Overview

Multiple sclerosis (MS) is a relatively uncommon disease, but the effects can be devastating for patients with this disease. A cure is elusive, and the cause is still unknown. Different MS subtypes are being described, and healthcare providers should stay abreast of the different clinical presentations, effective management, and progression of the disease. This comprehensive overview will serve as a refresher and an update on the clinical management of multiple sclerosis.

Education Category: Infection Control / Internal Medicine
Release Date: 01/01/2014
Expiration Date: 12/31/2016

Audience

This course is designed for physicians, primary care providers, and nurses who may intervene to improve the lives of patients with multiple sclerosis.

Accreditations & Approvals

NetCE is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NetCE is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. NetCE is accredited by the International Association for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 2 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. This home study course is approved by the Florida Board of Nursing Home Administrators for 5 credit hour(s). This course is approved by the California Nursing Home Administrator Program for 10 hour(s) of continuing education credit - NHAP#1622010-5386/P. California NHAs may only obtain a maximum of 10 hours per course. NetCE is authorized by IACET to offer 1 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through December 12, 2017); California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; Florida, Provider #50-2405; Iowa, Provider #295; Kentucky, Provider #7-0054 through 12/31/2017.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide a comprehensive review of current knowledge regarding multiple sclerosis, emphasizing new developments with respect to detection and treatment options, in order to improve patient care.

Learning Objectives

Upon completion of this course, you should be able to:

  1. Describe the risk factors for multiple sclerosis (MS).
  2. Define the etiology and pathophysiology of MS.
  3. Identify common signs and symptoms of MS.
  4. Compare and contrast early-onset and late-onset MS.
  5. Distinguish between the various MS disease courses, including relapsing-remitting, primary progressive, and secondary progressive subtypes.
  6. Identify and describe the effectiveness of the diagnostic tests and criteria used to diagnose MS.
  7. Assess the conditions that should be considered in the differential diagnosis of MS.
  8. Evaluate the various treatment options of acute exacerbations of MS crisis episodes with regard to indication, efficacy, and adverse effects.
  9. Evaluate the disease-modifying drugs used in the treatment of MS with regard to efficacy and adverse effects.
  10. Discuss options for managing the symptoms of MS.
  11. Determine possible treatment options in pregnant patients with MS.

Faculty

Jassin Jouria Jr., MD, graduated from Ross University School of Medicine, passed all USMLE medical board exams, and has held academic appointments. He has developed curricula and authored continuing education activities covering a variety of clinical topics.

Faculty Disclosure

Contributing faculty, Jassin Jouria Jr., MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Table of Contents

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#98590: Multiple Sclerosis: A Comprehensive Review

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INTRODUCTION

Multiple sclerosis (MS) is an acquired, life-long disease of the central nervous system (CNS) that usually begins in early adulthood. It initially follows a clinically remitting course but eventually is marked by fixed neurologic deficits. The etiology is unknown, and the pathogenesis complex and, in certain respects, baffling. Among cases, there is great variability in the clinical expression, neuroradiographic features, pathologic findings, and response to therapy.

In the early stage of disease, the dominant finding is a well-demarked, focal lymphocytic inflammatory process within white matter (the plaque) causing demyelination and axonal injury [1,6]. Initially, the inflammatory reaction subsides, healing and remyelination take place to some degree, and clinical symptoms and signs remit. Over time, new lesions usually develop and clinical exacerbations of disease recur. In later stages, there is evidence of neuronal injury and multiple areas of degenerative change with some degree of brain atrophy. Treatment is based on the emerging body of evidence that MS is an autoimmune disorder characterized by activated T-cell, cytokine-mediated inflammation directed against components of axonal myelin. ß-interferon, monoclonal antibody, and other agents that modify certain sequences of the immune reaction have been utilized in the effort to modify the natural history of the disease and limit neurologic deficits. The response to these targeted therapies is variable; while they do reduce the frequency and expression of new episodes, the impact on disease progression and long-term neurologic disability is unclear.

The lifetime incidence of MS in the general population is estimated to be 0.1%. The cumulative prevalence of MS in the United States is currently about 400,000, or 135 cases per 100,000 [1,2,11]. Globally, approximately 2.5 million persons suffer from this disease. In general, MS is more prevalent in industrialized nations and in countries north of the equator.

Although some patients with MS experience a relatively benign course, most have a protracted, somewhat debilitating course that ultimately impacts quality of life and imposes a significant financial burden. However, life expectancy is usually unaltered by the disease.

PREDISPOSING FACTORS

GENETICS

Genetic studies have demonstrated an inherited predisposition to acquiring MS, and epidemiologic investigations have identified several environmental factors that appear to increase the risk of developing MS [4,5,7]. Among first-degree relatives of an index case, the lifetime risk is 3% to 5%; for a monozygotic twin, the risk is 25%. The identification of specific risk alleles, and the expression of their related gene products, is the subject of much interest and ongoing investigation [4,5,8,9].

ENVIRONMENTAL FACTORS

Environmental factors are thought to play a significant role in the development of MS. Studies have shown an association between latitude and risk, with the risk increasing from south to north [13]. The lowest risk in found among persons living near the equator. As such, the prevalence of MS is higher in geographic locales having less sunlight exposure (and hence diminished production of vitamin D), suggesting that low levels of vitamin D may be a risk factor [14,15,17]. In addition, persons who smoke have an increased relative risk compared to those who do not [15,136]. It has been speculated that MS may be triggered by a complex interaction of multiple factors acting in concert, including genetic susceptibility, environmental exposures, smoking, and infection.

Certain infections acquired at a young age, and characterized by chronic latency and CNS trophism, have been implicated as risk factors [19]. These include mumps, rubella, Epstein-Barr virus, human herpesvirus 6, and Chlamydia pneumoniae [20,21,22]. Patients with MS are more likely to have detectable levels of C. pneumoniae DNA in the cerebrospinal fluid (CSF) than patients with other neurologic diseases [20]. The possibility that infection with one or more of these agents may be the principle cause, or trigger, for MS has also been investigated. Genetic material and proteins specific to microbial agents have been identified in MS brain lesions, and specific T-cell or antibody responses in blood and CSF have been found in some MS patients. However, the significance of these findings is uncertain, and the role of infection remains unclear.

PATHOGENESIS

Conceptually, MS is now considered to be an autoimmune inflammatory disorder with complex and variable pathologic features [1,3]. Susceptible individuals are those of genetic predisposition in combination with environmental factors and possibly latent infection. The etiology is unclear, but initiation of disease appears to involve the activation of peripheral T-lymphocytes, programed to recognize components of the CNS axonal myelin sheath. The disease is triggered by events that permit these autoactivated T-cells to breach the blood-brain barrier and cross-react with myelin components within the white matter of the brain and spinal cord. This precipitates a cascade of immune-mediated inflammatory tissue injury. As seen on radiographic imaging and pathologic examination, the hallmark of the disease is this well-defined, focal zone of injury ("plaque") containing elements of inflammation, demyelination, and axon degeneration [1,2]. Such lesions may be single or multiple, and over time, they may be partially reparative, relapsing, or recurrent in new locations. The location of lesions is variable; early in the disease they appear in white matter, often clustering near the ventricles and sparing peripheral nerves [9].

The autoimmune hypothesis of pathogenesis is supported in part by the following observations [3,23]:

  • Myelin antigen-specific, autoreactive T-cells have been isolated from peripheral blood lymphocytes.

  • Immunologic studies in MS patients have shown that relapses are preceded by expansion and activation of CD4+ T-cells in the peripheral immune compartment having myelin basic protein specificity.

  • The histopathology of the MS plaque often shows a T-cell mediated (Th1-type) pattern of inflammation with interleukin-2 (IL-2) and chemokine expression.

  • There is a linkage between these immunologic abnormalities and the activity of disease, as measured by clinical and magnetic resonance imaging (MRI) features.

  • Experimental autoimmune encephalomyelitis, with histopathologic features of inflammation and demyelination similar to that seen in MS, can be induced in an animal model by immunization with myelin autoantigen.

The pathologic examination of active lesions reveals considerable heterogeneity with respect to structural change and immunologic features, indicating that multiple pathogenetic mechanisms may be involved in the disease process. In one carefully conducted study, the pattern of demyelination was analyzed in a series of active lesions from MS patients [24]. The lesions could be grouped into four distinct patterns: two showed similarities to T-cell mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, and two showed a pattern reflective of primary oligodendrocytic dystrophy, similar to that seen with virus- or toxin-induced demyelination. The pattern of demyelination was heterogeneous among different patients, but homogeneous with respect to multiple lesions within the same patient.

The mechanism by which autoreactive T-lymphocytes traverse the blood brain barrier to initiate inflammation is poorly understood. There is some evidence that early in the disease process there is an increase in adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), on the vascular endothelium of brain and spinal cord. These molecules increase the permeability of the blood-brain barrier and could permit the entry of lymphocytes. Upon entry into the CNS compartment, previously activated T-lymphocytes proliferate and engage myelin-based antigens, triggering the autoimmune inflammatory cascade that leads to demyelination. The release of cytokines activates microglial cells (CNS macrophages) in turn promotes the expression of class II major histocompatibility complex (MHC) molecules and the accumulation of additional cytokines and other inflammatory mediators, such as nitric oxide, free radicals, and superoxide. The net result is a sustained proinflammatory state that destroys myelin, disrupts oligodendrocyte integrity and function, and damages axons. Table 1 provides an outline of the various components of the innate immune system, with a brief commentary on the role each cell type plays in the pathogenesis of MS [162].

ROLE OF INNATE IMMUNITY IN MS

Innate Immune System Component Impact on Pathogenesis of MS
Monocyte/macrophagesHematopoietic monocytes and macrophages are the most abundant phagocytic cells of the innate immune system that infiltrate the MS lesion. Their morphology is very heterogeneous depending on which area of the MS lesion they have infiltrated. Monocytes/macrophages can contribute to neuroinflammation as well as promote neuroprotection in MS.
Microglial cellsMicroglia provides the first-line of defense within the CNS. Microglial cells are phagocytic and clear debris resulting from inflammation. Upon activation, they can produce several proinflammatory cytokines (such as TNF) and reactive oxygen species that are toxic to infectious agents. They may also serve as antigen-presenting cells that directly activate T-cells.
Dendritic cellsDendritic cells are potent antigen presenting cells and are considered to be the critical link that bridges the innate and adaptive immune responses. Because the CNS lacks conventional lymphatic circuitry, it is thought that dendritic cells perform their antigen presenting function to directly activate T-cells within the perivascular spaces of the CNS. Therefore, dendritic cells in the periphery and within the CNS may contribute to the initiation and perpetuation of immune mechanisms germane to the disease process in MS.
Mast cellsMast cells release granules that are rich in histamine and other inflammatory mediators. Both mast cells and their mediators have been identified in MS lesions. Tryptase, an enzyme uniquely produced by mast cells, is increased in the CSF of MS patients.
Natural killer (NK) cellsNatural killer (NK) cells recognize and kill virally infected cells and tumor cells, and secrete cytokines including IFN-γ, IL-10, IL-5, and IL-13. NK cell numbers are decreased in the CSF and in lesions of MS patients, and cytolytic activity is diminished in comparison to healthy controls. In fact, studies suggest that increases in NK cells in pregnant MS patients may contribute to the decreased disease activity observed during pregnancy and indicate an immunoregulatory role for NK cells in MS.
NK-T cellsNK-T cells are T-cells that express an invariant TCR and some features of NK cells. NK-T cells have been identified in MS lesions and are thought to play a regulatory role in MS, but the conclusions of studies investigating NK-T cell numbers and function in MS patients are conflicting.
γδ T cellsγδ T cells are T lymphocytes that express the invariant γδ T cells receptor and are typically present in high numbers in the epithelium of the gut and are less frequent in the blood. γδ T cells have been identified in MS lesions but their contribution to the pathogenesis of MS has not yet been elucidated.
Non-cellular
components
Nitric oxide synthase (NOS) is an inducible enzyme produced by myeloid cells, such as monocytes/macrophages, granulocytes, and dendritic cells, that is used to generate nitric oxide. Nitric oxide is one of several reactive oxygen and nitrogen intermediates that function as potent antimicrobials. NOS is associated with MS lesions, but the role of NOS in MS remains undefined.
CSF = cerebral spinal fluid, IFN = interferon, IL = interleukin, TCR = T-cell receptor, TNF = tumor necrosis factor.

Demyelination impairs nerve impulse transmission and leads to abnormal patterns of nerve conduction, which accounts in large part for the various clinical symptoms and signs of MS. Oligodendrocytes are cells that elaborate the myelin sheath that envelops the axon. During the early, remittent stage of the disease, as inflammation subsides, the number and function of these cells are sufficient to renew the myelin sheath (remyelination) and restore neurologic function. Over time, the repeated inflammatory insults associated with relapsing MS lead to a gradual depletion of functioning oligodendrocytes, and to degenerative changes marked by central scarring within the lesion and focal areas of cerebral atrophy. The clinical correlate is the gradual accumulation of fixed neurological deficits as the patient with MS transitions to the chronic progressive stage of the disease.

The B-lymphocyte arm of the immune system may play a role in certain aspects of MS during the late stages of disease when inflammatory changes are more marked in the gray matter of the brain. In contrast to T-cell mediated inflammation of white matter, myelin-reactive B-lymphocytes and the secretion of myelin-specific antibodies appear to play a significant role in the pathogenesis of gray matter inflammatory injury. The natural history of the plaque lesion in MS also includes late-developing degenerative features that are irreversible, such as gliosis (scarring), functional abnormalities of damaged axons, neuronal degeneration, and cerebral atrophy.

SIGNS AND SYMPTOMS

The early signs and symptoms of MS are typically mild and difficult to detect. They differ in duration and severity from one individual to the other and at different times in the same individual. However, by the time they seek help, many patients have more than one symptom. Patients generally experience either acute attacks of neurological compromise or are afflicted by a steadily progressive deterioration in functional capabilities, as will be discussed in detail later in this course [162].

MS symptoms can be organized into three categories: primary, secondary, and tertiary.

PRIMARY SYMPTOMS

Primary symptoms of MS are caused by the demyelination of the CNS. The most common primary symptoms in patients with MS are:

  • Fatigue

  • Heat sensitivity

  • Muscle spasms

  • Dizziness

  • Pain

  • Paresthesias

  • Ataxia

  • Cognitive changes

  • Visual complaints

  • Bowel or bladder dysfunction

  • Sexual dysfunction

  • Gait problems

  • Nausea/vomiting

  • Speech problems

  • Tremor

  • Weakness

Fatigue

Fatigue is the most frequent and characteristic symptom of MS. It typically occurs in the mid-afternoon and may be associated with depression, increased muscle weakness, and drowsiness [27]. Fatigue is disabling in MS, resulting in a patient's inability to participate in daily activities and affecting quality of life and mental health [27].

Heat Sensitivity

Heat sensitivity (also known as Uhthoff phenomenon) is common in most individuals with MS. This occurs when the body becomes overheated due to fever, physical exercise, or exposure to a hot environment, such as hot weather, saunas, and hot baths. It is suspected that the increase in body temperature results in nerve conduction block in central pathways [29,30]. Patients with MS reach this stage earlier and at comparatively lower temperatures than healthy individuals because nerves are demyelinated. The greater the degree of demyelination, the smaller the necessary increase in temperature to induce symptoms. In individuals with MS, a small increase in body temperature can temporarily result in worsening of neurologic signs and symptoms, including fatigue, cognitive impairment, ataxia, weakness, and urinary incontinence [210].

Spasticity

The majority of patients with MS report some level of spasticity. Painful muscle spasm is experienced by approximately 15% and is often a source of debilitation [12]. Spasticity usually affects the muscles of the extremities (more prominent in the lower extremities than the upper extremities) and can impair an individual's ability to freely move his or her muscles.

Demyelinated nerves are primarily responsible for the spasticity seen in MS, as slowed or interrupted nerve conduction affects the motor function of the muscles. Muscle relaxation is slow and sluggish, and there is involuntary muscle tightening or contraction for long periods or constantly. Amyotrophy of the disuse type can be seen in some patients with MS, usually in the small muscles of the hand.

Dizziness and Vertigo

Approximately 49% to 59% of MS patient suffer from dizziness or vertigo, and this condition is usually associated with impairment of cranial nerves [16]. In one study, the effects of dizziness were reported to be moderate in 30.9% of patients and severe in nearly 8% [16]. It can substantially impact patients' quality of life, particularly if paired with other symptoms that affect mobility.

Pain

Up to 80% of patients with MS experience varying degrees of pain, and an estimated 50% experience chronic pain [18]. One study found that 63% of patients with MS reported one or more painful symptoms [12]:

  • Headache (43%)

  • Neuropathic extremity pain (26%)

  • Back pain (20%)

  • Painful spasms (15%)

  • Lhermitte's sign (16%)

  • Trigeminal neuralgia (3.8%)

MS pain is mainly neuropathic—the result of nerve damage and faulty conduction—and can include stabbing, burning, and shock-like sensations (e.g., allodynia, dysesthesias, paresthesia). Lhermitte's sign is often considered a classic sign of MS and consists of a brief, electric shock-like sensation that runs down the spine and is triggered by bending the neck forward or backward.

Some patients will experience musculoskeletal pain, likely the result of immobility and gait problems. Patients with spasticity are at greater risk for this type of pain.

Impaired Cognition

Approximately 40% to 70% of patients with MS experience varying degrees of cognitive impairment [33]. This may manifest as decreased capacity for concentration or memory and slowed thinking. Severe cognitive impairment can significantly impact patients' ability to carry out activities of daily living.

