46
Multiple Sclerosis
RAM N. NARAYAN, OLAF STÜVE, AND ANJALI SHAH
Multiple sclerosis (MS) is a chronic, inflammatory, neurodegen-
erative disorder of the central nervous system (CNS) and also the
most common cause of nontraumatic disability in young adults.136
Approximately 400,000 individuals are affected with MS in the
United States.134 It can present in numerous ways and affects
several functional and cognitive systems. This patient population
often develops challenges with gait, spasticity, cognition, fatigue,
weakness, bladder and bowel function, and wounds.
Physiatrists are well equipped to manage many of the chal-
lenges of MS that might otherwise go undetected or unacknowl-
edged. An understanding of the pathogenetic, pharmacologic,
and rehabilitative options for persons with MS (PwMS) is vital
for the practicing physiatrist. The first disease-modifying therapy
(DMT) for MS was approved in 1993. Since then, there has been
rapid progress, so that there are currently 10 DMT options for
PwMS. As the number of more and more effective DMTs for MS
increases, patients and families continue to expect an improved
quality of life and to hope for treatment options extending into
optimal management of their many symptoms. Therefore the role
of physiatry for PwMS will continue to expand, and it is vital
that the practitioner be familiar with the specificities of MS, what
differentiates it from other diseases, and the degree to which reha-
bilitation can be of help to this population.
Costs
The estimated US annual cost for MS is $28 billion, making it
one of the costliest illnesses to treat.59,134 Most DMTs for MS are
distributed by specialty pharmacies, and specialty drug costs in the
areas of oncology, rheumatoid arthritis, and MS comprised 51%
of the annual spending of a major insurance company.195 These
drugs cost approximately $87 billion in 2012 and comprised
approximately 3.1% of national health spending. As more effec-
tive treatment options become available for patients with chronic
illnesses, it is estimated that specialty drug spending will quadru-
ple and comprise approximately 9.1% of national health spending
over the next several years.139 The annual direct and indirect costs
of MS per person are estimated to range from $8528 to $54,244.2
Direct costs make up 77% of the total and are largely attributable
to the cost of prescription medications.2 Contrary to the laws of
supply and demand, each new DMT that is introduced has not
driven market competition to lower prices.  has been found to be strongly associated with the development of
Epidemiology
Females are typically affected two to three times as often as
males.104 Although females have a higher risk of having MS, those
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
males who are affected tend to have a more aggressive course,
more difficulty with recovery after an attack, and a more rapid
development of disability.25,37,38,175 The peak age of diagnosis is
believed to be 20 to 40 years (Fig. 46.1).118 Compared with Asian,
black, and Hispanic populations, the disease is more common in
non-Hispanic whites, with a lifetime incidence of approximately 1
in 400.36 It remains a disease that largely afflicts whites.
MS is more common in Europe, the United States, Canada, New
Zealand, and Australia and rare in the equatorial countries and on
the Asian continent.89,177 Migration studies have observed that indi-
viduals who move from high- to low-risk areas during adolescence
or early childhood adopt the risk of the new area. The opposite has
been shown to be true in those moving from low- to high-risk areas,
but with less robustness.7,64 In addition, birth month appears to be
of importance in MS development. In a metaanalysis of 145,672
MS patients across various geographic locations and populations,
it was found that MS births are higher in the spring as opposed to
autumn, specifically in the months of March, April, and May. A
lower number of MS births was found in November. The metaanal-
ysis concludes that the month and season of birth are significantly
associated with the later development of MS.140 This was thought
to result from low maternal sun exposure during pregnancy and
possibly low antenatal levels of vitamin D. 
Pathogenesis
Genetic Linkage
MS is thought to be an autoimmune disease in which immune
and inflammatory cells attack the CNS, damaging myelin, axons,
and neurons. Similar to many complex human diseases, MS devel-
ops in a genetically susceptible host who has experienced several
environmental triggers. This hypothesis is supported by the famil-
ial clustering of MS. Monozygotic twins have a 35% concordance
rate, whereas dizygotic twins and first-degree relatives both have
a concordance rate of approximately 4% if a family member or
sibling has MS.50,199 Also, serologic typing has found that human
leukocyte antigen (HLA) is associated with the major histocompat-
ibility complex (MHC) and various immune-mediated diseases;
this observation has given rise to the field of immunogenetics. In
MS, the HLA-DRB1*1501 gene, located on chromosome 6p21,
MS. The HLA genes have been the only consistent genetic linkage
noted in MS. Heterozygous carriers have a three times and homo-
zygous carriers a six times increased risk of developing MS.87,167
The DR15 haplotype is also associated with narcolepsy and sys-
temic lupus erythematosus (Table 46.1).188,201 
983
984 SE C T I O N 4    Issues in Specific Diagnoses

Incidence, per 100,000 patient years

30 Late EBV infection with IM
Men
25 Women Early EBV infection without IM

Multiple sclerosis incidence rate

20 No EBV infection

15

10

0
0 10 20 30 40 50 60 70 80 90 100
A Age at diagnosis
Prevalence, per 100,000 patient years

700
Men
600 Women 0 5 10 15 20 25 30 35 40 45 50 55 60
Age
500

400
• Fig. 46.2  Schematic representation of multiple sclerosis (MS) incidence
according to Epstein-Barr virus (EBV) infection. The shape of the incidence
300 curve labeled “Early EBV Infection Without IM” is based on the typical age-
specific incidence of MS in most populations; incidence begins to increase
200 in adolescence, peaks around age 25 to 30 years, and declines to nearly
100 zero by age 60 years.22 The age-specific incidence for the group with no
EBV infection has been drawn at one-tenth the incidence among individu-
0 als who are EBV positive based on the results of a previous review23 and
0 10 20 30 40 50 60 70 80 90 100 that of individuals with late EBV infection and infectious mononucleosis
B Age in 2010 (IM) has been estimated to be 2.3 times higher than that of individuals who
are EBV positive without history of IM (this metaanalysis). More accurate
• Fig. 46.1  Incidence and prevalence of multiple sclerosis in women and curves could be drawn by taking into account the proportion of individu-
men by age. (A) Incidence (per 100,000 patient years). (B) Prevalence (per als in the population who are infected with EBV early in childhood and
100,000 patient years). (From Mackenzie IS, Morant SV, Bloomfield GA, the age-specific prevalence of a history of IM. These adjustments have
et al: Incidence and prevalence of multiple sclerosis in the UK 1990-2010: been ignored for simplicity and because these proportions vary across
a descriptive study in the General Practice Research Database, J Neurol developed countries. (From Thacker EL, Mirzaei F, Ascherio A: Infectious
Neurosurg Psychiatry 85:76–84, 2014.) mononucleosis and risk for multiple sclerosis: a meta-analysis, Ann Neurol
59:499–503, 2006.)

research supports changing the minimum daily consumption of

TABLE vitamin D because it is found to be protective in several other
46.1
 Genetic Risk of Multiple Sclerosis (MS) diseases. Studies are currently being conducted to examine the
influence of vitamin D levels on disease progression in MS.9,132,133
Relative With MS Chance of Developing MS (%) Infection with Epstein-Barr virus (EBV) or human herpesvirus
Monozygotic twin 25–30 4 in an adolescent or young adult increases the risk of MS devel-
opment. Approximately 50% of children have EBV exposure by
Dizygotic twin 3–5 the age of 5 years and approximately 80% to 90% of the popula-
First-degree relative (child or 2–4 tion is exposed by 20 years of age.202 Primary EBV infection is
full sibling) typically symptomatic in infants; it presents as infectious mono-
nucleosis (IM) when reactivation occurs in adolescents or young
Data from Dyment DA, Ebers GC, Dessa Sadovnick A: Genetics of multiple sclerosis,
adults. Proponents of the “Epstein-Barr virus hypothesis” have
Lancet Neurol 3:104–110, 2004.
found that individuals exposed to late EBV and IM increase their
   risk of MS development by 2.3 times that of individuals exposed
to EBV without IM. Never having been exposed to EBV reduced
Environmental Factors the risk of MS by one-tenth compared with individuals who had
been exposed (Fig. 46.2).6,8,113,189
Environmental factors have been evaluated for their effect on the Cigarette smoking is now a known risk factor for the develop-
risk of developing MS as well as their influence on progression. ment of MS.47,84,86,91,161 MS risk is approximately 50% higher in
The incidence of MS increases with distance from the equator. smokers and is associated with the intensity and duration of smok-
It has also been found that reduced levels of vitamin D increase ing. Although it seems that men are more susceptible to the adverse
the risk of MS development, particularly in whites.9,132,133 A typi- effect of smoking, the increasing ratio of female to male smokers
cal multivitamin contains approximately 400 International Units has been proposed as an explanation for the increasing female-
(IU) of vitamin D. Twenty minutes of whole-body sun expo- to-male ratio in MS incidence in several countries.90 A cumula-
sure equates to approximately 10,000 IU of vitamin D. Further, tive dose response exists between years and intensity of smoking

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.

and MS risk; cigarette smoking also appears to increase the rate of
MS disease progression to secondary progressive MS (SPMS).88,90
The detrimental effects of smoking decline after 10 years of smok-
ing cessation despite the duration and intensity of abuse. Moist
tobacco “snuffing” did not have the same effect or causation, lead-
ing researchers to study the irritating effect of tobacco smoke on
the lungs and immune system as a possible cause.85 Interestingly,
alcohol consumption seems to protect a person from developing
MS in a dose-dependent manner and attenuates the detrimental
effects of smoking.87  and several MS disease–modifying drugs are thought to shift the
Other Factors
A strong correlation has been observed to exist between the body
mass index (BMI) of females at 10 and 20 years of age. A BMI of
>20 increased the risk of MS, and a BMI ≥27 increased the risk by
twofold.68,87 Obese females between 10 and 20 years of age seem
to be at greater risk than males during the same time period. An
even stronger correlation of developing MS was demonstrated in
females with a BMI ≥27 and HLA-DRB1*15 status.68
Increased clinical and radiologic activity with increased sodium
intake has been suggested as another cause of MS. This has been
demonstrated in small-scale studies and is under further investi-
gation.52 Concerns about the risk of exposure to mercury, trace
metals, organic solvents, or crude oil have not demonstrated con-
vincing evidence.121  ing phase.172,173 Measures of neurodegeneration, such as brain
Immunology
MS exhibits considerable heterogeneity in clinical presentation
and disease course. It is considered an autoimmune disease by
most experts, but what initiates the abnormal immune response
is not clear.
Most of the knowledge about the immunopathogenesis of MS
comes from the study of animal models, mainly experimental
autoimmune encephalomyelitis (EAE), in which immunization of
an animal (e.g., a mouse or rat) with myelin components leads to
a CD4+ lymphocyte-orchestrated inflammatory response in the
CNS.
The pathologic hallmarks of acute MS lesions are perivenu-
lar immune cell infiltrate, demyelination, myelin-laden mac-
rophages, edema, and axonal damage.63 Relapses in MS are
thought to be mediated by peripherally activated helper lym-
phocytes that target the CNS.98 These autoreactive lymphocytes
may be activated through “molecular mimicry,” in which foreign
antigens (e.g., viral or bacterial proteins) similar to CNS anti-
gens activate the lymphocytes that will eventually react against
the self-antigens. As an alternative explanation, antigens leaked
from the CNS, probably owing to a previous unknown insult,
can trigger the immune response by activating CD4+ helper T
cells. These cells facilitate the recruitment and activation of other
immune cells, which enter the brain and spinal cord by interact-
ing with endothelial cells of the blood-brain barrier. Upon reac-
tivation with autoantigens by CNS-resident antigen-presenting
cells, they damage myelin, axons, and neurons by various effec-
tor mechanisms.
It is not clear which autoantigens ignite the autoimmune pro-
cess in MS, which is partly why the disease is so heterogeneous.
In fact, as inflammation increases, access of the immune system
to previously compartmentalized antigens, or “epitope spreading,”
may occur, causing new epitopes in the same protein or other pro-
teins to become new targets of the immune attack.43
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
CHAPTER 46  Multiple Sclerosis 985
CD4+ T cells, based on the cytokine milieu during their acti-
vation, can differentiate into functionally different effector cells
and have been categorized into T helper 1 (Th1), Th2, and Th17
cells. It has been shown that both Th1 and Th17 cells are capable
of inducing EAE in mice. Some of the MS therapies—including
interferon-β (IFN-β), glatiramer acetate, and fingolimod—have
been shown to dampen both Th1 and Th17 responses.14,124,154 In
the context of autoimmune inflammatory demyelination, Th2 cell
responses are considered to be protective and antiinflammatory,
immune system toward the Th2 response.
Cerebrospinal fluid (CSF) oligoclonal bands, produced by B
cell–derived plasma cells, are the most consistent immunologic
abnormality in patients with MS. Also, B-cell depletion by mono-
clonal antibodies effectively decreases the inflammatory disease
activity in MS (as manifested by new gadolinium-enhancing
lesions on magnetic resonance imaging [MRI]).82 These observa-
tions suggest a strong role for B cells in the pathogenesis of MS.
Inflammation and degeneration are present right from the ear-
liest stages, and degeneration is thought to be the underlying cause
of the irreversible and progressive disability that develops in most
PwMS.61 Neurodegeneration is directly or indirectly the result
of inflammation and demyelination. Several studies have shown
that the risk and the latency of entering the secondary progressive
phase are not related to the number of exacerbations in the relaps-
atrophy and cortical gray matter lesion load, are more strongly
correlated with different measures of motor and cognitive disabil-
ity.27,28 The pathogenic processes involved in progressive MS are
quite complex and continue to pose a challenge in the discovery
of therapeutic targets. 
Subtypes
Relapsing-remitting MS (RRMS) is the most common subtype
and affects approximately 50% to 65% of PwMS. This condition
is characterized by periods of exacerbation followed by periods of
remission. SPMS becomes manifest when a patient with RRMS
no longer has exacerbations and now has a persistent accumulation
of disability occurring over time. There is no biomarker that signi-
fies the progression from RRMS to SPMS. The rate of disability
accumulation varies from patient to patient. Primary progressive
MS (PPMS) affects males and females equally (1:1) and comprises
approximately 10% to 15% of PwMS. This differs from RRMS in
a noticeable lack of exacerbations; instead, there is an accumula-
tion of disability over time. The speed of accumulation varies from
person to person. The least common and most aggressive type is
progressive relapsing. This affects less than 5% of PwMS and has
high rates of mortality. 
Diagnosis
Because MS has similarities with various other neurologic, rheu-
matologic, and vascular diseases, it remains a diagnosis of exclu-
sion. In addition, it is important to distinguish and exclude other
demyelinating disorders, including neuromyelitis optica spectrum
disorders (NMOSD), acute transverse myelitis, and acute dissemi-
nated encephalomyelitis (ADEM). The 2015 diagnostic criteria for
NMOSD include separate criteria in the presence and absence of
the aquaporin-4 (AQP4) antibody. Differentiation of NMOSD
from MS is vital because treatment is distinct for each disorder.
Acute transverse myelitis presents acutely, may be monophasic or
986 SE C T I O N 4    Issues in Specific Diagnoses

• BOX 46.1  Common Symptoms of Multiple Sclerosis In addition to clinical symptoms, MRI is recommended for
the diagnostic evaluation of MS. Radiologic imaging can supple-
•  ifficulty with activities of daily living
D ment or support clinical and laboratory data. The International
• Ataxia/apraxia Panel on Diagnosis of MS (the panel) recommends screening
• Neurogenic bowel with MR sequencing. The McDonald criteria are the most cur-
• Neurogenic bladder rent and widely used to diagnose MS (Table 46.2). These criteria
• Cognition defects went through updates in 2001, 2005, and 2010; the most recent
• Fatigue
• Heat sensitivity/intolerance
version was released in 2017.123,151,152,190 What has remained
• Gait disorders consistent throughout these updates is that MS can be diagnosed
• Mood disturbance based on clinical symptoms alone. Two clinical attacks involv-
• Pain ing different brain areas at two separate points (separated by at
• Spasticity least a month) in time fulfill the criteria required to diagnose a
• Optic neuritis PwMS. The criterion for dissemination in space on MRI is met
• Weakness by having one or more T2 lesions in two of five locations in the
• Sexual dysfunction CNS: periventricular, cortical, juxtacortical, infratentorial, and
• Numbness/paresthesias spinal cord (Box 46.3). Dissemination in time on MRI is met
by the simultaneous presence of asymptomatic or symptomatic
gadolinium-enhancing lesions and nonenhancing lesions or new
• BOX 46.2  Differential Diagnosis of Multiple T2 and/or a gadolinium-enhancing lesion or lesions on a follow-
Sclerosis up MRI (Box 46.4). 

•  euromyelitis optica
N
• Acute disseminated encephalomyelitis Clinical Decision-Making
• Transverse myelitis In addition to its usefulness in diagnostic decision-making, MRI
• Neurosyphilis is frequently used in making clinical decisions regarding the effec-
• Cerebral autosomal-dominant arteriopathy with subcortical infarcts and
leukoencephalopathy
tiveness of DMTs (Fig. 46.3). MRI can reflect subclinical and pre-
• Behçet disease clinical changes and is useful in monitoring any underlying disease
• Neurosarcoidosis activity.112 Suggested MR images for diagnostic and clinical deci-
• Vitamin B12 deficiency sion-making include T1 images with and without contrast, T2
• Folate deficiency images, and fluid-attenuated inversion recovery (FLAIR) sequenc-
• Vasculitis process ing. T1 images with and without contrast determine the presence
• Mixed connective tissue disease of “active” lesions. Areas of breakdown in the blood-brain barrier,
• Neurosarcoidosis characterized by an inflammatory defect or disruption, result in
• Rheumatoid arthritis perivascular changes and allow uptake of gadolinium. Such lesions
• Lyme disease subsequently enhance on T1 images. Contrast-enhancing lesions
• Systemic lupus erythematosus
• Sjögren syndrome
will remain visible for approximately 4 to 12 weeks, are associated
• Carcinoma with new or active lesions, and are indicative of clinically active
• Wegener granulomatosis disease.77,101 This observation is often used as a marker for disease
• Hypercoagulable state control in both clinical and research settings. Key technical fac-
• Migraine history tors include waiting approximately 15 minutes after contrast infu-
• Hypertension sion to ensure accurate imaging. Gadolinium-enhancing lesions
• Mitochondrial disorders have been weakly correlated with disability or the accumulation
• “Normal” of impairment.97,112
“Black hole” lesions are hypointense nonenhancing T1 lesions.
They are correlated with chronic axonal damage and loss on MR
multiphasic, and has a clearly defined sensory level with exclusion sequences as well as on histopathologic examination.112,196,197
of other causes. It is a focal inflammatory disorder of the spinal cord Their presence is associated with worsening cognitive function.
and can result in abnormalities in motor, sensory, and/or autonomic Widening of the third ventricle is also associated with cortical
function.191 Finally, the antimyelin-oligodendrocyte glycoprotein atrophy and is again correlated with cognitive dysfunction.19
(MOG) antibody syndrome is emerging as a mimic of MS and Reduction in T1 black hole formation is used as a biomarker for
NMOSD. It tends commonly to present as optic neuritis (usually neuroprotection.
bilateral), long-segment transverse myelitis, and ADEM, although FLAIR imaging suppresses the CSF hyperintense signal in
rarer and atypical presentations have been reported. Current treat- T2 images and allows for clearer demarcation of hyperintensities
ment guidelines are largely similar to those for NMOSD. associated with the MS plaques. The short T1 inversion recovery
Common presenting symptoms in MS include optic neuritis, (STIR) sequence is a relatively new technique used to better visu-
sensory loss, paresthesias, motor dysfunction, ataxia, and weak- alize the spinal cord. Plaques and hyperintensities are viewed sig-
ness. MS may also present as overwhelming fatigue or weakness. nificantly better with STIR imaging than previous T2 or proton
This symptom may be misconstrued as fatigue caused by other density views (Fig. 46.4).135
nonmedical factors (busy lifestyles or excessive demands because Imaging frequency is often a clinician preference. New T2 or
of family or work obligations). Fatigue may be attributable to met- FLAIR lesions as well as active lesions help to determine the effi-
abolic, hematologic, or other nonneurologic issues (Boxes 46.1 cacy of DMT and correlate with the long-term accumulation of
and 46.2). disability.

