80 - Multiple Sclerosis and Other Inflammatory Demyelinating Diseases of The Central Nervous System

80
Multiple Sclerosis and Other

Inflammatory Demyelinating Diseases
of the Central Nervous System
Michelle T. Fabian, Stephen C. Krieger, Fred D. Lublin
OUTLINE
Characteristic Clinical Symptoms and Physical Findings in Multi- Clinically Isolated Syndrome, 1240
ple Sclerosis, 1227 Factors Influencing Clinical Course, 1240
Cranial Nerve Dysfunction, 1227 Predictive Value of Magnetic Resonance Imaging in Conversion to
Impairment of Visual Pathways, 1227 Clinically Definite Multiple Sclerosis, 1240
Impairment of Ocular Motor Pathways, 1227 Prognosis Based on Patient Characteristics, 1240
Impairment of Other Cranial Nerves, 1227 Effect of Exogenous Factors on Clinical Course, 1241
Impairment of Cerebellar Pathways, 1227 Pregnancy in Multiple Sclerosis, 1241
Impairment of Sensory Pathways, 1228 Variants of Multiple Sclerosis, 1241
Impairment of Motor Pathways, 1228 Tumefactive Multiple Sclerosis, 1241
Impairment of Bladder, Bowel, and Sexual Functions, 1228 Marburg Variant, 1242
Pathophysiology, 1228 Baló Concentric Sclerosis, 1242
Changes in Axonal Conduction with Demyelination, 1228 Treatment and Management, 1242
Etiology, 1231 Treatment of Acute Attacks, 1243
Autoimmunity, 1231 Treatment Strategies and Goals of Therapy, 1243
Genetics, 1231 Disease-Modifying Therapy, 1244
Infection, 1231 Clinical Symptoms and Symptom Management, 1248
Vitamin D, 1231 Gait and Ambulatory Dysfunction, 1248
Smoking, 1231 Fatigue, 1248
Diet and the Microbiome, 1232 Cognitive Impairment, 1248
Epidemiology, 1232 Mood and Affective Disorders, 1249
Age of Onset, 1232 Spasticity, 1249
Sex Distribution, 1232 Tremor, 1249
Geographical Distribution, 1232 Bladder Dysfunction, 1250
Mortality, 1232 Sexual Dysfunction, 1250
Diagnosis, 1233 Transient and Paroxysmal Symptoms Particularly Characteristic
Diagnostic Criteria, 1233 of MS, 1250
Diagnostic Studies, 1233 Other Inflammatory Demyelinating Diseases of the Central Ner-
Differential Diagnosis, 1237 vous System, 1250
Multiple Sclerosis Misdiagnosis, 1238 Acute Disseminated Encephalomyelitis, 1250
Clinical Course and Prognosis, 1238 Acute Hemorrhagic Leukoencephalitis, 1251
Measures of Disability, 1238 Neuromyelitis Optica, 1252
Clinical Phenotypes (RRMS, SPMS, PPMS), 1238 Site-Restricted Forms of Demyelinating Disorders, 1253
Radiographically Isolated Syndrome, 1239

Diseases affecting central nervous system (CNS) myelin can be clas- exists include several hereditary disorders. Infectious demyelinating
sified on the basis of whether a primary biochemical abnormality of disease (progressive multifocal leukoencephalopathy [PML]), toxic
myelin exists (dysmyelinating) or whether some other process damages and metabolic demyelinating diseases, and vascular demyelinating dis-
the myelin or oligodendroglial cell (demyelinating). Demyelinating ease (Binswanger disease) are discussed elsewhere. The present chap-
diseases in which normal myelin is disrupted include autoimmune, ter concentrates on multiple sclerosis (MS) and other inflammatory
infectious, toxic and metabolic, and vascular processes. Dysmyelinat- demyelinating diseases of myelin as well as other CNS diseases that are
ing diseases in which a primary abnormality of the formation of myelin presumably immune mediated (Box 80.1).
1226
Downloaded for Fakultas Kedokteran Universitas Muslim Indonesia (01calcitonin2017@gmail.com) at University of Muslim Indonesia from
ClinicalKey.com by Elsevier on July 28, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
CHAPTER 80 Multiple Sclerosis and Other Inflammatory Demyelinating Diseases 1227
optic neuropathy, toxic optic neuropathy, neuromyelitis optica, or anti-

BOX 80.1 Diseases of Myelin
MOG antibody associated ON. In bilateral ON in MS cases, the impair-
Autoimmune ment usually begins asymmetrically and is more severe in one eye.
Acute disseminated encephalomyelitis
Acute hemorrhagic leukoencephalopathy Impairment of Ocular Motor Pathways
Multiple sclerosis Impairment of individual ocular motor nerves is infrequent in MS but
may occur in isolation or as part of a brainstem syndrome. When pres-
Infectious ent, the involved nerves are, in decreasing order of frequency, cranial
Progressive multifocal leukoencephalopathy nerves VI, III, and (rarely) IV.
Brainstem syndromes in MS causing eye movement abnormalities
Toxic/Metabolic are frequently those that reflect lesions of vestibulo-ocular connections
Carbon monoxide poisoning and internuclear connections. Nystagmus is a common finding in MS.
Vitamin B12 deficiency One form of nystagmus particularly characteristic of MS is acquired
Mercury intoxication (Minamata disease) pendular nystagmus, in which there are rapid small-amplitude pendu-
Alcohol/tobacco amblyopia lar oscillations of the eyes in the primary position. Patients frequently
Central pontine myelinolysis complain of oscillopsia (subjective oscillation of objects in the field of
Marchiafava-Bignami syndrome vision). This type of nystagmus is most often bilateral, but can also be
Hypoxia unilateral and may be seen as consequent of an optic neuropathy, or
Radiation because of involvement in the cerebellum or dorsal pontine tegmen-
tum (Brazis et al., 2011).
Vascular
Internuclear ophthalmoplegia (INO), defined as abnormal hori-
Binswanger disease
zontal ocular movements with lost or impaired adduction and hori-
Hereditary Disorders of Myelin Metabolism zontal nystagmus of the abducting eye, is secondary to a lesion of the
Adrenoleukodystrophy medial longitudinal fasciculus on the side of diminished adduction.
Metachromatic leukodystrophy Convergence is preserved. When present bilaterally, it is usually cou-
Krabbe disease pled with vertical nystagmus on upward gaze. Often a patient with an
Alexander disease INO does not complain of a visual disturbance and it is instead recog-
Canavan-van Bogaert-Bertrand disease nized first by the examiner. Ocular pursuit movements are frequently
Pelizaeus-Merzbacher disease saccadic rather than smooth. In the appropriate epidemiological con-
Phenylketonuria text, the identification of an INO is highly suggestive of MS and should
prompt a work-up for this diagnosis.
CHARACTERISTIC CLINICAL SYMPTOMS AND Impairment of Other Cranial Nerves

Impairment of facial sensation—subjective or objective—is a relatively
PHYSICAL FINDINGS IN MULTIPLE SCLEROSIS
common finding in MS and may occur in isolation or as part of a hemi-
MS is classically described as principally a demyelinating disorder that sensory syndrome. The occurrence of trigeminal neuralgia in a young
affects multiple white matter tracts within the CNS. The variability of MS adult may prompt a work-up for MS, yet is an uncommon present-
in clinical presentation is well known. This heterogeneity includes age of ing symptom and, if it occurs, it is typically later in the course. Facial
onset, mode of initial manifestation, frequency, severity and sequelae of myokymia, a fine, undulating wavelike facial twitching, and hemifa-
relapses, extent of progression, and cumulative deficit over time, as will be cial spasm can be caused by MS, but other causes of a focal brainstem
discussed across this chapter. The clinical features reflect the widespread lesion must be excluded (Mehanna and Jankovic, 2013). Unilateral
distribution of CNS injury, and we will begin with an overview of the signs facial paresis can occur. Complete hearing loss, usually unilateral, is
and symptoms of this disease, referable to characteristic demyelinating an infrequent complaint. Isolated dysfunction of taste sensation is
localizations: optic neuritis (ON), brainstem, and spinal cord. rare but has been well characterized with localization to the brainstem
(McGraw et al., 2012). Malfunction of the lower cranial nerves is usu-
CRANIAL NERVE DYSFUNCTION ally of the upper motor neuron type (pseudobulbar syndrome) and a
rather late finding in MS. Vertigo is a reported symptom in 30%–50%
Impairment of Visual Pathways of patients with MS and is commonly associated with dysfunction of
ON, inflammation at any point of the optic nerve, is common at some adjacent brainstem or cranial nerves.
point in the course of patients with relapsing MS, and frequently it
may be the presenting symptom. The optic nerve is the most com- Impairment of Cerebellar Pathways
monly affected site of the visual pathway. It usually manifests as an Cerebellar pathway impairment, due to a lesion or lesions in the poste-
acute or subacute unilateral syndrome characterized by pain in the eye rior fossa, results in gait imbalance, difficulty performing coordinated
that is accentuated by ocular movements, followed by a variable degree actions with the arms, and slurred speech. Examination reveals the
of visual loss affecting mainly central vision and sometimes decreased usual features of cerebellar dysfunction. Ocular findings of nystagmus,
color vision as well. Patients with ON often have a relative afferent ocular dysmetria, and frequent refixation saccades suggesting cerebel-
pupillary defect (Marcus Gunn pupil) and most have a normal fundo- lar or cerebellovestibular connection dysfunction are common. Speech
scopic exam; papillitis is rarely seen. Mapping of visual fields reveals a can be either scanning or explosive in character. Dysmetria, decompo-
central or cecocentral scotoma (central scotoma involving the physio- sition of complex movements, and hypotonia are most often observed
logical blind spot). After an attack of acute ON, 90% of patients regain in the upper extremities. An intention tremor in the limbs and tituba-
normal vision, typically over a period of 2–6 months. tion of the head may be seen. Walking is impaired by ataxia. In severe
It is important to note that bilateral, simultaneous ON is rare in MS, cases, even with full strength, there is inability to use the arms because
and its occurrence may suggest another diagnosis such as Leber hereditary of a violent intention tremor and inability to stand. Such profound
1228 PART III Neurological Diseases and Their Treatment
impairment of cerebellar function is rarely the permanent residua of interrupts bladder emptying will lead to frequent, small-volume urina-
acute relapse, and instead is typically a manifestation of progressive MS. tions combined with a large postvoid residual. Urinary tract infections
are common in MS, especially in women, and may present in atypical
Impairment of Sensory Pathways patterns without hallmark pain due to concomitant interruption of
Spinal cord white-matter lesions are common in MS, and as such, sen- ascending nociceptive signal in the spinal cord.
sory manifestations are a frequent initial feature of MS and are pres- Constipation is very common and is generally due to a combina-
ent in almost every patient at some time during the course of disease. tion of factors: spinal cord involvement, decreased general mobility,
The sensory features can reflect spinothalamic, posterior column, or dietary issues, and the tendency of some patients to restrict their fluid
dorsal root entry zone lesions. The sensory symptoms are commonly intake in a misguided attempt to decrease urinary urgency and incon-
described as numbness, tingling, pins and needles, tightness, coldness, tinence. Almost all patients with paraplegia require special measures
itching, or a feeling of swelling of limbs or trunk. Radicular sensations, to maintain regular bowel movements. Bowel urgency can also be a
unilateral or bilateral, can be present, and a bandlike abdominal sen- troubling symptom for patients.
sation may be described, euphemistically described as “the MS hug.” Sexual dysfunction, although frequently overlooked, occurs in
The most frequent sensory abnormalities on clinical examination 40%–80% of patients with MS (Schairer et al., 2014). Men experience
are varying degrees of impairment of vibration and joint position various degrees of erectile dysfunction, often trouble maintaining erec-
sense, decrease of pain and light touch in a distal distribution in the tion, whereas inability to ejaculate is less common. Sexual dysfunction
four extremities, and patchy areas of reduced pain and light touch per- in women manifests as inability to orgasm and decreased libido. Sexual
ception in the limbs and trunk. A bilateral sensory level, frequently dysfunction can be the result of multiple problems, including the
ascending in character, is a more frequent finding than a hemisensory direct effects of lesions on the motor, sensory, and autonomic path-
spinal cord (Brown-Séquard) syndrome. ways within the spinal cord as well as psychological factors that affect
The deafferented “useless” hand is a characteristic but uncommon libido: depression, self-image, self-esteem, and fear of rejection by the
feature, consisting of an impairment of function secondary to a pro- sexual partner. Mechanical difficulties created by spasticity, parapare-
nounced alteration of proprioception, without loss of power. A lesion sis, and incontinence may further aggravate the problem.
of the relevant root entry zones or posterior columns in the spinal cord
may be responsible in such cases.
PATHOPHYSIOLOGY
Impairment of Motor Pathways The symptoms and signs of MS are the result of the pathological pro-
Corticospinal tract dysfunction is common in MS, and can occur cess that occurs in the CNS. In early relapsing disease, new lesion for-
in the setting of acute relapse or progressive disease. Weakness as a mation is responsible for acute symptom development. In the natural
result of a relapse, typically due to a partial myelitis affecting motor history of the disease state, a progressive phenotype develops in most;
pathways, can involve one or all limbs, although a devastating relapse axonal loss then results in the gradual accumulation of neurological
resulting in permanent inability to walk is exceedingly rare. More deficit.
commonly, sustained motor weakness can be either partial, as the
residual of a relapse, or worsen gradually as a result of progressive Changes in Axonal Conduction with Demyelination
disease. Paraparesis, or paraplegia with a lower extremity preponder- A comparison of the physiological properties of normally myelinated
ance, occurs more frequently than significant weakness in the upper axons and demyelinated axons provides insight into the disease pro-
extremities (Giovannoni et al., 2017). A hemiparesis sparing the face is cess. Compacted myelin is the lipid-rich plasma membrane of oligo-
also common. Most patients with weakness develop spasticity to some dendrocytes that provides insulation for electrical impulses traveling
degree. This can manifest as a feeling of muscle tightness, cramping, along axons. Myelinated axons propagate nerve impulses rapidly in
and stiffness with walking. In advanced cases of paralysis and severe a saltatory fashion, with a high safety factor for transmission (five to
spasticity, joint contractures may occur. The physical findings include seven times above threshold). Current is induced by the opening of
an increased spastic tone, usually more marked in the legs than in the voltage-gated Na+ channels found at the nodes of Ranvier. The resul-
arms. The deep tendon reflexes of the affected limbs are exaggerated, tant Na+ influx creates a current that then moves toward the next node
sustained clonus may be elicited, and extensor plantar responses are of Ranvier, as current cannot flow outward in myelinated internodal
observed. Occasionally, reduced reflexes reflect hypotonia due to cer- segments (Fig. 80.1). K+ channel opening terminates current flow and
ebellar pathway lesions. Amyotrophy, when observed, most frequently leads to repolarization. Several types of K+ channels exist in the axon.
affects the small muscles of the hand; lesions of the motor root exit Fast K+ channels sensitive to 4-aminopyridine are located in internodal
zones may produce muscle denervation secondary to axon loss. axonal membrane and contribute to repolarization of demyelinated
axons. Slow K+ channels are found at the nodes of Ranvier and have
Impairment of Bladder, Bowel, and Sexual Functions a role in modulating repetitive firing. The Na+/K+-adenosine triphos-
The extent of sphincter and sexual dysfunction is typically the con- phatase (ATPase) in the axon membrane restores ionic balance after
sequence of MS-related myelopathy, and often parallels the degree of high-frequency firing.
motor impairment in the lower extremities. The most common com- Demyelination interrupts current flow by removing the insulator of
plaint related to urinary bladder dysfunction is initially urgency, usually internodal axon current flow. After a relapse, remyelination occurs with
the result of uninhibited detrusor contraction, reflecting a supraseg- recovery of clinical function to some degree in most cases. Transient
mental lesion. As the disease progresses, urinary incontinence due to worsening of function reflects a drop below the safety threshold for
urgency becomes more frequent. With involvement of sacral segments conduction because of physiological changes involving the partially
of the spinal cord, symptoms of bladder hypoactivity may evolve (e.g., demyelinated axon. This explains the characteristic Uhthoff phenom-
decreased urinary flow, interrupted micturition, incomplete bladder enon, a temporary worsening of previous symptoms with increased
emptying). An atonic dilated bladder that empties by overflow results body temperature. To contrast, persistent neurological deficit happens
from loss of perception of bladder fullness and is usually associated in areas that have been less completely myelinated. In those regions,
with urethral as well as anal and genital hypoesthesia, and sensory defi- severe conduction block remains or severe axonal destruction has
cits in the sacral dermatomes. A dyssynergic voluntary sphincter that taken place.
Formation of the Multiple Sclerosis Lesion consists of a discrete region of demyelination with relative preserva-
Although debated, it is generally thought that activation of myelin-spe- tion of axons, although spectroscopic and pathological studies sug-
cific T cells in the periphery precede the formation of an MS lesion, gest some axonal loss may be an integral part of the disease process.
as opposed to a CNS location as the origin of attack. The trigger for Examination of the brain in MS often reveals atrophy and ventricu-
each relapse is generally unknown, though some relapses may occur lar dilatation. Plaques may be visible on the surface of the spinal cord
after immune system activation secondary to a viral infection, or in on inspection. The cut surface of the brain reveals the plaques, which
the postpartum setting. One of the earliest features of acute MS lesion when active, appear whitish yellow or pink with somewhat indistinct
formation is the interruption of the blood-brain barrier (BBB). The borders. Older plaques appear translucent with a blue-gray discolor-
BBB normally functions to regulate protein transport and ion concen- ation and sharply demarcated margins. Individual lesions are generally
tration, and to block pathogens and immune cells from CNS entry. small (1–2 cm) but may become confluent, generating large plaques.
It is composed of a thick membrane of glycocalyx, non-fenestrated Plaques develop in a perivenular distribution and are seen most fre-
endothelial cells, a vascular basement membrane, the glia limitans, quently in the periventricular white-matter, brainstem, and spinal cord
and astrocytic end-feet. The endothelial cells of the BBB are connected (Figs. 80.2 and 80.3), a finding confirmed with magnetic resonance
through tight junctions (Varatharaj and Galea, 2017). imaging (MRI) studies. However, large numbers of small plaques,
During a relapse, activated CD4 T cells are likely the first to enter often detected only by microscopy, are found in cortical regions affect-
the CNS, bringing a plethora of immune cells behind. Grossly, the ing intracortical myelinated fibers. Histological examination of active
pathological hallmark of MS is the cerebral or spinal plaque, which plaques has revealed abnormal infiltration of lymphocytes, monocytes,
and macrophages, with occasional plasma cells around a central vein.
The process then propagates radially (Gaitán et al., 2011) and myelin
Fig. 80.1 Schematic diagram of impulse conduction in normal (upper)

and demyelinated (lower) regions of a nerve fiber. Solid arrow indicates
the direction of impulse conduction; red area indicates the region occu-
pied by the impulse. Current flow is indicated by broken arrows. In nor-
mally myelinated regions (upper), the high resistance, low capacitance
directs the majority of action current to the next node of Ranvier. In con-
trast, in demyelinated regions (lower), action current is short-circuited
through the damaged myelin sheath or denuded regions of the axon, so
further propagation of the action potential is blocked. (Reprinted with Fig. 80.2 Coronal section of brain showing large plaques adjacent to lateral
permission from Waxman, S.G., 1982. Membranes, myelin, and the ventricles and temporal horns. A plaque is also seen in the left internal
pathophysiology of multiple sclerosis. N Engl J Med 306, 1529–1533.) capsule (arrows) (Heidenhain myelin stain). (Courtesy Dr. S. Carpenter.)
A B C
Fig. 80.3 Brainstem and spinal cord sections from patient with multiple sclerosis stained with Heidenhain
myelin stain (A), Holzer stain for gliosis (B), and Bodian stain for axons (C). Note mirror image of myelin and
Holzer stains in the pons. Also note dramatic demyelination of sacral cord with preserved myelin in nerve
roots (A, bottom). (Courtesy Dr. S. Carpenter.)
is disrupted, resulting in myelin debris found in clumps and within Chronic inactive plaques are hypocellular and show astrocytic
lipid-laden “foamy” macrophages. Reactive astrocytes are prominent roliferation with denuded axons and an absence of oligodendroglia
p
in plaques. Immunohistochemical studies have found increased levels (Figs. 80.4 and 80.5). Axonal loss also may be noted to a variable extent.
of cytokines in active plaques, indicative of ongoing immunoreactivity. Microglia and macrophages are scattered throughout the lesion. The
Oligodendroglia numbers are reduced proportionate to myelin loss edge of chronic plaques may still exhibit hypercellularity, suggesting
in the plaque center, whereas at the plaque edge, oligodendroglia are continued disease activity.
preserved or even increased, suggesting an attempt at remyelination. In progressive MS, ongoing low-grade demyelination is found
Remyelination may involve either oligodendrocytes that previously at the borders of plaques, and this may explain the slow expansion
produced myelin or maturation of progenitor cells. Such remyelin- of plaques and occurrence of more diffuse inflammation leading to
ation may explain the clinical finding of slow and delayed recovery progressive loss of function (Kutzelnigg et al., 2005; Prineas et al.,
from an acute attack, whereas rapid clinical recovery presumably 2001).
reflects the resolution of edema, inflammation, and removal of toxic Recent pathological studies have focused on the gray matter in MS
factors associated with acute plaques in which myelin destruction is and have found a lesion load within the cortex and deep gray struc-
minimal. Pathological studies demonstrate that the extent of remyelin- tures. The nature of the intracortical plaques differs from those seen
ation can be quite extensive, even in patients with progressive disease in white matter because there is less inflammation but considerable
(Patrikios et al., 2006). reactive microgliosis (Bo et al., 2003).
Data derived from biopsy as well as autopsy material (Lucchinetti
et al., 2000) have emphasized the heterogeneity of the MS lesion. These
investigators have described four distinct pathological patterns. Some
lesions appear to be chiefly inflammatory (types I and II), with reten-
tion of active oligodendrocytes derived from identifiable precursor
cells and evidence of remyelination. The most common pathological
pattern seen (type II) had inflammatory infiltrates and deposition of
complement and immunoglobulin (Ig)G. In other patients, extensive
destruction of oligodendrocytes, little replacement, and closer resem-
blance to a viral or toxic cell apoptosis or necrosis was found (types
III and IV). All active lesions from an individual patient were of the
same type. A follow-up to this study reported that patients with repeat
biopsies continued to exhibit the same pathological subtype over time
(Metz et al., 2014). The specific target of the immune-mediated injury
in MS remains undetermined.
Lymphocytes in the lesion are specifically sensitized to myelin
Fig. 80.4 Punched-out appearance of an old multiple sclerosis plaque sur-
antigens. Reports vary with regard to the extent of restriction and the rounded by regions with varying amounts of myelin preservation (periodic
precise profile of the T-cell receptor repertoire of CNS T cells. T-cell acid-Schiff luxol fast blue; bar = 100 μm). (Courtesy Dr. S. C
arpenter.)
sensitization could occur via direct exposure to myelin antigens within
the CNS or within cervical lymph nodes, a site to which CNS antigens
are transported through draining, or via exposure to exogenous agents
sharing antigenic determinants with myelin, termed molecular mim-
icry. Microglial cells, endothelial cells, and astrocytes can be induced to
express major histocompatibility complex (MHC) antigens and func-
tion as antigen-presenting cells, thus potentially promoting myelin
antigen interaction with immune-mediating cells.
Activated T cells and the microglia-macrophages can contrib-
ute to tissue injury via non-antigen-restricted mechanisms. Each
of these cell types releases an array of soluble factors that can con-
tribute to tissue injury, including oligodendroglia. Cytokines char-
acteristic of T cells include interleukin 2 (IL-2), interferon gamma
(IFN-γ), and tumor necrosis factor β (TNF-β; lymphotoxin). A
shift toward TH1 cells expressing IFN-γ, TNF, and IL-2 and away
from TH2 cells is characteristic. Many of these immunologically
active substances can result in upregulation of adhesion molecules
that can promote or facilitate nonspecific lymphocyte-macrophage
migration to the site of immune injury and immune effector–target
cell interactions.
B cells and immunoglobulins are also found in MS lesions. To
date, no specific antibody has been identified in MS, but anti-myelin
antibodies have been shown to enhance disease severity in the exper-
imental allergic encephalomyelitis (EAE) model, suggesting that both
cellular and humoral mechanisms may be needed for full expression
of immune injury. Furthermore, the marked effect of B-cell deplet- Fig. 80.5 Plaque edge of an old plaque with a sharply demarcated zone
ing therapies such as rituximab and ocrelizumab allude to their critical of demyelination and normal myelin above (periodic acid-Schiff luxol
role in the pathogenic process. fast blue; bar = 50 μm). (Courtesy Dr. S. Carpenter.)
ETIOLOGY In recent years, multiple genome-wide association studies (GWAS)