Vision Problems

Impaired vision is frequently present in patients with MS, most commonly unilateral optic neuritis, which is present in approximately in 66% of cases [35]. Optic neuritis usually manifests as acute or subacute unilateral eye pain that increases with eye movements [31]. It can also lead to blurring or graying of vision or blindness in one eye. However, while unilateral optic neuritis is common in MS, simultaneous bilateral optic neuritis (resulting in total blindness) is rare [35]. Approximately 90% of patients with MS regain normal vision over a period of 2 to 6 months after an acute episode of optic neuritis [35].

Patients may also present with intranuclear ophthalmoplegia (INO), a condition characterized by impaired nystagmus and defective horizontal ocular movements of the abducting eye. This type of visual impairment is caused by a lesion of the medial longitudinal fasciculus on the side of diminished adduction. When present in young patients, bilateral internuclear ophthalmoplegia is suggestive of MS [35].

Sensory Symptoms

Patients with MS often experience various sensory symptoms through the course of the disease. This includes impairment of vibration and joint position sense, decreased pain and light touch perception, "pins-and-needles" sensation, tightness, and coldness of the extremities. A dysesthetic itching specifically present around the cervical dermatomes is indicative of MS.

Bowel, Bladder, and Sexual Dysfunction

The severity of bowel sphincter impairment and sexual dysfunction is directly proportional to the extent of motor impairment in the lower extremities. Urgency is the most frequent urinary complaint in patients with MS, with frequent urinary incontinence common as the disease progresses. MS can also lead to atonic dilated bladder. Upper and lower motor neuron impairment can result in constipation. Erectile dysfunction is common in men suffering from MS. As many as 91% of men and 72% of women with MS report some form of sexual dysfunction [42].

Gait Imbalance

Gait disturbances and imbalance are characteristic symptoms of MS. Patients will experience varying degrees of difficulty executing coordinated actions because of damaged cerebellar pathways. Dysmetria and hypotonia are frequently seen in the upper extremities. Some patients exhibit intention (cerebellar) tremor, particularly in the head and limbs. These tremors can be incapacitating and refractory to treatment. Walking is also affected due to truncal ataxia. In severe cases, patients lose the ability to stand (astasia).

Paroxysmal Symptoms

Patients with MS frequently exhibit paroxysmal attacks of motor or sensory symptoms causing facial paresthesia, trigeminal neuralgia, ataxia, and diplopia. Dystonia (painful tonic contractions of muscles) is seen when the motor system is involved.

SECONDARY SYMPTOMS

Secondary symptoms arise as a result of the presence of certain primary symptoms. For example, pressure ulcers may form as a complication of paralysis, a primary symptom. Bladder problems or urinary incontinence can cause frequent, recurring urinary tract infections. These symptoms are treatable, but ideally they should be avoided by treating the primary symptoms. The most common secondary symptoms present in patients with MS are [163]:

  • Urinary tract infections

  • Kidney or bladder stones

  • Pressure ulcers

  • Muscle contractures

  • Respiratory infections

  • Poor nutrition

  • Difficulty breathing (severe)

  • Disuse weakness

  • Poor postural alignment and trunk control

  • Decreased bone density

  • Back pain

TERTIARY SYMPTOMS

Tertiary symptoms may be described as the "trickle down" effects of MS and include the social, psychological, and vocational complications associated with the primary and secondary symptoms [163]. Depression is a frequent tertiary symptom present among people with MS. Social isolation, job loss, marital or interpersonal conflict, and anxiety may all develop as a result of various primary and secondary symptoms of MS.

DISEASE ONSET

MS diagnosed in the extremities of age may be categorized as either early- or late-onset. These types of MS tend to have different disease courses and variations in presentation.

LATE-ONSET MS

Late-onset MS is diagnosed in patients older than 50 years of age. Because many of the signs of late-onset MS are similar to other medical conditions associated with aging, misdiagnosis or delayed diagnosis is common. Late-onset MS is characterized by a progressive course, predominant motor symptoms, difficulties with treatment, and poor prognosis.

Some of the most frequent motor symptoms present in late-onset MS include:

  • Gait disturbances

  • Trouble moving arms and/or legs

  • Muscle spasms

  • Tremor

  • Clumsiness

  • Weakness

Most patients with late-onset disease experience only one symptom in the beginning and steadily accumulate more symptoms. The disease typically follows a primary-progressive course and is associated with poorer response to treatment than the relapse-remitting types seen more often in early-onset. Patients with late-onset MS frequently have memory and learning disabilities, difficulty with selective attention, and short-term memory deficits. Depression is also common. Disability progression appears to be faster and more severe in late-onset MS.

EARLY-ONSET MS

Early-onset MS is usually diagnosed in patients younger than 20 years of age. It accounts for approximately 0.4% to 10.5% of all MS cases [48]. Usually, the disease is characterized by a relapsing-remitting course, a high recovery rate from initial attack, and a long remission and slow progression rate. Sensory symptoms are more common than motor symptoms in these patients, and vision loss is a common initial symptom. Other functional systems are involved with a variable frequency. Seizures, malaise, irritability, and low-grade fever may also be present.

DISEASE PATTERN

The pattern and course of MS is categorized as relapsing-remitting, secondary progressive, primary progressive, progressive-relapsing, benign, malignant, or clinically isolated [32].

RELAPSING-REMITTING

Relapsing-remitting multiple sclerosis (RRMS) is characterized by alternating series of clearly defined relapses or exacerbations followed by remissions with no new signs of active disease. RRMS is the most common type of MS, accounting for about 85% of all cases [152]. Functional and structural impairments suffered during relapses may either resolve or leave sequelae.

The majority of patients with RRMS subsequently enter a secondary progressive disease course. Studies have demonstrated that the time from RRMS onset to secondary progression is approximately 20 years [152]. A minority of RRMS patients will have a relatively benign course.

The most frequent symptoms of RRMS include:

  • Episodes of visual loss or double vision

  • Tingling or numbness

  • Fatigue

  • Urinary urgency

  • Balance problems

  • Weakness

SECONDARY PROGRESSIVE

Secondary progressive MS (SPMS) is usually characterized by an initial presentation of RRMS followed by a progressive neurologic impairment between relapses without any well-defined periods of remission [32]. Of patients diagnosed with RRMS, 50% will develop SPMS within 10 years and 90% will progress to SPMS within 25 years [152]. Conversion of RRMS to SPMS is determined solely on clinical findings; biochemical markers or specific tests are not useful.

Persons with SPMS usually experience cognitive impairment, pain, and numbness. One of the characteristic features of SPMS is disabling tremor that can last for an extended period of time. This disease is characterized by a progressive deterioration of ability, and people with SPMS usually do not recover completely from a relapse.

PRIMARY PROGRESSIVE

Primary progressive MS (PPMS) is characterized by steady disease progression with occasional remissions and temporary minor improvements [32]. PPMS constitutes approximately 10% of cases at disease onset [34].

In PPMS, there is a progressive decline in function with an absence of acute inflammatory attacks. Patients exhibit steadily worsening motor dysfunction and increased disability. PPMS usually has a later age of onset and may have a worse prognosis for disability compared to patients with RRMS. Although the onset age is later for PPMS than for RRMS, the mean age at progression to SPMS is similar [1].

Patients with PPMS may experience symptoms similar to those seen with RRMS. However, PPMS usually involves the spinal cord, and signs and symptoms are often related to spinal involvement. Approximately 80% of patients with PPMS have progressive weakness of the lower limbs with spasticity, known as spastic paraparesis [153]. Approximately 15% of PPMS patients experience ataxia as a result of progressive cerebellar involvement. Other symptoms include altered sensation, muscle spasms and weakness, mobility problems, difficulty in speech or swallowing, visual impairments, fatigue, pain, and bladder and/or bowel difficulties. An estimated 6% of PPMS patients suffer from hemiparesis [153].

The lesions associated with PPMS show a reduction in the number of oligodendrocytes and myelin repair when compared to other types of MS. Widespread inflammation with diffuse axonal damage in white brain matter is often present. This leads to cortical tissue and axonal damage, with associated irreversible and progressive disability. There is increased intrathecal production of IgG antibodies, and oligoclonal bands are found in the CSF of approximately 90% of cases [153].

PROGRESSIVE-RELAPSING

Progressive-relapsing MS (PRMS) is characterized by a steady progression of clinical neurological damage with clear acute exacerbations (with or without full recovery) and no total remissions. Progression continues even between the relapses. This type is the rarest of all the main MS subtypes, occurring in about 5% of cases [32]. The functions lost in PRMS are permanent, and the disability accumulates by progressive decline in function. PRMS is associated with a severe disease course and a relatively high mortality rate.

BENIGN MS

Benign MS is a retrospective diagnosis characterized by long-term absence of symptoms with no functional impairments of neurologic systems 15 years after the disease onset. Approximately 15% of patients with an acute MS attack do not experience another relapse [158]. However, a relapse may occur after many years of inactivity, and it important not to assume that mild MS is truly benign.

MALIGNANT MS

Malignant MS (also known as Marburg's variant) is characterized by a rapidly progressive course resulting in major disability and usually death within one year of the onset. This disease course is most common in children, although older adults may be affected as well.

Malignant MS is associated with larger lesions, more often involving the brain stem. It shows poor response to treatment, but there may be some improvements with plasmapheresis or experimental therapies (e.g., stem cell transplantation).

CLINICALLY ISOLATED SYNDROME

The first neurological episode of MS due to inflammation or demyelination CNS is referred to as a clinically isolated syndrome. The symptoms of this episode may be unifocal or multifocal, and structural features of the brain and spinal cord on MRI make it possible to identify individuals at risk of developing MS during the clinically isolated syndrome. In additional cerebrospinal fluid analysis may be helpful in predicting likelihood of conversion to MS. Some studies have shown that starting a disease-modifying treatment at this stage can delay both conversion to MS and onset of the progressive phase [165].

DIAGNOSIS

Diagnosis of MS can be difficult, as its signs and symptoms are similar to many other medical problems. Lengthy neurological exams and various types of tests are often necessary. It is also important to determine MS subtype, whether the disease is definitive, and the extent of disability.

There is no single test or gold standard for the diagnosis of MS. The process of diagnosis typically involves:

  • Evidence from the patient history

  • Clinical examination

  • One or more laboratory tests

All three of these approaches are generally necessary in order to accurately diagnose MS and complete the differential diagnosis.

The diagnosis of MS is based on the multiple phases of the clinical course. Patients with MS experience various neurological dysfunctions at different stages that impair different regions of CNS. The diagnosis of MS must be concluded by careful assessment of all the evidence both for and against the disease. Final diagnosis will depend upon the extent to which the patient's overall picture has the expected findings typical of MS.

NEUROLOGIC EXAM

In order to properly diagnose MS, the following should be assessed:

  • Cranial nerve function

  • Coordination

  • Strength

  • Reflexes

  • Sensation

A variety of neurological tests are available to evaluate the many areas in which dysfunction may be present (Table 2). Because no particular neurological symptoms or findings are pathognomonic for MS, this process can be lengthy. Certain important clues from the history and/or physical exam often lead to the correct diagnosis. Because testing and patient history are so important to the accurate diagnosis of MS, it is vital to take into account patient literacy and preferred language. When there is an obvious disconnect in the communication process between the practitioner and patient, an interpreter is required.

NEUROLOGICAL SIGNS AND TESTS

TestDescriptionNotes
Romberg's testPatient stands erect with feet together and eyes closed. Swaying or falling is considered positive.Used for patients with ataxia. Indicates loss of proprioception.
Lhermitte's signPatient bends the head forward or clinician puts pressure on the posterior cervical spine. An electrical shock sensation is considered positive.Used to determine the presence of lesions on the cervical spine. Often considered a classic finding in MS but can be caused by a number of conditions.
Gait testsObserve patient walking normally, walking heel-to-toe, and walking on only toes/heels. Any abnormalities should be noted.This test evaluates ataxia in various parts of the body.
Point-to-point movement evaluationPatients alternate touching their extended index finger to their nose and the examiner's outstretched finger.These are tests to evaluate ataxia, dysmetria, and cerebellar dysfunction. Positive findings are indicative of loss of motor strength, loss of proprioception, or a cerebellar lesion.
Supine patient places right heel on left shin just below the knee and slides it down to the top of the foot as quickly as possible without making mistakes. Repeat on opposite side. Inability to complete quickly is considered positive.
Visual acuity and color testsPatient reads letters from a board to assess visual acuity and from the Ishihara Color Vision Test to assess color vision. Inability to distinguish figures is considered positive.These tests evaluate for the presence of optic neuritis, perhaps the most frequent symptom in MS.
Babinski's signThe lateral side of the sole of the foot is lightly stimulated from the heel along a curve to the toes. If the hallux dorsiflexes and the other toes fan out, this is considered a positive Babinski's sign.These tests evaluate for signs of disease process in the motor neurons of the pyramidal tract. They are positive in individuals with neurological problems of the corticospinal tract, including those with MS.
Chaddock's signSimilar to Babinski's sign, this test involves stimulation over the lateral malleolus rather than the bottom of the foot. A positive response elicits an extensor response similar to Babinski's sign.
Hoffman's reflexClinician taps the nail or flicks the terminal phalanx of the middle or ring finger. A positive response is seen with flexion of the terminal phalanx of the thumb.This test evaluates problems in the corticospinal tract. However, it is also positive in hyper-reflexive patients. Findings that are acute or asymmetrical are more indicative of disease.
Halmagyi-Curthoys head impulse testClinician randomly moves the patient's head side to side. If the eyes remain stationary while the head is moved, this is considered positive.Test reveals dissociation between movement of the eyes and of the head. Indicative of peripheral vestibular disease.
Perception testsA monofilament, tuning fork, or pin is applied to patient's body. Ability to perceive the touch or vibration is considered positive.Evaluates the level of sensory perception in certain parts of the body.
Muscle strength testsPatient attempts to resist pressure applied by the clinician to various muscle groups. Level of resistance can be rated on a scale from none to normal strength.Patterns of weakness can help localize a lesion to a particular cortical or white matter region, spinal cord level, nerve root, peripheral nerve, or muscle. Differences in strength between left and right sides are easier to evaluate than symmetrical loss unless the weakness is severe.
ReflexesThis is done with both ends of the hammer. The reflexes can be normal, brisk (i.e., too easily evoked), or non-existent.

INO, especially a bilateral INO in young patients, is suggestive of MS, as it is rare in other conditions. Altered color vision, unilateral optic pallor, and/or Marcus-Gunn pupil may be indicative of optic neuritis. Patients with MS may also exhibit nystagmus.

A mild intention tremor can be an early sign of MS. Patients with early MS may also exhibit a positive Romberg's sign, or decreased vibratory and proprioceptive sense in lower extremities. A positive Lhermitte's sign in an adult younger than 60 years of age may indicate MS [45].

For some patients, clinical symptomatology is inadequate to establish a diagnosis of MS, especially in individuals who have experienced separate episodes of neurologic symptoms [45]. As such, additional diagnostic tests may be necessary to fully evaluate the patient and determine the diagnosis. This can include imaging, laboratory tests, and nerve stimulation.

MAGNETIC RESONANCE IMAGING

MRI of the CNS is indicated to diagnose MS and to detect any changes in MS activity that might influence the management of the disease. MRI of the brain and spine will show areas of demyelination in most patients with MS. MRI of patients with MS often reveals multiple lesions in the CNS, even during the clinically isolated syndrome [162]. MRI with contrast (i.e., IV gadolinium) shows active plaques and, by elimination, can reveal the presence of older lesions not associated with current symptoms [38,45]. If present, these older lesions provide some evidence of a period of occult disease prior to the onset of symptoms. As MRI techniques become more sophisticated and pathologically specific, there is an increased likelihood of exploring the pathological classification of MS.

A radiologically isolated syndrome is a presentation without overt clinical symptoms but with MRI findings highly suggestive of MS based upon location and morphology within the CNS [45]. Studies have shown that the majority of patients with a radiologically isolated syndrome eventually develop more lesions and progress to a true clinical exacerbation. These patients are usually identified when MS lesions are found when they undergo an MRI for other reasons [162].

When there is a weak association between common neuroradiological markers of MS and clinical disability, this is referred to as a clinicoradiologic paradox. This partly relates to the principle of eloquence and non-eloquence. Non-eloquent lesions are lesions that tend to develop in particular anatomic locations and are not always associated with clinically consistent symptoms; they are also referred to as silent or subclinical. Eloquent lesions usually develop in particular anatomic locations or pathways and almost always result in the manifestation of a characteristic inflammatory demyelinating syndrome [162]. These lesions are associated with expected clinical neurological manifestations (Table 3).

ELOQUENT MS SYNDROMES

Eloquent SyndromeLocalizationClinical Manifestations
Optic neuritisOptic nerve
Visual acuity loss
Visual field suppression
Color desaturation
Pain
Relative afferent pupillary defect
Internuclear ophthalmoparesis (INO)Medial longitudinal fasciculus (MLF)
Slowing of adducting eye movements
Diplopia
Oscillopsia
Skew deviationOtolith pathways
Vertical or oblique diplopia
Subjective deviation of visual vertical
Cranial nerve palsiesBrainstem
Facial weakness
Facial numbness (cranial nerve V) or pain
Diplopia (cranial nerves III, IV, VI)
Vestibulopathy (cranial nerve VIII or nucleus)
Rubral tremorSuperior cerebellar peduncleTremor
AtaxiaCerebellumInstability and reduced postural control
Trigeminal neuralgiaTrigeminal systemParoxysmal facial pain
MyelitisSpinal cord
Sensory disturbances
Spasticity
Bowel/bladder/sexual dysfunction
Weakness

A number of MRI sequences are done to reveal different histopathological features of the MS plaque. These MRI sequences are "weighted" to demonstrate water or fat. T1-weighted, T2-weighted, and proton-density scans are used in the diagnosis of MS, and all are sensitive to the higher-than-normal water content found in MS lesions. These images are partially confounded by the intense signal of the water content of the CSF. Three-dimensional fluid-attenuated inversion recovery imaging is an imaging technique that nulls fluids and is used to suppress CSF effects and enhance the periventricular hyperintense lesions present in MS [40].

