Management of Multiple REVIEW ARTICLE


Sclerosis Symptoms C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE

and Comorbidities
By W. Oliver Tobin, MBBCh, BAO, PhD

ABSTRACT
PURPOSE OF REVIEW: This article discusses the prevalence, identification, and
management of multiple sclerosis (MS)–related symptoms and associated
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVHXBtH07/PgUIJCyDbnlCpCoQzHDe2e0FOnJO+3fv2SzcavGLeiz3Mc= on 06/03/2019

comorbidities, including complications that can present at all stages of the

disease course.

RECENT FINDINGS: Theimpact of comorbidities on the outcome of MS is

increasingly recognized. This presents an opportunity to impact the course
and outcome of MS by identifying and treating associated comorbidities
that may be more amenable to treatment than the underlying inflammatory
and neurodegenerative disease. The identification of MS-related
symptoms and comorbidities is facilitated by brief screening tools, ideally
CITE AS:
completed by the patient and automatically entered into the patient CONTINUUM (MINNEAP MINN)
record, with therapeutic suggestions for the provider. The development of 2019;25(3, MULTIPLE SCLEROSIS
AND OTHER CNS INFLAMMATORY
free, open-source screening tools that can be integrated with electronic DISEASES):753–772.
health records provides opportunities to identify and treat MS-related
symptoms and comorbidities at an early stage. Address correspondence to
Dr W. Oliver Tobin, Mayo Clinic,
Department of Neurology, 200
SUMMARY: Identification and management of MS-related symptoms and First St SW, Rochester, MN
comorbidities can lead to improved outcomes, improved quality of life, 55905, tobin.oliver@mayo.edu.
and reduced disease activity. The use of brief patient-reported screening
RELATIONSHIP DISCLOSURE:
tools at or before the point of care can facilitate identification of Dr Tobin receives research/
symptoms and comorbidities that may be amenable to intervention. grant support from Mallinckrodt
Pharmaceuticals.

UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
INTRODUCTION Dr Tobin discusses the

M
ultiple sclerosis (MS) is associated in the popular consciousness unlabeled/investigational use of
amantadine, armodafinil, and
with motor disability and gait dysfunction, which were modafinil for fatigue;
initially described by Charcot and his contemporaries over lacosamide, lamotrigine, and
150 years ago. Over the course of the past century, increased oxcarbazepine for paroxysmal
symptoms; gabapentin for
recognition of disabling and treatable complications of MS has restless legs syndrome and
led to several large controlled trials of medications aimed at reducing symptoms. spasticity; and nabiximols, oral
cannabis extract, and synthetic
More recently, it has become apparent that some comorbidities not only occur tetrahydrocannabinol for the
with increased prevalence in patients with MS but also increase the risks of treatment of spasticity.
developing the disease,1–3 delayed diagnosis,4,5 relapse,6 and disability progression
(TABLE 9-1).7,8 Thus, the reasons to identify and intervene early in MS-associated © 2019 American Academy
comorbidities are to reduce MS disease activity and the risk of progression and to of Neurology.

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MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES

improve quality of life and functional independence. A multidisciplinary team is

essential, as neurologists may not always be the best-equipped providers to
intervene on comorbidities. However, they are typically the main providers who
assess patients and, as such, are well placed to identify comorbidities. It is also
important to note that patient needs and comorbidities change over time, and
regular reassessment and proactive intervention are needed, particularly on
symptoms such as depression, spasticity, and obesity.
It is useful to separate the presence of symptoms directly related to MS
itself, such as spasticity, and the presence of comorbidities that are prevalent
in the MS population at higher rates than in the general population, such as
obesity. Sometimes the distinction between these two entities is less than clear. For
example, sexual dysfunction in MS is commonly present due to spinal cord
disease, but psychosocial factors unrelated to the underlying MS may also
contribute to sexual dysfunction. The American Academy of Neurology has issued
a quality measurement set to facilitate quality improvement by providers.9 This
document serves as a good foundation for evaluating the quality of clinic-based
assessments for the presence of MS complications and comorbidities, although
standardized tools to aid in this assessment are sometimes focused on research and
not always practical to use in routine clinical practice. Along with requiring
adequate documentation of the MS diagnosis and performing a comparison MRI
within 24 months of the diagnosis, this measurement set recommends recording
an MS disability scale score at each visit; evaluating for fall risk, urinary tract
infections, fatigue, cognitive impairment, depression, and physical activity; and
monitoring quality of life. TABLE 9-2 provides a summary of common symptoms
associated with MS and suggested treatments.