have been performed, allowing for the analysis of a larger number
Autoimmunity of genetic variants that individually have a small, but still signifi-
Low levels of autoreactive T cells and B cells are present in normal cant, impact on MS risk. Greater than 230 genetic variants have been
individuals. Presumably they have escaped from clonal deletion during identified through these studies, yet combined they account for only
the process of immune development and are now tolerant of their 20% of the heritability risk. Recently, an important study analyzed
antigens. Autoimmunity develops when these cells lose tolerance and 32,367 MS cases and 36,012 controls and found 4 novel gene variants
a complex process of immune reactivity in target tissues begins. One that independently contribute an additional 5% risk (International
potential way tolerance can be broken is by means of molecular mim- Multiple Sclerosis Genetics Consortium: chris.cotsapas@yale.edu
icry between self-antigens and foreign antigens—for example, viral & International Multiple Sclerosis Genetics Consortium, 2018).
components. Several viral and bacterial peptides share structural simi- Although there have been clear advancements in this area of study,
larities with important proteins of myelin, and a few of them are able to current knowledge of MS genetics has not enabled the creation of reli-
activate specific T-cell clones derived from patients with MS. Another able diagnostic or prognostic tools for use in the clinic.
way tolerance can be broken is by CNS infection that causes tissue
damage and antigen release into the peripheral circulation, where cor- Infection
responding autoreactive T cells may be encountered. A possible role for microbial infection in the causation of MS has been
Myelin basic protein (MBP) has long been considered one of the a matter of ongoing debate for decades. However, beyond speculation,
primary candidates for an autoimmune attack. T cells that respond to little direct evidence supports the concept. Specific efforts to recover a
MBP are found in the peripheral blood in both normal persons and known viral genome have been fruitless. Despite this, in recent decades
those with MS, possibly at higher levels in MS patients with active dis- pathogens such as human herpesvirus 6 (HHV6), Epstein-Barr virus
ease. MBP, which accounts for 30% of the protein of myelin, can be an (EBV), and Chlamydia pneumoniae have been the focus of interest as
antigen for EAE, the primary animal model of MS. potential triggers for MS.
Several other myelin proteins are also candidates for an autoim- Perhaps the most compelling argument has been made for a possible
mune attack. Proteolipid protein accounts for 50% of CNS myelin role for EBV in MS pathogenesis. Although EBV is extremely common
protein and is an integral membrane protein of the myelin leaflets. in the population, with a prevalence between 90% and 95%, multiple
Myelin-associated glycoprotein, myelin oligodendrocyte glycoprotein, studies have shown seroprevalence to be greater than 99%, though
and cyclic nucleotide phosphodiesterase are proteins that each account importantly not 100%, in MS patients. Furthermore, history of infec-
for a few percent of myelin. Myelin oligodendrocyte glycoprotein and tious mononucleosis, as opposed to the more common asymptomatic
cyclic nucleotide phosphodiesterase are not found in peripheral nerve EBV infection, seems to further predispose to risk for MS (Handel et al.,
myelin and are therefore of special interest. 2010). Potential mechanisms invoking EBV in the development of MS
Although the possibility of pure autoimmunity as the causal mech- include an inappropriate autoreactive immune response as the result of
anism for MS exists, the issue is not proven. The evidence for MS being molecular mimicry or a more direct role of the EBV virus promoting
a dysimmune condition is more compelling; with alterations in the persistent inflammation in the CNS (Pakpoor et al., 2013).
immune cell repertoire and activation state both in blood and cerebro-
spinal fluid (CSF) of MS patients compared to others (Conlon et al., Vitamin D
1999; Hafler et al., 2005). Although there is no definitive evidence for vitamin D deficiency as a
causative factor in the pathogenesis of MS, low levels of vitamin D have
Genetics now been associated with an increased risk for MS in many different
MS is a genetically complex disease. Compared to the general popula- studies. Early epidemiological studies in MS noted an increasing prev-
tion, a higher frequency of familial occurrence of MS suggests a strong alence of MS in populations at increasing distances from the equator.
but non-Mendelian inheritance of susceptibility. Twin studies estab- This led to the hypothesis that decreasing levels of vitamin D, related to
lished the importance of genetic factors: the concordance rate for a lower levels of sun exposure, could explain this phenomenon. Cohort
clinical diagnosis of MS in female monozygotic twins is about 30%, studies supported this theory, as vitamin D supplementation was
whereas in dizygotic twins it is 2%–5% (Ebers et al., 1995; Willer et al., inversely related to the risk for MS in two groups of nurses (Munger
2003). The risk is highest for siblings: 3%–5%, or 30–50 times the et al., 2004), and similarly, the highest serum levels of 25-hydroxy vita-
background risk for this same population. Adoptive relatives, when min D correlated to the lowest risk for MS and vice versa in a group of
raised from infancy with the patients with MS, are no more likely to 7 million US military recruits (Munger et al., 2006). Multiple studies
develop MS than the general population. since have also shown this association. Furthermore, the correlation
MS is associated with both MHC and human leukocyte anti- between low serum vitamin D levels and an increased risk for con-
gen (HLA) class I A3 and B7 antigens. The class II polymorphisms, tinued MS disease activity has been made both radiologically (Mowry
Dw2 and DR2, also show strong association, and specifically the HLA et al., 2012) and with data from a clinical trial cohort (Ascherio et al.,
DRB1*1501 allele (Oksenberg et al., 2004). Additional HLA alleles that 2014). The SOLAR trial is the largest completed trial to date of vitamin
carry protective as well as detrimental effects with regard to MS suscep- D supplementation in MS. This 48-week, double-blind placebo-con-
tibility have been identified. HLA-A*02, for example, has a protective trolled trial of high-dose (14,000 IU daily) vitamin D3 as an add-on to
effect relative to MS susceptibility. Additional MS susceptibility loci 44-μg scIFN β-1a did not find a difference in disease activity free status
outside of the MHC have been described. Specifically, the loci cod- or in relapse rate between the groups (Smolders, 2016). Thus, despite
ing for IL-7 receptor and IL-2 receptor are strongly linked with MS many indications of the role of vitamin D in MS, it remains to be seen
susceptibility (Zuvich et al., 2010). IL-7 and IL-2 receptor signaling if supplementing an MS patient can alter the disease course.
is critical for the differentiation of CD4− CD8− thymocytes and has a
role in survival of CD4+ CD8+ cells after positive selection. This may Smoking
be important not only in MS predisposition but also in disease course The association between smoking and an increased risk for MS has
and outcome. been established with evidence from multiple case control studies.
Smoking increases the risk of developing MS and the risk of conver- this is due to ascertainment bias (milder cases in females discovered
sion from CIS to clinically definite MS (CDMS; van der Vuurst de through increased use of MRI and more sensitive diagnostic criteria),
Vries et al., 2018). There is also evidence, albeit weaker, that smokers most agree that changes in childbearing patterns and epigenetic and
have a more severe course than nonsmokers (Manouchehrinia et al., environmental factors also likely contribute to this trend (Miller et al.,
2013). Smoking is thought to be a direct neurotoxin, but also may 2014). The female: male ratio in relapsing-remitting MS in most coun-
bring about immunomodulatory changes that promote inflammation tries is 2–3:1, although interestingly it has remained steady at 1:1 in
(Goodin, 2014). PPMS (Kalancik et al., 2013).
Diet and the Microbiome Geographical Distribution

Although several studies have linked MS and childhood obesity Hundreds of prevalence surveys have been carried out, serving as
(Hedstrom et al., 2014; Munger et al., 2013), there are no specific the basis for the delineation of geographical risk for MS depicted in
dietary factors that are known to provoke or ameliorate the MS course. Fig. 80.7. Worldwide, it is estimated that in 2016 2.2 million people
However, there is a plethora of ongoing research in this area. Likewise, had MS, which is 10.4% more cases than in 1990 (GBD 2016 Multiple
the human microbiome is also a topic of interest in relation to the Sclerosis Collaborators et al., 2019). High-frequency areas of the
risk of getting MS, as well as to its impact on the MS course. Thus world include all of Europe (including Russia), southern Canada, the
far, researchers have been able to show that both adult and pediat- northern United States, New Zealand, and the southeastern portion
ric patients with MS do have a different microbiome signature than of Australia. In many of these areas, the prevalence is far greater than
people without (Chen et al., 2016, Tremlett et al., 2016). Furthermore, 100 cases per 100,000. The largest increase in MS prevalence has been
treatment with MS disease-modifying therapies (DMTs) also has been in Canada where there has been an 82% upsurge in the last 25 years.
shown to impact the composition of the microbiome (Katz Sand et al., The number of cases of MS in the United States was estimated by
2019). However, further work needs to be done to understand the the National MS Society in 2002 to be approximately 400,000 per-
complexities of the relationship between the microbiome and MS. sons, yet more recent 2017 estimates are greater than 900,000 (Wallin
et al., 2019). The rise in numbers is likely due to a combination of
EPIDEMIOLOGY factors, including more sensitive criteria for diagnosis and increased
survival.
Age of Onset One possible conclusion, as mentioned above, regarding geograph-
Most studies agree that the mean and median age of onset in relapsing ical differences in prevalence is that MS is a location-related illness with
forms of MS is age 29–32. The peak age of onset is approximately 5 a latitude gradient. However, this risk is clearly modulated genetics, as
years earlier for women than for men. Primary progressive multiple notable exceptions exist. Japan, situated at the same latitude as areas
sclerosis (PPMS) has a mean age of onset of 35–39 years. It is well rec- of high prevalence in Europe, is a low-risk area. Second-generation
ognized that the onset of MS can occur well outside of these ranges; 5% Japanese in the United States retain their parents’ low risk of MS. The
of cases of MS have their onset before age 18. Most of these cases occur White population of South Africa, with medium prevalence of MS, is
in adolescence, but a small percentage have an onset in the first decade surrounded by a Black population in whom the disease is very uncom-
of life (Fig. 80.6). Patients may also present with first symptoms after mon. Native North Americans, especially of pure Amerindian back-
age 50, in 3%–12% of incident cases (Tremlett et al., 2006). ground, have a very low prevalence but are surrounded by a White
population with a medium or high risk for MS. People of Asian,
Sex Distribution African, or Native American origin have the lowest risk.
Similar to most other autoimmune conditions, MS affects more Migration data have often been used to support the view that an
women than men. During the 20th century the female: male ratio of environmental agent is involved in the pathogenesis of MS. The data
incident relapsing MS cases has increased in most geographic loca- indicate that persons migrating from an area of high risk to an area of
tions (Westerlind et al., 2014). Although some have hypothesized that low risk after the age of puberty carry their former high risk with them.
With migration during childhood, the risk seems to be that of the new
60 area to which the person has migrated.
Mortality
50
Most studies of MS and mortality have shown that MS shortens life
span, on average, by a period of 7–14 years (Lunde et al., 2017, Scalfari
Number of patients
40
et al., 2013). Death due to a catastrophic MS relapse is extraordinarily
uncommon. Although MS is listed as the primary cause of death on an
30 MS patient’s death certificate approximately 50% of the time (Leray
et al., 2015), more typically an infection or other complication of
20 progressive MS is the actual cause. Cardiovascular disease, accidents,
and suicide seem to be represented in a higher proportion in the MS
10 population.
The evidence suggests that the increased rate of death in patients
0 with MS does seem to be declining relative to that of the general pop-
10 20 30 40 50 60 ulation. In Denmark, an exceptionally complete survey of the country
Age of onset (years) found the median survival after diagnosis for men was 28 years and for
Fig. 80.6 Age at onset of symptoms of multiple sclerosis in 940 patients women 33 years, compared with matched population death rates of 37
followed at the Multiple Sclerosis Clinic of the Montreal Neurological and 42 years, respectively. The 10-year excess mortality was reduced
Institute. Mean age of onset is 30.6 years, median is 27 years, and peak by 50% in recent decades, even before the introduction of DMTs
incidence is 25 years. (Bronnum-Hansen et al., 2004). This trend seems to have continued
Fig. 80.7 Worldwide distribution of multiple sclerosis as of 2016. (From GBD 2016 Multiple Sclerosis Collab-
orators., 2019. Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis
for the Global Burden of Disease Study 2016. Lancet Neurol. 18(3), 269–285.)
in the post-DMT era. In another important study, a 21-year follow-up meet dissemination in space (DIS) and dissemination in time (DIT).
that included 98.4% of the patients enrolled in the pivotal IFN-β-1b These criteria maintained an acceptable level of diagnostic sensitivity
trial, the risk for death in patients initially randomized to IFN-β-1b and specificity despite less rigorous clinical requirements. Importantly,
250 μg was found to be decreased, with a hazard ratio (HR) of 0.53 incorporating subclinical activity on MRI into the criteria allowed for
versus those initially on placebo (Goodin et al., 2012), thus suggesting the diagnosis of MS to be made sooner, instead of waiting for addi-
that early initiation of DMT might further alter mortality outcomes. tional clinical episodes as diagnostic confirmation.
These findings were replicated in a case-control study where greater The McDonald criteria were most recently revised in 2017
than 3 years of IFN-β reduced the chance for death by 32% in a cohort (Thompson et al., 2018) (Table 80.1). This version aimed to refine
composed of Canadian and French patients (Kingwell, 2019). the earlier iterations, with only minor changes made. Like the previ-
ous 2010 criteria, at least one characteristic demyelinating episode is
DIAGNOSIS required in order to diagnosis relapsing-remitting multiple sclerosis
(RRMS). DIS is satisfied if MRI reveals ≥f1 lesion in two out of four
Diagnostic Criteria typical locations: periventricular, cortical/juxtacortical, infratento-
In a condition such as MS, where a diagnosis proven by biopsy is rare rial, and spinal cord. Here, the most important change is that cortical
and undesirable in almost all cases, formulating criteria that produce lesions were added as a typical lesion location interchangeable for a
an accurate diagnosis through other means is of crucial import. There juxtacortical lesion. For the DIT criteria, the requirement is met when
have been multiple sets of diagnostic criteria utilized over the years, in there is simultaneous presence of gadolinium-enhancing and nonen-
an effort to assist the clinician in making the correct diagnosis as well hancing lesions at any time, or a new T2 or T1 gadolinium-enhancing
as to allow the researcher to identify those appropriate for studies. The lesion on a follow-up MRI scan. To contrast, the 2010 criteria man-
common thread among all MS diagnostic criteria has been the require- dated that symptomatic lesions in the brainstem and spinal cord could
ment for symptoms and signs that are disseminated in time and space not be used to support DIS or DIT.
(more than one episode involving more than one area of the CNS). One key addition to the 2017 criteria is the use of lumbar punc-
Before 2001, the accepted criteria allowed for the diagnosis of ture to confirm a diagnosis. For patients with only one clinical event
MS based on clinical features alone—namely, history and physical that meets DIS criteria, positive oligoclonal bands (OCBs) in the CSF
examination—with support for the diagnosis gained by the use of now can substitute for DIT. This decision was made based on multiple
CSF analysis, evoked potentials, and neuroimaging. In the Poser cri- studies that show that positive bands are an independent risk factor
teria, used from 1983 to 2001, a patient must have had two clinical for further clinical activity (Thompson et al., 2018). Additionally, the
attacks with evidence to support this on examination in order to be panel maintained that the clinician should ascertain disease phenotype
diagnosed with CDMS. at diagnosis, and should periodically reassess.
The McDonald Criteria Diagnostic Studies

In 2001, McDonald and colleagues initiated the modern era of MS Magnetic Resonance Imaging
diagnosis by proposing diagnostic criteria that permitted activity on MRI is the preferred imaging modality for both making the diagnosis of
follow-up MRIs to substitute for a second clinical attack in order to MS and longitudinal follow-up of patients. MRI is based on relaxation
properties of water in tissues and is sensitive to T2 (transverse) and T1 are also frequently present. Posterior fossa lesions are commonly pres-
(longitudinal) relaxation rates of protons. Gadolinium (Gd) diethylen- ent in the cerebellum, middle cerebral peduncles, and in areas adjacent
etriamine penta-acetic acid (DTPA) is a paramagnetic contrast agent. to the fourth ventricle (Fig. 80.8).
It crosses the disrupted BBB, indicating increased vascular permeabil- MRI is a helpful tool to distinguish between acute, subacute, and
ity in association with inflammation. Gd enhancement is best seen on chronic MS lesions. Acute lesions of less than 12 weeks duration often
spin-echo T1-weighted imaging. These fundamental properties of MR show Gd contrast enhancement on T1-weighted sequences, indicat-
image acquisition provide a sensitive measure of pathology; areas of ing inflammation and BBB disruption. Enhancement patterns can
brain inflammation, demyelination, and loss of axons can be especially appear as incomplete or, less commonly, complete rings, or as patchy
well seen with this technique. Virtually all patients with MS have T2 or homogeneously enhancing lesions (Fig. 80.9). Ring-enhancing
and fluid-attenuated inversion recovery (FLAIR) abnormalities. New lesions are associated with significant tissue destruction (Minneboo
lesions occur 9–10 times more often than new clinical attacks in RRMS. et al., 2005). They may also be associated with a bright signal on dif-
Characteristic cerebral lesions, or plaques, are focal and discrete, fusion-weighted imaging (DWI). Contrast-enhancing lesions are most
have an ovoid appearance, and are oriented perpendicularly to the plane often associated with a bright T2 or FLAIR signal, denoting an acute
of the lateral ventricles. These are classically referred to as Dawson’s MS lesion. Acute MS lesions tend to be larger in size, with less well-de-
fingers and are thought to represent perivenular inflammation, seen fined margins. Infrequently, acute T2 bright lesions can disappear
pathologically in MS plaques. Additionally, lesions are characteristi- on subsequent scans, indicating reversible tissue inflammation and
cally located in the deep white matter and the centrum semiovale, as edema. At times, acute MS lesions may show an associated dark sig-
well as in cortical and deep gray-matter structures. Juxtacortical lesions nal on T1 noncontrast scan (acute T1 lesion), consistent with edema
affecting U-fibers are often seen in MS. Posterior optic radiation lesions and demyelination. Subacute MS plaques may no longer show contrast
TABLE 80.1 McDonald Criteria for the Diagnosis of Multiple Sclerosis (MS)
2017 revised McDonald MS diagnostic criteria*
Diagnosis of MS requires elimination of more likely diagnoses and demonstration of dissemination of lesions in space (DIS) and time (DIT)
Clinical (Attacks) Lesions Additional Criteria to Make DX

2 or more Objective clinical evidence of ≥2 lesions or objective clinical None. Clinical evidence alone will suffice; additional
evidence of 1 lesion with reasonable historical evidence evidence desirable but must be consistent with MS
of a prior attack
2 or more Objective clinical evidence of 1 lesion DIS; OR await further clinical attack implicating a different
CNS site
1 Objective clinical evidence of ≥2 lesions DIT; OR await a second clinical attack OR demonstration of
CSF-specific oligoclonal bands
1 Objective clinical evidence of 1 lesion DIS; OR await further clinical attack implicating a different
CNS site AND DIT; OR demonstrations of CSF-specific
oligoclonal bands OR await a second clinical attack
0 (progression from onset) One year of disease progression (retrospective or pro-
spective) AND at least two of: DIS in the brain based on
≥1 T2 lesion in periventricular, cortical/juxtacortical or
infratentorial regions; DIS in the spinal cord based on ≥2
T2 lesions; positive CSF
*Thompson, A, Banwell, B, Barkoff, F., 2018. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald Criteria. Lancet Neurol. 17(2), 162–173.
A B C
Fig. 80.8 Typical Magnetic Resonance Imaging Appearance of Multiple Sclerosis Lesions in Brain. A,
Axial view with presence of both periventricular (PV) and juxtacortical lesions. B, Sagittal view with classic
Dawson’s finger appearance of PV lesions. Also present are juxtacortical and posterior fossa lesions. C, Axial
view of posterior fossa lesions. T2 images are often best for viewing infratentorial lesions.
enhancement but may continue to show bright DWI abnormality. Brain Atrophy
Chronic MS plaques appear hyperintense on T2 or FLAIR sequences, Progressive MS-related cerebral atrophy has been documented with
are usually smaller, and have sharper margins. Persistent and profound various MRI techniques for over a decade. The rate of atrophy is esti-
T1 hypointensity (also known as a “black hole”) usually reflects irre- mated to be between 0.6% and 1.35% per year (Bermel and Bakshi,
versible tissue damage such as axonal loss and permanent demyelin- 2006). Semi-automated (atlas-based) and fully automated (voxel-
ation (Neema et al., 2007; Fig. 80.10). based) segmentation tools are used in imaging research and clinical
trials to assess loss of cerebral volume in MS. The brain parenchymal
High-Field Strength Magnetic Resonance Imaging fraction (BPF), defined as the ratio of brain parenchymal volume to
High (3 T) and ultra-high (7 T) MRI scanners greatly improve sensitiv- the total volume within the brain surface contour, is used to mea-
ity for detecting T2 and Gd-enhancing lesions. Cerebral lesion volume sure whole brain atrophy (Rudick et al., 1999). In clinical practice,
also increases with higher field strength (Bachmann et al., 2006; Sicotte cerebral volume loss is immediately apparent through progressive
et al., 2003), and cortical lesions are easier to detect. Moreover, more enlargement of CSF spaces including lateral ventricles and subarach-
patients fulfill the diagnostic criteria for MS when studied with 3 T or noid spaces (gyri and sulci) seen on conventional MRI. Gray matter
higher MRI because of improved lesion detection in both supra- and is affected by atrophy more profoundly than white matter, and deep
infratentorial compartments (Bakshi et al., 2008; Sicotte et al., 2003). gray-matter nuclei are even more susceptible. Higher rates of atrophy
A B
Fig. 80.9 Common Enhancement Patterns in the Brain. A, Homogeneous uptake of contrast. B, Open-ring
pattern, specific for demyelinating lesions.
Fig. 80.10 Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging with corresponding T1
image showing evidence of black holes, areas believed to represent permanent tissue destruction and atrophy.
have been correlated with progressive disease and have become a tar- Cerebrospinal Fluid Analysis
get in clinical trials, functioning as a surrogate marker for progression CSF findings alone neither make nor exclude the diagnosis of MS.
itself (University of California, San Francisco MS-EPIC Team et al., However, CSF analysis remains important in atypical clinical syn-
2019). While cerebral tissue loss in MS is an important factor, the dromes, atypical or nondiagnostic MRI findings, or unusual clinical
ability to reliably measure it in a clinical setting remains suboptimal. manifestations such as a course of progressive neurological impairment
Confounding factors include effects of aging, osmotic agents, and without history of relapses. CSF does not show any gross abnormalities
even anti-inflammatory treatments—all of which can decrease cere- in MS; it is clear, colorless, and has a normal opening pressure. Cell
bral water content and result in a skewed finding of atrophy progres- counts are typically normal but may be slightly elevated in 15%–20%
sion (Fig. 80.11). of patients. The predominant cells are T lymphocytes. Significant pleo-
Spinal cord imaging. Over 90% of MS patients have spinal cytosis with greater than 50 white blood cells should raise suspicion
cord lesions at some point in their disease course, and 30% of of another etiology. Determining the presence of OCBs is the most
patients presenting with CIS other than transverse myelitis have important diagnostic test. These bands represent excess antibody pro-
(asymptomatic) disease in the spinal cord (Dalton et al., 2003). They duced by one or more clones of plasma cells. The pattern of banding
typically involve fewer than two contiguous segments of the spinal remains relatively stable in an individual patient throughout the course
cord and are asymmetric (Fig. 80.12). Spinal cord lesions can be in of the disease. However, 10%–20% of patients with confirmed CDMS
the form of discrete isolated plaques or manifest as more confluent do not have OCBs at any given point in time. Presence of OCBs in a
affected areas, especially in SPMS or PPMS patients. It is less common patient with CIS independently confers a higher rate of conversion to
to have T1 hypointensities in the spinal cord. Lesions in the spinal cord CDMS (Ferraro et al., 2013), and thus substitutes for DIT in the 2017
produce neurological symptoms with a greater frequency than those in McDonald criteria. MBP in the CSF is a marker of tissue damage and
the brain, and cord atrophy has a strong correlation with neurological has been used as a measure of CNS myelin breakdown. The levels of
disability (Lukas, 2013). the protein may be quite increased in MS patients, but the specificity
A B C
Preclinical Relapsing Secondary progressive
Relapses and impairment