An MRI scan, particularly a T2-weighted scan, is considered strongly predictive of MS if it shows at least four lesions in the brain or three lesions with at least one present in the periventricular region. However, while these criteria are considered sensitive, they are not very specific. More accurate criteria require at least three lesions be present, fulfilling at least two of the following criteria:

  • Periventricular lesion

  • Lesion at least 6 mm in diameter

  • Infratentorial lesion

T1-weighted, T2-weighted, and proton-density scans also reveal complementary information about the nature of MS. T1-weighted scans provide a better anatomical picture of the brain and are useful for detecting older lesions and abnormal areas. These scans are often used with contrast to illuminate areas of recent inflammation that may be associated with active MS. T2-weighted scans do not show the best anatomical picture of brain compared to T1-weighted scans, but they can detect both new and old lesions. These scans are repeated over a period of time to track the development of MS. Proton-density scans also detect both old and new lesions and are particularly useful in detecting periventricular plaques.

High-field and ultra-high-field MRI can detect a greater number and volume of T2-hyperintense and gadolinium-enhancing brain lesions than those operating at lower fields [195,196]. These high power MRIs can detect MS at a very early stage and are more sensitive to cortical lesions [197].

The diverse disease processes associated with the subtypes of MS can be detected by MRI as well. In PPMS, MRI will show small lesions that do not enhance with a contrast agent, indicating little or minimal inflammation. This particular characteristic is a clear differentiation from relapsing-remitting disease. The severity and extent of the physical symptoms of MS can be confirmed by visualization of the anatomical location of lesions within the CNS. For example, a lesion present in the spinal cord may result in numbness in the limbs and bladder disturbance. Lesions in the optic nerve are usually responsible for optic neuritis, leading to blurred vision and a loss of color perception.

There is a correlation between the "lesion load" (i.e., total volume of CNS tissue affected by the MS disease process) and the probability that a key part of the brain or spinal cord will be affected, resulting in clinical symptoms. However, studies have demonstrated only weak correlation between MRI lesion load and age at disease onset, disease duration, and progression [41]. MRI lesion burden is not considered a good indicator of disease progression, especially in cases of advanced MS.

MS lesions found in the spinal cord usually give rise to identifiable symptoms and are highly eloquent of the disease process; new spinal MS lesions are strongly correlated to new clinical manifestations. Approximately 75% of patients with MS have lesions within the spinal cord, and most spinal cord lesions are located in the dorsal columns [167]. These lesions are usually oval or cigar-shaped and can span one or two vertebral segments (referred to as skip lesions).

Advances in MRI Imaging

Despite its many advantages, the principal handicap of MRI is its low sensitivity in detecting grey-matter involvement and diffuse damage in white matter. Advances made in conventional and non-conventional MRI methods are enabling better assessment of CNS tissue damage in patients with MS. New techniques that can provide more insight into MS include:

  • Proton magnetic resonance spectroscopy (1H-MRS)

  • Magnetization transfer imaging

  • Diffusion imaging

  • Functional MRI

  • Optic-nerve imaging

  • Spinal-cord imaging

  • Myelin water fraction (MWF) imaging

  • Perfusion MRI

  • Ultra-high-field MRI

MRI assessment of lesions on noncontrast T1- and T2-weighted images and on gadolinium-enhanced T1-weighted images provides an important imaging tool for close monitoring of the disease course [171]. However, conventional MRI is weakly correlated with clinical status of MS and has low sensitivity [172,173]. New approaches in the field of data management and post-processing have the potential to change the way MS is diagnosed currently. With the help of serial analysis of images, it is now possible to detect a shift in the patient's disease from more inflammatory to more degenerative pathological processes. This shift may be indicative of possible atrophy and clinical disability [174]. Another method called subtraction imaging displays changes over time between two scans in a single map [175]. This method is more sensitive to lesion evolution compared to conventional techniques.

Voxel-based morphometry is a novel method that explores the association between regional patterns of atrophy and particular functional impairment [176,177]. Researchers are searching for a method that delineates the relationship between regional atrophy and white matter tract damage and the resulting clinical implications. Diffusion tensor MRI technique has the potential to map the white-matter architecture in details. This novel technique can then be used to correlate quantitative measures of CNS tissue damage and its functional significance, leading to more clinically relevant assessment of the burden of disease.

Newer MRI contrast agents composed of iron particles (i.e., nano-size particles of iron oxide or superparamagnetic iron oxide particles) are being used in patients with MS to track macrophages [179,180]. Studies using these agents have confirmed a mismatch of MRI enhancement, signifying heterogeneity of the underlying MS pathology [179,180]. Tracking macrophages with these tiny iron particles can help monitor the efficacy of drugs in MS treatment. Gadofluorine M, a gadolinium-based MRI contrast agent, is very sensitive in the detection of inflammatory CNS lesions, as it selectively accumulates in nerve fibers undergoing Wallerian degeneration [181].

1H-MRS

1H-MRS can be used to measure N-acetylaspartate levels to monitor CNS damage. Levels of choline-containing compounds usually increase during myelin breakdown, remyelination, and inflammation. 1H-MRS is helpful in detecting levels of glutamate, glutamine, and gamma-aminobutyric acid (GABA), and advances in 1H-MRS techniques could revolutionize the diagnosis of MS.

Magnetization Transfer MRI

Another nonconventional technique, magnetization transfer MRI, can detect the magnetization transfer ratio (MTR), which helps in monitoring disease progression in patients with MS. A low MTR indicates damage to neurons, particularly myelin and axonal membranes. Decreased MTR is particularly pronounced in patients with the progressive forms of MS and has a tendency to deteriorate over time [183]. Studies have demonstrated that this technique has prognostic value for subsequent disease evolution [183].

Diffusion MRI

Diffusion MRI is helpful in noninvasively mapping the diffusion process of molecules in biological tissues and can detect focal MS lesions. Research is focusing on the role of direct MRI detection of neuronal activation, either by diffusion-weighted imaging or by the effect that neuronal currents have on a local, externally applied magnetic field [184,185]. In the future, this technique could provide vital information about the disease processes of MS and the effects of these processes on motor and cognitive function.

Functional MRI

Functional MRI, or fMRI, measures brain activity by detecting the changes in blood oxygenation and flow that occur in response to neural activity. fMRI uses the blood-oxygen-level-dependent contrast mechanism and may be useful in detecting alterations in visual, cognitive, and motor networks in patients with MS.

Myelin Imaging

Research on MS has emphasized the need to develop MRI techniques that can measure the invisible burden of disease in the CNS and establish highly sensitive and specific markers of disease progression. Myelin-selective MRI is a promising technique that allows accurate mapping of MWF, a parameter that is linked to brain white matter myelination. Studies suggest that a 30% to 50% decrease in MWF occurs in MS lesions and a 7% to 15% decrease is seen in normal-appearing white matter in patients with MS [190,191].

OPTIC-NERVE IMAGING

Imaging of the optic nerves is difficult because of the limited resolution of MRI and patient motion artefacts. However, optic neuritis can be an excellent model to understand the pathophysiology of MS. A link has been observed between acute inflammation and conduction block in optic neuritis [186]. Dynamic MTR changes indicate myelin damage and repair due to axonal degeneration and demyelination [187].

Optical coherence tomography shows promise as a potential marker of axonal loss in assessing neurodegeneration in MS [188]. This technique can detect thinning of the retinal nerve fiber layer.

CEREBROSPINAL FLUID ANALYSIS

Performing lumbar puncture for CSF analysis is not essential for confirming diagnosis of MS; however, it can be helpful in the differential diagnosis. CSF analysis can detect intrathecal synthesis of antibodies, which is evident by the presence of oligoclonal bands, IgG index elevation, and an increased IgG synthesis rate. It is important to note that the presence of oligoclonal bands in CSF is suggestive of MS, but its presence in serum is not. CSF analysis should always be interpreted with regard to the clinical situation.

Oligoclonal bands are found in the CSF of approximately 75% to 85% of patients with MS [43,45]. However, a similar pattern of antibody synthesis is present in various types of infectious, inflammatory, vascular, neoplastic, and paraneoplastic conditions as well. Conditions other than MS are considered when CSF analysis reveals pleocytosis (>50 white blood cells/mm3) or a CSF protein concentration greater than 100 mg/dL [178].

Detection of oligoclonal bands in CSF by isoelectric focusing is the most sensitive laboratory test for MS and the most sensitive predictor of conversion from clinically isolated syndrome to MS. It is also the best test to show local intrathecal IgG synthesis. Patients with suspected MS who lack oligoclonal IgG bands in CSF should be investigated for other diagnoses, although it is important to remember that not all patients with MS display oligoclonal bands. Studies have demonstrated that the frequency of oligoclonal bands in the CSF of patients with MS varies in different regions of the world, with higher rates in Northern Europe and North America and lower rates in Asia [178].

The association between the presence of oligoclonal bands in CSF and progression of disability in MS is not yet clear. The oligoclonal band pattern in CSF does not change during the course of the disease, but banding patterns do vary among patients.

EVOKED POTENTIAL TESTING

Evoked potential testing consists of electrical tests of the nerve pathways, which are less responsive to stimulation in individuals with MS. This noninvasive and sensitive test checks brain responses by visual- and sensory-evoked potentials, identifying CNS lesions or damaged areas.

There are three main types of evoked potential tests used in the diagnosis of MS:

  • Brainstem auditory evoked potentials: A series of clicks played in each ear via headphones

  • Visual evoked potentials: A series of alternating checkerboard patterns shown on a screen

  • Somatosensory evoked potentials: Short, mild electrical shocks administered to a patient's arm or leg

The patient's responses are analyzed carefully for response size and the speed in which the brain receives the signal. Demyelination can be indicated by weak or slow brain response to the test, suggesting possible MS.

Only visual evoked potentials findings are considered part of the diagnostic criteria for MS. Visual evoked potentials can detect sluggish neurotransmission along the optic nerve pathways, a finding common in individuals with asymptomatic MS. However, a positive finding on evoked potential testing is not specific to MS, and the abnormalities detected may also be present in other conditions.

DIAGNOSTIC CRITERIA

The McDonald criteria established by the International Panel on the Diagnosis of MS are used to determine both diagnosis and subtype of MS based on brain imaging, extent of symptoms, and duration of symptoms (Table 4) [45]. These criteria were first introduced in 2001 and were most recently revised in 2010.

2010 MCDONALD CRITERIA FOR THE DIAGNOSIS OF MS

Clinical PresentationAdditional Data Needed for MS Diagnosis
≥2 attacksa; objective clinical evidence of≥2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attackbNonec
≥2 attacksa; objective clinical evidence of 1 lesionDissemination in space, demonstrated by:≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord)d; or await a further clinical attacka implicating a different CNS site
1 attacka; objective clinical evidence of≥2 lesionsDissemination in time, demonstrated by: Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or a new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or await a second clinical attacka
1 attacka; objective clinical evidence of 1 lesion (clinically isolated syndrome)

Dissemination in space and time, demonstrated by:

For dissemination in space: ≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord)d; or await a second clinical attacka implicating a different CNS site

For dissemination in time: Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or a new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or await a second clinical attacka

Insidious neurological progression suggestive of MS (primary progressive)

1 year of disease progression (retrospectively or prospectively determined) plus 2 of 3 of the following criteriad:

  • Evidence for dissemination in space in the brain based on≥1 T2 lesions in the MS-characteristic (periventricular, juxtacortical, or infratentorial) regions

  • Evidence for dissemination in space in the spinal cord based on≥2 T2 lesions in the cord

  • Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index)

If the criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is MS. If suspicious, but the criteria are not completely met, the diagnosis is possible MS. If another diagnosis arises during the evaluation that better explains the clinical presentation, then the diagnosis is not MS.

aAn attack (relapse, exacerbation) is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous neurological examination, but some historical events with symptoms and evolution characteristic for MS, but for which no objective neurological findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports of paroxysmal symptoms (historical or current) should, however, consist of multiple episodes occurring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurological examination, visual evoked potential response in patients reporting prior visual disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of neurological symptoms.

bClinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack, in the absence of documented objective neurological findings, can include historical events with symptoms and evolution characteristics for a prior inflammatory demyelinating event; at least 1 attack, however, must be supported by objective findings.

cNo additional tests are required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these criteria. If imaging or other tests (for instance, CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS, and alternative diagnoses must be considered. There must be no better explanation for the clinical presentation, and objective evidence must be present to support a diagnosis of MS.

dGadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in subjects with brainstem or spinal cord syndromes.

The latest revision of the McDonald criteria improves the sensitivity from 46% to 74%, with a slight tradeoff in specificity (decreased from 94% to 92%) [45]. Major changes in the 2010 revision include simplification of the demonstration of CNS lesions in space and time through MRI imaging and consideration of application to non-Western white populations [45].

DIFFERENTIAL DIAGNOSIS

Because there are a variety of conditions that may mimic MS, differential diagnosis can be complicated (Table 5) [164]. A diagnosis of MS should be questioned if clinical or laboratory findings are unexpected or atypical. These unusual features, or "red flags," should raise suspicion that another condition is the underlying cause of symptoms.

CONDITIONS THAT MAY MIMIC MS

DiseaseSymptoms Similar to MSDifferentiating Symptoms
Systemic lupus erythematousCommon in young women and may affect the nervous system, especially the optic nerve and spinal cord. MRI white-matter changes are common, and up to 60% have oligoclonal bands and IgG abnormalities in CSF.Positive serology with ANA and double-stranded DNA autoantibodies. Systemic involvement, especially including the kidneys and skin, and hematologic changes.
Sjögren syndromeOccasional reports of neurologic symptoms, especially progressive myelopathy. MRI may show white-matter lesions and CSF may show oligoclonal bands with increased IgG.Positive serology for SS-A (Ro) and SS-B (La) autoantibodies. Prominent dry eyes and mouth. Salivary gland biopsy can be definitive.
Lyme diseaseCan cause persistent focal neurologic findings and signal abnormalities on MRI scan of the brain.History of erythema migrans rash. Western blot is the most definitive serology, and CSF will show positive PCR.
SyphilisCan cause optic neuritis, myelopathy, and other focal neurologic findings.MRI is usually normal. Negative serology rules out syphilis. Advanced infection now rare except in HIV-positive or immunocompromised patients.
HIV/AIDSMay cause optic neuritis, myelopathy, mental status changes, and focal deficits with white-matter changes on MRI scan and abnormal CSF.Occurs in high-risk populations who may have diminished CD4 cell counts and positive HIV serology.
Vitamin B12 deficiencyMay cause CNS deficits, especially a progressive myelopathy, rarely with MRI signal abnormalities.Complete blood count is often abnormal and serum B12 levels are low. Methylmalonic acid and homocysteine are often abnormal.
CNS lymphomaFocal neurologic deficits with multifocal enhancing MRI lesions.CSF does not have IgG abnormalities but will often show positive cytology. Lesions are highly steroid responsive. Brain biopsy may be necessary.
Chiari malformationMay cause cranial neuropathies, including ophthalmoplegia, nystagmus, and ataxia.MRI scanning, especially on sagittal images, will detect the malformation. MRI of the brain is otherwise normal, as is CSF.
Chronic fatigue syndrome and
fibromyalgia
May report neurologic symptoms that mimic MS in a similar population (young women).Neurological examination is objectively normal. Difficulties arise when the MRI shows "nonspecific" abnormalities, but MRI, CSF, and VERs should be normal.
ANA = antinuclear antibody, CSF = cerebral spinal fluid, HIV/AIDS = human immunodeficiency virus/ acquired immunodeficiency syndrome, MRI = magnetic resonance imaging, PCR = polymerase chain reaction, VER = visual evoked response.

Unusual signs and symptoms that may arise during the history and examination include [164]:

  • Normal neurologic examination

  • Abnormality in a single location (i.e., no dissemination in space)

  • Progressive from onset (i.e., no dissemination in time)

  • Onset in childhood or at an age older than 50 years

  • Psychiatric disease present

  • Systemic disease present

  • Prominent family history (may suggest genetic disease)

  • Gray matter symptoms (e.g., dementia, seizures, aphasia)

  • Peripheral symptoms (e.g., peripheral neuropathy, fasciculations)

  • Acute hemiparesis

  • Lack of typical symptoms (e.g., no optic neuritis, bladder problems, Lhermitte's sign)

  • Prolonged benign course (i.e., diagnosis made several years ago with few current findings)

Unusual laboratory findings that may indicate that MS is not the cause of symptoms include [164]:

  • Normal or atypical MRI

  • Normal CSF

  • Abnormal blood tests (though false positives are possible)

Most patients with other diseases will be identified by the presence of one or more of these atypical features. A number of studies have demonstrated that patients who do not have MS have two things in common: absence of typical MS symptoms such as optic neuritis, Lhermitte's sign, sensory dysfunction, neurogenic bladder, or other common deficits; and absence of typical findings on MRI and CSF examination [164]. Very few patients with MS have a normal brain MRI and/or normal CSF.

TREATMENT

There is no cure for MS. However, effective treatment strategies are available to modify the disease course, treat or reduce exacerbations, prevent relapses, manage signs and symptoms, improve overall function and safety, and provide psychological support. The treatment strategy depends on the patient's clinical condition and disease course. In cases of mild MS without relapses, usually no treatment is necessary. If a patient experiences relapses or if symptoms become more severe, treatment should be initiated as soon as possible.