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
 CHAPTER 46  Multiple Sclerosis 987

TABLE
46.2
 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS)

Clinical Presentation Additional Data Needed for MS Diagnosis

≥2 attacks,a objective clinical evidence of ≥2 lesions, or objective Nonec
clinical evidence of 1 lesion with reasonable historical evidence of
a previous attackb
≥2 attacks,a objective clinical evidence of 1 lesion DIS, demonstrated by:
≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacor-
tical, infratentorial, or spinal cord)d or
Await a further clinical attacka implicating a different CNS site
1 attack,a objective clinical evidence of ≥2 lesions DIT demonstrated by:
Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing
lesions at any time or
A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI irrespective of its
timing with reference to a baseline scan or
Await a second clinical attacka
1 attack,a objective clinical evidence of 1 lesion (clinically isolated Dissemination in space and time, demonstrated by:
syndrome) For DIS:
≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacor-
tical, infratentorial, or spinal cord)d or
Await a second clinical attacka implicating a different CNS site
For DIT:
Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing
lesions at any time or
A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI irrespective of its
timing with reference to a baseline scan or
Await a second clinical attacka
Insidious neurologic progression suggestive of MS (PPMS) 1 year of disease progression (retrospectively or prospectively determined) plus 2 of 3
of the following criteriad:
Evidence of DIS in the brain based on ≥1 T2 lesions in the MS-characteristic regions
(periventricular, juxtacortical, or infratentorial)
Evidence for DIS in the spinal cord based on ≥2 T2 lesions in the cord
Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index)
aAn attack (relapse or exacerbation) is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of
at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous neurologic examination, but some historical events with symptoms and evolution characteristic for
MS but for which no objective neurologic findings are documented can provide reasonable evidence of a previous demyelinating event. Reports of paroxysmal symptoms (historical or current) should,
however, consist of multiple episodes occurring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurologic examination,
visual-evoked potential response in patients reporting previous visual disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of neurologic symptoms.
bA clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack in the absence of documented objective neurologic findings can include

historical events with symptoms and evolution characteristics for a previous inflammatory demyelinating event; at least 1 attack, however, must be supported by objective findings.
cNo additional tests required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these criteria. If imaging or other tests (e.g., CSF) are undertaken and are negative,
extreme caution must be taken before making a diagnosis of MS and alternative diagnoses must be considered. There must be no better explanation for the clinical presentation, and objective evidence
must be present to support a diagnosis of MS.
dGadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in individuals with brainstem or spinal cord syndromes.
If the criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is “MS”; if there is suspicion but the criteria are not completely met, the diagnosis is “possible MS”;
if another diagnosis arises during the evaluation that better explains the clinical presentation, the diagnosis is “not MS.”
CNS, Central nervous system; CSF, cerebrospinal fluid; DIS, dissemination in space; DIT, dissemination in time; IgG, immunoglobulin G; MRI, magnetic resonance imaging; PPMS, primary progressive
multiple sclerosis.
From Polman CH, Reingold SC, Banwell B, et al: Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria, Ann Neurol 69:292–302, 2011.
  

Some studies have evaluated clinical and radiologic risk fac-
tors to help predict conversion to clinically definite MS. The term
clinically isolated syndrome (CIS) refers to the first demyelinat-
ing event incurred by a patient. A 14-year longitudinal study of
patients with CIS evaluated the correlation between T2 lesion
burden and conversion to MS. Study participants with one T2
lesion or more had an almost 90% chance of conversion to MS.
Another important observation from this study was the modest
correlation between lesion burden and disability, which is clini-
cally significant for the physiatrist.26 The radiologically isolated
syndrome has been used to help determine a patient’s risk for con-
version to clinically definite MS. This suggests that asymptomatic
lesions—ovoid, well-circumscribed lesions in the brain or spinal
cord—that cannot be explained by other causes may predict a
patient’s risk for MS conversion.137 Current predictors of a demy-
elinating event are age younger than 37 years, male sex, and spinal
cord involvement.138 Optical coherence tomography (OCT) is a
noninvasive technique to determine the thickness of the retinal
nerve fiber layer. It is sensitive in detecting the subclinical presence
of optic neuropathy, which affects approximately 25% to 50%
of PwMS.122 It is used as a biomarker for disease progression,
response to DMT, and disability in MS (Fig. 46.5).62
Although MRI is often helpful in the diagnostic workup pro-
cess, it is not required for the diagnosis. As stated previously,

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
988 SE C T I O N 4    Issues in Specific Diagnoses
• BOX 46.3  2017 McDonald Magnetic Resonance
Imaging Criteria for the Demonstration
of Dissemination in Space
Dissemination in space (DIS) can be demonstrated by one or more symptomatic
or asymptomatic multiple sclerosis–typical T2 lesionsa in at least two of five
following areas of the central nervous system:
• Periventricular
• Juxtacortical
• Cortical
• Infratentorial
• Spinal cord
aGadoliniumenhancement of lesions is not required for DIS.
From Thompson AJ, Banwell BL, Barkhof F, et al: Diagnosis of multiple sclerosis: 2017 revisions
of the McDonald criteria, Lancet Neurol 17(2): 162–173, 2018.
• BOX 46.4  2017 McDonald Magnetic Resonance
Imaging Criteria for the Demonstration
of Dissemination in Time
Dissemination in time can be demonstrated by any one of the following:
• A new T2 and/or gadolinium-enhancing lesion on follow-up magnetic
resonance imaging (MRI) with reference to a baseline scan irrespective
of the timing of the baseline MRI
• The simultaneous presence of both gadolinium-enhancing and
nonenhancing symptomatic or asymptomatic lesions at any time
From Thompson AJ, Banwell BL, Barkhof F, et al: Diagnosis of multiple sclerosis: 2017 revisions
of the McDonald criteria, Lancet Neurol 17(2): 162–173, 2018.
clinical impression alone can suffice. In the setting of a patient
with no abnormal or nonspecific MRI findings, other testing—
including CSF analysis and evoked potential studies—may be
needed for additional support. The “gold standard” for analyzing
CSF fluid is isoelectric focusing, which has the highest sensitiv-
ity and specificity in diagnosing MS.60 The presence of oligoclo-
nal bands represents intrathecal synthesis. The role of oligoclonal
bands in MS remains unclear; however, their presence correlates
with a diagnosis of MS.60 An elevated albumin index represents
disruption of the blood-brain barrier because albumin is synthe-
sized and metabolized outside of the CNS.4 Other factors to con-
sider include abnormalities in the IgG index, IgG synthesis, and
an elevated leukocyte count.194 CSF fluid analysis not the sine qua
non for a diagnosis of MS; however, it can provide corroborative
evidence in support of the diagnosis.
Neurophysiologic testing—such as visual, somatosensory, and
brainstem auditory evoked potentials—may also be helpful in
cases where clinical, radiologic, or CSF testing is inconclusive.
Evoked potential testing is noninvasive and detects abnormalities
throughout the length of the sensory pathway. This is helpful in
cases where patients may have clinical symptoms of optic neuri-
tis, including periorbital pain, photosensitivity, or visual changes.
A prolongation in the p100 pathway is considered abnormal.
Occasionally a prolongation in the p100 pathway of the unaf-
fected eye may also be seen.106 Somatosensory evoked potentials
detect delays along the median and tibial motor pathways. Brain-
stem auditory evoked potentials detect delays along the auditory
pathway. There is some evidence that combining visual evoked
potential and somatosensory evoked potential testing significantly
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
increases the diagnostic yield.192 Currently only visual evoked
potentials are included in the MS diagnostic guidelines.151
The Expanded Disability Status Scale (EDSS) is an ordinal
clinical rating scale ranging from 0 (no impairment) to 10 (death)
(Fig. 46.6). It is based on a detailed neurologic examination and
includes functional systems evaluating pyramidal, cerebellar,
brainstem, sensory, bowel and bladder, visual, cerebral/mental,
and miscellaneous functions. An EDSS score of 4.0 or less implies
minimal disability with no ambulation restriction; a score 6.0 or
more signifies ambulation with the use of an assistive device; and
a score 8.0 or more identifies a person who is essentially restricted
to bed or chair. The EDSS is one of the most widely used scales
clinically and for research purposes. From a functional perspec-
tive, Kurtzke should be credited for his emphasis on disability
measurement and its correlation to other systems at such an early
time.108,109 
Pharmacologic Management
Disease-Modifying Therapies
IFN-β1b was the first DMT and was introduced for the treat-
ment of RRMS in the mid-1990s. Over time, several doses of
IFN-β became available as well as glatiramer acetate. However,
the landscape of DMT has remarkably changed within the past
5 years. This has added new complexities for the decision-making
process of both physicians and patients. What was previously a
fairly simple treatment process has become more complex as more
medications with different degrees of efficacy and different safety
profiles are becoming available.
First-Generation Disease-Modifying Therapies
Interferon-β. Although its mechanism of action is not fully
understood, IFN-β (Avonex, Betaseron, Extavia, Rebif) reduces
blood-brain barrier disruption and modulates T-cell, B-cell, and
cytokine function.202 IFN-β1a is available in low and high doses.
Low-dose IFN-β1a is a once-weekly intramuscular injection. The
high-dose IFN medications are all given subcutaneously three times
a week in various dosing regimens. IFNs are associated with flu-like
side effects including increased fatigue, headache, myalgia, and joint
pain. These gradually decrease over time and can be well controlled
with nonsteroidal antiinflammatory drugs (NSAIDs) taken in con-
junction with the injections. All of the IFNs are associated with
possible blood and bone marrow abnormalities, liver dysfunction,
hypothyroidism, and mood dysfunction. There is a possibility of
developing IFN antibodies, and persistently high titers of IFN anti-
bodies are associated with diminished efficacy. It is recommended
to monitor the patient’s complete blood count, liver profile, and
thyroid function during treatment. IFN treatment has been known
to be associated with an increased risk of depression. Gradual titra-
tion of medication and routine screening are advised. 
Glatiramer Acetate. The mechanism of glatiramer acetate
(Copaxone) is also unclear but is probably attributable to the
stimulation of Treg cells.202 The initial dose was 20 mg/day
administered by subcutaneous injection. The US Food and Drug
Administration (FDA) recently approved a new dose of 40 mg
three times a week. Occasionally patients experience postinjec-
tion systemic reactions associated with flushing, palpitations, and
shortness of breath; these resolve after 5 to 10 minutes. All of
the medications administered by subcutaneous injection, includ-
ing glatiramer acetate, are associated with injection site reactions.
They can also result in lipoatrophy over time.
 CHAPTER 46  Multiple Sclerosis 989

MRI images

A
T2 FLAIR
FLAIR images

Dawson’s
fingers

B
Cervical cord T2 lesion

C
Fig. 46.3  Suggested magnetic resonance images for diagnostic and clinical decision-making. (A) Left, T2;
right, fluid-attenuated inversion recovery (FLAIR). (B) FLAIR. (C) Cervical cord T2 lesion.
Continued

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
990 SE C T I O N 4    Issues in Specific Diagnoses

Gad enhancement lesion

D
34-year-old female with RRMS with perioral numbness over the left side of her face

Natural history of brain atrophy in MS

E
Currently 67-year-old female with RRMS
These images are of the same patient: 2004, 2009 and 2013
• Fig. 46.3 cont’d  (D) Gadolinium-enhanced lesion in a 34-year-old woman with relapsing-remitting multiple
sclerosis (RRMS) with perioral numbness over the left side of her face. The red circle represents a demyelin-
ating lesion at the root entry zone of the left facial nerve corresponding to her symptoms. (E) Natural history of
brain atrophy in a 67-year-old woman with RRMS. Left to right, The same patient in 2004, 2009, and 2013.

Because IFNs and glatiramer acetate have favorable long-
term safety profiles, they remain the common first-line treatment
choices for most practitioners despite the recent availability of new
oral medications. These are similar in efficacy and reduce relapses
by 30% in the platform studies. However, adherence remains a
problem, with greater than 25% of patients discontinuing therapy
within 1 to 2 years. IFNs and glatiramer acetate are limited in
their ability to control disease activity in some patients. There-
fore patients with progressive disability related to ongoing disease
activity may have to escalate DMTs.  risk of viral infections. Documentation of varicella zoster immu-
Oral Therapies
Fingolimod. Fingolimod (Gilenya) was the first oral agent to
become commercially available for the treatment of RRMS. The
dose is 0.5 mg once daily. It is phosphorylated by sphingosine
kinase 2 and mimics sphingosine 1-phosphate (S1P) binding to
lymphocytes, which results in lymphocyte sequestration within
the lymph nodes. Fingolimod also enters the CNS; it affects neu-
rons and supports glia that express S1P receptors.160 It is associ-
ated with a 50% reduction in relapse rate versus placebo.
Adverse effects of fingolimod are related to lymphopenia as
well as the other subtypes of S1P receptors expressed on tissues.
Although few opportunistic infections have occurred, there is a
nity is required before starting therapy. Disseminated zoster infec-
tion has occurred.202 Before starting treatment, all patients must
obtain a baseline electrocardiogram because of the known risk of
bradycardia and possible risk of arrhythmias and must undergo

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
 CHAPTER 46  Multiple Sclerosis 991

• Fig. 46.4  Superior lesion conspicuity of short T1 inversion recovery (STIR) (right) and T2 (left) as char-
acterized by lesions at C1 to C2, C4, and C7. The lesion at the C4 level (arrows) is not readily visible on
T2 (left) but is easily identifiable on STIR (right). (From Nayak NB, Salah R, Huang JC, et al: A comparison
of sagittal short T1 inversion recovery and T2-weighted FSE sequences for detection of multiple sclerosis
spinal cord lesions, Acta Neurol Scand 129:198–203, 2014.)

subsequent cardiovascular monitoring. Other possible safety con-
cerns include the possibility of macular edema and elevated liver
enzymes. Safety assessments include ophthalmology assessments
and ongoing laboratory monitoring including complete blood
counts with manual differential and liver function tests.  reduction in annualized relapse rate. This drug appears to have a rela-
Teriflunomide. Teriflunomide (Aubagio) is a selective immu-
nosuppressant with antiinflammatory properties. It is the active
ring malononitrile metabolite of leflunomide, a prodrug that is
used to treat rheumatoid arthritis. It exerts immunologic effects
by inhibiting dihydroorotate dehydrogenase, an enzyme required
for de novo pyrimidine synthesis in proliferating cells. Alternative
modes of action may include reduced IFN-γ and interleukin-10
production by T cells, interference in the interaction between T
cells and antigen-presenting cells, and changes in integrin signal-
ing during T-cell activation as well as possible antioxidant effects.
Two doses of teriflunomide, 7 and 14 mg, were approved fol-
lowing two large placebo-controlled studies that revealed a 31%
reduction in annualized relapse rate. Improvements in disability
progression were shown only with the 14-mg dose. Common side
effects include lymphopenia, elevated transaminases, acute renal
failure, and alopecia. It is classified in pregnancy category X owing
to the teratogenicity associated with this drug. It has a prolonged
half-life and is contraindicated in pregnancy. It is excreted in
breast milk and semen. Cholestyramine may help to fully elimi-
nate the drug.  RRMS in 2004 and was voluntarily removed from the market
Dimethyl Fumarate. Dimethyl fumarate (BG-12; Tecfidera),
a fumaric acid ester, is a newly approved twice-daily oral DMT for
relapsing MS. It is hydrolyzed into monomethylfumarate and is elim-
inated through respiration. The starting dose is 120 mg twice daily
for 7 days followed by an increase to the maintenance dose of 240
mg twice daily. It has minimal hepatic or renal excretion. Its mecha-
nism of action is not completely clear, but it is known to activate the
nuclear-related factor-2 transcriptional pathway. This can affect oxi-
dative stress and modulate nuclear factor-κB, which could have anti-
inflammatory effects. There have been two large placebo-controlled
trials involving dimethyl fumarate, which revealed a 45% to 50%
tively favorable safety profile, although concern was raised regarding
the recent publication of a few cases of progressive multifocal leuko-
encephalopathy (PML) with dimethyl fumarate treatment in Ger-
many. There has been no association of PML related to treatment
of dimethyl fumarate for MS. Risk factors appear to be prolonged
lymphopenia and cotreatment with other immunosuppressive medi-
cations. Other potential side effects with treatment include flushing,
gastrointestinal upset, lymphopenia, and elevated liver enzymes. 
Intravenous Therapies
Natalizumab. Natalizumab (Tysabri) is a humanized mono-
clonal antibody targeting α4β1-integrin. It inhibits leukocyte
migration across the blood-brain barrier by blocking the interac-
tion between α4-integrin on leukocytes and vascular cell adhesion
molecule-1 on endothelial cells and other CNS ligands. Two large
placebo-controlled trials revealed a 68% reduction rate in relapses
as well as a 43% reduction in disability.150 The most common
treatment regimen used is 300 mg infused over 1 hour every 4
weeks. Natalizumab was initially approved for the treatment of
after the development of three cases of PML in 2005. Two of the
cases were in patients treated for MS who were also receiving IFN-
β1a. Natalizumab was reapproved for treatment in conjunction
with a safety monitoring program (the Touch program) in 2006.
Risk factors for developing PML include evidence of previous
John Cunningham (JC) virus exposure, duration of natalizumab
therapy, and previous use of immunosuppressant treatment, as

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
992 SE C T I O N 4    Issues in Specific Diagnoses

µm 138 137
160 117
300 89 106 S
OD 58 55 69 T N 74
200
61 63 I
100 137 177 136 Signal strength (max 10) 10
150
0
0 20 40 60 80 100 120 140 160 180 200 220 240 84
71 99 83
T S N I T 61 31 S
µm 31 22 42 N T 26
300 OS 25 I
36
76 107 65 Signal strength (max 10) 9
200 83

100 OD (n=3) OS (n=3) OD.OS

Imas/Smax 1.02 0.96 0.06
0 Smas/Imax 0.98 1.04 –0.06
0 20 40 60 80 100 120 140 160 180 200 220 240 Smax/Tavg 2.63 4.77 –2.14 100%
T S N I T Imax/Tavg 2.68 4.58 –1.90
95% Normal
Smax/Navg 2.43 2.93 –0.51 distribution
5%
Max-min 138.00 106.00 32.00 percentiles
1%
Smax 181.00 124.00 57.00
0%
Imax 184.00 119.00 65.00
Savg 137.00 84.00 53.00
lavg 150.00 83.00 67.00
Mean thickness 107.62 58.83 48.78

• Fig. 46.5  Optical coherence tomography (OCT) assessment from a patient with a remote (>2 years) his-
tory of acute optic neuritis. The thickness of the retinal nerve fiber layer (RNFL) is shown. Left, The distribu-
tion of the RNFL thickness measures circumferentially around the retina. Note the greater thickness of the
superior and inferior zones of the retina (the so-called double hump histogram). Center, Retinal thickness
by clock-face and quadrant sector analyses. The values in green are normal based on information derived
from a normative population database. The table provides complex analysis of these values; however, the
last row provides average thickness measures, which are those most commonly used in analysis. Right,
Images of the optic disc, centered within the scan target (an important technical aspect of image analysis).
To the right are the corresponding OCT-generated images of the retinal layers. The top red layer consti-
tutes the RNFL. The signal intensity is a measure of scan quality and should be greater than or equal to
level 7. Note the reduction in the average RNFL on the affected side compared with the unaffected eye.
I, Inferior; N, nasal; OD, right eye; OS, left eye; S, superior; T, temporal. (Reprinted with permission from
Frohman E, Costello F, Zivadinov R, et  al: Optical coherence tomography in multiple sclerosis, Lancet
Neurol 5:853–863, 2006.)