MRI burden of disease
Brain volume
MRI activity
D
Fig. 80.11 Changes in magnetic resonance imaging (MRI ) scans with duration of disease. A–C, Comparison
of three scans from patients with different disease duration, indicating the appearance of atrophy and ven-
tricular dilation with time. D, As brain atrophy appears, it is common to observe that the number of gadolini-
um-enhancing lesions declines.
of these findings is not known and thus it is not recommended for use Evoked Potentials
in diagnosis. An abnormality in CSF IgG production (as measured by Evoked potentials (EPs) are CNS electrical events generated by periph-
the IgG index, or as a percentage of total protein or albumin) is found eral stimulation of a sensory organ and are useful to determine abnor-
in over 90% of patients with confirmed MS (Table 80.2). mal function that may be clinically unapparent. Detecting a subclinical
lesion at a site remote from the region of clinical dysfunction supports
Optic Coherence Tomography the multifocal disease portion of the diagnostic criteria for MS. The
Optic coherence tomography (OCT) can measure the retinal nerve three most commonly used EPs are visual evoked potentials (VEPs),
fiber layer (RNFL) using a process analogous to ultrasound imaging, somatosensory evoked potentials (SSEPs), and brainstem audito-
with light instead of sound. The RNFL is devoid of myelin and contains ry-evoked responses (BAER). In a review of the role of EPs in MS, only
axons that converge to form the optic nerve. OCT can be used to non- VEPs were thought to be useful to determine increased risk for MS
invasively quantify axonal damage following an ON event. There is a (Gronseth and Ashman, 2000). Using pattern shift VEPs, abnormal-
correlation between optic nerve atrophy and RNFL thinning, suggest- ities (P100 wave prolongation) are detected in over 90% of patients
ing that OCT may be useful in clinical trials aiming at neuroprotection. with a history of ON, even in a setting of complete restoration of vision
Despite the important information that OCT may provide, it is not (Table 80.3). Although VEPs may be abnormal in many MS patients,
used in the diagnosis of MS at this point in time. they have not been used in the McDonald criteria. Furthermore, the
use of MRI has supplanted their utility in most cases and thus VEPs are
not routinely included as a part of the diagnostic work-up.
Differential Diagnosis
In a person of typical age for onset of MS with two or more clinically
distinct episodes of CNS dysfunction with at least partial resolution,
there is little in the way of a differential diagnosis. In this case, doing
testing beyond MRI and basic laboratory tests rarely, if ever, leads to
an alternate diagnosis. However, the differential broadens with atypical
presentations, monophasic episodes, or progressive deficits (Box 80.2).
A monophasic illness with symptoms attributable to one site of the CNS
creates a large differential diagnosis that includes neoplasms, vascular
events, and infections. Appropriate imaging studies may help clarify the
situation, depending on the site of involvement and clinical progression.
Great care must be taken in those with progressive CNS dysfunction
to exclude treatable etiologies (e.g., vitamin B12 deficiency, compressive
spinal cord lesions, arteriovenous malformations, cavernous angiomas,
Arnold-Chiari malformation), infectious causes (syphilis, human T-cell
lymphotropic virus type 1 [HTLV-1], human immunodeficiency virus
[HIV]), and hereditary disorders (adult metachromatic leukodystrophy,
adrenomyeloneuropathy, spinocerebellar disorders, CADASIL).
A common diagnostic error is to misinterpret multiple hyperin-
tense lesions on MRI as equivalent to MS. A few white-matter lesions
on T2-weighted MRI scans are not infrequent, particularly in the
Fig. 80.12 Sagittal, T2-weighted image of spinal cord with multiple, elderly or migraineurs, but do not indicate a diagnosis of MS. CNS
characteristic cord lesions. vasculitides such as systemic lupus erythematosus (SLE), Sjögren disease,
TABLE 80.2 Cerebrospinal Fluid Abnormalities in Multiple Sclerosis

Oligoclonal
Albumin IgG/TP IgG/Albumin IgG Index Banding of Ig
Clinically definite 23% 67% 60%–73% 70%–90% 85%–95%
multiple sclerosis
Normal controls 3% — 36% 3% 7%*
IgG/TP, Immunoglobulin G value/total protein.
*Other neurological disease.
TABLE 80.3 Comparison of Sensitivity of Laboratory Testing in Multiple Sclerosis

VER BAER SSEP OCB MRI
Clinically definite 80%–85%* 50%–65% 65%–80% 85%–95% 90%–97%
multiple sclerosis
BAER, Brainstem auditory evoked response; MRI, magnetic resonance imaging; OCB, oligoclonal band; SSEP, somatosensory evoked potential;
VER, visual evoked response.
*Numbers show the percentage of patients with abnormal study results.
polyarteritis nodosa, syphilis, retroviral diseases, and Behçet disease may remains a significant issue. This problem has been highlighted by a
all produce multifocal lesions with or without a relapsing-remitting number of recent articles (Kaisey et al., 2019, Solomon et al., 2016) that
course. SLE can present as a recurrent neurological syndrome before the reported that a relatively high proportion of patients referred to MS
systemic manifestations of this disease declare themselves. Behçet disease centers with a diagnosis of MS were subsequently given alternate diag-
is characterized by buccogenital ulcerations in addition to the multifo- noses. The clinician must remain vigilant with every patient in order to
cal neurological findings. CNS sarcoidosis can be mistaken for MS with accurately diagnosis MS, or to exclude it as a possibility.
multifocal neurological and MRI lesions. An MS-like phenotype associ-
ated with mitochondrial gene defects has been described. CLINICAL COURSE AND PROGNOSIS
More important than features characteristic for MS are features that
should prompt the clinician to reconsider the diagnosis of MS—red Measures of Disability
flags indicating that another diagnosis is more likely (see Miller et al., MS clinical course is characterized by both relapsing and progressive con-
2008 for a complete discussion on this topic). Some features that tributions to the accumulation of disability. The most commonly used
should alert the clinician to the possibility of other diseases include index for characterizing MS disability, the Kurtzke Expanded Disability
(1) family history of neurological disease, (2) a well-demarcated spinal Status Scale (EDSS), uses numbers ranging from 0 for normal examina-
level in the absence of disease above the foramen magnum, (3) prom- tion and function to 10 for death caused by MS. This scale is nonlinear,
inent back pain that persists, (4) symptoms and signs that can be with great emphasis on ambulation capabilities with scores above 4. Most
attributed to one anatomical site, (5) patients who are older than age MS populations have bimodal distributions of EDSS scores, with peaks
60 or younger than age 15 at onset, and (6) progressive disease. at values of 1 and 6 (ambulation with unilateral assistance). In a cohort
of patients followed for 25 years (in the pretreatment era), the follow-
Multiple Sclerosis Misdiagnosis ing data emerged: 80% of the patients had reached the progressive phase
Despite significant gains made in accurate diagnosis of MS over the by 25 years, 15% had died, 65% had reached EDSS 6 (requiring aids
years through more sensitive and specific criteria, misdiagnosis of MS for walking), and 50% reached EDSS 6 within 16 years of onset. More
recent studies suggest a somewhat slower course of progression (Pittock
et al., 2004; Tremlett et al., 2006). The EDSS, although universally used
BOX 80.2 Differential Diagnosis in Multiple in clinical trials, has a number of limitations. Even with special training
Sclerosis and examiner blinding, interrater and intrarater variations in scoring are
Inflammatory Diseases common. EDSS scores of 4 and higher depend almost entirely on the
Granulomatous angiitis ability to walk; developing dementia, vision loss, and weakness of hands
Systemic lupus erythematosus may pass undetected by the scoring once one reaches these levels. An
Sjögren disease obvious implication of these facts is that other outcome measures should
Behçet disease be used as well, and that minor changes in EDSS score alone should not be
Polyarteritis nodosa overinterpreted. The Multiple Sclerosis Functional Composite (MSFC)
Paraneoplastic encephalomyelopathies is a clinical tool designed to avoid the problems encountered with the
Acute disseminated encephalomyelitis, postinfectious encephalomyelitis EDSS (Cutter et al., 1999). The MSFC consists of three parts: paced audi-
Neuromyelitis optica tory serial addition test (PASAT), nine-hole peg test (9HPT), and timed
MOG antibody-associated disease 25-foot walk (T25FW). These three measures take into account cogni-
tion, upper-extremity function, and lower-extremity function. A z-score
Infectious Diseases is obtained for each measure, and a combined z-score is then derived.
Neuroborreliosis The MSFC has been validated in several clinical trials. Additional mea-
Human T-cell lymphotropic virus type 1 infection* sures including patient reported outcomes and quality-of-life indices
Human immunodeficiency virus infection have been developed and validated in MS populations.
Progressive multifocal leukoencephalopathy*
Neurosyphilis* Clinical Phenotypes (RRMS, SPMS, PPMS)
Approximately 80%–90% of MS cases begin as a relapsing disease char-
Granulomatous Diseases acterized by acute neurological events referable to focal inflammatory
Sarcoidosis lesions. MS relapses are defined as the acute or subacute onset of clinical
Granulomatosis with polyangiitis (formerly, Wegener’s granulomatosis) dysfunction, usually reaching its peak in days to several weeks, followed
Lymphomatoid granulomatosis by a remission during which the symptoms and signs usually resolve
partially or completely. The minimum duration for a relapse has been
Diseases of Myelin arbitrarily established at 24 hours. Clinical symptoms of shorter dura-
Metachromatic leukodystrophy (juvenile and adult)* tion are less likely to represent what is considered a true relapse (i.e.,
Adrenomyeloleukodystrophy* new lesion formation or extension of previous lesion size). Worsening
of previous clinical dysfunction can occur concurrently with fever,
Miscellaneous
infection, physical activity, or metabolic upset and last for hours to a
Spinocerebellar disorders*
day or more and is referred to as pseudo-relapse. Summaries of many
Arnold-Chiari malformation
studies provide an average figure of 0.4–0.6 relapses per year in patients
Vitamin B12 deficiency*
in the relapsing-remitting phase of the illness, though this varies widely
Optic neuritis
across individuals. In general, relapses are more frequent during the
Cerebellitis
first years of the disease and tend to wane in later years, at which point
Brainstem encephalitis
it is more common for worsening to occur via a progressive course.
* Indicates disorders that are predominantly important to differentiate A standardization of terms used to describe the pattern and course
in the setting of progressive disease. of the illness was introduced in 1996 (Lublin and Reingold, 1996) and
revised in 2013. The current classification identifies three main clinical cord and optic nerves—the simplest, most linear structures commonly
course phenotypes: affected by MS lesions—have the least redundancy and capacity for
1. RRMS: Clearly defined relapses with full recovery or with sequelae organizational plasticity, while the cerebral hemispheres possess the
and residual deficit on recovery. The periods between disease greatest such structural and functional resilience (Laitman et al.,
relapses are characterized by a lack of disease progression. 2018). In the topographical model, lesions rise as focal peaks emerging
2. SPMS: Initial relapsing-remitting disease course followed by pro- from the base of the pool; those that cross the surface of the water—
gression with or without occasional relapses, minor remissions, and the clinical threshold—cause demonstrable signs and symptoms of an
plateaus. MS relapse. Disease activity in the shallow end—spinal cord and optic
3. PPMS: Disease progression from onset, with occasional plateaus nerves—is predisposed to causing the hallmark clinical relapses of MS:
and temporary minor improvements allowed. symptoms referable to partial myelitis and ON.
The 2013 revisions to the clinical courses advise sub-categoriz- It is hypothesized that the accelerated loss of brain volume in MS
ing the clinical course by whether there is evidence of activity and, in yields a loss of the compensatory mechanisms that constitute neuro-
progressive forms of the illness, whether there is evidence of ongo- logical reserve, and that MS progression may become clinically appar-
ing progression. Both characterizations should be qualified by a time ent after reserve is depleted. The topographical model depicts this, in
frame. Activity is defined as either the occurrence of an acute relapse that as time passes and functional reserve (the water level) declines,
or new MRI changes defined as a new or, unequivocally, an enlarg- progression clinically recapitulates a patient’s prior relapse symptoms
ing T2 lesion or a gadolinium-enhancing lesion. Thus a patient with and unmasks previously clinically silent lesions, incrementally man-
RRMS who has had a relapse or new MRI lesion over the past year ifesting above the clinical threshold of a patient’s underlying disease
would be characterized as RRMS with activity. Patients with PPMS or topography (Laitman et al., 2018). This recapitulation hypothesis is
SPMS are further sub-categorized as progressing or not progressing over based on the observation that the clinical signs and symptoms of a
a defined period of time. Thus a progressive patient might be active or patient’s progression manifest as a permanent, incremental recapitula-
inactive and progressive or not progressing over the defined period of tion of prior relapse symptoms and a cumulative unmasking of previ-
time (Lublin et al., 2014). PPMS remains a distinct clinical phenotype, ously clinically silent lesions.
although it is recognized that disease activity as seen on MRI can occur In addition to the heterogeneity of clinical course as encapsulated
even in the absence of a history of relapses. Besides being able to more in the distinct phenotypes and the topographical model, the disease is
accurately describe a patient’s course, the new categorizations differ also notably heterogeneous in severity and prognosis. Two extremes of
from previous in that progressive relapsing MS would be categorized disease severity have been described: benign MS is disease in which the
as progressive with disease activity instead of being a separate disease patient remains fully functional in all neurological systems 15 years after
classification (Fig. 80.13, A, B). the disease onset, and malignant MS is disease with a rapid progressive
The topographical model of MS was proposed as a unified depic- course leading to significant disability in multiple neurological systems
tion of MS clinical course across the spectrum of relapsing and pro- or death in a relatively short time after disease onset. These terms should
gressive forms of the disease (Krieger et al., 2016). This conceptual be used judiciously as MS is an unpredictable condition that is difficult
model blurs the distinctions between phenotypic categories and ani- to characterize in broad terms, particularly for individual patients.
mates dynamic periods of transition across them, taking into account
that in practice there can be a long period of diagnostic uncertainty as Radiographically Isolated Syndrome
patients transition from RRMS to SPMS (Katz Sand et al., 2014) and The diagnostic entity of radiographically isolated syndrome (RIS)
a precise moment of “conversion to SPMS” can rarely be identified. addresses the category of asymptomatic patients who have MRI-detected
In the topographical model the CNS is visualized as a pool with anomalies highly suggestive of MS. Typically, these patients get an MRI
increasing levels of depth, where the depth of the water corresponds for a completely unrelated reason, such as an accident or a headache
with the degree of functional reserve, or compensatory ability, intrin- syndrome. A multi-center, retrospective study found that the risk for a
sic to these different regions of the CNS (Fig. 80.14). Thus the spinal clinical event in a group of RIS patients was 34% within 5 years of the
2013 MS Phenotype Descriptions 2013 MS Phenotype Descriptions

Relapsing-Remitting Disease Progressive Disease
Clinically not active*

Isolated (PP) active* and with progression#
Syndrome
(CIS) active*
active but without progression
Progressive
Disease
not active and with
Relapsing-Remitting not active* progression
Disease
(RRMS) (SP) not active and without
active* progression (stable disease)
*activity = clinical relapses and/or MRI (Gd-enhancing MRI

*activity = clinical relapses and/or MRI (Gd-enhancing lesions; new/enlarging T2 lesions)
MRI lesions; new/enlarging T2 lesions)
#progression measured by clinical evaluation at least annually
A B
Fig. 80.13 A and B, The 2013 clinical courses of multiple sclerosis. Gd, Gadolinium; MRI, magnetic r esonance
imaging; MS, multiple sclerosis. (Courtesy F. Lublin.)
first brain MRI (Okuda et al., 2014). RIS patients with enhancing lesions within 1–5 years following CIS. Increasingly higher numbers of T2
and spinal cord lesions have a higher risk for conversion. It is import- lesions result in greater likelihood of conversion to CDMS and higher
ant to recall that without a characteristic clinical syndrome suggestive of disability scores at 5 years. Two long-term follow-up studies of 10–14
demyelinating disease, patients with RIS cannot be formally diagnosed years show that most patients with CIS and MRI abnormalities will
with MS according to the McDonald criteria. The question of which RIS develop CDMS (70%–80%), while only 20% of patients with normal
patients, if any, should be started empirically on DMTs remains unan- cerebral MRI scans will be diagnosed with MS over this time period
swered and is currently under study. (Beck et al., 2003; Brex et al., 2002; O’Riordan et al., 1998). These
data in part have led to the 2010 and 2017 revisions to the McDonald
Clinically Isolated Syndrome criteria, allowing for an earlier diagnosis of MS in CIS cases meeting
Although many more patients with a first clinical demyelinating event DIS on MRI.
are now immediately given a diagnosis of MS based on the clinical his-
tory and an MRI that meets the current McDonald criteria, there still Prognosis Based on Patient Characteristics
exist those patients who present with an event that is clinically consistent Although great individual variability exists with regard to disease prog-
with MS and accompanied by typical multifocal white-matter lesions on nosis, a variety of factors have been identified as possible prognostic
MRI, yet the MRI does not meet criteria for DIS and time. This situation indicators:
is referred to as the clinically isolated syndrome (CIS). In the long-term • Sex: MS may follow a less severe course in women than in men.
study by Brex et al. (2002) that followed patients with initial demyelin- • Age at onset: Average is 29–32 years. Onset at an early age is a favor-
ating episodes for up to 14 years, in practical terms no diagnoses were able factor, whereas onset at a later age carries a less-favorable prog-
encountered other than MS or suspected MS. Multiple clinical trials nosis. RRMS is more common in younger patients, and PPMS and
have been completed which show favorable outcomes in reduction of SPMS are more common in the older age group. Data are lacking
recurrent MRI and clinical activity for CIS patients who begin DMTs. as to whether prognosis differs as a function of age in patients with
similar patterns of disease.
FACTORS INFLUENCING CLINICAL COURSE • Initial disease course: Relapsing form of the disease is associated
with a better prognosis than progressive disease. A high rate of
Predictive Value of Magnetic Resonance Imaging in relapses early in the illness and a short first interval between attacks
Conversion to Clinically Definite Multiple Sclerosis may correlate with shorter time to reach EDSS 6.
Studies suggest that MRI may provide some prediction of the risk of • Initial manifestations: Among initial symptoms, impairment of
conversion to CDMS based on the presence and number of T2 lesions sensory pathways or ON has been found in several studies to be a
Clincal threshold
Spinal cord/Optic nerve Brainstem/Cerebellum Cerebral hemispheres
Fig. 80.14 The topographical model visualizes the central nervous system as a pool with increasing levels
of depth, with the spinal cord and optic nerves at the shallow end, the brainstem and cerebellum with inter-
mediate depth, and the cerebral hemispheres comprising the deep end. Focal inflammatory disease activity
is represented as topographical peaks that rise up from the pool base. The single view shown represents a
snapshot of a patient’s disease at a single point in time; the water is translucent, with both above-threshold
clinical signs and subthreshold lesions shown. The combined volume of above-threshold topographical peaks
corresponds with the degree of accumulated disability, unmasked as functional reserve declines.
favorable prognostic feature, whereas pyramidal and, particularly, those who did not (median time to progression, 13–15 years vs. 22–23
brainstem and cerebellar symptoms carry a poor prognosis. years). Overall, there is no compelling evidence of adverse effects of
In general, when considering disability as measured by the EDSS pregnancy on MS progression. However, potential risks of prolonged
(which prioritizes ambulatory function), patients with mild disease MS therapy discontinuation, level of baseline neurological disability,
(EDSS score 0-3) 5 years after diagnosis only uncommonly progress and other factors need to be taken into consideration when counseling
to severe disease (EDSS score 6) by 10 years (7.5% of patients) and patients on family planning.
15 years (11.5% of patients). It remains difficult to effectively prog- Although MS is not known to affect fertility, in patients who require
nosticate at the individual level, and clinical, imaging, and laboratory assisted reproductive technologies (ART) for other fertility issues there
biomarkers for disease severity such as neurofilament light chain (NfL) is evidence through multiple case series that ART utilizing a gonad-
are still being investigated (Siller et al., 2019). otropin-releasing hormone agonist (GnRH agonist) can increase the
risk for MS relapse, especially in the case of an unsuccessful trial (Bove
Effect of Exogenous Factors on Clinical Course et al, 2020; Correale et al., 2012).
The role of a variety of exogenous factors either influencing the devel- Another related issue is whether the disease has any effects on
opment of MS or inducing disease exacerbations has been examined pregnancy outcomes, risk of malformations, fetal birth weight, or
using epidemiological techniques. Relapses may occur with higher duration of pregnancy. Some groups report no increased risk in inci-
frequency in MS patients who have suffered recently from viral infec- dence of pregnancy and labor and delivery–related adverse events in
tions, and a high number of such infections are followed by acute MS patients (Mueller et al., 2002). Other reports indicate higher rates
attacks. Controversy exists about co-occurrence of stressful events and of operative deliveries and induced labor as well as greater numbers
exacerbation of MS, though in the authors’ view stress may commonly of neonates with low birth weight or being small for gestational age
worsen existent MS symptoms without inciting a new focal inflamma- (Dahl et al., 2005). Kelly and colleagues evaluated obstetric outcomes
tory event. Trauma appears not to be implicated in disease induction in women with MS, epilepsy, or pregestational diabetes mellitus (DM)
or relapse. Performance of neurological diagnostic procedures such as and in healthy controls. MS patients had a 30% higher risk for cesarean
myelography and lumbar puncture has not been linked to aggravation delivery and 70% higher rate of intrauterine growth restriction (IUGR)
of the MS, nor has administration of local or general anesthetics or than healthy women. There were no long-term adverse pediatric out-
surgery. There is no established link between acellular (non-live virus) comes (Kelly et al., 2009).
vaccinations and disease exacerbations, and there are no convincing
data to support withholding immunizations—for example, for influ- VARIANTS OF MULTIPLE SCLEROSIS
enza or hepatitis. However, caution should be used in the administra-
tion of live, attenuated vaccines, such as yellow fever, as an increased Tumefactive Multiple Sclerosis
risk for relapse may exist. Rarely, patients present with a large (>2 cm), acute demyelinat-
ing lesion in one hemisphere, the brainstem, or even the spinal cord
Pregnancy in Multiple Sclerosis (Fig. 80.15), known as tumefactive MS. A tumefactive lesion may be
MS preferentially affects women of childbearing age. Pregnancy is rec- the cause of the initial presentation, or may occur as part of a relapsing
ognized to induce changes in the maternal immune system, includ- MS course. In a series of 54 Turkish patients, the tumefactive lesion
ing both immunosuppression on a local level and a heightened state was the initial event in 54% of cases and occurred in RRMS patients
of immunocompetence on a global level. Several retrospective stud- in 46% of cases (Altintas et al., 2012). Depending on the size of the
ies reported an overall increase in relapse rate during the postpartum lesion, there may be prominent mass effect with compression of the
period and a lower relapse rate during pregnancy itself (Weinshenker lateral ventricle and shift across the midline. Clinical presentation in
et al., 1989). Pregnancy in Multiple Sclerosis (PRIMS) was a seminal such patients is variable, ranging from mild to severe, and is at times
prospective study of 254 women (269 pregnancies) regarding MS and
pregnancy. Subjects were followed for 2 years after delivery (Confavreux
et al., 1998; Vukusic et al., 2004; Vukusic and Confavreux, 2006). In
the cohort, a pre-pregnancy rate of 0.7 relapses per year decreased to
0.2 per year in the third trimester. The relapse rate increased to 1.2
per year in the first 3 months postpartum. However, 72% of women
did not experience any relapses during the study period. An increased
relapse rate in the year before pregnancy, an increased relapse rate
during pregnancy, and a higher EDSS score at the beginning of preg-
nancy correlated significantly with occurrence of a postpartum relapse.
Epidural anesthesia and breastfeeding were not predictive of a subse-
quent relapse or disability progression. More recent studies have sug-
gested a protective benefit to exclusive breastfeeding in the postpartum
period (Hellwig et al., 2015). There are no contraindications to cesar-
ean section or vaginal delivery in MS patients.
A prospective 5-year study compared the rate of progression in dis-
ability between childless women, women who had onset of MS after
childbirth, and women who had onset before or during their preg-
nancy (Stenager et al., 1994). The rates of disability increased most
rapidly in nulliparous women. Another study retrospectively exam-
ined childbirth’s effects on disability progression in 330 women with Fig. 80.15 A tumefactive lesion in the setting of other, more typical
MS (D’hooghe et al., 2010). Women who gave birth after MS onset multiple sclerosis lesions. Note the vasogenic edema and mass effect
reached EDSS scores of 6 significantly later in the disease course than on the ipsilateral ventricle.
atypical for MS and more reflective of a space-occupying lesion, with appear as concentric rings or a whorled appearance on T2-weighted
symptoms including encephalopathy, seizure, hemiparesis, neglect, or and contrast-enhanced T1-weighted images (Fig. 80.17) (Karaarslan
other cortical syndromes. Important diagnostic clues toward a demye- et al., 2001). Symptomatically, patients may present similar to a typ-
linating etiology include typical location for an MS lesion, presence of ical MS relapse; however, symptoms may also reflect the fact that
other more characteristic MS lesions, an incomplete ring of enhance- these lesions are space occupying in nature and may include head-
ment (classically open toward the gray matter), and peripheral restric- ache, cognitive difficulty, behavioral changes, muteness, urinary
tion on DWI (Hardy and Chataway, 2013). Ultimately, biopsy may be incontinence, seizures, aphasia, and hemiparesis (Hardy and Miller,
necessary to establish the correct diagnosis. 2014). Before the advent of MRI, it was thought that Baló disease
In terms of prognosis, in another large series of 168 patients with a was a universally lethal condition, presumably because all cases were
biopsy-proven tumefactive lesion, after a median follow-up time of 4.8 recognized only at autopsy. However, multiple series have been pub-
years 70% developed MS, 9% were called probable MS, and only 14% lished that show this not to be the case, and patients may have a
were still free of a second event. Furthermore, in a comparison to a MS good recovery and long-term prognosis that is similar to those with
cohort matched for disease duration, disability seemed to be similar in RRMS.
the tumefactive MS group (Luchinetti et al., 2008).
Marburg Variant TREATMENT AND MANAGEMENT

