0001) compared with placebo.[8]

Glatiramer acetate

Glatiramer acetate (Copaxone) is a synthetic polypeptide approved for the reduction of the frequency of relapses in patients with relapsing-remitting MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. Glatiramer acetate’s mechanism of action is unknown, but this agent could theoretically modify some of the immune processes thought to be involved in the pathogenesis of MS.[9]

In a double-blind trial that included 251 patients with relapsing-remitting MS (RRMS), treatment with glatiramer acetate 20 mg SC once daily resulted in a 29% reduction in the relapse rate over 2 years; a positive effect on disability was suggested but this effect was not shown on predetermined disability measures in this trial.[93] For this reason, glatiramer acetate is not approved by the FDA for slowing disability progression in MS. A follow-up open-label study demonstrated continued efficacy of glatiramer over 6 years.[94]

In January 2014, a higher dose and lower-frequency dosage regimen of glatiramer was approved. The 20-mg/mL SC injection is specific for the original once-daily regimen, whereas the new 40-mg/mL SC injection is specific for the 3-times-per-week dosage regimen. Approval for the new regimen was based on the phase 3 Glatiramer Acetate Low-Frequency Administration (GALA) study. The GALA trial included 1,404 patients and showed that treatment with 40 mg SC 3 times/wk reduced mean annualized relapse rates by 34% compared with placebo (0.331 vs 0.505; P< .0001) at 12 months.[95]

Natalizumab

Natalizumab (Tysabri) is a humanized monoclonal antibody that binds to the adhesion molecule alpha-4 integrin, inhibiting its adherence to its receptors. Natalizumab is indicated as monotherapy for the treatment of patients with relapsing forms of MS, to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. It is generally used in patients who have not responded to a first-line disease-modifying therapy or who have very active disease.[11]

In a placebo-controlled clinical trial, the use of natalizumab reduced the relapse rate (68%) and progression of disability (42%) over a period of 2 years.[96] Natalizumab is given as a 300 mg IV infusion over 1 hour every 4 weeks.

Natalizumab has been associated with progressive multifocal leukocephalopathy (PML), an opportunistic infection of the brain that can lead to death or severe disability. The risk of PML seems to increase with a history of previous immunosuppression, duration of exposure to natalizumab beyond 2 years, and JC virus antibody positivity.

Three cases of PML associated with natalizumab use prompted its temporary withdrawal from the market in 2005; however, it was reapproved in 2006 by the FDA for commercialization under a special restricted distribution program known as Tysabri Outreach Unified Commitment to Health (TOUCH). Use of natalizumab is limited to patients, physicians, and infusion centers that are registered with the TOUCH program.

A retrospective review of 906 patients from 5 clinical trials by Cadavid et al found that after treatment with natalizumab, disabled patients with relapsing-remitting MS were more likely to complete a timed 25-foot walk significantly faster; responders took an average of 24–44% less time to walk 25 ft than nonresponders. Natalizumab also appeared to have some efficacy in disabled patients with SPMS.[97]

Sphingosine 1-phosphate receptor modulators

Fingolimod

Fingolimod (Gilenya) is the first oral disease-modifying treatment for relapsing forms of MS approved by the FDA. Like other disease-modifying agents for MS, fingolimod can reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. The recommended dosage for fingolimod is 0.5 mg once a day.[13]

Fingolimod is a novel compound produced by chemical modification of a fungal precursor. Its active metabolite, formed by in vivo phosphorylation, modulates sphingosine 1-phosphate receptors, which are a subset of a larger family of cell-surface, G protein–coupled receptors that mediate the effects of bioactive lipids known as lysophospholipids. Lysophospholipids are membrane-derived bioactive lipid mediators that can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis.

The mechanism of action of fingolimod is incompletely understood but appears to be fundamentally different from other MS medications. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Fingolimod promotes sequestration of lymphocytes within the lymph nodes, which may reduce lymphocyte migration into the central nervous system.[98]

Fingolimod can be associated with macular edema, pulmonary dysfunction, and cardiac adverse effects.

In 2012, the FDA determined that new label changes are required for fingolimod. Within an hour of administering fingolimod, heart rate decreases are noted. The nadir in heart rate typically occurs at 6 hours, but it can be observed up to 24 hours after the first dose in some patients. Because of its cardiac adverse effects, the first dose of fingolimod should be administered in a setting in which resources are available to appropriately manage symptomatic bradycardia. Therefore, all patients started on fingolimod must be monitored for at least 6 hours following the first dose. Additionally, an ECG should be performed prior to dosing fingolimod, blood pressure and pulse should be monitored hourly, and an ECG should be performed at the end of the observation period.

Additional observation beyond 6 hours should be instituted if bradycardia occurs and until the finding has resolved in the following situations: the heart rate 6 hours post dose is less than 45 beats per minute, the heart rate 6 hours post dose is the lowest value observed post dose, or the ECG 6 hours post dose shows new-onset second-degree or higher (atrioventricular) AV block.

Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first dose monitoring strategy (described above) should be repeated after the second dose of fingolimod.

Fingolimod is now contraindicated in patients with recent myocardial infarction, unstable angina, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or class III/IV heart failure; history or presence of Mobitz type II second- or third-degree AV block or sick-sinus syndrome, unless the patient has a functioning pacemaker; baseline QTc interval greater than or equal to 500 ms; or treatment with class Ia or class III antiarrhythmic drugs.

The following are recommendations for the use of fingolimod in patients with preexisting cardiovascular conditions:

  • Patients with some preexisting conditions (eg, ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, and sinoatrial heart block) may poorly tolerate the fingolimod-induced bradycardia or may experience serious rhythm disturbances after the first dose of fingolimod.

  • Prior to treatment, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such an evaluation, and, if treated with fingolimod, should be monitored overnight with continuous ECG in a medical facility after the first dose.

  • Since initiation of fingolimod treatment results in decreased heart rate and may prolong the QT interval, overnight continuous ECG monitoring is recommended in patients who have prolonged QTc interval before or during the 6-hour observation (>450 ms males, >470 ms females), are at higher risk for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome), are on concurrent therapy with drugs that prolong the QT interval, and have a known risk of torsades de pointes. The list of drugs associated with risk of torsades de pointes can be found at AzCERT (CredibleMeds).

The following are recommendations for the use of fingolimod with concomitant medications that slow the heart rate or AV conduction:

  • Experience is limited when coadministered with drugs that slow the heart rate or AV conduction (eg, beta-blockers, heart rate–lowering calcium channel blockers such as diltiazem, verapamil, or digoxin).

  • Because the initiation of fingolimod treatment is also associated with slowing of the heart rate, coadministration of other drugs that cause bradycardia may be associated with severe bradycardia or heart block.

  • The possibility to switch to drugs that do not slow the heart rate or AV conduction should be evaluated by the prescribing physician before initiating fingolimod. In patients who cannot switch, overnight continuous ECG monitoring is recommended after the first dose.

The reduction of peripheral lymphocyte count by fingolimod can possibly lead to an increased risk of infection. Reversible, asymptomatic elevations of liver enzymes may also occur. Other adverse reactions that have been commonly reported include headache, diarrhea, ALT/AST elevations and back pain.

If an MS patient is being switched from natalizumab to fingolimod oral therapy, a washout period of 8 weeks or less is advisable. In an observational cohort study involving 350 such patients, those with a washout time longer than 2 months had a higher risk of relapse; in a second study involving 142 patients, shorter washout periods of 8 or 12 weeks were associated with fewer active lesions and less disease recurrence than was a washout period of 16 weeks.[99, 100, 101]

Siponimod

Siponimod (Mayzent) is an oral S1p receptor modulator that was approved by the FDA in 2019. It is indicated for treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Approval was based on results of the phase 3 EXPAND trial, which randomly assigned 1651 patients with SPMS and an Expanded Disability Status Scale score of 3–6.5 to siponimod 2 mg once daily (1105 patients) or placebo (546 patients) for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression events. At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years and the mean time since conversion to SPMS was 3.8 years; 64% of patients had not relapsed in the previous 2 years, and 56% needed walking assistance.

The primary endpoint was time to 3-month confirmed disability progression. This occurred in 26% of the siponimod group and 32% of those receiving placebo (hazard ratio, 0.79; 95% confidence interval [CI], 0.65 - 0.95; relative risk reduction, 21%; P = .013). Siponimod also meaningfully delayed the risk of 6-month confirmed disability progression (26% vs placebo, p=0.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression.[14]

Cladribine

Cladribine gained FDA approval in 2019 for relapsing forms of MS, to include relapsing-remitting disease and active secondary progressive disease. Because of its safety profile, use is generally recommended for patients with inadequate response to, or inability to tolerate, an alternate MS drug therapy. 

The ORACLE MS trial (n=903) demonstrated that cladribine significantly delayed MS diagnosis compared with placebo (p < 0.0001) when initiated in patients following a first clinical demyelinating event.[25]  In the CLARITY study, cladribine treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening.[26]

Teriflunomide

Teriflunomide (Aubagio) was approved by the FDA in September 2012 for the treatment of patients with relapsing forms of MS (approved tablet forms are 7 mg and 14 mg). The prescribing information contains a black box warning for the risks of hepatotoxicity and teratogenicity (pregnancy category X). It is an oral pyrimidine synthesis inhibitor for treatment of relapsing forms of MS. Approval was based on a randomized trial (TEMSO) of 1088 patients with a minimum of 1 relapse in the previous year or 2 relapses in the last 2 years. Teriflunomide was shown to significantly reduce annualized relapse rates (31% relative risk reduction compared with placebo [P< .001]). It was also shown in the TEMSO trial to reduce disability progression at doses of 14 mg/day.[102] However, the FDA has not approved the use of teriflunomide to slow disability progression.

Phase III of the TEMSO study found that teriflunomide significantly slowed brain volume loss compared with placebo over 2 years in patients with relapsing MS. Data obtained from MRI were used to assess patients treated with 14 mg or 7 mg of the drug, or placebo. By month 12, median percent reduction from baseline in brain volume was 0.39, 0.40, and 0.61 for teriflunomide 14 mg, 7 mg, and placebo, respectively.[103]

The most common adverse reactions of teriflunomide are headache, alopecia, diarrhea, nausea, increased ALT, influenza, and paresthesias.

Teriflunomide can predispose to infections (due to a decrease in the white blood cell count that remains throughout treatment) and increases in blood pressure. To assess safety, it is recommended to obtain transaminase levels, bilirubin levels, and a CBC count within 6 months before initiation; screen for latent tuberculosis infection with a tuberculin skin test; and check the blood pressure before the first dose and periodically thereafter.

Teriflunomide is contraindicated in patients with severe hepatic impairment, patients who are pregnant or women of childbearing potential not using reliable contraception, or patients on current treatment with leflunomide. If liver injury occurs, teriflunomide should be immediately discontinued and an accelerated elimination procedure using either activated charcoal or cholestyramine should be initiated. Monitor liver tests weekly until normalized.

Upon discontinuing teriflunomide and based on the teratogenicity risk, it is recommended that all women of child-bearing potential undergo the accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to pose minimal risk. Without an accelerated elimination procedure, it takes teriflunomide on average of 8 months (and up to 2 y) to reach plasma concentrations less than 0.02 mg/L.

Teriflunomide or its parent compound, leflunomide, can also be associated with peripheral neuropathy and acute renal failure, hyperkalemia, hypophosphatemia, serious skin reactions, and interstitial lung disease.