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0
No Minimal Moderate Relatively Disability Assistance Restricted Restricted Confined
disability disability disability severe affects required to to bed to bed
disability daily to work wheelchair or
routine wheelchair
• Fig. 46.6  The Expanded Disability Status Scale. (Courtesy My-MS.org.)

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.

with mitoxantrone, azathioprine, or methotrexate. The risk of
PML increases with increasing duration of therapy (0.6 per 1000
at less than 2 years, 5 per 1000 at 2 to 4 years), particularly if there
is a history of immunosuppression (1.6 per 1000 at less than 2
years, 11 per 1000 at 2 to 4 years). There are concerns regarding
possible rebound disease activity after stopping natalizumab.
In terms of monitoring for PML, patients using natalizumab
who are JC seropositive should undergo MRI surveillance every 6
months to detect early, subtle signs that would be suggestive of PML.
Clinical or MRI evidence of PML should prompt natalizumab
discontinuation until further assessment is obtained. Diagnosis is
confirmed by CSF analysis for JC virus DNA by polymerase chain
reaction. Treatment by rapid removal of natalizumab with plasma-
pheresis is needed. A short course of intravenous methylpredniso-
lone may be administered in an effort to mitigate additional damage,
which can occur from the immune reconstitution syndrome.
Additional adverse effects that can occur from natalizumab
treatment include a mildly increased risk of infections, such as
urinary tract or upper respiratory tract infections. Approximately
6% of patients can develop infusion reactions. These individuals
are at a higher risk of developing antibodies against natalizumab,
which may lessen the efficacy of treatment. There is also a poten-
tial for elevated liver enzymes.  two or more DMTs. Treatment with alemtuzumab requires special
Mitoxantrone. Mitoxantrone (Novantrone) is a chemothera-
peutic agent that has been approved to treat aggressive-relapsing
MS and SPMS. It is a cytotoxic agent that inhibits B cells, T cells,
and the proliferation of macrophages. It is administered as an
intravenous infusion four times per year (12 mg/m2) with a maxi-
mal cumulative dose of 100 to 140 mg/m2. It is known that there
is a dose-dependent risk of cardiomyopathy. Before initiation of
therapy, left ventricular ejection fraction should be obtained by
echocardiogram, multigated radionuclide angiography, or MRI.
Before each infusion with mitoxantrone, an electrocardiogram
should be performed. A qualitative reevaluation of left ventricular
ejection fraction should be obtained after termination of mito-
xantrone using the same method that was performed at baseline.
Other potential adverse reactions of mitoxantrone are lympho-
penia and elevated liver enzymes. Mitoxantrone should not be
administered when the neutrophil count falls below 1500 mm2. A
complete blood count with manual differential and liver enzymes
should be tested before administration. During therapy patients
should avoid receiving live virus vaccinations. Mitoxantrone is
assigned to pregnancy category D. If they have not completed
their family planning, patients should be informed of the poten-
tial risk that it may cause sterility. A pregnancy test should be
completed before each dose.  confirmed disability progression (30% vs 36%, HR 0.75, 95% con-
Alemtuzumab. Alemtuzumab (Lemtrada) is a humanized
monoclonal antibody against the CD52 glycoprotein that is
expressed on T and B lymphocytes, natural killer cells, and mono-
cytes; it causes rapid and profound lymphopenia.165 The recovery
of lymphopenia is variable and subset dependent. Alemtuzumab
significantly reduced the proportion of patients with any relapse
at 2 years as compared with subcutaneous IFN-β1a (22% with
alemtuzumab vs 40% for IFN-β1a, rate ratio 0.45, 95% confi-
dence interval 0.23 to 0.63) with a lower annualized relapse rate
(0.18 vs 0.39) in the CARE-MS I trial.34 However, there was no
significant difference between groups for sustained accumulation
of disability in this trial. Similarly, in the CARE-MS II trial study-
ing patients with at least one relapse while on IFN or glatiramer
therapy, alemtuzumab significantly reduced the proportion of
patients with any relapse at 2 years (35%, vs 53% for IFN-β1a,
rate ratio 0.52, 95% confidence interval 0.39 to 0.65), with a
lower annualized relapse rate (0.26 vs 0.52) and a significantly
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
CHAPTER 46  Multiple Sclerosis 993
lower rate of sustained disability accumulation (13% vs 20%, haz-
ard ratio [HR] 0.58, 95% confidence interval 0.38 to 0.87).35 In
both trials, the alemtuzumab group had significantly fewer new
or enlarging T2-lesions and fewer gadolinium-enhancing lesions.
Alemtuzumab is infused intravenously at 12 mg/day for 5 days at
the start of treatment and for 3 days after 12 months.
Secondary autoimmunity has been reported in up to 20% to
30% of treated patients.164 Although the etiology is unclear, it may
be related to secondary immune reconstitution syndrome, which
results in B cells emerging before Treg cells.89 Patients can develop
thyroid disease (16% to 18%), idiopathic thrombocytopenia, and
possibly Goodpasture syndrome. Treatment requires frequent lab-
oratory monitoring including complete blood count with manual
differential, thyroid function, and liver function tests.
Other potential side effects include infusion reactions such as urti-
caria, pyrexia, and rigor (in about 90% of patients). Pretreatment with
corticosteroids and antihistamines may improve tolerability. Infec-
tions can occur with alemtuzumab; herpesvirus infections have been
reported in about 16% to 18%, thus justifying the use of prophylactic
acyclovir during and after infusion for about 28 days (Table 46.3). Cur-
rently in the United States, alemtuzumab is usually reserved for patients
with highly active RRMS who have had an inadequate response to
registration through a restricted distribution program (the Lemtrada
Restricted Evaluation and Mitigation Strategy, or REMS) for both the
center and patient in order to ensure adequate follow-up. 
Ocrelizumab. Ocrelizumab is a recombinant human anti-
CD20 (B-cell marker) monoclonal antibody that binds to a differ-
ent although related epitope of its congener rituximab. It results in
B-cell depletion by modification of the Fc region, which is respon-
sible for antibody-dependent cytotoxicity (ADCC) and comple-
ment-dependent cytotoxicity. The most commonly used treatment
regimen is 300 mg on day 1, followed by 300 mg 2 weeks later with
subsequent doses of 600 mg administered once every 6 months.
Ocrelizumab has been proven to be superior to subcutaneous IFN-
β1a in reducing the annualized relapse rate (0.16 vs 0.29; absolute
risk reduction [ARR] of 0.13), in reducing the mean number of
gadolinium-enhancing MRI lesions (0.02 vs 0.29, ARR 0.27 in
OPERA I and 0.02 vs 0.42, ARR 0.40 in OPERA II), and in the
reduction of proportion of subjects with confirmed disability pro-
gression at 24 weeks (6.9% vs 10.5%, HR 0.60, 95% confidence
interval 0.43 to 0.84, ARR 3.6%) in the OPERA I and OPERA
II trials for RRMS. Ocrelizumab is the first medication to reduce
the risk of disability progression in patients with PPMS. In the
ORATORIO trial, ocrelizumab reduced both 12- and 24-week
fidence interval 0.58 to 0.98, ARR 6%) as compared with placebo.
The medication is given intravenously under close medical supervi-
sion. Infusions-related reactions do occur, but at a much lower rate
than with rituximab (34% vs 78%) It is contraindicated in patients
with active hepatitis infection; therefore patients must be screened
for the hepatitis B virus before the medication is administered. Live
vaccines and live attenuated vaccines are not recommended during
treatment with this medication until the B cells are depleted. Neo-
plasms were found to be more common in the treatment group than
in the placebo group in the ORATORIO trial, the basis and signifi-
cance of which remain unclear. 
Other Disease-Modifying Therapies in the Pipeline. Laqui-
nimod, ofatumumab, ozanimod, ponesimod, and cladribine are
among the medications currently in phase III studies for RRMS.
Masitinib and biotin are in phase III trials for progressive forms
of MS. The details of these medications are beyond the scope for
this chapter. 
994 SE C T I O N 4    Issues in Specific Diagnoses

TABLE
46.3
 Disease-Modifying Therapies for Multiple Sclerosis

Medication Route Frequency Adverse Effects Pregnancy Class

IFN-β1a IM Weekly Interferon side effects, leukopenia, hepatotoxicity, thyroid C
changes, mood changes
IFN-β1a SQ MWF three times weekly Interferon side effects, leukopenia, hepatotoxicity, thyroid C
IFN-β1b changes, mood changes, injection site reactions
Glatiramer acetate SQ 20 mg SQ daily or 40 Injection site reactions, postinjection systemic reactions B
mg three times per
week
Fingolimod PO Daily Lymphopenia, macular edema, bradycardia/AV block, C
risk of infections
Teriflunomide PO Daily Lymphopenia, risk of infections, alopecia, hepatotoxicity, X
renal failure, teratogenicity Requires negative pregnancy test
before starting treatment
Dimethyl fumarate PO Twice a day Lymphopenia, gastrointestinal upset, hepatotoxicity C
Natalizumab IV Every 4 weeks Increased risk of infection, primarily concerning risk of C
PML; infusion reactions, hepatotoxicity
Mitoxantrone IV Every 12 weeks Lymphopenia, cardiotoxicity, increased risk of infections, D
risk of malignancy, possibility of sterility Requires negative pregnancy test
before starting treatment

Ocrelizumab IV 600 mg every 6 months Infections (herpes infection, upper respiratory infections), D
infusion reaction, hepatitis B reactivation, increased
risk for malignancies

AV, Atrioventricular; IFN, interferon; IM, intramuscular; IV, intravenous; MWF, Monday, Wednesday, Friday; PML, progressive multifocal leukoencephalopathy; PO, oral; SQ, subcutaneous.
  

Rehabilitation, Exercise, and Symptom
Management
Physical Activity
A person with a disability is prone to become inactive and decon-
ditioned.162 Current recommendations for physical activity are
meant for individuals without physical disability, and those guide-
lines are often not applicable to the disabled. PwMS were pre-
viously advised to not exercise for fear of worsening the disease
course. In addition, PwMS would be advised to avoid exercise so
as to prevent overheating. Immune profile studies have demon-
strated no change in the physiologic variables of patients with MS
compared with control groups after being subjected to 30 min-
utes of aerobic exercise.70 Indeed, multiple studies have demon-
strated the safety and benefit of exercise in PwMS regardless of
MS subtype in terms of aerobic fitness, quality of life, and overall
health.41,146 Advice on exercise and physical fitness was most com-
monly sought after by individuals with MS and was surprisingly
more often requested than information about medications.182
The first and only consensus panel was convened in an effort to
review the available evidence and formulate guidelines for physical
fitness in PwMS.111 The review determined that there was suffi-
cient evidence to formulate guidelines to improve aerobic capacity
and muscle strength. The consensus panel did not find sufficient
evidence to provide guidelines for mobility, fatigue, or health-
related quality of life benefits (Table 46.4). These recommenda-
tions are based on the recommendations for physical activity of
the MS Society of Canada.134
Patients with MS commonly report fatigue, mood disorders,
inadequate access to equipment, heat intolerance, and insufficient
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
time as barriers to exercising.5 Clinicians should continue to rein-
force the importance of fitness as well as make efforts to remove or
treat those barriers when possible. In summary, exercise is helpful
for PwMS, with no evidence of deleterious effects. The intensity,
duration, and frequency of exercise must be considered in rela-
tion to each patient’s symptoms, heat intolerance, strength, and
endurance. 
Gait Impairment
Mobility impairment is among the most common single disabili-
ties in PwMS. Approximately 75% of PwMS have mobility chal-
lenges.163 Natural history studies conducted before the availability
of DMTs reported that 50% of PwMS who had the onset of gait
impairment would require an assistive device 15 years after their
diagnosis.200 Physiatrists are well aware of the detrimental effects
mobility impairments have on individuals with disabilities. There
is an increased risk of weakness, spasticity, contractures, bone min-
eral changes, cardiovascular changes, reduced independence, and
reduced quality of life. Overall, long-term positive prognostic indi-
cators for disability and gait impairment include female gender,
young age, complete recovery of initial exacerbation (specific to
the RRMS subtype), and reduced relapse rate in the first 5 years.193
The Timed 25 (T25) Foot Walk Test is a validated measure of
walking speed in MS. A 20% change in walking speed is consid-
ered significant and clinically meaningful.100 A time of 5 seconds
or less is expected in unaffected individuals. Other gait tests, such
as the Two- and Six-Minute Walk Tests, have demonstrated corre-
lation to ambulation and physical fatigue in PwMS.69,72,171 These
tests take longer to administer, but additional information such
as fatigue resistance or sensitivity, speed, heart rate monitoring,

TABLE
46.4
 Canadian Physical Activity Guidelines for Adults With Multiple Sclerosis
Aerobic Activity
How often? Twice a week
• A erobic and strength-training activities can be done on the same day
• Muscles should be allowed to rest for at least 1 day between strength-training sessions
How much? Gradual increase in activity so that at least 30 min
of aerobic activity are done during each workout
session
How hard? These activities should be performed at a moderate
intensity.
Moderate-intensity physical activity is usually a 5
or 6 on a scale of 10 and causes the heart rate
to go up. As a general rule, moderate-intensity
activity can be done while talking but not sing-
ing a song during the activity.
How to? Some options for activity include the following:
Aerobic activities
• Upper body exercises such as arm cycling
• Lower body exercises such as walking, leg
cycling
• Combined upper and lower body exercises as
on an elliptical trainer
Other types of exercise that may bring benefits:
• Elastic resistance bands
• Aquatic exercise
• Calisthenics
From Canadian Physical Activity Guidelines for Adults with Multiple Sclerosis, ©2012. Used, with permission, from the Canadian Society for Exercise Physiology.
and endurance may be obtained.43 However, the greater output of
energy required combined with the possibility that some patients
may not be able to complete either test makes the T25 Foot Walk
Test more feasible in a clinical and research setting.
Dalfampridine is the extended release version of immediate-
release 4-aminopyridine. It is a potassium channel agonist that
potentiates the duration of the action potential, promoting
nerve signal transmission and thereby prolonging its mechanism
of action. This agent was very appealing because of its ability to
enhance nerve conduction in areas of demyelination.149 However,
although initially promising, the immediate-release version had a
significant adverse event profile and a short duration of action.204
In 2010, dalfampridine was approved for the use of PwMS
with walking impairment based on the results of two phase III
randomized placebo-controlled trials. Approximately one-third
of participants displayed 25% improvement in their T25 walking
speed. The impact of this improvement in PwMS should not be
overlooked. Study participants had T25 walking times of greater
than 8 seconds to 45 seconds. Dalfampridine is given at a dose of
10 mg every 12 hours. A history of seizures is an absolute con-
traindication because dalfampridine lowers the seizure threshold.
Other adverse events include increased frequency of urinary tract
infections, vertigo, insomnia, headache, and falls. Dalfampridine
is renally excreted; therefore a baseline basic metabolic panel is
advised because adequate creatinine clearance (51 to 80 mL/min)
is vital.53,74-76
What remains unclear is why only 30% to 40% of patients are
dalfampridine “responders” and others are not. Various theories
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
CHAPTER 46  Multiple Sclerosis 995
Strength-Training Activity
Twice a week
Repetitions are the number of times you lift and lower a weight.
Try to do 10–15 repetitions of each exercise. This counts as 1 set.
Gradually work up to doing 2 sets of 10–15 repetitions of each
exercise.
A heavy enough resistance (free weights, cable pulleys, bands,
etc.) should be chosen that one can barely but safely finish
10–15 repetitions of the last set.
It is important to rest for 1–2 min between each set and exercise.
Strength-training activities for the upper and lower body
• Weight machines
• Free weights
• Cable pulleys
explaining this include varying sites of demyelination. A once-
daily formulation of dalfampridine is currently being researched. 
Inpatient Rehabilitation
Annual expenses of Medicare beneficiaries with MS were almost
twice those of other Medicare beneficiaries.153 Also, 57.9% of
Medicare beneficiaries with MS were younger than 65 years and
55.3% of these beneficiaries were individuals with disabilities; this
is in stark contrast to only 11% of the Medicare sample group
being younger than 65 years of age. In that same group, only 9%
were individuals with disabilities.116 The Medicare MS population
had lower overall admission, discharge, and change in Functional
Independence Measure (FIM) scores during their acute inpatient
admission. The same was true for all subscales except cognition.
No significant difference was noted in discharge destination. The
mean overall inpatient rehabilitation length of stay was 1.5 days
longer for the Medicare patient with MS than for those with
other neurologic conditions requiring inpatient rehabilitation.
Most Medicare patients with MS were discharged to their pre-
hospital living community. Home Health Service use was much
more common in the Medicare population with MS. In general,
Medicare beneficiaries with MS have lower changes in functional
scores and longer lengths of stay compared with other Medicare
beneficiaries. A notable finding in this study is that Medicare
beneficiaries with MS had significantly increased rates of depres-
sion compared with the Medicare group without MS. Clinicians
managing PwMS admitted to the inpatient unit should be acutely
996 SE C T I O N 4    Issues in Specific Diagnoses
aware of and screen for mood issues because that may have an
impact on improvement; moreover, this is an area where physiat-
rists can have a significant impact.
Despite lower FIM scores in patients with MS versus patients
without MS, multiple studies have demonstrated the benefit of
a multidisciplinary inpatient admission for patients with MS.41  Sleep disturbance
Fatigue
Fatigue remains one of the most common and debilitating symp-
toms in MS and is quoted as one of the single most disabling
symptoms. This is a silent symptom and patients may have dif-
ficulty comprehending and articulating the nature of it; they also
face challenges in explaining to others why “they look so good”
but may feel entirely the contrary. Patients commonly describe
fatigue as a “reversible motor and cognitive impairment (CI) with
reduced motivation and desire to rest.”127
Individuals with MS may experience two types of fatigue:
peripheral and central. Peripheral fatigue is associated with fatiga-
bility—that is, a generalized sense of exhaustion after a few min-
utes of physical activity that is alleviated with rest. Central fatigue
is subjective and is associated with dysfunction in arousal and
attention. The individual reports a feeling of constant exhaustion
or lassitude that can lead to worsening vision and/or function.
Rest will not have an effect on central fatigue and thereby has a
significant impact on function, quality of life, relationships, and
even the maintenance of an occupation/vocation.
The Fatigue Severity Scale, the Fatigue Impact Scale, and the
Modified Fatigue Impact Scale are the most commonly used scales
for fatigue assessment in patients with MS.56,127 These are self-
report scales. The Modified Fatigue Impact Scale was modified
from the Fatigue Impact Scale and was created for clinical settings;
it takes 5 to 10 minutes to complete. Long (21 questions) and
short (5 questions) versions are available.107
Fatigue can also be classified as primary and secondary. Pri-
mary fatigue is attributable to the disease process (MS) and sec-
ondary fatigue is a result of other causes. Screening for secondary
causes of fatigue—including metabolic, endocrine, hematologic,
and medication side effect profiles—is advised (Box 46.5). Mood
disturbances may mimic fatigue or lassitude. There is up to a 50%
lifetime prevalence of depression in PwMS.33,176 The treatment
of depression in PwMS is associated with reduction in fatigue
symptoms.
Aggressive screening for and treatment of fatigue is advised.
Awareness of triggering factors such as heat, stress, or overexer-
tion should be emphasized. Also, energy conservation techniques
and training are advised. Education of family and caregivers is
helpful because MS fatigue may present suddenly. Patients report
social isolation because they feel unable to keep up with family
or friends. Job productivity and efficiency may also be negatively
affected with the presence of fatigue. In addition to energy con-
servation and avoidance of triggers, pharmacologic treatment is
advised to help maintain energy and focus. Patients respond dif-
ferently to these medications and the clinician is encouraged to try
another agent if the patient experiences a subtherapeutic response
to one of them (Table 46.5).  with RLS should undergo screening for iron deficiency because
Sleep Disorders
Approximately 10% of the general population suffer from insom-
nia, whereas approximately 40% to 50% of PwMS report dif-
ficulty with sleep initiation/maintenance or have early morning
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
• BOX 46.5  Secondary Factors in Fatigue
Thermosensitivity/heat dysregulation
Mood disorder
Anxiety
Infection
Thyroid dysfunction
Anemia
Medications
• Disease-modifying therapies (typically interferon)
• Antidepressants
• Antispasmodics
• Narcotics
• Sedatives
awakening.115 Any discussion about fatigue in PwMS should
include a discussion about sleep hygiene. The clinician should
encourage sleep-promoting behaviors such as avoiding eating,
drinking, watching television, or even reading in bed. Symptoms
of MS that may interfere with sleep include spasticity, pain/pares-
thesias, and nocturia.148 Reviewing side effects of DMT, particu-
larly IFNs, may reveal myalgias or low-grade fever on injection
days that cause sleep disruption. Finally, screening for mood dis-
orders is advised owing to their high prevalence in this population.
It is vitally important to address and adequately treat these symp-
toms. Patients have demonstrated benefit with guided imagery,
biofeedback, cognitive behavioral therapy, and meditation prac-
tice. If pharmacologic treatment is required, a determination of
long-term or short-term use is needed. Treatment agents include
zolpidem, trazodone, benzodiazepine, sedating antidepressants,
and antihistamines.30
Sleep-disordered breathing, obstructive sleep apnea, and cen-
tral sleep apnea may be the etiology of persistent fatigue in PwMS.
Obstructive sleep apnea is a result of upper airway obstruction
during sleep. Central sleep apnea is the lack of respiratory effort
during sleep. Patients with clinical or radiologic evidence of brain-
stem involvement were found to have a higher Apnea-Hypopnea
Index (episodes of obstructive apneas, central apneas, or hypop-
neas per hour of sleep) than those without brainstem involve-
ment.21,115 There is a suggestion that DMT use results in lower
apnea scores.21,148 Referral for polysomnography testing is advised
in the patient who is not helped by fatigue-mitigating treatment.
Treatment may include weight loss, tobacco cessation, respiratory
support with continuous positive airway pressure, or surgery.
Besides obstructive sleep apnea and central sleep apnea, other
sleep-related movement disorders include restless legs syndrome
(RLS) and periodic limb movement disorder (PLMD). Patients
with RLS typically report an inability to keep their legs still.
PLMDs typically manifests while sleeping and are involuntary
movements. Legs are much more commonly involved. PLMD
is quantified and confirmed via polysomnography testing. It is
reported that RLS is two to six times more common in MS than
in healthy controls.115 An increased risk for RLS is seen with older
age, increased disability, cervical lesions, and PPMS. Patients
this may contribute to symptoms. Treatment for both RLS and
PLMD includes dopaminergic agents, benzodiazepine (clonaz-
epam), and anticonvulsants.96
Narcolepsy is a chronic sleep disorder characterized by sleep
paralysis, cataplexy, hypnagogic hallucinations, and nocturnal
sleep disruption.115 MS is the fourth most common cause of
 CHAPTER 46  Multiple Sclerosis 997