Marburg variant MS refers to an exceptionally uncommon form of Since the introduction of IFN-β-1b in the early 1990s, MS has mor-
MS with a relentless, fulminant course. Classically, the presentation is phed from being a virtually untreatable disease to arguably the most
multifocal and may include encephalopathy, motor and sensory defi- dynamic area of new treatment methodologies and applied research in
cits, seizures, and aphasia. Imaging shows many bilateral, large, acute all of neurology (Krieger, 2011).
lesions that may all enhance (Fig. 80.16). There may be prominent Nine distinct agents have been approved by the US Food and
subcortical and brainstem involvement. Pathology reveals confluent, Drug Administration (FDA) that are capable of modifying the disease
destructive lesions consistent with demyelination and with relative course in RRMS. The existing medications are, however, only partially
preservation of axons (Letournel et al., 2008). Untreated, the prog- effective in preventing MS relapses, and have a limited impact on the
nosis is extremely poor, and death may occur within 1 year of symp- accrual of disability. Modifying the course of progressive forms of the
tom onset. Thus, aggressive treatment with steroids, plasma exchange disease remains a major unmet need.
(PLEX), and/or immunosuppressive therapy should be given immedi- Treatment of the MS patient should be directed toward these fun-
ately when the condition is recognized (Cappello and Mancardi, 2004). damental goals:
• Treating acute relapses to shorten their duration and limit their
Baló Concentric Sclerosis residual effects
Baló concentric sclerosis is often thought of as an MS variant, • Disease modification to reduce the frequency of relapses and pre-
though it is possible that it represents a separate demyelinating syn- vent the accrual of disability
drome (Hardy et al., 2016). The characteristic pathological findings • Relief or modification of symptoms.
are alternating rings of myelin preservation or remyelination and • Supporting family and patient, alleviating social and economic
myelin loss, consistent with demyelination. On MRI, Baló lesions effects, and advocating for the disabled.
A B
Fig. 80.16 Marburg variant multiple sclerosis in a 29-year-old male. A, Brain magnetic resonance imaging
(MRI) at onset of symptoms. Patient presented with altered mental status and dysarthria as well as focal
motor deficits. B, Brain MRI 1 month later. Despite aggressive immunosuppression, the patient died within
1 year of disease onset.
decrease IgG synthesis in the CNS. Intravenous methylprednisolone

may decrease the entry of cells into the brain by stabilizing the BBB.
In 2015 a randomized, double-blind study was done in 199 MS
patients in acute relapse that showed that high-dose oral methylpred-
nisolone (1000 mg daily × 3 days) was not inferior to the equivalent
IV dose of methylprednisolone in regard to improvement in disability
scores 1 month after steroid administration (Le Page et al., 2015). Side
effects and adverse events were similar in both groups, except for a
higher rate of insomnia in those on oral treatment. Based on this study,
high-dose oral steroids provide another option for relapse treatment.
For refractory or steroid-nonresponsive relapses, adrenocorti-
cotropic hormone (ACTH) and plasmapheresis are additional treat-
ment strategies. Placebo-controlled studies (Rose et al., 1970) have
demonstrated the ability of ACTH to hasten recovery in MS relapses,
and there is a commercially available form for this indication given by
subcutaneous injection. Accelerated recovery from acute MS relapses
with ACTH may be due to its effects on both corticosteroid and the
melanocortin pathways. Updated evidence-based guidelines from
the American Academy of Neurology (AAN) characterized plasma
exchange as “probably effective” for the management of corticoste-
roid-resistant acute relapses of relapsing forms of MS based on the
strength of a study by Weinshenker (2001). Plasma exchange typically
requires inpatient hospitalization, and adverse events resulting from
the procedure include heparin-associated thrombocytopenia, anemia,
and hypotension.
Treatment Strategies and Goals of Therapy