TABLE 9-1 Common Comorbidities and Their Impact on the Diagnosis and Disease
Course of Multiple Sclerosis

Increases the Risk of Developing Increases the Risk of

Clinically Isolated Syndrome/ Increases the Risk Multiple Sclerosis Increases the
Comorbidity Multiple Sclerosis of Diagnostic Delay Relapse Risk of Disability

Depression X X

Anxiety X X

Hypertension X X

Migraine X

Hyperlipidemia X

Ischemic heart X X
disease

Cerebrovascular X X
disease

Obesity X X X

Multimorbidity (≥3 X X X
comorbidities)

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FATIGUE KEY POINTS
Fatigue is the most common symptom in patients with MS,10 present in almost
● Fatigue is the most
half of patients with clinically isolated syndrome11 and over 80% of patients over common symptom in
the course of the disease.10,12 The majority of patients report fatigue as their patients with multiple
worst symptom.5 Fatigue present at the onset of clinically isolated syndrome is sclerosis, present in almost
associated with a higher risk of future conversion to clinically definite MS.11 half of patients with
clinically isolated syndrome
Fatigue is multifactorial and requires a multifaceted approach to evaluation
and over 80% of patients
and management. A suggested algorithm for the evaluation and management over the course of the
of fatigue in the clinical setting is outlined in FIGURE 9-1.13 Polypharmacy is disease.
common in MS and is associated with fatigue.14 Medications for the treatment
of other symptoms associated with MS, including interferon beta and ● Restless legs syndrome
has been reported in 13% to
anticholinergic, antispasticity, and pain medications, can all contribute to fatigue 65% of patients with multiple
and cognitive symptoms. Use of complementary and alternative medicines can sclerosis and appears to be
further complicate the picture, as these are not commonly inquired about related to spinal cord
by physicians nor reported by patients.15 Prioritizing a patient’s symptom list and disease.
rationalizing medications is the first suggested step in evaluation and ● Limited evidence exists
management of fatigue. for commonly used but
Screening for depression is the next step in fatigue evaluation. It can be unapproved medications,
performed using freely available screening tools, such as the Patient Health such as amantadine,
modafinil, armodafinil,
Questionnaire-9 (PHQ-9)16,17 or its shorter derivative, the Patient Health
methylphenidate, and
Questionnaire-2 (PHQ-2),18,19 or using a combination screening instrument for amphetamine compounds
depression and anxiety such as the Patient Health Questionnaire-4 (PHQ-4).20 for management of fatigue in
Depression is strongly correlated with fatigue.21 Sedation may be minimized multiple sclerosis.
by the use of cognitive-behavioral therapy for mild depression or, if
pharmacotherapy is required, by using nonsedating selective serotonin reuptake
inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
When contributing medications and depressive symptoms have been
eliminated as a cause for fatigue, screening for other reversible causes is
recommended. Narcolepsy, rapid eye movement (REM) sleep behavior disorder,
sleep-disordered breathing, and insomnia are associated with MS.22 Initial
screening can identify coexisting treatable sleep disorders such as obstructive
sleep apnea and RLS, which can impact both fatigue and health-related quality
of life.23 RLS has been reported in 13% to 65% of patients with MS24–28 and
appears to be related to spinal cord disease.29,30 It is unclear whether
MS-associated RLS responds to treatments for idiopathic RLS, such as iron
supplementation, pramipexole, or gabapentin; however, these are reasonable
strategies to employ.
When secondary causes of fatigue have been ruled out, a tailored program to
reduce fatigue should be discussed with the patient. This involves components of
a regular exercise program,31 energy conservation strategies (education about
balancing, modifying, and prioritizing activities; rest; self-care; effective
communication; biomechanics; ergonomics; and environmental modification),32
mindfulness-based interventions,32 and environmental modifications such as
gait aids or using a cooling vest when walking or exercising in the heat.
Pharmacologic management for fatigue may be considered when secondary
causes for fatigue have been addressed and nonpharmacologic strategies have
been unsuccessful. Limited evidence exists for commonly used but unapproved
medications, such as amantadine, modafinil, armodafinil, methylphenidate,
and amphetamine compounds for management of fatigue in MS. Although
these medications are commonly used in general practice and in some MS