Other trials for teriflunomide (TOWER) are completed (not yet published) or ongoing. Results from the TENERE study (n= 324) observed similar efficacy and safety between teriflunomide and interferon beta-1a for relapsing forms of MS.[104] Another study of teriflunomide added to beta interferon therapy is currently ongoing.[105]

Dimethyl fumarate

Dimethyl fumarate (DMF) is an oral Nrf2 pathway activator indicated for relapsing forms of MS. The active metabolite, monomethyl fumarate (MMF), activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a transcription factor encoded by the NFE2L2 gene.

FDA approval for DMF in adults with relapsing forms of multiple sclerosis[16, 17] was based on data from 2 phase 3 studies, the DEFINE[18] and CONFIRM[19] studies, that involved more than 2600 patients. An ongoing extension study (ENDORSE) includes some patients that have been followed for longer than 4 years.

In the DEFINE trial, dimethyl fumarate significantly reduced[18] : (1) the proportion of patients who relapsed by 49%, (2) the annualized relapse rate by 53%, and (3) the 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS), by 38% relative to placebo at 2 years. In the CONFIRM study, dimethyl fumarate significantly reduced the annualized relapse rate by 44% and the proportion of patients who relapsed by 34% compared with placebo at 2 years.[19] Although not statistically significant, dimethyl fumarate also showed a 21% reduction in the CONFIRM trial's 12-week confirmed disability progression.[19] Both studies also showed that dimethyl fumarate significantly reduced lesions in the brain relative to placebo, as measured by magnetic resonance imaging.[18, 19]

Alemtuzumab

Alemtuzumab (Lemtrada) was approved by the FDA in November 2014 for relapsing forms of multiple sclerosis. Because of the risk for severe autoimmune adverse effects, it is reserved for use in patients who have an inadequate response to 2 or more other drugs for MS. Alemtuzumab is a recombinant monoclonal antibody against CD52 (lymphocyte antigen). This action promotes antibody-dependent cell lysis.

Approval was based on 2 randomized Phase III open-label rater-blinded studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). In CARE-MS I, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates; the difference observed in slowing disability progression did not reach statistical significance.[20] In CARE-MS II, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was also significantly slowed.[21] The clinical development program for alemtuzumab use in MS involved nearly 1,500 patients with more than 6,400 patient-years of safety follow-up.[22]

In a single-arm, open-label study in 45 patients with MS that was refractory to treatment with interferon, alemtuzumab effectively reduced relapse rates and improved clinical scores.[106]

In subsequent subgroup analysis of 101 MS patients with multiple recent relapses and MRI-detected gadolinium-enhancing lesions, researchers found alemtuzumab to be more effective than interferon.[107] The study showed that after 2 years, almost a quarter of patients had achieved a disease activity–free state, whereas none of those treated with interferon and reached such a state.

In this study, disease activity–free was defined as no relapse, no sustained accumulation of disability (SAD) as measured by the Expanded Disability Status Scale (EDSS), and no new gadolinium-enhancing lesions or new or enlarging T2-hyperintense lesions.[107] Relapses occurred in 35.8% of the alemtuzumab group and 60.0% of the interferon group. Respective percentages for SAD were 7.4% and 17.5%; for gadolinium-enhancing lesion activity, 22.1% and 52.5%; and for T2 lesion activity, 60.0% and 92.5%.

Ocrelizumab

Ocrelizumab (Ocrevus) was approved in March 2017 for adults with relapsing or primary progressive forms of multiple sclerosis. Approval for RRMS was based on the OPERA 1 and 2 phase 3 trials that included about 800 patients with RMS who received intravenous ocrelizumab or subcutaneous interferon-beta1a. Results showed the annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P< 0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P< 0.001). The percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; P< 0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted MRI was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P< 0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P< 0.001).[23]

Further analysis of participants from the OPERA studies in October 2017 showed that ocrelizumab may improve visual outcomes in adult patients with RMS. Patients who received the drug intravenously had significantly greater improvement on low-contrast letter acuity (LCLA) tests compared with those who received subcutaneous interferon β-1a. Within the visually impaired subgroup, significantly more patients receiving ocrelizumab showed at least a 7-letter improvement at 12 weeks compared to the interferon group.[108]

Treatment of Aggressive MS

High-dose cyclophosphamide (Cytoxan) has been used for induction therapy to stabilize aggressive MS. In a retrospective study of 32 patients, Harrison et al reported that induction with cyclophosphamide (200 mg/kg IV infusion over 4 days) followed by long-term maintenance therapy with glatiramer was well tolerated and appeared to be effective in reducing the risk of relapse, disability progression, and new MRI lesions.[109] Adverse effects of cyclophosphamide include leukemia, lymphoma, infection, and hemorrhagic cystitis.

Mitoxantrone is an immunosuppressive agent approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing-remitting MS. Mitoxantrone is not indicated in the treatment of patients with primary progressive MS.

Mitoxantrone has a black-box warning for cardiotoxicity. The risk of cardiotoxicity increases with cumulative mitoxantrone dose and can occur whether or not cardiac risk factors are present. Mitoxantrone therapy in MS patients and in patients with cancer increases the risk of developing secondary acute myeloid leukemia (AML). Mitoxantrone also has a black-box warning for secondary leukemia. Mitoxantrone treatment in MS patients and in patients with cancer increases the risk of developing secondary AML.

Immunomodulatory Therapy for Progressive MS

Few treatments are available for primary progressive MS (PPMS). Ocrelizumab was approved in March 2017 for adults with relapsing or primary progressive forms of multiple sclerosis. Approval for PPMS was based on results from the ORATORIO phase 3 trial that included 732 patients with PPMS who received the treatment or matching placebo. Ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04). The total volume of brain lesions on T2-weighted MRI decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P< 0.001), while the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02).[24]

Siponimod was approved by the FDA in 2019 for adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Siponimod approval was based on results of the phase 3 EXPAND trial, which randomly assigned 1651 patients with SPMS and an Expanded Disability Status Scale score of 3–6.5 to siponimod 2 mg once daily (1105 patients) or placebo (546 patients) for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression events. At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years and the mean time since conversion to SPMS was 3.8 years; 64% of patients had not relapsed in the previous 2 years, and 56% needed walking assistance.

The primary endpoint was time to 3-month confirmed disability progression. This occurred in 26% of the siponimod group and 32% of those receiving placebo (hazard ratio, 0.79; 95% confidence interval [CI], 0.65 - 0.95; relative risk reduction, 21%; P = .013). Siponimod also meaningfully delayed the risk of 6-month confirmed disability progression (26% vs placebo, p=0.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression.[14]

Cladribine

Cladribine gained FDA approval in 2019 for relapsing forms of MS, to include relapsing-remitting disease and active secondary progressive disease. Because of its safety profile, use is generally recommended for patients with inadequate response to, or unable to tolerate, an alternate MS drug therapy. 

The ORACLE MS trial (n=903) demonstrated that cladribine significantly delayed MS diagnosis compared with placebo (p < 0.0001) when initiated in patients following a first clinical demyelinating event.[25]  In the CLARITY study, cladribine treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening.[26]

A literature review by Rojas et al. indicated that interferon beta could not be linked to reduced disability progression in patients with PPMS.[110] The authors also stated, however, that the studies reviewed employed too few patients to permit a definitive conclusion to be drawn.

Patients with secondary progressive MS (SPMS) who experience relapses are sometimes started on a DMAMS approved for relapsing-remitting MS. Methotrexate has shown some effectiveness in delaying progression of impairment of the upper extremities in patients with SPMS.[111] }

In a European study of SPMS, patients receiving interferon beta-1b showed a highly significant delay in time to disease progression. FDA approval has not been granted yet for this indication, however.[112, 113, 114]

Mitoxantrone is another treatment option for progressive MS. It is approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing remitting MS, but not for primary progressive MS.

Experimental Agents

More oral agents are under development (eg, laquinimod).[115, 116]

In a randomized, double-blind trial involving 30 patients with relapsing-remitting MS, a skin patch delivering a mixture of 3 myelin peptides (MBP85-99, PLP139-151, and MOG35-55) significantly reduced the number of gadolinium-enhanced (Gd+) lesions on MRI, as well as reduced the annual relapse rate in patients wearing the patch for 1 year.[117, 118] The most common adverse effect in those receiving myelin peptides was local reaction in the area of the skin patch, followed by redness and moderate itching.

Stem Cell Transplantation

Autologous hematopoietic stem cell transplantation (AHSCT) may be effective for slowing the course of MS and for repairing damage to the nervous system.

One retrospective study evaluated 281 patients with MS who underwent AHSCT between 1995 and 2006. Almost half of the patients (46%) remained free from neurological progression for 5 years after transplant. However, 8 deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. 

It is important to note that patients with a relapsing form of MS fared better than those with progressive MS. This suggests that AHSCT may not necessarily treat a neurodegenerative component of the disease that is operative in the later stages of the disease.[119]

In a trial of 110 patients with relapsing-remitting disease, stem cell therapy helped control MS. After 1 year, just one stem cell recipient had experienced a relapse, versus 39 relapses in drug therapy recipients. Additionally, during a mean follow-up of 3 years, treatment failure occurred in just 6% of stem cell patients, compared with 60% of those on drug therapy.[120]

Treatment of MS in Pregnancy

Confavreux et al found that the frequency of MS relapses decreases during pregnancy, particularly in the third trimester, when it drops by as much as 70%.[121] In the first 3 months post partum, however, the frequency of relapses returns to the prepregnancy rate, probably as a result of postpregnancy hormone loss. Overall, pregnancy does not have a negative effect on the course of MS. Initial data suggested that breast-feeding reduced MS relapses, but the most recent study found no significant benefit.[122]

Few negative outcomes have been reported with exposure to interferon beta or glatiramer during pregnancy, which suggests the possibility of offering treatment until conception.[122] However, the absence of conclusive data should not encourage physicians to treat patients who are pregnant with these agents; the use of disease-modifying treatments in women planning to become pregnant should be considered on a case-by-case basis, weighing the risks of drug exposure against risks of relapses. Agents with known teratogenicity risks, such as teriflunomide (Aubagio), are clearly contraindicated in this setting.

Symptom Management

Treatment of symptoms is an essential part of the management of MS. Pharmacologic and nonpharmacologic measures can be used to address the following:

  • Fatigue

  • Spasticity

  • Bladder problems

  • Bowel problems

  • Cognitive dysfunction

  • Pain

  • Paroxysmal symptoms

  • Sexual dysfunction

  • Tremor

  • Heat intolerance

  • Optic neuritis

Cognitive dysfunction

Cognitive dysfunction is a major problem that affects quality of life, family and social relationships, and employment. Cognitive dysfunction can impact memory, comprehension, problem solving, and speech. Treatment for cognitive dysfunction in patients with MS should include supportive therapy provided by speech pathologists or occupational therapists. In addition, depression may contribute to cognitive dysfunction and should be treated if it is diagnosed.

Pharmacologic therapy has not been shown to be beneficial for cognitive impairment in MS. For example, a multicenter randomized clinical trial in MS patients with memory impairment found that donepezil (Aricept) was no better than placebo for improving memory.[123]

Depression

Selective serotonin reuptake inhibitors are preferred for treating depressive symptoms in patients with MS. Second-line treatment options include the use of tricyclic antidepressants. The anticholinergic side effects of tricyclic antidepressants may be helpful to patients with symptoms of bladder spasticity or chronic pain. For more information, see the Medscape Reference article Depression.