TABLE
46.5
 Adult Doses for Fatigue Treatment

Name Dosage Mechanism of Action Side Effects Controlled Off-Label Use

Amantadine Up to 100 mg twice Unknown Vertigo, orthostatic No Yes
a day hypotension, dry
mouth, livedo
reticularis
Dextroamphet- Extended release: up to Unknown Hypertension, tachycar- Schedule II Yes
amine/amphet- 20 mg/day dia, irritability, xero-
amine Immediate release: stomia, headache,
5–60 mg/day in insomnia
divided doses
Lisdexamfetamine Up to 70 mg/day Unknown Xerostomia, insomnia Schedule II Yes
dimesylate
Methylphenidate Available in immediate CNS stimulant Decreased appetite, Schedule II Yes
and extended- tachycardia, head-
release formulations. ache, insomnia
Up to 60 mg/day of
either version
Modafinil Up to 400 mg/day in CNS activation, Insomnia, anxiety Schedule IV Yes
divided doses improves wakeful
state
Armodafinil 50–150 mg/day CNS activation, Headache Schedule IV Yes
improves wakeful
state
Atomoxetine 40–100 mg/day Norepinephrine reup- Tachycardia, decreased No Yes
take inhibitor appetite, nausea,
erectile dysfunction

CNS, Central nervous system.

  

narcolepsy. The same gene is responsible for both MS and narco-
lepsy: HLA DRB1*1501, suggesting an autoimmune component
to the disorder.  patients who are borderline may need further testing or more fre-
Mood Disorders
The most common mood disorder in MS is depression. It is pres-
ent in at least 50% of patients; many have theorized that one
disease may predispose the other.143 The lifetime prevalence of
depression is MS is three times that of the general population. The
overlap of symptoms in both depression and MS (fatigue, poor
concentration, sleepiness/fatigue, and appetite disturbance) can
lead to underdiagnosis of depression and has delayed the diagnosis
of MS. No clear relation between cognition and depression has
been determined despite multiple studies. Depression has nega-
tive implications on quality of life and poses an increased risk of
suicide. The suicide rate of patients with MS is 7.5 times higher
than that of the general population and higher than that in people
with other neurologic disorders.168
Screening for DMT-related side effects, particularly IFNs, is
advised. Some patients may have mood disorders secondary to
DMT and may benefit from a change. Other symptomatic medi-
cations may have a similar side-effect profile, in which case an
alternative medication may be tried. The Beck Depression Inven-
tory (BDI) and the Beck Depression Inventory–Fast Screen (BDI-
FS) is a validated scale to screen for depression in PwMS.20,186
Both are patient-reported scales; the BDI has 21 items and the
BDI-FS has 7. The BDI has a sensitivity of 71% and a specificity
of 79%. The high false-negative rate (30%) should be noted; those
quent evaluations.
Although limited studies are available regarding controlled
studies of pharmacologic treatment in depression, The Goldman
Consensus Group, an expert panel convened by the National MS
Society to review depression in MS, recommends treating depres-
sion with individualized treatment using pharmacologic and/or
psychological counseling.71 In addition, a new area of focus is
reviewing one’s coping skills for living an enriching, fulfilling life
despite one’s disability. 
Thermoregulation
The pathophysiology of MS is one of central demyelination.63
Physiatrists are keenly aware of the effects of segmental demyelin-
ation: reduction in conduction velocity, altered saltatory conduc-
tion, and eventual conduction block. The safety factor (ratio of
action current available at a node to threshold current) is respon-
sible for successful conduction. Advanced demyelination reduces
the safety factor. Heat causes alteration of the sodium channels
and also reduces the safety factor and amplitude of nerve action
potentials. A demyelinated nerve is more vulnerable to heat-
related changes than an unaffected nerve.103
Heat intolerance is a well-established symptom in PwMS.
The Uhthoff phenomenon, a transient worsening of neurologic

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
998 SE C T I O N 4    Issues in Specific Diagnoses
function (initially described as blurry vision after a hot bath), with
heat exposure, physical exhaustion (exercise), infection, or dehy-
dration is very common in MS patients.46 Heat causes transient
worsening of many symptoms of MS and can cause fatigue. The
“hot bath test” was used before the availability of MRI to diag-
nose patients with MS.120 Patients were immersed in warm water
ranging from 35°C to 40°C and observed for worsening of long
tract corticobulbar and corticospinal signs. This was discontinued
after some patients had irreversible changes after heating as well
as following the advent of MRI.78 Approximately 58% to 93%
of patients are affected by heat-induced fatigue.24 Exposure to
heat can cause worsening of both physical and cognitive function.
Autonomic dysfunction also contributes to poor temperature reg-
ulation in PwMS.46
Patients should be counseled about prevention and treat-
ment options to avoid the occurrence of potentially fatal injuries.
Avoidance of warm baths or swimming in heated pools is advised.
In general, water temperatures no greater than 84°F (26.7°C to
28.9°C) are advised.169 Precooling with an ice water slurry or a
cool water bath can effectively lower the core body temperature.
Head cooling compared with sham cooling has also been found
to be effective in PwMS.159 Various evaporative cooling garments
can be used when patients are outside.174 Contrary to early theo-
ries, when exercise was discouraged by health professionals, PwMS
are now encouraged to exercise in moderation for strength, fitness,
and the maintenance of health.  reduced the time that many MS specialists give to the treatment
Spasticity
Spasticity affects up to 85% of PwMS.163 Lower limb spasticity is
much more common (97%) than upper limb spasticity (50%).12
Unsurprisingly, there is a negative correlation between the pres-
ence of lower limb spasticity and mobility.183
The Consortium of MS Centers recommends that spasticity
be screened for as part of routine MS patient visits. In addition
to evaluating a patient’s strength, range of motion, deep tendon
reflexes, and muscle tone with the patient seated on the examina-
tion table, the patient should be examined in a dynamic setting.
This includes observing the patient’s gait pattern, observing how
his or her intrinsic hand muscles move with flexion and exten-
sion, and observing for signs of muscle cocontraction. The patient
may also report difficulty falling or staying asleep as a result of
increased muscle spasticity at night.
Many tools are available to assess spasticity. These include the
Ashworth, Modified Ashworth, and Tardieu tests; the Penn Spasm
Frequency Scale; and the Timed Up and Go Test. In addition, the
T25 Foot Walk Test, the Ambulation Index, and the MS Spas-
ticity Scale are MS-specific tests that can be used in the clinical
setting.81,92 The MS Spasticity Scale has been validated for use in
PwMS and is an 88-item self-reported scale.
Treatment options for spasticity are discussed in Chapter 23. A
brief overview is presented here. Both physical and occupational
therapy are helpful in early stages and as adjunctive treatment
to supplement oral, injected, and intrathecal medications. Oral
baclofen is the usual first-line oral agent. Tizanidine may be lim-
ited given its sedating side effects. Clonazepam is helpful in cases
of PLMD or nighttime spasms.
The American Academy of Neurology released a guideline stat-
ing that oral cannabis is “the only complementary and alternative
medicine unequivocally effective for helping patients with MS,
specifically easing their pain and symptoms of spasticity, possibly
for as long as 1 year of treatment.”203 The consensus statement
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
reported on the beneficial effects of oral cannabis in the treatment
of spasticity, pain, muscle spasms, and poor sleep.207
The benefit of chemodenervation with botulinum toxin
(BoNT) injections in MS is paramount; its use results from the
difficulty in tolerating oral antispasmodics, as these can commonly
cause sedation or fatigue. Intrathecal baclofen (ITB) therapy
via an implanted drug delivery device is indicated when oral or
injectable treatment becomes ineffective. The clinician is encour-
aged to use this therapy before the onset of significant walking
impairment or lower limb weakness. ITB trials may require dose
adjustment for PwMS. The use of ITB pumps in patients with
MS has demonstrated improvements in spasticity, quality of life,
sleep quality, bowel and bladder performance, skin integrity, and
ambulation with low complication rates in numerous studies.16,145
Physiatrists are encouraged to educate patients about ITB therapy
and to provide it as a treatment option for PwMS. Studies have
demonstrated that ITB therapy in PwMS is not introduced as a
result of a greater focus on DMT management. Also, the patient
or clinician may not fully recognize the effect of spasticity on qual-
ity of life and may not know how to manage ITB therapy; hence
the need for the physiatrist, who will be better able to recognize
and effectively treat and manage spasticity.51 Phenol injections or
surgical intervention may be used in patients with severe mobility
problems or contractures who have failed conservative therapies.
The growing complexity and availability of DMTs for MS has
of symptoms. Many specialists will refer to physiatry for the treat-
ment of gait and spasticity problems. The preservation of clini-
cally useful mobility and overall function is most important to the
PwMS. A multimodal and multidisciplinary approach is vital in
approaching the patient with a chronic, progressive disease such
as MS. Improving function while mitigating the effects of fatigue
is vital. 
Pain
Patients with MS experience neuropathic and nociceptive pain.
Prevalence studies report that 29% to 86% of patients are affected
by pain.179,181 The Neuropathic Pain Special Interest Group of
the International Association for the Study of Pain defines neuro-
pathic pain arising as a direct consequence of a lesion or disease
that affects the somatosensory system.66 Nociceptive pain is attrib-
utable to stimulation of nociceptors that signal tissue irritation or
injury to elicit an appropriate response. Pain has a negative effect
on mood, energy, daily activities, vocation, and social interaction
and has been linked with reduced quality of life in PwMS.
Patients may complain of pain at injection sites associated
with DMT. A large-scale review found that subcutaneous drug
formulations have increased injection site reactions compared
with intramuscular injections.11 Patient- and clinician-reported
injection site reactions include the presence of localized burning,
tenderness, swelling, or necrosis. Glatiramer acetate is strongly
associated with localized lipoatrophy. Clinicians are encouraged
to discuss this with patients because injection site reactions have
been associated with reduced medication compliance. Suggested
techniques to reduce injection site reactions include encouraging
the use of an autoinjector, topical anesthetic agents, massage, and
cooling packs. Injection site rotation and avoiding known sensi-
tive areas is also advised.184
Neuropathic pain has a prevalence of 50% in MS and is
believed to be a result of the presence of plaques in the CNS
(particularly the corticospinal and dorsal column tracts), causing

symptoms of allodynia and hyperalgesia.181 Patients respond well
to anticonvulsant treatment, particularly gabapentin, which has
little interaction and a wide dose range. Another agent in the same
class is pregabalin. Although effective for its treatment effect, its
side effects (edema, sedation, weight gain, constipation) are dif-
ficult for some patients to tolerate. Finally, other agents in the
anticonvulsant class worthy of consideration include levetirace-
tam, lamotrigine, and zonisamide. The tricyclic antidepressant
class may also be used to treat neuropathic pain; again, the side
effects (dry mouth, constipation, drowsiness, urinary retention)
may pose a challenge for patients.
Patients who are unable to tolerate the side effects or obtain
clinically meaningful relief from oral medications may consider
intrathecal therapy via an implanted drug delivery device. Mor-
phine and ziconotide are both approved for the management of
neuropathic pain via intrathecal infusion. Morphine, an opioid,
is useful for patients unable to tolerate oral/systemic medications.
One small study demonstrated the safety and effectiveness of
intrathecal morphine and baclofen for the treatment of spastic-
ity and neuropathic pain.166 Ziconotide is a nonopioid agent that
has demonstrated significant pain reduction over placebo.105,156
It selectively targets voltage-gated calcium channels and prevents
the primary afferent transmission of pain signals in the spinal
cord. Extremely slow titration is advised to prevent side effects.105
Common side effects of ziconotide include dizziness, nausea, and
confusion. It is a viable option for patients who do not respond to
opioids and does not cause tolerance, dependence, or respiratory
depression.55 Most patients with MS have limited tolerance for
medications that may cause fatigue; therefore pump delivery is an
appealing alternative to oral/systemic agents and may provide pain
relief without the burdensome effects of sedation or confusion.
Trigeminal neuralgia (TN) affects approximately 2% to 6% of
patients with MS and is 20 times more common in PwMS than in
the general population.99 It may be a result of focal compression
of the trigeminal nerve root near its entry at the pons (primary
TN); it can also stem from a neurologic diagnosis, such as demy-
elinating plaques in the same region or a posterior fossa tumor
(symptomatic TN). Patients complain of spontaneous, unilateral,
lancinating “electrical sparks.” Light, tactile sensation or pressure
may stimulate the pain, which can last for seconds to hours. Diag-
nosis may be challenging, as the pain may be referred from any
of the three branches of the trigeminal nerve, and patients may
misconstrue their symptoms for dental pain. Blink reflex stud-
ies have reported delays of the R1 response on the symptomatic
side.42 There is no standardized MRI sequence to screen for neuro-
vascular compression. Treatment options include anticonvulsants
(carbamazepine, gabapentin, lamotrigine, topiramate); antispas-
modics (baclofen); and, in rare instances, narcotics. Again, most
PwMS are hesitant to take opiates because of the cognitive and
physical clouding that may occur. Finally, misoprostol, a prosta-
glandin E analog, relieved pain in patients with TN and should be
considered.48 Misoprostol is believed to be effective because the
T-cell inhibition caused by prostaglandins leads to an antiinflam-
matory effect in plaques. Doses of misoprostol ranged from 100
to 200 µg titrated up to four times a day. Patients refractory to
or unable to tolerate oral medications may consider BoNT injec-
tions or neurosurgery referral for microvascular decompression,
rhizotomy, or gamma knife repair.
Some other MS symptoms that the clinician should be aware
of include pain associated with optic neuritis, a Lhermitte sign,
and the “MS hug.” Inflammation of the optic nerve causes
optic neuritis. It is often painful and worse with movement;
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
CHAPTER 46  Multiple Sclerosis 999
photosensitivity and/or blurred vision may also be present. The
symptom is occasionally self-limiting and can also be treated with
steroids (intravenous methylprednisolone). A Lhermitte sign is an
electrical sensation that occurs down the length of the spine and
is exacerbated with neck flexion. Some patients report a Lhermitte
sign with fatigue, heat exposure, or during an exacerbation. This
symptom is typically self-limited. Finally, there is the “MS hug,”
which is described by patients as a feeling of tightness across the
ribs, as if they were being hugged very tightly. Burning and tin-
gling sensations are common. Treatment with anticonvulsants or
topical compound mixtures of anticonvulsants and lidocaine is
suggested. The causes of the Lhermitte sign and the “MS hug” are
unknown. 
Neurogenic Bladder, Neurogenic Bowel, and
Sexual Dysfunction
Patients with MS are highly disposed to bladder, bowel, and sexual
dysfunction (SD). The following three sections focus on areas spe-
cific for MS. The reader is advised to consult Chapters 20, 21, and
22 for further detail on each area.
Neurogenic Bladder
The presence of lesions in the brain and/or spinal cord may lead
to disorders of emptying (double voiding, incomplete emptying,
slow or intermittent stream), storage (urinary urgency, frequency,
nocturia, incontinence), or a mixture of both (detrusor sphincter
dyssynergia). It affects up to 75% of PwMS.131 Patients may iso-
late themselves socially because of the unpredictable nature of the
lower urinary tracts. The presence of gait dysfunction is correlated
with the presence of neurogenic bladder.58 Many studies have
corroborated the presence of increased urinary dysfunction in
patients with MS when plaques are present in the spinal cord.1,73
Guidelines for the screening of lower urinary tract dysfunc-
tion include an appropriate history and evaluation of the postvoid
residual. The need and utility of urodynamic evaluation remains
controversial. Early screening is advised to prevent long-term
complications in the urinary tract.
Treatment includes pelvic muscle training, medication, BoNT
injection, and surgery. Pharmacologic treatment consists of anti-
muscarinic agents for treating disorders of storage. Alpha antago-
nists are commonly recommended for the treatment of voiding
disorders. Desmopressin may be indicated for symptoms of noc-
turia. Appropriate screening for the side effects of medications
(constipation, dry mouth, fatigue, cognitive slowing) and electro-
lyte monitoring (hyponatremia) is advised.
BoNT type A (BoNT-A), specifically onabotulinum toxin, is
FDA-approved for the treatment of neurogenic detrusor over-
activity in PwMS. Intravesical injections of BoNT-A have been
found to increase the bladder capacity and reduce episodes of uri-
nary incontinence. Acetylcholine release is inhibited, causing the
bladder wall to relax. The benefits have been reported to last up
to 8 to 10 months, although injections may be performed every 6
months. The clinician should be aware of the specific serotype of
BoNT to be used and that other toxins may not be interchanged
or interconverted.95,102 Adverse effects include urinary tract infec-
tion and urinary retention. Patients should be advised of a possible
need to catheterize postinjection if postvoid residuals are elevated.
Given the ever-expanding role of BoNT, the clinician is advised
to ask the patient about exposure to the toxin. In instances where
1000 SE C T I O N 4    Issues in Specific Diagnoses

BoNT injections are occurring in the same patient for multiple 60

indications, coordination of care between disciplines is essential.

