3462 PART 13 Neurologic Disorders

parietal regions have been reported. However, increased SUVR in these

regions was not significantly associated with neuropsychologic and

neuropsychiatric function. Taken together, further study is required to

better refine the clinical and postmortem diagnostic criteria of CTE,

enhance clinicopathologic correlation, and ultimately improve patient

care and management. CTE is also discussed in Chap. 424.

■ FURTHER READING

Johnson VE et al: Axonal pathology in traumatic brain injury. Exp

Neurol 246:35, 2013.

Kowalski R et al: Recovery of consciousness and functional outcome

in moderate and severe traumatic brain injury. JAMA Neurol 78:548,

2021.

McCrory P et al: Consensus statement on concussion in sport—the

5th international conference on concussion in sport held in Berlin,

October 2016. Br J Sports Med 51:838, 2017.

Mez J et al: Clinicopathological evaluation of chronic traumatic

encephalopathy in players of American football. JAMA 318:360,

2017.

Nelson L et al: Recovery after mild traumatic brain injury in patients

presenting to US level I trauma centers: A Transforming Research

and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI)

study. JAMA Neurol 76:1049, 2019.

Taylor CA et al: Traumatic brain injury-related emergency department visits, hospitalizations, and deaths—United States, 2007 and

2013. MMWR Surveill Summ 66:1, 2017.

MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by chronic inflammation, demyelination, gliosis (plaques or scarring), and neuronal loss; the course can

be relapsing or progressive. MS plaques typically develop at different

times and in different CNS locations (i.e., MS is said to be disseminated

in time and space). More than 900,000 individuals in the United States

and millions of individuals worldwide are affected. The clinical course

is extremely variable, ranging from a relatively benign condition to a

rapidly evolving and incapacitating disease requiring profound lifestyle

adjustments.

■ CLINICAL MANIFESTATIONS

The onset of MS may be abrupt or insidious. Symptoms may be severe

or seem so trivial that a patient may not seek medical attention for

months or years. Indeed, at autopsy, ~0.1% of individuals who were

asymptomatic during life will be found, unexpectedly, to have pathologic evidence of MS. Similarly, an MRI scan obtained for an unrelated

reason may show evidence of asymptomatic MS. Symptoms of MS are

extremely varied and depend on the location and severity of lesions

within the CNS (Table 444-1). Examination often reveals evidence of

neurologic dysfunction, often in asymptomatic locations. For example,

a patient may present with symptoms in one leg but signs in both.

Sensory symptoms are varied and include both paresthesias (e.g., tingling, prickling sensations, formications, “pins and needles,” or painful

burning) and hypesthesia (e.g., reduced sensation, numbness, or a

“dead” feeling). Unpleasant sensations (e.g., feelings that body parts

are swollen, wet, raw, or tightly wrapped) are also common. Sensory

impairment of the trunk and legs below a horizontal line on the torso

(a sensory level) indicates that the spinal cord is the origin of the

444 Multiple Sclerosis

Bruce A. C. Cree, Stephen L. Hauser

TABLE 444-1 Initial Symptoms of Multiple Sclerosis (MS)

SYMPTOM

PERCENTAGE

OF CASES SYMPTOM

PERCENTAGE

OF CASES

Sensory loss 37 Lhermitte 3

Optic neuritis 36 Pain 3

Weakness 35 Dementia 2

Paresthesias 24 Visual loss 2

Diplopia 15 Facial palsy 1

Ataxia 11 Impotence 1

Vertigo 6 Myokymia 1

Paroxysmal attacks 4 Epilepsy 1

Bladder 4 Falling 1

Source: Data from RJ Swingler, DA Compston: The morbidity of multiple sclerosis.

Q J Med 83:325, 1992.

sensory disturbance. It is often accompanied by a bandlike sensation of

tightness around the torso. Pain is a common symptom of MS, experienced by >50% of patients. Pain can occur anywhere on the body and

can change locations over time.

Optic neuritis (ON) presents as diminished visual acuity, dimness, or

decreased color perception (desaturation) in the central field of vision.

These symptoms can be mild or may progress to severe visual loss.

Rarely, there is complete loss of light perception. Visual symptoms are

generally monocular but may be bilateral. Periorbital pain (aggravated

by eye movement) often precedes or accompanies the visual loss. An

afferent pupillary defect (Chap. 32) is usually present. Fundoscopic

examination may be normal or reveal optic disc swelling (papillitis).

Pallor of the optic disc (optic atrophy) commonly follows ON. Uveitis

is uncommon and should raise the possibility of alternative diagnoses

such as sarcoidosis or lymphoma.

Weakness of the limbs may manifest as loss of strength, speed, or

dexterity; as fatigue; or as a disturbance of gait. Exercise-induced weakness is a characteristic symptom of MS. The weakness is of the upper

motor neuron type (Chap. 24) and is usually accompanied by other

pyramidal signs such as spasticity, hyperreflexia, and Babinski signs.

Occasionally, a tendon reflex may be lost (simulating a lower motor

neuron lesion) if an MS lesion disrupts the afferent reflex fibers in the

spinal cord (see Fig. 24-2).

Facial weakness due to a lesion in the pons may resemble idiopathic

Bell’s palsy (Chap. 441). Unlike Bell’s palsy, facial weakness in MS is

usually not associated with ipsilateral loss of taste sensation or retroauricular pain.

Spasticity (Chap. 24) is commonly associated with spontaneous and

movement-induced muscle spasms. More than 30% of MS patients

have moderate to severe spasticity, especially in the legs. This is often

accompanied by painful spasms interfering with ambulation, work, or

self-care. Occasionally, spasticity provides support for the body weight

during ambulation, and in these cases, treatment of spasticity may

actually do more harm than good.

Visual blurring in MS may result from ON or diplopia (double

vision); if the symptom resolves when either eye is covered, the cause

is diplopia. Diplopia may be caused by internuclear ophthalmoplegia

(INO) or palsy of the sixth cranial nerve (rarely the third or fourth).

An INO consists of impaired adduction of one eye due to a lesion in the

ipsilateral medial longitudinal fasciculus (Chaps. 32 and V3). Prominent nystagmus is often observed in the abducting eye, along with a

small skew deviation. A bilateral INO is particularly suggestive of MS.

Other common gaze disturbances in MS include (1) a horizontal gaze

palsy, (2) a “one and a half ” syndrome (horizontal gaze palsy plus an

INO), and (3) acquired pendular nystagmus.

Ataxia usually manifests as cerebellar tremors (Chap. 439). Ataxia

may also involve the head and trunk or the voice, producing a characteristic cerebellar dysarthria (scanning speech).

Vertigo may appear suddenly from a brainstem lesion, superficially

resembling acute labyrinthitis (Chap. 22). Hearing loss (Chap. 34) may

also occur in MS but is uncommon.

3463 Multiple Sclerosis CHAPTER 444

■ ANCILLARY SYMPTOMS

Paroxysmal symptoms are distinguished by their brief duration (10 s

to 2 min), high frequency (5–40 episodes per day), lack of any alteration of consciousness or change in background electroencephalogram

during episodes, and a self-limited course (generally lasting weeks to

months). They may be precipitated by hyperventilation or movement.

These syndromes may include Lhermitte’s symptom; tonic contractions of a limb, face, or trunk (tonic seizures); paroxysmal dysarthria

and ataxia; paroxysmal sensory disturbances; and several other less

well-characterized syndromes. Paroxysmal symptoms probably result

from spontaneous discharges, arising at the edges of demyelinated

plaques and spreading to adjacent white matter tracts.

Lhermitte’s symptom is an electric shock–like sensation (typically

induced by flexion or other movements of the neck) that radiates down

the back into the legs. Rarely, it radiates into the arms. It is generally

self-limited but may persist for years. Lhermitte’s symptom can also

occur with other disorders of the cervical spinal cord (e.g., cervical

spondylosis).

Trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia (Chap. 441) can occur when the demyelinating lesion involves the

root entry (or exit) zone of the fifth, seventh, and ninth cranial nerve,

respectively. Trigeminal neuralgia (tic douloureux) is a very brief lancinating facial pain often triggered by an afferent input from the face or

teeth. Most cases of trigeminal neuralgia are not MS related; however,

atypical features such as onset before age 50 years, bilateral symptoms,

objective sensory loss, or nonparoxysmal pain should raise the possibility that MS could be responsible.

Facial myokymia consists of either persistent rapid flickering contractions of the facial musculature (especially the lower portion of the

orbicularis oculus) or a contraction that slowly spreads across the face.

It results from lesions of the corticobulbar tracts or brainstem course

of the facial nerve.

Heat sensitivity refers to neurologic symptoms produced by an elevation of the body’s core temperature. For example, unilateral visual blurring may occur during a hot shower or with physical exercise (Uhthoff’s

symptom). It is also common for MS symptoms to worsen transiently,

sometimes dramatically, during febrile illnesses. Such heat-related symptoms probably result from transient conduction block.

Bladder dysfunction is present in >90% of MS patients, and in

one-third of patients, dysfunction results in weekly or more frequent

episodes of incontinence. During normal reflex voiding, relaxation of

the bladder sphincter (α-adrenergic innervation) is coordinated with

contraction of the detrusor muscle in the bladder wall (muscarinic

cholinergic innervation). Detrusor hyperreflexia, due to impairment

of suprasegmental inhibition, causes urinary frequency, urgency, nocturia, and uncontrolled bladder emptying. Detrusor sphincter dyssynergia, due to loss of synchronization between detrusor and sphincter

muscles, causes difficulty in initiating and/or stopping the urinary

stream, producing hesitancy, urinary retention, overflow incontinence,

and recurrent infection.

Constipation occurs in >30% of patients. Fecal urgency or bowel

incontinence is less common (<15%) but can be socially debilitating.

Sexual dysfunction may manifest as decreased libido, impaired genital sensation, impotence in men, and diminished vaginal lubrication or

adductor spasms in women.