Fatigue

Fatigue is one of the most common and disabling symptom of MS, occurring in approximately 76-92% of MS patients.[124] Fatigue can worsen before and during exacerbations and with increased temperatures. There are no FDA-approved drugs for treatment of MS-related fatigue.

Amantadine is perhaps the first-line drug for treatment of fatigue in MS, although this is an off-label use. The usual dosage is 100 mg orally twice a day. Approximately 40% of MS patients experience some fatigue relief with amantadine. Pemoline was found to be effective in some people, but it was removed from the US market in 2005 after the FDA concluded that the overall risk of liver toxicity from pemoline outweighs the benefits.[125]

Other drugs that have been tried in fatigue management include methylphenidate and fluoxetine (Prozac). A disadvantage of methylphenidate is that it is a controlled substance, with potential for abuse. Methylphenidate has been recommended at dosages of 10-60 mg/day in 2-3 divided doses, using extreme caution. For patients with concurrent depression, fluoxetine may be tried to manage both problems.

Modafinil (Provigil), a drug approved for the treatment of narcolepsy, has demonstrated some success in MS patients at doses of 200 mg/day. In addition, armodafinil (Nuvigil) has also been suggested as being helpful with fatigue.

Nonpharmacologic treatment of fatigue involves energy conservation, work simplification, scheduled rest periods, and the use of cooling garments (eg, vest, hat, collar). Regular exercise also may help alleviate fatigue.

Medications used in MS management often can contribute to fatigue. These drugs include analgesics, anticonvulsants, antidepressants, muscle relaxants, sedatives, and immune-modulating medications.

Pain

Pain can be a common occurrence in patients with MS, with 30-50% of patients experiencing pain at some time in the course of their illness. Treatment for pain accounts for nearly 30% of the medications used for symptom management in MS patients.[126]

Pain in MS may be primary or secondary, and the two may be experienced at the same time. Primary pain is related to the demyelinating process and is often characterized as having a burning, gnawing, or shooting quality. Tricyclic antidepressants are first-line drugs for primary pain. Anticonvulsants, such as carbamazepine, phenytoin, and gabapentin, can be added as second-line agents.

Secondary pain in MS is primarily musculoskeletal in nature, possibly due to poor posture, poor balance, or the abnormal use of muscles or joints as a result of spasticity. Pharmacologic agents for this type of pain include nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics. The use of narcotics is seldom indicated.

Heat intolerance

Steps to manage heat intolerance are as follows:

  • Time outside activities for early morning or evening hours to avoid the heat of the day

  • Spread activities throughout the course of the day to avoid overheating

  • Use air conditioning in homes and cars, cooling garments, light-colored clothes, and wide-brimmed hats

  • Avoid exposure to saunas, hot tubs, or even hot showers or baths

  • Avoid exposure to excessive humidity; dehumidifiers can help indoors

  • Treat fevers aggressively with around-the-clock antipyretics.

Spasticity

Treat spasticity when it interferes with function, mobility, positioning, hygiene, or activities of daily living. Reducing spasticity can give the patient more freedom of movement with less energy expenditure, as well as avoiding complications such as pain, contractures, and decubitus.

Spasticity can be managed through nonpharmacologic means. Pharmacologic treatment of spasticity includes baclofen (Gablofen, Lioresal), which is particularly useful for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity in MS patients with reversible spasticity. Baclofen is effective in most cases, is inexpensive, and is titrated easily from 10-140 mg/day in divided doses. Adverse effects include fatigue and weakness.

Second-line agents include benzodiazepines (eg, diazepam, clonazepam). These agents can be sedating and habit-forming; however, for patients who also have sleep disorders, the sedative effects can be beneficial, allowing the clinician to manage the spasticity and the sleep problem with a single medication. For patients with cognitive impairment, benzodiazepines may be contraindicated due to their adverse CNS effects.

Dantrolene sodium (Dantrium) acts directly on skeletal muscle to decrease spasticity. This agent is used less frequently than baclofen because of its hepatotoxicity at higher doses and numerous drug interactions.

The anticonvulsant drug gabapentin (Neurontin) is particularly useful in patients who experience spasticity and neuropathic pain. It is easily titrated from 300 to 3600 mg/day in divided doses. However, along with being relatively expensive, gabapentin often causes significant sedation, which is effectively dose limiting.

Tizanidine (Zanaflex), a centrally acting alpha-adrenergic agonist, is also used to manage spasticity. Tizanidine has effects similar to those of baclofen, but it produces less weakness and more sedation. This drug is titrated from 2 to 32 mg/day in divided doses.

Additional treatments for severe spasticity management include intramuscular botulinum toxin, phenol nerve blocks, and intrathecal baclofen pump placement. Because of their greater invasiveness, these treatments are usually reserved for the most difficult cases.

Impaired ambulation

Oral, sustained-release dalfampridine (Ampyra) has been shown to improve walking ability in patients with MS. It is the only medication approved by the FDA for this indication for MS patients.

Fourteen weeks of treatment with dalfampridine was found to improve walking ability in a significant percentage of patients in a randomized, multicenter, double-blind, phase III trial (which was not limited to any specific form of MS).[127] The mechanism of action of dalfampridine appears to be restoration of action potential conduction via blockade of an as-yet uncharacterized subset of potassium channels in demyelinated axons.

An increased risk of seizures has been observed in patients taking dalfampridine; therefore, it is contraindicated in patients with a history of seizures. Most seizure events in patients taking dalfampridine occur within days to weeks after starting the recommended dose, and they happen in patients without a history of seizures. Because dalfampridine is eliminated through the kidneys and its blood levels (along with the risk of seizures) can be enhanced in patients with kidney dysfunction, now the FDA has changed the dalfampridine label (July 2012) to recommend that kidney function be checked in patients before starting the drug (moderate-to-severe renal impairment is a contraindication) and monitored at least annually while the treatment continues. Additionally, patients who miss a dose of should not take an extra dose, since an extra dose can increase seizure risks. Dalfampridine should be discontinued permanently if a seizure occurs.

For details on recommendations to patients and physicians, see FDA Drug Safety Communication: Seizure risk for multiple sclerosis patients who take Ampyra (dalfampridine).

Urinary tract infections have been reported more frequently in patients receiving dalfampridine 10 mg twice daily (12%) than in those receiving placebo (8%).[128]

Bladder problems

Bladder dysfunction in MS may consist of failure to store, failure to empty, or a combination of the two. Interventions for failure to store include the following[129] :

  • Scheduled voiding

  • Limiting fluid intake in the evening

  • Using anticholinergic medications (eg, oxybutynin)

  • Eliminating diuretics (eg, caffeine)

  • Injecting onabotulinumtoxinA (Botox) into the bladder[130]

Failure to empty is characterized by a large, flaccid bladder and an inability of the urinary sphincter to relax. Symptoms include urgency, frequency, hesitancy, nocturia, incontinence, incomplete emptying, and frequent urinary tract infections. Interventions include intermittent catheterization or the use of alpha-blockers (eg, prazosin) and, possibly, the Crede maneuver.

Combined dysfunction is due to incoordination of the detrusor and sphincter (dyssynergia). Symptoms in combined dysfunction are similar to those of failure to empty. Interventions may include anticholinergic medications or intermittent catheterization.

Bladder problems usually can be managed appropriately after a careful history, physical examination, and urinalysis. If initial attempts at symptom management are not effective, more studies, such as renal ultrasonography, voiding cystourethrography, renal scanning, or urodynamic studies, may be indicated to better characterize the problem. Recurrent urinary tract infections are common in MS patients with end-stage bladder disability.

Bowel problems

Constipation, the most common bowel problem in MS patients, may result from neurogenic bowel, immobility, or restricted fluid intake. The first step in management of constipation is to increase fluid intake to 8-10 cups daily and increase dietary fiber to 15 g.

Next, it is essential to establish a consistent bowel program time. A bowel program is most effective if done at least every other day and preferably after a meal, which takes advantage of the body's gastrocolic reflex. Sitting in an upright position, rather than lying in bed, permits gravity to assist in evacuation. The patient should also be involved in an exercise program, consisting of walking or simply performing chair exercises.

Pharmacologic management of constipation includes stool softeners, bulk formers, or laxatives. Stool softeners, such as docusate sodium, work by decreasing surface tension, allowing water to enter the stool. Bulk formers (eg, Metamucil, Per Diem, Citrucel, FiberCon) work by increasing the bulk and weight of the stool. Laxatives act as an irritant to the bowel, increasing peristalsis; they generally work within 8-12 hours. Examples include milk of magnesia and Peri-Colace.

For patients with a neurogenic bowel or with poor abdominal muscle tone, rectal suppositories may be part of an effective bowel program that can help prevent incontinence episodes. Suppositories provide rectal stimulation and lubricate the stool. Typically, they act within 30 minutes to 1 hour. Examples include bisacodyl and glycerin.

Nonpharmacologic techniques of bowel management include proper positioning, abdominal massage, and digital stimulation. Abdominal massage performed in the direction of bowel peristalsis, from ascending toward the descending colon, can be useful. Finally, digital stimulation, in which a lubricated finger is inserted gently into the rectum and moved side to side along the wall of the rectum, can stimulate a bowel movement.

Diarrhea

Diarrhea, if it occurs, typically is not related to MS per se. Rather, it is more likely from fecal impaction, diet, irritation of the bowel, or overuse of laxatives or stool softeners. Diarrhea may also be an adverse effect of medications.

Diarrhea is treated first by eliminating the cause and then, possibly, with bulk formers (eg, psyllium). Drugs that slow the muscles of the bowel, such as Lomotil (diphenoxylate and atropine) are rarely indicated.

Sexual dysfunction

Sexual dysfunction in patients with MS may be associated with other symptoms of the disease, such as fatigue, spasticity, depression and bowel dysfunction. Erectile dysfunction is common in men with MS and may be treated with oral phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra, Staxyn); for more information, see Erectile Dysfunction. Penile prostheses are an alternative for men with erectile dysfunction who do not respond to medical management.

Tremor

Tremor is difficult to manage in MS patients. Several treatments have been used for tremor, with little success. Treatments have included anticonvulsants, isoniazid, primidone, benzodiazepines, propranolol, and ondansetron.

Optic neuritis

In the Optic Neuritis Treatment Trial (ONTT), patients recovered visual function regardless of whether they were treated with oral prednisone, intravenous methylprednisolone (IVMP), or placebo.[131] However, patients who received IVMP recovered faster. IVMP also seemed to decrease the incidence of the development of MS over a 2-year period, but this effect was not sustained after year 3. Patients treated with oral prednisone demonstrated an increased incidence of recurrent optic neuritis compared with those who were administered IVMP or placebo.

Rehabilitation

Patients with MS may benefit from referral to physical therapists, occupational therapists, and speech therapists. Speech therapists assess the patient's speech, language, and swallowing abilities and may work with the patient on compensatory techniques to manage cognitive problems.

Physical therapy

Physical therapists provide assessment of gross motor skills (eg, ambulation) and assessment and training in appropriate assistive devices to improve mobility in patients with MS. They evaluate and train the patient in appropriate exercise programs to decrease spasticity, maintain range of motion, strengthen muscles, and improve coordination. They also provide invaluable input into the prescription of appropriate seating systems for the nonambulatory patient.