Percentage of patients impaired

Nerve stimulation has also been evaluated for the treatment 50
of neurogenic bladder disorders. Posterior tibial nerve stimulation
involves needle insertion superior and medial to the medial mal- 40
leolus with stimulation sufficient to induce toe flexion and tin-
gling distal to and including the ankle. The procedure is indicated 30
in patients who have failed or are unable to tolerate conservative
treatment for overactive bladder and typically involves twelve 20
30-minute weekly sessions. The use of posterior tibial nerve stimu-
10
lation has demonstrated a clear reduction in urinary incontinence,
urgency, frequency, and number of incontinence pads used.94 Its 0
exact mechanism of action is unknown. Long-term effectiveness

d)

ed

n
te

te
up to 12 months has been reported.117

nc

tio

ee

io
ye

ye

pe
ia

ia

at
ue

sp
ed

la

ed

la
ce

rm
s
Sacral nerve stimulation is another option for the treatment

Fl

y/

ng
m

m
er

(d

(d

fo
or
(im

(im
lp

si
of hyperreflexia, urge incontinence, and urgency/frequency disor-

em
y

pt
es
or

or
tia

ce
y

m
em

em

oc
or

or
a
ders. Its exact mechanism of action is unknown, but it is believed

on
sp

g
em

em

Pr
lm

lm

C
o

ki
to restore the balance between excitatory and inhibitory stimu-

lm

lm
su

or
rb

su
Vi

W
a

a
Ve
lation of the sacral and suprasacral regions.15 A trial period is

Vi
rb

su
Ve

Vi
advised for 3 to 7 days, with a pretrial and posttrial voiding diary Cognitive domain
evaluation for effectiveness.44 This is a surgical procedure and its
use in MS is limited because of limited MRI compatibility of the • Fig. 46.7 Frequency of impairment in 291 patients with multiple scle-
rosis by cognitive domain. (Reprinted with permission from Chiaravalloti
devices. Currently some devices are contraindicated with the use
ND, DeLuca J: Cognitive impairment in multiple sclerosis, Lancet Neurol
of MRI, whereas others permit brain MRI only.  7:1139–1151, 2008.)

Neurogenic Bowel
Neurogenic bowel presents as constipation or fecal incontinence.
Patients with MS have reported spending more than 30 min-
utes per day on their bowel regimen. Constipation is believed to
be caused by immobilization or abnormal colonic contractility,
tone, or rectoanal reflexes.10 Medication side effects must also be
considered. For patients with overactive bladder symptoms, fluid
intake may be intentionally limited so as to prevent incontinence,
which may further contribute to constipation. Fecal incontinence
may be attributable to loss of control of the external anal sphinc-
ter, abnormal rectosigmoid compliance, or rectoanal reflexes. The
use of probiotics can help both constipation and incontinence.
Referral to gastroenterology may be needed to evaluate any other
underlying medical issues that may be causing the incontinence.  they are to blame. Education and communication are important.
Sexual Dysfunction
SD is present in approximately 42% to 90% of PwMS.31,119
Despite the high prevalence, only 20% of patients report being
asked about SD during clinical visits. Women commonly report
decreased libido and loss of lubrication. Men report erectile and
ejaculatory dysfunction. Both sexes report challenges with achiev-
ing orgasm. Side effects of DMT and their treatment (antide-
pressants, antispasmodics, α-antagonists) and fatigue should be
evaluated.
Primary SD may be caused by CNS demyelination that directly
impairs sexual feelings and/or the response. This includes symp-
toms of decreased libido or its loss as well as paresthesias that make
the sexual encounter painful or unpleasurable. Secondary SD is
attributable to disability secondary to MS, and includes items that
indirectly affect the sexual response, such as neurogenic bladder or
bowel symptoms, spasticity, tremor, or immobility. Medical con-
ditions unrelated to MS—such as mood disorders, hypertension,
and diabetes—are also included. Finally, tertiary SD involves one’s
view of self and the culture’s view of sex, physical intimacy, and
their importance. Family dynamics, interpersonal conflict, poor
self-esteem, and altered views of one’s body image are included.
Screening for SD may be done in the course of the intake his-
tory or examination. The MS Intimacy and Sexuality Question-
naire is a 19-item patient self-report that asks about sexual activity,
satisfaction, and presence of symptoms or other issues that may
interfere with sexual encounters.170 It can also help the clinician
to determine if the problem is attributable to primary, secondary,
or tertiary causes. The scale has demonstrated validity in terms of
marital satisfaction, including communication, problem solving,
sexual dissatisfaction, and level and extent of neurologic impair-
ment as a result of MS, psychological well-being, and global SD
in MS.
Clinicians are encouraged to ask and discuss SD. Patients may
not be aware of the high prevalence of SD in MS and may feel that
Reducing the dependence on medications for side effects that
impair libido or energy as well as using medications that reduce
spasms or pain may be needed. Sildenafil citrate is effective for
male patients with erectile dysfunction.57 Women with SD were
trialed on sildenafil citrate for improvement in sexual response,
blood flow, and improved neurophysiologic response. Although
lubrication improved, no change was noted in quality of life or
in tibial and pudendal nerve–evoked studies.45 Psychological
counseling for the patient and/or the couple may be helpful. In
addition, referral to a neuropsychologist is advised for additional
evaluation and management options. 
Cognitive Impairment
CI may be present at any stage of MS. Approximately 40% to
70% of patients have CI. Impairments that are commonly seen in
PwMS include episodic memory loss, attention deficits, delayed
processing speed, and difficulty in executive function. Dementia
is less commonly present in MS (Fig. 46.7).125
Although neuropsychological testing remains the most sensi-
tive and comprehensive assessment tool for CI, the expense and
time involved for testing remain formidable barriers. In addition,
PwMS are often affected by fatigue, making testing even more

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.

challenging for this patient population. Other tests to evaluate
and assess cognitive function have been studied. The Rao Brief
Repeatable Battery of Neuropsychological Tests and the Minimal
Assessment of Cognitive Function in MS both assess working
memory, processing speed, new learning, and language.17,155 The
Paced Auditory Serial Addition Test and Symbol Digit Modality
Test assess processing speed, one of the most common challenges
in patients with long-standing MS.
Various structural factors on MRI have correlated with CIs in
PwMS. Increased cortical atrophy, widening of the third ventricle,
and overall loss of brain volume are seen in persons with CI.19,32
Further research into the significance of gray matter changes and
CI is under way. Longitudinal studies have demonstrated early
brain atrophy as a predictor for future CI.
The effect of DMT in PwMS has been studied. Subcutaneous
IFN-β1a and IFN-β1b can stabilize or delay the progression of
CI in persons with RRMS.54,144 One year of natalizumab treat-
ment actually demonstrated significant improvement in cognitive
performance and fatigue in patients with RRMS.93 Many patients
also benefit from the use of psychostimulants such as methylphe-
nidate and l-amphetamine to improve attention, learning, and the
ability to focus.18,80 Memantine and donepezil have been tested,
with conflicting results, for the treatment of memory disorders;
large-scale studies are still needed for further clarification.83 The
supplement Gingko biloba did not improve cognitive performance
in PwMS.114
Factors that may affect CI include disease duration, MS sub-
type, level of disability, and premorbid level of verbal competence.
One striking feature is the concomitant presence of depression
or depressive symptoms in patients with CI, further emphasizing
the need for vigorous screening for mood disorders in this patient
population.
Two hypotheses prevail in what determines the extent of cogni-
tive dysfunction and why individuals are affected differently. Brain
reserve or maximal lifetime brain volume (MLBV) is determined
primarily by genetics.13,187 Those individuals with larger MLBVs
are believed to be less susceptible to cognitive decline and have a
lower risk of dementia. The cognitive reserve hypothesis states that
learning is acquired from life experiences, education, and cogni-
tive leisure activities. A positive correlation was found between
cognition and both education and early life cognitive leisure
activities. A higher MLBV and robust cognitive reserve are both
protective against CI.
In addition to DMT, various rehabilitative interventions have
been used for prevention and the treatment of CI in PwMS.
Cognitive behavioral therapy has reduced distress and improved
cognitive performance in several small studies.130,185 Long-term
benefit is unknown.
Swallowing
Dysphagia, or difficulty with swallowing liquids or solids, may
present at any stage of MS. An estimated 33% to 43% of patients
are affected.180 The prevalence of dysphagia increases with increas-
ing disability, EDSS scores, and disease duration.23,29 The etiology
of dysphagia in MS is likely to be attributable to the involvement
of corticobulbar, cerebellar, or brainstem regions.
A thorough history is crucial when a patient is being screened
for dysphagia and can assist in localizing what phase of swallow-
ing is affected. The presence of xerostomia or globus (nonpainful
sensation of a lump or fullness in the throat) should be excluded.39
Many symptomatic medications can cause xerostomia. The
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
CHAPTER 46  Multiple Sclerosis 1001
pharyngeal phase is most commonly affected in MS. The presence
of another unrelated comorbidity may also be present, causing dif-
ficulty with swallowing.
Patients may complete the 10-item self-report called Screening
with Dysphagia in MS (DYMUS) questionnaire to assess their
risk for dysphagia. This has been validated to screen both solid
and liquid dysphagia. It may serve as a screening tool to assess the
need for additional testing as well as to identify patients at risk for
aspiration pneumonia.22,23 Clinical assessment alone may under-
estimate the risk of aspiration by 50%.39 A videoradiographic
swallow study, also called the modified barium swallow, is the tool
of choice for evaluating the presence of silent aspiration. Patients
may require referral for additional testing, including esophageal
manometry or an endoscopy.
Treating dysphagia with compensatory strategies is often effec-
tive. This includes (1) postural changes, (2) modifying the size
of the food bolus consumed, and (3) changing the food’s con-
sistency.29 Other treatments include electrical stimulation and
neurotoxin injection. Pharyngeal electrical stimulation to treat
oropharyngeal dysphagia significantly reduces the amount of pen-
etration and aspiration.157 Injection of BoNT into the cricopha-
ryngeal muscle has been reported to be effective for the treatment
of upper esophageal hyperactivity.158 
Pseudobulbar Affect
Pseudobulbar affect (PBA) is a disorder of uncontrollable laughter
or crying that is incongruent with the social or professional situ-
ation.65,126 Although PBA can be seen in almost any illness, this
is commonly seen in persons with neurologic disorders includ-
ing MS, amyotrophic lateral sclerosis, stroke, and traumatic brain
injury. The prevalence in MS is believed to be 6.5% to 46.26%.128
The emotional lability in PBA is spontaneous and brief. Patients
who suffer from this may feel socially isolated owing to their lack
of control over such laughing or crying episodes. PBA should be
differentiated from depression, in which one’s mood is congru-
ent with the situation. Also, the duration of symptoms is brief in
PBA, whereas a depressed mood typically lasts weeks to months.
PBA constitutes a true disorder and should be differentiated from
pseudobulbar syndrome, in which corticobulbar damage may lead
to oromotor dysfunction, dysphonia, and slow slurred speech.
The pathophysiology is not clear but PBA is believed to be a
disorder of the cortico-pontine-cerebellar circuit.67,126,141 This
circuit of neuroanatomic pathways descends to the basis pontis,
brainstem, and cerebellum. It is thought that disruption here can
lower the threshold for emotional response141-143 and thus lead to
an emotionally incongruent response (Fig. 46.8).
The Center for Neurologic Study–Lability Scale (CNS-LS) is a
seven-item self-reported scale to screen for PBA. It has been vali-
dated in both MS and amyotrophic lateral sclerosis. Although a
score of 13 or more on the CNS-LS is indicative of PBA, one
study noted a sensitivity of 94% and a specificity of 83% with a
score of 17 or more in PwMS.129,178 This screening tool is quick
and efficient and can be used to track a patient once treatment
has begun.
Various agents including selective serotonin reuptake inhibi-
tors and tricyclic antidepressants have been used with varying suc-
cess to treat PBA. These studies had small numbers of patients and
varied in methodology (Table 46.6). The combination of dextro-
methorphan with low-dose quinidine has resulted in a treatment
for patients with PBA. Its mechanism of action is unknown. A
double-blind placebo-controlled study using dextromethorphan/
1002 SE C T I O N 4    Issues in Specific Diagnoses

• Fig. 46.8  Proposed brain circuitry involved in emotional expression and its hypothesized dysfunction in
pseudobulbar affect (PBA). (A) Normally an emotional motor expression network including cortico-pontine-
cerebellar afferentation (upper blue arrows) enables the cerebellum to act as a “gate control” for the motor
expression of emotion (lower blue arrows). Inputs to this network (green and red arrows) include an inhibi-
tory influence from sensory cortices. (B) In PBA, reduced inhibitory influence at the cortical level (broken
red cortical arrows) results in increased aberrant activation within the network (broken blue arrows), giving
rise to the motor manifestations of pathologic laughing/crying. (From Miller A, Pratt H, Schiffer RB: Pseu-
dobulbar affect: the spectrum of clinical presentations, etiologies and treatments, Expert Rev Neurother
11:1077–1088, 2011.)

low-dose quinidine in patients with amyotrophic lateral sclero-
sis and MS resulted in a significantly reduced rate of pseudobul-
bar episodes per day compared with placebo (49% reduction, P
<.0001)147; participants in the active arm noticed improvement as
soon as week 1 into the study. The most common adverse events
included headache, falls, diarrhea, and vertigo. Dextrometho-
rphan/quinidine may cause QTc prolongation. All patients in
the study were screened for respiratory or cardiac disorders before
being included. The recommended dosage is 1 capsule daily for
7 days followed by 1 capsule every 12 hours beginning on day 8.
Most patients noticed a reduction in lability after 1 to 2 weeks of
treatment.  of the potential genetic and environmental factors that drive this
Evidence for Rehabilitation in Multiple Sclerosis
In a recent Cochrane review3 comprising 164 randomized con-
trolled trials and four controlled clinical trials with a total of
10,396 subjects, moderate-quality evidence suggested that
physical therapeutic modalities (exercise and physical activities)
improved functional outcomes (mobility, muscular strength),
reduced impairment (fatigue), and improved participation (qual-
ity of life). Moderate-quality evidence suggested that inpatient or
outpatient multidisciplinary rehabilitation programs led to lon-
ger-term gains at the levels of activity and participation, and inter-
ventions that provided information improved patient knowledge.
Low-quality evidence suggested that neuropsychological interven-
tions, symptom-management programs (especially for spasticity),
whole-body vibration, and tele-rehabilitation improved some
patient outcomes. Evidence for other rehabilitation modalities was
inconclusive in this review due to lack of quality research studies. 
Pediatric Multiple Sclerosis
Our understanding of demyelinating disorders in children has
increased in recent years. According to the International Pediat-
ric MS Study Group, pediatric MS can be diagnosed after two
clinical episodes of CNS demyelination that are separated by at
least 30 days. Pediatric MS accounts for 5% of all MS cases.206
It provides a unique opportunity to increase our understanding
complex disease.
In North America, there is a greater diversity in ethnicity
among pediatric patients with MS than among adults with MS,
possibly reflecting changing demographic trends.195 The female/
male ratio varies by age. Below the age of 6 years, the ratio of girls
to boys is 0.8 to 1. The ratio increases to 1.6 to 1 between the ages
of 6 and 10 years. It is 2 to 1 for children over the ages of 10 years
compared with the ratio of 3 to 1 that is typically seen in adults.206
In terms of CSF, the IgG index is elevated in 68% of patients
that are 11 years old or older.198 CSF studies implicate activation
of an innate immune response in patients who are below 11 years
of age because they are less likely to have oligoclonal bands or an
elevated IgG index on CSF analysis. They may also have pleocyto-
sis with a neutrophil predominance compared with the lympho-
cytic predominance that is commonly seen in adult patients with
MS.198

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
 CHAPTER 46  Multiple Sclerosis 1003

TABLE
46.6
 Placebo-Controlled Trials of Pharmacotherapeutic Options in Pseudobulbar Affect

Active Drug vs
Drug Class Study (Year) Placebo Study Design PBA Setting N Main Findings
Tricyclic antide- Schiffer et al. Amitriptyline Crossover; 1 month MS 12 Reduced episode
pressants (1985) per treatment rate
Robinson et al. Nortriptyline Parallel group; 6 Stroke 28 Reduced severity
(1993) weeks on validated
scale (PLACS)
Selective Andersen et al. Citalopram Crossover; 3 weeks Stroke 16 Reduced episode
serotonin (1993) per treatment rate
reuptake
inhibitors
Brown et al. (1998) Fluoxetine Parallel group; 10 Stroke 20 Reduced severity
days on unvalidated
scale
Burns et al. (1999) Sertraline Parallel group; 8 Stroke 28 Reduced lability
weeks on unvalidated
scale
Choi-Kwon et al. Fluoxetine Parallel group; 6 Stroke 91 Reduced crying
(2006) months on unvalidated
scale
Antiglutamater- Panitch et al. DMQ Parallel group; 12 MS 150 Reduced severity
gics (2006) weeks on validated
scale (CNS-LS);
reduced episode
rate
Pioro et al. (2010) DMQ Parallel group; 12 ALS or MS 326 Reduced severity
weeks on validated
scale (CNS-LS);
reduced episode
rate

ALS, Amyotrophic lateral sclerosis; CNS-LS, Center for Neurologic Study–Lability Scale; DMQ, dextromethorphan/quinidine; MS, multiple sclerosis; PBA, pseudobulbar affect; PLACS, Pathological Laughter
and Crying Scale
From Miller A, Pratt H, Schiffer RB: Pseudobulbar affect: The spectrum of clinical presentations, etiologies and treatments, Expert Rev Neurother 11:1077–1088, 2011.
Studies cited:
Schiffer R, Herndon RM, Rudick RA: Treatment of pathological laughing and weeping with amitriptyline, N Engl J Med 312:1480–1482, 1985.
Robinson RG, Parikh RM, Lipsey JR, et al: Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study, Am J Psychiatry 150:286–293, 1993.
Andersen G, Vestergaard K, Riis JO: Citalopram for post-stroke pathological crying, Lancet 342:837–839, 1993.
Brown KW, Sloan RL, Pentland B: Fluoxetine as a treatment for post-stroke emotionalism, Acta Psychiatr Scand 98:455–458, 1998.
Burns A, Russell E, Stratton-Powell H, et al: Sertraline in stroke-associated lability of mood, Int J Geriatr Psychiatry 14:681–685, 1999.
Choi-Kwon S, Han SW, Kwon SU, et al: Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study, Stroke 37:156–161, 2006.
Panitch HS, Thisted RA, Smith RA, et al: Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis, Ann Neurol 59:780–787, 2006.
Pioro EP, Brooks BR, Cummings J, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect, Ann Neurol 68:693–702, 2010.
  