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MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES

TABLE 9-2 Symptomatic Management of Multiple Sclerosis

Symptom Description Treatments

Fatigue Multifactorial Limit sedating medications

Most common symptom in patients with multiple Screen for and treat depression, obesity, obstructive
sclerosis (MS) sleep apnea
80% lifetime prevalence Energy conservation measures
Prescribe a regular exercise regimen

Depression 30% point prevalence
Associated with higher Expanded Disability Status
Scale (EDSS) score and anxiety
Screen with Beck Depression Inventory, Patient
Health Questionnaire-2, or Patient Health
Questionnaire-4
Evaluate all patients with a positive screen for
depression
Treat with cognitive-behavioral therapy, selective
serotonin reuptake inhibitor (SSRI), or serotonin
norepinephrine reuptake inhibitor (SNRI)
Choose treatment strategy depending on
depression severity and side effect profile

Pseudobulbar Involuntary crying or laughing that is often Dextromethorphan/quinidine 1 tablet 2 times a day
affect disproportionate or inappropriate to the social
Tricyclic antidepressant, SSRI, or SNRI
context

Cognitive Can occur at any stage in the disease, including
impairment clinically isolated syndrome
Prevalence and severity are higher in patients
with progressive MS
Can occur in the absence of accumulating T2
brain lesions
Best screened for using serial assessments with
Symbol Digit Modalities Test or similarly validated
test
Evaluate for and manage tobacco use, polypharmacy,
depression, fatigue, and sleep disruption
Use of diaries, calendars, regular physical exercise,
and regular social contact
No evidence for efficacy of acetylcholinesterase
inhibitors unless the patient has coexistent
Alzheimer-type dementia

Paroxysmal Trigeminal neuralgia, Lhermitte sign, tonic spasms Typically exquisitely sensitive to sodium channel
symptoms (commonly mistaken for spasticity) blockade: carbamazepine 200 mg 2 times a day
Typically sensory with variable motor Oxcarbazepine, gabapentin, or lacosamide can be
involvement; duration 1–90 seconds considered for second-line treatment

Temperature Most common in patients with a high EDSS score; Counsel regarding maintaining an adequate ambient
dysregulation symptoms include recurrent increase in prior MS temperature and wearing adequate clothing
symptoms, encephalopathy, pupillary dilation,
and thrombocytopenia

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CONTINUED FROM PAGE 756

Symptom Description Treatments

Spasticity Primarily driven by brainstem and spinal cord
disease; patients report pain and leg spasms,
particularly at night and after periods of immobility
Stretching exercises twice daily; hold stretches for
30–60 seconds
Baclofen, tizanidine, or gabapentin; use limited by
fatigue and worsening weakness; elevated liver
enzymes with tizanidine
Oral cannabis extract, synthetic
tetrahydrocannabinol, or oral nabiximols spray
where available
Diazepam or dantrolene can be considered as a
third-line treatment, but use is limited by toxicities
For nonambulatory patients with severe spasticity,
intrathecal baclofen pump

Gait dysfunction Commonly associated with other comorbidities, Ankle-foot orthosis, gait aids, dalfampridine; monitor
including spasticity, weakness, fatigue, and renal function before commencing dalfampridine;
sensory dysfunction monitor response with a timed 25-foot walk test

Bladder Common in MS, although typically does not cause
dysfunction a nephropathy
Can present as urinary frequency, urinary urgency,
or mixed urinary dysfunction
May be exacerbated by constipation and obesity
Perform urinalysis and postvoid residual ultrasound
of bladder in patients with urinary symptoms
Fluid restriction at night; scheduled voiding; and
avoidance of bladder irritants such as caffeine,
tobacco, alcohol, carbonated beverages (including
sparkling water), chili peppers, citrus fruits, and
vitamin C supplements
If postvoid residual volume is >100 mL, consider
intermittent self-catheterization
If postvoid residual volume is <100 mL, treat with
anticholinergic medications such as oxybutynin,
trospium, or darifenacin
Third-line treatment includes intravesical botulinum
toxin injection, tibial nerve stimulation, and
consideration of surgical interventions in carefully
selected patients