TREATMENT OF ACUTE EXACERBATIONS

Treatment of the acute exacerbations seen with relapsing types of MS relies primarily on corticosteroids and adrenocorticotropic hormone (ACTH). These agents have been found to promote speedier resolution of the neurologic deficits, lessen the severity of an attack, and effectively reduce the risk of permanent residual deficits. Both corticosteroids and ACTH are capable of restoring the breakdown of the blood brain barrier, reducing inflammation, and immunomodulating mononuclear trafficking mechanisms.

Corticosteroids also promote quick recovery from disability [110,111]. The first-line treatment of MS-related exacerbations involves administration of high doses of IV corticosteroids, particularly methylprednisolone (1 g), for 3 to 7 days [108,109]. Alternative approaches include:

  • ACTH: 80–120 units daily for 1 to 3 weeks

  • Oral prednisone: 500–1250 mg daily divided for 3 to 7 days

  • "Smoothie Medrol:" 1 g methylprednisolone mixed in smoothie or juice taken orally with breakfast for 3 to 7 days

  • Dexamethasone: 160–200 mg orally/IV daily divided for 3 to 7 days

Although frequently used, the evidence to support low-dose oral prednisone in the treatment of acute relapses is poor and is therefore not recommended [169].

An evidence-based assessment of the use of ACTH and corticosteroids in the treatment of MS was undertaken by the Therapeutics and Technology Assessment Committee of the American Academy of Neurology. The Committee concluded that [111]:

  • Treatment with corticosteroids promotes quicker recovery from acute attacks of MS.

  • Long-term benefits of corticosteroids and ACTH on the course of MS are yet to be seen.

  • Although high-does corticosteroids are used to treat acute exacerbations, there is no compelling evidence that using a specific type of agent, route of administration, or dose is more beneficial.

Potential side effects of corticosteroids include osteoporosis, changes in mood, and memory defects [112,113]. Patients treated with oral corticosteroids also may experience alterations in blood glucose, glaucoma, gastrointestinal symptoms, and psychiatric disorders [114].

Patients on interferons or glatiramer acetate can receive the initial pulse of corticosteroids or ACTH with or without a taper for the treatment of acute MS exacerbations. Patients taking natalizumab should limit corticosteroids to a shorter duration (i.e., 2 to 3 days) without a taper to avoid progressive multifocal leukoencephalopathy [111]. An oral steroid taper is not generally recommended. However, if there has been a dramatic response to IV corticosteroids (the so-called "Lazarus" effect), then a short taper may prevent rebound edema and a consequent deterioration [169].

IV immunoglobulins (0.4 g/kg/day for 5 days) are also used in some cases to treat MS relapse in patients who are intolerant or refractory to steroid treatment (second- or third-line) [189]. However, clinical studies have not resulted in conclusive supporting evidence for its efficacy.

Several other drugs that suppress the immune system (e.g., cyclophosphamide, methotrexate, azathioprine, cladribine, cyclosporine) can also reduce the symptoms of MS. These agents suppress the number of circulating immune cells, which in turn slows the autoimmune process and prevents neural damage. However, use of immunosuppressive agents results in increased susceptibility to various types of infection, and the long-term use of these medications may result in additional side effects.

IMMUNOMODULATION

The use of disease-modifying drugs has been shown to decrease the relapse rate, reduce progression of disability, and slow the accumulation of lesions for patients with RRMS (Table 6) [84,85,86]. The exact mechanism of action of these drugs is still not clear, but it is believed to be the result of immunomodulation regulating the activation of impaired immune cells. Additionally, the blood-brain barrier becomes less permeable with immunomodulation, allowing fewer immune cells to enter the brain and reducing the autoimmune reaction between the immune cells and neurons. All medications differ in their efficacy, and additional data related to their long-term effects are necessary [92,93,94,95,166].

APPROVED LONG-TERM TREATMENTS FOR MS

DrugTypeSide EffectsAdministrationNotes
Self-injected medications
ß-interferon 1aa(Avonex)Immunomodulator with antiviral propertiesFlu-like symptoms, headache
30 mcg IM injection
weekly
Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies.
ß-interferon 1ba(Betaseron, Extavia)Immunomodulator with antiviral propertiesFlu-like symptoms, injection-site skin reaction, blood count and liver test abnormalities250 mcg SC injection every other daySide effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies.
Glatiramer acetate (Copaxone)Immunomodulator that inhibits attacks on myelinInjection-site skin reaction as well as an occasional systemic reaction—occurring at least once in approximately 10% of those tested20 mg SC injection once dailySystemic reactions such as flushing, dizziness, anxiety, and chest tightness arise 5 to 15 minutes following injection. The symptoms persist for a few minutes and lack long-term adverse effects; specific treatment is unnecessary.
ß-interferon 1aa(Rebif)Immunomodulator with antiviral propertiesFlu-like symptoms, injection-site skin reaction, blood count and liver test abnormalities44 mcg SC injection 3 times per weekSide effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies.
Infused medications
Mitoxantrone (Novantrone)Antineoplastic immunomodulator/ immunosuppressorUsually well tolerated; side effects include nausea, thinning hair, amenorrhea, bladder infection, and mouth sores. Additionally, urine and whites of the eyes may turn a bluish color temporarily.IV infusion once every 3 months (for 2 to 3 years maximum)Carries the risk of cardiotoxicity and leukemia; it may not be given beyond 2 or 3 years. People undergoing treatment must have regular testing for cardiotoxicity, white blood cell counts, and liver function. Because of the potential risks, it is seldom prescribed for MS. Anyone who is taking or has taken mitoxantrone should have annual evaluations of his or her heart function, even if no longer receiving this medication.
Natalizumab (Tysabri)Humanized monoclonal antibodyHeadache, fatigue, depression, joint pain, abdominal discomfort, infectionIV infusion every 4 weeksRisk of infection (including pneumonia) was the most common serious adverse event (occurring in a small percentage of patients). The TOUCH Prescribing Program monitors patients for signs of PML, an often-fatal viral infection of the brain. Risk factors for PML include the presence of JC virus antibodies, previous treatment with immunosuppressive drugs, and taking natalizumab for more than 2 years.
Oral medications
Teriflunomide (Aubagio)Immunomodulator affecting the production of T and B cellsHeadache, elevations in liver enzymes, hair thinning, diarrhea, nausea, neutropenia, paresthesia7–14 mg tablet once dailyMore severe adverse events include the risk of severe liver injury and the risk of birth defects if used during pregnancy. A TB test and blood tests for liver function must be performed within 6 months prior to initiation of therapy, and liver function must be checked regularly. If liver damage is detected, or if a patient becomes pregnant while taking this drug, accelerated elimination is prescribed.
Fingolimod (Gilenya)S1P-receptor modulatorHeadache, flu, diarrhea, back pain, abnormal liver tests, cough0.5 mg capsule once dailyOther adverse events include a reduction in heart rate (dose-related and transient); infrequent transient AV conduction block of the heart; a mild increase in blood pressure; macular edema; reversible elevation of liver enzymes; and a slight increase in lung infections (primarily bronchitis). Infections, including herpes infection, are also of concern. A 6-hour observation period is required immediately after the first dose to monitor for cardiovascular changes.
Dimethyl fumarate (Tecfidera)Immunomodulator with anti-inflammatory propertiesFlushing and gastrointestinal events, reduced lymphocyte counts, elevated liver enzymes (rare)240 mg tablet twice dailyOther possible adverse events include mild or moderate upper respiratory infection, pruritus, and erythema. In studies, the only serious adverse events to occur in two or more patients were gastroenteritis and gastritis. Reduced lymphocyte counts were seen during the first year of treatment. Liver enzymes were elevated in 6%, compared to 3% on placebo.
aAdditional information about interferons: Some individuals develop neutralizing antibodies to the interferons, but their impact on the effectiveness of these medications has not been established. Many continue to do well on these drugs despite the presence of neutralizing antibodies. Others may have sub-optimal results even without neutralizing antibodies present. The MS Council and the American Academy of Neurology have concluded that the higher-dosed interferons are likely to be more effective than lower-dosed interferons. Several factors, however, must be considered when selecting one of these drugs, and this decision must be made on an individual basis.
AV = atrioventricular, IM = intramuscular, IV = intravenous, JC = John Cunningham virus, PML = progressive multifocal leukoencephalopathy, SC = subcutaneous, TB = tuberculosis.

ß-Interferons

The main disease-modifying drugs used in the treatment of MS are ß-interferons. These are naturally occurring immunomodulating agents that inhibit inflammatory reactions and limit cytokine secretion and lymphocyte migration. Two types of ß-interferon are available: ß-interferon 1a and ß-interferon 1b. ß-interferon 1a is produced by mammalian cells, while ß-interferon 1b is produced in modified Escherichia coli. The mechanisms of these two types are similar, but the dosage and method/frequency of administration may vary.

The use of ß-interferon reduces the risk and severity of clinical exacerbations of MS by about 30%, reduces the risk of developing new MRI lesions by 70% to 90%, and improves the integrity of the blood-brain barrier [111]. As such, it has been shown to slow disease progression and positively impact physical, emotional, and intellectual capacities.

The potential side effects of the interferons include flu-like symptoms and headache. Arthralgias may occur but can be reduced significantly by starting nonsteroidal anti-inflammatory drugs (NSAIDs) before the treatment. Patients treated with interferon should be monitored with periodic laboratory tests to check for liver dysfunction, anemia, leukopenia, and thyroid dysfunction. These studies should be performed at baseline, at three months after initiating the interferon therapy, and every six months thereafter [111]. Skin breakdown at the injection site is also possible.

Approximately 30% of patients with MS do not respond to treatment with a ß-interferon [96,103]. For these individuals, other pharmacotherapies are available.

Glatiramer Acetate

Another disease-modifying drug approved for the treatment of RRMS is glatiramer acetate (also known as copolymer-1). Glatiramer is believed to block myelin-damaging T-cells, although its exact mechanism of action is not clearly understood. It is a potent immunomodulator that increases the number of immune regulatory cells. These cells reduce inflammation by suppressing the immune response.

Glatiramer acetate reduces the risk and severity of MS attacks and reduces MRI lesions over time. Studies comparing treatment with ß-interferon 1b or glatiramer have demonstrated similar efficacy. Glatiramer acetate has fewer adverse effects compared to the ß-interferons. Good injection technique and site rotation can help to reduce post-injection site reactions, but in some cases, repetitive injection of glatiramer acetate can cause lipoatrophy [213].

Mitoxantrone

Mitoxantrone, a cytostatic drug and a powerful anti-inflammatory, is used in the treatment of both RRMS and progressive forms of MS [99,100]. It is considered one of the most effective drugs in resolving relapses; however, due to the risks for leukemia and cardiotoxicity, it should only be prescribed to patients with rapidly advancing disease who are refractory to other therapies [87]. Some patients, especially with a subtype of RRMS called rapidly worsening MS, do not respond to immunomodulators and are managed with immunosuppressants, particularly mitoxantrone [101,102].

Mitoxantrone promotes quick resolution of relapses due to larger lesions in the brain and spinal cord. Various studies have demonstrated a positive effect in people with relapsing-remitting, secondary progressive, and progressive-relapsing subtypes of MS, but it is most beneficial in secondary progressive subtype [49]. Mitoxantrone is discontinued as soon as remission is achieved and replaced with another disease-modifying agent with a better safety profile.

Mitoxantrone causes reduced contraction of cardiac muscles, which can be confirmed by a reduction in ejection fraction measured through multiple gated acquisition scan. Studies have shown that patients receiving doses greater than 140 mg/m2 have an increased risk of vacuolar cardiomyopathy. As such, it is contraindicated in patients with an estimated ejection fraction less than 50% or a 10% to 15% interval reduction of the ejection fraction [213].

Natalizumab

Natalizumab, a monoclonal antibody, may be used in the treatment of RRMS, and it is considered one of the most effective drugs in reducing the relapse rate (although long-term studies are lacking) [88,97,98]. Natalizumab prevents migration of autoreactive lymphocytes into the brain, which results in a profound decrease in CNS mononuclear cell trafficking that reduces MS exacerbations by 70% and disease progression by about 50% [50]. It also accelerates repair of myelin sheath lesions. Some studies have demonstrated that natalizumab can reduce new gadolinium-enhancing lesions by more than 90% [50,51].

Natalizumab should be prescribed to patients with active RRMS that is refractory or resistant to ß-interferons and glatiramer or patients who cannot tolerate these medications [89]. Natalizumab may be indicated as a first-line treatment in patients with very active disease or in individuals with poor prognosis (e.g., MS targeting the brainstem, cerebellum, and/or spinal cord motor tracks). Studies have demonstrated that a combination of natalizumab with ß-interferon 1a reduces relapses and disability progression more than ß-interferon 1a alone [52].

Several potential side effects are associated with natalizumab. Approximately 1% of patients treated with natalizumab suffer from infusion-related hypersensitivity. This reaction usually occurs at the time of the second dose in natalizumab-naïve patients and can result in the development of a natalizumab-neutralizing antibody that can reduce the bioavailability of the agent and even render the drug useless. Natalizumab is also associated with an increased risk of developing progressive multifocal leukoencephalopathy. This disorder is caused by the John Cunningham virus, a type of human polyomavirus that infects oligodendrocytes and causes rapid and potentially life-threatening demyelination.

Fingolimod

Treatment with fingolimod, a sphingosine-1-phosphate receptor modulator, results in reduction of the relapse rate in patients with RRMS; however, it is associated with an increased risk of opportunistic infections, which can be fatal [53,54,90,91]. Fingolimod was the first oral agent with a labelled indication for relapsing forms of MS [54]. It promotes the redistribution of lymphocytes from the circulation to the lymphoid organs and prevents the entry of lymphocytes back into circulation. Several studies have demonstrated that it significantly reduces both clinical and radiographic MS disease activity. Its side effects include first-dose bradycardia, arrhythmia, reactive airway events, macular edema, skin cancers, and increased susceptibility to infections [213]. Fingolimod is the only drug approved for the treatment of highly active (or rapidly worsening) RRMS.

Dimethyl Fumarate

In 2013, dimethyl fumarate was approved for the initial treatment of relapsing forms of MS [26]. It has not been evaluated in either SPMS or PPMS, so it is generally not recommended in patients without evidence of active inflammation. This agent acts through modulation of oxidative pathways to decrease autoimmunity. Clinical trials indicated a 69% reduction in contrast-enhancing lesions (phase II trial), a 53% reduction in annualized relapse rate, a 38% reduction in disability progression, and a 49% reduction in disability progression after 2 years [26]. Dimethyl fumarate is taken orally at a dose of 120–240 mg three times a day [26]. Possible side effects include elevated liver enzymes, nausea, diarrhea, flushing, and cramps.

Teriflunomide

Teriflunomide, an active metabolite of the antirheumatic drug leflunomide, is approved for the treatment of RRMS [206]. It has been shown to inhibit cell division in certain immune cells. Results from a phase III trial showed a significantly reduced annualized relapse rate compared to placebo. The risk of disability progression was reduced by 30% for the 14-mg dose and by 24% for the 7-mg dose. Common side effects include headache, nausea, diarrhea, and hair thinning. Use has been associated with rare reports of hepatotoxicity, hepatic failure, and death [213]. Treatment with teriflunomide should not be initiated in patients with pre-existing acute or chronic liver disease, and use is contraindicated in patients with severe hepatic impairment.

PLASMAPHERESIS

It is now known that B-cell immunity also plays a key role in the pathogenesis of MS. Plasma exchange can be effective as a secondary therapy for exacerbations that are refractory to corticosteroid treatment. It can also be beneficial in severe, rapidly progressive MS and similar disorders; however, it does not show any efficacy for SPMS or PPMS.

Plasmapheresis is indicated for patients with severe relapses who have failed to respond to IV corticosteroids, and treatment effects can be dramatic. Research has linked treatment response to type II pathology (i.e., IgG deposition and complement activation) [169].

SYMPTOM MANAGEMENT

The primary goal of symptomatic MS therapy is to improve quality of life by eliminating or reducing symptoms affecting patients' functional abilities. The approaches to symptomatic treatment focus on controlling the symptom rather than the underlying disease process.

The interventions chosen will depend on the patient's symptoms, medical history, and overall health. A comprehensive approach that incorporates pharmacotherapy, physiotherapy, and psychotherapy is superior to medical management alone.

Fatigue

Approximately 80% of patients with MS experience significant fatigue at some stage of their disease, often to the point of affecting their ability to complete activities of daily living [209]. This fatigue differs from normal exhaustion or tiredness, which usually increases during the day; it may be present at any time, even upon waking, and can limit a patient's professional and social life. MS-associated fatigue is aggravated by increases in body temperature (referred to as Uhthoff phenomenon). Depression can often be masked by symptoms of fatigue, so this is an important differential diagnosis, particularly in early stages of MS.

The Fatigue Severity Scale is commonly used in patients with MS to monitor change in fatigue over time or in response to therapeutic interventions [209]. Patients are asked to respond to each of the following statements on a scale of 1 to 7 (with 1 indicating "strongly disagree" and 7 indicating "strongly agree") [209]:

  • My motivation is lower when I am fatigued.

  • Exercise brings on my fatigue.

  • I am easily fatigued.

  • Fatigue interferes with my physical functioning.

  • Fatigue causes frequent problems for me.

  • My fatigue prevents sustained physical functioning.

  • Fatigue interferes with carrying out certain duties and responsibilities.

  • Fatigue is among my three most disabling symptoms.

  • Fatigue interferes with my work, family or social life.

The scale is scored by taking the average of the responses. A higher score indicates higher levels of fatigue.

There are no licensed therapies for MS-related fatigue, but both amantadine and modafinil are widely prescribed off-label [169]. These drugs and pemoline and L-carnitine have been shown to be effective in improving fatigue severity [211]. However, stimulants should be used with caution—there is little evidence to support their efficacy, and they commonly cause anxiety and insomnia [169]. Physiotherapy, occupational therapy, and lowering body temperature may also help reduce fatigue and improve quality of life. Aminopyridines are effective in the amelioration of Uhthoff phenomenon [210].