Cognitive dysfunction can include memory loss; impaired attention;

difficulties in executive functioning, memory, and problem solving;

slowed information processing; and problems shifting between cognitive

tasks. Euphoria (elevated mood) was once thought to be characteristic of

MS but is actually uncommon, occurring in <20% of patients. Cognitive

dysfunction sufficient to impair activities of daily living is rare.

Depression, experienced by approximately half of patients, can be

reactive, endogenous, or part of the illness itself and can contribute to

fatigue.

Fatigue (Chap. 23) is experienced by 90% of patients; this symptom

is the most common reason for work-related disability in MS. Fatigue

can be exacerbated by elevated temperatures, depression, expending

exceptional effort to accomplish basic activities of daily living, or sleep

disturbances (e.g., from frequent nocturnal awakenings to urinate).

ADisability

Time

RMS

CDisability

Time

PPMS

BDisability

Time

SPMS

FIGURE 444-1 Clinical course of multiple sclerosis (MS). A. Relapsing MS (RMS).

B. Secondary progressive MS (SPMS). C. Primary progressive MS (PPMS).

DISEASE COURSE

Three clinical types of MS exist (Fig. 444-1):

1. Relapsing or bout onset MS (RMS) accounts for 90% of MS cases and

is characterized by discrete attacks of neurologic dysfunction that

generally evolve over days to weeks (rarely over hours). With initial

attacks, there is often substantial or complete recovery over the

ensuing weeks to months. However, as attacks continue, recovery

may be less evident (Fig. 444-1A). Between attacks, patients were

traditionally thought to be neurologically stable; however it is now

clear that many patients with RMS experience subtle “silent” progression even when relapse-free.

2. Secondary progressive MS (SPMS) always begins as RMS

(Fig. 444-1B). At some point, however, the clinical course changes

so that the patient experiences progressive deterioration in function

unassociated with acute attacks. SPMS produces a greater amount

of fixed neurologic disability than RMS. For a patient with RMS, the

risk of developing SPMS was approximately 3% each year in the pretreatment era, meaning that the great majority of RMS would ultimately evolve into SPMS. However, recent case series have indicated

a much lower rate of evolution to SPMS, estimated at slightly >1%

each year, likely due to widespread use of effective therapies for MS.

3. Primary progressive MS (PPMS) accounts for ~10% of cases. These

patients do not experience attacks but rather steadily decline in

function from disease onset (Fig. 444-1C). Compared to RMS, the

sex distribution is more even, the disease begins later in life (mean

age ~40 years), and disability develops faster (relative to the onset of

the first clinical symptom). Despite these differences, PPMS appears

to represent the same underlying illness as RMS.

Progressive MS and Disease Activity Patients with SPMS or even

PPMS will occasionally experience relapses, albeit less often than in

RMS. Progressive MS patients experiencing relapses or who are found

to have acute new lesions on MRI are considered to have “active”

progressive MS.

■ EPIDEMIOLOGY

MS is approximately threefold more common in women than men.

The age of onset is typically between 20 and 40 years (slightly later in

men than in women), but the disease can present across the lifespan.

Approximately 10% of cases begin before the age of 18 years, and a

small percentage of cases begin before the age of 10 years.

Geographic gradients are observed in MS, with the highest known

prevalence for MS (250 per 100,000) in the Orkney Islands, located

north of Scotland. In other temperate zone areas (e.g., northern

3464 PART 13 Neurologic Disorders

North America, northern Europe, southern Australia, and southern

New Zealand), the prevalence of MS is 0.1–0.2%. By contrast, in the

tropics (e.g., Asia, equatorial Africa, and the Middle East), the prevalence is often tenfold to twentyfold less.

The prevalence of MS has increased steadily (and dramatically) in

several regions around the world over the past half-century, presumably reflecting the impact of some environmental shift. Moreover, the

fact that this increase appears to have occurred primarily in women

indicates that women are more responsive to this environmental

change.

Well-established risk factors for MS include a genetic predisposition,

vitamin D deficiency, Epstein-Barr virus (EBV) exposure after early

childhood, and cigarette smoking.

Vitamin D deficiency is associated with an increase in MS risk, and

data suggest that ongoing deficiency also increases disease activity after

MS begins. Immunoregulatory effects of vitamin D could explain these

apparent relationships. Exposure of the skin to ultraviolet-B (UVB)

radiation from the sun is essential for the biosynthesis of vitamin D,

and this endogenous production is the most important source of

vitamin D in most individuals. A diet rich in fatty fish represents

another source of vitamin D. At high latitudes, the amount of UVB

radiation reaching the earth’s surface is often insufficient, particularly

during winter months, and consequently, low serum levels of vitamin D

are common in temperate zones. The common practice to avoid direct

sun exposure and the widespread use of sunblock would be expected to

exacerbate any population-wide vitamin D deficiency (sun protection

factor [SPF] 15 blocks 94% of incoming UVB radiation).

Evidence of a remote EBV infection playing some role in MS is supported by numerous epidemiologic and laboratory studies. A higher

risk of infectious mononucleosis (associated with relatively late EBV

infection) and higher antibody titers to latency-associated EBV nuclear

antigen have been repeatedly associated with MS risk, although a

causal role for EBV is not established.

A history of cigarette smoking also is associated with MS risk.

Interestingly, in an animal model of MS, the lung was identified as a

critical site for activation of pathogenic T lymphocytes responsible for

autoimmune demyelination.

GENETIC CONSIDERATIONS

Whites are inherently at higher risk for MS than Africans or

Asians, even when residing in a similar environment. Recent

studies in the United States, however, have shown that MS risk in

persons of African descent is as high, and possibly higher, than in

whites. MS also aggregates within some families, and adoption,

half-sibling, twin, and spousal studies indicate that familial aggregation

is primarily due to genetic factors. Nonetheless, family studies also

support a contribution of environment, as fraternal twins of MS

patients are at higher risk than nontwin siblings (Table 444-2).

Susceptibility to MS is polygenic, with each gene contributing a

relatively small amount to the overall risk. The strongest susceptibility

signal genome-wide maps to the human leukocyte antigen (HLA)-

DRB1 gene in the class II region of the major histocompatibility

complex (MHC) and specifically to HLA-DR15 (formerly designated

DR2), and this association accounts for ~10% of the disease risk. This

HLA association, first described in the early 1970s, suggests that MS,

at its core, is an autoimmune disease. Whole-genome association

studies have now identified ~230 other MS susceptibility variants, each

of which individually has only a very small effect on MS risk. Many

of these MS-associated genes have known roles in the adaptive and

innate immune system, for example the genes for the interleukin (IL)

7 receptor (CD127), IL-2 receptor (CD25), and T-cell costimulatory

molecule LFA-3 (CD58); some variants also influence susceptibility to

other autoimmune diseases in addition to MS. The variants identified

so far all lack specificity and sensitivity for MS; thus, at present, they

are not useful for diagnosis or prediction of the future disease course.

PATHOGENESIS

■ PATHOLOGY

Demyelination New MS lesions begin with perivenular cuffing by

inflammatory mononuclear cells, predominantly T cells and macrophages, which also infiltrate the surrounding white matter. At sites of

inflammation, the blood-brain barrier (BBB) is disrupted, but unlike

in vasculitis, the vessel wall is preserved. At the leading edge of lesions,

large numbers of cytotoxic CD8 cells are found. Involvement of the

humoral immune system is also evident; small numbers of B lymphocytes infiltrate the nervous system, myelin-specific autoantibodies are

present on degenerating myelin sheaths, and complement is activated.

Sharply demarcated areas of demyelination are the pathologic hallmark of MS lesions, and evidence of myelin degeneration is found at

the earliest time points of tissue injury. Although relative sparing of

axons is typical, partial or total axonal destruction can also occur, especially within highly inflammatory lesions. In some lesions, surviving oligodendrocytes or those that differentiate from precursor cells partially

remyelinate the surviving axons, producing so-called shadow plaques.

However, in many lesions oligodendrocyte precursor cells are present

but they fail to differentiate into mature myelin-producing cells. Therefore, promoting remyelination to protect axons remains an important

therapeutic goal. As lesions evolve, there is prominent astrocytic proliferation (gliosis) and the term sclerosis refers to these gliotic plaques

that have a rubbery or hardened texture at autopsy.

Neurodegeneration Cumulative axonal and neuronal loss is the

most important contributor to irreversible neurologic disability and

progressive symptoms. With paraplegia due to MS, as many as 70%

of axons are ultimately lost from the lateral corticospinal (e.g., motor)

tracts. Demyelination can reduce trophic support for axons, redistribute ion channels, and destabilize action potential membrane potentials.

Axons can adapt initially to these injuries, but over time distal and

retrograde degeneration (“dying-back” axonopathy) occurs.

Multiple pathologies appear to contribute to progressive symptoms

in longstanding MS. Chronic active plaques are preexisting white matter lesions that show evidence of persistent inflammation, progressive

axonal loss, and gradual concentric expansion, with large numbers of

microglial cells at the leading edge of enlarging lesions but without

BBB disruption. Recent studies have also highlighted the importance

of a primary injury to the cerebral cortex. Cortical plaques are frequent in MS but are generally not well visualized by MRI; these can

extend upward from adjacent white matter lesions, or may be located

within the cortex or underneath the pia. Ectopic lymphoid follicles are

aggregates of B, T, and plasma cells located in the superficial meninges,

especially overlying deep cortical sulci; similar clusters are also present

in perivascular spaces. Ectopic lymphoid follicles are topographically

associated with underlying demyelination and neuronal loss in the

cerebral cortex, and diffusible factors from these lymphoid cells are

believed to mediate subpial cortical demyelination and neurodegeneration.

Neuronal and axonal death may result from glutamate-mediated

excitotoxicity, oxidative injury, iron accumulation, and/or mitochondrial failure.