Sexual Affects up to 90% of patients Broaden the definition of sexual activity

dysfunction
Erectile dysfunction is common in men with spinal Adaptive modifications for positioning
disease
Consider lubricants, moisturizers, and vibrators
Anorgasmia, reduced vaginal lubrication, and
Erectile dysfunction can be treated with
reduced libido are common in women and
phosphodiesterase inhibitors
associated with fatigue

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MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES

FIGURE 9-1
Suggested algorithm for evaluation and management of fatigue in patients with multiple
sclerosis.
OSA = obstructive sleep apnea.
Reprinted from Khan, et al, Front Neurol.13 © 2014 The Authors.

specialty practices for treatment of MS-associated fatigue, the paucity of

evidence and side effect profile make it difficult to recommend their routine
use. Amantadine at a dose of 100 mg 2 times a day may have modest efficacy.33
Four randomized controlled trials of modafinil and one small crossover study
of armodafinil have failed to demonstrate efficacy for management of
MS-related fatigue, but some patients report benefit during off-label use.34–37
No trials of methylphenidate or amphetamine compounds have been
completed for treatment of MS-related fatigue, although an adequately
powered Patient-Centered Outcomes Research Institute–funded study to
address these questions is currently under way.38

DEPRESSION
The point prevalence of depressive symptoms in patients with MS is approximately
30%.8,39,40 Depression prevalence in MS is approximately double that of the
general population41; despite this, limited evidence exists regarding both
screening and treatment of MS-related depression.42 Depression is associated
with lower quality-of-life scores,43 higher Expanded Disability Status Scale
(EDSS) scores in women, and anxiety.8 Identification of depression and anxiety
can be challenging because some MS symptoms can mimic those of depression,
including psychomotor retardation, diminished ability to think or concentrate,
sleep disruption, and fatigue.
It is recommended that all patients with MS be screened for depression at
annual visits. Several brief screening tools are available, including the Beck
Depression Inventory44 and the patient health questionnaire screener tools
(PHQ-9,17 PHQ-218). More evidence supports the use of the Beck Depression
Inventory in MS,42 although the PHQ family of screeners is in the public domain
and free to use (refer to the Useful Website section). It is important to note that

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although these tools provide suggested cutoff points, a score above the cutoff KEY POINTS
point is not diagnostic of depression. Rather, a suggestive score warrants further
● It is recommended that all
evaluation to see if the patient truly has depression. Sequentially following patients with multiple
patient responses over time can give the provider valuable insight regarding sclerosis be screened for
response to treatment. depression at annual visits.
Because of the common coexistence of anxiety and depression, screening
● Screening for depression
with a concurrent anxiety screening tool can be useful. The Hospital Anxiety
and anxiety can be
and Depression Scale45 and PHQ-420 are brief tools that are useful in the completely automated, with
primary care setting. One of the barriers to screening for depression is the patient responding
uncertainty about immediate management in patients who report suicidal electronically to brief
intent. In patients who express suicidal intent, the P4 screener may be helpful screening questionnaires
and the responses
to prioritize patients for urgent evaluation.46 This brief tool asks about the automatically recorded in
“four Ps”: past suicide attempts, suicide plan, probability of completing the patient's electronic
suicide, and preventive factors. Very few patients who express thoughts of health record.
self-harm are classified as high risk using this tool; the patients who are high
● Patients may develop
risk require an urgent psychiatry evaluation. cognitive dysfunction in the
The use of electronic health records greatly simplifies this screening process. absence of a significant
Screening for depression and anxiety can be completely automated, with patients burden of white matter
responding electronically to brief screening questionnaires and the responses disease and in the absence
of accumulating T2-
automatically recorded in the patients’ electronic health records. Provider
hyperintense brain lesions.
intervention is only required in a very small subset of patients.
Unless the patient is acutely unwell and requires hospitalization, the timing
and type of treatment for depression is typically a collaborative decision
between the provider and the patient. The treating neurologist may wish to
involve a psychiatrist in the patient’s care, depending on the neurologist’s level of
expertise in treating patients with depression. For mild to moderate depression
of recent onset, psychoeducation and subsequent follow-up may be sufficient.
With more severe or prolonged depression, evidence-based psychotherapies
or pharmacotherapy can be considered. The choice of pharmacotherapy
depends on patient response, tolerance, and other conditions that a particular
antidepressant might benefit (eg, anxiety, pain, smoking cessation, insomnia)
or aggravate (eg, weight gain, sexual dysfunction).
It is important to distinguish pseudobulbar affect, which affects 6.5% to 46.2%
of patients with MS,42 from depression. Pseudobulbar affect is characterized by
involuntary crying or laughing that is often disproportionate or inappropriate to
the social context. The only approved medication for treatment of pseudobulbar
affect is dextromethorphan/quinidine, although other medications, such as SSRIs
and tricyclic antidepressants, are commonly used in clinical practice.42