Spasticity

More than 80% of patients with MS experience some spasticity, with 30% having symptoms so significant that they modify or eliminate daily activities as a result. Patients should be screened for pain, infection, fever, and bowel distention, as these factors are associated with more severe spasticity.

Spasticity may be classified as:

  • Tonic: Muscle tone is constantly elevated.

  • Phasic: Muscle tone is intermittently elevated and is usually accompanied by pain.

Classification is usually done using the Modified Ashworth Scale, which measures resistance to passive stretch (Table 7) [168]. A higher score is indicative of more severe spastic hypertonia. Clinical assessment of spasticity may also include muscle grading, deep tendon reflexes, and measurements of range of motion. The Modified Ashworth Scale is also useful for evaluating and determining the response to therapy over time.

MODIFIED ASHWORTH SCALE FOR SPASTIC HYPERTONIA

ScoreDescription
0No increase in tone
1Slight increase in muscle tone, manifested by a catch and release or minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension
1+Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the range of motion
2More marked increase in muscle tone through most of the range of motion, but affected part(s) easily moved
3Considerable increase in muscle tone, passive movement difficult
4Affected part(s) rigid in flexion or extension

Treatment of spasticity involves an optimum amalgamation of drug therapy, maintenance and restorative therapies, and assistive devices. In addition to reducing hypertonia, the multidisciplinary approach may include interventions to relieve pain, improve overall motor function, and prevent or treat complications such as pressure ulcers and contractures.

Tonic spasms usually manifest as part of an acute relapse and are self-limiting. They typically respond to low or moderate doses of sodium-channel blockers [169]. However, phasic spasms require more intensive treatments.

Baclofen and tizanidine are commonly used to treat and reduce spasticity, and the benzodiazepines (e.g., diazepam) also have a beneficial effect. Other possible agents include gabapentin and dantrolene [169]. In general, baclofen is considered the drug of choice for spasticity in patients with MS [212]. An intrathecal baclofen pump may be indicated for patients with unilateral or bilateral phasic lower limb spasticity. Dantrolene should be used with caution because of the potential for hepatotoxicity [169].

Injectable forms of botulinum toxin, phenol, or alcohol are especially beneficial in patients with focal spasticity or difficulty tolerating oral medications [214]. Surgical intervention (tenotomy) is indicated in severe cases.

Patients should be advised to avoid or minimize exposure to triggers and maintain proper positioning, posture, and ergonomics as much as possible. Stretching exercises are recommended for patients with MS in order to maintain normal muscle tone, especially in the popliteus, gastrocnemius, and lumbricals. Patients with significant lower limb weakness often rely on spasticity to splint their legs for weight bearing and walking [169].

Bladder Dysfunction

Bladder dysfunction is seen in approximately 80% of patients with newly diagnosed MS and in 96% of patients after 10 years [215]. Bladder dysfunction can lead to urgency, detrusor hyperactivity with restricted storage capacity, incontinence, and frequent micturition. A careful history and physical examination should be conducted on these patients, usually involving urinalysis and uroflowmetry (ultrasound) with a postvoid residual. This is especially important because a patient's subjective assessment of his or her bladder function may not correlate with postvoid residual volumes. High postvoid residual volumes (>100 cc) are associated with an increased risk for recurrent infections, calculi, and hydronephrosis. In such cases, the patient should be referred to a neurourologist for further evaluation. A thorough pelvic floor examination is required.

Patients who experience failure-to-store syndrome (also referred to as a "spastic" or "small" bladder) will usually report urgency, frequency, and nocturia. They usually have small bladder volumes and demonstrate a spastic detrusor muscle pattern on urodynamic testing. Failure-to-store may be treated with an antimuscarinic, an anticholinergic, or a mixed agent like oxybutynin [169]. The tricyclic antidepressant imipramine may also be beneficial in such cases.

Patients with the primary problem of failure to empty usually have an outlet disorder, such as an overactive sphincter or a hyporeflexic or areflexic bladder. These patients often suffer from frequency, hesitation, slow stream/dribbling, and prolonged voiding time. Failure-to-empty conditions are generally treated with an alpha-antagonist, such as doxazosin, prazosin, terazosin, or tamsulosin. The highly selective agent silodosin may also produce good results, although its affinity for the prostate can cause erectile dysfunction. Prophylactic antibiotic treatment with nitrofurantoin or sulfamethoxazole/trimethoprim may be indicated in patients with recurrent urinary tract infections.

Patients who experience nocturia or nocturnal enuresis should be advised to empty their bladder before going to bed and decrease or avoid fluid intake 2 to 3 hours prior bedtime. Caffeinated products, alcoholic beverages, and spicy and acidic foods can cause bladder irritation and urinary frequency and should be avoided. If these behavioral strategies are ineffective, treatment with oral desmopressin is indicated [217].

Sacral neuromodulation may be beneficial for patients with incontinence related to overactive bladder, particularly if it is refractory to other treatments. Patients can be instructed to practice the Valsalva or Credé maneuver to help with hesitancy (in conjunction with pharmacotherapy). Chemical denervation of the detrusor muscle using intravesical capsaicin or botulinum toxin injections may be helpful in some cases [169].

Clean, intermittent or permanent catheterization is used for patients who do not respond to other treatments. A suprapubic catheter is preferred over intraurethral (Foley) because of the lower risk of infection and urethral damage. Surgical options (e.g., augmentation cystoplasty, ileovesicostomy, ileal conduit urinary diversion) should be considered for patients with severely impaired emptying or patients with repeated MS exacerbations triggered by recurrent infections. Other nonpharmacological that may be incorporated into the treatment plan include:

  • Pelvic floor muscle strength training

  • Bladder retraining

  • Biofeedback

  • Pessaries

Bowel Dysfunction

Bowel dysfunction affects approximately 70% of patients with MS [217]. The majority of patients experience either constipation or fecal incontinence.

Constipation

Clinically, constipation is defined as infrequent bowel movements (fewer than three per week). The etiology of constipation in patients with MS is multifactorial, and a careful assessment of diet and fluid intake is essential. Reduced fluid intake due to bladder disturbances or dysphagia may be a contributing factor. Certain drugs used to treat other symptoms of MS, such as spasticity, pain, or bladder dysfunction, can also result in constipation. Decreased physical activity and mobility can, in turn, reduce the frequency of bowel movements. A screening of secondary medical causes should also be completed.

The first step in addressing mild-to-moderate constipation is to start behavioral changes. This includes increasing physical activity, ensuring appropriate fluid intake (1.5–2 liters per day), and increasing dietary fiber (at least 25–35 g per day) [169]. Biofeedback therapy may also be effective in improving motility.

Osmotic agents, such as magnesium oxide and magnesium sulfate, are often used in the treatment of mild-to-moderate constipation. Compared to magnesium oxide, magnesium sulfate can lead to violent bowel movements with liquid-like consistency, and therefore, it should be avoided in the elderly and those with limited mobility [217]. Prokinetic agents such as lubiprostone increase intestinal fluid secretion and may be used in some cases. In MS, chronic constipation is often due to gastrointestinal hypomotility; therefore, bulk laxatives may exacerbate the problem [169]. A combination of prokinetic and bulk laxatives may be necessary. Lactulose, polyethylene glycol, and sorbitol are helpful for patients with more severe chronic constipation [217].

Enemas or suppository agents can work quickly and efficiently to soften and expel stool. Saline enemas are reported to be the safest approach [217]. Caregivers should be encouraged to monitor the type of enema being used and its frequency in order to prevent electrolyte imbalance. Various commercial enema products are available, and these may be used at home in cases of chronic constipation. Analgesic or antiemetic rectal suppositories help relieve rectal pain or nausea and vomiting in constipated patients with MS.

Stimulant agents such as senna, cascara, and castor oil increase intestinal motility and secretions and are effective in combating constipation. Senna is the preferred agent because of greater tolerability [217]. Docusate sodium, a stool softener, in combination with senna is effective in treating mild-to-moderate constipation in patients with MS. Surgery is indicated in rare cases of refractory constipation and fecal impaction [217].

Fecal Incontinence

Fecal incontinence is defined as the loss of regular control of the bowels, and in patients with MS, it is usually caused by reduced anal squeeze pressures, correlating with duration of disease and disability status. It is experienced by approximately 24% of mildly disabled patients and 66% of those with severe disease [217]. Evaluation of the patient's diet and fluid history is essential to determining possible triggers. The overall goal is to treat the underlying cause of fecal incontinence.

The opioid-receptor agonist loperamide can be prescribed to patients with chronic diarrhea with or without fecal incontinence, but it is not recommended in patients with symptoms of diarrhea and concomitant constipation [217]. Biofeedback training is helpful in strengthening pelvic floor muscles and improving anal squeeze pressures. Surgical repair (e.g., pelvic floor muscle repair, forming a new external anal sphincter, use of hydraulic rings) is indicated for medically refractory cases.

Cognitive Impairment

Approximately 40% to 70% of patients with MS experience intellectual impairments that progressively increase with disease duration and result in significant disability, decreased quality of life, and inability to maintain employment [217]. The most common cognitive deficits include poor attention and executive functioning, slowed information processing, and reduced memory retrieval. Patients with MS are capable of consolidating new memories; dementia is rare.

Baseline neuropsychological investigations should be performed at the time of an MS diagnosis so future monitoring of cognitive changes is accurate and can guide medical interventions. Cognitive-behavioral therapy, psychotherapy, and counseling are effective interventions; pharmacotherapy may also be indicated. Some studies have found amphetamines to be effective in improving cognitive performance; however, this may be due to reduction in fatigue and mood changes rather than a beneficial effect on cognition [217]. There is emerging evidence that suggests the centrally acting acetylcholinesterases, such as donepezil, improve memory in subjects with memory impairment [169].

Depression

Due to the potentially overwhelming nature of the medical consequences of MS, psychiatric issues are often overlooked and undertreated. However, an estimated 50% of patients with MS have clinical depression, and the suicide rate is higher among persons with MS than the general population [217,218]. Common signs and symptoms include insomnia, early morning awakening, loss of appetite, anhedonia, loss of concentration, fatigue, short-term memory deficits, and cognitive impairment.

The Beck Depression Inventory (BDI-II) is often used in the diagnosis and evaluation of depression in patients with MS [218]. The BDI-II is a questionnaire that consists of 21 multiple choice questions that allow self-reporting of a multitude of depressive symptoms. It also is used to measure the severity of depression; higher total scores indicate more severe depressive symptoms.

All patients should be reassured that depression is treatable. A sedating tricyclic antidepressant such as amitriptyline or one of the newer selective serotonin reuptake inhibitors (e.g., citalopram) may be effective in the treatment of depression in patients with emotional lability and/or depression [169]. Venlafaxine or bupropion may be prescribed for mood stabilization if lack of energy or loss of concentration is the main presenting symptom [218]. Patients with anxiety may be treated with an anxiolytic, such as lorazepam, alprazolam, or clonazepam [218]. Buspirone is also prescribed in patients with anxiety and is particularly effective for panic attacks. Hypomania and psychosis are rare manifestations of MS and should be managed according to standard psychiatric principles [169].

Cognitive-behavioral therapy is helpful in patients with MS to address depressive symptoms and maintain commitment to the established care plan. Patients who express suicidal ideation or planning should be referred to emergency psychiatric care immediately.

Uhthoff Phenomenon

Approximately 60% to 80% of patients with MS experience Uhthoff phenomenon, which is characterized by reversible and often stereotypic worsening of neurologic symptoms triggered by increased body temperature [210]. Exposure to high temperature, intense exercise, various infections, and stress can all increase core body temperature. Any factors that cause sweating can result in worsening of neurologic symptoms.

The neurological deficits caused by Uhthoff phenomenon can be reversed by removing heat, stopping exercise, and avoiding psychosocial stressors while promoting subsequent cooling. Simple strategies to cool the body, such as cold showers, ice packs, and regional cooling devices, provide mild-to-moderate benefits [210]. Cooling suits may be helpful in patients with profound heat sensitivity [169]. Although efficacious, use of 4-aminopyridine, a centrally acting potassium-channel blocker, is limited by side effects [169].

Oculomotor Symptoms

Oculomotor symptoms are experienced by approximately 30% to 50% of all patients with MS [219]. Internuclear ophthalmoplegia and nystagmus are the most common oculomotor conditions, although other visual disturbances can develop.

Oculomotor symptoms that emerge in the relapse period should be treated with high-dose IV methylprednisolone [219]. An eye patch is beneficial during the acute phase to avoid diplopia. Patients with pendular nystagmus are usually treated with gabapentin or memantine; baclofen is the drug of choice for treatment of upbeat/downbeat nystagmus [219]. 3, 4-DAP 20 mg is also effective in treating downbeat nystagmus. In internuclear ophthalmoplegia, drug treatment is rarely needed.

Sexual Dysfunction

Sexual dysfunction is a frequent complication of MS, usually in combination with bladder dysfunction. It tends to develop later in the disease course and is more common in men (90%) than women (70%) [42]. Sexual health and activity should be a part of the regular assessment of patients with MS.

Sexual dysfunction can adversely affect patients' self esteem, quality of life, and spousal relationships. It can be categorized as primary, secondary, or tertiary depending on cause, and each type requires a different therapeutic approach. Primary sexual dysfunction is the direct consequence of the demyelinating lesions formed in the CNS influencing sexual response and sexual feelings. Secondary sexual dysfunction occurs as a result of other MS symptoms (e.g., spasticity) and/or secondary to the side effects of medications used to treat MS. Tertiary sexual dysfunction is the result of psychological, emotional, and/or cultural influences that may adversely affect sexual response and activity.

Type of sexual dysfunction varies. Reduced libido is the most frequent manifestation of primary sexual dysfunction for women with MS. Among ambulatory men with MS, approximately 60% experience erectile dysfunction, 50% report orgasmic dysfunction, and 40% experience reduced libido [220].

Prostaglandin-5 inhibitors (e.g., sildenafil, vardenafil, tadalafil) are used in the treatment of primary sexual dysfunction in men. Penile prostheses, meatal urethral alprostadil suppository, testosterone supplements, vacuum erection devices, and intracavernosal injections of alprostadil may also be helpful [42,217].

The EROS Clitoral Therapy Device is the only U.S. Food and Drug Administration (FDA)-approved therapy for women experiencing sexual dysfunction, and it is only indicated in cases of impaired sexual response [37]. This device stimulates clitoral engorgement, resulting in significantly improved vaginal/clitoral sensations, lubrication, ability to achieve orgasm, and overall sexual satisfaction [37]. Use of high-frequency wall-power vibrator devices may be recommended for women who have diminished arousal, sensation, and difficulty achieving orgasm. Over-the-counter water-soluble lubrication agents are helpful for women with vaginal dryness and related pain with intercourse.

Tertiary sexual dysfunction is managed with counseling or therapy, either as monotherapy or as adjunctive treatment in combination with pharmacotherapy or devices. The patient should be educated about sexual stimulation techniques and interpersonal communication. Body mapping, a self-exploration technique in which the patient gently touches all parts of the body to identify erogenous stimulation, may be incorporated into the treatment plan.

Dysphagia

Dysphagia is a relatively common development in patients with MS. Studies indicate that it is more likely to occur in patients with severe brainstem impairment and more severe disease [170]. The potential risk of aspiration, pneumonia, and malnutrition and the high efficacy of swallowing rehabilitation suggest that patients with MS should have a careful evaluation of swallowing function, especially high-risk patients [170].

Screening for dysphagia, both solid and liquid, is required at each office visit. Individuals with liquid dysphagia usually complain of coughing or choking while eating, whereas those with solid food dysphagia have a sensation of food "sticking" in the throat or chest. Other clinical manifestations include dysphonia, coughing, and gastroesophageal reflux disease.

Patients with dysphagia should undergo a thorough assessment that includes a comprehensive history and examination related to particular symptoms of dysphagia, ear/nose/throat and neurological examination, and a functional swallowing test. A videofluorographic swallowing study or transnasal fiberoptic endoscopic examination of swallowing is also helpful. A careful physical examination should include inspection and palpation of the neck and throat for structural abnormalities or masses. A videofluoroscopic swallowing study can be performed in the form of a modified barium swallow.

If present, treatment focuses on proper fluid and food intake, prevention of aspiration and secondary pneumonia, and improvements in quality of life using pharmacologic, rehabilitative, and/or surgical interventions. Anticholinergic drugs (e.g., scopolamine) may be prescribed if hypersalivation is an issue; transdermal patches are the preferred administration method. Injections of botulinum toxin can increase esophageal sphincter tone. Proton pump inhibitors are highly effective in controlling symptoms of gastroesophageal reflux.

However, the basis of dysphagia treatment in patients with MS is functional swallowing therapy. This involves restitution (restoration of impaired function using exercises), compensation (postural changes and dietary modifications), and adaptation (modification of the environment to improve nutrition). This therapy is conducted by a speech-language pathologist.

For patients with severe neurogenic dysphagia or hypersecretion, a nasogastric or percutaneous endoscopic gastrostomy tube may be temporarily or permanently required to maintain adequate nutritional and fluid intake. These tubes have been found to lower choking risk and improve quality of life and survival rate in certain patients. A nasogastric tube is indicated when enteral feeding is required for a short duration (i.e., less than 30 days). However, direct enteral access is preferred when enteral feeding is required for a longer period, as nasogastric tubes cause considerable discomfort and epistaxis.

Dysarthria

Dysarthria is a motor speech disorder caused by impairment of the nerves that control the muscles involved with speaking. Approximately 40% of patients with MS experience some level of dysarthria, which is usually heightened during times of stress or fatigue [47].