Fig. 80.17 Baló concentric sclerosis. Note the alternating rings of Much controversy has arisen since the introduction of the approved
demyelinated and, presumably, normal tissue. medications for RRMS as to how best to choose and utilize them in
practice. The diverse array of disease-modifying agents makes MS
one of the more unique neurological diseases. As a general rule, all
Treatment of Acute Attacks patients with active relapsing forms of MS should be receiving one of
High-dosage corticosteroids are considered most effective for the the immunomodulatory agents indefinitely. Numerous clinical trials
management of acute relapses of MS. Numerous studies have found of initiating these agents at the time of the CIS have demonstrated with
that this treatment is associated with a faster recovery rate, though the remarkable consistency the benefit of early treatment at preventing
final recovery from a relapse is thought to be independent from ste- conversion to clinically definite or McDonald criteria MS, the preven-
roid. Thus, indications for treatment of a relapse include functionally tion of subsequent relapses or new MRI lesions, and the prevention of
disabling symptoms with objective evidence of neurological impair- accumulated disability.
ment or those that result in pain, yet mild sensory attacks may not The availability of newer, highly efficacious DMTs has made it pos-
be treated. Treatment with short courses of intravenous (IV) methyl- sible for clinicians to aim for much better disease control than in pre-
prednisolone, typically 1000 mg daily for 3–5 days, with or without vious times. In recent years, the goal of MS disease control has been
a short prednisone taper, has commonly been used. The 1992 Optic more sharply defined as no evidence of disease activity (NEDA). A
Neuritis Treatment Trial demonstrated that patients treated with oral patient meets NEDA when there is no evidence for new or enlarging
prednisone alone were more likely to suffer recurrent episodes of ON MRI lesions, no new clinical relapse, and no evidence upon examina-
compared with those treated with IV methylprednisolone followed by tion of disease progression over time (Banwell et al., 2013). NEDA-4
oral prednisone. Furthermore, definite MS developed in 7.5% of the IV also includes no evidence for brain atrophy above and beyond the
methylprednisolone group, 14.7% of the oral prednisone group, and normal physiological rate. Although NEDA is a worthy treatment goal
16.7% of the placebo group over a 2-year period. Development of dis- (Giovannoni et al., 2018a) it may not be achievable over the long term
ability, even when the diagnosis of MS had been made, was very rare, for most patients who, despite DMT treatment, may still have ongoing,
reemphasizing the need for follow-up periods of decades and the some- subclinical activity. Furthermore, it has not been definitively established
times benign nature of MS presenting with ON. These data support the that those that have minimal evidence for disease activity (MEDA) have
use of high-dose IV methylprednisolone for acute MS attacks, and do a worse prognosis than those that are NEDA (Río et al., 2018).
not support the use of low-dose oral steroid regimens for this purpose Most experts do agree that a patient should be switched to a dif-
(Beck et al., 1992). High-dose IV methylprednisolone is accompanied ferent DMT if they have had a clinical relapse after the drug would be
by relatively few side effects in most patients, although psychiatric expected to be fully effective, as relapses on DMT portends a poorer
changes (insomnia, anxiety, mania), gastrointestinal disturbances, long-term outcome (Jokubaitis et al., 2016). However, the decision to
fluid retention, and hyperglycemia may occur, and an increased pre- switch DMTs based on MRI activity alone is more debatable. In certain
dilection for infections, fractures, or avascular necrosis of the femoral circumstances, brain MRI may be particularly helpful. MRI scans can be
head has been observed. The immunological mechanisms of high-dose evaluated and compared at baseline and within 6–12 months after the
corticosteroids include reduction of CD4+ cells and decrease in cyto- initiation of a DMT. If a patient has two or more active lesions, modify-
kine release from lymphocytes, including TNF, IFN-γ, and decreased ing the DMT should be considered as this confers a risk of suboptimal
MHC complex class II expression. Corticosteroids have been shown to clinical response to therapy (Rio et al., 2009). An MRI scan can be done
after a relapse to evaluate the number of new lesions. Unfortunately, comparison trial of weekly IM IFN-β-1a versus the thrice-weekly 44 μg
general agreement about the definition of treatment failure does not subcutaneous dose (Panitch et al., 2002), the latter was approved by
currently exist, though a lower tolerance for breakthrough disease activ- the FDA in March 2002.
ity certainly exists now compared to previous times. Side-effect profile is similar between all IFNs and includes influen-
za-like symptoms, which usually diminish over weeks to months and
Disease-Modifying Therapy can be well managed by nonsteroidal anti-inflammatory drugs. Local
Variability of signs and symptoms, in both type and timing, is the hall- reactions at the injection site are common. Elevated liver enzymes,
mark of MS. The disease confers a considerable degree of randomness leukopenia, and anemia can occur, and blood monitoring is recom-
in terms of frequency and severity of relapses, and in the extent and mended every 3–6 months. Depression has been associated with IFN
onset of gradual development of disability. The profound individual therapy and mood should be monitored. Furthermore, a variable
clinical variability poses challenges at all levels of MS management— number of patients develop neutralizing antibodies against IFNs that
diagnosis, prognosis, clinical trial design, and particularly DMT deci- may reduce the clinical efficacy of the drug.
sions for an individual patient (Krieger et al., 2009). Glatiramer acetate. Glatiramer acetate (GA) is a synthetic
For some patients, MS is a disease with one or two acute relapses, polypeptide administered by daily subcutaneous injection. In a large
with no further evidence of disease activity. In others, it is a chronic double-blind trial in RRMS involving 251 randomized patients
relapsing or progressive disease wherein neurological disability accu- (Johnson et al., 1995), the patients receiving GA had a 29% reduction
mulates. Treatment of MS, as with other diseases, is based on the in the relapse rate over 2 years. Extension data show that over 140
results of prospective well-controlled clinical trials. Most of these weeks, 41% of patients receiving placebo experienced worsening of
trials have been designed to establish efficacy in RRMS but have not their disability by 1.5 EDSS steps or greater, whereas only 21.6% of
followed patients in controlled fashion for longer than 2 or 3 years, GA-treated patients had worsening (Johnson et al., 1998). There were
and have provided only limited insight as to the long-term results of also modest MRI effects, with an observed decrease in new T2 lesion
treatment. Long-term placebo-controlled trials are not ethically possi- load, enhancing lesions, and T1 hypointense lesions (T1 black holes).
ble once effective therapies are established. Patients in clinical practice The mechanism by which GA may work in humans is unknown but
may differ markedly from those who have been treated in clinical trials, may relate to interference with antigen presentation and induction
yet therapeutic decisions must be made, and these trials provide best of regulatory cells (TH2) that traffic to the CNS and induce bystander
evidence. Despite the evidence for efficacy in clinical trials, inter-in- suppression of immune responses.
dividual treatment response to these agents is heterogeneous (Aktas In 2014, a new dosing strategy for GA was approved by the FDA,
et al., 2010), and it is as yet not possible to prospectively identify likely based on the 40 mg subcutaneous (SC) injections given TIW as studied in
responders or nonresponders to a given treatment modality. The fol- the GALA trial (Khan et al., 2013). In this trial, a 34% reduction was seen
lowing section will provide an overview of available DMTs, followed in annualized relapse rate between GA 40 mg TIW and placebo, which
by a discussion of treatment strategy. satisfied the primary endpoint for the trial. Secondary outcomes includ-
ing T2 lesion formation and T1 gadolinium-enhancing lesions were also
Injectable Agents reduced by 35% and 45%, respectively. These data were roughly congru-
Interferons. The first medicine for use in RRMS was approved by ent with those seen in the pivotal trials of GA 2 decades earlier.
the FDA in 1993. It was a recombinant IFN-β-1b, which was shown Side effects included local injection site reactions and lipoatrophy
in a double-blind placebo-controlled trial of 372 patients to decrease with cutaneous indentations at the injection sites after prolonged use.
the frequency of relapses by 34% after 2 years. Treatment had an Transient systemic postinjection reactions may be seen, characterized
additional effect on decreasing MRI T2 lesion burden (an increase by chest pain, flushing, dyspnea, palpitations, and anxiety. No labora-
in lesion volume of 3.6% compared with 30.2% in the placebo group tory monitoring is necessary.
over 5 years). No significant change in disease progression occurred Comparison between interferon and glatiramer acetate. The
over 5 years. The mechanism of action of IFN-β-1b may relate to REGARD study examined the effects of high-dose IFN against GA
antiproliferative effects, cytokine changes, effects at the BBB, and in RRMS patients (Mikol et al., 2008). The study had an open-label,
alterations of T-cell subsets. randomized, multicenter, comparative, assessor-blinded design and
A second double-blind placebo-controlled study in 301 patients enrolled close to 800 subjects. There was no difference between the
with relapsing-remitting disease investigated the efficacy of weekly two agents in reaching the primary endpoint, which was time to the
intramuscular (IM) injections of 30 μg of IFN-β-1a, a glycosylated first relapse. There was also no difference in the annualized relapse
recombinant IFN-β (Jacobs et al., 1996). Over 2 years, the annual rate. The BEYOND study was designed to compare a 500-μg IFN-β-1b
exacerbation rate decreased by 29%. MRI data revealed significantly subcutaneous injection treatment every other day with the currently
decreased T2 lesion volume and number of enhancing lesions over the approved 250 μg Betaseron subcutaneous treatment every other day,
2 years of the study. There was also a 37% reduction in progression of to assess in a double-blinded manner whether efficacy can be further
neurological disability in the treatment group. improved while maintaining safety and tolerability. Treatment with
Another randomized double-blind placebo-controlled study GA as an active comparator arm examined the difference between
of IFN-β-1a in higher doses was conducted in Europe and Canada the MS treatments, IFN-β-1b and GA, in a rater-blinded manner
(Ebers, 1998). This involved 560 patients with relapsing-remitting (Comi et al., 2009). No significant difference in risk for relapses was
disease given subcutaneous IFN-β-1a. Patients were randomized to found between the treatment arms. BECOME examined IFN-β-1b
placebo, 22 μg, or 44 μg of IFN-β-1a three times a week for 2 years. versus GA in MS with triple-dose Gd and 3 T MRI endpoints in this
There was a 27% reduction in the relapse rate in the group receiving investigator-initiated randomized prospective rater-blinded trial to
66 μg/week and a 33% reduction in the group receiving 132 μg/week. directly compare these two agents in the treatment of MS (Cadavid
There was also a significant reduction in disability. The MRI lesion et al., 2009). No difference in MRI or clinical outcomes was observed
burden showed a decrease of 1.2% in the group receiving 66 μg/week, between the drugs. Therefore, there is no clear evidence of superior
a decrease of 3.8% in the group receiving 132 μg/week, and an increase efficacy between GA and high-dose IFN in multiple head-to-head
of 10.9% in the group receiving a placebo. Based on these data and a trials, and these agents are generally thought to be equivalent.
Infusion Therapies action, and is dosed intravenously for 5 or 3 consecutive days only
Natalizumab. Natalizumab is a monoclonal antibody directed once yearly.
against the adhesion molecule α4-integrin. Blocking this molecule CARE-MS I was a multicenter, rater-blind phase III trial that ran-
inhibits trafficking of lymphocytes from the blood into the CNS. Two domized treatment-naïve RRMS patients to alemtuzumab (12 mg/day
well-designed trials led to FDA approval of this agent. In a placebo- for 5 days by IV infusion followed by a second 3-day infusion 1 year
controlled clinical trial (AFFIRM), natalizumab reduced relapse rate later) or IFN-β-1a (44 μg subcutaneous three times per week) and fol-
by 68% and progression of disability by 42% over 2 years (Polman lowed them over 2 years (Cohen et al., 2012). Treatment with alemtu-
et al., 2006). MRI metrics were similarly affected. In a second study zumab resulted in a 55% reduction in relapse rate compared to IFN
(SENTINEL), significant improvements in both clinical and MRI (adjusted risk ratio [AR] 0.18 vs. 0.39, P < .0001), satisfying one of
outcomes were seen when subjects who had had an exacerbation the study’s primary endpoints. However, there was no significant dif-
while on IFN-β-1a once weekly were treated concomitantly with ference in the other primary endpoint, 6-month confirmed disability
natalizumab (an add-on study), as compared to those who received progression measured by EDSS. As for MRI endpoints, the number
a placebo add-on (Rudick et al., 2006). During the studies, the safety of new GEL, new T2 lesions, and new T1 lesions were all significantly
profile was quite good; however, during the extension phase, two cases reduced in the alemtuzumab group. CARE-MS II, a second phase III,
of PML occurred in subjects receiving both natalizumab and IFN rater-blind, active-comparator trial, randomized RRMS patients who
(Kleinschmidt-DeMasters and Tyler, 2005; Langer-Gould et al., 2005). had experienced at least one relapse while on some DMT to either
A third case of PML occurred in a subject who had received natalizumab alemtuzumab or IFN-β-1a (both administered as in CARE-MS I)
in a Crohn disease study. This led to withdrawal of natalizumab from (Coles et al., 2012). In this study, evaluating patients with more active
the market until July 2006, when it was reintroduced with a risk and treatment-refractory MS, both co-primary outcomes were satis-
management program to try to better determine the risks of this agent fied: alemtuzumab demonstrated a 49% reduction in relapse rate (P
and monitor its use. Enrollment in a TOUCH (Tysabri Outreach: < .0001) and a 42% reduction in disability progression measured by
Unified Commitment to Health) prescribing program is mandatory EDSS (P = .0084).
for those patients who are receiving natalizumab. This program is Several safety concerns were raised by the above studies, partic-
designed to monitor monthly for new neurological symptoms that ularly an increased risk of infection and emergent autoimmune dis-
may be concerning for PML. Over 800 cases of natalizumab-related eases in patients treated with alemtuzumab. All three studies showed
PML have been identified as of mid-2019. a modest increase in the incidence of infections, though there have
Data published in 2012 allow for the risk of natalizumab-associ- been no treatment-related fatalities reported in the phase III studies.
ated PML to be estimated with increased precision and these data have Approximately 18% and 16% of alemtuzumab patients developed an
stood constant since. Three risk factors for PML have since been iden- autoimmune thyroid disorder and 0.8% and 1% developed immune
tified that allow for the stratification of individual patients by relative thrombocytopenic purpura (ITP) in CARE-MS I and II, respectively.
risk of PML. Positive status with respect to anti-JC virus antibodies, Of note in the two phase III studies, these adverse events were antici-
prior use of immunosuppressants, and increased duration of natali- pated, detected by monitoring, and appropriately managed.
zumab treatment are associated with distinct increased levels of PML Ocrelizumab. Ocrelizumab was approved by the FDA in 2017
risk in natalizumab-treated patients with MS (Bloomgren et al., 2012). for relapsing-remitting MS. Many would argue that its approval has
Among the risk factors, the JCV Ab has emerged as the crucial pre- made the most dramatic impact on the ability of the practitioner to
dictor of risk for development of PML. Approximately 50%–60% of effectively treat even the most aggressive cases of RRMS with a safe and
adults are seropositive for the JC Ab. Patients who test JCV Ab negative tolerable therapy. Notably, it is the only treatment that has also been
have a less than 1:10,000 risk of developing PML; JC-negative patients FDA-approved for PPMS (see below). Ocrelizumab is a humanized
are however at an annual risk for seroconversion of approximately monoclonal antibody aimed at CD20, a cell surface antigen specific
2%–3% per year. As such, the current recommendations are to re-test to pre-B cells, memory B cells, and mature B cells. Administration of
JCV Ab status every 6 months in seronegative patients on natalizumab ocrelizumab produces profound and sustained depletion of B cells.
therapy. JC-positive patients should be counseled regarding risk strat- Importantly, plasma cells are spared, which allows for preservation
ification and treatment decisions as the cumulative exposure to natal- of humoral immunity (Hauser et al., 2017). Ocrelizumab is almost
izumab increases. Patients who are JC positive have a PML risk of identical to rituximab, a chimeric mouse/human anti-CD20 antibody.
approximately 1:200 after 2 years of natalizumab treatment; this rises Early trials using rituximab showed potent efficacy in treating patients
to 1:150 after 4 years. These data have significant implications regard- with active MS (Hauser et al., 2008, Naismith et al., 2010). Based on
ing patient selection for natalizumab therapy, as well as for the ongoing these results, phase III trials in RRMS and PPMS were conducted with
decision to keep JC Ab-positive patients on natalizumab for prolonged ocrelizumab, an analogous but humanized antibody.
duration (Sorenson, 2012). OPERA I and OPERA II were identical trials that were carried out
Alemtuzumab. Alemtuzumab is a recombinant humanized in over 1650 RRMS patients (Hauser et al., 2017). These trials were
monoclonal antibody that has been used in the treatment of B-cell both 96-week randomized, placebo-controlled trials of ocrelizumab
chronic lymphocytic leukemia. It targets CD52, a glycoprotein (300 mg IV once, repeated in 2 weeks and then 600 mg IV q24 weeks)
expressed mainly by B and T lymphocytes, though also by various against an active comparator, IFN-β-1a (44 μg SC, three times a week).
other components of the immune system such as dendritic cells, Both trials found marked efficacy of ocrelizumab over IFN with an
monocytes/macrophages, natural killer cells, and some granulocytes ARR difference of 0.16 vs. 0.29 (47% absolute decrease, P < .001) and
(Hu et al., 2009). Administration of alemtuzumab by IV infusion causes a difference in mean number of new T1-enhancing lesion per MRI of
widespread and sustained depletion of lymphocytes, followed first by 0.02 vs. 0.29 (94%–95% reduction, P < .001). These results were cou-
slow repopulation of B cells and eventually of T cells. Several studies pled with a favorable side-effect profile. Infusion reactions consisting
have suggested a “sparing” of T cells with a regulatory phenotype, mainly of rash, itching, and throat irritation were reported in 34.3%
thus inducing a durable regulatory “resetting” of the immune system of patients on ocrelizumab. No fatal infusion reactions were reported.
that may contribute to alemtuzumab’s effect in MS (Cox et al., 2005). Overall infections were slightly higher in the ocrelizumab group (56.9%
Unlike other MS therapies, this agent has a durable mechanism of vs. 54.3%). The main infections reported were sinusitis, bronchitis,
and urinary tract infection. Herpes infections of mild to moderate 2011). The study met its primary endpoint with significant reduction
severity were also more common in those on ocrelizumab (5.9% vs. in ARR, from 0.54 in the placebo group to 0.37 in both terifluno-
3.4%). Surprisingly, serious infection was reported to be slightly higher mide groups, corresponding to relative risk reduction of 31.2% and
in the IFN group. Although infrequent cases of PML in patients on rit- 31.5% for the 7- and 14-mg doses of teriflunomide, respectively (P <
uximab have occurred, PML has not been reported in patients on ocre- .001). The key secondary endpoint, reduction in confirmed disability
lizumab, except a few case reports of so called “carry-over” PML. In progression as defined by sustained increase in EDSS over 12 weeks,
these cases, the patient was previously on either natalizumab or fingo- was met at the 14-mg dose (20.2% vs. 27.3%; P = .03). The key MRI
limod, switched to ocrelizumab and subsequently diagnosed with the endpoint, change in total lesion volume, was also met by both doses,
infection (Genentech, 2019). Thus, unlike natalizumab, the treatment with the higher dose of teriflunomide demonstrating somewhat more
is not limited by a patient’s JC antibody status. Furthermore, the ben- robust efficacy than the lower. There was no statistically significant
efit of ocrelizumab was maintained across different demographics and difference in serious adverse events, or adverse events requiring dis-
levels of disease activity (Turner et al., 2019). Based on these results, continuation of the study drug. Adverse events that were more com-
ocrelizumab has become a widely used DMT for RRMS patients. mon with teriflunomide include diarrhea, nausea, and hair thinning,
which only very rarely resulted in discontinuation of the study drug.
Oral Therapies Those receiving teriflunomide were more likely to have mildly ele-
Fingolimod. Fingolimod (Gilenya) is a compound with structural vated alanine aminotransferase levels, but no case of severe hepatic
similarity to sphingosine-1-phosphate (S1P). It was initially dysfunction was seen.
investigated to prevent renal allograft rejection and primarily acts to A second randomized, double-blind, placebo-controlled phase
sequester circulating lymphocytes into secondary lymphoid organs. III study (TOWER) (Confavreux et al., 2014) also demonstrated
Fingolimod causes reduction of CD3+, CD4+, CD8+, CD45RA+ (naive lower annualized relapse rates with teriflunomide 7 mg/day (0.39,
T cells), CD45RO+ (memory T cells), and CD19+ cells but has no P = .0183) and teriflunomide 14 mg/day (0.32, P = .001) compared
effect on lymphocyte induction, proliferation, or memory function. with placebo (0.50) in 1169 patients with relapsing MS. Similar
FREEDOMS was a 24-month, randomized, double-blind, placebo- to results seen in the TEMSO trial, only the teriflunomide 14 mg/
controlled, parallel-group multicenter study to investigate fingolimod day dose significantly decreased the risk of sustained accumulation
1.25 mg versus 0.5 mg versus placebo on the annualized relapse rate of disability (relative HR reduction 32%, P = .0442). A third phase
(primary endpoint) and EDSS and MRI progression (secondary III study, TENERE (Vermersch et al., 2014), was performed in 324
endpoints) over 24 months (Kappos et al., 2010). There was 60% patients with relapsing MS, and compared the same two doses of
reduction in annualized relapse rate and significant decrease in disability teriflunomide with injectable IFN-β-1a (44 μg) (Rebif). The primary
progression and MRI lesions. No improved efficacy was reported at the composite endpoint, time to failure as defined by first occurrence of
higher dose of fingolimod. TRANSFORMS compared daily fingolimod a confirmed relapse or permanent treatment discontinuation for any
0.5 mg against weekly IM IFN 30 μg. Superior efficacy was seen in the cause, did not differ between the three treatment groups. The annu-
fingolimod group with annualized relapse rate reduction and the MRI alized relapse rates did not significantly differ between teriflunomide
metrics of disease activity and progression. Adverse events observed in 14 mg/day (0.26) and IFN-β-1a (44 μg) (0.22, P = .6). When con-
these trials included bradycardia, herpesvirus infections, basal cell skin sidering treatment initiation with teriflunomide, patients should be
cancer, macular edema, and pulmonary function test abnormalities. screened for latent tuberculosis and women of childbearing poten-
Safety monitoring for fingolimod includes baseline blood tests tial should undergo pregnancy testing. Liver function tests should be
including pre-screening for varicella-zoster virus (VZV) immu- obtained monthly during the first 6 months of treatment, and inter-
nity, ophthalmological evaluation to screen for macular edema, and mittently thereafter.
electrocardiographic (ECG) testing to rule out cardiac conduction Dimethyl fumarate (BG-12). An oral fumaric acid ester
abnormalities. Fingolimod should not be prescribed to patients with (Fumaderm) was previously shown to be effective in patients with
a recent myocardial infarction, unstable angina, stroke, transient psoriasis and various formulations of fumaric acid esters have been
ischemic attack, decompensated heart failure requiring hospitaliza- in use for this disease in Germany for many years (Katz Sand and
tion, a history or presence of Mobitz type II second- or third-degree Krieger, 2012). Dimethyl fumarate is rapidly metabolized to its main
atrioventricular block, baseline QTc interval ≥ 500 ms, or treatment active metabolite, monomethylfumarate. The mechanism of action in
with class Ia or class III anti-arrhythmic drugs (Gilenya, 2012). MS is still under investigation; however, it seems that at least some
Siponimod. Siponimod was approved in 2019 by the FDA for the of the drug’s activity is related to monomethylfumarate’s release of
treatment of CIS and relapsing-remitting MS. The pivotal trial for the transcription factor Nrf-2, which ultimately leads to a decrease in
siponimod, EXPAND, was conducted in secondary progressive MS several inflammatory cytokines, chemokines, and adhesion molecules
patients. It is discussed below in the section on DMT use in progressive (Gold et al., 2012b). Work in animal models suggests BG-12 may have
MS. neuroprotective properties, with positive effects on the preservation
Teriflunomide. Teriflunomide (Aubagio) is a metabolite of of oligodendrocytes, myelin, and axons through the reduction of
leflunomide (Arava) that is approved for treatment of rheumatoid oxidative stress (Linker et al., 2011).
arthritis. This agent reversibly inhibits the mitochondrial enzyme Dimethyl fumarate has had positive outcomes in two phase III tri-
dihydroorotate dehydrogenase, which provides the rate-limiting step als, leading to its FDA approval in 2013. DEFINE (Gold et al., 2012a)
in de novo pyrimidine synthesis, a crucial pathway for proliferating was a multicenter, double-blind trial of dimethyl fumarate 240 mg
lymphocytes. Teriflunomide therefore selectively targets blasting twice daily (BID), and three times daily (TID) versus placebo for 2
rather than quiescent lymphocytes. This agent became the second years. The study met its primary endpoint with a 49% (BID) and 50%
oral agent approved for RRMS in 2012 after several successful phase (TID) reduction in the proportion of patients who relapsed during the
III trials. study period (P < .0001). The annualized relapse rate at 2 years was
TEMSO was a multicenter double-blind trial that randomized 0.36 for placebo, 0.17 for dimethyl fumarate 240 mg BID, and 0.19 for
1088 patients with relapsing forms of MS to placebo or 7- or 14-mg dimethyl fumarate 240 mg TID, corresponding to a relative reduction
doses of oral teriflunomide daily for 108 weeks (O’Connor et al., by dimethyl fumarate of 53% and 48%, respectively (P < .001 for either
dose). Risk of 12-week disability progression was reduced by 38% with agents tend to limit or preclude chronic or repetitive dosing, further
dimethyl fumarate BID (P < .01) and 34% with dimethyl fumarate TID restricting their usefulness.
(P < .05). The most successful historical trial for progressing patients was
CONFIRM (Fox et al., 2012) was also a multicenter, double-blind performed in Europe using the chemotherapeutic agent mitoxantrone
trial comparing the same two doses of dimethyl fumarate with placebo (Novantrone), which produced a reduction in the progression of dis-
and daily subcutaneous injection of GA for 2 years. The study met its ability and a considerable decrease in relapse rate in patients with wors-
primary endpoint with reduction in ARR of 44% for dimethyl fuma- ening RRMS, PPMS, and SPMS over a 2-year period (Hartung et al.,
rate BID (P < .0001) and 51% for dimethyl fumarate TID (P < .0001) 2002). Improvement in MRI measures of disease was also demon-
compared to placebo, while glatiramer reduced ARR by 29% com- strated. At 3 years, an appreciable benefit was still evident, even though
pared to placebo. The study was not designed to test for superiority or the dosing had been stopped at 2 years. The agent has dose-related car-
noninferiority of dimethyl fumarate versus GA. There was no statisti- diac toxicity that limits lifetime dosing to 140 mg/m2. Other side effects
cally significant difference in the remaining clinical endpoint, 12-week include nausea, alopecia, and neutropenia. Secondary leukemias have
confirmed disability progression, possibly due to the unexpectedly low been uncommonly reported, though this combined risk profile has sig-
rate of progression in the placebo group. nificantly limited the use of mitoxantrone in MS in recent years.
The incidence of serious adverse events and events leading to A number of studies of cyclophosphamide treatment of progres-
drug discontinuation was similar in all groups in both trials. There sive MS have been conducted, with some suggesting a benefit and oth-
were neither opportunistic infections nor treatment-related fatalities ers not. Comparison between trials is always hazardous, and various
in either phase III trial. Flushing and gastrointestinal adverse effects induction protocols have been used, some with the addition of steroids
(nausea, abdominal pain, diarrhea) were more common with dimethyl or plasmapheresis. Nevertheless, many anecdotal reports of success led
fumarate than with placebo. Because of the partially transient nature to use of this agent in rapidly progressive cases.
of these adverse effects, patient education and close monitoring is IFN-β-1b has been used in two studies of SPMS. The first was a
important, particularly during the first weeks of treatment, to ensure European multicenter controlled trial of IFN-β-1b in 718 patients with
treatment tolerability and adherence. Because dimethyl fumarate may SPMS treated with either IFN-β-1b, 8 MIU subcutaneously every other
cause lymphopenia, a complete blood count should be obtained prior day, or placebo. The study was planned for 3 years but was stopped
to treatment and repeated as suggested by the prescribing information. after enrollees had completed 2 years because an interim analysis
Cladribine. Cladribine is a purine nucleoside analogue that demonstrated efficacy (Kappos, 1998). Analysis of this study revealed
primarily interferes with DNA synthesis in B and T cells with less that patients treated with IFN-β-1b had significant delays in progres-
impact on innate immunity (Cree et al., 2019). Previous indications sion of disability. On average, this delay amounted to 9–12 months. A
include the treatment of multiple forms of leukemia and lymphoma. second study of IFN-β-1b was performed in North America. In this
Cladribine is dosed 4–5 days of the first month based on weight, study, SPMS patients were treated with placebo, IFN-β-1b, 8 MIU
with this cycle repeated 4 weeks later. In year 2, the cycle is repeated. every other day, or IFN-β-1b 5 MIU/m2 every other day (this group
Redosing after the second cycle is not advised for at least another 2 had an average dose of 9.6 MIU). As opposed to the European study, in
years. this study no effect on the primary outcome assessment of reduction in
CLARITY was a study published in 2010 that enrolled 1330 patients time to worsening disability was found (Kappos et al., 2004). Further
in a 1:1:1 fashion to 3.5 mg/kg of cladribine, 5.25 mg/kg, or placebo analysis of these two studies suggested that the marked difference in
(Giovannoni et al., 2010). The study found that cladribine decreased their outcomes might relate in part to differences in the degree of MS
the rate of relapse compared to placebo (ARR 0.14 and 0.15 vs. 0.33 (P disease activity between the groups. Although the entrance criteria
< .001) and decreased MRI activity as well. A second study, ORACLE, were very similar, the actual groups differed in several ways (Kappos
was conducted in patients with CIS. Cladribine decreased the risk for et al., 2004). This highlights the difficulty in trying to compare results
a second MS relapse by 67% versus placebo. Although Russia and across studies, even those that attempt to evaluate the same problem
Australia approved cladribine for use in 2010, both the EMA and the with the same type of subject.
FDA delayed approval with concern over risk. A total of 867 of the orig- Ocrelizumab became the first FDA-approved DMT for use in
inal CLARITY patients were enrolled in the CLARITY Extension study. PPMS in 2017 after a successful trial, ORATORIO. ORATORIO ran-
This study showed sustained effect for up to 4 years in the majority of domized 732 PPMS patients 2:1, ocrelizumab:placebo. Key inclusion
patients treated with cladribine and provided additional information criteria were age less than 55 years old, presence of elevated IgG index
on tolerability and risk (Giovannoni et al., 2018b). Overall, the side or OCBs in CSF, and an EDSS between 3.0 and 6.5. ORATORIO found
effects reported in the trials were minimal. Lymphopenia was the most that ocrelizumab-treated patients had a 30% less chance for sustained
commonly reported adverse event, with sustained, severe lymphopenia 24-week disability progression compared to patients on placebo (P =
occurring very rarely. Malignancy was also reported in 1.4% of patients .04). The side-effect and risk profiles were similar to the RRMS tri-
in the study. Infections were increased over placebo, though they were als (Montalban, 2017). Furthermore, the rate of brain atrophy was
typically mild. The data from the Extension study ultimately resulted less in treated patients. ORATORIO was designed after a failed trial
in EMA approval in 2017 and FDA approval in 2019. of rituximab in PPMS, OLYMPUS, suggested that younger patients
with enhancing lesions on baseline MRI did benefit from rituximab.
Treatment of Progressive Disease Extension studies have showed continued benefit of those treated ear-
A number of clinical trials have investigated treatments for progressive lier with ocrelizumab versus placebo.
MS. Since the last edition of this chapter, there are have been 2 DMTs Siponimod was approved for the treatment of SPMS with activity
that have shown efficacy in progressive MS in phase II I clinical trials: in 2019. Siponimod targets the S1P1 and S1P5 receptors, similar to
ocrelizumab in PPMS and siponimod in SPMS. fingolimod, though notably it has less specificity for the S1P3 recep-
Most past clinical trials in progressive MS have used chemother- tor, and thus bradycardia during first-day dosing is less of a concern.
apeutic agents. These all have the disadvantage of producing gener- Siponimod was tested in the EXPAND trial, a study of 1600 patients