COGNITIVE IMPAIRMENT
Cognitive impairment affects 45% to 65% of patients with MS,47 with the exact
prevalence depending on the classification.48 It can occur at any stage during the
disease, including in patients with clinically isolated syndrome,49 although the
prevalence and severity of cognitive impairment tends to be worse in patients
with progressive MS.50,51 True cognitive dysfunction can be challenging to
distinguish from cognitive inefficiencies secondary to depression, fatigue, and
sleep disruption. The cognitive domains most frequently affected in MS are
recent memory, attention, information-processing speed, executive function,
and visuospatial perception,47 indicating a mixture of cortical and subcortical
dysfunction. Patients may develop cognitive dysfunction in the absence of a

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MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES

significant burden of white matter disease and in the absence of accumulating

T2-hyperintense brain lesions.52 The effects on processing speed and attentional
domains can result in variable performance on individual neuropsychometric
tests over time.53 Interpretation of a cognitive assessment at a single point in time
may not provide an adequate assessment of an individual’s overall performance
(FIGURE 9-2). In addition, it is common for patients with MS to report difficulties
with multitasking and processing speed.51,54,55 This impairment is not well
evaluated by using brief clinic-based cognitive assessment tools such as the
Mini–Mental State Examination (MMSE).56

FIGURE 9-2
Neuropsychometric results for a patient with multiple sclerosis (A) and a typical patient with
Alzheimer-type dementia (B). Note the variability in scores over time and the inconsistent
pattern of scores in the patient with multiple sclerosis.
AVLT % Ret = Auditory Verbal Learning Test, percent retained; AVLT Recog = Auditory Verbal Learning Test,
recognition; BNT = Boston Naming Test; Cat Flu = Category Fluency Test; Letter Flu = Letter Fluency Test; LM
% Ret = Logical Memory subtest of the Wechsler Memory Scale, percent retained; SD = standard deviation;
TMT A = Trail Making Test Part A; TMT B = Trail Making Test Part B; VR % Ret = Visual Recognition subtest of
the Wechsler Memory Scale, percent retained.
Reprinted from Tobin WO, et al, Mult Scler.52 © 2016 SAGE Publications