Physical therapy for spasticity in patients with MS includes the establishment of a stretching program in which joints are moved slowly to positions that stretch the spastic muscles. Each position is held for at least a minute to allow the stretched muscle to slowly relax. Stretching exercises may be performed in a cool (85°F) pool, which provides buoyancy and cooling. Mechanical aids, such as ankle-foot orthoses, also can be useful in spasticity management.

Nonpharmacologic treatments for primary pain in MS, such as the use of imagery or distraction, can be helpful. Transcutaneous electrical nerve stimulation (TENS) is useful in some patients.

Nonpharmacologic treatment for secondary pain includes moist moderate heat, massage, physical therapy, and exercise (eg, stretching). Devices such as the WalkAide and Bioness use functional electrical stimulation to aid walking and may be helpful to some MS patients.

Occupational therapy

Occupational therapists are skilled in assessing the patient's functional abilities in completing activities of daily living, assessing fine motor skills, and evaluating for adaptive equipment and assistive technology needs. They can provide treatment for cognitive dysfunction.

Treatment approaches for cognitive dysfunction include cognitive retraining and the use of compensatory strategies. Cognitive retraining involves the employment of repetitive drills and mentally stimulating exercises designed to strengthen areas of cognition that are weak.

Compensatory strategies emphasize coping methods or organizational skills to help patients use their strengths to compensate for areas of relative weakness. Such strategies can include the following:

  • Maintaining a consistent routine

  • Making lists

  • Keeping a daily planner

  • Organizing the home or work environment

In providing education on MS management to patients with cognitive impairment, it is important to involve family or caregivers in training, provide step-by-step instructions, and present information in a visual and verbal format. New topics should be presented at times when fatigue is less likely to be an issue.

Surgery for Alleviating Symptoms

Surgical procedures that relate to MS are directed primarily at alleviating symptoms, such as dysphagia, significant limb spasticity or contractures, or severe neuropathic pain. Measures include gastrojejunal tube placement, adductor leg muscle tendon release, and rhizotomy, respectively.

Intrathecal pumps for delivery of antispasticity medications (eg, baclofen) can be implanted surgically. Caution should be used with baclofen pumps due to the risk of malfunction and baclofen overdose.

Deterrence and Prevention

Preliminary evidence suggests that persons with high circulating levels of vitamin D are at lower risk of MS[39] ; thus, vitamin D supplementation may reduce the risk of developing MS and of conversion from a first clinical event suggestive of MS to clinically definite MS. Vitamin D may also reduce the relapse rate among patients with relapsing-remitting MS.[132]

For healthy individuals, serum vitamin D concentrations of 50-125 nmol/L (20-50 ng/mL) are generally considered adequate for bone and overall health, according to the Institute of Medicine.[133] Serum vitamin D concentrations of 75-100 nmol/L (30-40 ng/mL) have been proposed as optimal for patients with MS.[134]

Achieving these levels may require the use of supplemental vitamin D in doses up to 3000 IU daily; maintaining these levels appears to require doses of 500 to 800 IU daily.[134] The safety and effectiveness of vitamin D supplementation among patients with MS remains unclear, however.[135]

Early treatment with immunomodulatory drugs has been associated with decreased disability progression and lower secondary relapse rates. Patients with MS must understand, however, that current immunomodulatory drugs are not curative.

The Uhthoff phenomenon is an exacerbation of MS symptoms that is induced by exercise, a hot meal, or a hot bath. The most notable symptoms seen with this phenomenon are transient visual obscurations, dyschromatopsia, and contrast sensitivity changes. The symptoms tend to resolve with restoration of euthermia, typically within 60 minutes to 24 hours. Sunlight by itself is not considered to be deleterious, but excessive exposure may mimic the effects of high temperatures.

On the other hand, the impact of stress on MS exacerbations is thought to be minimal or noncontributory. Likewise, trauma has no demonstrated impact on the disease course.

Consultations

Patients with MS may require multiple consultations to rule out other causes of their symptoms. A significant number of MS patients will need a multidisciplinary approach to their care. For instance, patients with dysphonia may need an evaluation by an otolaryngologist (ie, ear, nose, and throat specialist) to rule out laryngeal lesions unrelated to MS. In addition, having MS does not exclude the possibility of concomitant peripheral neuropathy or other illnesses that may cause pain.

The following are the most common consultation services involved in referrals from an MS clinic:

  • Physical therapy and rehabilitation specialist

  • Speech therapist

  • Ophthalmologist

  • Urologist: Urologic consultation may be warranted to help in the assessment and treatment of incontinence

  • Gastroenterologist

  • Neuropsychologist: Neuropsychologic consultation is advisable so that a baseline assessment for future reference can be obtained; such consultation is especially important in patients with primary cognitive involvement

  • Psychiatrist

  • Otolaryngologist

It is not unusual for patients with more advanced MS to lose all family support, become separated from their spouse, lose the ability to walk, and require constant psychiatric and nursing assistance. These patients create a challenge for the physician who is not trained in handling the demanding administrative or ancillary aspects of medical care. A social worker specialist can be instrumental in helping to address these issues.

For the newer oral therapies with specific adverse effects, consultations with specialists may be warranted. Consultation with a cardiologist to evaluate the appropriateness of fingolimod in a patient with a history of nonrecent myocardial infarction, with an ophthalmologist to examine the appropriateness of fingolimod in patients with visual symptoms (to evaluate potential macular edema), or with a nephrologist for MS patients with mild-to-moderate renal insufficiency (for consideration of treatment with dalfampridine or teriflunomide) may be required.

Long-Term Monitoring

Recommended follow-up is yearly at minimum. Patients receiving therapy with certain agents (eg, natalizumab, fingolimod) require monitoring as often as every 3-4 months. Clinicians who also provide primary care for the patient with MS can perform routine health maintenance at these annual visits. For patients with worsening symptoms, a medical cause, such as infection, should be ruled out first before assuming that the patient is having an exacerbation.

Once a patient/provider relationship is established, a great deal of symptom management can be provided through careful telephone triage. More frequent visits, such as bimonthly or quarterly, may be necessary for patients with difficult symptoms, such as intractable spasticity, or for individuals whose social support system is not as stable as necessary.

Vaccination

MS specialists generally advise against the use of live-attenuated virus vaccines in patients with MS, particularly in patients receiving immunosuppressive therapy. Despite concerns that vaccination may trigger the onset or relapses of MS, almost all killed-virus vaccines studied have been found safe in this regard.[48]

The Vaccine Safety Datalink Research Group of the US Centers for Disease Control and Prevention (CDC) found that vaccination against hepatitis B, influenza, tetanus, measles, or rubella did not increase the risk of developing MS or optic neuritis.[136] The Vaccines in Multiple Sclerosis Study Group reported that vaccination for tetanus, hepatitis B, or influenza does not increase the short-term risk of relapses.[137]

Injectable influenza vaccine has been extensively studied in MS and found to be safe. However, the form of influenza vaccine that is delivered via a nasal spray (FluMist) is a live-virus vaccine and is not recommended for MS patients.

Varicella-zoster vaccine (Zostavax) is also a live-attenuated vaccine. However, in a patient with a definite history of chicken pox or a positive antibody test, this vaccine is likely to be safe and beneficial, although full discussion of the risks and benefits must precede its use. Discussion of risks and benefits is also important before a close family member of an MS patient receives this or any other live-virus vaccine.[48]

A study in 7 patients with relapsing-remitting MS who received yellow fever vaccine found a significantly increased risk of MS relapse during the 6 weeks following the vaccination. For MS patients who must travel to areas where yellow fever is endemic, these researchers advise careful weighing of the risk of relapse with the risk of contracting yellow fever, which is a potentially fatal illness.[138]

No studies have been published addressing the safety of the following vaccines in MS:

  • Pneumonia

  • Meningitis

  • Typhoid

  • Polio

  • Hepatitis A

  • Human papillomavirus (HPV)

  • Pertussis

There are rare reports of demyelination syndromes following administration of the HPV vaccine. Thus, physicians should thoroughly discuss the possible benefits and risks of this vaccine before administering it.[48]

Some special considerations for vaccination in MS patients from the National Multiple Sclerosis Society are as follows[48] :

  • In patients experiencing a serious relapse that affects their ability to carry out activities of daily living, defer vaccination until 4-6 weeks after the onset of the relapse

  • Vaccine response may be blunted in patients who have received immune globulin in the past 3 months or who are taking natalizumab or fingolimod.

 

Guidelines

Guidelines Summary

Imaging

The following organizations have issued guidelines for the use of imaging in the diagnosis of MS:[73, 139, 140, 141]

  • Consortium of Multiple Sclerosis Centers (CMSC)
  • MAGNIMS (Magnetic Resonance Imaging in MS) Network
  • European Academy of Neurology (EAN)

Although MRI alone cannot be used to diagnose MS, all four guidelines (MAGNIMS has two) concur that it is the imaging procedure of choice for confirming MS and monitoring disease progression in the brain and spinal cord.

Consortium of Multiple Sclerosis Centers (CMSC)

CMSC revised guidelines recommend using higher-resolution three-dimensional (3D) imaging over two-dimensional (2D) imaging whenever possible. Recommended studies for patients with CIS or suspected MS include the following:

Brain MRI protocol with gadolinium at baseline

  • Spinal cord MRI if transverse myelitis, inconclusive brain MRI, or age older than 40 with non-specific brain MRI findings
  • Cervical cord MRI performed simultaneously with brain MRI is advantageous in patients with or without transverse myelitis
  • Orbital MRI if severe optic neuritis with poor recovery

Recommended schedules for follow-up brain MRI in patients with a CIS or suspected MS are as follows:

  • 6–12 months for high-risk CIS (≥2 ovoid lesions on first MRI)
  • 12–24 months for low-risk CIS (normal brain MRI findings) and/or uncertain clinical syndrome with suspicious brain MRI features (eg, radiologically isolated syndrome [RIS])

Follow-up brain MRI with gadolinium is recommended for patients with an established diagnosis of MS in the following circumstances:

  • No recent prior imaging available (eg, patient with MS transferring to a new clinic)
  • Postpartum, to establish a new baseline
  • Prior to starting or switching disease-modifying therapy
  • Approximately 6 months after switching disease-modifying therapy, to establish a new baseline on the new therapy
  • Every 1–2 years while on disease-modifying therapy, to assess subclinical disease activity
  • In the event of unexpected clinical deterioration or reassessment of original diagnosis

In addition, brain MRI is recommended to monitor for progressive multifocal leukoencephalopathy (PML) at the following intervals:

  • Every 12 months for patients negative for serum JC virus antibody
  • Every 3–6 months for patients positive for serum JC virus antibody treatment and treatment duration with natalizumab ≥18 months

MAGNIMS (Magnetic Resonance Imaging in MS) Network

In 2005, the MAGNIMS Network released two separate guidelines for use of MRI in MS. One covers diagnosis of suspected MS and the other covers use of MRI in disease monitoring.

The MAGNIMS guidelines find currently available evidence insufficient to support the use of advanced MRI to establish the initial diagnosis or differential diagnosis of MS in patients with CIS. 