alized immunosuppression and have considerable potential systemic with SPMS. Siponimod reduced 6-month sustained disability progres-
toxicity. In addition, the toxic and long-term residual effects of these sion 24% versus placebo and decreased ARR and new lesion formation
as all. Despite subanalyses that showed that patients who had evidence relapse prevention in MS, the efficacy of which can only be assessed in
for inflammatory disease activity in the 2 years leading up to the study groups of patients, the symptomatic effects of BID oral dalfampridine
received the most benefit, statistical analysis also found that much of are rapid and reversible, which makes it possible to detect response in
the benefit of siponimod was unrelated to this effect (Cree et al., 2019). individuals (Goodman et al., 2008). The medication is contraindicated
This implies that there may be a neuroprotective effect of siponimod in in patients with a history of seizure.
addition to the known anti-inflammatory mechanism.
In summary, there is now a treatment option for patients with Fatigue
PPMS and an additional treatment option for patients with SPMS. It Fatigue is very common, though not universal, and is usually described
is likely that younger patients with progressive MS with evidence for as physical exhaustion unrelated to the amount of activity performed.
ongoing disease activity will benefit more from the currently available Fatigue occurs in as many as 78% of patients and often interferes with
treatments versus those with a purely progressive phenotype. Although daily activities. The degree of fatigue correlates poorly with the overall
there have been significant advancements made in the treatment of severity of disease or the presence of any symptom or sign. In contrast
progressive MS, further work needs to be done to provide treatments to the situation with cognitive deficits, no MRI findings correlate with
that prevent neurodegeneration and repair previous neurological fatigue. Fatigue may often be reported in association with an attack
injury. and persist long after resolution of other neurological symptoms.
The initial treatment approach to fatigue in MS should include an
CLINICAL SYMPTOMS AND SYMPTOM evaluation of sleep habits, including consideration of treating insom-
nia, anxiety, depression, nocturia, spasticity, and pain, all of which can
MANAGEMENT undermine sleep integrity and contribute to fatigue. For primary MS
Symptom recognition and management is an essential component fatigue, amantadine (Symmetrel), 100 mg BID, has relatively few side
of MS care, and necessarily evolves over the course of the disease. effects and is well tolerated by most patients. Caution must be used
Symptom management also goes beyond the pharmacological treat- in patients with renal insufficiency or seizure disorders. Studies have
ment of individual symptoms; it represents an opportunity to reassess reported an efficacy rate of 40%.
polypharmacy, increase safety (such as minimizing risk of urinary Modafinil (Provigil) is a wakefulness-promoting agent approved
infections and hospitalizations), prevent injury (such as due to falls), for use in narcolepsy that is chemically and pharmacologically dis-
reduce social isolation and promote satisfying personal relationships, tinct from CNS stimulants, although the precise mechanism of action
enable self-sufficiency with activities of daily living, and relieve care- is unknown. A single-blind crossover study suggested improvement,
giver burden when possible. The AAN published a Multiple Sclerosis but a double-blind placebo-controlled parallel group study failed to
Quality Measurement Set in 2015, and the majority of it included mea- demonstrate a benefit. Oral dosage starts at 100 mg in the morning
sures directly pertaining to symptom management: fall risk, bladder and can be increased up to 400 mg/day. Armodafinil is a related vig-
infection, physical activity, fatigue, cognitive impairment, depression ilance-promoting agent that can be utilized. Some patients also may
screening, depression outcomes, and overall quality of life (Rae-Grant respond to methylphenidate (Ritalin), 10–60 mg/day in 2–3 divided
et al., 2015). doses, or to other stimulants such as atomoxetine. In addition to treat-
ing the depressive symptoms associated with MS, selective serotonin
Gait and Ambulatory Dysfunction reuptake inhibitors (SSRIs), especially those with activating properties,
Loss of mobility is an important symptom of MS, a major concern have been used to treat fatigue. Bupropion may also alleviate fatigue
for patients diagnosed with this condition and a significant contrib- at times, even in the absence of overt depression. The drug should be
utor to quality of life. Physical rehabilitation, bracing, and assistive avoided in patients with a history of seizures.
devices all can confer an improvement in mobility for appropriate MS
patients. Minimizing fall risk is an essential goal of mobility manage- Cognitive Impairment
ment. Physical and occupational therapy are important components Cognitive involvement in MS was documented as early as 1877 by
of comprehensive care and can be employed early in disease course to Charcot. He observed that patients with “multilocular sclerosis” are
maximize compensatory strategies and optimize energy utilization to slow to form conceptions, have “marked enfeeblement of the mem-
help preserve function and limit fatigue. ory, and blunting of intellectual and emotional faculties.” However,
The first medication designed to engender functional improve- the subsequent era of research in MS focused primarily on physical
ment in MS patients, the oral medication dalfampridine was disability. There was a paucity of rigorous studies, with a focus on cog-
approved in 2010 (Krieger, 2011). Dalfampridine is a potassium nition. In 1981, Kurtzke reported that only 5% of patients with MS
channel blocker that has been hypothesized to restore conduction suffered from cognitive impairment. The Kurtzke EDSS focused pri-
in demyelinated axons and potentiate synaptic transmission via volt- marily on somatic disability measures. A decade later, data from for-
age-dependent potassium channel blockade (Judge et al., 2006). In a mal neuropsychological studies indicated that cognitive involvement
series of clinical trials, dalfampridine (sustained-release fampridine) has been underreported in MS (Rao et al., 1991). Neuropsychological
was studied with a primary outcome measure based on changes in test results have shown that 34%–65% of patients with MS have some
walking speed as measured by the timed 25-feet walk (T25FW). In degree of cognitive impairment (Nocentini et al., 2006).
several trials, approximately 35% of patients receiving dalfampridine Cognitive abnormalities affect patients across the disease spec-
were timed-walk responders compared with 8% of those given pla- trum and involve all MS subtypes. Some 49%–53.7% of CIS and early
cebo (Goodman et al., 2008, 2009). While modest, this improvement RRMS patients show significant impairment in one or more cognitive
was associated with a reduction of patients’ reported ambulatory dis- domains that impacts their quality of life (Achiron and Barak, 2003;
ability, indicating a clinically meaningful therapeutic benefit for this Glanz et al., 2007). A longitudinal study reported 29% of early PPMS
subset of MS patients. patients (within 5 years from disease onset) as cognitively impaired
Dalfampridine is unique among MS agents in having an indication (Penny et al., 2010; Ukkonen et al., 2009). It is increasingly recog-
specifically for improving walking (as opposed to reducing relapses nized that low physical disability can coexist with significant cognitive
or delaying disability). Unlike the immunomodulator treatments for disease.
In general, the most frequently reported abnormalities are with compared to patients with other chronic illnesses (Bronnum-Hansen
working memory, attention, and speed of information processing. et al., 2005). Frontal or subcortical white-matter disease may also be a
Patients complain of memory loss, difficulties at work or with inter- contributory causative factor.
personal relations, inability to multitask, and “mental fog and fatigue.” Depression in MS is a treatable condition, irrespective of whether it
Comorbid depression, anxiety disorders, and emotional lability may is considered a symptom or a comorbidity. SSRIs are the medications
further affect cognitive performance. Mild to moderate abnormali- of choice for depressive symptoms in patients with MS, and any of the
ties are usually not apparent during a routine office visit, and simple other medications in this class may be used. More stimulating SSRIs
screening tools for cognitive dysfunction such as the Symbol Digit may help to address concurrent fatigue; Serotonin and norepineph-
Modalities Test (SDMT) offer increased sensitivity to MS-related cog- rine reuptake inhibitors (SNRIs) such as duloxetine are also potentially
nitive dysfunction (Benedict et al., 2017). Longer neuropsychological effective for depression in MS, and may have benefit for MS-related
testing batteries are designed to assess cognitive impairment in MS pain in patients with both symptoms. Amitriptyline is a second-line
patients and are used primarily in research trials. The Brief Repeatable choice because of its anticholinergic side effects. However, anticho-
Battery of Neuropsychological Tests (BRB-N) (Rao et al., 1991) and linergic properties may also be helpful to patients with symptoms of
Minimal Assessment of Cognitive Function in Multiple Sclerosis bladder spasticity or chronic pain.
(MACFIMS) (Benedict et al., 2002) are the most widely used cognitive Euphoria, formerly considered to be common in MS, is actually
batteries for MS assessment. infrequent and is usually associated with moderate or severe cognitive
Treatment of cognitive impairment in MS is challenging. There are impairment and greater disease burden on MRI. However, emotional
limited data on the effectiveness of DMTs at preventing the develop- “dyscontrol,” also known as pseudobulbar affect, is quite common,
ment of cognitive dysfunction. A trial of IM IFN-β-1a showed a 47% and patients with this condition may oscillate frequently between
reduction in cognitive decline on PASAT testing over 2 years of fol- expressing sad and happy states, at times without clear precipitants
low-up (Fischer et al., 2000). A subsequent randomized study of 469 and in situations not congruent with the emotional expression.
patients showed that treatment with higher versus lower doses of SC Dextromethorphan with quinidine has been shown to be effective for
IFN-β-1a was predictive of lower cognitive impairment at 3 years of MS patients with pseudobulbar affect (PBA) (Pioro et al., 2010).
follow-up (Patti et al., 2010).
Pharmacological therapy focuses on treatment of underlying dis- Spasticity
ease as well as symptomatic manifestations of declining mental func- Spasticity slows voluntary movement, impairs balance and gait, and
tion, such as difficulties with attention, memory, and fatigue. There is may cause painful flexor or extensor spasms. Rehabilitation interven-
no convincing evidence that cholinesterase inhibitors improve mem- tions like stretching, Pilates, yoga, and functional electrical stimula-
ory in MS patients. A small study assessed the effects of donepezil on tion, along with weight-bearing exercises, and pool/aquatic therapy are
SPMS patients who were residents in a nursing home, documenting important nonpharmacological management approaches.
improvement in several cognitive domains after 8 weeks of therapy Baclofen is a γ-aminobutyric acid (GABA) agonist that can effectively
(Greene et al., 2000). There are additional anecdotal reports of effi- relieve spasms and has modest effects in improving performance. Daily
cacy in small numbers of subjects, though these agents are not widely divided doses of 20–120 mg and occasionally more are used. Too large a
employed in MS. Modafinil may also improve focused attention. It has dose may produce drowsiness or hypotonicity that may aggravate weak-
a favorable safety profile and can be used for symptomatic manage- ness, especially in those individuals who require a degree of spasticity to
ment of MS patients with severe fatigue and decreased focus. There is stand and transfer. Intrathecal baclofen via an implanted pump can be
some evidence that treatment with l-amphetamine is associated with effective against spasticity in suitable patients. Its effectiveness has been
improved learning and memory in cognitively impaired MS patients demonstrated in several controlled trials, and the side effects are few.
(Benedict et al., 2008; Morrow et al., 2009). Tizanidine (Zanaflex), a centrally active α2-noradrenergic ago-
Appropriate management of superimposed or comorbid psychiat- nist, may be used alone or in combination with baclofen because the
ric disease (notably depression and/or anxiety) often improves cogni- mechanism of action is different. The medication should be gradually
tive performance. Cognitive-behavioral therapy, family and individual increased, starting with 2 mg at bedtime. The side effects are similar to
counseling, strategies to improve day-to-day function, physical and those seen with baclofen; however, a blind prospective trial in patients
occupational therapy evaluations, and necessary job modifications and with MS showed that tizanidine relieved spasticity without adversely
accommodations can be of great help to MS patients suffering from affecting strength.
cognitive decline. Benzodiazepines contribute to the control of spasticity, although
sedation and possible drug dependency are limiting factors, and these
Mood and Affective Disorders agents can worsen cognition and ataxia, and potentially increase the
Cross-sectional studies have shown some degree of affective dis- risk of falls.
turbance in a significant number of patients with MS (Goldman Botulinum toxin type A (Botox) injections into spastic or con-
Consensus Group, 2005). The AAN quality measure set recommends tracted muscles may also be effective in cases with more focal or local-
screening for depression and assessing depression as two separate com- ized spasticity.
ponents of comprehensive MS care. Depression is the most common
manifestation and may in part be due to the burden of having to cope Tremor
with an unpredictable and chronic disease. However, it is more preva- Tremor is one of the most disabling and difficult-to-treat symptoms
lent in MS than in other chronic diseases, suggesting a disease-related in MS. Appendicular tremors are usually seen in action or inten-
component as well. The lifetime risk of major depression in patients tion and may limit activities of daily living. Weighted wrist brace-
with MS is up to 50% (Sadovnick et al., 1996). Patients taking mul- lets and specially adapted utensils are nonpharmaceutical options.
tiple medications are prone to depression, and the side-effect profile Most attempts at pharmacological amelioration of tremor are mini-
of the IFN-β medications includes depression. Some data indicate a mally successful. Anticonvulsants have been tried with little success.
comorbid association between bipolar illness and MS. Suicide rates are Carbamazepine (Tegretol) in divided doses up to 800 mg/day has been
higher in patients with MS than in the general population or when used. Gabapentin (Neurontin) in daily divided doses up to 3600 mg
has shown some benefit, and anecdotal reports of a benefit with topi- burden, and self-image, which can be addressed through counseling
ramate (Topamax) have been noted. Primidone (Mysoline), 125–250 and sexual therapy.
mg BID or TID, may be tried. Dizziness, somnolence, and nausea are
the primary side effects. Transient and Paroxysmal Symptoms Particularly
Clonazepam (Klonopin), 0.5–2 mg one to four times daily, may be Characteristic of MS
mildly effective. i 20–40 mg BID or TID, is another option, and may Clinical features that are characteristic, though not pathognomonic of
help with an anxiety or underlying essential tremor component than MS include bilateral INO, the Lhermitte sign, paroxysmal episodes, and
be medication responsive. Caution must be exercised in patients with the Uhthoff phenomenon (Table 80.4). Lhermitte sign is the brief occur-
concomitant cardiac, circulatory, or respiratory disorders. rence of an electrical sensation down the spine and/or into the limbs, usu-
Surgical thalamotomy or deep brain stimulation may be used in ally provoked by flexion of the neck. It is experienced commonly in MS
patients with refractory tremors. patients with spinal cord disease, but other spinal cord pathologies may
also cause the same symptomatology. Paroxysmal episodes refer to brief,
Bladder Dysfunction stereotyped attacks of motor or sensory phenomena such as diplopia,
Symptomatic bladder dysfunction occurs at some time during the focal paresthesia, trigeminal neuralgia and other paroxysmal pain syn-
course of MS in 50%–80% of patients. Recurrent urinary tract infec- dromes, ataxia, dysarthria, and tonic spasms, including hemifacial spasm
tions should alert the practitioner to the need for a urological eval- and dystonia (Mehanna and Jankovic, 2013). They may be triggered by
uation, if this has not been done previously. The severity of bladder a specific movement or stimulus, but frequently there is no identifiable
symptoms is unrelated to the duration of the disease but often parallels inciting factor. They do not always occur as the result of a new disease
the severity of other myelopathic symptoms. Differentiating between activity, but may occur as a consequence of a pre-existing lesion.
bladder spasticity (urinary frequency, urgency, incontinence) and Anticonvulsants have been used for their membrane-stabilizing
hypotonia (urinary hesitancy, retention, and overflow incontinence) properties in their usual or lower doses with some benefit at decreasing
is important before initiating therapy, because different therapies the frequency and intensity of paroxysmal symptoms. Carbamazepine
are employed for each condition. Initial steps in managing bladder is perhaps the most widely utilized, particularly extended-release for-
dysfunction include fluid management, timed voiding, and the use mulations. Benzodiazepines also have been effective in some patients.
of a bedside commode. Anticholinergic medications are often used Baclofen, acetazolamide, and bromocriptine have been cited as poten-
for patients with a hyperreflexic bladder without outlet obstruction. tially beneficial for these paroxysmal symptoms. A new onset of a
Oxybutynin (Ditropan) is often a first-line medication because it is “flurry” of paroxysmal symptoms may be considered an MS relapse,
available generically at relatively low cost and has been very extensively and a course of high-dose IV steroids as described in the section on
used. Dosage usually ranges from 2.5 to 5 mg one to three times daily. treatment of acute attacks may be employed.
An extended-release formulation is available. Other medications with Heat sensitivity is a well-known occurrence in MS. Specifically,
similar action include tolterodine (Detrol), trospium (Sanctura), dar- Uhthoff phenomenon describes the recurrence or worsening of a focal
ifenacin (Enablex), and solifenacin (VESIcare). MS deficit (i.e., visual blurring) due to decreased conduction through
Desmopressin is also effective for hyperreflexic bladder without demyelinated fibers at higher body temperatures. Similarly, recru-
outlet obstruction, especially when taken at bedtime. Doses of 20–40 descence of prior symptoms in the setting of a febrile illness such as
mg daily are suggested. Adverse effects include nausea, flushing, and urinary tract infection, often termed a pseudoexacerbation, is a conse-
headache. Detrusor hyperreflexia with outlet obstruction may respond quence of the same process and needs to be distinguished from a true
to Credé maneuvers, antispasticity medications, or anticholinergics new relapse before steroids are utilized.
in combination with α-sympathetic blocking agents such as terazosin
hydrochloride (Hytrin). Adverse effects include tachycardia, dizziness, OTHER INFLAMMATORY DEMYELINATING
syncope, headache, and asthenia. Botulinum toxin injection to the DISEASES OF THE CENTRAL NERVOUS SYSTEM
bladder musculature may be helpful in medication-refractory hyper-
reflexic bladder. Intermittent catheterization, often self-performed, Acute Disseminated Encephalomyelitis
may be very helpful for patients with retention. Occasionally, chronic Acute disseminated encephalomyelitis (ADEM) is a demyelinating
indwelling catheterization may be required. Surgical correction, syndrome that often occurs in association with an immunization or
such as augmentation of bladder capacity with an exteriorized loop vaccination (postvaccination ADEM) or systemic viral infection (para-
of bowel, is another alternative for appropriate patients, when other infectious ADEM), but may also occur without any known trigger.
measures have failed. This disorder is almost always monophasic. Recurrent cases have been
reported, but this occurs rarely and distinction from MS or other CNS
Sexual Dysfunction demyelinating disorders is unclear.
Studies suggest that 45%–74% of women with MS experience sexual
dysfunction. These symptoms have been associated with depression,
bowel dysfunction, fatigue, spasticity, and pelvic floor weakness. Referral TABLE 80.4 Characteristic Clinical
for urogynecological evaluation and consideration of pelvic floor exer- Features of Multiple Sclerosis
cises, lubricants, stimulator devices, and therapeutic techniques may be Clinical Features Suggestive of Multiple Sclerosis
of value. Erectile dysfunction in men is common, especially in patients Onset between ages 15 and 50
with spinal cord involvement. Adverse effects of medication or psycho- Involvement of multiple areas of the central nervous system
logical issues may also be associated with sexual dysfunction. Optic neuritis
Sildenafil and multiple similar medications have supplanted older Lhermitte sign
approaches to erectile dysfunction in men. Caution should be taken in Internuclear ophthalmoplegia
patients with cardiovascular disease and concomitant cardiac medica- Fatigue
tions. In both women and men with MS, consequent effects of sexual Worsening with elevated body temperature
dysfunction involve social isolation, depression, anger, guilt, spousal
Postvaccination Acute Disseminated Encephalomyelitis reflecting cerebral, brainstem, and spinal cord involvement. Clinically,
The occurrence of “neuroparalytic accidents” as a consequence of the fever, encephalopathy, and multifocal presentation can be most helpful
Pasteur rabies vaccine prepared from spinal cords of rabbits inoculated in distinguishing ADEM from the first episode of MS. Other reported
with fixed rabies virus was recorded soon after introduction of the findings include movement disorders and ataxia.
treatment. Similar neurological complications were associated with the Recovery can begin within days; complete resolution is occasion-
Jenner vaccine used for smallpox prevention. Reports have associated ally noted within a few days but more often evolves over the course
ADEM with other vaccines including pertussis, rubella, diphtheria, and of weeks or months. Poor prognosis is correlated with severity and
measles. The association of the swine influenza vaccine with ADEM abruptness of onset of the clinical syndrome. Measles virus-associated
has been the subject of medicolegal controversy. ADEM is not known ADEM may carry a worse prognosis than vaccine-associated disease.
to be clearly associated with any vaccine currently used in the United
States. ADEM developing after drug administration has been reported Laboratory and Radiological Features
with sulfonamides and para-aminosalicylic acid/streptomycin. The usual CSF findings are normal opening pressure, little or modest
increase in cell count (<100 cells/mL), and a moderate increase in pro-
Parainfectious Acute Disseminated Encephalomyelitis tein. Cases with high cell counts, including some polymorphonuclear
Descriptions of cerebral and cerebellar abnormalities after measles cells and high protein values, occur. The high counts usually return
appeared in the mid- to late 19th century. The overall experience to normal within a few days. OCBs occur less commonly than in MS.
suggests that neurological sequelae complicate 1 in 400 to 1 in 1000 Radiologically, an important feature of ADEM is that the great
cases of measles infection, and that patients do not develop periph- majority of the T2 lesions enhance, suggesting they were of recent
eral nerve damage, nor do relapses occur. Less compelling associations onset, consistent with a monophasic illness (Fig. 80.18). Unlike MS,
with ADEM have been made with a wide array of viral and bacterial in ADEM, after several weeks, lesions show at least partial resolution
infections including rubella, mumps, herpes zoster, herpes simplex, without the appearance of new lesions.
influenza, EBV, coxsackievirus, Borrelia burgdorferi, Mycoplasma, and Pathologically, ADEM lesions display perivascular inflammation
Leptospira. and surrounding demyelination within the CNS. Vessel necrosis is
frequently observed. The demyelinating aspect may be minimal or
Clinical Features widespread, with coalescence of the multiple lesions. Some meningeal
Cases of acute encephalomyelitis occurring in a setting without a reaction may also be apparent.
recent known infection or vaccination or with only nonspecific viral The diagnosis of ADEM can usually be made with confidence in the
symptoms are difficult to diagnose with certainty and distinguish from setting of a clear-cut antecedent event strongly associated with the dis-
episodes of MS. An initial attack of MS is considerably more common order, such as measles infection or vaccination. The occurrence of an
than ADEM. Cases occurring in children at an extremely young age are acute focal or multifocal CNS syndrome subsequent to a nonspecific
perhaps the most readily delineated. viral illness creates a wider differential diagnosis. Apart from the first
The hallmark clinical feature of ADEM is the development of a episode of MS, CNS vasculitis, embolic disease, direct infection, and
focal or multifocal neurological disorder following exposure to virus granulomatous disease should be considered.
or receipt of vaccine. In some but not all cases, a prodromal phase of
several days of fever, malaise, and myalgia occurs. Onset of the CNS Acute Hemorrhagic Leukoencephalitis
disorder is usually rapid (abrupt or up to several hours), with peak dys- Acute hemorrhagic leukoencephalitis is a rare entity that represents
function within several days. Initial features include encephalopathy a hyperacute form of ADEM. The most frequent antecedent history
ranging from lethargy to coma, seizures, and focal and multifocal signs is that of an upper respiratory infection. The clinical manifestations
A B
Fig. 80.18 Acute disseminated encephalomyelitis in a 20-year-old male. A, Fluid-attenuated inversion recovery
(FLAIR) images. B, Corresponding postcontrast images showing enhancement of all lesions. The patient pre-
sented with encephalopathy, headache, and a dense left hemiplegia. Two years later he had developed no
further symptoms or magnetic resonance imaging lesions, but a left hemiparesis was still present.
mimic ADEM but are more abrupt and more severe. MRI usually African descent being commonly affected (Mata and Lolli, 2011). The
shows large, confluent FLAIR bright lesions with petechial hemor- course of NMO also differs from that of MS. Although NMO patients
rhages. Pathology shows necrotizing vasculitis involving venules and are much less likely to transition to a progressive course, the disabil-
capillaries and features perivascular accumulations of polymorphonu- ity accumulated from NMO relapses tends to be more severe; patients
clear cells and red blood cells. more commonly have a deficit of total blindness or paralysis from
NMO attacks, something that is uncommon in MS patients.
Treatment Classically, NMO patients have relapses consisting of ON, myeli-
The current favored therapy for ADEM is high-dose corticoste- tis, or area postrema syndrome. ON in NMO is typically severe, more
roids, although no controlled clinical studies have been conducted. likely to be bilateral, and the recovery may not be as complete. Spinal
Plasmapheresis and immunosuppressants, such as cyclophosphamide, cord relapses, another hallmark of NMO, are often a longitudinally
have been used in refractory cases. extensive myelitis (LETM), defined as a spinal cord lesion that is con-
tiguous and greater than three vertebral segments but may be many
Neuromyelitis Optica more, often extending from the cervical junction throughout the cer-
Eugene Devic coined the phrase “neuromyelitis optica” (NMO) in vical and thoracic cord (Fig. 80.19). Myelitides in NMO may involve
the late 1800s to describe a devastating demyelinating syndrome char- motor, sensory, and/or bowel and bladder functions. Although clas-
acterized by ON and myelitis, either simultaneously or in sequential sically NMO was defined as a condition that spared the brain itself,
relapses. Despite Devic’s and others’ belief that NMO was a unique it is now well recognized that NMO lesions can also cause brainstem
disease entity, until 2004 many considered NMO to be a severe variant and cerebral symptoms. Brainstem symptoms may include intractable
of MS. In 2004, the aquaporin-4 antibody was identified in a majority nausea and vomiting and hiccupping (also known as the area postrema
of patients with the clinical syndrome of NMO, while at the same time syndrome, the presenting symptom in up to 10% of NMO patients),
showing a high specificity (Lennon et al., 2004), thus confirming long- double vision, dysphagia, and respiratory compromise. Cerebral symp-
standing suspicions that NMO is a different disease entirely than MS. toms may include motor or sensory deficits and encephalopathies.
The target of the NMO antibody is the aquaporin-4 (AQP4), a The key diagnostic test in NMO is the NMO antibody. Depending on
transmembrane protein which facilitates water transport in the CNS. the assay employed, sensitivity ranges from 70% to 80%, with specificity
AQP4 is heavily expressed at astrocytic foot processes at the BBB. The close to 100% (Wingerchuk et al., 2015). Patients with NMO often have
NMO lesion is a result of compliment activation at the site of the AQP4 positive antibodies for other conditions such as Sjögren syndrome or
protein, leading to a distinctive “rim and rosette” pattern of immune lupus. If they have clinical symptoms suggestive of these other condi-
complexes in the NMO lesion (Luchinetti et al., 2002). The result is tions as well, it is likely that there are two coexisting autoimmune syn-
astrocyte death and tissue necrosis in both gray and white matter. dromes. The reverse scenario, a patient with another rheumatological
Although T cells, B cells, and macrophages are important in NMO condition displaying seropositivity for the NMO antibody, is rare. CSF
pathophysiology similar to MS, in NMO, neutrophils and eosinophils shows OCB positivity in only 10% of cases. Commonly there can be a
also contribute to tissue damage (Jacob et al., 2013). mild elevation in CSF white blood cell (WBC) count and protein.
Epidemiologically, NMO patients differ significantly from MS The currently accepted diagnostic criteria for NMO spectrum disor-
patients. NMO is a much rarer condition, with an overall preva- ders (NMOSD) from Wingerchuk et al., (2015) requires that a patient
lence thought to be approximately 2–4/100,000 in most populations with AQP4 IgG have a history of a core clinical syndrome (ON, myeli-
(Flanagan et al., 2016; Houzen et al., 2017). The female to male ratio tis, area postrema syndrome, brainstem syndrome, narcolepsy or other
is even more disparate in NMO versus MS at 9:1. The age of onset acute diencephalic syndrome, or symptomatic cerebral syndrome with
is older (median age 40 years vs. 28 years). There is a non-Caucasian typical NMOSD lesions) along with a positive anti-AQP4-IgG test and
predominance in the NMO population, with patients of Hispanic and exclusion of other causes. The requirements for a diagnosis of NMOSD
A B
Fig. 80.19 Neuromyelitis optica in a 30-year-old female of Caribbean origin. A, Longitudinally extensive
cervical spine lesion. B, Avid enhancement of left optic nerve.
for seronegative cases are more rigorous in order to maintain diagnos- followed by a prednisone taper. Depending on treatment response,
tic accuracy (Table 80.5). plasmapheresis or IVIG may be used for relapses with incomplete
One important subset of AQP4-seronegative NMOSD patients are recovery after steroid. Early plasmapheresis is encouraged for those
those patients that are now known to test positive for myelin oligo- patients with serious deficit or those that do not respond initially to
dendrocyte glycoprotein (MOG) antibody. Transient seropositivity of steroid, and treatment of subsequent attacks may be treated with
MOG antibody has been associated with a monophasic course versus plasmapheresis as a first line, as it has been shown to bring about
those with a persistently high titer who had a higher risk for relapsing a better outcome when used earlier in the course (Kleiter et al.,
disease (Hennes et al., 2017; Hyun et al., 2017). As with NMO, MOG 2016). Historically, azathioprine, mycophenolate mofetil, rituximab,
antibody-associated disorders include ON, myelitis, and brainstem mitoxantrone, and cyclophosphamide have all been used as preven-
syndromes, though there are subtle differences between the condi- tive treatments in NMO (Kimbrough et al., 2012). Recently, three
tions. MOG antibody disease is more common in males than in NMO. randomized, controlled studies to assess efficacy of disease-modifying
ADEM is a common presenting feature. The ON in MOG antibody- treatments in NMO have been completed. Eculizumab, a comple-
associated disease often presents with disc edema, involves a long sec- ment inhibitor, showed a 94% reduction risk for new relapses when
tion of the optic nerve, and is bilateral (Chen et al., 2018). Myelitis is it was added on to a patient’s previous immunosuppressive regimen
often lower in the spinal cord than in AQP4-positive patients and may versus patients who were given placebo and continued their previ-
be longitudinally extensive or involve only a short segment (Weber ous DMT treatment. It is now FDA-approved for the treatment of
et al., 2018). The area postrema syndrome is less common. Overall, the NMOSD. Satralizumab and inebilizumab both showed marked
prognosis for MOG antibody-associated disorders appears to be bet- reduction in new NMOSD relapse versus the comparison group
ter than for AQP4-IgG disorder. Patients are less likely to have severe as well (Collongues et al., 2019). Importantly, multiple disease-
neurological deficits after a relapse and more likely to maintain func- modifying agents commonly in MS, including IFNs and natalizumab,
tion, though bowel/bladder/erectile dysfunction may be permanent in are suspected to worsen the disease course in NMO. This makes early
MOG antibody disease patients (Jurynczyk et al., 2017). and accurate diagnosis that much more critical.
The approach to treatment in NMOSD and MOG antibody dis-
ease is currently almost identical and contains three parts: treat- Site-Restricted Forms of Demyelinating Disorders
ment of relapse, prevention of relapse, and treatment of chronic Transverse Myelitis
symptoms. Treatment of an NMOSD attack should be prompt and Acute transverse myelitis is defined as the development of isolated spinal
aggressive, as it may influence the neurological outcome. Typically, cord dysfunction over hours or days in patients in whom no evidence
high-dose IV methylprednisolone is given for a period of 5 days of a compressive or vascular lesion exists. Further categorization can
TABLE 80.5 Diagnostic Criteria for NMOSD with AQP4 IgG