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 The Consortium of Multiple Sclerosis Centers and the International Multiple KEY POINTS
Sclerosis Cognition Society have recently endorsed a recommendation for early
● Interpretation of a
baseline screening with the Symbol Digit Modalities Test or similarly validated cognitive assessment at a
test when the patient is clinically stable, with annual reassessment with the single point in time may not
same instrument.57 provide an adequate
Although these batteries are typically brief, they can take up to 15 minutes assessment of an
individual’s overall
to complete.58 In addition, the Symbol Digit Modalities Test is a proprietary
performance.
test with associated fees, which may present a barrier to widespread use
outside of a research setting.57 The Perceived Deficits Questionnaire is a ● Paroxysmal symptoms in
patient-reported cognitive dysfunction screen but has a low correlation with multiple sclerosis are
objective neuropsychological testing, suggesting that the Perceived Deficits typically sensory with
variable motor involvement.
Questionnaire does not measure cognitive dysfunction but other factors They usually last between 1
related to how patients perceive their functioning.59 Other patient-reported and 90 seconds and are
computer-based and tablet-based screening tools are in development. exquisitely sensitive to
When evaluating cognitive impairment in patients with MS, it is important sodium channel blockade.
to remember that the frequency of Alzheimer disease pathology in patients
65 years and older with MS is similar to that of the general population.60
CSF tau, phosphorylated tau, and amyloid-β1-42 are normal in patients with
clinically isolated syndrome and relapsing-remitting MS.61 In patients for
whom it is unclear whether MS is significantly contributing to cognitive
impairment, the use of both amyloid-β and neurodegeneration biomarkers
should allow accurate discrimination of MS from Alzheimer disease as the
etiology of cognitive impairment.62 Medications that are modestly effective
in neurodegenerative conditions, such as donepezil, have been studied for
the treatment of cognitive impairment in MS, but results have been
disappointing.63 Although a phase 2 trial indicated that simvastatin may
have beneficial effects on frontal lobe function and brain atrophy,64 this has yet
to be confirmed in a phase 3 trial. No pharmacologic therapy is currently
recommended for cognitive impairment in MS.
Strategies to improve cognition that can be recommended to patients include
conservative measures, such as using diaries and calendars, regular physical
exercise, and regular social contact. Comorbid conditions that may impact
cognition and may be amenable to intervention include tobacco use, depression,
fatigue, sleep disruption, and polypharmacy.

PAROXYSMAL SYMPTOMS
The classic paroxysmal symptoms of MS are trigeminal neuralgia and Lhermitte
sign, but paroxysmal symptoms can include a wide variety of transient,
stereotyped symptoms. The symptoms are thought to be secondary to ephaptic
transmission across adjacent demyelinated axons. Paroxysmal symptoms in MS
are typically sensory with variable motor involvement. They usually last
between 1 and 90 seconds and are exquisitely sensitive to sodium channel
blockade.
Tonic spasms refer to painful flexion of the arm and leg, sometimes with
contraction of ipsilateral facial muscles.65 These tend to be activation dependent
and recur multiple times during the day, as illustrated in CASE 9-1. Localization is
typically within the ipsilateral spinal cord, the posterior limb of the contralateral
internal capsule, or the cerebral peduncle.66 The presence of tonic spasms should
alert the provider to the possibility of neuromyelitis optica (NMO),67 and it
should be noted that even the original descriptions of tonic spasms included

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MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES

patients with “Devic’s syndrome.”65 Tonic spasms usually remit within several
weeks but can be distressing. If treatment is needed, first-line therapy is
carbamazepine,68 which typically is effective in eliminating symptoms at low
doses (approximately 200 mg 2 times a day). Other options include
oxcarbazepine,68 gabapentin,68 or lacosamide.69
Trigeminal neuralgia is a recurrent unilateral brief electric shock–like pain
that is abrupt in onset and termination; it occurs in 2% to 5% of patients with
MS.70 The pain is restricted to one or more of the trigeminal divisions and is
triggered by innocuous sensory stimuli. Trigeminal neuralgia is often a
heralding feature of MS71 but can exist independent of the diagnosis. The
diagnosis of trigeminal neuralgia attributed to MS requires demonstration of a
trigeminal root entry zone or pontine plaque affecting the intrapontine primary
afferents either on MRI or suggested by the presence of abnormal routine
electrophysiologic studies showing impairment of the trigeminal pathways.
Approximately three-fourths of patients respond to treatment with
carbamazepine, although patients with MS are less likely to benefit from
pharmacologic and surgical interventions than patients with idiopathic
trigeminal neuralgia.72

CASE 9-1 A 52-year-old woman with a history of multiple sclerosis (MS) diagnosed
5 years earlier presented for evaluation of arm pain. She had a history of
multiple spinal attacks and had a normal MRI brain 1 year previously.
Six weeks before presentation, she had developed right shoulder
numbness that progressed over 1 week to involve her right hand. The
symptoms were maximal for 3 weeks and were associated with painful
flexion contractions of the right hand and neck every time she moved her
right arm. She had been treated with gabapentin with no effect on
symptoms.
On examination, she had a painful flexion contraction of the right hand
when she got up to walk. She had brisk reflexes in the right arm and leg, a
right extensor plantar response, and pyramidal weakness in the right arm.
Cervical spine MRI demonstrated a dorsally located T2 hyperintensity
at C2-C3 that enhanced following gadolinium administration.
She was diagnosed with tonic spasms and treated with
carbamazepine, which completely relieved her symptoms over the
course of 1 week. Subsequent testing for neuromyelitis optica (NMO)
IgG was positive, and her diagnosis was changed to NMO spectrum
disorder.