Other recommendations include the following:

  • Spinal cord MRI should always be performed in patients with spinal cord symptoms at disease onset
  • Spinal cord MRI should be performed when brain MRI results are inconclusive, and for all patients with brain MRI suggestive for RIS

The MAGNIMS guidelines recommend more frequent follow-up than the CMSC guidelines, as follows:

  • 3–6 months after baseline brain scan for patients with RIS or CIS and abnormal MRI
  • If the second brain scan is inconclusive, a third can be done 6-12 months later
  • Follow-up spinal cord MRI in patients with CIS, to demonstrate dissemination in space (DIS) and dissemination in time (DIT), has limited value and should not be done routinely

The recommendation for monitoring of patients with established diagnosis of MS include the following:

  • T2-weighted and contrast-enhanced T1-weighted brain MRI are the modalities of choice for MS disease monitoring
  • The use of spinal cord MRI in addition to brain MRI is not recommended for routine monitoring  and should be limited to certain clinical situations (eg, unexplained and/or unexpected spinal cord symptoms)
  • Although assessment of brain volume does not have a role in the diagnosis of MS, it can be a good predictor of long-term disability
  • Rates of change in brain volume are not recommended as a marker of disease progression in individual patients, owing to the technical, biological and pharmacological factors that can influence the measurement and interpretation of atrophy rate
  • MRI should be included in drug monitoring to screen for opportunistic infections, unexpected disease activity (including paradoxical reactions), and comorbidities
  • In patients at high risk of developing opportunistic infections who are switching disease-modifying drugs (DMDs), brain MRI should be performed at the time the current treatment is discontinued and after the new treatment is started
  • Enhanced pharmacovigilance, including brain MRI every 3–4 months for up to 12 months, is required in patients who switch from natalizumab to other therapeutics (including fingolimod, alemtuzumab, and dimethyl fumarate)

European Academy of Neurology (EAN)

The 2011 guidelines from the European Academy of Neurology (EAN) offer no significant variance with the CMSC and MAGNIMS guidelines.

Disease-modifying therapies

Currently, most disease-modifying agents have been approved for use only in relapsing forms of MS. To address the need for early intervention, the Multiple Sclerosis Coalition developed a consensus document in 2014 to provide support for broader access to US Food and Drug Administration (FDA)-approved MS disease-modifying therapies.[142]  

The guidelines recommend treatment with an FDA-approved disease-modifying agent as soon as possible after any of the following events:

  • Diagnosis of relapsing MS
  • First episode of neurologic symptoms with MRI findings consistent with MS, and other possible causes have been ruled out
  • Diagnosis of secondary-progressive MS (SPMS) but patient continues to have relapses and/or inflammatory changes on MRI

The guidelines further recommend that treatment with any disease-modifying medication should be continued indefinitely, unless any of the following occur:

  • The patient or healthcare provider determines that the treatment is failing to adequately control the disease
  • The side effects are intolerable
  • The patient is unable to follow the recommended treatment regimen
  • A more appropriate treatment becomes available

Additional recommendations include the following:

  • Switch from one disease-modifying treatment to another should only occur for medically appropriate reasons
  • When a medication is not providing adequate benefit, another agent with a different mechanism of action should be considered
  • Factors affecting choice of treatment are complex and should be addressed collaboratively by the patient and healthcare provider
  • Access to treatment should not be limited by frequency of relapses, level of disability, or personal characteristics such as age, gender, or ethnicity
  • Absence of relapses may indicate that the treatment is working and should not be considered a justification for discontinuing the treatment

European Committee for Research and Treatment of Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN)

In 2017, the ECTRIMS and EAN released the first set of guidelines on the use of disease-modifying therapies in multiple sclerosis. The European guidelines cover the treatment of adults with MS or clinically isolated syndrome (CIS), the monitoring of treatment response, the stopping and switching of treatment strategies, and treatment in special situations, such as pregnancy. There are 20 main recommendations.[143] Those with strong evidence include the following:

  • Offer interferon or glatiramer acetate to patients with CIS and abnormal MRI findings with lesions suggesting MS who do not fulfill full criteria for MS.
  • Offer early treatment with disease-modifying drugs in patients with active relapsing-remitting MS (RRMS), as defined by clinical relapses and/or MRI activity (active lesions: contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed at least annually).
  • Offer a more efficacious drug to patients treated with interferon or glatiramer acetate who show evidence of disease activity.

American Academy of Neurology (AAN) 

Released in 2018, guidelines from the AAN on the use of disease-modifying therapies in patients with multiple sclerosis provide updated guidance on starting, switching, and stopping treatment and recommend an earlier start to treatment rather than later in the disease course. These guidelines are endorsed by the Multiple Sclerosis Association of America and the National Multiple Sclerosis Society. In all, 30 recommendations were developed: 17 on starting DMTs, 10 on switching from one therapy to another if breakthrough disease develops, and 3 on considerations related to stopping therapy.[144, 145, 146]

Immunization

In 2019, the American Academy of Neurology (AAN) issued guidelines for vaccine-preventable infections and immunization in multiple sclerosis. Recommendations include the following:[147]

  • Discuss the evidence regarding immunizations in MS with patients.
  • Recommend that MS patients follow all local vaccine standards, unless there are specific contraindications.
  • Recommend annual influenza vaccination to MS patients.
  • Counsel MS patients about infection risks associated with specific immunosuppressive/ immunomodulating (ISIM) medications and treatment-specific vaccination guidance according to prescribing information (PI).
  • Vaccinate patients with MS as needed at least 4–6 weeks before initiating ISIM therapy.
  • Screen for infections according to PI before initiating ISIM medications and treat patients testing positive for latent infections. In high-risk populations, screen for latent infections before starting ISIM therapy even when not specifically mentioned in PI.
  • Recommend against using live-attenuated vaccines in MS patients receiving ISIM therapies.
  • Delay vaccination in MS patients experiencing a relapse.
 

Medication

Medication Summary

Treatment and management of multiple sclerosis should be targeted toward relieving symptoms of the disease, treating acute exacerbations, shortening the duration of an acute relapse, reducing frequency of relapses, and preventing disease progression.

Drugs approved for use in MS that reduce the frequency of exacerbations or slow disability progression are referred to as disease-modifying drugs (DMDs). These DMDs can be further classified as immunomodulating (or receptor modulating) or immunosuppressives. Some immunosuppressants are also FDA-approved as antineoplastic agents.

Drugs that treat MS-related symptoms (eg, acute exacerbations, cognitive dysfunction, fatigue, spasticity, bowel and bladder problems, and pain) but do not modify the course of the disease are referred to as symptom-management medications.

Immunomodulators

Class Summary

Immunomodulators or receptor modulators are indicated for the treatment of patients with relapsing forms of MS. They help to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations.

Interferon beta-1b (Betaseron, Extavia)

Interferon beta-1b was the first medication approved by the FDA for MS. It is approved for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. It has shown efficacy in patients who have experienced a first clinical episode and have MRI features consistent with MS.

The exact mechanism by which interferon beta-1b exerts its effects is unknown. Interferon beta inhibits the expression of pro-inflammatory cytokines, including interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha and TNF-beta, interferon gamma (IFN-γ), and IL-6. IFN-γ is believed to be a major factor responsible for triggering the autoimmune reaction leading to MS.

Interferon beta-1a (Avonex, Rebif)

Interferon beta-1a is approved for the treatment of patients with relapsing forms of MS. It helps to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations.

The exact mechanism by which interferon beta-1a exerts its effects is not fully defined. Interferon beta inhibits the expression of proinflammatory cytokines, including interferon gamma (IFN-γ), which is believed to be a major factor responsible for triggering the autoimmune reaction leading to MS.

Alemtuzumab (Lemtrada)

Alemtuzumab is a recombinant monoclonal antibody against CD52 (lymphocyte antigen). This action promotes antibody-dependent cell lysis. It is indicated for relapsing forms of multiple sclerosis. Because of the risk for severe and lasting autoimmune adverse effects, use is reserved for patients who have an inadequate response to 2 or more other drugs for MS.

Peginterferon beta-1a (Plegridy)

Precise mechanism by which peginterferon beta-1a exerts its effects in patients with multiple sclerosis is unknown. Interferons are thought to alter response to surface antigen and may enhance immune cell activities. It is indicated for treatment of relapsing forms of multiple sclerosis.

Natalizumab (Tysabri)

Natalizumab is indicated as monotherapy for MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. Natalizumab is a recombinant humanized monoclonal antibody that binds with alpha-4 integrins and inhibits their adherence to their counterreceptors. The specific mechanism by which natalizumab exerts its effects in MS has not been defined.

Natalizumab has a black-box warning for progressive multifocal leukoencephalopathy (PML). Because of the risk of PML, natalizumab is available only through a special restricted distribution prescribing program called the Tysabri Outreach Unified Commitment to Health (TOUCH).

Glatiramer acetate (Copaxone, Glatopa)

Glatiramer acetate is approved for the reduction of the frequency of relapses in patients with relapsing-remitting MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. Glatiramer acetate's mechanism of action is unknown, but this agent is thought to modify immune processes believed to be responsible for the pathogenesis of MS. The recommended dosage is 20 mg/day administered subcutaneously. The sites for injection include the arms, abdomen, hips, and thighs.

Teriflunomide (Aubagio)

Teriflunomide is an oral immunomodulatory agent that elicits anti-inflammatory effects by inhibiting dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis. It is indicated for relapsing forms of MS.

Dimethyl fumarate (Tecfidera)

Dimethyl fumarate (DMF) is an oral Nrf2 pathway activator indicated for relapsing forms of multiple sclerosis. DMF is metabolized rapidly by presystemic hydrolysis by esterases in the GI tract, blood, and tissues (before it reaches systemic circulation) and is converted to its active metabolite, monomethyl fumarate (MMF). MMF activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a transcription factor encoded by the NFE2L2 gene. The Nrf2 antioxidant response pathway is a cellular defense against oxidative stress. MMF has been identified as a nicotinic acid receptor agonist in vitro.

Ocrelizumab (Ocrevus)

Ocrelizumab is a humanized monoclonal antibody designed to selectively target CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. Following 2 initial IV doses administered 2 weeks apart, subsequent IV doses are administered every 6 months. It is indicated for adults with relapsing or primary progressive forms of multiple sclerosis.

Corticosteroids

Class Summary

Corticosteroids are used to reduce inflammation and expedite recovery from acute relapses. The most commonly used corticosteroids in MS include methylprednisolone, dexamethasone and prednisone. Short courses of intravenous methylprednisolone with or without a short prednisone taper have been used.

Methylprednisolone (Solu-Medrol, Depo-Medrol, Medrol)

Methylprednisolone is given for acute exacerbations of MS. By reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity, methylprednisolone may decrease inflammation. In addition, it may alter the expression of some proinflammatory cytokines.

Dexamethasone (Dexamethasone Intensol, DoubleDex, Decadron, Active Injection D)

Dexamethasone can be given for acute exacerbations of MS. It stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines. Dexamethasone is available as an injection that can be administered intravenously or intramuscularly and in various oral formulations (tablets, elixir, and solution).

Prednisone (Deltasone, Rayos)

Prednisone prevents or suppresses inflammation and immune responses when administered at pharmacological doses. Prednisone's actions include inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, and suppression of humoral immune responses. Oral prednisone tapers are commonly administered with or without methylprednisolone.