Diagnostic Criteria for NMOSD with AQP4 IgG
• At least one core clinical characteristic
• Positive test for AQP4 IgG using best available assay
• Exclusion of other alternative diagnosis
Diagnostic Criteria for NMO without AQP4-IgG or NMOSD with unknown AQP4-IgG status
• At least two core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:
a. At least one core clinical characteristic must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis, or area postrema syndrome
b. Dissemination in space (2 or more different core clinical characteristics)
c. Fulfillment of additional MRI requirements, as applicable
• Negative tests for AQP4 IgG using best-available method or unavailable
• Exclusion of alternative diagnoses
Core Clinical Characteristics

• Optic neuritis
• Acute myelitis
• Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting
• Acute brainstem syndrome
• Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
• Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Additional MRI Requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG Status
• Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific white-matter lesions, OR (b) optic nerve MRI with T2-hyperintense lesion
or T1-weighted gadolinium-enhancing lesion extending over more than half optic nerve length or involving optic chiasm
• Acute myelitis: requires associated intramedullary MRI lesion extending over ≥c3 contiguous segments of focal spinal cord atrophy in patients with history
compatible with acute myelitis
• Area postrema syndrome: requires associated dorsal medulla/areas postrema lesions
• Acute brainstem syndrome: requires associated periependymal brainstem lesions
AQP4, Aquaporin-4; IgG, immunoglobulin G; MRI, magnetic resonance imaging; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica syndrome
disorder.
Adapted from Wingerchuk, D.M., Banwell, B., Bennett, J.L., et al., 2015. International consensus diagnostic criteria for neuromyelitis optica spec-
trum disorders. Neurology 85(2), 177–189.
be made into acute complete transverse myelitis (ACTM), idiopathic Cases have been reported following measles, rubella, mumps, and var-
inflammation of the spinal cord causing symmetrical and moderate or icella. Most patients had bilateral optic nerve involvement; additional
severe loss of function relative to a distinct spinal cord level and acute neurological abnormalities occurred in only a minority of patients.
partial transverse myelitis (APTM), asymmetric involvement or partial The young age of the patients further suggests that these events are not
involvement of the spinal cord (Scott, 2007). the initial manifestations of MS. The prognosis for recovery of vision is
In the absence of a brain MRI that is characteristic, ACTM rarely good in most cases, perhaps less so in post-varicella cases.
evolves into MS and is typically a monophasic event. Conversely,
APTM is a precursor to MS in 50%–90% of patients who have two or Chronic Relapsing Inflammatory Optic Neuropathy
more typical MS lesions on cerebral imaging and 20%–30% in those Chronic relapsing inflammatory optic neuropathy (CRION), first
with negative brain MRIs (Scott, 2007). Acute transverse myelitis is described in 2003, is a condition characterized by relapsing ON with-
also known to occur on a background of systemic vasculitis. NMO out known involvement in other areas of the CNS. Presentations of
antibody and a complete rheumatological panel should be tested. this condition vary and include a unilateral relapsing ON, sequen-
Positivity of OCBs may help in differentiating between idiopathic cases tial relapses of both optic nerves, and simultaneous, bilateral ON.
and either MS or NMO, as they are rarely present without an under- Characteristic features used to make a diagnosis include history of ON
lying cause. Similarly, an elevation in CSF white count and CSF viral with at least one relapse, objective loss of visual function, NMO IgG
testing may be associated with an infectious or parainfectious etiology negative, contrast enhancement of the affected optic nerve on MRI,
(Scott et al., 2011). and often there is a response to steroid treatment followed by relapse
with dose reduction or discontinuation (Petzold and Plant, 2014). The
Isolated Optic Neuritis differential diagnosis for CRION includes NMOSD, MOG-associated
The clinical features of ON are described earlier in the chapter. The ON, SLE, sarcoidosis, and atypical MS presentation.
issue remains whether some cases of isolated ON represent formes
frustes of ADEM. In this regard, cases of ON occurring after childhood The complete reference list is available online at https://expertconsult.
exanthemas would represent the best example of parainfectious ON. inkling.com/.
REFERENCES Capello, E., & Mancardi, G. (2004). Marburg type and Balo’s concentric scle-
rosis: Rare and acute variants of multiple sclerosis. Neurological Sciences,
Achiron, A., & Barak, Y. (2003). Cognitive impairment in probable multiple 25(4), s361–s363.
sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry, 74(4), 443–446. Chen, J., Chia, N., Kalari, K. R., Yao, J. Z., Novotna, M., Paz Soldan, M. M.,
Aktas, O., Kieseier, B., & Hartung, H. (2010). Neuroprotection, regeneration et al. (2016). Multiple sclerosis patients have a distinct gut microbiota
and immunomodulation: Broadening the therapeutic repertoire in multi- compared to healthy controls. Scientific Reports, 6(1), 284844. https://doi.
ple sclerosis. Trends in Neurosciences, 33(3), 140–152. org/10.1038/srep28484.
Altintas, A., Petek, B., Isik, N., et al. (2012). Clinical and radiological charac- Chen, J. J., Flanagan, E. P., Jitprapaikulsan, J., López-Chiriboga, A., Sebastian,
teristics of tumefactive demyelinating lesions: Follow-up study. Multiple S., Fryer, J. P., et al. (2018). Myelin oligodendrocyte glycoprotein anti-
Sclerosis, 18(10), 1448–1453. body–positive optic neuritis: Clinical characteristics, radiologic clues, and
Ascherio, A., Munger, K. L., White, R., et al. (2014). Vitamin D as an early outcome. American Journal of Ophthalmology, 195, 8–15.
predictor of multiple sclerosis activity and progression. JAMA Neurology, Cohen, J. A., Coles, A. J., Arnold, D. L., et al. (2012). Alemtuzumab versus
71(3), 306–314. interferon beta 1a as first-line treatment for patients with relapsing-
Bachmann, R., Reilmann, R., Schwindt, W., et al. (2006). FLAIR imaging for remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet,
multiple sclerosis: A comparative MR study at 1.5 and 3.0 Tesla. European 380(9856), 1819–1828.
Radiology, 16(4), 915–921. Coles, A. J., Twyman, C. L., Arnold, D. L., et al. (2012). Alemtuzumab
Bakshi, R., Thompson, A. J., Rocca, M. A., et al. (2008). MRI in multiple sclerosis: for patients with relapsing multiple sclerosis after disease-modifying
Current status and future prospects. The Lancet Neurology, 7(7), 615–625. therapy: A randomised controlled phase 3 trial. Lancet, 380(9856),
Banwell, B., Giovannoni, G., Hawkes, C., & Lublin, F. (2013). Editors’ 1829–1839.
welcome and a working definition for a multiple sclerosis cure. Multiple Collongues, N., Ayme-Dietrich, E., Monassier, L., & de Seze, J. (2019).
Sclerosis and Related Disorders, 2(2), 65–67. Pharmacotherapy for neuromyelitis optica spectrum disorders: Current
Beck, R. W., Cleary, P. A., Anderson, M. M., Keltner, J. L., Shults, W. T., management and future options. Drugs, 79(2), 125–142.
Kaufman, D. I., et al. (1992). A randomized, controlled trial of cortico- Comi, G., Martinelli, V., Rodegher, M., et al. (2009). Effect of glatiramer ace-
steroids in the treatment of acute optic neuritis. New England Journal of tate on conversion to clinically definite multiple sclerosis in patients with
Medicine, 326(9), 581–588. clinically isolated syndrome (PreCISe study): A randomised, double-blind,
Beck, R. W., Trobe, J. D., Moke, P. S., et al.; Optic Neuritis Study Group. placebo-controlled trial. Lancet, 374(9700), 1503–1511.
(2003). High- and low-risk profiles for the development of multiple scle- Confavreux, C., Hutchinson, M., Hours, M. M., et al. (1998). Rate of pregnan-
rosis within 10 years after optic neuritis: Experience of the optic neuritis cy-related relapse in multiple sclerosis. New England Journal of Medicine,
treatment trial. Archives of Ophthalmology, 121(7), 944–949. 339(5), 285–291.
Beecham, A. H., Patsopoulos, N. A., Xifara, D. K., et al. (2013). Analysis of Confavreux, C., O’Connor, P., Comi, G., et al. (2014). Oral teriflunomide
immune-related loci identifies 48 new susceptibility variants for multiple for patients with relapsing multiple sclerosis (TOWER): A randomised,
sclerosis. Nature Genetics, 45(11), 1353–1360. double-blind, placebo-controlled, phase 3 trial. The Lancet Neurology,
Benedict, R. H., DeLuca, J., Phillips, G., LaRocca, N., Hudson, L. D., Rudick, 13(3), 247–256.
R., et al. (2017). Validity of the Symbol Digit Modalities Test as a cognition Conlon, P., Oksenberg, J. R., Zhang, J., & Steinman, L. (1999). The immu-
performance outcome measure for multiple sclerosis. Multiple Sclerosis nobiology of multiple sclerosis: An autoimmune disease of the central
Journal, 23(5), 721–733. nervous system. Neurobiology of Disease, 6(3), 149–166.
Benedict, R. H., Fischer, J. S., Archibald, C. J., et al. (2002). Minimal neuropsy- Correale, J., Farez, M. F., & Ysrraelit, M. C. (2012). Increase in multiple scle-
chological assessment of MS patients: A consensus approach. The Clinical rosis activity after assisted reproduction technology. Annals of Neurology,
Neuropsychologist, 16(3), 381–397. 72(5), 682–694.
Benedict, R. H., Munschauer, F., Zarevics, P., et al. (2008). Effects of l-amphet- Cox, A. L., Thompson, S. A., Jones, J. L., et al. (2005). Lymphocyte homeo-
amine sulfate on cognitive function in multiple sclerosis patients. Journal stasis following therapeutic lymphocyte depletion in multiple sclerosis.
of Neurology, 255(6), 848–852. European Journal of Immunology, 35(11), 3332–3342.
Bermel, R. A., & Bakshi, R. (2006). The measurement and clinical relevance of Coyle, P. K. (2008). Switching algorithms: From one immunomodulatory
brain atrophy in multiple sclerosis. The Lancet Neurology, 5(2), 158–170. agent to another. Journal of Neurology, 255(1), 44–50.
Bloomgren, G., Richman, S., Hotermans, C., et al. (2012). Risk of natalizumab- Cree, B. A. C., Mares, J., & Hartung, H. P. (2019). Current therapeutic
associated progressive multifocal leukoencephalopathy. New England landscape in multiple sclerosis. Current Opinion in Neurology, 32(3),
Journal of Medicine, 366(20), 1870–1880. 365–377.
Bo, L., Vedeler, C. A., Nyland, H., et al. (2003). Intracortical multiple sclerosis Cutter, G. R., Baier, M. L., Rudick, R. A., et al. (1999). Development of a
lesions are not associated with increased lymphocyte infiltration. Multiple multiple sclerosis functional composite as a clinical trial outcome measure.
Sclerosis, 9(4), 323–331. Brain, 122(Pt 5), 871–882.
Bove, R., Rankin, K., Lin, C., Zhao, C., Correale, J., Hellwig, K., et al. (2020). D’hooghe, M. B., Nagels, G., & Uitdehaag, B. M. (2010). Long-term effects of
Effect of assisted reproductive technology on multiple sclerosis relapses: childbirth in MS. Journal of Neurology, Neurosurgery, and Psychiatry, 81(1),
Case series and meta-analysis. Sclerosis, 26(11), 1410–1419. 38–41.
Brazis, P. W., Masdeu, J. C., & Biller, J. (2011). Localization in clinical neurol- Dahl, J., Myhr, K. M., Daltveit, A. K., Hoff, J. M., & Gilhus, N. E. (2005).
ogy (6th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Pregnancy, delivery, and birth outcome in women with multiple sclerosis.
Wilkins. Neurology, 65(12), 1961–1963.
Brex, P. A., Ciccarelli, O., O’Riordan, J. I., et al. (2002). A longitudinal study of Dalton, C. M., Brex, P. A., Miszkiel, K. A., et al. (2003). Spinal cord MRI in
abnormalities on MRI and disability from multiple sclerosis. New England clinically isolated optic neuritis. Journal of Neurology, Neurosurgery, and
Journal of Medicine, 346(3), 158–164. Psychiatry, 74(11), 1577–1580.
Bronnum-Hansen, H., Koch-Henriksen, N., & Stenager, E. (2004). Trends Disanto, G., Dobson, R., Pakpoor, J., et al. (2014). The refinement of genetic
in survival and cause of death in Danish patients with multiple sclerosis. predictors of multiple sclerosis. PloS One, 9(5), e96578.
Brain, 127(Pt 4), 844–850. Durelli, L., Verdun, E., Barbero, P., et al. (2002). Every-other-day interferon
Bronnum-Hansen, H., Stenager, E., NylevStenager, E., & Koch-Henriksen, N. beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: Results
(2005). Suicide among Danes with multiple sclerosis. Journal of Neurology, of a 2-year prospective randomised multicentre study (INCOMIN). Lancet,
Neurosurgery, and Psychiatry, 76(10), 1457–1459. 359(9316), 1453–1460.
Cadavid, D., Wolansky, L. J., Skurnick, J., et al. (2009). Efficacy of treatment Ebers, G. C. (1998). Randomised double-blind placebo-controlled study of
of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the interferon β-1a in relapsing/remitting multiple sclerosis. Lancet, 352(9139),
BECOME study. Neurology, 72(23), 1976–1983. 1498–1504.
1254.e1
1254.e2 References
Ebers, G., Sadovnick, A., & Risch, N. (1995). A genetic basis for familial aggre- Greene, Y. M., Tariot, P. N., Wishart, H., et al. (2000). A 12-week, open trial of
gation in multiple sclerosis. Nature, 377(6545), 150–151. donepezil hydrochloride in patients with multiple sclerosis and associated
Ferraro, D., Simone, A. M., Bedin, R., et al. (2013). Cerebrospinal fluid oligo- cognitive impairments. Journal of Clinical Psychopharmacology, 20(3),
clonal IgM bands predict early conversion to clinically definite multiple 350–356.
sclerosis in patients with clinically isolated syndrome. Journal of Neuroim- Gronseth, G. S., & Ashman, E. J. (2000). Practice parameter: The usefulness
munology, 257(1), 76–81. of evoked potentials in identifying clinically silent lesions in patients with
Fischer, J. S., Priore, R. L., Jacobs, L. D., et al. (2000). Neuropsychological ef- suspected multiple sclerosis (an evidence-based review): Report of the
fects of interferon β-1a in relapsing multiple sclerosis. Annals of Neurology, Quality Standards Subcommittee of the American Academy of Neurology.
48(6), 885–892. Neurology, 54(9).
Flanagan, E. P., Cabre, P., Weinshenker, B. G., Sauver, J. S., Jacobson, D. J., Hafler, D. A., Slavik, J. M., Anderson, D. E., et al. (2005). Multiple sclero-
Majed, M., et al. (2016). Epidemiology of aquaporin-4 autoimmunity and sis. Immunological Reviews, 204(1), 208–231.
neuromyelitis optica spectrum. Annals of Neurology, 79(5), 775–783. Handel, A. E., Williamson, A. J., Disanto, G., et al. (2010). An updated meta-
Fox, R. J., Miller, D. H., Phillips, J. T., et al. (2012). Placebo-controlled phase analysis of risk of multiple sclerosis following infectious mononucleosis.
3 study of oral BG-12 or glatiramer in multiple sclerosis. New England PloS One, 5(9), pii: e6.
Journal of Medicine, 367(12), 1087–1097. Hardy, T. A., & Chataway, J. (2013). Tumefactive demyelination: An approach
Freedman, M. S., Selchen, D., Arnold, D. L., et al.; Canadian Multiple Sclerosis to diagnosis and management. Journal of Neurology, Neurosurgery, and
Working Group. (2013). Treatment optimization in MS: Canadian MS Psychiatry, 84(9), 1047–1053.
Working Group updated recommendations. The Canadian Journal of Hardy, T. A., & Miller, D. H. (2014). Baló’s concentric sclerosis. The Lancet
Neurological Sciences, 40(3), 307–323. Neurology, 13(7), 740–746.
Gaitán, M. I., Shea, C. D., Evangelou, I. E., Stone, R. D., Fenton, K. M., Hardy, T. A., Tobin, W. O., & Lucchinetti, C. F. (2016). Exploring the overlap
Bielekova, B., et al. (2011). Evolution of the blood-brain barrier in newly between multiple sclerosis, tumefactive demyelination and Baló’s concen-
forming multiple sclerosis lesions. Annals of Neurology, 70(1), 22–29. tric sclerosis. Multiple Sclerosis Journal, 22(8), 986–992.
GBD 2016 Multiple Sclerosis Collaborators, M.T., Culpepper, W.J., Nichols, E., Hartung, H., Gonsette, R., Konig, N., et al. (2002). Mitoxantrone in progres-
Bhutta, Z.A., Gebrehiwot, T.T., Hay, S.I., et al. (2019). Global, regional, and sive multiple sclerosis: A placebo-controlled, double-blind, randomised,
national burden of multiple sclerosis 1990-2016: A systematic analysis for the multicentre trial. Lancet, 360.
global burden of disease study 2016. The Lancet Neurology, 18(3), 269-285. Hauser, S. L., Bar-Or, A., Comi, G., Giovannoni, G., Hartung, H. P., Hemmer,
Genentech. (2019). Retrieved June 23, 2019, from https://www.ocrelizuma- B., et al. (2017). Ocrelizumab versus interferon beta-1a in relapsing multi-
binfo.com/content/dam/gene/ocrelizumabinfo/pdfs/progressive-multifo- ple sclerosis. New England Journal of Medicine, 376(3), 221–234.
cal-leukoencephalopathy.pdf. Hauser, S. L., Waubant, E., Arnold, D. L., Vollmer, T., Antel, J., Fox, R. J., et al.
Gilenya. (2012). Package insert. East Hanover, NJ: Novartis Pharmaceuticals (2008). B-cell depletion with rituximab in relapsing–remitting multiple
Corporation. sclerosis. New England Journal of Medicine, 358(7), 676–688.
Giovannoni, G., Bermel, R., Phillips, T., & Rudick, R. (2018a). A brief history of Hedstrom, A. K., Lima Bomfim, I., Barcellos, L., Gianfrancesco, M., Schaefer,
NEDA. https://doi.org/10./j.msard.2017.07.011. C., Kockum, I., et al. (2014). Interaction between adolescent obesity and
Giovannoni, G., Comi, G., Cook, S., Rammohan, K., Rieckmann, P., Sørensen, HLA risk genes in the etiology of multiple sclerosis. Neurology, 82(10),
P. S., et al. (2010). A placebo-controlled trial of oral cladribine for relaps- 865–872.
ing multiple sclerosis. New England Journal of Medicine, 362(5), 416–426. Hellwig, K., Rockhoff, M., Herbstritt, S., Borisow, N., Haghikia, A., Elias-
Giovannoni, G., Cutter, G., Sormani, M.P., et al. (2017). Multiple Sclerosis and Hamp, B., et al. (2015). Exclusive breastfeeding and the effect on postpar-
Related Disorders, 12, 70–78. tum multiple sclerosis relapses. JAMA Neurology, 72(10), 1132–1138.
Giovannoni, G., Soelberg Sorensen, P., Cook, S., Rammohan, K., Rieckmann, P., Hennes, E. M., Baumann, M., Schanda, K., Anlar, B., Bajer-Kornek, B., Blaschek,
Comi, G., et al. (2018b). Safety and efficacy of cladribine tablets in patients A., et al. (2017). Prognostic relevance of MOG antibodies in children with an
with relapsing–remitting multiple sclerosis: Results from the randomized acquired demyelinating syndrome. Neurology, 89(9), 900–908.
extension trial of the CLARITY study. Multiple Sclerosis Journal, 24(12). Höftberger, R., Sabater, L., Marignier, R., et al. (2013). An optimized
Glanz, B. I., Healy, B. C., Rintell, D. J., et al. (2010). The association between immunohistochemistry technique improves NMO-IgG detection: Study
cognitive impairment and quality of life in patients with early multiple comparison with cell-based assays. PloS One, 8(11), e3.
sclerosis. Journal of the Neurological Sciences, 290(1), 75–79. Hommes, O. R., Sørensen, P. S., Fazekas, F., et al. (2004). Intravenous im-
Glanz, B. I., Holland, C. M., Gauthier, S. A., et al. (2007). Cognitive dysfunc- munoglobulin in secondary progressive multiple sclerosis: Randomised
tion in patients with clinically isolated syndromes or newly diagnosed placebo-controlled trial. Lancet, 364(9440), 1149–1156.
multiple sclerosis. Multiple Sclerosis, 13(8). Houzen, H., Kondo, K., Niino, M., Horiuchi, K., Takahashi, T., Nakashima,
Gold, R., Kappos, L., Arnold, D. L., et al. (2012a). Placebo-controlled phase 3 I., et al. (2017). Prevalence and clinical features of neuromyelitis
study of oral BG-12 for relapsing multiple sclerosis. New England Journal optica spectrum disorders in northern Japan. Neurology, 89(19),
of Medicine, 367(12). 1995–2001.
Gold, R., Linker, R., & Stangel, M. (2012 b). Fumaric acid and its esters: An Hu, Y., Turner, M. J., Shields, J., et al. (2009). Investigation of the mechanism
emerging treatment for multiple sclerosis with antioxidative mechanism of of action of alemtuzumab in a human CD52 transgenic mouse model.
action. Clinical Immunology, 142(1), 44–48. Immunology, 128(2), 260–270.
Goldman Consensus Group. (2005). The Goldman Consensus statement on Hyun, J. W., Woodhall, M. R., Kim, S. H., Jeong, I. H., Kong, B., Kim, G., et al.
depression in multiple sclerosis. Multiple Sclerosis, 11(3), 328–337. (2017). Longitudinal analysis of myelin oligodendrocyte glycoprotein anti-
Goodin, D. S. (2014). The epidemiology of multiple sclerosis: Insights to dis- bodies in CNS inflammatory diseases. Journal of Neurology, Neurosurgery,
ease pathogenesis. Handbook of Clinical Neurology, 122, 231–266. and Psychiatry, 88(10), 811–817.
Goodin, D. S., Ebers, G. C., Cutter, G., et al. (2012). Cause of death in MS: International Multiple Sclerosis Genetics Consortium. (2018a). Electronic
Long-term follow-up of a randomised cohort, 21 years after the start of the address: Chris.cotsapas@yale.edu, I. M. S. G., & international multiple
pivotal IFNbeta-1b study. BMJ Open, 2(6), e72 pii. sclerosis genetics Consortium. Low-Frequency and Rare-Coding Variation
Goodman, A. D., Brown, T. R., Cohen, J. A., et al.; Fampridine MS-F202 Study Contributes to Multiple Sclerosis Risk Cell, 175(6), 1679–1687.e7. https://
Group. (2008). Dose comparison trial of sustained-release fampridine in doi.org/10.1016/j.cell.2018.09.049.
multiple sclerosis. Neurology, 71(15). International Multiple Sclerosis Genetics Consortium. (2018b). Inter-
Goodman, A. D., Brown, T. R., Krupp, L. B., et al. (2009). Sustained-release national multiple sclerosis genetics Consortium. Low-Frequency and
oral fampridine in multiple sclerosis: A randomised, double-blind, con- Rare-Coding Variation Contributes to Multiple Sclerosis Risk Cell,
trolled trial. Lancet, 373, 732–738. 175(6), 1679–1687.
References 1254.e3
Jacob, A., McKeon, A., Nakashima, I., et al. (2013). Current concept of Kingwell, E., Leray, E., Zhu, F., Petkau, J., Edan, G., Oger, J., et al. (2019).
neuromyelitis optica (NMO) and NMO spectrum disorders. Journal of Multiple sclerosis: Effect of beta interferon treatment on survival. Brain,
Neurology, Neurosurgery, and Psychiatry, 84(8), 922–930. 142(5), 1324–1333.
Jacobs, L. D., Cookfair, D. L., Rudick, R. A., et al. (1996). Intramuscular inter- Kleinschmidt-DeMasters, B., & Tyler, K. L. (2005). Progressive multifocal
feron beta-1a for disease progression in relapsing multiple sclerosis. Annals leukoencephalopathy complicating treatment with natalizumab and
of Neurology, 39(3), 285–294. interferon beta-1a for multiple sclerosis. New England Journal of Medicine,
Johnson, K. P., Brooks, B. R., Cohen, J. A., et al.; The Copolymer 1 Multiple 353(4), 369–374.
Sclerosis Study Group. (1995). Copolymer 1 reduces relapse rate and Kleiter, I., Gahlen, A., Borisow, N., Fischer, K., Wernecke, K. D., Wegner, B.,
improves disability in relapsing-remitting multiple sclerosis: Results of a et al. (2016). Neuromyelitis optica: Evaluation of 871 attacks and 1,153
phase III multicenter, double-blind placebo-controlled trial. Neurology, treatment courses. Annals of Neurology, 79(2), 206–216.
45(7), 1268–1276. Krieger, S. (2011). Multiple sclerosis therapeutic pipeline: Opportunities and
Johnson, K. P., Brooks, B. R., Cohen, J. A., et al.; Copolymer 1 Multiple Sclero- challenges. Mount Sinai Journal of Medicine, 78(2), 192–206.
sis Study Group. (1998). Extended use of glatiramer acetate (Copaxone) is Krieger, S. C., Cook, K., De Nino, S., & Fletcher, M. (2016). The topographical
well tolerated and maintains its clinical effect on multiple sclerosis relapse model of multiple sclerosis. Neurology, Neuroimmunology & Neuroinflam-
rate and degree of disability. Neurology, 50(3), 701–708. mation, 3(5), e279.
Jokubaitis, V. G., Spelman, T., Kalincik, T., Lorscheider, J., Havrdova, E., Krieger, S. C., Oynhausen, S., & Lublin, F. D. (2009). Clinical overview
Horakova, D., et al. (2016). Predictors of long-term disability accrual in and outcomes in multiple sclerosis. In N. , Putzki, H.P., & H. (Eds.),
relapse-onset multiple sclerosis. Annals of Neurology, 80(1), 89–100. Treatment of multiple sclerosis (pp. 24–36). Uni-Med Science Bremen.
Judge, S. I., Lee, J. M., Bever, C. T., & Hoffman, P. M. (2006). Voltage-gated Kutzelnigg, A., Lucchinetti, C. F., Stadelmann, C., et al. (2005). Cortical
potassium channels in multiple sclerosis: Overview and new implications demyelination and diffuse white matter injury in multiple sclerosis. Brain,
for treatment of central nervous system inflammation and degeneration. 128(Pt 11), 2705–2712.
Journal of Rehabilitation Research and Development, 43(1), 111. Laitman, B. M., Cook, K., Fletcher, M., & Krieger, S. C. (2018). The topo-
Jurynczyk, M., Messina, S., Woodhall, M. R., Raza, N., Everett, R., Roca-Fer- graphical model of MS: Empirical evaluation of the recapitulation hypoth-
nandez, A., et al. (2017). Clinical presentation and prognosis in MOG-an- esis. Multiple Sclerosis Journal—Experimental, Translational and Clinical,
tibody disease: A UK study. Brain, 140(12), 3128–3138. 4(4), 652205521731880652.
Kaisey, M., Solomon, A. J., Luu, M., Giesser, B. S., & Sicotte, N. L. (2019). Langer-Gould, A., Atlas, S. W., Green, A. J., et al. (2005). Progressive mul-
Incidence of multiple sclerosis misdiagnosis in referrals to two academic tifocal leukoencephalopathy in a patient treated with natalizumab. New
centers. Multiple Sclerosis and Related Disorders, 30, 51–56. England Journal of Medicine, 353(4), 375–381.
Kalancik, T., Vivek, V., Jokubaitis, V., et al. (2013). Sex as a determinant of re- Le Page, E., Veillard, D., Laplaud, D. A., Hamonic, S., Wardi, R., Lebrun, C.,
lapse incidence and progressive course of multiple sclerosis. Brain, 136(Pt et al. (2015). Oral versus intravenous high-dose methylprednisolone for
12), 3609–3617. treatment of relapses in patients with multiple sclerosis (COPOUSEP):
Kappos, L. European Study Group on Interferon beta-1b in Secondary Pro- A randomised, controlled, double-blind, non-inferiority trial. Lancet,
gressive MS. (1998). Placebo-controlled multicentre randomised trial of 386(9997), 974–981.
interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lennon, V. A., Wingerchuk, D. M., Kryzer, T. J., et al. (2004). A serum
Lancet, 352(9139), 1491–1497. autoantibody marker of neuromyelitis optica: Distinction from multiple
Kappos, L., Radue, E., O’Connor, P., et al. (2010). A placebo-controlled trial sclerosis. Lancet, 364(9451), 2106–2112.
of oral fingolimod in relapsing multiple sclerosis. New England Journal of Leray, E., Vukusic, S., Debouverie, M., Clanet, M., Brochet, B., Sèze, J., et al.
Medicine, 362(5), 387–401. (2015). Excess mortality in patients with multiple sclerosis starts at 20
Kappos, L., Weinshenker, B., Pozzilli, C., et al.; European (EU-SPMS) Inter- years from clinical onset: Data from a large-scale French observational
feron beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering study. PloS One, 10(7), e0132033.
Committee and Independent Advisory Board; North American (NA- Letournel, F., Cassereau, J., Scherer-Gagou, C., et al. (2008). An autopsy case
SPMS) Interferon beta-1b in Secondary Progressive Multiple Sclerosis Trial of acute multiple sclerosis (Marburg’s type) during pregnancy. Clinical
Steering Committee and Independent Advisory board. (2004). Interferon Neurology and Neurosurgery, 110(5), 514–517.
beta-1b in secondary progressive MS: A combined analysis of the two Linker, R. A., Lee, D. H., Ryan, S., et al. (2011). Fumaric acid esters exert
trials. N
eurology, 63(10), 1779–1787. neuroprotective effects in neuroinflammation via activation of the Nrf2
Karaarslan, E., Altintas, A., Senol, U., et al. (2001). Balo’s concentric sclerosis: antioxidant pathway. Brain, 134(Pt 3), 678–692.
Clinical and radiologic features of five cases. American Journal of Neurora- Lublin, F. D., & Reingold, S. C. (1996). Defining the clinical course of multiple
diology, 22(7), 1362–1367. sclerosis: Results of an international survey. National Multiple Sclerosis
Karussis, D., Biermann, L., Bohlega, S., et al. (2006). A recommended treat- Society (USA) Advisory Committee on Clinical Trials of New Agents in
ment algorithm in relapsing multiple sclerosis: Report of an international Multiple Sclerosis. Neurology, 46(4), 907–911.
consensus meeting. European Journal of Neurology, 13(1), 61–71. Lublin, F. D., Reingold, S. C., Cohen, J. A., et al. (2014). Defining the clinical
Katz Sand, I. B., & Krieger, S. (2012). Emerging strategies for the treatment of course of multiple sclerosis: The 2013 revisions. Neurology, 46(4), 907–911.
multiple sclerosis. Future Neurology, 7(2), 193–207. Lucchinetti, C., Bruck, W., Parisi, J., et al. (2000). Heterogeneity of multiple
Katz Sand, I., Krieger, S., Farrell, C., & Miller, A. E. (2014). Diagnostic uncer- sclerosis lesions: Implications for the pathogenesis of demyelination.
tainty during the transition to secondary progressive multiple sclerosis. Annals of Neurology, 47(6), 707–717.
Multiple Sclerosis, 20(12), 1654–1657. Lucchinetti, C. F., Gavrilova, R. H., Metz, I., et al. (2008). Clinical and
Katz Sand, I., Zhu, Y., Ntranos, A., Clemente, J. C., Cekanaviciute, E., Brandstad- radiographic spectrum of pathologically confirmed tumefactive multiple
ter, R., et al. (2019). Disease-modifying therapies alter gut microbial composi- sclerosis. Brain, 131(Pt 7), 1759–1775.
tion in MS. Neurology, Neuroimmunology & Neuroinflammation, 6(1), e517. Lucchinetti, C. F., Mandler, R. N., McGavern, D., et al. (2002). A role for
Kelly, V. M., Nelson, L. M., & Chakravarty, E. F. (2009). Obstetric outcomes in humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica.
women with multiple sclerosis and epilepsy. Neurology, 73(22), 1831–1836. Brain, 125(Pt 7), 1450–1461.
Khan, O., Rieckmann, P., Boyko, A., et al. (2013). Three times weekly glati- Lukas, C., Sombekke, M. H., Bellenberg, B., et al. (2013). Relevance of spinal
ramer acetate in relapsing–remitting multiple sclerosis. Annals of Neurolo- cord abnormalities to clinical disability in multiple sclerosis: MR imaging
gy, 73(6), 705–713. findings in a large cohort of patients. Radiology, 269(2), 542–552.
Kimbrough, D. J., Fujihara, K., Jacob, A., et al. (2012). Treatment of neuromy- Lunde, H. M. B., Assmus, J., Myhr, K. M., Bø, L., & Grytten, N. (2017). Survival
elitis optica: Review and recommendations. Multiple Sclerosis and Related and cause of death in multiple sclerosis: A 60-year longitudinal population
Disorders, 1(4), 180–187. study. Journal of Neurology, Neurosurgery, and Psychiatry, 88(8), 621–625.
1254.e4 References
Manouchehrinia, A., Tench, C. R., Maxted, J., et al. (2013). Tobacco smoking Oksenberg, J. R., Barcellos, L. F., Cree, B. A., et al. (2004). Mapping multiple
and disability progression in multiple sclerosis: United Kingdom cohort sclerosis susceptibility to the HLA-DR locus in African Americans. The
study. Brain, 136(Pt 7), 2298–2304. American Journal of Human Genetics, 74(1), 160–167.
Mata, S., & Lolli, F. (2011). Neuromyelitis optica: An update. Journal of the Okuda, D. T., Siva, A., Kantarci, O., et al. (2014). Radiologically isolated
Neurological Sciences, 303(1–2), 13–21. syndrome: 5-year risk for an initial clinical event. PloS One, 9(3),
McGraw, C., Wong, J., Fabian, M., & Krieger, S. C. (2012). The food critic who e90509.
couldn’t taste and six other cases of dysgeusia in multiple sclerosis. Presented Pakpoor, J., Giovannoni, G., & Ramagopalan, S. V. (2013). Epstein-Barr
at American Academy of Neurology. New Orleans, LA: April. virus and multiple sclerosis: Association or causation? Expert Review of
Mehanna, R., & Jankovic, J. (2013). Movement disorders in multiple sclerosis Neurotherapeutics, 13(3), 287–297.
and other demyelinating diseases. Journal of the Neurological Sciences, Panitch, H., Goodin, D. S., Francis, G., et al.; EVIDENCE (EVIdence of Inter-
328(1–2), 1–8. feron Dose-response: European North American Comparative Efficiency)
Metz, I., Weigand, S. D., Popescu, B. F., et al. (2014). Pathologic heterogeneity Study Group; University of British Columbia MS/MRI Research Group.
persists in early active multiple sclerosis lesions. Annals of Neurology, 75(5), (2002). Randomized, comparative study of interferon beta-1a treatment
728–738. regimens in MS: The EVIDENCE trial. Neurology, 59(10), 1496–1506.
Mikol, D. D., Barkhof, F., Chang, P., et al. (2008). Comparison of subcutane- Patrikios, P., Stadelmann, C., Kutzelnigg, A., et al. (2006). Remyelination
ous interferon beta-1a with glatiramer acetate in patients with relapsing is extensive in a subset of multiple sclerosis patients. Brain, 129(Pt 12),
multiple sclerosis (the REbif vs. Glatiramer acetate in relapsing MS disease 3165–3172.
[REGARD] study): A multicentre, randomised, parallel, open-label trial. Patti, F., Amato, M. P., Bastianello, S., et al.; COGIMUS Study Group. (2012).
The Lancet Neurology, 7(10), 903–914. Effects of immunomodulatory treatment with subcutaneous interferon
Miller, D. H., Fazekas, F., Montalban, X., et al. (2014). Pregnancy, sex and beta-1a on cognitive decline in mildly disabled patients with relapsing-re-
hormonal factors in multiple sclerosis. Multiple Sclerosis, 20(5), 527–536. mitting multiple sclerosis. Multiple Sclerosis, 16(1), 68–77.
Miller, D., Weinshenker, B., Filippi, M., et al. (2008). Differential diagnosis Penny, S., Khaleeli, Z., Cipolotti, L., et al. (2010). Early imaging predicts later
of suspected multiple sclerosis: A consensus approach. Multiple Sclerosis, cognitive impairment in primary progressive multiple sclerosis. Neurology,
14(9), 1157–1174. 74(7), 545–552.
Miller, D. M., Weinstock-Guttman, B., Bethoux, F., et al. (2000). A meta-anal- Petzold, A., & Plant, G. T. (2014). Chronic relapsing inflammatory optic neu-
ysis of methylprednisolone in recovery from multiple sclerosis exacerba- ropathy: A systematic review of 122 cases reported. Journal of Neurology,
tions. Multiple Sclerosis, 6(4), 267–273. 261(1), 17–26.
Minneboo, A., Uitdehaag, B. M., Ader, H. J., et al. (2005). Patterns of en- Pioro, E. P., Brooks, B. R., Cummings, J., Schiffer, R., Thisted, R. A., Wynn,
hancing lesion evolution in multiple sclerosis are uniform within patients. D., et al. (2010). Dextromethorphan plus ultra low-dose quinidine reduces
Neurology, 65(1), 56–61. pseudobulbar affect. Annals of Neurology, 68(5), 693–702.
Montalban, X., Hauser, S. L., Kappos, L., Arnold, D. L., Bar-Or, A., Comi, G., Pittock, S. J., Mayr, W. T., McClelland, R. L., et al. (2004). Change in MS-re-
et al. (2017). Ocrelizumab versus placebo in primary progressive multiple lated disability in a population-based cohort: A 10-year follow-up study.
sclerosis. New England Journal of Medicine, 376(3), 209–220. Neurology, 62(1), 51–59.
Montalban, X., Tintore, M., Swanton, J., et al. (2010). MRI criteria for MS in Polman, C. H., O’Connor, P. W., Havrdova, E., et al. (2006). A randomized,
patients with clinically isolated syndromes. Neurology, 74(5), 427–434. placebo-controlled trial of natalizumab for relapsing multiple sclerosis.
Morrow, S. A., Kaushik, T., Zarevics, P., et al. (2009). The effects of L-am- New England Journal of Medicine, 354(9), 899–910.
phetamine sulfate on cognition in MS patients: Results of a randomized Polman, C. H., Reingold, S. C., Banwell, B., et al. (2011). Diagnostic criteria
controlled trial. Journal of Neurology, 256(7), 1095–1102. for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of
Mowry, E. M., Waubant, E., McCulloch, C. E., et al. (2012). Vitamin D status Neurology, 69(2), 292–302.
predicts new brain magnetic resonance imaging activity in multiple sclero- Prineas, J. W., Kwon, E. E., Cho, E., et al. (2001). Immunopathology of sec-
sis. Annals of Neurology, 72(2), 234–240. ondary-progressive multiple sclerosis. Annals of Neurology, 50(5), 646–657.
Mueller, B. A., Zhang, J., & Critchlow, C. W. (2002). Birth outcomes and need Rae-Grant, A., Bennett, A., Sanders, A. E., Phipps, M., Cheng, E., & Bever,
for hospitalization after delivery among women with multiple sclerosis. C. (2015). Quality improvement in neurology: Multiple sclerosis quality
American Journal of Obstetrics and Gynecology, 186(3), 446–452. measures: Executive summary. Neurology, 85(21), 1904–1908.
Munger, K. L., Bentzen, J., Laursen, B., Stenager, E., Koch-Henriksen, N., Rao, S. M., Leo, G. J., Bernardin, L., & Unverzagt, F. (1991). Cognitive
Sørensen, T. I., et al. (2013). Childhood body mass index and multiple dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction.
sclerosis risk: A long-term cohort study. Multiple Sclerosis Journal, 19(10), Neurology, 41(5), 685–691.
1323–1329. Rio, J., Castillo, J., Rovira, A., et al. (2009). Measures in the first year of thera-
Munger, K. L., Levin, L. I., Hollis, B. W., et al. (2006). Serum 25-hydroxyvita- py predict the response to interferon beta in MS. Multiple Sclerosis, 15(7),
min D levels and risk of multiple sclerosis. Journal of the American Medical 848–853.
Association, 296(23), 2832–2838. Río, J., Rovira, À., Tintoré, M., Otero-Romero, S., Comabella, M., Vidal-Jor-
Munger, K. L., Zhang, S. M., O’Reilly, E., et al. (2004). Vitamin D intake and dana, Á., et al. (2018). Disability progression markers over 6–12 years in
incidence of multiple sclerosis. Neurology, 62(1), 60–65. interferon-β-treated multiple sclerosis patients. Multiple Sclerosis Journal,
Naismith, R. T., Piccio, L., Lyons, J. A., Lauber, J., Tutlam, N. T., Parks, B. J., 24(3), 322–330.
et al. (2010). Rituximab add-on therapy for breakthrough relapsing Rose, A. S., Kuzma, J. W., Kurtzke, J. F., et al. (1970). Cooperative study in
multiple sclerosis: A 52-week phase II trial. Neurology, 74(23), 1860–1867. the evaluation of therapy in multiple sclerosis. ACTH vs. placebo—final
Neema, M., Stankiewicz, J., Arora, A., et al. (2007). T1- and T2-based MRI report. Neurology, 20(5), 1–59.
measures of diffuse gray matter and white matter damage in patients with Rudick, R. A., Fisher, E., Lee, J. C., et al. (1999). Use of the brain parenchymal
multiple sclerosis. Journal of Neuroimaging, 17(s1), 16S–21S. fraction to measure whole brain atrophy in relapsing-remitting MS. Multi-
Nocentini, U., Pasqualetti, P., Bonavita, S., et al. (2006). Cognitive dysfunction ple Sclerosis Collaborative Research Group. Neurology, 53(8), 1698–1704.
in patients with relapsing-remitting multiple sclerosis. Multiple Sclerosis, Rudick, R. A., & Polman, C. H. (2009). Current approaches to the identifica-
12(1), 77–87. tion and management of breakthrough disease in patients with multiple
O’Connor, P., Wolinsky, J. S., Confavreux, C., et al. (2011). Randomized trial sclerosis. The Lancet Neurology, 8(6), 545–559.
of oral teriflunomide for relapsing multiple sclerosis. New England Journal Rudick, R. A., Stuart, W. H., Calabresi, P. A., et al. (2006). Natalizumab plus
of Medicine, 365(14), 1293–1303. interferon beta-1a for relapsing multiple sclerosis. New England Journal of
O’Riordan, J. I., Thompson, A. J., Kingsley, D. P., et al. (1998). The prognostic Medicine, 354(9), 911–923.
value of brain MRI in clinically isolated syndromes of the CNS. A 10-year Sadovnick, A. D., Remick, R. A., Allen, J., et al. (1996). Depression and multi-
follow-up. Brain, 121(Pt 3), 495–503. ple sclerosis. Neurology, 46(3), 628–632.
References 1254.e5
Sawcer, S., Franklin, R. J., & Ban, M. (2014). Multiple sclerosis genetics. The Ukkonen, M., Vahvelainen, T., Hamalainen, P., et al. (2009). Cognitive dys-
Lancet Neurology, 13(7), 700–709. function in primary progressive multiple sclerosis: A neuropsychological
Scalfari, A., Knappertz, V., Cutter, G., et al. (2013). Mortality in patients with and MRI study. Multiple Sclerosis, 15(9), 1055–1061.
multiple sclerosis. Neurology, 81(2), 184–192. University of California, San Francisco MS-EPIC Team, U. of, Cree, B. A.
Schairer, L. C., Foley, F. W., Zemon, V., et al. (2014). The impact of sexual C., Hollenbach, J. A., Bove, R., Kirkish, G., Sacco, S., et al. (2019). Silent
dysfunction on health-related quality of life in people with multiple sclero- progression in disease activity-free relapsing multiple sclerosis. Annals of
sis. Multiple Sclerosis, 20(5), 610–616. Neurology, 85(5), 653–666.
Scott, T. F. (2007). Nosology of idiopathic transverse myelitis syndromes. Acta Varatharaj, A., & Galea, I. (2017). The blood-brain barrier in systemic inflam-
Neurologica Scandinavica, 115(6), 371–376. mation. Brain, Behavior, and Immunity, 60, 1–12.
Scott, T. F., Frohman, E. M., De Seze, J., et al.; Therapeutics and Technology Vermersch, P., Czlonkowska, A., Grimaldi, L. M., et al. (2014). Teriflunomide
Assessment Subcommittee of American Academy of Neurology. (2011). versus subcutaneous interferon beta-1a in patients with relapsing multiple
Evidence-based guideline: Clinical evaluation and treatment of trans- sclerosis: A randomised, controlled phase 3 trial. Multiple Sclerosis, 20(6),
verse myelitis: Report of the Therapeutics and Technology Assessment 705–716.
Subcommittee of the American Academy of Neurology. Neurology, 77(24), Vukusic, S., & Confavreux, C. (2006). Pregnancy and multiple sclerosis: The
2128–2134. children of PRIMS. Clinical Neurology and Neurosurgery, 108(3), 266–270.
Sicotte, N. L., Voskuhl, R. R., Bouvier, S., et al. (2003). Comparison of mul- Vukusic, S., Hutchinson, M., Hours, M., et al. (2004). Pregnancy and multiple
tiple sclerosis lesions at 1.5 and 3.0 Tesla. Investigative Radiology, 38(7), sclerosis (the PRIMS study): Clinical predictors of post-partum relapse.
423–427. Brain, 127(Pt 6), 1353–1360.
Siller, N., Kuhle, J., Muthuraman, M., Barro, C., Uphaus, T., Groppa, S., van der Vuurst de Vries, R. M., Mescheriakova, J. Y., Runia, T. F., Siepman,
et al. (2019). Serum neurofilament light chain is a biomarker of acute and T. A. M., Wokke, B. H. A., Samijn, J. P. A., et al. (2018). Smoking at time
chronic neuronal damage in early multiple sclerosis. Multiple Sclerosis, of CIS increases the risk of clinically definite multiple sclerosis. Journal of
25(5), 678–686. Neurology, 265(5), 1010–1015.
Smolders, J., Hupperts, R. M. M., Vieth, R., et al. (2016). High dose chole- Wallin, M. T., Culpepper, W. J., Campbell, J. D., Nelson, L. M., Langer-Gould,
calciferol (vitamin D3) oil as add-on therapy in subjects with relapsing- A., Marrie, R. A., et al. (2019). The prevalence of MS in the United States:
remitting multiple sclerosis (RRMS) receiving subcutaneous interferon A population-based estimate using health claims data. Neurology, 92(10),
β-1a (scIFNβ-1a). ECTRIMS Online Library. e1029–e1040.
Solomon, A. J., Bourdette, D. N., Cross, A. H., Applebee, A., Skidd, P. M., Weber, M. S., Derfuss, T., Metz, I., & Brück, W. (2018). Defining distinct features
Howard, D. B., et al. (2016). The contemporary spectrum of multiple of anti-MOG antibody associated central nervous system demyelination.
sclerosis misdiagnosis. Neurology, 87(13), 1393–1399. Therapeutic Advances in Neurological Disorders, 11, 1756286418762083.
Sorensen, P. S., Bertolotto, A., Edan, G., et al. (2012). Risk stratification for Weinshenker, B. G. (2001). Plasma exchange for severe attacks of inflammato-
progressive multifocal leukoencephalopathy in patients treated with natali- ry demyelinating diseases of the central nervous system. Journal of Clinical
zumab. Multiple Sclerosis, 18(2), 143–152. Apheresis, 16(1), 39–42.
Stenager, E., Stenager, E., & Jensen, K. (1994). Effect of pregnancy on the Weinshenker, B. G., Bass, B., Rice, G. P., et al. (1989). The natural history of
prognosis for multiple sclerosis: A 5-year follow up investigation. Acta multiple sclerosis: A geographically based study. I. Clinical course and
Neurologica Scandinavica, 90(5), 305–308. disability. Brain, 112(Pt 1), 133–146.
Thompson, A. J., Banwell, B. L., Barkhof, F., Carroll, W. M., Coetzee, T., Westerlind, H., Boström, I., Stawiarz, L., Landtblom, A. M., Almqvist, C., &
Comi, G., et al. (2018). Diagnosis of multiple sclerosis: 2017 revisions of Hillert, J. (2014). New data identify an increasing sex ratio of multiple
the McDonald criteria. The Lancet Neurology, 17(2), 162–173. sclerosis in Sweden. Multiple Sclerosis, 20(12), 1578–1583.
Thrower, B. W. (2009). Relapse management in multiple sclerosis. The Willer, C. J., Dyment, D. A., Risch, N. J., et al.; Canadian Collaborative Study
Neurologist, 15(1), 1–5. Group. (2003). Twin concordance and sibling recurrence rates in multiple
Tremlett, H., Fadrosh, D. W., Faruqi, A. A., Zhu, F., Hart, J., Roalstad, S., et al. sclerosis. Proceedings of the National Academy of Sciences of the United
(2016). Gut microbiota in early pediatric multiple sclerosis: A case−control States of America, 100(22), 12877–12882.
study. European Journal of Neurology, 23(8), 1308–1321. Wingerchuk, D. M., Banwell, B., Bennett, J. L., Cabre, P., Carroll, W., Chitnis,
Tremlett, H., Paty, D., & Devonshire, V. (2006). Disability progression in T., et al. (2015). International consensus diagnostic criteria for neuromy-
multiple sclerosis is slower than previously reported. Neurology, 66(2), elitis optica spectrum disorders. Neurology, 85(2), 177–189.
172–177. Zuvich, R. L., McCauley, J. L., Oksenberg, J. R., et al. (2010). Genetic variation
Turner, B., Cree, B. A. C., Kappos, L., Montalban, X., Papeix, C., Wolinsky, J. in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility.
S., et al. (2019). Ocrelizumab efficacy in subgroups of patients with relaps- Human Genetics, 127(5), 525–535.
ing multiple sclerosis. Journal of Neurology, 266(5), 1182–1193.