In relapsing MS, inflammation is associated with focal perivenular

parenchymal infiltration of lymphocytes and monocytes associated

with BBB disruption and active demyelination. By contrast, inflammation in progressive MS is more diffuse and is characterized by

widespread microglial activation across large areas of white matter,

associated with reduced myelin staining and axonal injury (“dirty

white matter”). Activated astrocytes induced by microglia may also

contribute to tissue damage (Chap. 425). These observations imply

TABLE 444-2 Risk of Developing Multiple Sclerosis (MS)

1 in 3 If an identical twin has MS

1 in 15 If a fraternal twin has MS

1 in 25 If a sibling has MS

1 in 50 If a parent or half-sibling has MS

1 in 100 If a first cousin has MS

1 in 1000 If a spouse has MS

1 in 1000 If no one in the family has MS

3465 Multiple Sclerosis CHAPTER 444

that ongoing inflammation occurs behind an intact BBB in many

patients with progressive MS, and this feature could explain the failure

of immunotherapies not capable of crossing the BBB to benefit patients

with progressive MS.

■ PHYSIOLOGY

Nerve conduction in myelinated axons occurs in a saltatory manner,

with the nerve impulse jumping from one node of Ranvier to the next

without depolarization of the axonal membrane underlying the myelin

sheath between nodes (Fig. 444-2). This produces faster conduction

velocities (~70 m/s) than the slow velocities (~1 m/s) produced by

continuous propagation in unmyelinated nerves. Conduction block

occurs when the nerve impulse is unable to traverse the demyelinated

segment. This can happen when the resting axon membrane becomes

hyperpolarized due to exposure of voltage-dependent potassium channels that are normally buried underneath the myelin sheath. A temporary conduction block often follows a demyelinating event before

sodium channels (originally concentrated at the nodes) redistribute

along the naked axon (Fig. 444-2). This redistribution ultimately

allows continuous propagation of nerve action potentials through the

demyelinated segment. Conduction block may be incomplete, affecting

high- but not low-frequency volleys of impulses. Variable conduction

block can occur with raised body temperature or metabolic alterations

and may explain clinical fluctuations that vary from hour to hour or

appear with fever or exercise. Conduction slowing occurs when the

demyelinated segments of the axonal membrane are reorganized to

support continuous (slow) nerve impulse propagation.

■ IMMUNOLOGY

A proinflammatory autoimmune response directed against a component of CNS myelin, and perhaps other neural elements as well,

remains the cornerstone of current concepts of MS pathogenesis.

■ AUTOREACTIVE T LYMPHOCYTES

Myelin basic protein (MBP), an intracellular protein involved in myelin

compaction, is an important T-cell antigen in experimental allergic

encephalomyelitis (EAE), a laboratory model, and possibly also in

human MS. Activated MBP-reactive T cells have been identified in

the blood, in cerebrospinal fluid (CSF), and within MS lesions. The

MS associated HLA-DR15 protein binds with high affinity to a fragment of MBP (spanning amino acids 89–96), potentially stimulating

T-cell responses to this self-protein. Several different populations of

proinflammatory T cells are likely to mediate autoimmunity in MS.

T-helper type 1 (TH1) cells producing interferon γ (IFN-γ) are one

key effector population; TH1 cytokines, including IL-2, tumor necrosis

factor (TNF)-α, and IFN-γ, also play key roles in activating and maintaining autoimmune responses, and TNF-α and IFN-γ may directly

injure oligodendrocytes or the myelin membrane. As noted above,

CD8 cytotoxic T cells are present at the active edges of expanding MS

lesions, and activated CD8 cells also appear to be enriched for reactivity against myelin antigens in MS patients.

■ HUMORAL AUTOIMMUNITY

B-cell activation and antibody responses are centrally involved in the

development of demyelinating lesions, as evidenced by the efficacy of

B cell–based treatments in all forms of MS (see “Treatment” below).

Clonally restricted populations of activated, antigen-experienced,

memory B cells and plasma cells are present in MS lesions, in meningeal lymphoid follicle-like structures overlying the cerebral cortex, and

in the CSF. Similar populations are found in each compartment, indicating that a highly focused B-cell response occurs locally within the

CNS. Myelin-specific autoantibodies, some directed against an extracellular myelin protein, myelin oligodendrocyte glycoprotein (MOG),

have been detected bound to vesiculated myelin debris in MS plaques.

In the CSF, elevated levels of locally synthesized immunoglobulins and

oligoclonal antibodies, derived from clonally restricted CNS B cells and

plasma cells, are also characteristic of MS. The pattern of oligoclonal

banding is unique to each individual, and attempts to identify the targets of these antibodies have been largely unsuccessful; they appear to

recognize a diverse array of antigens including intracellular ubiquitous

proteins. Therefore, although intrathecal oligoclonal antibodies and

elevated intrathecal synthesis of immunoglobulins are characteristic of

MS, their role in disease pathogenesis remains uncertain.

Recent data suggest that the antigen presenting cell (APC) function

of B cells may explain their role in MS pathogenesis. Remarkably,

fragments of self-peptides derived from HLA-DR2 proteins themselves

were found to bind intact DR2 molecules on B cells and serve as antigens for presentation to T cells. Memory CD4+ T cells derived from

CSF responded to these self-peptides bound to DR2 molecules and, in

some cases, these self-peptides were cross-reactive with myelin antigens, RAS guanyl-releasing protein 2 (RASGRP2) previously found

to be a possible T-cell autoantigen in MS, EBV, and Akkermansia

muciniphila, a commensal gut bacterium associated with dysbiosis in

MS patients. Thus, the MS-associated HLA proteins contain fragments

that might trigger autoimmunity through molecular mimicry with

viral, bacterial, or cell-surface autoantigens.

DIAGNOSIS

There is no single diagnostic test for MS. Diagnostic criteria for clinically definite MS require documentation of two or more episodes of

symptoms and two or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS (Table 444-3).

Symptoms must last for >24 h and occur as distinct episodes that are

separated by a month or more. In patients who have only one of the

two required signs on neurologic examination, the second may be

documented by abnormal tests such as MRI or evoked potentials (EPs).

Similarly, in the most recent diagnostic scheme, the second clinical

event (in time) may be supported solely by MRI findings, consisting of

either the development of new focal white matter lesions on MRI or the

simultaneous presence of both an enhancing lesion and a nonenhancing lesion in an asymptomatic location. In patients whose course is

progressive from onset for ≥6 months without superimposed relapses,

documentation of intrathecal IgG synthesis may be used to support a

diagnosis of PPMS.

DIAGNOSTIC TESTS

■ MAGNETIC RESONANCE IMAGING

MRI has revolutionized the diagnosis and management of MS

(Fig. 444-3); characteristic abnormalities are found in >95% of

patients, although >90% of the lesions visualized by MRI are asymptomatic. An increase in vascular permeability from a breakdown of

the BBB is detected by leakage of intravenous gadolinium (Gd) into

Saltatory nerve impulse

Myelin sheath

Axon

Na Node of Ranvier + channels

Continuous nerve impulse Myelin sheath Myelin sheath

Axon

Na+ channels

A

B

FIGURE 444-2 Nerve conduction in myelinated and demyelinated axons. A. Saltatory

nerve conduction in myelinated axons occurs with the nerve impulse jumping from

one node of Ranvier to the next. Sodium channels (shown as breaks in the solid

black line) are concentrated at the nodes where axonal depolarization occurs.

B. Following demyelination, additional sodium channels are redistributed along the

axon itself, thereby allowing continuous propagation of the nerve action potential

despite the absence of myelin.

3466 PART 13 Neurologic Disorders

the parenchyma. Such leakage occurs early in the development of

an MS lesion and serves as a useful marker of inflammation. Gd

enhancement typically persists for <1 month, and the residual MS

plaque remains visible indefinitely as a focal area of hyperintensity

(a lesion) on T2-weighted images. Lesions are frequently oriented

perpendicular to the ventricular surface, corresponding to the pathologic pattern of perivenous demyelination (Dawson’s fingers). Lesions

are multifocal within the brain, brainstem, and spinal cord. Lesions

>6 mm located in the corpus callosum, periventricular white matter,

brainstem, cerebellum, or spinal cord are particularly helpful diagnostically. Current criteria for the use of MRI in the diagnosis of MS

are shown in Table 444-3.

Serial MRI studies in early relapsing-remitting MS reveal that bursts

of focal inflammatory disease activity occur far more frequently than

would have been predicted by the frequency of relapses. Thus, early in

MS, most disease activity is clinically silent.

The total volume of T2-weighted signal abnormality (the “burden

of disease”) shows a significant (albeit weak) correlation with clinical

disability. Quantitative measures of brain and spinal cord atrophy are

evidence of diffuse tissue injury and correlate more strongly with measures of disability or progressive MS. Serial MRI studies also indicate

that progressive whole-brain atrophy occurs even in very early MS and

continues throughout the disease course. Approximately one-third of

T2-weighted lesions appear as hypointense lesions (black holes) on

T1-weighted imaging. Black holes may be a marker of irreversible

demyelination and axonal loss, although even this measure depends

on the timing of the image acquisition (e.g., most acute Gd-enhancing

T2 lesions are T1 dark).

■ EVOKED POTENTIALS

EP testing assesses function in afferent (visual, auditory, and somatosensory) or efferent (motor) CNS pathways. EPs use computer

averaging to measure CNS electric potentials evoked by repetitive

stimulation of selected peripheral nerves or of the brain. These tests

provide the most information when the pathways studied are clinically

uninvolved. For example, in a patient with a relapsing spinal cord syndrome with sensory deficits in the legs, an abnormal somatosensory EP

following posterior tibial nerve stimulation provides little new information. By contrast, an abnormal visual EP in this circumstance would

permit a diagnosis of clinically definite MS (Table 444-3). Abnormalities on one or more EP modalities occur in 80–90% of MS patients. EP

abnormalities are not specific to MS, although a marked delay in the

latency of a specific EP component (as opposed to a reduced amplitude

or distorted wave-shape) is suggestive of demyelination.