Studies have indicated that EBV seropositivity is more com-
mon among pediatric patients with MS. Smoking, including pas-
sive smoking, is associated with a higher risk of developing MS.
Low vitamin D level has also been linked to developing MS.
In terms of differential diagnosis, monophasic demyelinating
conditions such as ADEM are often difficult to differentiate from
a first demyelinating episode of pediatric MS. ADEM is defined
as a first clinical event affecting the CNS—an event of inflamma-
tory and demyelinating etiology with an acute or subacute onset
involving a polysymptomatic presentation.206 Encephalopathy
can be defined as behavioral change with confusion, excessive
irritability, or alteration of consciousness. Interestingly, data sug-
gest that encephalopathy can be associated with a first episode of
MS, especially in younger patients. Rather than being specific for
a disease process, it may be an indication of an immature brain or
immune system.
Children tend to have a larger lesion burden, particularly with
brainstem and cerebellar involvement.205 Younger children may
have MRIs with atypical features, with large T2/FLAIR hyper-
intense confluent lesions having irregular borders. Lesions often

Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
1004 SE C T I O N 4    Issues in Specific Diagnoses
resolve on repeat scans. In a small study, pediatric patients with MS
had fewer T2 lesions and more frequent tumefactive MS lesions
on imaging studies than has been reported with adult patients.
Pediatric patients with MS develop marked CI with difficulties
with complex attention, information processing, executive func-
tioning, processing speed, and long-term memory. In one study,
patients with MS with an average disease duration of 3 years met
criteria for significant CI.
Data using DMT in children is limited; however, the approach
remains similar to treatment strategies for adults. The current first-
line therapies seem to be safe and well tolerated in this patient
population. As with adults, compliance remains a concern and
guides medication decisions.  globulin G has been shown in some studies to reduce the risk of
Multiple Sclerosis in Pregnancy
There is a strong female predominance in MS. Patients are often
diagnosed in their childbearing years. As such, pregnancy becomes
an important topic for female patients with MS at some point dur-
ing their disease course. At least 20% to 30% of patients will have
children after their diagnosis of MS.40 Fortunately, MS has little to
no direct effect on pregnancy. Patients can be counseled with con-
fidence that their disease will not affect their ability to conceive,
the safety and health of the pregnancy, or fetal well-being. There
is no increased risk for spontaneous abortion, ectopic pregnancy,
cesarean delivery, or major neonatal or obstetric complications.
It has been well known that pregnancy is a time of stability
for patients with MS. Disease activity is markedly reduced during
the third trimester. Pregnancy is considered an immune-tolerant
state in which the maternal immune system adapts to an alloge-
neic pregnancy. Several biologic changes occur during pregnancy
that may affect MS. Hormone levels increase during pregnancy—
including estrogens (especially estriol), progesterone, prolactin,
and glucocorticoids—and then fall dramatically during the post-
partum period. These hormones affect the immune system and
help to shift cytokines, decrease adhesion molecules and matrix
metalloproteinases, decrease antigen presentation, and boost Treg
cells.40 This results in an overall decrease in inflammatory pro-
cesses. There are also significant immune cell shifts that involve
Treg cells, Th17 cells, and natural killer cells. Third, fetal antigens
interact with and modulate the maternal immune system. Periph-
eral Treg cells appear that are specific for fetal antigens. Finally,
pregnancy may result in positive benefits to the CNS by promot-
ing endogenous recovery mechanisms and enhancing the ability to
respond to immune-mediated injury.
There is concern about medication use during pregnancy. For
patients with MS, medication concerns can be related to DMTs,
treatments for relapses, or management of symptoms. Typically
DMTs should not be used in patients with MS who are pregnant
or trying to become pregnant. When needed, glatiramer acetate
has the most favorable safety rating (class B). Acute relapses can be
treated with a short course of high-dose glucocorticoids as deter-
mined by the patient’s practitioner. If possible, it is preferable to
forego treatment during the first trimester because of the associa-
tion of cleft palate and lower birth rate. However, corticosteroids
are commonly used in the second and third trimester. Prednisone,
prednisolone, or methylprednisolone are preferred because they
are metabolized to inactive forms by the placenta, rather than
betamethasone or dexamethasone, which crosses the placenta with
minimal metabolism. As a general principle, medications for the
treatment of symptoms are minimized during pregnancy. How-
ever, if a medication is needed to prevent suffering or maintain
quality of life, it can be continued.
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
Compared with prepregnancy, annualized relapse rates fall by
70% during the third trimester. During the 3 months postpar-
tum, the relapse rate rebounds to 70% above the prepregnancy
level and then comes down and stays down at the prepregnancy
rate. The most consistent marker associated with postpartum
activity is the disease activity in the year before pregnancy.110
There are conflicting data regarding the potential benefit from
breastfeeding in reducing MS activity. Some studies suggest that
exclusive breastfeeding results in prolonged lactational amenor-
rhea with ovarian suppression, high prolactin levels, and low
nonpulsatile luteinizing hormone levels, all of which may be ben-
eficial. Although it is not FDA-approved, intravenous immuno-
postpartum relapse.79 
Summary
The past decade has seen more than a doubling of treatment
options for patients with MS. One of the biggest and most impact-
ful changes with regard to medication compliance and ease has
been the approval of oral DMTs. Diagnoses of MS are occurring
earlier and also with improved accuracy. Patients are no longer
satisfied with “not getting worse.” They want and demand options
that will increase their strength and endurance and maintain their
ability to ambulate; in essence, they want us as clinicians to help
them enhance their quality of life. The varying nature of MS
symptoms presents unique challenges to the clinician. The disease
is progressive; symptoms change often and are affected by exter-
nal factors including heat, fatigue, and side effects of DMTs. As
physiatrists, we hold the answers and options for this in our treat-
ment tool bags. We have therapeutic and symptomatic options for
fitness and symptom management, and we can effectively educate
and guide these patients. In addition, our training and expertise
can help these patients develop coping strategies so that they can
manage the physical, mental, and/or cognitive challenges they
may face.
Key References
2. Adelman G, Rane SG, Villa KF: The cost burden of multiple scle-
rosis in the United States: a systematic review of the literature, J
Med Econ 16:639–647, 2013.
5. Asano M, Duquette P, Andersen R, et  al.: Exercise barriers and
preferences among women and men with multiple sclerosis, Disabil
Rehabil 35:353–361, 2013.
9. Ascherio A, Munger KL, White R, et al.: Vitamin D as an early pre-
dictor of multiple sclerosis activity and progression, JAMA Neurol
71:306–314, 2014.
12. Barnes MP, Kent RM, Semlyen JK, et  al.: Spasticity in multiple
sclerosis, Neurorehabil Neural Repair 17:66–70, 2003.
20. Benedict RHB, Fishman I, McClellan MM, et al.: Validity of the
beck depression inventory-fast screen in multiple sclerosis, Mult
Scler 9:393–396, 2003.
28. Calabrese M, Poretto V, Favaretto A, et  al.: Cortical lesion load
associates with progression of disability in multiple sclerosis, Brain
135:2952–2961, 2012.
37. Confavreux C, Vukusic S: [The natural history of multiple sclero-
sis], Rev Prat 56:1313–1320, 2006. [in French].
38. Confavreux C, Vukusic S, Adeleine P: Early clinical predictors and
progression of irreversible disability in multiple sclerosis: an amne-
sic process, Brain 126:770–782, 2003.
41. Craig J, Young CA, Ennis M, et al.: A randomised controlled trial
comparing rehabilitation against standard therapy in multiple scle-
rosis patients receiving intravenous steroid treatment, J Neurol Neu-
rosurg Psychiatry 74:1225–1230, 2003.