Immunosuppressants

Class Summary

Immunosuppressants are used for their ability to suppress immune reactions. Agents such as methotrexate have shown some effectiveness in delaying progression of impairment of the upper extremities in patients with secondary progressive MS. Azathioprine has been studied in clinical trials and has shown modest effects on relapses and progression of disease. Methotrexate and azathioprine have not been approved by the US Food and Drug Administration for use in MS. Antineoplastic agents with immunosuppressive properties, such as cyclophosphamide and mitoxantrone, have been used in patients with MS.

Azathioprine (Azasan, Imuran)

This immunosuppressive antimetabolite drug is an imidazolyl derivative of 6-mercaptopurine. It is cleaved in vivo to mercaptopurine and converted to 6-thiouric acid by xanthine oxidase. Azathioprine is generally used in the treatment of transplant rejection or severe, active, erosive rheumatoid arthritis, but it has been used off-label for MS.

Methotrexate (Rheumatrex, Otrexup, Rasuvo, Trexall, Xatmep)

Methotrexate interferes with DNA synthesis, repair, and cellular replication. It inhibits dihydrofolic acid reductase, which participates in the synthesis of thymidylate and purine nucleotides. Methotrexate has been used off-label for MS.

Mitoxantrone

Mitoxantrone is an immunosuppressive agent approved for the treatment of secondary progressive or aggressive relapsing-remitting MS. It is used for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing-remitting MS (ie, patients whose neurologic status is significantly abnormal between relapses). Mitoxantrone is not indicated in the treatment of patients with primary progressive MS.

Mitoxantrone therapy can increase the risk of developing secondary acute myeloid leukemia (AML) in MS patients and in patients with cancer.

Cyclophosphamide

Cyclophosphamide has been used for the treatment of progressive MS. Evidence of benefit is mixed. This agent has not been approved for MS but has been used off-label in MS patients. Cyclophosphamide is associated with leukemia, lymphoma, infection, and hemorrhagic cystitis.

Cladribine (Mavenclad)

Cladribine is a prodrug of the active moiety Cd-ATP. The mechanism by which it is used for multiple sclerosis is not fully elucidated, but is thought to involve cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes. It is indicated for relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease; because of its safety profile, use is generally recommended for patients with inadequate response to, or inability to tolerate, alternate indicated drugs.

Sphingosine 1-Phosphate Receptor Modulators

Class Summary

Sphingosine-1-phosphate (S1P) receptor modulators bind with high affinity to S1P receptors 1 and 5. This action blocks lymphocytes to egress from lymph nodes, therefore reducing the number of lymphocytes in peripheral blood. The precise mechanism by which SP1 receptor modulators exert therapeutic effects in MS is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

Siponimod (Mayzent)

Siponimod is indicated for treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. The dose requires a brief upward titration to mitigate decreased HR associated with initial dosing. Titration and maintenance dose regimens are determined by CYP2C9 genotype.

Fingolimod (Gilenya)

Fingolimod is the first oral therapy for relapsing forms of MS approved by the FDA. Like other disease-modifying drugs (DMDs) for MS, fingolimod can reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. The recommended dosage for fingolimod is 0.5 mg once a day.

The mechanism by which fingolimod exerts therapeutic effects in MS is unknown, but it appears to be fundamentally different from that of other MS medications. Its activity may involve a reduction of lymphocyte migration into the central nervous system.

Dopamine Agonists

Class Summary

Amantadine is approved for the prophylaxis and treatment of influenza A and Parkinson disease and has been used off-label to relieve fatigue in patients with MS. It has relatively few side effects and is well tolerated .

Amantadine

Amantadine is not FDA approved for use in MS, but dosages of 100 mg given orally twice a day have commonly been used for fatigue. The mechanism by which amantadine counteracts fatigue in MS patients is unclear.

Skeletal Muscle Relaxant

Class Summary

Pharmacologic treatment of spasticity includes baclofen (Lioresal, Gablofen) as a first-line agent. Baclofen can be titrated easily in divided doses. Patients using this medication may report fatigue or weakness as an adverse effect. Dantrolene (Dantrium) acts within muscles on excitation-contraction coupling; however, it is rarely used because it can cause liver damage.

Baclofen (Lioresal, Gablofen)

Baclofen is a skeletal muscle relaxant used as a first-line treatment for spasticity in patients with MS. It can effectively relieve spasms and has modest effects in improving performance. Intrathecal baclofen via an implanted pump can be effective against spasticity in suitable patients. The pump can be electronically regulated to deliver small amounts of baclofen at a constant or variable dose over a 24-hour period to increase efficacy and decrease side effects.

Dantrolene (Dantrium, Revonto, Ryanodex)

Dantrolene is a skeletal muscle relaxant that acts directly on skeletal muscle to decrease spasticity. Dantrolene is believed to decrease muscle contraction by directly interfering with calcium ion release from the sarcoplasmic reticulum within skeletal muscle cells. It affects all muscles of the body and is used less frequently than baclofen because of hepatotoxicity at higher doses and numerous drug interactions.

Neuromuscular Blockers, Botulinum Toxins

Class Summary

The FDA has approved the use of botulinum toxin (Botox) for the treatment of upper limb spasticity in MS. The FDA has also approved this agent for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (eg, MS) in adults who have an inadequate response to, or are intolerant of, an anticholinergic medication.

OnabotulinumtoxinA toxin (Botox)

OnabotulinumtoxinA toxin is an injectable neurotoxin that temporarily blocks connections between the nerves and the muscles, leading to short-term relaxation of the targeted muscle. The drug can be injected again when the muscle-relaxing effects have worn off, but not more frequently than every 3 months.

It is approved for the treatment of upper limb spasticity in adults to decrease the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digitorum sublimis).

Alpha2-Adrenergic Agonists

Class Summary

Tizanidine (Zanaflex) is a centrally active alpha2 -adrenergic agonist that is also used to treat spasticity in patients with MS. It can be used alone or in combination with baclofen.

Tizanidine (Zanaflex)

This centrally acting alpha-adrenergic agonist is presumed to decrease spasticity by increasing presynaptic inhibition of motor neurons. Tizanidine has effects similar to those of baclofen, but it produces less weakness and more sedation. This drug can be titrated starting with 2 mg, with maximum doses of 36 mg/day.

Benzodiazepines

Class Summary

Benzodiazepines are used as second-line agents for the treatment of spasticity in patients with MS. Agents in the benzodiazepine class that are commonly used include diazepam and clonazepam. While these compounds can be useful adjunct medications, they can be sedating and habit-forming and are not FDA approved for use in MS.

For patients who also experience sleep disorders, the provider may take advantage of the sedating effects of the benzodiazepines to manage the spasticity and sleep problem with a single medication. For patients with cognitive impairment, benzodiazepines may be contraindicated due to their adverse CNS effects.

Clonazepam (Klonopin)

Clonazepam is a long-acting benzodiazepine that increases presynaptic gamma-aminobutyric acid (GABA) inhibition and reduces monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.

Diazepam (Valium)

Diazepam modulates the postsynaptic effects of GABA-A transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the limbic system, the thalamus, and the hypothalamus to induce a calming effect. Diazepam also has been found to be an effective adjunct for the relief of skeletal muscle spasms caused by upper motor neuron disorders.

Stimulants

Class Summary

Modafinil (Provigil), armodafinil (Nuvigil), dextroamphetamine (Dexedrine), and methylphenidate (Concerta, Metadate CD, Metadate ER, Ritalin, Ritalin SR) are wakefulness-promoting agents approved for the treatment of narcolepsy. These agents are also used for the treatment of fatigue without interfering with normal sleep architecture in patients with MS. Modafinil and methylphenidate have also been used as cognitive-enhancing drugs to treat cognitive dysfunction in MS.

Modafinil (Provigil)

Modafinil is listed in Schedule IV of the Controlled Substances Act. It promotes wakefulness, and is used for treatment of fatigue without interfering with normal sleep architecture. Patients should be observed for signs of use or abuse, as the drug has psychoactive and euphoric effects similar to those seen with other scheduled CNS stimulants (eg, methylphenidate). The mechanism of action of modafinil is unknown.

Armodafinil (Nuvigil)

Armodafinil elicits wakefulness-promoting actions similar to those of sympathomimetic agents, although its pharmacologic profile is not identical to sympathomimetic amines. It is indicated to improve wakefulness in individuals with excessive sleepiness associated with narcolepsy, obstructive sleep apnea–hypopnea syndrome (OSAHS), or shift-work sleep disorder. It is also used for treatment of fatigue without interfering with normal sleep architecture. It may also be used as a cognitive-enhancing drug to treat cognitive dysfunction in MS.

Methylphenidate (Concerta, Daytrana, Metadate ER, Methylin, Ritalin, Ritalin LA, Aptensio XR)

Methylphenidate is a piperidine derivative. It stimulates the cerebral cortex and subcortical structures.

Dextroamphetamine (Dexedrine, ProCentra, Zenzedi)

This agent increases the amount of circulating dopamine and norepinephrine in the cerebral cortex by blocking the reuptake of norepinephrine or dopamine from synapses.

Anticonvulsants, Other

Class Summary

Gabapentin is an anticonvulsant drug that is particularly useful in patients who experience spasticity and neuropathic pain. Anticonvulsants (eg, carbamazepine, phenytoin) can also be used for the treatment of secondary pain in MS. Topiramate (Topamax) is an anticonvulsant that can be used for MS patients with tremor or spasms and has also been used for paroxysmal symptoms.

Gabapentin (Neurontin, Gralise, Fanatrex FusePaq)

Gabapentin is a membrane stabilizer, a structural analogue of the inhibitory neurotransmitter GABA. Paradoxically, gabapentin is thought not to exert an effect on GABA receptors. It is used to manage pain and provide sedation in patients with neuropathic pain.

Carbamazepine (Tegretol, Tegretol XR, Epitol, Carbatrol)

Carbamazepine is a sodium channel blocker that typically provides substantial or complete relief of pain in 80% of individuals with MS within 24-48 hours. It reduces sustained high-frequency repetitive neural firing and is a potent enzyme inducer that can induce its own metabolism.

Pregabalin (Lyrica)

Pregabalin is a structural derivative of GABA with an unknown mechanism of action. It is used to relieve neuropathic pain.

Topiramate (Topamax, Qudexy, Trokendi)

The exact mechanism of topiramate's anticonvulsant effects is unknown. Topiramate's actions involve several mechanisms, including reduction of the duration of abnormal discharges and the number of action potentials within each discharge. This is probably secondary to its ability to block voltage-sensitive sodium channels. Topiramate also increases the frequency at which GABA activates GABA-A receptors. Finally, it inhibits excitatory transmission by antagonizing some types of glutamate receptors.

Anticonvulsants, Hydantoin

Class Summary

Anticonvulsants, such as phenytoin, can also be used for the treatment of secondary pain in MS.

Phenytoin (Dilantin, Phenytek)

Phenytoin blocks sodium channels nonspecifically and therefore reduces neuronal excitability in sensitized C-nociceptors. It is effective in neuropathic pain, but it suppresses insulin secretion and may precipitate hyperosmolar coma in patients with diabetes.

Selective Serotonin/Norepinephrine Reuptake Inhibitors

Class Summary

Selective serotonin/norepinephrine reuptake inhibitors (SNRIs) are principally used as antidepressants; however, duloxetine is also indicated for relief of several types of pain.