■ CEREBROSPINAL FLUID

CSF abnormalities found in MS include a mononuclear cell pleocytosis and an increased level of intrathecally synthesized IgG. The total

CSF protein is usually normal or mildly elevated. Various formulas

distinguish intrathecally synthesized IgG from IgG that entered the

CNS passively from the serum. The CSF IgG index expresses the ratio

of IgG to albumin in the CSF divided by the same ratio in the serum.

The IgG synthesis rate uses serum and CSF IgG and albumin measurements to calculate the rate of CNS IgG synthesis. The measurement

of oligoclonal bands (OCBs) by agarose gel electrophoresis in the

CSF also assesses intrathecal production of IgG. Two or more discrete

OCBs, not present in a paired serum sample, are found in >90% of

patients with MS. OCBs may be absent at the onset of MS, and in individual patients, the number of bands may increase with time.

A mild CSF pleocytosis (>5 cells/μL) is present in ~25% of cases,

usually in young patients with RMS. A pleocytosis of >75 cells/μL, the

presence of polymorphonuclear leukocytes, or a protein concentration

>1 g/L (>100 mg/dL) in CSF should raise concern that the patient may

not have MS.

DIFFERENTIAL DIAGNOSIS

The possibility of an alternative diagnosis should always be considered (Table 444-4), particularly when (1) symptoms are localized

exclusively to the posterior fossa, craniocervical junction, or spinal

cord; (2) the patient is <15 or >60 years of age; (3) the clinical course

is progressive from onset; (4) the patient has never experienced visual,

sensory, or bladder symptoms; or (5) laboratory findings (e.g., MRI,

CSF, or EPs) are atypical. Similarly, uncommon or rare symptoms in

MS (e.g., aphasia, parkinsonism, chorea, isolated dementia, severe

muscular atrophy, peripheral neuropathy, episodic loss of consciousness, fever, headache, seizures, or coma) should increase concern

TABLE 444-3 Diagnostic Criteria for Multiple Sclerosis (MS)

CLINICAL PRESENTATION ADDITIONAL DATA NEEDED FOR MS DIAGNOSIS

2 or more attacks;

objective clinical evidence

of 2 or more lesions or

objective clinical evidence

of 1 lesion with reasonable

historical evidence of a

prior attack

None

2 or more attacks;

objective clinical evidence

of 1 lesion

Dissemination in space, demonstrated by ≥1 T2

lesion on MRI in at least 2 out of 4 MS-typical

regions of the CNS (periventricular, juxtacortical,

infratentorial, or spinal cord)

OR

• Await a further clinical attack implicating a

different CNS site

1 attack; objective clinical

evidence of 2 or more

lesions

Dissemination 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 attack

1 attack; 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 out of 4 MS-typical

regions of the CNS (periventricular, juxtacortical,

infratentorial, or spinal cord)

OR

• Await a second clinical attack implicating a

different CNS site

AND

• 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 attack

Insidious neurologic

progression suggestive of

MS (PPMS)

1 year of disease progression (retrospectively or

prospectively determined)

PLUS

2 out of the 3 following criteria:

• 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)

Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; MRI,

magnetic resonance imaging; PPMS, primary progressive multiple sclerosis.

Source: Reproduced with permission from AJ Thompson et al: Diagnosis of multiple

sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17:162, 2018.

3467 Multiple Sclerosis CHAPTER 444

about an alternative diagnosis. Diagnosis is also difficult in patients

with a rapid or explosive (strokelike) onset or with mild symptoms

and a normal neurologic examination. Rarely, intense inflammation

and swelling may produce a mass lesion that mimics a primary or

metastatic tumor. Disorders possibly mistaken for MS include: neuromyelitis optica (Chap. 437), sarcoidosis, vascular disorders (antiphospholipid syndrome and vasculitis), rarely CNS lymphoma, and

still more rarely infections such as syphilis or Lyme disease. The specific tests required to exclude alternative diagnoses will vary with each

clinical situation; however, an erythrocyte sedimentation rate, serum

B12 level, antinuclear antibodies, and treponemal antibody should

probably be obtained in all patients with suspected MS.

PROGNOSIS

Historically, most patients with MS ultimately experienced progressive neurologic disability. In older studies conducted before

disease-modifying therapies for MS were available, 15 years after onset,

only 20% of patients had no functional limitation, and between onethird and one-half of RMS patients progressed to SPMS and required

assistance with ambulation; furthermore, 25 years after onset, ~80% of

MS patients reached this level of disability. The long-term prognosis

for MS has improved substantially in recent years, and transition from

RMS to SPMS now occurs at approximately a 1% annual rate compared with 2–3% in the pretreatment era. This improvement is almost

certainly due, at least in part, to widespread use of disease-modifying

therapies for RMS, and it is hoped that the prognosis will continue to

improve as highly efficacious agents are increasingly employed early in

the disease course.

Although the prognosis in an individual is difficult to establish, certain clinical features suggest a more favorable prognosis. These include

ON or sensory symptoms at onset; fewer than two relapses in the first

year of illness; and minimal impairment after 5 years. Predictors of

an early aggressive course of the illness include older age at symptom

onset and greater disability and the appearance of motor signs during

the first year of the illness. By contrast, patients with truncal ataxia,

action tremor, pyramidal symptoms, or a progressive disease course

are more likely to become disabled. Patients with a long-term favorable course are likely to have developed fewer MRI lesions and have

A B

C D

FIGURE 444-3 Magnetic resonance imaging findings in multiple sclerosis (MS). A. Axial first-echo image from T2-weighted sequence demonstrates multiple bright signal

abnormalities in white matter, typical for MS. B. Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) image in which the high signal of cerebrospinal fluid (CSF)

has been suppressed. CSF appears dark, whereas areas of brain edema or demyelination appear high in signal, as shown here in the corpus callosum (arrows). Lesions in

the anterior corpus callosum are frequent in MS and rare in vascular disease. C. Sagittal T2-weighted fast spin echo image of the thoracic spine demonstrates a fusiform

high-signal-intensity lesion in the midthoracic spinal cord. D. Sagittal T1-weighted image obtained after the intravenous administration of gadolinium DTPA reveals focal

areas of blood-brain barrier disruption, identified as high-signal-intensity regions (arrows).

3468 PART 13 Neurologic Disorders

TABLE 444-4 Disorders That Can Mimic Multiple Sclerosis (MS)

Acute disseminated encephalomyelitis (ADEM)

Antiphospholipid antibody syndrome

Behçet’s disease

Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and

leukoencephalopathy (CADASIL)

Congenital leukodystrophies (e.g., adrenoleukodystrophy, metachromatic

leukodystrophy)

Human immunodeficiency virus (HIV) infection

Ischemic optic neuropathy (arteritic and nonarteritic)

Lyme disease

Mitochondrial encephalopathy with lactic acidosis and stroke (MELAS)

Neoplasms (e.g., lymphoma, glioma, meningioma)

Neuromyelitis optica

Sarcoidosis

Sjögren’s syndrome

Stroke and ischemic cerebrovascular disease

Syphilis

Systemic lupus erythematosus and related collagen vascular disorders

Tropical spastic paraparesis (HTLV-1/2 infection)

Vascular malformations (especially spinal dural AV fistulas)

Vasculitis (primary CNS or other)

Vitamin B12 deficiency

Abbreviations: AV, arteriovenous; CNS, central nervous system; HTLV, human T-cell

lymphotropic virus.

less brain atrophy during the early years of disease, and vice versa.

Importantly, some MS patients have a benign variant of MS and never

develop neurologic disability even when untreated. The likelihood of

having benign MS is thought to be <10%. Patients with benign MS

15 years after onset who have entirely normal neurologic examinations

are likely to maintain their benign course.

In patients with their first demyelinating event (i.e., a clinically

isolated syndrome), the brain MRI provides prognostic information.

With three or more typical T2-weighted lesions, the risk of developing

MS after 20 years is ~80%. Conversely, with a normal brain MRI, the

likelihood of developing MS is <20%. Similarly, the presence of two or

more Gd-enhancing lesions at baseline is highly predictive of future

MS, as is the appearance of either new T2-weighted lesions or new Gd

enhancement ≥3 months after the initial episode.

■ EFFECT OF PREGNANCY

Pregnant MS patients experience fewer attacks than expected during gestation (especially in the last trimester), but more attacks than

expected in the first 3 months postpartum. When considering the

pregnancy year as a whole (i.e., 9 months of pregnancy plus 3 months

postpartum), the overall disease course is unaffected. Decisions about

childbearing should thus be made based on (1) the mother’s physical

state, (2) her ability to care for the child, and (3) the availability of social

support. Disease-modifying therapy is generally discontinued during

pregnancy, although the actual risk from the interferons and glatiramer

acetate (see below) appears to be low.

TREATMENT

Therapy for MS can be divided into several categories: (1) treatment of

acute attacks, (2) treatment with disease-modifying agents that reduce

the biologic activity of MS, and (3) symptomatic therapy. Treatments

that promote remyelination or neural repair do not currently exist, but

several promising approaches are being actively investigated.

The Expanded Disability Status Scale (EDSS) is a widely used measure of neurologic impairment in MS (Table 444-5). Most patients

with EDSS scores <3.5 walk normally, and are generally not disabled;

by contrast, patients with EDSS scores >4.0 have progressive MS (SPMS

or PPMS), are gait-impaired, and often are occupationally disabled.

■ ACUTE ATTACKS OR INITIAL

DEMYELINATING EPISODES

When patients experience acute deterioration, it is important to

consider whether this change reflects new disease activity or a

“pseudoexacerbation” resulting from an increase in ambient temperature, fever, or an infection. When the clinical change is thought to

reflect a pseudoexacerbation, glucocorticoid treatment is inappropriate. Glucocorticoids are used to manage either first attacks or acute

exacerbations. They provide short-term clinical benefit by reducing

the severity and shortening the duration of attacks. Whether treatment

provides any long-term benefit on the course of the illness is less clear.

Therefore, mild attacks are often not treated. Physical and occupational

therapy can help with mobility and manual dexterity.