80 - Multiple Sclerosis and Other Inflammatory Demyelinating Diseases of The Central Nervous System

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

80 - Multiple Sclerosis and Other Inflammatory Demyelinating Diseases of The Central Nervous System

Uploaded by

Copyright:

Available Formats

80

Multiple Sclerosis and Other

optic neuropathy, toxic optic neuropathy, neuromyelitis optica, or anti-

CHARACTERISTIC CLINICAL SYMPTOMS AND Impairment of Other Cranial Nerves

Fig. 80.1 Schematic diagram of impulse conduction in normal (upper)

ETIOLOGY In recent years, multiple genome-wide association studies (GWAS)

Diet and the Microbiome Geographical Distribution

The McDonald Criteria Diagnostic Studies

Clinical (Attacks) Lesions Additional Criteria to Make DX

Preclinical Relapsing Secondary progressive

Relapses and impairment

TABLE 80.2 Cerebrospinal Fluid Abnormalities in Multiple Sclerosis

TABLE 80.3 Comparison of Sensitivity of Laboratory Testing in Multiple Sclerosis

2013 MS Phenotype Descriptions 2013 MS Phenotype Descriptions

Clinically not active*

*activity = clinical relapses and/or MRI (Gd-enhancing MRI

Spinal cord/Optic nerve Brainstem/Cerebellum Cerebral hemispheres

Marburg Variant TREATMENT AND MANAGEMENT

decrease IgG synthesis in the CNS. Intravenous methylprednisolone

Treatment Strategies and Goals of Therapy

TABLE 80.5 Diagnostic Criteria for NMOSD with AQP4 IgG

Core Clinical Characteristics

You might also like