No drug treatment is effective for the treatment of dysarthria, but speech therapy can be very beneficial in improving voice volume and language. Speech-language pathologists can also recommend the use of voice amplifiers to aid communication.

Pain

Acute MS-associated pain is predominantly caused by optic neuritis, trigeminal neuralgia, dysesthesias, or Lhermitte's sign, and treatment is dependent on the causative condition [73]. Corticosteroids are the drug of choice in the treatment of optic neuritis. Acute pain due to trigeminal neuralgia can be successfully managed with anticonvulsants such as carbamazepine or phenytoin [74,75]. Carbamazepine, clonazepam, or amitriptyline is effective in reducing pain resulting from Lhermitte's sign or dysesthesias [78,79]. Both intermittent neuralgias and central pain respond to sodium-channel blockers. Pain associated with clonic muscle spasms may respond to antispasticity agents [169].

Subacute pain is often secondary to the disease; treatment will depend on the condition. Chronic pain is very common and is usually caused by dysesthesias. It is difficult to manage, but carbamazepine, phenytoin, gabapentin, lamotrigine, topiramate, and tricyclic antidepressants are options [169].

Tremor

Tremor is one of the most disabling and difficult to treat neurological impairments in MS [169]. Available treatments, depending on severity of the tremor, include mechanical damping (e.g. diving weights), high doses of isoniazid (600–1200 mg/day), clonazepam, beta blockers, or neurosurgery (thalamotomy or thalamic deep brain stimulation). It is important to monitor liver function tests when using high-dose isoniazid, which should be taken in combination with pyridoxine to prevent the development of peripheral neuropathy [169]. Clonazepam is only moderately effective and is limited by sedation. Thalamotomy and deep brain stimulation can provide dramatic short-term results, but often fail because of long-term disease progression.

REHABILITATION

Disease-modifying treatments slow the progression of MS but do not stop it; symptoms will continue to increase. As ultimate cure is as yet unattainable, management of these functional deficits is of utmost importance. Neurorehabilitation together with occupational therapy is the best approach.

Few studies have assessed the effectiveness of neurorehabilitation on outcomes and disease progression in patients with MS, partly because the highly variable and unpredictable nature of the disease course makes such research difficult [55,56]. Its general effectiveness is well established in conditions such as stroke and head trauma, and it is believed to be of use in cases of MS [58]. Furthermore, even if rehabilitation has no direct influence on disease progression, it has been shown to improve ability to carry out activities of daily living, participation in social activities, and quality of life [182].

A multidisciplinary approach is best when establishing a rehabilitation program for patients with MS [65,66]. This rehabilitation consists of physiotherapy, cognitive rehabilitation, speech and language therapy, and occupational therapy to control symptoms and disabilities [59,60]. Cognitive rehabilitation is supervised by neuropsychologists, while psychologists and psychiatrists play a key role in the treatment of depression and emotional distress [63,64]. Several studies have demonstrated that exercise, cognitive therapy and energy conservation instruction have a beneficial effect on self-reported quality of life [67,68,69]. Physical therapy, specifically gait training, can result in fatigue reduction [71]. Robotic-assisted, body-weight-supported treadmill training has demonstrated positive impact in rehabilitation of patients with severe walking disabilities, whereas over-ground gait training shows more beneficial effects in patients with less severe impairments [72].

INDIVIDUAL TREATMENT PLANS

Clinically Isolated Syndrome

As discussed, clinically isolated syndrome is considered one of the earliest clinical presentations of RRMS. Studies have demonstrated that treatment with an immunomodulatory drug (specifically interferon) early in this initial period can decrease the likelihood of developing into symptomatic MS [81,82,83]. It is believed that immediate treatment has modest efficacy compared to delayed initiation of treatment [81,82,83].

RRMS

Managing attacks or exacerbations is the cornerstone of the treatment of patients with RRMS. An attack of RRMS is defined as the onset of new or exacerbation of existing neurological symptoms resulting in deterioration of the patient's condition by at least 1 step on a validated disability status scale that persists for a minimum period of 24 hours and is not related to infection [45]. It is important to remember that even with appropriate and adequate use of drugs, the majority of patients with RRMS will still experience some attacks and many will develop some degree of disability. The aim of treating an acute exacerbation is to reduce the duration and intensity of neurological impairment. A complete recovery to the baseline level and prevention of long-term disability remains elusive.

It is essential to rule out infection before initiating therapy, as symptoms may be similar and the most common treatment used for acute attacks (glucocorticoids) can be life-threatening in patients with pre-existing infection [111]. Because most of the immune response in MS occurs early in the disease course, aggressive early treatment with disease-modifying drugs is essential [192]. The choice of agent is usually guided by available evidence, but patient response and tolerability are the most important factors.

The later stages of RRMS tend to be less inflammatory and more degenerative, and treatment during these stages focuses on symptom reduction and quality of life. Immunomodulation with disease-modifying drugs continues, although, as noted, the long-term efficacy is not well established.

Progressive Types

Both SPMS and PRMS are comparatively more difficult to treat than the relapsing forms of MS. Several types of immunosuppressive therapies have shown at least some beneficial effects in the treatment of progressive MS disease. However, these immunosuppressive therapies only briefly halt a rapidly progressive course and are dangerous if prescribed for longer periods [111]. The interventions that have shown some efficacy in progressive types of MS include cyclosporine, total lymphoid radiation, mitoxantrone, methotrexate, interferon, cyclophosphamide, azathioprine, corticosteroids, and IV immunoglobulins [193].

Mitoxantrone is beneficial in patients with SPMS and PRMS and effectively reduces the disease progression and frequency of relapses in patients in short-term follow-up [104]. However, long-term use of this medication causes cardiotoxicity.

Treatment with interferon leads to fewer relapses and less disease activity. Interferons show a great promise in treating SPMS, but more validation is required for their widespread use [105].

Intravenous cyclophosphamide and glucocorticoid monthly pulses may have a beneficial effect in younger patients with progressive MS. Methotrexate may alter the disease course in patients with SPMS and PPMS, but this is not proven [106].

No therapy has been approved specifically for the treatment of PPMS. Several trials are being conducted to explore treatment options for patients with PPMS, including trials with interferons and mitoxantrone, glatiramer acetate, methylprednisolone pulses, and an open-label study of riluzole [107,126,128].

Benign MS

As discussed, benign MS is mild form of MS in which the patients do not develop any disability. Benign MS is typically treated with one of the disease-modifying drugs immediately after a confirmed MS or clinically isolated syndrome diagnosis [111,158].

ALTERNATIVE TREATMENTS

Approximately 60% of MS patients use complementary and alternative medicine. However, with the exception of vitamin D, there is little or no available evidence to support the use of these therapies to improve MS symptoms or disease course [115].

Vitamin D's ability to modulate the immune system may prevent or slow the progression of MS [198]. Results of a study presented at the European Committee for Treatment and Research in Multiple Sclerosis meeting indicated that every 50 nmol/L increase in average serum vitamin D levels translated into a 57% decrease in the rate of new active MS-defining lesions [194]. In fact, the presence of rare variants in CYP27B1, which encodes the enzyme that converts vitamin D to its active form, is strongly associated with MS risk; this supports a causal role of vitamin D deficiency in the development of MS [198]. However, one small study found that high-dose vitamin D supplementation did not result in improvements in symptoms compared to patients with adequate vitamin D [199]. More research is necessary to determine the role of vitamin D supplementation (e.g., dose, optimum time to initiate therapy) in the treatment of MS.

Some ecologic studies have found a correlation between high intake of polyunsaturated fats and low MS prevalence, and some have suggested that increasing intake of omega fatty acids might improve MS symptoms [200]. However, no specific diet has been shown to have any effect on MS lesions or symptoms [116]. Furthermore, a 2012 trial found no beneficial effects on disease activity with omega-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a [200].

The use of cannabis to alleviate symptoms of MS remains controversial. Some patients report that smoking cannabis reduces spasticity and other MS-related symptoms [117,118]. The impairment of neurotransmission seen with MS can be controlled by endocannabinoid receptors and endogenous cannabinoid ligands, which can limit spasticity and may influence the processes that drive the accumulation of progressive disability [201]. However, the cognitive deficit experienced by smoking cannabis that is currently available (e.g., "street" cannabis) may outweigh the benefits [202]. Researchers continue to explore the role of cannabinoids in the treatment of MS symptoms, particularly muscle stiffness and spasms, neuropathic pain, and sleep and bladder disturbance [203].

Derivatives of the herb Ruta graveolens, also known as common rue, have been traditionally used to reduce MS symptoms [120]. However, strong evidence of efficacy is lacking.

Bee venom therapy is also believed to have beneficial effects because of its anti-inflammatory properties and possibly its ability to block IL-6 as a pro-inflammatory cytokine, but the research has shown only marginal evidence of benefit [204]. Bee venom therapy can also be potentially lethal because of high risk of anaphylactic shock [115].

Hyperbaric oxygen therapy has been used in patients with MS based on the theory that poor oxygenation of affected nerves may exacerbate symptoms. Studies have demonstrated that hyperbaric oxygenation has no proven benefits on MS patients [121].

Antioxidants are believed to reduce blood-brain barrier permeability, and levels are reduced in patients with MS [28,216]. It has been reported that raising uric acid levels protects the integrity of the blood-brain barrier by removing peroxynitrite, an oxidant that is linked to axonal degeneration. Further research is necessary to explore the role of antioxidants in the treatment of MS.

Studies have demonstrated that intestinal parasites such as hookworm may have a protective role against MS by inducing changes in immunoregulation [39,44]. One study found that the introduction of helminths reduced the number of lesions detected by MRI [46]. Preliminary trials indicate that helminthic therapy is safe, but serious adverse effects are possible.

Yoga and general exercise have been found to reduce fatigue and improve overall quality of life in patients with MS [122]. Small studies of acupuncture in patients with MS have found improvements in pain, muscle spasm, and quality of life [208]. Further clinical trials are necessary to establish efficacy.

ONGOING RESEARCH: POSSIBILITIES FOR FUTURE TREATMENT

Advances in MS treatment have progressed at a rapid pace since 2000. Ongoing research for new treatments is aimed at drugs that:

  • Have improved efficacy and are well tolerated

  • Target both inflammation and neurodegeneration

  • Promote remyelination and repair

  • Are conveniently administered, preferably orally

  • Effectively treat PPMS

  • Effectively treat the chronic symptoms of MS, particularly fatigue

  • Improve patient adherence

Alemtuzumab

Alemtuzumab is used off-label for the treatment of RRMS, and researchers continue to explore its efficacy. It is a humanized monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation, and is approved for the treatment of chronic lymphocytic leukemia and T-cell lymphoma. In phase III studies, alemtuzumab showed greater reductions in MS relapse rate and disease activity compared to ß-interferon [76]. It has also shown a beneficial effect on disability progression. Significant side effects include idiopathic thrombocytopenic purpura and Graves' disease.

Daclizumab

Daclizumab is an anti-IL2 monoclonal antibody under investigation for treating RRMS. It is currently approved for the prevention of rejection after organ transplantation. In Phase IIb clinical trials, daclizumab reduced the relapse rate in RRMS by approximately 50% compared to placebo [77].

BG00012

BG00012, also known as BG12 or oral fumarate, is a fumaric acid ester [205]. Phase III trials have shown that BG00012 reduced the annualized relapse rate by 44% for 240 mg twice daily and by 51% for 240 mg three times daily versus placebo. There was also a significant reduction in the number of new or newly enlarging T2-hyperintense lesions and new T1-hypointense lesions. The exact mechanism of action of BG00012 is still unknown, and phase III trials are ongoing.

Tcelna

Tcelna is a therapeutic vaccine against autologous T-cells utilizing myelin-reactive lymphocytes from peripheral blood. A phase IIb trial of Tcelna demonstrated a 55% reduction in annualized relapse rate as compared to placebo [80]. Financial issues experienced by the manufacturer have made research progress slow [207].

PROGNOSIS

A number of factors have been identified as potential prognostic indicators in MS, capable of modifying the disease course or predicting exacerbations. These include demographics, type of MS, lesion load, and psychosocial stress.

DEMOGRAPHIC FACTORS

As discussed, white patients, especially of Northern European ancestry, are more susceptible to developing MS, while people living near the equator carry the lowest risk [2]. Some studies have demonstrated that while whites are more prone to suffer from MS compared to blacks (2:1), black patients tend to experience a more severe course and greater MS risks [2]. Black Americans are usually at an older age at disease onset and have more variety of symptoms at disease onset (caused by multiple lesions in different places in the CNS) compared to whites [2].

Older studies suggest that women tend to have a more benign course then men [123]. However, studies have challenged this notion and have concluded that sex does not determine the disease prognosis independently [124]. Younger age at disease onset has a better prognosis compared with late onset [123]. One study observed that disability in MS is correlated more with the patient's age than on the type of onset (i.e., relapsing or progressive) [129,130].

SUBTYPE OF MS

The relapsing form of MS has a much more favorable prognosis compared with progressive disease [123,124]. One observational study showed that patients with a progressive form of MS acquired irreversible disability earlier compared to patients with relapsing-remitting onset [125]. After irreversible disability occurred, however, the time course of progressive disability was similar in the two groups. Data have suggested that the development of a progressive course in patients with MS may be the most important prognostic factor [127].

EARLY SYMPTOMS

In the past, the presence of specific MS symptoms at disease onset was believed to indicate a favorable (e.g., sensory symptoms, optic neuritis) or unfavorable (e.g., pyramidal, brainstem, and cerebellar symptoms) prognosis [123]. However, subsequent studies have observed that this theory is false and the onset symptoms are not independent prognostic factors [124,131]. An observational study found that clinical variables assessed early in RRMS predicted time to irreversible disability (i.e., Expanded Disability Status Scale score of 4 or limited walking without aid); however, this was not true for subsequent disability progression [132].

LESION LOAD

A serial MRI study observed a strong relationship between the development of lesions early in the disease course and long-term disability [133]. The correlation seems to plateau at higher levels of disability, indicating that MRI lesion burden is a poor determinant of disease progression in patients with advanced disease. A pooled data study showed that MRI lesion load is weakly correlated with age at disease onset, duration of the disease, and disease progression [134].

PSYCHOSOCIAL STRESS

Some studies have suggested that MS relapses may be more frequent after stressful life events, although others have found no relationship between MS exacerbations and life-event stress [135,137]. It appears that the number, not the severity, of stressful life events is most important. The exact mechanism of a relationship between stress and MS exacerbations is still unknown. Stress management therapy may have a beneficial effect in reducing the development of new MRI brain lesions while patients are in treatment [119].

PREGNANCY AND MS

MS is more prevalent in women of child-bearing age, and pregnancy can pose a challenge in the management of MS [138]. In the last decade, the incidence of MS has increased, with a corresponding higher female-to-male ratio [139,140]. These factors emphasize the need for more research in the subject of pregnancy in women with MS. Previously, women with MS were discouraged from having children, but this has not been supported by evidence. Today, pregnancy is believed to have no adverse effect on the course and prognosis of MS [141].

The significant hormonal changes that occur during pregnancy result in a physiological shift from T-helper 1 to T-helper 2 immune response, leading to an increase in anti-inflammatory cytokines [142]. This shift is partly responsible for the reduction in MS relapses in pregnant women [141]. The increase in estrogen levels during this period also suppresses T-cell proliferation and cytokine production [143,144]. Alpha-fetoprotein, which is produced by the liver and yolk sac of a developing fetus, decreases neuroinflammation and disease severity [145]. Overall, pregnancy appears to have a beneficial effect on MS disease activity.

There is no evidence that MS affects fertility and conception. However, patients with MS have a high rate of sexual dysfunction that may be associated with a number of neurological symptoms and disabilities [147]. These factors can adversely affect the overall quality of sexual life and impede conception [148].

In cases of very aggressive MS, there is a risk of inadequate maternal care. Therefore, adequate disease control should be achieved prior to pregnancy. Women with MS who are pregnant or considering pregnancy are often concerned about the genetic transmission of MS to their child. The absolute risk of disease transmission ranges from 2% to 4%, but there are no genetic or prenatal screening tests that can detect MS [146].

TREATMENT DURING PREGNANCY

If safe, women intending to conceive should stop their MS treatment for at least 3 months prior to conception. A study conducted in Sweden concluded that pregnancies that were not exposed to the ß-interferon in utero for at least a two-week period prior to conception resulted in healthier infants than pregnancies with such exposure [149]. A small Canadian study found that pregnancies exposed to ß-interferon resulted in a higher number of miscarriages, low birth weight, and prematurity [150]. However, a larger study did not find a significantly higher rate of complications in pregnancies accidentally exposed to immunomodulators [151]. In general, even the higher incidence of complications observed in some studies was only slightly greater than that of the general population. If continued treatment is necessary, modifications to the prescribed regimen (with preference for lower risk options) may be necessary. Many drugs used to treat MS and its related symptoms are contraindicated during pregnancy.

For disease modification, the safest options are glatiramer acetate and immunoglobulin, which appear to do no harm to the fetus and are pregnancy category B. ß-interferons, mitoxantrone, and corticosteroids are pregnancy category C, as animal studies have demonstrated adverse effects to the fetus. The risk-benefit ratio should be considered prior to using these medications in pregnant women. Category D drugs, which have evidence of fetal risk and should only be considered in life-threatening situations or when safer drugs are ineffective, include azathioprine, cyclophosphamide, and mitoxantrone. Category X drugs such as methotrexate pose an extremely high risk to the fetus and should not be used for women who are or may become pregnant.