Glucocorticoid treatment is usually administered as intravenous

methylprednisolone, 500–1000 mg/d for 3–5 days, either without a

taper or followed by a course of oral prednisone beginning at a dose of

60–80 mg/d and gradually tapered over 2 weeks. Orally administered

methylprednisolone, prednisone, or dexamethasone (in equivalent

dosages) can be substituted for the intravenous portion of the therapy.

Outpatient treatment is almost always possible.

Side effects of short-term glucocorticoid therapy include fluid

retention, potassium loss, weight gain, gastric disturbances, acne, and

emotional lability. Concurrent use of a low-salt, potassium-rich diet

and avoidance of potassium-wasting diuretics are advisable. Lithium

carbonate (300 mg orally bid) may help manage emotional lability

and insomnia associated with glucocorticoid therapy. Patients with a

history of peptic ulcer disease may require cimetidine (400 mg bid) or

ranitidine (150 mg bid). Proton pump inhibitors such as pantoprazole

(40 mg orally bid) may reduce the likelihood of gastritis, especially

when large doses are administered orally. Plasma exchange (five to

seven exchanges: 40–60 mL/kg per exchange, every other day for

14 days) may benefit patients with fulminant attacks of demyelination

that are unresponsive to glucocorticoids. However, the cost is high, and

conclusive evidence of efficacy is lacking.

■ DISEASE-MODIFYING THERAPIES FOR

RELAPSING FORMS OF MS (RMS, SPMS WITH

EXACERBATIONS)

Regulatory bodies have approved more than a dozen immunomodulatory and immunosuppressive agents for treatment of RMS. In phase

3 clinical trials, each was shown to reduce the frequency of clinical

relapses and evolution of new brain MRI lesions in relapsing forms

of MS (Table 444-6). Each can also be used in SPMS patients who

continue to experience attacks, both because SPMS can be difficult

to distinguish from relapsing MS and because the available clinical

trials, although not all definitive, suggest that such patients may sometimes derive therapeutic benefit. Moreover, regulators now consider

patients with recent relapses to be a “relapsing form of MS” regardless

of whether these patients previously had progressive disability independent from relapses. When considering the data in Table 444-6,

however, it is important to note that the relative efficacy of the different

agents has not been directly tested in head-to-head studies and that

cross-trial comparisons are inaccurate. However, given the increasingly

complex landscape of therapeutics for MS, for convenience the discussion of these agents has been divided into those used more and less

frequently; and also by an estimate of their relative (high, moderate, or

modest) perceived level of efficacy. These are meant to serve as rough

guides only, and considerable variance exists in practice patterns, as

well as availability of these agents, in different parts of the world.

FREQUENTLY USED AGENTS FOR RMS

■ ANTI-CD20 MONOCLONAL ANTIBODIES

(HIGHLY EFFECTIVE)

Ocrelizumab is a humanized monoclonal antibody directed against the

CD20 molecule present on the surface of mature B cells. CD20 is not

expressed on early B-cell precursors or on antibody-producing plasma

cells, thus treatment with ocrelizumab selectively depletes mature

B cells while preserving preexisting humoral immunity and the capacity

3469 Multiple Sclerosis CHAPTER 444

TABLE 444-5 Scoring Systems for Multiple Sclerosis (MS)

Expanded Disability Status Scale (EDSS)

0.0 = Normal neurologic examination (all grade 0 in functional status

[FS])

1.0 = No disability, minimal signs in one FS (i.e., grade 1)

1.5 = No disability, minimal signs in more than one FS (more than one

grade 1)

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

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

3.0 = Moderate disability in one FS (one FS grade 3, others 0 or 1) or

mild disability in three or four FS (three/four FS grade 2, others 0

or 1) although fully ambulatory

3.5 = Fully ambulatory but with moderate disability in one FS (one grade 3)

and one or two FS grade 2; or two FS grade 3; or five FS grade 2

(others 0 or 1)

4.0 = Ambulatory without aid or rest for ~500 m

4.5 = Ambulatory without aid or rest for ~300 m

5.0 = Ambulatory without aid or rest for ~200 m

5.5 = Ambulatory without aid or rest for ~100 m

6.0 = Unilateral assistance required to walk about 100 m with or without resting

6.5 = Constant bilateral assistance required to walk about 20 m without resting

7.0 = Unable to walk beyond about 5 m even with aid; essentially restricted to wheelchair;

wheels self and transfers alone

7.5 = Unable to take more than a few steps; restricted to wheelchair; may need aid to transfer

8.0 = Essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most

of day; retains many self-care functions; generally has effective use of arms

8.5 = Essentially restricted to bed much of the day; has some effective use of arm(s); retains

some self-care functions

9.0 = Helpless bed patient; can communicate and eat

9.5 = Totally helpless bed patient; unable to communicate or eat

10.0 = Death due to MS

Functional Status (FS) Score

A. Pyramidal functions

0 = Normal

1 = Abnormal signs without disability

2 = Minimal disability

3 = Mild or moderate paraparesis or hemiparesis, or severe

monoparesis

4 = Marked paraparesis or hemiparesis, moderate quadriparesis, or

monoplegia

5 = Paraplegia, hemiplegia, or marked quadriparesis

6 = Quadriplegia

B. Cerebellar functions

0 = Normal

1 = Abnormal signs without disability

2 = Mild ataxia

3 = Moderate truncal or limb ataxia

4 = Severe ataxia all limbs

5 = Unable to perform coordinated movements due to ataxia

C. Brainstem functions

0 = Normal

1 = Signs only

2 = Moderate nystagmus or other mild disability

3 = Severe nystagmus, marked extraocular weakness, or moderate

disability of other cranial nerves

4 = Marked dysarthria or other marked disability

5 = Inability to swallow or speak

D. Sensory functions

0 = Normal

1 = Vibration or figure-writing decrease only, in 1 or 2 limbs

2 = Mild decrease in touch or pain or position sense, and/or moderate

decrease in vibration in 1 or 2 limbs, or vibratory decrease alone in

3 or 4 limbs

3 = Moderate decrease in touch or pain or position sense, and/or

essentially lost vibration in 1 or 2 limbs, or mild decrease in touch

or pain, and/or moderate decrease in all proprioceptive tests in 3

or 4 limbs

4 = Marked decrease in touch or pain or loss of proprioception, alone

or combined, in 1 or 2 limbs or moderate decrease in touch or pain

and/or severe proprioceptive decrease in >2 limbs

5 = Loss (essentially) of sensation in 1 or 2 limbs or moderate decrease in touch or pain and/or

loss of proprioception for most of the body below the head

6 = Sensation essentially lost below the head

E. Bowel and bladder functions

0 = Normal

1 = Mild urinary hesitancy, urgency, or retention

2 = Moderate hesitancy, urgency, retention of bowel or bladder, or rare urinary incontinence

3 = Frequent urinary incontinence

4 = In need of almost constant catheterization

5 = Loss of bladder function

6 = Loss of bowel and bladder function

F. Visual (or optic) functions

0 = Normal

1 = Scotoma with visual acuity (corrected) better than 20/30

2 = Worse eye with scotoma with maximal visual acuity (corrected) of 20/30 to 20/59

3 = Worse eye with large scotoma, or moderate decrease in fields, but with maximal visual

acuity (corrected) of 20/60 to 20/99

4 = Worse eye with marked decrease of fields and maximal acuity (corrected) of 20/100 to

20/200; grade 3 plus maximal acuity of better eye of 20/60 or less

5 = Worse eye with maximal visual acuity (corrected) <20/200; grade 4 plus maximal acuity of

better eye of ≤20/60

6 = Grade 5 plus maximal visual acuity of better eye of ≤20/60

G. Cerebral (or mental) functions

0 = Normal

1 = Mood alteration only (does not affect EDSS score)

2 = Mild decrease in mentation

3 = Moderate decrease in mentation

4 = Marked decrease in mentation

5 = Chronic brain syndrome—severe or incompetent

Source: Adapted from JF Kurtzke: Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 33:1444, 1983.

for B-cell reconstitution by lymphoid stem cells. Ocrelizumab rapidly

depletes circulating B cells through antibody-dependent cellular toxicity and complement-dependent cytotoxicity. The beneficial effects

of B-cell depletion in MS may involve interruption in trafficking of

B cells from the periphery to the CNS and reduction in antigen presentation and/or modulation of cytokine secretion by B cells (see “Immunology”, above). In two phase 3 trials, ocrelizumab demonstrated a

high degree of efficacy against RMS, reducing annualized relapse rates

by 47%, reducing new MRI lesions by 95%, and improving other measures of inflammatory and degenerative disease activity, compared with

three times per week interferon β-1a (Rebif). Ocrelizumab 600 mg is

administered by intravenous infusion every 24 weeks (administered as

two 300-mg infusions spaced 2 weeks apart for the first dose, and as

a single 600-mg infusion thereafter); intravenous methylprednisolone

3470 PART 13 Neurologic Disorders

100 mg is given prior to each infusion and optional prophylaxis with

analgesics/antipyretics and antihistamines is recommended, along with

adjustment of the infusion rate to manage infusion-related reactions.

Ocrelizumab is generally well tolerated with infusion-related reactions

occurring in a minority of patients; these are most often observed with

the first infusion and are usually mild in degree. Vaccination responses

may be blunted in patients receiving ocrelizumab or other anti-CD20

based therapies; whenever possible, immunizations should be administered prior to initiating treatment, and live vaccines should not be

given in actively treated patients.

Ofatumumab is a fully human anti-CD20 monoclonal antibody

that can be self-administered at home by monthly 20 mg subcutaneous

injection, after initial 20-mg loading doses on days 1, 7, and 14. Two

pivotal phase 3 trials demonstrated superiority of ofatumumab tested

against teriflunomide with an efficacy profile against relapses similar

to ocrelizumab, reduction of new MRI lesions by 95%, reduction of

disability, and lowering of serum neurofilament light chain levels,

a biomarker of neuronal damage. A high degree of safety was also

observed in the trials.