53. Fernandez O, Berger T, Hartung HP, et al.: Historical overview of
the rationale for the pharmacological use of prolonged-release fam-
pridine in multiple sclerosis, Expert Rev Clin Pharmacol 5:649–665,
2012.
56. Fisk JD, Pontefract A, Ritvo PG, et al.: The impact of fatigue on
patients with multiple sclerosis, Can J Neurol Sci 21:9–14, 1994.
58. Fowler CJ, Panicker JN, Drake M, et al.: A UK consensus on the
management of the bladder in multiple sclerosis, Postgrad Med J
85:552–559, 2009.
60. Freedman MS, Thompson EJ, Deisenhammer F, et  al.: Recom-
mended standard of cerebrospinal fluid analysis in the diagnosis of
multiple sclerosis: a consensus statement, Arch Neurol 62:865–870,
2005.
63. Frohman EM, Racke MK, Raine CS: Multiple sclerosis—the
plaque and its pathogenesis, N Engl J Med 354:942–955, 2006.
65. Garnock-Jones KP: Dextromethorphan/quinidine: in pseudobul-
bar affect, CNS Drugs 25:435–445, 2011.
67. Ghaffar O, Chamelian L, Feinstein A: Neuroanatomy of pseudo-
bulbar affect: a quantitative MRI study in multiple sclerosis, J Neu-
rol 255:406–412, 2008.
69. Gijbels D, Eijnde B, Feys P: Comparison of the 2- and 6-minute
walk test in multiple sclerosis, Mult Scler J 17:1269–1272, 2011.
71. Goldman Consensus Group: The Goldman consensus statement
on depression in multiple sclerosis, Mult Scler 11:328–337, 2005.
74. Goodman AD, Brown TR, Edwards KR, et al.: A phase 3 trial of
extended release oral dalfampridine in multiple sclerosis, Ann Neu-
rol 68:494–502, 2010.
79. Haas J: High dose IVIG in the post partum period for prevention
of exacerbations in multiple sclerosis, Mult Scler 6(Suppl 2):S18–
S20, 2000, discussion S33.
80. Harel Y, Appleboim N, Lavie M, et al.: Single dose of methylpheni-
date improves cognitive performance in multiple sclerosis patients
with impaired attention process, J Neurol Sci 276:38–40, 2009.
84. Healy BC, Ali EN, Guttmann CR, et al.: Smoking and disease pro-
gression in multiple sclerosis, Arch Neurol 66:858–864, 2009.
87. Hedstrom AK, Lima Bomfim I, Barcellos L, et  al.: Interaction
between adolescent obesity and HLA risk genes in the etiology of
multiple sclerosis, Neurology 82:865–872, 2014.
93. Iaffaldano P, Viterbo RG, Paolicelli D, et  al.: Impact of natali-
zumab on cognitive performances and fatigue in relapsing multiple
sclerosis: a prospective, open-label, two years observational study,
PLoS ONE 7:e35843, 2012.
94. Kabay SC, Yucel M, Kabay S: Acute effect of posterior tibial nerve
stimulation on neurogenic detrusor overactivity in patients with
multiple sclerosis: urodynamic study, Urology 71:641–645, 2008.
95. Kalsi V, Gonzales G, Popat R, et al.: Botulinum injections for the
treatment of bladder symptoms of multiple sclerosis, Ann Neurol
62:452–457, 2007.
97. Kappos L, Moeri D, Radue EW, et al.: Predictive value of gado-
linium-enhanced magnetic resonance imaging for relapse rate and
changes in disability or impairment in multiple sclerosis: a meta-
analysis. Gadolinium MRI Meta-analysis Group, Lancet 353:964–
969, 1999.
98. Kasper LH, Shoemaker J: Multiple sclerosis immunology: the
healthy immune system vs the multiple sclerosis immune system,
Neurology 74(Suppl 1):2–8, 2010.
100. Kaufman M, Moyer D, Norton J: The significant change for the
timed 25-foot walk in the multiple sclerosis functional composite,
Mult Scler 6:286–290, 2000.
108. Kurtzke JF: Neurologic impairment in multiple sclerosis and the
disability status scale, Acta Neurol Scand 46:493–512, 1970.
116. Ma VY, Chan L, Carruthers KJ: Incidence, prevalence, costs, and
impact on disability of common conditions requiring rehabilitation
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
CHAPTER 46  Multiple Sclerosis 1005
in the United States: stroke, spinal cord injury, traumatic brain
injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb
loss, and back pain, Arch Phys Med Rehabil 95:986–995, 2014.
122. McDonald WI, Barnes D: The ocular manifestations of multiple
sclerosis. 1. Abnormalities of the afferent visual system, J Neurol
Neurosurg Psychiatry 55:747–752, 1992.
126. Miller A, Pratt H, Schiffer RB: Pseudobulbar affect: the spectrum
of clinical presentations, etiologies and treatments, Expert Rev Neu-
rother 11:1077–1088, 2011.
130. Moss-Morris R, Dennison L, Landau S, et al.: A randomized con-
trolled trial of cognitive behavioral therapy (CBT) for adjusting to
multiple sclerosis (the saMS trial): does CBT work and for whom
does it work? J Consult Clin Psychol 81:251–262, 2013.
132. Munger KL, Levin LI, Hollis BW, et al.: Serum 25-hydroxyvita-
min D levels and risk of multiple sclerosis, JAMA 296:2832–2838,
2006.
136. Noseworthy JH, Lucchinetti C, Rodriguez M, et al.: Multiple scle-
rosis, N Engl J Med 343:938–952, 2000.
138. Okuda DT, Siva A, Kantarci O, et al.: Radiologically isolated syn-
drome: 5-year risk for an initial clinical event, PLoS ONE 9:e90509,
2014.
146. Petajan JH, Gappmaier E, White AT, et  al.: Impact of aerobic
training on fitness and quality of life in multiple sclerosis, Ann Neu-
rol 39:432–441, 1996.
150. Polman CH, O’Connor PW, Havrdova E, et  al.: A randomized,
placebo-controlled trial of natalizumab for relapsing multiple scle-
rosis, N Engl J Med 354:899–910, 2006.
151. Polman CH, Reingold SC, Banwell B, et al.: Diagnostic criteria for
multiple sclerosis: 2010 revisions to the McDonald criteria, Ann
Neurol 69:292–302, 2011.
155. Rao SM, Leo GJ, Bernardin L, et  al.: Cognitive dysfunction in
multiple sclerosis. I. Frequency, patterns, and prediction, Neurology
41:685–691, 1991.
163. Rizzo MA, Hadjimichael OC, Preiningerova J, et  al.: Prevalence
and treatment of spasticity reported by multiple sclerosis patients,
Mult Scler 10:589–595, 2004.
170. Sanders A, Foley F, LaRocca N, et al.: The multiple sclerosis inti-
macy and sexuality questionnaire-19 (multiple sclerosis ISQ-19),
Sexual Disabil 18:3–26, 2000.
174. Schwid SR, Petrie MD, Murray R, et al.: A randomized controlled
study of the acute and chronic effects of cooling therapy for mul-
tiple sclerosis, Neurology 60:1955–1960, 2003.
179. Solaro C, Brichetto G, Amato MP, et al.: The prevalence of pain
in multiple sclerosis: a multicenter cross-sectional study, Neurology
63:919–921, 2004.
183. Sosnoff JJ, Gappmaier E, Frame A, et al.: Influence of spasticity on
mobility and balance in persons with multiple sclerosis, J Neurol
Phys Ther 35:129–132, 2011.
186. Sullivan MJ, Weinshenker B, Mikail S, et al.: Screening for major
depression in the early stages of multiple sclerosis, Can J Neurol Sci
22:228–231, 1995.
191. Transverse Myelitis Consortium Working Group: Proposed diag-
nostic criteria and nosology of acute transverse myelitis, Neurology
59:499–505, 2002.
200. Weinshenker BG, Bass B, Rice GP, et al.: The natural history of
multiple sclerosis: a geographically based study. I. Clinical course
and disability, Brain 112:133–146, 1989.
202. Wingerchuk DM, Lennon VA, Pittock SJ, et al.: Revised diagnostic
criteria for neuromyelitis optica, Neurology 66:1485–1489, 2006.
The full reference list for this chapter is available online.
References
1. Abrams P, Cardozo L, Fall M, et  al.: The standardisation of
terminology in lower urinary tract function: report from the
standardisation sub-committee of the international continence
society, Urology 61:37–49, 2003.
2. Adelman G, Rane SG, Villa KF: The cost burden of multiple
sclerosis in the United States: a systematic review of the litera-
ture, J Med Econ 16:639–647, 2013.
3. Amatya B, Khan F, Galea M: Rehabilitation for people with
multiple sclerosis: an overview of cochrane reviews, Cochrane
Database of System Rev (1), 2019. Art. No.: CD012732.
4. Andersson M, Alvarez-Cermeno J, Bernardi G, et al.: Cerebro-
spinal fluid in the diagnosis of multiple sclerosis: a consensus
report, J Neurol Neurosurg Psychiatry 57:897–902, 1994.
5. Asano M, Duquette P, Andersen R, et al.: Exercise barriers and
preferences among women and men with multiple sclerosis, Dis-
abil Rehabil 35:353–361, 2013.
6. Ascherio A: Epstein-Barr virus in the development of multiple
sclerosis, Expert Rev Neurother 8:331–333, 2008.
7. Ascherio A, Munger KL: Environmental risk factors for multiple
sclerosis. Part I: the role of infection, Ann Neurol 61:288–299,
2007.
8. Ascherio A, Munger KL: Epstein-Barr virus infection and mul-
tiple sclerosis: a review, J Neuroimmune Pharmacol 5:271–277,
2010.
9. Ascherio A, Munger KL, White R, et al.: Vitamin D as an early
predictor of multiple sclerosis activity and progression, JAMA
Neurol 71:306–314, 2014.
10. Awad RA: Neurogenic bowel dysfunction in patients with spinal
cord injury, myelomeningocele, multiple sclerosis and Parkin-
son’s disease, World J Gastroenterol 17:5035–5048, 2011.
11. Balak DM, Hengstman GJ, Cakmak A, et al.: Cutaneous adverse
events associated with disease-modifying treatment in multiple
sclerosis: a systematic review, Mult Scler 18:1705–1717, 2012.
12. Barnes MP, Kent RM, Semlyen JK, et al.: Spasticity in multiple
sclerosis, Neurorehabil Neural Repair 17:66–70, 2003.
13. Bartley AJ, Jones DW, Weinberger DR: Genetic variability of
human brain size and cortical gyral patterns, Brain 120:257–
269, 1997.
14. Begum-Haque S, Sharma A, Kasper IR, et al.: Downregulation
of IL-17 and IL-6 in the central nervous system by glatiramer
acetate in experimental autoimmune encephalomyelitis, J Neu-
roimmunol 204:58–65, 2008.
15. Bemelmans BL, Mundy AR, Craggs MD: Neuromodulation by
implant for treating lower urinary tract symptoms and dysfunc-
tion, Eur Urol 36:81–91, 1999.
16. Ben Smail D, Peskine A, Roche N, et al.: Intrathecal baclofen for
treatment of spasticity of multiple sclerosis patients, Mult Scler
12:101–103, 2006.
17. Benedict RH, Fischer JS, Archibald CJ, et al.: Minimal neuro-
psychological assessment of MS patients: a consensus approach,
Clin Neuropsychol 16:381–397, 2002.
18. Benedict RH, Munschauer F, Zarevics P, et  al.: Effects of
l-amphetamine sulfate on cognitive function in multiple sclerosis
patients, J Neurol 255:848–852, 2008.
19. Benedict RH, Weinstock-Guttman B, Fishman I, et  al.: Predic-
tion of neuropsychological impairment in multiple sclerosis: com-
parison of conventional magnetic resonance imaging measures of
atrophy and lesion burden, Arch Neurol 61:226–230, 2004.
20. Benedict RHB, Fishman I, McClellan MM, et al.: Validity of the
beck depression inventory-fast screen in multiple sclerosis, Mult
Scler 9:393–396, 2003.
21. Beran RG, Braley TJ, Segal BM, et al.: Sleep-disordered breath-
ing in multiple sclerosis, Neurology 80:1354–1355, 2013.
22. Bergamaschi R, Crivelli P, Rezzani C, et al.: The DYMUS ques-
tionnaire for the assessment of dysphagia in multiple sclerosis, J
Neurol Sci 269:49–53, 2008.
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
23. Bergamaschi R, Rezzani C, Minguzzi S, et al.: Validation of the
DYMUS questionnaire for the assessment of dysphagia in mul-
tiple sclerosis, Funct Neurol 24:159–162, 2009.
24. Bol Y, Smolders J, Duits A, et al.: Fatigue and heat sensitivity in
patients with multiple sclerosis, Acta Neurol Scand 126:384–389,
2012.
25. Bove R, Chitnis T: Sexual disparities in the incidence and course
of MS, Clin Immunol 149:201–210, 2013.
26. Brex PA, Ciccarelli O, O’Riordan JI, et al.: A longitudinal study
of abnormalities on MRI and disability from multiple sclerosis,
N Engl J Med 346:158–164, 2002.
27. Calabrese M, Favaretto A, Martini V, et al.: Grey matter lesions
in MS: from histology to clinical implications, Prion 7:20–27,
2013.
28. Calabrese M, Poretto V, Favaretto A, et al.: Cortical lesion load
associates with progression of disability in multiple sclerosis,
Brain 135:2952–2961, 2012.
29. Calcagno P, Ruoppolo G, Grasso MG, et al.: Dysphagia in mul-
tiple sclerosis—prevalence and prognostic factors, Acta Neurol
Scand 105:40–43, 2002.
30. Caminero A, Bartolomé M: Sleep disturbances in multiple scle-
rosis, J Neurol Sci 309:86–91, 2011.
31. Celik DB, Poyraz EC, Bingol A, et  al.: Sexual dysfunction in
multiple sclerosis: gender differences, J Neurol Sci 324:17–20,
2013.
32. Chiaravalloti ND, DeLuca J: Cognitive impairment in multiple
sclerosis, Lancet Neurol 7:1139–1151, 2008.
33. Chwastiak L, Ehde DM, Gibbons LE, et al.: Depressive symp-
toms and severity of illness in multiple sclerosis: epidemiologic
study of a large community sample, Am J Psychiatry 159:1862–
1868, 2002.
34. Cohen JA, Coles AJ, Arnold DL, et  al.: Alemtuzumab versus
interferon beta 1a as first-line treatment for patients with relaps-
ing-remitting multiple sclerosis: a randomised controlled phase
3 trial, Lancet 380:1819, 2012.
35. Coles AJ, Twyman CL, Arnold DL, et  al.: Alemtuzumab for
patients with relapsing multiple sclerosis after disease-modifying
therapy: a randomised controlled phase 3 trial, Lancet 380:1829,
2012.
36. Compston A, Coles A: Multiple sclerosis, Lancet 359:1221–
1231, 2002.
37. Confavreux C, Vukusic S: The natural history of multiple sclero-
sis, Rev Prat 56:1313–1320, 2006. [in French].
38. Confavreux C, Vukusic S, Adeleine P: Early clinical predictors
and progression of irreversible disability in multiple sclerosis: an
amnesic process, Brain 126:770–782, 2003.
39. Cook IJ: Diagnostic evaluation of dysphagia, Nature Clin Pract
Gastroenterol Hepatol 5:393–403, 2008.
40. Coyle PK: Multiple sclerosis in pregnancy, Continuum: Lifelong
Learn Neurol 20:42–59, 2014.
41. Craig J, Young CA, Ennis M, et  al.: A randomised controlled
trial comparing rehabilitation against standard therapy in mul-
tiple sclerosis patients receiving intravenous steroid treatment, J
Neurol Neurosurg Psychiatry 74:1225–1230, 2003.
42. Cruccu G, Biasiotta A, Di Rezze S, et al.: Trigeminal neural-
gia and pain related to multiple sclerosis, Pain 143:186–191,
2009.
43. Dalgas U, Severinsen K, Overgaard K: Relations between 6 min-
ute walking distance and 10 meter walking speed in patients
with multiple sclerosis and stroke, Arch Phys Med Rehabil
93:1167–1172, 2012.
44. Das AK, White MD, Longhurst PA: Sacral nerve stimulation for
the management of voiding dysfunction, Rev Urol 2:43–60, 2000.
45. Dasgupta R, Wiseman OJ, Kanabar G, et al.: Efficacy of silde-
nafil in the treatment of female sexual dysfunction due to mul-
tiple sclerosis, J Urol 171:1189–1193, 2004.
46. Davis SL, Wilson TE, White AT, et  al.: Thermoregulation in
multiple sclerosis, J Appl Physiol 109:1531–1537, 2010.
1005.e1
1005.e2    References
47. Di Pauli F, Reindl M, Ehling R, et al.: Smoking is a risk factor
for early conversion to clinically definite multiple sclerosis, Mult
Scler 14:1026–1030, 2008.
48.  DMKG Study Group: Misoprostol in the treatment of tri-
geminal neuralgia associated with multiple sclerosis, J Neurol
250:542–545, 2003.
49. Deleted in review.
50. Ebers GC, Sadovnick AD, Risch NJ: A genetic basis for familial
aggregation in multiple sclerosis. Canadian Collaborative Study
Group, Nature 377:150–151, 1995.
51. Erwin A, Gudesblatt M, Bethoux F, et al.: Intrathecal baclofen
in multiple sclerosis: too little, too late? Mult Scler 17:623–629,
2011.
52. Farez MF, Fiol MP, Gaitán MI, et al.: Sodium intake is associ-
ated with increased disease activity in multiple sclerosis, J Neurol
Neurosurg Psychiatry 86:26–31, 2015.
53. Fernandez O, Berger T, Hartung HP, et al.: Historical overview
of the rationale for the pharmacological use of prolonged-release
fampridine in multiple sclerosis, Expert Rev Clin Pharmacol
5:649–665, 2012.
54. Fischer JS, Priore RL, Jacobs LD, et  al.: Neuropsychological
effects of interferon β-1a in relapsing multiple sclerosis, Ann
Neurol 48:885–892, 2000.
55. Fisher R, Hassenbusch S, Krames E, et al.: A consensus statement
regarding the present suggested titration for prialt (ziconotide),
Neuromodulation 8:153–154, 2005.
56. Fisk JD, Pontefract A, Ritvo PG, et al.: The impact of fatigue on
patients with multiple sclerosis, Can J Neurol Sci 21:9–14, 1994.
57. Fowler CJ, Miller JR, Sharief MK, et al.: A double blind, ran-
domised study of sildenafil citrate for erectile dysfunction in men
with multiple sclerosis, J Neurol Neurosurg Psychiatry 76:700–
705, 2005.
58. Fowler CJ, Panicker JN, Drake M, et al.: A UK consensus on the
management of the bladder in multiple sclerosis, Postgrad Med J
85:552–559, 2009.
59. Fox R. Multiple sclerosis. www.clevelandclinicmeded.com/medi-
calpubs/diseasemanagement/neurology/multiple_sclerosis/.
60. Freedman MS, Thompson EJ, Deisenhammer F, et al.: Recom-
mended standard of cerebrospinal fluid analysis in the diag-
nosis of multiple sclerosis: a consensus statement, Arch Neurol
62:865–870, 2005.
61. Friese MA, Schattling B, Fugger L: Mechanisms of neurodegen-
eration and axonal dysfunction in multiple sclerosis, Nat Rev
Neurol 10:225–238, 2014.
62. Frohman E, Costello F, Zivadinov R, et  al.: Optical coherence
tomography in multiple sclerosis, Lancet Neurol 5:853–863, 2006.
63. Frohman EM, Racke MK, Raine CS: Multiple sclerosis—the
plaque and its pathogenesis, N Engl J Med 354:942–955, 2006.
64. Gale CR, Martyn CN: Migrant studies in multiple sclerosis, Prog
Neurobiol 47:425–448, 1995.
65. Garnock-Jones KP: Dextromethorphan/quinidine: in pseudo-
bulbar affect, CNS Drugs 25:435–445, 2011.
66. Geber C, Baumgartner U, Schwab R, et al.: Revised definition
of neuropathic pain and its grading system: an open case series
illustrating its use in clinical practice, Am J Med 122(Suppl
10):S3–S12, 2009.
67. Ghaffar O, Chamelian L, Feinstein A: Neuroanatomy of pseu-
dobulbar affect: a quantitative MRI study in multiple sclerosis, J
Neurol 255:406–412, 2008.
68. Gianfrancesco M, Acuna B, Shen L, et al.: Obesity during child-
hood and adolescence increases susceptibility to multiple sclero-
sis after accounting for established genetic and environmental
risk factors, Obes Res Clin Pract 8:e435–e447, 2014.
69. Gijbels D, Eijnde B, Feys P: Comparison of the 2- and 6-minute
walk test in multiple sclerosis, Mult Scler J 17:1269–1272, 2011.
70. Gold SM, Schulz KH, Hartmann S, et al.: Basal serum levels and
reactivity of nerve growth factor and brain-derived neurotrophic
factor to standardized acute exercise in multiple sclerosis and
controls, J Neuroimmunol 138:99–105, 2003.
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
71. Goldman Consensus Group: The Goldman consensus statement
on depression in multiple sclerosis, Mult Scler 11:328–337,
2005.
72. Goldman MD, Ann Marrie R, Cohen JA: Evaluation of the six-
minute walk in multiple sclerosis subjects and healthy controls,
Mult Scler 14:383–390, 2008.
73. Goldstein I, Siroky MB, Sax DS, et  al.: Neurourologic abnor-
malities in multiple sclerosis, J Urol 128:541–545, 1982.
74. Goodman AD, Brown TR, Edwards KR, et al.: A phase 3 trial
of extended release oral dalfampridine in multiple sclerosis, Ann
Neurol 68:494–502, 2010.
75. Goodman AD, Brown TR, Krupp LB, et al.: Sustained-release
oral fampridine in multiple sclerosis: a randomised, double-
blind, controlled trial, Lancet 373:732–738, 2009.
76. Goodman AD, Stone RT: Enhancing neural transmission in
multiple sclerosis (4-aminopyridine therapy), Neurother 10:106–
110, 2013.
77. Grossman RI, Gonzalez-Scarano F, Atlas SW, et  al.: Multiple
sclerosis: gadolinium enhancement in MR imaging, Radiology
161:721–725, 1986.
78. Guthrie TC, Nelson DA: Influence of temperature changes on
multiple sclerosis: critical review of mechanisms and research
potential, J Neurol Sci 129:1–8, 1995.
79. Haas J: High dose IVIG in the postpartum period for preven-
tion of exacerbations in multiple sclerosis, Mult Scler 6(Suppl
2):S18–S20, 2000. discussion S33.
80. Harel Y, Appleboim N, Lavie M, et al.: Single dose of methyl-
phenidate improves cognitive performance in multiple sclerosis
patients with impaired attention process, J Neurol Sci 276:38–
40, 2009.
81. Hauser SL, Dawson DM, Lehrich JR, et  al.: Intensive immu-
nosuppression in progressive multiple sclerosis. A randomized,
three-arm study of high-dose intravenous cyclophosphamide,
plasma exchange, and ACTH, N Engl J Med 308:173–180,
1983.
82. Hauser SL, Waubant E, Arnold DL, et al.: B-cell depletion with
rituximab in relapsing-remitting multiple sclerosis, N Engl J Med
358:676–688, 2008.
83. He D, Zhang Y, Dong S, et al.: Pharmacological treatment for
memory disorder in multiple sclerosis, Cochrane Database Syst
Rev 12:CD008876, 2013.
84. Healy BC, Ali EN, Guttmann CR, et  al.: Smoking and dis-
ease progression in multiple sclerosis, Arch Neurol 66:858–864,
2009.
85. Hedstrom AK, Baarnhielm M, Olsson T, et al.: Tobacco smok-
ing, but not Swedish snuff use, increases the risk of multiple scle-
rosis, Neurology 73:696–701, 2009.
86. Hedstrom AK, Hillert J, Olsson T, et al.: Smoking and multiple
sclerosis susceptibility, Eur J Epidemiol 28:867–874, 2013.
87. Hedstrom AK, Lima Bomfim I, Barcellos L, et al.: Interaction
between adolescent obesity and HLA risk genes in the etiology
of multiple sclerosis, Neurology 82:865–872, 2014.
88. Hedstrom AK, Ryner M, Fink K, et  al.: Smoking and risk of
treatment-induced neutralizing antibodies to interferon beta-1a,
Mult Scler 20:445–450, 2014.
89. Health Union MultipleSclerosis.net. MS statistics. Available at
http://multiplesclerosis.net/what-is-ms/statistics/.
90. Hernan MA, Jick SS, Logroscino G, et  al.: Cigarette smoking
and the progression of multiple sclerosis, Brain 128:1461–1465,
2005.
91. Hernan MA, Olek MJ, Ascherio A: Cigarette smoking and inci-
dence of multiple sclerosis, Am J Epidemiol 154:69–74, 2001.
92. Hobart JC, Riazi A, Thompson AJ, et al.: Getting the measure of
spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity
Scale (MSSS-88), Brain 129:224–234, 2006.
93. Iaffaldano P, Viterbo RG, Paolicelli D, et al.: Impact of natali-
zumab on cognitive performances and fatigue in relapsing mul-
tiple sclerosis: a prospective, open-label, two years observational
study, PLoS ONE 7:e35843, 2012.