Apart from immunomodulatory or immunosuppressive agents, the medications used to control the symptoms of MS should also be reconsidered. Oxybutynin and pemoline, prescribed for incontinence and fatigue respectively, are pregnancy category B, and their continued use should be safe. Many of the drugs used in the treatment of MS are category C, including:

  • Gabapentin and carbamazepine for paroxysmal disorders

  • Amantadine and potassium channel blockers for fatigue

  • Selective serotonin reuptake inhibitors for depression

  • Baclofen and dantrolene for spasticity

Benzodiazepines and phenytoin (used for pain and insomnia) are category D and should be avoided.

Unplanned pregnancy, without proper adjustment of treatment, carries a high inherent risk to the fetus. As such, women should be counseled to discuss childbearing plans with their physician prior to conception and to maintain adequate birth control if pregnancy is not desired.

MS AND DELIVERY

The mode of delivery is guided by obstetric indications rather than the presence of MS. However, a study conducted in the United States found that the rate of non-vaginal delivery was higher among women with MS than the general population [154]. If cesarean delivery is necessary, proper attention should be provided during preoperative evaluation to reduce postoperative neurological complications. During labor, epidural injection is considered to be a safer option than spinal block for anesthesia in patients with MS, as spinal block is suspected to be associated with neurotoxic effects [155,156]. Autonomic dysreflexia, a very rare, potentially life-threatening condition related to spinal cord lesions, can arise in women with MS during delivery [157]. Patients should be duly informed about the type of anesthesia and its possible side effects and complications.

RELAPSE RISK AFTER DELIVERY

The rate of MS relapse increases after delivery. One study observed that a rapid increase in the number of interferon-γ-producing T-cells may be responsible for the increased risk of relapse [159]. Women with higher Expanded Disability Status Scale scores and higher relapse rates before pregnancy tend to have a greater risk of relapse during the postpartum period [160].

BREASTFEEDING

As with all women, the rate of breastfeeding among women with MS varies widely and depends upon various factors. Several studies have demonstrated a possible beneficial effect of breastfeeding on postpartum relapse rates, but the higher risk of relapses during the postpartum period may make breastfeeding difficult or impossible, especially if adequate treatment with immunomodulatory or immunosuppressive agents is indicated [161]. There is insufficient information regarding the levels of many MS drugs in human milk.

CONCLUSION

MS is a relatively uncommon disease, but the effects can be devastating for patients. Unfortunately, a cure is elusive, and the cause is still unknown. Different MS subtypes are being described, and healthcare providers should stay abreast of the different clinical presentations, effective management, and progression of the disease. There is also a need for healthcare providers to be able to communicate with and educate patients regarding important treatment options available and disease prognosis. At every follow-up visit, healthcare professionals should encourage their patients to participate actively in decision making and self-management. Although a variety of specialists is often involved in the care of individuals with MS, the primary care team has a pivotal role in the overall management of these patients. Rapid strides have been made in the understanding MS, and without a doubt one can say that future holds better prospects for patients with this debilitating disease.

Works Cited

1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-1517.

2. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9(5):520-532.

3. Weiner H. Multiple sclerosis is an inflammatory T-cell-mediated disorder. Arch Neurol. 2004;61(10):1613-1615.

4. Hafler DA, Compston A, Sawcer S, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007;357(9):851-862.

5. Sawcer S, Hellenthal G, Pirenen M, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214-219.

6. Frohman EM, Racke MK, Raine CS. Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med. 2006;354(9):942-955.

7. Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol. 2008;7(3):268-277.

8. Dyment DA, Ebers GC, Sadovnick AD. Genetics of multiple sclerosis. Lancet Neurol. 2004;3(92):104-110.

9. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359(9313):1221-1231.

10. Lincoln MR, Montpetit A, Cader MZ, et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet. 2005;37(10):1108-1112.

11. Multiple Sclerosis Association of America. Frequently Asked Questions about Multiple Sclerosis. Available at http://www.mymsaa.org/about-ms/faq/. Last accessed November 12, 2013.

12. Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.

13. Alonso A, Hernán MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology. 2008;71(2):129-135.

14. Marrie RA. Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol. 2004;3(12):709-718.

15. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann Neurol. 2007;61(6):504-513.

16. Marrie RA, Cutter G, Tyry T. Substantial burden of dizziness in multiple sclerosis. Mult Scler Relat Disord. 2013;2(1):21-28.

17. Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol. 2010;9(6):599-612.

18. Piwko C, Desjardins OB, Bereza BG, et al. Pain due to multiple sclerosis: analysis of the prevalence and economic burden in Canada. Pain Res Manag. 2007;12(4):259-265.

19. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007;61(4): 288-299.

20. Sriram S, Yao SY, Stratton C, Moses H, Narayana PA, Wolinsky JS. Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS. J Neurol Sci. 2005;234(1-2):87-91.

21. Pender MP. Does Epstein-Barr virus infection in the brain drive the development of multiple sclerosis? Brain. 2009;132(Pt 12):3196-3198.

22. Bagert BA. Epstein-Barr virus in multiple sclerosis. Curr Neurol Neurosci Rep. 2009;9(5):405-410.

23. Korn T. Pathophysiology of multiple sclerosis. J Neurol. 2008;255(Suppl 6):2-6.

24. Lucchinetti C Bruck W Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47:407-417.

25. Iglesias A, Bauer J, Litzenburger T, Schubart A, Linington C. T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Glia. 2001;36(2):220-234.

26. U.S. Food and Drug Administration. FDA Approves New Multiple Sclerosis Treatment: Tecfidera. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345528.htm. Last accessed November 12, 2013.

27. Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler. 2003;9(3):219-227.

28. Oztaş B, Kiliç S, Dural E, Ispir T. Influence of antioxidants on the blood-brain barrier permeability during epileptic seizures. J Neurosci Res. 2001;66(4):674-678.

29. Davis SL, Frohman TC, Crandall CG, et al. Modeling Uhthoff's phenomenon in MS patients with internuclear ophthalmoparesis. Neurology. 2008;70(13 Pt 2):1098-1106.

30. Humm AM, Beer S, Kool J, et al. Quantification of Uhthoff's phenomenon in multiple sclerosis: a magnetic stimulation study.Clin Neurophysiol. 2004;115(11):2493-2501.

31. Balcer LJ. Clinical practice: optic neuritis. N Engl J Med. 2006;354(12):1273-1280.

32. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46(4):907-911.

33. Siengsukon K. The Effect of Exercise on Sleep and Cognitive Function in People with Multiple Sclerosis. Available at http://www.nationalmssociety.org/chapters/KSG/chapter-news/chapter-news-detail/index.aspx?nid=7734. Last accessed November 12, 2013.

34. Koch M, Kingwell E, Rieckmann P, Tremlett H. The natural history of primary progressive multiple sclerosis. Neurology. 2009;73(23):1996-2002.

35. National Multiple Sclerosis Society. Optic Neuritis. Available at http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/visualsymptoms/optic-neuritis/index.aspx. Last accessed November 12, 2013.

36. Trojano M, Paolicelli D. The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes. Neurol Sci. 2001;22(Suppl 2):S98-S102.

37. Kessler TM, Fowler CJ, Panicker JN. Sexual dysfunction in multiple sclerosis. Expert Rev Neurother. 2009;9(3):341-350.

38. Rashid W, Miller DH. Recent advances in neuroimaging of multiple sclerosis. Semin Neurol. 2008;28(1):46-55.

39. Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol. 2007;61(2): 97-108.

40. Polak P, Magnano C, Zivadinov R, Poloni G. 3D FLAIRED: 3D fluid attenuated inversion recovery for enhanced detection of lesions in multiple sclerosis. Magn Reson Med. 2012;68(3):874-881.

41. Li DK, Held U, Petkau J, et al. MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology. 2006;66(9):1384-1389.

42. National Multiple Sclerosis Society. Sexual Dysfunction. Available at http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/sexual-dysfunction/index.aspx. Last accessed November 12, 2013.

43. Link H, Huang YM. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J Neuroimmunol. 2006;180(1-2):17-28.

44. Correale J, Farez M, Razzitte G. Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol. 2008;64(2):187-199.

45. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.Ann Neurol. 2011;69(2):292-302.

46. Fleming JO, Isaak A, Lee J, et al. Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study.Mult Scler J. 2011;17(6):1-12.

47. Hartelius L, Runmarker B, Anderson O. Prevalence and characteristics of dysarthria in a multiple sclerosis incidence cohort: in relation to neurological data. Folia Phoniatr Logop. 2000;52:160-177.

48. Renoux C, Vukusic S, Mikaeloff Y, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med. 2007;356(25):2603-2613.

49. Fox E. Management of worsening multiple sclerosis with mitoxantrone: a review. Clin Ther. 2006;28(4):461-474.

50. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing forms of multiple sclerosis. N Engl J Med. 2006;354(9):899-910.

51. Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68(17):1390-1401.

52. Natalizumab: new drug. Multiple sclerosis: risky market approval. Prescrire Int. 2008;17(93):7-10.

53. Drugs.com. Gilenya. Available at http://www.drugs.com/gilenya.html. Last accessed November 11, 2013.

54. U.S. Food and Drug Administration. FDA Approves First Oral Drug to Reduce MS Relapses. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226755.htm. Last accessed November 11, 2013.

55. Kesselring J, Beer S. Symptomatic therapy and neurorehabilitation in multiple sclerosis. Lancet Neurol. 2005;4(10):643-652.

56. Beer S, Khan F, Kesselring J. Rehabilitation interventions in multiple sclerosis: an overview. J Neurol. 2012;259(9):1994-2008.

57. Langhorne P. Organised inpatient (stroke unit) care for stroke. Stroke Unit Trialists' Collaboration. Cochrane Database Syst Rev. 2000;(2):CD000197.

58. Turner-Stokes L, Disler PB, Nair A, Wade DT. Multi-disciplinary rehabilitation for acquired brain injury in adults of working age. Cochrane Database Syst Rev. 2005;(3):CD004170.

59. Heesen C, Romberg A, Gold S, Schulz KH. Physical exercise in multiple sclerosis: supportive care or a putative disease-modifying treatment. Expert Rev Neurother. 2006;6(3):347-355.

60. Rietberg MB, Brooks D, Uitdehaag BM, Kwakkel G. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2005;(1):CD003980.

61. Merson RM, Rolnick MI. Speech-language pathology and dysphagia in multiple sclerosis. Phys Med Rehabil Clin N Am. 1998;9(3):631-641.

62. Baker NA, Tickle-Degnen L. The effectiveness of physical, psychological, and functional interventions in treating clients with multiple sclerosis: a meta-analysis. Am J Occup Ther. 2001;55(3):324-331.

63. Benedict RH, Bobholz JH. Multiple sclerosis. Semin Neurol. 2007;27(1):78-85.

64. Ghaffar O, Feinstein A. The neuropsychiatry of multiple sclerosis: a review of recent developments. Curr Opin Psychiatry. 2007;20(3):278-285.

65. Khan F, Turner-Stokes L, Ng L, Kilpatrick T. Multidisciplinary rehabilitation for adults with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2008;79(2):114.

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

67. Gallien P, Nicolas B, Robineau S, Pétrilli S, Houedakor J, Durufle A. Physical training and multiple sclerosis. Ann Readapt Med Phys. 2007;50(6):373-376, 369-372.

68. Rietberg MB, Brooks D, Uitdehaag BMJ, Kwakkel G. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2005;(1):CD003980.

69. Thomas PW, Thomas S, Hillier C, Galvin K, Baker R. Psychological interventions for multiple sclerosis. Cochrane Database Syst Rev. 2006;(1):CD004431.

70. Mathiowetz V, Matuska KM, Murphy ME. Efficacy of an energy conservation course for persons with multiple sclerosis. Arch Phys Med Rehabil. 2001;82(4):449-456.

71. Sacco R, Bussman R, Oesch P, Kesselring J, Beer S. Assessment of gait parameters and fatigue in MS patients during inpatient rehabilitation: a pilot trial. J Neurol. 2011;258(5):889-894.

72. Vaney C, Gattlen B, Lugon-Moulin V, et al. Robotic-assisted step training (lokomat) not superior to equal intensity of over-ground rehabilitation in patients with multiple sclerosis. Neurorehabil Neural Repair. 2012;26(3):212-221.

73. Kerns RD, Kassirer M, Otis J. Pain in multiple sclerosis: a biopsychosocial perspective. J Rehabili Res Dev. 2002;39(2):225-232.

74. MedlinePlus. Carbamazepine. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682237.html. Last accessed November 11, 2013.

75. MedlinePlus. Phenytoin. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682022.html. Last accessed November 11, 2013.

76. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab versus interferon ß-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011;10(4):338-348.

77. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9884):2167-2175.

78. MedlinePlus. Clonazepam. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682279.html. Last accessed November 11, 2013.

79. MedlinePlus. Amitriptyline. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682388.html. Last accessed November 11, 2013.

80. Opexa Therapeutics. TERMS Phase 2b Overview. Available at http://www.opexatherapeutics.com/tcelna/terms-phase-2b-overview/default.aspx. Last accessed November 12, 2013.

81. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343(13):898-904.

82. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357(9268):1576-1582.

83. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet. 2007;370(9585):389-397.

84. MedlinePlus. Interferon Beta-1a Intramuscular Injection. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a693040.html. Last accessed November 13, 2013.

85. MedlinePlus. Interferon Beta-1a Subcutaneous Injection. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a604005.html. Last accessed November 11, 2013.

86. MedlinePlus. Interferon Beta-1b Injection. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601151.html. Last accessed November 11, 2013.

87. Goodin DS, Arnason BG, Coyle PK, et al. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61(10):1332-1338.

88. Medline Plus. Natalizumab Injection. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a605006.html. Last accessed November 11, 2013.

89. Goodin DS, Cohen BA, O'Connor P, et al. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;71(10):766-773.

90. Cohen J, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. NEJM. 2010;362:402-415.

91. Novartis. Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis. Available at http://clinicaltrials.gov/show/NCT00289978. Last accessed November 11, 2013.

92. Ruggieri M, Avolio C, Livrea P, Trojano M. Glatiramer acetate in multiple sclerosis: a review. CNS Drug Rev. 2007;13(2):178-191.

93. Munari L, Lovati R, Boiko A. Munari, Luca M. Therapy with glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2004;(1):CD004678.

94. Rice GP, Incorvaia B, Munari L, et al. Interferon in relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev. 2001;(4):CD002002.

95. Martinelli Boneschi F, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2005;(4):CD002127.

96. Fernández O, Fernández V, Mayorga C, et al. HLA class II and response to interferon-beta in multiple sclerosis. Acta Neurol Scand. 2005;112(6):391-394.

97. Johnson KP. Control of multiple sclerosis relapses with immunomodulating agents. J Neurol Sci. 2007;256(Suppl 1):S23-S28.

98. Herbert J, Kappos L, Calabresi P, et al. Natalizumab Reduces Multiple Sclerosis Severity: Analysis of Patients from the AFFIRM and SENTINEL Studies using the Multiple Sclerosis Severity Scale. Paper presented at: 6th Annual Meeting of the American Academy of Neurology; Chicago, IL; April 12-19, 2008.

99. Gonsette RE. Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis. Expert Opin Pharmacother. 2007;8(8):1103-1116.

100. Murray TJ. The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks? Expert Opin Drug Safety. 2006;5(2):265-274.

101. Buttinelli C, Clemenzi A, Borriello G, Denaro F, Pozzilli C, Fieschi C. Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up. Euro J Neurol. 2007;14(11):1281-1287.

102. Boster A, Edan G, Frohman E, et al. Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician. Lancet Neurol. 2008;7(2):173-183.

103. Bertolotto A, Gilli F. Interferon-beta responders and non-responders: a biological approach. Neurol Sci. 2008;29(Suppl 2):S216-S217.

104. Martinelli Boneschi F, Vacchi L, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2013;5:CD002127.

105. McCormack PL, Scott LJ. Interferon-beta-1b: a review of its use in relapsing-remitting and secondary progressive multiple sclerosis. CNS Drugs. 2004;18(8):521-546.

106. Sørensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12(11):817-827.

107. MedlinePlus. Riluzole. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a696013.html. Last accessed at November 11, 2013.

108. MedlinePlus. Methylprednisolone Oral. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682795.html. Last accessed November 11, 2013.

109. MedlinePlus. Methylprednisolone Sodium Succinate Injection. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601157.html. Last accessed November 11, 2013.

110. Sellebjerg F, Barnes D, Filippini G, et al. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. Eur J Neurol. 2005;12(12):939-946.

111. Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58(2):169-178.

112. Dovio A, Perazzolo L, Osella G, et al. Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis. J Clin Endocrinol Metab. 2004;89(10):4923-4928.

113. Uttner I, Müller S, Zinser C, et al. Reversible impaired memory induced by pulsed methylprednisolone in patients with MS. Neurology. 2005;64(11):1971-1973.

114. Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database of Syst Rev. 2000;(4):CD001331.

115. Namaka M, Crook A, Doupe A, et al. Examining the evidence: complementary adjunctive therapies for multiple sclerosis.Neurol Res. 2008;30(7):710-719.

116. Farinotti M, Simi S, Di Pietrantonj C, et al. Dietary interventions for multiple sclerosis. Cochrane Database Syst Rev. 2007;(1):CD004192.

117. Chong MS, Wolff K, Wise K, Tanton C, Winstock A, Silber E. Cannabis use in patients with multiple sclerosis. Mult Scler. 2006;12(5):646-651.

118. Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatr. 2005;76(12):1664-1669.

119. Mohr DC, Lovera J, Brown T, et al. A randomized trial of stress management for the prevention of new brain lesions in MS. Neurology. 2012;79(5):412-419.

120. Bodendiek SB, Mahieux C, Hänsel W, Wulff H. 4-Phenoxybutoxy-substituted heterocycles: a structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3. Eur J Med Chem. 2008;44(5):1838-1852.

121. Bennett M, Heard R. Hyperbaric oxygen therapy for multiple sclerosis. Cochrane Database Syst Rev. 2004;(1):CD003057.