Duloxetine (Cymbalta)

A potent inhibitor of neuronal serotonin and norepinephrine uptake, duloxetine is used as an antidepressant and for relief of neuropathic pain.

Nonsteroidal Anti-Inflammatory Drugs

Class Summary

Pharmacologic agents used for the treatment of secondary pain in MS are nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics. Ibuprofen has also been cited as potentially having beneficial effects with paroxysmal symptoms. The use of narcotics seldom is indicated. Commonly used NSAIDs include ibuprofen (Motrin, Advil) and naproxen (Naprosyn, Aleve, Anaprox, Anaprox DS, Naprelan).

Ibuprofen (Motrin, Advil, Caldolor, Addaprin, Dyspel, Genpril)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen (Naprosyn, Aleve, Anaprox DS, Naprelan, Naproxen DR)

Naproxen is used for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Diclofenac (Cambia, Zipsor, Zorvolex)

Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors.

Indomethacin (Indocin, Tivorbex)

Indomethacin is thought to be the most effective NSAID for the treatment of AS, although no scientific evidence supports this claim. It is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Antispasmodic Agents, Urinary

Class Summary

Treatment of bladder dysfunction in MS patients includes suppressing urgency and ensuring effective urinary drainage. Antispasmodic agents that help decrease muscle spasms of the bladder and the frequent urge to urinate caused by spasms include oxybutynin (Ditropan, Ditropan XL) or tolterodine (Detrol, Detrol LA).

Tolterodine (Detrol, Detrol LA)

Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors.

Oxybutynin (Gelnique, Ditropan XL, Oxytrol)

Oxybutynin is an antispasmodic that exerts a direct effect on smooth muscle and inhibits the muscarinic effects of acetylcholine on smooth muscle. This results in relaxation of bladder smooth muscle. It is indicated for the relief of urinary symptoms in patients with uninhibited and reflex neurogenic bladder. It is metabolized by the liver and excreted renally.

Laxatives

Class Summary

Pharmacologic management of constipation in patients with MS includes the use of stool softeners. Stool softeners, such as docusate sodium (Colace), work by decreasing surface tension, allowing water to enter the stool.

Docusate sodium (Colace, Silace, Sof-Lax, Promolaxin, Kao-Tin)

Docusate sodium allows the incorporation of water and fat into stools, causing stools to soften. By its surface active properties, docusate sodium keeps stools soft for easy, natural passage. Docusate sodium is not a laxative and, thus, is not habit-forming. Tachyphylaxis may occur with long-term use. This agent is effective acutely and does not induce defecation.

Psyllium (Fiber Therapy, Gen-Mucil, Konsyl, Metamucil MultiHealth Fiber, Reguloid)

Psyllium is administered orally and absorbs liquid in the GI tract, thereby altering intestinal fluid and electrolyte transport. Absorption of liquid also causes expansion of the stool, and the resultant bulk facilitates peristalsis and bowel motility.

Methylcellulose (Citrucel)

Methylcellulose increases the bulk of the stool and thereby stimulates peristalsis, which increases bowel motility and decreases GI transit time. These actions of methylcellulose result in easy passage of stool in patients with chronic constipation.

Acetylcholinesterase Inhibitors, Central

Class Summary

Multiple sclerosis may affect cognition, and cognition-enhancing drugs have been met with some success in MS patients. Treatments used in Alzheimer disease, such as donepezil (Aricept), may have some potential beneficial effects; however, it has not been proven in clinical trials. Donepezil is not FDA-approved for use in MS. Depression may also contribute to cognitive dysfunction and should be treated if it is diagnosed.

Donepezil (Aricept)

Donepezil selectively inhibits acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine, and improves the availability of acetylcholine.

Antidiarrheals

Class Summary

Diarrhea, if it occurs, typically is not related to MS per se; it is more likely due to fecal impaction, diet, irritation of the bowel, or overuse of laxatives or stool softeners, or it is an adverse effect of medications. Diphenoxylate and atropine (Lomotil) is an antidiarrheal that helps slow the muscles of the bowel.

Diphenoxylate and atropine (Lomotil)

Diphenoxylate appears to exert its effect locally and centrally on the smooth muscle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. A subtherapeutic dose of anticholinergic atropine sulfate is added to discourage overdosage, in which case diphenoxylate may clinically mimic the effects of codeine.

Potassium Channel Blockers

Class Summary

By delaying repolarization and prolonging duration of action potential, agents in this class improve conduction in focally demyelinated axons, which may strengthen skeletal muscle fiber twitch activity and improve peripheral motor neurologic function.

Dalfampridine (Ampyra)

Dalfampridine, a broad-spectrum potassium blocker is approved as a treatment to improve walking in patients with MS. The improvement in walking was demonstrated by an increase in walking speed.

 

Questions & Answers

Overview

What is multiple sclerosis (MS)?

What are the signs and symptoms of multiple sclerosis (MS)?

How is multiple sclerosis (MS) diagnosed, and which tests are used?

What are the different types of multiple sclerosis (MS)?

What are the main aspects of treatment of multiple sclerosis (MS)?

What treatments are available for acute relapses of multiple sclerosis (MS)?

Which disease-modifying agents for multiple sclerosis (MS) (DMAMS) have been FDA-approved for use?

Which agents are used in the treatment of aggressive multiple sclerosis (MS)?

Which medications are used to treat the symptoms of multiple sclerosis (MS)?

What is multiple sclerosis (MS)?

What is the etiology of multiple sclerosis (MS)?

How is multiple sclerosis (MS) diagnosed?

Is any attack of CNS demyelination diagnostic for multiple sclerosis (MS)?

What treatments are available for multiple sclerosis (MS)?

What is revealed in the exam of the demyelinating lesions in the spinal cord and brain of patients with multiple sclerosis (MS)?

What is myelocortical multiple sclerosis (MCMS)?

How does the location of multiple sclerosis (MS) lesions affect how the disease manifests?

How are lesions formed in multiple sclerosis (MS)?

What do molecular studies of white matter plaque tissue reveal in multiple sclerosis (MS)?

What is the role of T-lymphocytes in the pathophysiology of multiple sclerosis (MS)?

In addition to T cells, what other immune cells are involved in the pathogenesis of multiple sclerosis (MS)?

What is spinal multiple sclerosis (MS)?

What is optic neuritis (ON) in multiple sclerosis (MS)?

What causes multiple sclerosis (MS)?

What is the role of genetics in multiple sclerosis (MS)?

What is the molecular mimicry hypothesis in multiple sclerosis (MS)?

What is the role of viral illness in multiple sclerosis (MS)?

What is the role of geography in the etiology of multiple sclerosis (MS)?

What is the role of vitamin D in the etiology of multiple sclerosis (MS)?

What is the chronic cerebrospinal venous insufficiency (CCSVI) hypothesis in the etiology of multiple sclerosis (MS)?

Should patients with multiple sclerosis (MS) get a hepatitis B vaccination?

What is the prevalence of multiple sclerosis (MS) in the US, and which patient populations are most commonly affected?

What is the worldwide prevalence of multiple sclerosis (MS), and what is the role of ethnicity in MS?

What is the prognosis of multiple sclerosis (MS)?

What is the life expectancy of patients with multiple sclerosis (MS)?

What educational information should be provided to patients with multiple sclerosis (MS) and their caregivers?

What information resources are available for patients with multiple sclerosis (MS)?

Presentation

What is the significance of optic neuritis (ON) in multiple sclerosis (MS)?

How is spasticity characterized in multiple sclerosis (MS)?

How is constipation characterized in multiple sclerosis (MS)?

How are attacks or exacerbations of multiple sclerosis (MS) characterized?

How does multiple sclerosis (MS) present?

What are the classic symptoms of multiple sclerosis (MS)?

What are uncommon signs and symptoms of multiple sclerosis (MS)?

What are the indications of acute transverse myelitis in patients with multiple sclerosis (MS)?

What is the role of fatigue in multiple sclerosis (MS)?

How is cognitive dysfunction characterized in multiple sclerosis (MS)?

How is pain characterized in multiple sclerosis (MS)?

How is bladder dysfunction characterized in multiple sclerosis (MS)?

How is heat intolerance characterized in multiple sclerosis (MS)?

Which body systems are evaluated in the physical exam of multiple sclerosis (MS)?

Which clinical findings are consistent with multiple sclerosis (MS)?

How does optic neuritis (ON) manifest in multiple sclerosis (MS)?

How is the loss of visual acuity characterized in optic neuritis (ON) in the setting of multiple sclerosis (MS)?

How is demyelinating optic neuritis (ON) characterized in multiple sclerosis (MS)?

What visual changes are associated with optic neuritis (ON) in patients with multiple sclerosis (MS)?

In addition to optic neuritis (ON) what other visual disorders are associated with multiple sclerosis (MS)?

Which disability scale is most commonly used to rate the status of a patient with multiple sclerosis (MS)?

Which neurologic systems are evaluated in the Kurtzke Expanded Disability Status Scale (EDSS) in multiple sclerosis (MS)?

How are the grades of the 10-point Kurtzke Expanded Disability Status Scale (EDSS) defined in multiple sclerosis (MS)?

What are the advantages and limitations of the 10-point Kurtzke Expanded Disability Status Scale (EDSS) in multiple sclerosis (MS)?

What scales other than the Kurtzke Expanded Disability Status Scale (EDSS) can be used to rate the disability of a patient with multiple sclerosis (MS)?

What are the categories of multiple sclerosis (MS)?

How is relapsing-remitting multiple sclerosis (MS) (RRMS) characterized?

How is the progression of relapsing-remitting multiple sclerosis (MS) (RRMS) characterized?

What is the role of disease-modifying agents in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

How are primary progressive multiple sclerosis (MS) (PPMS) and progressive-relapsing multiple sclerosis (PRMS) characterized?

DDX

How is acute disseminated encephalomyelitis (ADEM) distinguished from multiple sclerosis (MS)?

How is Schilder disease distinguished from multiple sclerosis (MS)?

How is Bal concentric sclerosis distinguished from multiple sclerosis (MS)?

How is sarcoidosis distinguished from multiple sclerosis (MS)?

What is CADASIL, and how is it distinguished from multiple sclerosis (MS)?

How is infarction of the spinal cord distinguished from multiple sclerosis (MS)?

How is an arteriovenous fistula distinguished from multiple sclerosis (MS)?

Is CNS demyelination diagnostic for multiple sclerosis (MS)?

What is a common challenge in diagnosing multiple sclerosis (MS)?

What are the main differential diagnoses for multiple sclerosis (MS)?

How are spinal cord neoplasms distinguished from multiple sclerosis (MS)?

How is transverse myelitis distinguished from multiple sclerosis (MS)?

How are vasculitic processes distinguished from multiple sclerosis (MS)?

How is radiation myelitis distinguished from multiple sclerosis (MS)?

What are the differential diagnoses for Multiple Sclerosis?

Workup

How is multiple sclerosis (MS) diagnosed?

Why is early diagnosis of multiple sclerosis (MS) important?

What are the McDonald criteria for a diagnosis of multiple sclerosis (MS)?

Which conditions should be excluded by blood tests in suspected multiple sclerosis (MS)?

Which imaging procedure is used to confirm and monitor multiple sclerosis (MS)?

What are the current guidelines for the use of MRI in the workup of multiple sclerosis (MS)?

What are the advantages of MRI over CT scanning and clinical exam in multiple sclerosis (MS)?

What do MRI results reveal in multiple sclerosis (MS)?