Rituximab, another anti-CD20 antibody, was tested against MS

in preliminary trials, and appears also to be highly effective based

on numerous reports of real-world experience with this agent; rituximab (1g IV Q6 mo) is used in some settings despite lack of pivotal

trial data. Rituximab is associated with a very small risk (estimated

at <1:25,000/year) of progressive multifocal leukoencephalopathy

(PML), a life-threatening condition resulting from infection by the

John Cunningham (JC) virus, thus it is possible that ocrelizumab and

ofatumumab will also carry a nonzero risk.

■ NATALIZUMAB (HIGHLY EFFECTIVE)

Natalizumab is a humanized monoclonal antibody directed against the

α4 subunit of α4β1 integrin, a cellular adhesion molecule expressed on

the surface of lymphocytes. It prevents lymphocytes from binding to

endothelial cells, thereby preventing lymphocytes from penetrating the

BBB and entering the CNS. Natalizumab is highly effective in reducing

the attack rate and significantly improves all measures of disease severity in MS (both clinical and MRI). Moreover, it is well tolerated, and the

dosing schedule of monthly intravenous infusions makes it convenient

for patients. Natalizumab, 300 mg, is administered by IV infusion each

month. Treatment is, in general, well tolerated. A small percentage

(<10%) of patients experience hypersensitivity reactions (including

anaphylaxis), and ~6% develop neutralizing antibodies to the molecule

(only half of which persist).

The major concern is risk for PML, occurring in ~0.4% of patients

treated with natalizumab. The incidence of PML is very low in the first

year of treatment but then rises in subsequent years of treatment to

TABLE 444-6 Outcomes for FDA-Approved Therapies for Multiple Sclerosisa

RELAPSING MS

CLINICAL OUTCOMESb MRI OUTCOMESc

DOSE, ROUTE, AND SCHEDULE

STUDY DURATION

(WEEKS) COMPARATOR

ATTACK RATE,

MEAN

CHANGE IN DISEASE

SEVERITY

NEW T2

LESIONSd

TOTAL BURDEN

OF DISEASE

OCR, 600mg IV, Q6 mo 96 IFN-β-1a, 44 μg SC tiw −46%e,h −33%e,h −80%e,h NR

OFA 20 months1 TF 14 mg PO qd −55%e −34%2 −96%e NR

NTZ, 300 mg IV qmo 96 PBO −68%e −42%e −83%e −18%e

FNG, 0.5 mg PO qd 96 PBO −55%e −34%f −74%e −23%e

FNG, 0.5 mg PO qd 48 IFN-β-1a, 30 μg IM qw −52%e NS −35%e NS

OZN, 1 mg PO qd 52 IFN-β-1a, 30 μg IM qw –48%e NS –48%e NR

OZN, 1 mg PO qd 104 IFN-β-1a, 30 μg IM qw –38%e NS –42%e NR

PNS, 20 mg

PO qd

108 Teriflunomide 14 mg

PO qd

–30%e NS –56%e NR

DMF, 240 mg PO bid 96 PBO −52%e −40%f −71%e NR

IFN-β-1b, 250 μg SC qod 96 PBO −34%e −29% (NS) −83%f −17%e

IFN-β-1a, 30 μg IM qw 96 PBO −18%g −37%g −36%f NS

IFN-β-1a, 44 μg SC tiw 96 PBO −32%e −30%g −78%e −15%e

Peg- IFN-β-1a, 125 μg SC q2w 48 PBO −36%e −38%g −67%e −2%e

GA, 20 mg SC qd 96 PBO −29%f −12% (NS) −38%f −8%f

TF, 14 mg PO qd 96 PBO −31%e −26%g −70%e −20%g

CLAD 3.5 mg/kg PO 96 PBO −43% −23% −73% −24%

ALEM, 12mg/m2

 IV/5d 104 IFN-β-1a, 44 μg SC tiw −49%e −42%f −32%e NS

MTX, 12 mg/m2

 IV q3mo 96 PBO −66%e −75%g −79%g NR

Secondary Progressive MS

SIP, 2 mg PO qd 12–36 monthsi PBO −55%e −21%f −81%e −22%e

Primary Progressive MS

OCR, 600 mg IV, Q6 mo 96 PBO NR −24%g −92%e −11%e

1

Variable duration study with median time in randomized controlled period of 20 months.

2

p = 0.002

a

Percentage reductions (or increases) have been calculated by dividing the reported rates in the treated group by the comparable rates in the placebo group, except

for magnetic resonance imaging (MRI) disease burden, which was calculated as the difference in the median percent change between the treated and placebo groups. b

Severity = 1 point Expanded Disability Status Scale score progression, sustained for 3 months (in the IFN-β-1a 30 μg qw trial, this change was sustained for 6 months; in

the IFN-β-1b trial, this was over 3 years). c

Different studies measured these MRI measures differently, making comparisons difficult (numbers for new T2 represent the bestcase scenario for each trial). d

New lesions seen on T2-weighted MRI. e

p = .001. f

p = .01. g

p = .05. h

Pooled analysis from OPERA 1 and 2 studies. i

Variable duration study with

median time in randomized controlled period of 18 months.

Abbreviations: ALEM, alemtuzumab; CLAD, cladribine; DMF, dimethyl fumarate; FDA, food and drug administration; FNG, fingolimod; GA, glatiramer acetate; IFN-β, interferon

β; IM, intramuscular; IV, intravenous; MTX, mitoxantrone; NR, not reported; NS, not significant; NTZ, natalizumab; OFA, ofatumumab; OFR, ocrelizumab; OZN, ozanimod;

PNS, ponesimod; PO, oral; q3mo, once every 3 months; qd, daily; qmo, once per month; qod, every other day; qw, once per week; qyr, once per year; SC, subcutaneous; SIP,

siponimod; TF, teriflunomide; tiw, three times per week.

3471 Multiple Sclerosis CHAPTER 444

reach a level of about 2 cases per 1000 patients per year. Nevertheless,

the measurement of antibodies against the JC virus in the serum can

be used to stratify this risk. Approximately half of the adult population

is JC antibody positive, indicating that they experienced an asymptomatic infection with the JC virus at some time in the past. Thus, in

patients who do not have these antibodies, the risk of PML is minimal

(<1:10,000 as long as they remain JC antibody free). Conversely, in

patients who have these antibodies (especially those who have them

in high titer), the risk may be as high as ≥1.1%. Up to 2% of seronegative MS patients undergoing treatment with natalizumab seroconvert annually; thus, it is recommended that JC antibody status be

assessed at 6-month intervals in all patients receiving natalizumab. In

antibody-positive patients, a change to another disease-modifying

therapy should be strongly considered. The risk of PML is also high

in patients who previously received immunosuppressive therapy.

Natalizumab is generally recommended only for JC antibody-negative

patients, unless they have failed alternative therapies or if they have a

particularly aggressive disease course.

■ S1P RECEPTOR MODULATORS

(MODERATELY EFFECTIVE)

Fingolimod is a sphingosine-1-phosphate (S1P) modulator that

prevents the egress of lymphocytes from secondary lymphoid organs

such as the lymph nodes and spleen. Fingolimod binds to S1P1, S1P3,

S1P4, and S1P5 receptors. Its mechanism of action is probably due

to sequestration of lymphocytes in the periphery, thereby inhibiting

their trafficking to the CNS. Fingolimod reduces the attack rate and

significantly improves all measures of disease severity in MS. It is well

tolerated, and the daily oral dosing schedule makes it convenient for

patients. A head-to-head phase 3 randomized study demonstrated

the superiority of fingolimod over low-dose (weekly) IFN-β-1a. Fingolimod, 0.5 mg, is administered orally each day. Mild abnormalities

on routine laboratory evaluation (e.g., elevated liver function tests or

lymphopenia) are more common than in controls, sometimes requiring discontinuation of the medication. First- and second-degree heart

block and bradycardia can also occur when fingolimod therapy is

initiated. A 6-h period of observation (including electrocardiogram

monitoring) is recommended for all patients receiving their first dose.

Other side effects include macular edema and, rarely, disseminated

varicella-zoster virus (VZV) and cryptococcal infections; prior to initiating therapy with fingolimod, an ophthalmic examination and VZV

vaccination for seronegative individuals are indicated. Fingolimod can

also cause QT prolongation with the potential for drug–drug interactions with other medications that also prolong the QT interval.

Ozanimod is a S1P1- and S1P5-selective S1P inhibitor that, like fingolimod, prevents the egress of lymphocytes from secondary lymphoid

organs. Ozanimod was shown to be superior to low-dose (weekly)

IFN-β-1a in preventing relapses and new lesion formation on brain

MRI. Because ozanimod binds only weakly to S1P3 receptors, cardiac

conduction-related side effects, such as QT prolongation and secondarydegree heart block that are associated with modulation of myocardial

S1P3 receptors, are not associated with ozanimod. An up-titration

scheme is used when starting this medication to reduce the risk of transient decreases in heart rate and atrioventricular conduction delays that

may occur after the first dose. In contrast to fingolimod, cardiovascular

monitoring is not required during first-dose administration in most

patients. Ozanimod was not studied in patients with severe untreated

sleep apnea, class III/IV heart failure, significant cardiac conduction

disorders, or in those who experienced thromboembolic events in

the last 6 months, and is relatively contraindicated in these patients.

Patients starting ozanimod should undergo a CBC, LFTs, ECG, and

eye examination before starting therapy. Infections and hypertension

should be monitored for during treatment. Live vaccines should be

avoided during treatment and for 3 months after discontinuation.

Ponesimod is a S1P1-selective modulator. Ponesimod was shown

to be superior to teriflunomide in preventing relapses and new MRI

lesion formation. An up-titration scheme is used when starting this

medication to reduce the risk of transient decreases in heart rate and

atrioventricular conduction delays that may occur after the first dose.