122. Oken BS, Kishiyama S, Zajdel D, et al. Randomized controlled trial of yoga and exercise in multiple sclerosis. Neurology. 2004;62(11):2058-2064.

123. Weinshenker BG. Natural history of multiple sclerosis. Ann Neurol. 1994;36 Suppl:S6-S11.

124. Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported. Neurology. 2006;66(2):172-177.

125. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343(20):1430-1438.

126. de Araújo EA, de Freitas MR. Benefit with methylprednisolone in continuous pulse therapy in progressive primary form of multiple sclerosis: study of 11 cases in 11 years. Arq Neuropsiquiatr. 2008;66(2B):350-353.

127. Kremenchutzky M, Rice GP, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006;129(3):584-594.

128. Killestein J, Kalkers NF, Polman CH. Glutamate inhibition in MS: the neuroprotective properties of riluzole. J Neurol Sci. 2005;233(1-2):113-115.

129. Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain. 2006;129(Pt 3):595-605.

130. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129(Pt 3):606-616.

131. Langer-Gould A, Popat RA, Huang SM, et al. Clinical and demographic predictors of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review. Arch Neurol. 2006;63(12):1686-1691.

132. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126(Pt 4):770-782.

133. Brex PA, Ciccarelli O, O'Riordan JI, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis.N Engl J Med. 2002;346:158-164.

134. Li DK, Held U, Petkau J, et al. MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology. 2006;66(9):1384-1389.

135. Mohr DC, Hart SL, Julian L, et al. Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis. BMJ. 2004;328:731.

136. Wingerchuk DM. Smoking: effects on multiple sclerosis susceptibility and disease progression. Ther Adv Neurol Disord. 2012;5(1):13-22.

137. Buljevac D, Hop WC, Reedeker W, et al. Self reported stressful life events and exacerbations in multiple sclerosis: prospective study. BMJ. 2003;327:646.

138. Ghezzi A and Zaffaroni M. Female-specific issues in multiple sclerosis. Expert Rev Neurother. 2008;8(6):969-977.

139. Koutsouraki E, Costa V, Baloyannis S. Epidemiology of multiple sclerosis in Europe: a review. Int Rev Psychiatry. 2010;22(1):2-13.

140. Bentzen J, Flachs EM, Stenager E, Bronnum-Hansen H, Koch-Henriksen N. Prevalence of multiple sclerosis in Denmark 1950–2005. Mult Scler. 2010;16(5):520-525.

141. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med. 1998;339(5):283-291.

142. Devonshire V, Duquette P, Dwosh E, Guimond C, Sadovnik AD. The immune system and hormones: review and relevance to pregnancy and contraception in women with MS. Int MS J. 2003;10(2):61-66.

143. Zhu WH, Lu CZ, Huang YM, Link H, Xiao BG. A putative mechanism on remission of multiple sclerosis during pregnancy: estrogen-induced indoleamine 2;3-dioxygenase by dendritic cells. Mult Scler. 2007;13(1):33-40.

144. Kahler DJ and Mellor AR. T cell regulatory plasmacytoid dendritic cells expressing indoleamine 2;3 dioxygenase. Handbof Exp Pharmacol. 2009;188(III):165-196.

145. Nizri E, Irony-Tur-Sinai M, Grigoriadis N, Abramsky O, Amitai G, Brenner T. Novel approaches to treatment of autoimmune neuroinflammation and lessons for drug development. Pharmacology. 2007;79(1):42-49.

146. Dyment DA, Ebers GC, Sadovnick AD. Genetics of multiple sclerosis. Lancet Neurol. 2004;3(2):104-110.

147. Fletcher SG, Castro-Borrero W, Remington G, Treadaway K, Lemack GE, Frohman EM. Sexual dysfunction in patients with multiple sclerosis: a multidisciplinary approach to evaluation and management. Nat Clin Pract Urol. 2009;6(2):96-107.

148. Tepavcevic DK, Kostic J, Basuroski ID, Stojsavljevic N, Pekmezovic T, Drulovic J. The impact of sexual dysfunction on the quality of life measured by MSQoL-54 in patients with multiple sclerosis. Mult Scler. 2008;14(8):1131-1136.

149. Sandberg-Wollheim M, Frank D, Goodwin TM, et al. Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis. Neurology. 2005;65(6):802-806.

150. Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology. 2005;65(6):807-811.

151. De las Heras V, De Andres C, Tellez N, Tintore M. Pregnancy in multiple sclerosis patients treated with immunomodulators prior to or during part of the pregnancy: a descriptive study in the Spanish population. Mult Scler. 2007;13(8):981-984.

152. National Multiple Sclerosis Society. Four Disease Courses of MS. Available at http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/what-is-ms/four-disease-courses-of-ms/index.aspx. Last accessed November 12, 2013.

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

154. Kelly VM, Nelson LM, Chakravarty EF. Obstetric outcomes in women with multiple sclerosis and epilepsy. Neurology. 2009;73(22):1831-1836.

155. Dorotta IR, Schubert A. Multiple sclerosis and anesthetic implications. Curr Opin Anaesthesiol. 2002;15(3):365-370.

156. Vercauteren M, Heytens L. Anesthetic considerations for patients with a pre-existing neurological deficit: are neuraxial techniques safe? Acta Anaesthesiol Scand. 2007;51(7):831-838.

157. Bateman AM, Goldish GD. Autonomic dysreflexia in multiple sclerosis. J Spinal Cord Med. 2002;25(1):40-42.

158. National Multiple Sclerosis Society. Research Topic: Understanding "Benign MS." Available at http://www.nationalmssociety.org/chapters/mnm/msconnectionnews/research/understanding-benign-ms/index.aspx. Last accessed November 12, 2013.

159. Langer-Gould A, Gupta R, Huang S, et al. Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis. Arch Neurol. 2010;67(1):51-57.

160. Vukusic S, Hutchinson M, Hours M, et al. Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain. 2004;127(Pt 6):1353-1360.

161. Langer-Gould A, Huang SM, Gupta R, et al. Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch Neurol. 2009;66(8):958-963.

162. Frohman TC, O'Donoghue DL, Northrop D (eds). Multiple Sclerosis for the Physician Assistant: A Practical Primer. New York, NY: National Multiple Sclerosis Society; 2011.

163. National MS Society. Symptoms. Available at http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/index.aspx. Last accessed October 17, 2013.

164. Rolak LA, Fleming JO. The differential diagnosis of multiple sclerosis. The Neurologist. 2007;13:57-72.

165. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374:1503-1511.

166. Multiple Sclerosis Association of America. Long-Term Treatments for MS. Available at http://www.mymsaa.org/about-ms/treatments/long-term. Last accessed October 22, 2013.

167. Atlas SW (ed). Magnetic Resonance Imaging of the Brain and Spine. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

168. Bohannon RW, Smith MB. Interrater reliability of a Modified Ashworth Scale of Muscle Spasticity. Phys Ther. 1987;67:206-207.

169. Rejdak K, Jackson S, Giavonnoni G. Multiple sclerosis: a practical overview for clinicians. Br Med Bull. 2010;95:79-104.

170. Calcagno P, Ruoppolo G, Grasso MG, De Vincentiis M, Paolucci S. Dysphagia in multiple sclerosis: prevalence and prognostic factors. Acta Neurol Scand. 2002;105(1):40-43.

171. Neema M, Stankiewicz J, Arora A, Guss ZD, Bakshi R. MRI in multiple sclerosis: what's inside the toolbox? Neurotherapeutics. 2007;4(4):602-617.

172. Pirko I, Lucchinetti CF, Sriram S, Bakshi R. Gray matter involvement in multiple sclerosis. Neurology. 2007;68:634-642.

173. Miller DH, Thompson AJ, Filippi M. Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis. J Neurol. 2003;250:1407-1419.

174. Meier D, Weiner HL, Guttmann CRG. MR imaging intensity modeling of damage and repair in multiple sclerosis: relationship of short-term lesion recovery to progression and disability. AJNR Am J Neuroradiol. 2007;28:1956-1963.

175. Duan Y, Hildenbrand PG, Sampat MP, et al. Segmentation of subtraction images for measurement of lesion change in multiple sclerosis. AJNR Am J Neuroradiol. 2008;29:340-346.

176. Prinster A, Quarantelli M, Orefice G, et al. Grey matter loss in relapsing-remitting multiple sclerosis: a voxel-based morphometry study. Neuroimage. 2006;29:859-867.

177. Morgen K, Sammer G, Courtney SM, et al. Evidence for a direct association between cortical atrophy and cognitive impairment in relapsing-remitting MS. Neuroimage. 2006;30:891-898.

178. Stangel M, Fredrikson S, Meinl E, Petzold A, Stüve O, Tumani H. The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nat Rev Neurol. 2013;9(5):267-276.

179. Dousset V, Brochet B, Deloire MS, et al. MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium. AJNR Am J Neuroradiol. 2006;27:1000-1005.

180. Vellinga MM, Oude Engberink RD, Seewann A, et al. Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement. Brain. 2008;131:800-807.

181. Wessig C, Bendszus M, Stoll G. In vivo visualization of focal demyelination in peripheral nerves by gadofluorine M-enhanced magnetic resonance imaging. Exp Neurol. 2007;204:14-19.

182. Kesselring J. Neurorehabilitation in multiple sclerosis: what is the evidence-base? J Neurol. 2004;251(4 Supplement):iv25-iv29.

183. Filippi M, Rocca MA. Magnetization transfer magnetic resonance imaging of the brain, spinal cord, and optic nerve. Neurotherapeutics. 2007;4:401-413.

184. Bodurka J, Bandettini PA. Toward direct mapping of neuronal activity: MRI detection of ultraweak, transient magnetic fields changes. Magn Reson Med. 2002;47:1052-1058.

185. Truong TK, Song AW. Finding neuroelectric activity under magnetic-field oscillations (NAMO) with magnetic resonance imaging in vivo. Proc Natl Acad Sci USA. 2006;103:12598-12601.

186. Jenkins T, Ciccarelli O, Toosy A, et al. Dissecting structure-function interactions in acute optic neuritis to investigate neuroplasticity. Hum Brain Mapp. 2010;31(2):276-286.

187. Hickman SJ, Toosy AT, Jones SJ, et al. Serial magnetization transfer imaging in acute optic neuritis. Brain. 2004;127:692-700.

188. Frohman E, Costello F, Zivadinov R, et al. Optical coherence tomography in multiple sclerosis. Lancet Neurol. 2006;5:853-863.

189. Elovaara I, Apostolski S, van Doorn P, et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases.Eur J Neurol. 2008;15:893-908.

190. Oh J, Han ET, Lee MC, Nelson SJ, Pelletier D. Multislice brain myelin water fractions at 3T in multiple sclerosis. J Neuroimaging. 2007;17:156-163.

191. Laule C, Vavasour IM, Moore GR, et al. Water content and myelin water fraction in multiple sclerosis: a T2 relaxation study.J Neurol. 2004;251:284-293.

192. Olak MJ. Treatment of Relapsing-Remitting Multiple Sclerosis in Adults. Available at http://www.uptodate.com/contents/treatment-of-relapsing-remitting-multiple-sclerosis-in-adults. Last accessed October 25, 2013.

193. Olak MJ. Treatment of Progressive Multiple Sclerosis in Adults. Available at http://www.uptodate.com/contents/treatment-of-progressive-multiple-sclerosis-in-adults. Last accessed October 25, 2013.

194. Susman E. Higher Vitamin D Levels Linked to Less MS Activity. Available at http://www.medpagetoday.com/MeetingCoverage/ECTRIMS/42036. Last accessed November 11, 2013.

195. Neema M, Stankiewicz J, Arora A, Guss ZD, Bakshi R. MRI in multiple sclerosis: what's inside the toolbox? Neurotherapeutics. 2007;4:602-617.

196. Sicotte NL, Voskuhl RR, Bouvier S, Klutch R, Cohen MS, Mazziotta JC. Comparison of multiple sclerosis lesions at 1.5 and 3.0 Tesla. Invest Radiol. 2003;38:423-427.

197. Kangarlu A, Bourekas EC, Ray-Chaudhury A, Rammohan KW. Cerebral cortical lesions in multiple sclerosis detected by MR imaging at 8 Tesla. AJNR Am J Neuroradiol. 2007;28:262-266

198. Simon KC, Munger KL, Ascherio A. Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. Curr Opin Neurol. 2012;25(3):246-251.

199. Stein MS, Liu Y, Gray OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011;77:1611-1618.

200. Torkildsen O, Wergeland S, Bakke S, et al. ω-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial. Arch Neurol. 2012;69(8):1044-1051.

201. Baker D, Pryce G, Jackson SJ, Bolton C, Giovannoni G. The biology that underpins the therapeutic potential of cannabis-based medicines for the control of spasticity in multiple sclerosis. Mult Scler Relat Disord. 2012;1(2):64-75.

202. Honarmand K, Tierney MC, O'Connor P, Feinstein A. Effects of cannabis on cognitive function in patients with multiple sclerosis. Neurology. 2011;76(13):1153-1160.

203. Ribeiro R, Yu F, Wen J, Vana A, Zhang Y. Therapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis. Neuroscience. 2013; [Epub ahead of print].

204. Namaka M, Crook A, Doupe A, et al. Examining the evidence: complementary adjunctive therapies for multiple sclerosis.Neurol Res. 2008;30(7):710-719.

205. Kappos L, Miller DH, MacManus DG, et al. BG00012, a novel fumarate is effective in patients with relapsing-remitting multiple sclerosis. Mult Scler. 2006;12(Suppl 1):S85.

206. Medical News Today. Investigational Oral Multiple Sclerosis Therapy Teriflunomide Significantly Reduced Relapse Rate and Disability Progression. Available at http://www.medicalnewstoday.com/releases/235702.php. Last accessed November 11, 2013.

207. Opexa Therapeutics. Opexa Completes Successful Meetings with FDA to Pursue Phase 3 Clinical Study for Tovaxin in Multiple Sclerosis. Available at http://www.opexatherapeutics.com/news-and-resources/press-releases/press-releases-details/2011/Opexa-Completes-Successful-Meetings-with-FDA-to-Pursue-Phase-3-Clinical-Study-for-Tovaxin-in-Multiple-Sclerosis/default.aspx. Last accessed November 11, 2013.

208. Quispe-Cabanillas JG, Damasceno A, von Glehn F, et al. Impact of electroacupuncture on quality of life for patients with Relapsing-Remitting Multiple Sclerosis under treatment with immunomodulators: a randomized study. BMC Complement Altern Med. 2012;12:209.

209. National Multiple Sclerosis Society. Fatigue. Available at http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/fatigue/index.aspx. Last accessed November 12, 2013.

210. Frohman TC, Davis SL, Beh S, Greenberg BM, Remington G, Frohman EM. Uhthoff's phenomena in MS—clinical features and pathophysiology. Nat Rev Neurol. 2013;9(9):535-540.

211. Dunmore FR. Fatigue in multiple sclerosis: an overview of assessment and pharmacologic treatment. Adv NPs PAs. 2013;4(4): 23-25, 32.

212. Rekand T, Grønning M. Treatment of spasticity related to multiple sclerosis with intrathecal baclofen: a long-term follow-up.J Rehabil Med. 2011;43(6):511-514.

213. LexiComp Online. Available at http://online.lexi.com. Last accessed November 12, 2013.

214. Habek M, Karni A, Balash Y, Gurevich T. The place of the botulinum toxin in the management of multiple sclerosis. Clin Neurol Neurosurg. 2010;112(7):592-596.

215. Foster HE Jr. Bladder Symptoms and Multiple Sclerosis. Available at http://www.unitedspinal.org/msscene/2002/04/16/bladder-symptoms-and-multiple-sclerosis/. Last accessed November 12, 2013.

216. Koch M, De Keyser J. Uric acid in multiple sclerosis. Neurol Res. 2006;28(3):316-319.

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

218. Feinstein A. Multiple sclerosis and depression. Mult Scler. 2011;17(11):1276-1281.

219. de Sa JCC, Airas L, Bartholome E, et al. Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice. Ther Adv Neurol Disord. 2011;4(3):139-168.

220. Zorzon M, Zivadinov R, Bosco A, et al. Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups. Mult Scler. 1999;5(6):418-427.

221. Bagos PG, Nikolopoulos G, Ioannidis A. Chlamydia pneumoniae infection and the risk of multiple sclerosis: a meta-analysis.Mult Scler. 2006;12(4):397-411.

Evidence-Based Practice Recommendations Citations

1. Filippi M, Rocca A, Arnold DL, et al. Use of imaging in multiple sclerosis. In: Gilhus NE, Barnes MP, Brainin M (eds). European Handbook of Neurological Management. 2nd ed. Vol. 1. Oxford: Wiley-Blackwell; 2011. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=34911. Last accessed December 6, 2013.

2. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58(2):169-178. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=4099. Last accessed December 6, 2013.

3. National Institute for Health and Clinical Excellence. Fingolimod for the Treatment of Highly Active Relapsing-Remitting Multiple Sclerosis. London: National Institute for Health and Clinical Excellence; 2012. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=36885. Last accessed December 6, 2013.

4. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):294-300. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=25656. Last accessed December 6, 2013.

5. American Association of Neuroscience Nurses, Association of Rehabilitation Nurses, International Organization of Multiple Sclerosis Nurses. Nursing Management of the Patient with Multiple Sclerosis. Glenview, IL: American Association of Neuroscience Nurses; 2011. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=38259. Last accessed December 6, 2013.

6. National Clinical Guideline Centre. Urinary Incontinence in Neurological Disease: Management of Lower Urinary Tract Dysfunction in Neurological Disease. London: National Institute for Health and Clinical Excellence; 2012. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=38411. Last accessed December 6, 2013.


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