What are the limitations of using MRI in multiple sclerosis (MS)?

What is the role of functional MRI (fMRI) in multiple sclerosis (MS)?

What is the role of magnetic resonance spectroscopy in multiple sclerosis (MS)?

What are the roles of radiography, angiography, and ultrasonography in the investigation of multiple sclerosis (MS)?

Which evoked potential tests are useful in the evaluation of multiple sclerosis (MS)?

What is the role of EEG in the evaluation of multiple sclerosis (MS)?

What is the role of LP in the workup of multiple sclerosis (MS)?

Treatment

What are the 2 main approaches to treatment for multiple sclerosis (MS)?

What is the role of clinically isolated syndrome (CIS) in multiple sclerosis (MS)?

What is the treatment for clinically isolated syndrome (CIS), and what are the implications for the development of multiple sclerosis (MS)?

What are the goals of emergency medical care in cases of acute exacerbation of multiple sclerosis (MS)?

What is the role of plasmapheresis in the emergent treatment of acute fulminant multiple sclerosis (MS)?

How can known precipitants of multiple sclerosis (MS) exacerbation be managed in the emergent setting?

What are the preoperative considerations for emergency surgery in fulminant multiple sclerosis (MS)?

What treatments are available for acute relapses of multiple sclerosis (MS)?

What have the DECIDE and SELECT studies shown about the effectiveness of daclizumab (Zinbryta) in the treatment of relapsing multiple sclerosis (MS)?

Which DMAMS have been approved to treat in multiple sclerosis (MS)?

How are DMAMS administered in the treatment of multiple sclerosis (MS)?

What factors should be considered when choosing a DMAMS for multiple sclerosis (MS)?

What is the role of interferon beta-1b (Betaseron, Extavia) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

How effective is interferon beta-1b (Betaseron, Extavia) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

How is interferon beta-1b (Betaseron, Extavia) administered in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS), and what are the potential adverse reactions?

How effective is interferon beta-1a (Avonex or Rebif) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is the safety and efficacy of high-dose interferon beta-1a (Rebif) in relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is the effect of switching to a higher dosage of interferon beta-1a (Avonex or Rebif) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is peginterferon beta-1a (Plegridy), and how is it administered in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What are the findings of the ADVANCE trial on the use of peginterferon beta-1a (Plegridy) to treat relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is the role of glatiramer acetate (Copaxone) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

How effective is glatiramer acetate (Copaxone) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is the dosage regimen for glatiramer acetate (Copaxone) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is natalizumab (Tysabri), and when is it indicated in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

How effective is natalizumab (Tysabri) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS), and what is its dosage regimen?

What risk factors are associated with natalizumab (Tysabri) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS), and how is its use restricted by the FDA?

Does natalizumab (Tysabri) improve ambulation in relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is fingolimod (Gilenya), and what is the recommended dosage in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is the mechanism of action of fingolimod (Gilenya) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What adverse effects are associated with the use of fingolimod (Gilenya), and what are the FDA recommendations for first-dose monitoring?

When is fingolimod (Gilenya) contraindicated in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What are the recommendations for the use of fingolimod (Gilenya) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS) with preexisting cardiovascular conditions?

Can fingolimod (Gilenya) be used to treat relapsing-remitting multiple sclerosis (MS) (RRMS) in patients who are also on cardiac medications?

What adverse reactions are associated with fingolimod (Gilenya) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is the protocol for switching from natalizumab to fingolimod (Gilenya) in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What is teriflunomide (Aubagio), and how is it administered in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What has the TEMSO trial demonstrated on the use of teriflunomide (Aubagio) to treat relapsing-remitting multiple sclerosis (MS) (RRMS)?

What are the most common adverse reactions associated with teriflunomide (Aubagio), and how are the risks of infection and hypertension mitigated?

When is teriflunomide (Aubagio) contraindicated in the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

Is teriflunomide (Aubagio) safe to use during pregnancy for the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS)?

What adverse effects are associated with the use of teriflunomide (Aubagio) in the treatment of relapsing multiple sclerosis (MS)?

Can teriflunomide (Aubagio) and interferon beta-1a be used together for the treatment of relapsing multiple sclerosis (MS)?

What is dimethyl fumarate (DMF), and how does it work to treat multiple sclerosis (MS)?

What have the DEFINE, CONFIRM, and ENDORSE studies shown about the effectiveness of dimethyl fumarate (DMF) in the treatment of relapsing multiple sclerosis (MS)?

What is alemtuzumab (Lemtrada), and when is it indicated in the treatment of relapsing multiple sclerosis (MS)?

How effective is alemtuzumab (Lemtrada) in the treatment of relapsing multiple sclerosis (MS)?

What have the OPERA studies shown about the effectiveness of ocrelizumab (Ocrevus) in the treatment of relapsing multiple sclerosis (MS)?

When is high-dose cyclophosphamide (Cytoxan) indicated in the treatment of aggressive multiple sclerosis (MS)?

When is mitoxantrone indicated in the treatment of multiple sclerosis (MS)?

What risks are associated with the use of mitoxantrone in the treatment of multiple sclerosis (MS)?

What treatments are available for primary progressive multiple sclerosis (MS) (PPMS), and how effective are they?

Is interferon beta effective in reducing disability progression in primary progressive multiple sclerosis (MS) (PPMS)?

What treatments are available for secondary progressive multiple sclerosis (MS) (SPMS)?

What experimental agents are currently in development for the treatment of multiple sclerosis (MS), and what are the adverse effects?

Is autologous hematopoietic stem cell transplantation (AHSCT) a safe and effective treatment for multiple sclerosis (MS)?

What is the effect of pregnancy and breastfeeding on the course of multiple sclerosis (MS)?

Should treatment of multiple sclerosis (MS) be modified in patients who are pregnant or are planning to become pregnant?

Which symptoms of multiple sclerosis (MS) can be treated?

When does diarrhea occur in patients with multiple sclerosis (MS), and how is it treated?

How is cognitive dysfunction treated in patients with multiple sclerosis (MS)?

How is depression treated in patients with multiple sclerosis (MS)?

How is fatigue treated in patients with multiple sclerosis (MS)?

Which nonpharmacological treatments for fatigue are available for patients with multiple sclerosis (MS)?

Which multiple sclerosis (MS) medications contribute to fatigue?

Is pain a symptom of multiple sclerosis (MS)?

What types of pain are associated with multiple sclerosis (MS), and how are they managed?

What steps can be taken to manage heat intolerance associated with multiple sclerosis (MS)?

When is treatment of spasticity indicated in patients with multiple sclerosis (MS)?

What medications are available to manage spasticity in patients with multiple sclerosis (MS)?

Which medications are used to treat spasticity in multiple sclerosis (MS), and what are the standard dosages and side effects?

Which medication is used to improve walking ability in patients with multiple sclerosis (MS), and how effective is it?

What risks are associated with the use of dalfampridine (Ampyra) in the treatment of multiple sclerosis (MS)?

How is bladder dysfunction managed in multiple sclerosis (MS)?

What are the symptoms of bladder dysfunction in multiple sclerosis (MS), and how are they treated?

What studies are indicated if initial attempts at symptom management for bladder dysfunction in multiple sclerosis (MS) are not effective?

What is the most common bowel problem in multiple sclerosis (MS), and how is it managed?

Which medications are used to manage constipation in multiple sclerosis (MS)?

What are the nonpharmacologic treatments for managing constipation in multiple sclerosis (MS)?

How is sexual dysfunction characterized in multiple sclerosis (MS), and how is it treated?

Which medications can be used to manage tremor in multiple sclerosis (MS), and how effective are they?

Which medications are used to treat optic neuritis in multiple sclerosis (MS), and how effective are they?

Which kinds of therapists may be beneficial to a rehabilitation program for patients with multiple sclerosis (MS)?

What is the role of physical therapy in the management of multiple sclerosis (MS)?

How is stretching used to treat spasticity in multiple sclerosis (MS)?

What nonpharmacologic treatments can be used to relieve pain in multiple sclerosis (MS)?

What is the role of occupational therapy in the management of multiple sclerosis (MS)?

What are the treatment approaches for cognitive dysfunction in multiple sclerosis (MS)?

Who should participate in patient education programs for multiple sclerosis (MS) management?

What is the role of surgical procedures to alleviate symptoms of multiple sclerosis (MS)?

What is the role of vitamin D in multiple sclerosis (MS), and what are the optimal levels of serum vitamin D?

What is the benefit of early treatment with immunomodulatory drugs in multiple sclerosis (MS)?

What is the Uhthoff phenomenon, what are the symptoms, and how is it resolved in multiple sclerosis (MS)?

How does stress or trauma affect the course of multiple sclerosis (MS)?

What consultations should be considered in multiple sclerosis (MS), and which specialists are most commonly involved in a multidisciplinary approach to MS management?

How can a social worker assist patients with multiple sclerosis (MS)?

Which consultations are indicated when a patient with multiple sclerosis (MS) is considering treatment with a medication with known adverse effects?

What is the recommended follow-up and long-term monitoring of multiple sclerosis (MS)?

Which vaccinations are safe in patients with multiple sclerosis (MS)?

Which vaccines have an unknown safety profile in the setting of multiple sclerosis (MS)?

What are the special considerations for vaccination in multiple sclerosis (MS)?

Guidelines

Which organizations have issued guidelines for the use of imaging in the diagnosis of multiple sclerosis (MS)?

What are the guidelines from the CMSC for imaging studies in the diagnosis and monitoring of clinically isolated syndrome (CIS) or suspected multiple sclerosis (MS)?

When is follow-up brain MRI with gadolinium indicated in established multiple sclerosis (MS), according to CMSC guidelines?

What are the MAGNIMS (Magnetic Resonance Imaging in MS) Network guidelines for the use of MRI in multiple sclerosis (MS)?

What are the MAGNIMS (Magnetic Resonance Imaging in MS) Network guidelines for monitoring established multiple sclerosis (MS)?

Are the European Academy of Neurology (EAN) guidelines similar to CMSC and MAGNIMS guidelines?

What are the guidelines for treatment of multiple sclerosis (MS) with an FDA-approved disease-modifying agent?

What are the guidelines on discontinuing DMAMS in the treatment of multiple sclerosis (MS)?

What are the ECTRIMS and EAN guidelines on disease-modifying therapies (DMAMS) for the treatment of multiple sclerosis (MS)?

Medications

What are the goals of multiple sclerosis (MS) treatment and management?

What are the two categories of drugs approved for use in multiple sclerosis (MS)?

Which medications in the drug class Immunomodulators are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Corticosteroids are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Immunosuppressants are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Sphingosine 1-Phosphate Receptor Modulators are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Dopamine Agonists are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Skeletal Muscle Relaxant are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Neuromuscular Blockers, Botulinum Toxins are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Alpha2-Adrenergic Agonists are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Benzodiazepines are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Stimulants are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Anticonvulsants, Other are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Anticonvulsants, Hydantoin are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Selective Serotonin/Norepinephrine Reuptake Inhibitors are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Nonsteroidal Anti-Inflammatory Drugs are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Antispasmodic Agents, Urinary are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Laxatives are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Acetylcholinesterase Inhibitors, Central are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Antidiarrheals are used in the treatment of Multiple Sclerosis?

Which medications in the drug class Potassium Channel Blockers are used in the treatment of Multiple Sclerosis?