A 4-h first-dose observation period with cardiovascular monitoring is

necessary in patients whose resting heart rate is <55 beats/min. Ponesimod is contraindicated in patients who have in the prior 6 months

experienced stroke, heart attack, unstable angina, class III or IV decompensated heart failure or have a Mobitz type II or greater degree

of heart block without a pacemaker. Patients should undergo a CBC,

LFTs, ECG, and eye examination before starting therapy, and be monitored for infections and hypertension during treatment. Live vaccines

should be avoided during treatment.

■ DIMETHYL FUMARATE (MODERATELY EFFECTIVE)

Dimethyl fumarate (DMF) is a small-molecule and a Krebs cycle

metabolite with anti-inflammatory effects. DMF is metabolized to the

active compound monomethyl fumarate. Although the precise mechanisms of action are not fully understood, it seems to modulate the

expression of proinflammatory and anti-inflammatory cytokines. Also,

DMF inhibits the ubiquitylation and degradation of nuclear factor

E2-related factor 2 (Nrf2)—a transcription factor that binds antioxidant response elements (AREs) located on DNA and induces transcription of several antioxidant proteins. DMF reduces the attack rate and

significantly improves all measures of disease severity in MS patients.

However, its twice-daily oral dosing schedule makes it somewhat less

convenient for patients than daily oral therapies. In addition, compliance is likely to be less with a twice-daily dosing regimen—a factor that

could be of concern given the observation (in a small clinical trial) that

once-daily DMF lacks efficacy. A head-to-head trial provided evidence

that DMF was superior to glatiramer acetate on some outcome measures. DMF, 240 mg, is administered orally twice each day. Gastrointestinal side effects (abdominal discomfort, nausea, vomiting, flushing,

and diarrhea) are common at the start of therapy but generally subside

with continued administration. Other adverse events include flushing,

mild decreases in neutrophil and lymphocyte counts, and elevations

in liver enzymes. Nevertheless, in general, treatment with DMF is well

tolerated after an initial period of adjustment. Following the release of

DMF, several cases of PML were reported in patients receiving products that contained DMF. Most of these patients were lymphopenic and

monitoring for lymphopenia every 6 months is recommended. Patients

who are persistently lymphopenic (lymphocyte count <500 cells/mL)

are recommended to consider alternate treatments due to the PML

risk. Clinically significant liver injury has been reported with DMF

treatment. Liver function tests should be assessed before treatment

and when clinically indicated. Elevations in liver function tests resolve

following treatment discontinuation.

Diroximel fumarate is, like DMF, metabolized to monomethyl

fumarate. The efficacy of diroximel fumarate is based upon bioavailability studies in patients with RMS and healthy subjects. The adverse

event profile and monitoring requirements are the same as with DMF.

■ GLATIRAMER ACETATE (MODESTLY EFFECTIVE)

Glatiramer acetate is a synthetic, random polypeptide composed of

four amino acids (l-glutamic acid, l-lysine, l-alanine, and l-tyrosine).

Its mechanism of action may include (1) induction of antigen-specific

suppressor T cells; (2) binding to MHC molecules, thereby displacing

bound MBP; or (3) altering the balance between proinflammatory

and regulatory cytokines. Glatiramer acetate reduces the attack rate

(whether measured clinically or by MRI) in RRMS. Glatiramer acetate

also benefits disease-severity measures, although, for clinical disability,

this is less well established than for IFN-β. Nevertheless, two headto-head trials demonstrated that the impact of glatiramer acetate on

clinical relapse rates and disability was comparable to high-dose, highfrequency IFN-β. Therefore, glatiramer acetate should be considered as

an equally effective alternative to IFN-β in RRMS patients. Its usefulness

in progressive disease is unknown. Glatiramer acetate is administered

by subcutaneous injection of either 20 mg every day or 40 mg thrice

weekly. Injection-site reactions can occur. In addition, ~15% of patients

experience one or more episodes of flushing, chest tightness, dyspnea,

palpitations, and anxiety after injection. This systemic reaction is unpredictable, brief (duration <1 h), and tends not to recur. Finally, some

3472 PART 13 Neurologic Disorders

patients experience lipoatrophy, which, on occasion, can be disfiguring

and require cessation of treatment. Recently, glatiramer acetate was U.S.

Food and Drug Administration (FDA) approved as a biosimilar medication (Glatopa) and is dosed at 20 mg every day. Although clinical trials

were not performed with biosimilar glatiramer acetate, the efficacy and

safety are presumed to be similar to the branded product.

■ INTERFERON β (MODESTLY EFFECTIVE)

Interferon β (IFN-β) is a class I interferon originally identified by its

antiviral properties. Efficacy in MS probably results from immunomodulatory properties including: (1) downregulating expression of

MHC molecules on antigen-presenting cells, (2) reducing proinflammatory and increasing regulatory cytokine levels, (3) inhibiting T-cell

proliferation, and (4) limiting the trafficking of inflammatory cells

in the CNS. IFN-β reduces the attack rate, and slows accumulation

of disability and MRI-documented disease burden. IFN-β should be

considered in patients with either relapsing forms of MS (either RRMS

or SPMS with superimposed relapses). Head-to-head trials suggest that

dosing IFN-β more frequently and at higher doses has better efficacy

but is also more likely to induce neutralizing antibodies (see below).

IFN-β-1a (Avonex), 30 μg, is administered by intramuscular injection

once every week. IFN-β-1a (Rebif), 44 μg, is administered by subcutaneous injection three times per week. IFN-β-1b (Betaseron or Extavia),

250 μg, is administered by subcutaneous injection every other day.

Pegylated IFN-β-1a (Plegridy), 125 μg, is administered by subcutaneous injection once every 14 days. Pegylated IFN-β-1a is an interferon

to which a single, linear 20,000 dalton methoxy poly(ethyleneglycol)-O-2-methylproprionaldehyde molecule is covalently attached; the

pegylated molecule contributes to reduced in vivo clearance allowing

less frequent administration. Common side effects of IFN-β therapy

include flulike symptoms (e.g., fevers, chills, and myalgias) and mild

abnormalities on routine laboratory evaluation (e.g., elevated liver

function tests or lymphopenia). Rarely, more severe hepatotoxicity may

occur. Subcutaneous IFN-β also causes reactions at the injection site

(e.g., pain, redness, induration, or, rarely, skin necrosis). Side effects can

usually be managed with concomitant nonsteroidal anti-inflammatory

medications. Depression, increased spasticity, and cognitive changes

have been reported, although these symptoms can also be due to the

underlying disease. Side effects due to IFN-β therapy usually subside

over time. Rates of serious infection are lower with IFN-β therapy than

many other disease-modifying medications.

Approximately 2–10% of IFN-β-1a (Avonex) recipients, 15–25%

of IFN-β-1a (Rebif) recipients, and 30–40% of IFN-β-1b (Betaseron/

Extavia) recipients develop neutralizing antibodies to IFN-β, which

may disappear over time. Less than 1% of patients treated with pegylated IFN-β-1a develop neutralizing antibodies. For a patient doing

well on therapy, the presence of antibodies should not affect treatment.

Conversely, for a patient doing poorly on therapy, alternative treatment

should be considered, even if there are no detectable antibodies.

LESS COMMONLY USED AGENTS FOR RMS

■ TERIFLUNOMIDE (MODESTLY EFFECTIVE)

Teriflunomide inhibits the mitochondrial enzyme dihydro-orotate

dehydrogenase, which is a key part of the pathway for de novo pyrimidine biosynthesis from carbamoyl phosphate and aspartate. It is the

active metabolite of the drug leflunomide (FDA-approved for rheumatoid arthritis), and it exerts its anti-inflammatory effects by limiting

the proliferation of rapidly dividing T and B cells. This enzyme is not

involved in the so-called salvage pathway, by which existing pyrimidine

pools are recycled for DNA and RNA synthesis in resting and homeostatically proliferating cells. Consequently, teriflunomide is considered

to be cytostatic rather than cytotoxic. Teriflunomide reduces the attack

rate and significantly improves all measures of disease severity in MS

patients. It is well tolerated, and its daily oral dosing schedule makes

it very convenient for patients. A head-to-head trial suggested the

equivalence, but not superiority, of teriflunomide and thrice-weekly

IFN-β-1a. Teriflunomide, either 7 or 14 mg, is administered orally each

day. In the pivotal clinical trials, mild hair thinning and gastrointestinal

symptoms (nausea and diarrhea) were more common than in controls,

but in general, treatment with teriflunomide was well tolerated. Teriflunomide rarely causes toxic epidermal necrolysis or Stevens-Johnson

syndrome. A major limitation, especially in women of childbearing

age, is its possible teratogenicity (pregnancy category X); teriflunomide

can remain in the bloodstream for 2 years due to hepatobiliary reabsorption. Therefore, it is recommended that exposed men and women

who wish to conceive receive cholestyramine or activated charcoal to

eliminate residual drug.

■ CLADRIBINE (MODERATELY EFFECTIVE)

Cladribine is a prodrug that when phosphorylated by deoxycytidine

kinase to its metabolite 2-chlorodeoxyadenosine becomes active and is

incorporated into nuclear and mitochondrial DNA causing apoptosis.

Because deoxycytidine kinase is expressed at high levels in lymphocytes, cladribine can be administered as a relatively specific lymphotoxic therapy. In intravenous or subcutaneously administered forms,

cladribine is indicated for treatment of hairy cell leukemia. Cladribine’s

oral formulation is indicated for treatment of relapsing forms of MS

including active SPMS. Cladribine reduces the attack rate and disability measures in RMS patients. It is well tolerated, and is dosed based

on body weight (3.5 mg/kg divided into 2 yearly treatment courses).