94. Kabay SC, Yucel M, Kabay S: Acute effect of posterior tibial
nerve stimulation on neurogenic detrusor overactivity in patients
with multiple sclerosis: urodynamic study, Urology 71:641–645,
2008.
95. Kalsi V, Gonzales G, Popat R, et al.: Botulinum injections for
the treatment of bladder symptoms of multiple sclerosis, Ann
Neurol 62:452–457, 2007.
96. Kaminska M, Kimoff RJ, Schwartzman K, et al.: Sleep disorders
and fatigue in multiple sclerosis: evidence for association and
interaction, J Neurol Sci 302:7–13, 2011.
97. Kappos L, Moeri D, Radue EW, et al.: Predictive value of gad-
olinium-enhanced magnetic resonance imaging for relapse rate
and changes in disability or impairment in multiple sclerosis:
a meta-analysis. Gadolinium MRI Meta-analysis Group, Lancet
353:964–969, 1999.
98. Kasper LH, Shoemaker J: Multiple sclerosis immunology: the
healthy immune system vs the multiple sclerosis immune system,
Neurology 74(Suppl 1):2–8, 2010.
99. Katusic S, Williams DB, Beard CM, et  al.: Epidemiology and
clinical features of idiopathic trigeminal neuralgia and glosso-
pharyngeal neuralgia: similarities and differences, Rochester,
Minnesota, 1945-1984, Neuroepidemiology 10:276–281, 1991.
100. Kaufman M, Moyer D, Norton J: The significant change for the
timed 25-foot walk in the multiple sclerosis functional compos-
ite, Mult Scler 6:286–290, 2000.
101. Kermode AG, Thompson AJ, Tofts P, et al.: Breakdown of the
blood-brain barrier precedes symptoms and other MRI signs of
new lesions in multiple sclerosis. Pathogenetic and clinical impli-
cations, Brain 113:1477–1489, 1990.
102. Khan S, Game X, Kalsi V, et al.: Long-term effect on quality of
life of repeat detrusor injections of botulinum neurotoxin-A for
detrusor overactivity in patients with multiple sclerosis, J Urol
185:1344–1349, 2011.
103. Kimura J: Electrodiagnosis in diseases of nerve and muscle, 3rd ed,
New York, 2001, Oxford University Press.
104. Kingwell E, Marriott JJ, Jette N, et al.: Incidence and prevalence
of multiple sclerosis in Europe: a systematic review, BMC Neurol
13:128, 2013.
105. Klotz U: Ziconotide—a novel neuron-specific calcium channel
blocker for the intrathecal treatment of severe chronic pain—a
short review, Int J Clin Pharmacol Ther 44:478–483, 2006.
106. Kraft GH: Evoked potentials in multiple sclerosis, Phys Med
Rehabil Clin N Am 24:717–720, 2013.
107. Krupp LB, LaRocca NG, Muir-Nash J, et  al.: The Fatigue
Severity Scale. Application to patients with multiple sclerosis
and systemic lupus erythematosus, Arch Neurol 46:1121–1123,
1989.
108. Kurtzke JF: Neurologic impairment in multiple sclerosis and the
disability status scale, Acta Neurol Scand 46:493–512, 1970.
109. Kurtzke JF: Rating neurologic impairment in multiple sclero-
sis: an Expanded Disability Status Scale (EDSS), Neurology
33:1444–1452, 1983.
110. Langer-Gould A, Beaber BE: Effects of pregnancy and breast-
feeding on the multiple sclerosis disease course, Clin Immunol
149:244–250, 2013.
111. Latimer-Cheung AE, Martin Ginis KA, Hicks AL, et al.: Devel-
opment of evidence-informed physical activity guidelines for
adults with multiple sclerosis, Arch Phys Med Rehabil 94:1829–
1836, 2013.
112. Lavery AM, Verhey LH, Waldman AT: Outcome measures in
relapsing-remitting multiple sclerosis: capturing disability and
disease progression in clinical trials, Mult Scler Int 2014:262350,
2014.
113. Levin LI, Munger KL, O’Reilly EJ, et al.: Primary infection with
the Epstein-Barr virus and risk of multiple sclerosis, Ann Neurol
67:824–830, 2010.
114. Lovera JF, Kim E, Heriza E, et  al.: Ginkgo biloba does not
improve cognitive function in MS: a randomized placebo-con-
trolled trial, Neurology 79:1278–1284, 2012.
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
References 1005.e3
115. Lunde HM, Bjorvatn B, Myhr KM, et al.: Clinical assessment
and management of sleep disorders in multiple sclerosis: a litera-
ture review, Acta Neurol Scand 196(Suppl):24–30, 2013.
116. Ma VY, Chan L, Carruthers KJ: Incidence, prevalence, costs, and
impact on disability of common conditions requiring rehabilita-
tion in the United States: stroke, spinal cord injury, traumatic
brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthri-
tis, limb loss, and back pain, Arch Phys Med Rehabil 95:986–995,
2014.
117. MacDiarmid SA, Peters KM, Shobeiri SA, et  al.: Long-term
durability of percutaneous tibial nerve stimulation for the treat-
ment of overactive bladder, J Urol 183:234–240, 2010.
118. Mackenzie IS, Morant SV, Bloomfield GA, et al.: Incidence and
prevalence of multiple sclerosis in the UK 1990-2010: a descrip-
tive study in the general practice research database, J Neurol Neu-
rosurg Psychiatry 85:76–84, 2014.
119. Mahajan ST, James R, Frasure H: Pelvic floor disorders and mul-
tiple sclerosis: are patients satisfied with their care? Int J MS Care
16:20–25, 2014.
120. Malhotra AS, Goren H: The hot bath test in the diagnosis of
multiple sclerosis, JAMA 246:1113–1114, 1981.
121. Marrie RA: Environmental risk factors in multiple sclerosis aeti-
ology, Lancet Neurol 3:709–718, 2004.
122. McDonald WI, Barnes D: The ocular manifestations of multiple
sclerosis. 1. Abnormalities of the afferent visual system, J Neurol
Neurosurg Psychiatry 55:747–752, 1992.
123. McDonald WI, Compston A, Edan G, et  al.: Recommended
diagnostic criteria for multiple sclerosis: guidelines from the
international panel on the diagnosis of multiple sclerosis, Ann
Neurol 50:121–127, 2001.
124. Mehling M, Lindberg R, Raulf F, et al.: Th17 central memory T
cells are reduced by FTY720 in patients with multiple sclerosis,
Neurology 75:403–410, 2010.
125. Messina S, Patti F: Gray matters in multiple sclerosis: cognitive
impairment and structural MRI, Mult Scler Int 2014:609694,
2014.
126. Miller A, Pratt H, Schiffer RB: Pseudobulbar affect: the spec-
trum of clinical presentations, etiologies and treatments, Expert
Rev Neurother 11:1077–1088, 2011.
127. Mills RJ, Young CA: A medical definition of fatigue in multiple
sclerosis, QJM 101:49–60, 2008.
128. Minden SL, Feinstein A, Kalb RC, et al.: Evidence-based guide-
line: assessment and management of psychiatric disorders in
individuals with MS: report of the guideline development sub-
committee of the American Academy of Neurology, Neurology
82:174–181, 2014.
129. Moore SR, Gresham LS, Bromberg MB, et al.: A self-report mea-
sure of affective lability, J Neurol Neurosurg Psychiatry 63:89–93,
1997.
130. Moss-Morris R, Dennison L, Landau S, et  al.: A randomized
controlled trial of cognitive behavioral therapy (CBT) for adjust-
ing to multiple sclerosis (the saMS trial): does CBT work and for
whom does it work? J Consult Clin Psychol 81:251–262, 2013.
131. Multiple Sclerosis Society of Canada. Physical activity. Available
at http://mssociety.ca/physicalactivity.
132. Munger KL, Levin LI, Hollis BW, et al.: Serum 25-hydroxyvi-
tamin D levels and risk of multiple sclerosis, JAMA 296:2832–
2838, 2006.
133. Munger KL, Zhang SM, O’Reilly E, et al.: Vitamin D intake and
incidence of multiple sclerosis, Neurology 62:60–65, 2004.
134. National Multiple Sclerosis Society. MS prevalence: estimating
the prevalence of MS. Available at www.nationalmssociety.org/
About-the-Society/MS-Prevalence.
135. Nayak NB, Salah R, Huang JC, et al.: A comparison of sagittal
short T1 inversion recovery and T2-weighted FSE sequences for
detection of multiple sclerosis spinal cord lesions, Acta Neurol
Scand 129:198–203, 2014.
136. Noseworthy JH, Lucchinetti C, Rodriguez M, et  al.: Multiple
sclerosis, N Engl J Med 343:938–952, 2000.
1005.e4    References
137. Okuda DT, Mowry EM, Beheshtian A, et al.: Incidental MRI
anomalies suggestive of multiple sclerosis: the radiologically iso-
lated syndrome, Neurology 72:800–805, 2009.
138. Okuda DT, Siva A, Kantarci O, et  al.: Radiologically isolated
syndrome: 5-year risk for an initial clinical event, PLoS ONE
9:e90509, 2014.
139. Palmer L, Abouzaid S, Shi N, et al.: Impact of patient cost shar-
ing on multiple sclerosis treatment, Am J Manage Care 4:1–4,
2012.
140. Pantavou KG, Bagos PG: Season of birth and multiple sclerosis,
a systematic review and meta-analysis, J Neurol 2019. https://
doi.org/10.1007/s00415-019-09346-5.
141. Parvizi J, Anderson SW, Martin CO, et al.: Pathological laugh-
ter and crying: a link to the cerebellum, Brain 124:1708–1719,
2001.
142. Parvizi J, Arciniegas DB, Bernardini GL, et al.: Diagnosis and
management of pathological laughter and crying, Mayo Clin
Proc 81:1482–1486, 2006.
143. Parvizi J, Joseph J, Press DZ, et  al.: Pathological laughter and
crying in patients with multiple system atrophy-cerebellar type,
Mov Disord 22:798–803, 2007.
144. Patti F, Morra VB, Amato MP, et al.: Subcutaneous interferon
beta-1a may protect against cognitive impairment in patients
with relapsing-remitting multiple sclerosis: 5-year follow-up of
the COGIMUS study, PLoS ONE 8:e74111, 2013.
145. Penn RD, Savoy SM, Corcos D, et al.: Intrathecal baclofen for
severe spinal spasticity, N Engl J Med 320:1517–1521, 1989.
146. Petajan JH, Gappmaier E, White AT, et al.: Impact of aerobic
training on fitness and quality of life in multiple sclerosis, Ann
Neurol 39:432–441, 1996.
147. Pioro EP, Brooks BR, Cummings J, et al.: Dextromethorphan
plus ultra low-dose quinidine reduces pseudobulbar affect, Ann
Neurol 68:693–702, 2010.
148. Pokryszko-Dragan A, Bilinska M, Gruszka E, et al.: Sleep distur-
bances in patients with multiple sclerosis, Neurol Sci 34:1291–
1296, 2013.
149. Polman CH, Bertelsmann FW, van Loenen AC, et al.: 4-Ami-
nopyridine in the treatment of patients with multiple sclerosis:
long-term efficacy and safety, Arch Neurol 51:292–296, 1994.
150. Polman CH, O’Connor PW, Havrdova E, et al.: A randomized,
placebo-controlled trial of natalizumab for relapsing multiple
sclerosis, N Engl J Med 354:899–910, 2006.
151. Polman CH, Reingold SC, Banwell B, et al.: Diagnostic criteria
for multiple sclerosis: 2010 revisions to the McDonald criteria,
Ann Neurol 69:292–302, 2011.
152. Polman CH, Reingold SC, Edan G, et  al.: Diagnostic criteria
for multiple sclerosis: 2005 revisions to the “McDonald criteria”,
Ann Neurol 58:840–846, 2005.
153. Pope GC, Urato CJ, Kulas ED, et al.: Prevalence, expenditures,
utilization, and payment for persons with MS in insured popula-
tions, Neurology 58:37–43, 2002.
154. Prinz M, Kalinke U: New lessons about old molecules: how type
I interferons shape Th1/Th17-mediated autoimmunity in the
CNS, Trends Mol Med 16:379–386, 2010.
155. Rao SM, Leo GJ, Bernardin L, et al.: Cognitive dysfunction in
multiple sclerosis. I. Frequency, patterns, and prediction, Neurol-
ogy 41:685–691, 1991.
156. Rauck RL, Wallace MS, Leong MS, et al.: A randomized, dou-
ble-blind, placebo-controlled study of intrathecal ziconotide
in adults with severe chronic pain, J Pain Symptom Manage
31:393–406, 2006.
157. Restivo DA, Casabona A, Centonze D, et al.: Pharyngeal electri-
cal stimulation for dysphagia associated with multiple sclerosis: a
pilot study, Brain Stimul 6:418–423, 2013.
158. Restivo DA, Marchese-Ragona R, Patti F, et  al.: Botulinum
toxin improves dysphagia associated with multiple sclerosis, Eur
J Neurol 18:486–490, 2011.
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
159. Reynolds LF, Short CA, Westwood DA, et al.: Head pre-cooling
improves symptoms of heat-sensitive multiple sclerosis patients,
Can J Neurol Sci 38:106–111, 2011.
160. Rice CM: Disease modification in multiple sclerosis: an update,
Pract Neurol 14:6–13, 2014.
161. Riise T, Nortvedt MW, Ascherio A: Smoking is a risk factor for
multiple sclerosis, Neurology 61:1122–1124, 2003.
162. Rimmer JH: Health promotion for people with disabilities: the
emerging paradigm shift from disability prevention to preven-
tion of secondary conditions, Phys Ther 79:495–502, 1999.
163. Rizzo MA, Hadjimichael OC, Preiningerova J, et  al.: Preva-
lence and treatment of spasticity reported by multiple sclerosis
patients, Mult Scler 10:589–595, 2004.
164. Rommer PS, Zettl UK, Kieseier B, et al.: Requirement for safety
monitoring for approved multiple sclerosis therapies: an over-
view, Clin Exp Immunol 175:397–407, 2014.
165. Ruck T, Bittner S, Wiendl H, Meuth SG: Alemtuzumab in mul-
tiple sclerosis: mechanism of action and beyond, Int J Mol Sci
16:16414, 2015.
166. Sadiq SA, Poopatana CA: Intrathecal baclofen and morphine in
multiple sclerosis patients with severe pain and spasticity, J Neu-
rol 254:1464–1465, 2007.
167. Sadovnick AD: Genetic background of multiple sclerosis, Auto-
immun Rev 11:163–166, 2012.
168. Sadovnick AD, Eisen K, Ebers GC, et  al.: Cause of death in
patients attending multiple sclerosis clinics, Neurology 41:1193–
1196, 1991.
169. Salem Y, Csiza L, Harrison M, et al. Aquatic exercise and mul-
tiple sclerosis: a healthcare professional’s guide. http://support.
mymsaa.org/site/DocServer/AquaticsBookletHCP_MSAA.
pdf?docID=1301.
170. Sanders A, Foley F, LaRocca N, et  al.: The multiple sclerosis
intimacy and sexuality questionnaire-19 (multiple sclerosis ISQ-
19), Sexual Disabil 18:3–26, 2000.
171. Savci S, Inal-Ince D, Arikan H, et al.: Six-minute walk distance
as a measure of functional exercise capacity in multiple sclerosis,
Disabil Rehabil 27:1365–1371, 2005.
172. Scalfari A, Neuhaus A, Daumer M, et al.: Early relapses, onset of
progression, and late outcome in multiple sclerosis, JAMA Neu-
rol 70:214–222, 2013.
173. Scalfari A, Neuhaus A, Degenhardt A, et al.: The natural history
of multiple sclerosis: a geographically based study 10: relapses
and long-term disability, Brain 133:1914–1929, 2010.
174. Schwid SR, Petrie MD, Murray R, et  al.: A randomized con-
trolled study of the acute and chronic effects of cooling therapy
for multiple sclerosis, Neurology 60:1955–1960, 2003.
175. Scott TF, Schramke CJ: Poor recovery after the first two attacks
of multiple sclerosis is associated with poor outcome five years
later, J Neurol Sci 292:52–56, 2010.
176. Siegert RJ, Abernethy DA: Depression in multiple sclerosis: a
review, J Neurol Neurosurg Psychiatry 76:469–475, 2005.
177. Simon KC, Munger KL, Ascherio A: XVI European Charcot
Foundation Lecture: nutrition and environment: can MS be
prevented? J Neurol Sci 311:1–8, 2011.
178. Smith RA, Berg JE, Pope LE, et  al.: Validation of the CNS
emotional lability scale for pseudobulbar affect (pathological
laughing and crying) in multiple sclerosis patients, Mult Scler
10:679–685, 2004.
179. Solaro C, Brichetto G, Amato MP, et al.: The prevalence of pain
in multiple sclerosis: a multicenter cross-sectional study, Neurol-
ogy 63:919–921, 2004.
180. Solaro C, Rezzani C, Trabucco E, et al.: Prevalence of patient-
reported dysphagia in multiple sclerosis patients: an Italian mul-
ticenter study (using the DYMUS questionnaire), J Neurol Sci
331:94–97, 2013.
181. Solaro C, Uccelli MM: Management of pain in multiple sclerosis:
a pharmacological approach, Nat Rev Neurol 7:519–527, 2011.

182. Somerset M, Campbell R, Sharp DJ, et al.: What do people with
MS want and expect from health-care services? Health Expect
4:29–37, 2001.
183. Sosnoff JJ, Gappmaier E, Frame A, et al.: Influence of spastic-
ity on mobility and balance in persons with multiple sclerosis, J
Neurol Phys Ther 35:129–132, 2011.
184. Stewart TM, Tran ZV: Injectable multiple sclerosis medications:
a patient survey of factors associated with injection-site reac-
tions, Int J MS Care 14:46–53, 2012.
185. Stuifbergen AK, Becker H, Perez F, et al.: A randomized con-
trolled trial of a cognitive rehabilitation intervention for persons
with multiple sclerosis, Clin Rehabil 26:882–893, 2012.
186. Sullivan MJ, Weinshenker B, Mikail S, et  al.: Screening for
major depression in the early stages of multiple sclerosis, Can J
Neurol Sci 22:228–231, 1995.
187. Sumowski JF, Rocca MA, Leavitt VM, et al.: Brain reserve and
cognitive reserve in multiple sclerosis: what you’ve got and how
you use it, Neurology 80:2186–2193, 2013.
188. Svejgaard A: The immunogenetics of multiple sclerosis, Immuno-
genetics 60:275–286, 2008.
189. Thacker EL, Mirzaei F, Ascherio A: Infectious mononucleo-
sis and risk for multiple sclerosis: a meta-analysis, Ann Neurol
59:499–503, 2006.
190. Thompson AJ, Banwell BL, Barkhof F, et al.: Diagnosis of mul-
tiple sclerosis: 2017 revisions of the McDonald criteria, Lancet
Neurol 17:162–173, 2018.
191. 
Transverse Myelitis Consortium Working Group: Proposed
diagnostic criteria and nosology of acute transverse myelitis,
Neurology 59:499–505, 2002.
192. Trojaborg W, Petersen E: Visual and somatosensory evoked cor-
tical potentials in multiple sclerosis, J Neurol Neurosurg Psychia-
try 42:323–330, 1979.
193. Tullman MJ: Overview of the epidemiology, diagnosis, and dis-
ease progression associated with multiple sclerosis, Am J Manage
Care 19(Suppl 2):S15–S20, 2013.
194. Tumani H, Hartung HP, Hemmer B, et al.: Cerebrospinal fluid
biomarkers in multiple sclerosis, Neurobiol Dis 35(2):117–127,
2009.
195. 
UnitedHealth Center for Health Reform and Moderniza-
tion: The growth of specialty pharmacy: current trends and future
Descargado para Sergio Navarrete (sergionavarrete@udec.cl) en University of Concepción de ClinicalKey.es por Elsevier en octubre 09, 2020.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2020. Elsevier Inc. Todos los derechos reservados.
References 1005.e5
opportunities. April 2014. www.unitedhealthgroup.com/∼/
media/UHG/PDF/2014/UNH-The-Growth-Of-Specialty-
Pharmacy.ashx.
196. van Walderveen MA, Kamphorst W, Scheltens P, et al.: Histo-
pathologic correlate of hypointense lesions on T1-weighted spin-
echo MRI in multiple sclerosis, Neurology 50:1282–1288, 1998.
197. van Walderveen MA, Truyen L, van Oosten BW, et al.: Develop-
ment of hypointense lesions on T1-weighted spin-echo magnetic
resonance images in multiple sclerosis: relation to inflammatory
activity, Arch Neurol 56:345–351, 1999.
198. Vargas-Lowy D, Chitnis T: Pathogenesis of pediatric multiple
sclerosis, J Child Neurol 27:1394–1407, 2012.
199. Weinshenker BG: Epidemiology of multiple sclerosis, Neurol
Clin 14:291–308, 1996.
200. Weinshenker BG, Bass B, Rice GP, et al.: The natural history of
multiple sclerosis: a geographically based study. I. Clinical course
and disability, Brain 112:133–146, 1989.
201. Willer CJ, Ebers GC: Susceptibility to multiple sclerosis: inter-
play between genes and environment, Curr Opin Neurol 13:241–
247, 2000.
202. Wingerchuk DM, Carter JL: Multiple sclerosis: current and
emerging disease-modifying therapies and treatment strategies,
Mayo Clin Proc 89:225–240, 2014.
203. Yadav V, Bever Jr C, Bowen J, et al.: Summary of evidence-based
guideline: complementary and alternative medicine in multiple
sclerosis: report of the guideline development subcommittee of
the American Academy of Neurology, Neurology 82:1083–1092,
2014.
204. Yamaguchi S, Rogawski MA: Effects of anticonvulsant drugs on
4-aminopyridine-induced seizures in mice, Epilepsy Res 11:9–16,
1992.
205. Yeh EA: Multiple sclerosis: which MRI findings predict MS
development in children? Nat Rev Neurol 8:185–186, 2012.
206. Yeh EA, Chitnis T, Krupp L, et  al.: Pediatric multiple sclero-
sis, Nat Rev Neurol 5:621–631, 2009.
207. Zajicek J, Fox P, Sanders H, et al.: Cannabinoids for treatment
of spasticity and other symptoms related to multiple sclerosis
(CAMS study): multicentre randomised placebo-controlled
trial, Lancet 362:1517–1526, 2003.