Patients are treated with 1 or 2 doses of cladribine daily for 4 or 5 consecutive days, receive a second similar cycle of treatment 23 to 27 days

after the first cycle, and then are retreated after 1 year. Cladribine has

beneficial effects in MS that are sustained beyond the 2-year course of

administration. The basis for these benefits is poorly understood but

is presumably related to immune reconstitution by nonpathogenic

lymphocytes. Cladribine is associated with malignancy, including

in the MS clinical trials, and for this reason is not recommended in

treatment-naïve patients. Cladribine is also contraindicated in pregnant women because it is a known teratogen in animals and can cause

embryolethality. Despite cladribine’s relatively short terminal half-life

of 1 day, women and men treated with cladribine are recommended to

not plan conception for 6 months after the last dose. Prior to treatment,

patients should undergo a complete blood count including lymphocyte

count and liver function tests; be screened for HIV, tuberculosis, and

hepatitis B and C; be vaccinated for varicella zoster virus; and undergo

a brain MRI within 3 months of treatment because of a presumed risk

of treatment-emergent PML.

■ ALEMTUZUMAB (HIGHLY EFFECTIVE)

Alemtuzumab is a humanized monoclonal antibody directed against the

CD52 antigen that is expressed on both monocytes and lymphocytes. It

causes lymphocyte depletion (of both B and T cells) and a change in the

composition of lymphocyte subsets. Both of these changes, particularly

the impact on lymphocyte subsets, are long lasting. In two phase 3 trials, which used the active comparator of thrice-weekly, high-dose IFNβ-1a, alemtuzumab markedly reduced the attack rate and significantly

improved measures of disease severity in MS patients although its

impact on clinical disability was found in only one of the two trials. The

European and Canadian drug agencies were the first to approve this

agent for use in RRMS; the FDA has also approved alemtuzumab, but

only after an appeal following initial disapproval. The reasons for initial

disapproval were based on a perceived lack of a convincing disability

effect and concerns over potential toxicity. The toxicities of concern

were the occurrence of (1) autoimmune diseases including thyroiditis,

Graves’ disease, thrombocytopenia, hemolytic anemia, pancytopenia,

antiglomerular basement membrane disease, and membranous glomerulonephritis; (2) malignancies including thyroid cancer, melanoma,

breast cancer, human papillomavirus (HPV)-related cancers, and lymphoproliferative disorders including lymphoma; (3) serious infections;

and (4) infusion reactions. Because of its toxicity profile, alemtuzumab

is indicated by the U.S. FDA only in patients who have tried and failed

at least two other DMTs.

■ MITOXANTRONE HYDROCHLORIDE

(HIGHLY EFFECTIVE)

Mitoxantrone, an anthracenedione, exerts its antineoplastic action

by (1) intercalating into DNA and producing both strand breaks

3473 Multiple Sclerosis CHAPTER 444

and interstrand cross-links, (2) interfering with RNA synthesis, and

(3) inhibiting topoisomerase II (involved in DNA repair). The FDA

approved mitoxantrone on the basis of a single phase 3 clinical trial

in Europe, in addition to even smaller phase 2 studies. Mitoxantrone

is indicated for use in patients with rapidly worsening MS (defined

as patients whose neurologic status remains significantly abnormal

between MS attacks). Despite this broad indication, however, data

supporting its efficacy are less robust compared to other approved

therapies. Mitoxantrone is cardiotoxic (e.g., cardiomyopathy, reduced

left ventricular ejection fraction, and irreversible congestive heart failure). As a result, a cumulative dose >140 mg/m2

 is not recommended.

At currently approved doses (12 mg/m2

 every 3 months), the maximum

duration of therapy can be only 2–3 years. Furthermore, >40% of

women will experience amenorrhea, which may be permanent. Finally,

there is risk of acute leukemia from mitoxantrone, estimated as at least

a 1.4% lifetime risk. Because of these risks, and the availability of alternative therapies, mitoxantrone is now rarely used for MS.

DECISION-MAKING FOR

TREATMENT OF RMS

First-line therapy should be initiated in patients with a clinically isolated syndrome at high risk for MS or in patients diagnosed with RMS

(according to 2017 McDonald criteria).

We favor use of the most highly effective DMTs as first-line options

for most patients with active MS, rather than the more traditional

“treat to target” approach in which a treatment of modest or moderate

effectiveness is first used, and therapy advanced to a more effective

agent when breakthrough disease (evident clinically or by MRI) occurs.

As noted above, observational studies suggest that early use of highefficacy therapy could improve long-term outcomes. For many patients,

we begin with an anti-CD20 agent, either ocrelizumab or ofatumumab,

or with natalizumab in JCV-negative patients. Anti-CD20 agents are

attractive given their high level of efficacy, relative ease of use, favorable

safety profile, and absence of rebound following discontinuation. For

patients who prefer oral treatment, either an S1P modulator or fumarate is also reasonable for first-line therapy.

Switching DMTs may be required in the following situations: suboptimal response, experiencing more than one relapse with active MRI scans

while on treatment, and safety issues including development of persistent

high-titer neutralizing antibodies in patients receiving IFN-β. Discontinuation of DMTs is required in cases of serious adverse events that may

be drug-related and for many DMTs in women who become pregnant

while on treatment. Exceptions to this practice include glatiramer acetate

that can be continued during pregnancy, and in some cases prior use of

ocrelizumab, alemtuzumab, and cladribine that have prolonged pharmacodynamic effects that persist after the drug has been eliminated.

For patients who present with a mild initial course—e.g., normal

examination or minimal impairment (EDSS ≤2.5) and low disease

activity by MRI—either an oral (fumarates, S1P modulators, teriflunomide) or injectable (IFN-β or glatiramer acetate) agent can be considered. The injectable agents (IFN-β and glatiramer acetate) have a superb

long-term track record for safety but have a high nuisance factor due to

the need for frequent injections, as well as bothersome side effects that

contribute to noncompliance.

The safety and value of combination therapy is also largely unknown

and is generally not recommended. One clinical trial demonstrated

no added benefit to the combination of glatiramer acetate with onceweekly IFN-β-1a. The optimal duration of therapy is also unknown.

The long-term impact of these treatments on the disease course

remains controversial, although as noted above (“Prognosis”) several

observational studies showed that these agents improve the long-term

outcome of MS including a prolongation of the time to reach certain

disability outcomes (e.g., SPMS and requiring assistance to ambulate) and

reduction in MS-related mortality. These benefits seem most conspicuous

when treatment begins early in the relapsing stage of the illness. It may

be reasonable to delay initiating treatment in patients with (1) normal

neurologic examinations, (2) a single attack or a low attack frequency, and

(3) a low burden of disease as assessed by brain MRI. Untreated patients,

however, should be followed closely with periodic brain MRI scans; the

need for therapy is reassessed if scans reveal evidence of ongoing, subclinical disease. Finally, vitamin D deficiency should be corrected in all

patients with MS, and generally this requires oral supplementation with

vitamin D3, 4000 IU daily. Several clinical trials showed that supplementation with vitamin D in relapsing MS patients reduces MRI measures

of disease activity and may also reduce the relapse frequency in patients

actively treated with either interferon or glatiramer acetate.

DISEASE-MODIFYING THERAPIES

FOR PROGRESSIVE MS

■ SPMS

Siponimod is a selective S1P1 S1P5 receptor modulator (see S1P receptor modulators above) that was shown in a single phase 3 study to be

superior to placebo in reducing the risk of progression in SPMS patients.

Siponimod also reduced the risk of relapse and MRI measures of the

burden of disease. Subgroup analysis showed that patients with a relapse

in the 2 years prior to treatment and those with contrast-enhancing

lesions on brain MRI received the most therapeutic benefit. Siponimod

was subsequently approved for patients with SPMS who had active disease. Siponimod is dosed based on CYP2C9 genotype. For patients with

CYP2C9 1/*

3 or 2/*

3, siponimod is administered as 1 mg daily. Siponimod dosage is reduced in patients with the CYP2C9 *

3/*

3 genotype

(<0.5% of the population) due to substantially elevated drug levels. Prior

to treatment patients should undergo a complete blood count, ophthalmic evaluation, electrocardiogram, liver function tests, and vaccination

for varicella zoster virus. Unlike fingolimod, first-dose monitoring is

required only in patients with sinus bradycardia, first- or second-degree

heart block, or a history of myocardial infarction or heart failure.

Ocrelizumab, cladribine, and ponesimod are also indicated in active

SPMS although none of these therapies were specifically studied in this

patient population. High-dose IFN-β probably has a modest beneficial

effect in patients with SPMS with active disease (see above). IFN-β

is probably ineffective in patients with SPMS who do not have active

disease. Although mitoxantrone was approved for patients with rapidly progressive MS, this is not the population studied in the pivotal

trial; therefore, no evidence-based recommendation can be made with

regard to its use in this setting.

■ PPMS

Ocrelizumab (see above) was shown in a phase 3 trial to reduce progression of clinical disability in PPMS by 24%, and also to improve

other clinical and MRI markers of inflammatory and degenerative

disease activity. Ocrelizumab represents the first agent to convincingly

modify the course of PPMS. The dosing of ocrelizumab for PPMS is

identical as for RMS (above).

■ OFF-LABEL TREATMENT OPTIONS

FOR RMS AND SPMS

Azathioprine (2–3 mg/kg per day) has been used primarily in relapsing MS. Meta-analysis of published trials suggests that azathioprine

is marginally effective at lowering relapse rates, although a benefit on

disability progression has not been demonstrated.

Methotrexate (7.5–20 mg/week) was shown in one study to slow

the progression of upper-extremity dysfunction in SPMS. Because of

the possibility of developing irreversible liver damage, some experts

recommend a blind liver biopsy after 2 years of therapy.

Cyclophosphamide (700 mg/m2, every other month) may be helpful

for treatment-refractory patients who are (1) otherwise in good health,

(2) ambulatory, and (3) <40 years of age. Because cyclophosphamide

can be used for periods in excess of 3 years, it may be preferable to

mitoxantrone in these circumstances.

Intravenous immunoglobulin (IVIg), administered in monthly pulses

(up to 1 g/kg) for up to 2 years, appears to reduce annual exacerbation

rates. However, its use is limited because of its high cost, questions

about optimal dose, and uncertainty about its having any impact on

long-term disability.

Methylprednisolone in one study, administered as monthly highdose intravenous pulses, reduced disability progression (see above).