COMMENT Tonic spasms are commonly mistaken for spasticity or other forms of
neuropathic pain. They typically occur in patients with brainstem or spinal
lesions and are short-lived painful contractions of the arm and face,
typically precipitated by activation of an ipsilateral limb. The symptom is
exquisitely responsive to carbamazepine. The presence of tonic spasms
should alert clinicians to the possibility of an underlying diagnosis of NMO
spectrum disorder, as tonic spasms are more common in this disorder.

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THERMOREGULATION DISORDERS
Temperature dysregulation in MS is a poorly recognized phenomenon of uncertain
prevalence. Patients typically present with an increase in prior MS symptoms
associated with other signs of hypothermia, including encephalopathy, pupillary
dilation, and thrombocytopenia, as illustrated in CASE 9-2. Commonly used
aural thermometers are often inaccurate in the setting of hypothermia, and
identification of hypothermia requires the use of a low-reading rectal
thermometer.73 Although a low-reading rectal thermometer is usually the
most convenient, rectal temperature can lag behind core temperature
during rewarming.74
The etiology of hypothermia is likely to be multifactorial, with thalamic,
hypothalamic, and spinal disease being implicated.75–78 Patients most commonly
have secondary progressive MS at the time of onset of hypothermia, with a
high degree of disability, suggesting at least a contribution by involvement of
the autonomic tracts within the brainstem and spinal cord. As sepsis can be
associated with hypothermia, particularly in patients who are elderly, infection
should be ruled out before making a diagnosis of primary hypothermia. Some
patients have been demonstrated to start sweating at a normal or subnormal
body temperature, suggesting that these patients have an altered thermoregulatory
sweat test balance point, compatible with a central autonomic network lesion.79
Consequently, following rewarming, patients should be counseled regarding
maintaining adequate ambient temperature and wearing adequate clothing, as a

A 62-year-old woman with a 37-year history of secondary progressive CASE 9-2

multiple sclerosis, with an Expanded Disability Status Scale (EDSS) score
of 8.0 (mobilizes in a wheelchair only), presented to her local emergency
department with recurrent encephalopathy. She had previously been
diagnosed with urinary tract infections as the cause of her encephalopathy,
although a causative organism was not identified. On each of her previous
admissions, she typically recovered within 24 to 48 hours in the absence
of any specific treatment. On this admission, she was noted to have a mild
elevation in liver enzymes and thrombocytopenia. Examination revealed
a bilateral internuclear ophthalmoplegia, a left relative afferent pupillary
defect, severe pyramidal weakness and spasticity in all four limbs, with
bilateral extensor plantar responses.
EEG demonstrated nonspecific background slowing. Lumbar puncture
was performed to assess for meningitis or encephalitis; CSF analysis was
normal, except for elevated oligoclonal bands. A low-reading rectal
thermometer recorded a temperature of 33°C (91.4°F). She returned to
her baseline over 24 hours with gentle rewarming.

Recurrent encephalopathy in patients with multiple sclerosis can be COMMENT

associated with hypothermia. This typically occurs in patients with high
motor impairment and can often be underrecognized. Prevention includes
education regarding wearing warm clothes and maintaining a high ambient
temperature within the living environment.

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MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES

temperature that is comfortable for another member of the household may be

sufficient to cause hypothermia in patients with an altered thermoregulatory
sweat test balance point.

SPASTICITY AND WEAKNESS

Spasticity and weakness in MS are predominantly driven by brainstem and spinal
cord disease. Loss of γ-aminobutyric acid–mediated (GABA-ergic) inhibition of
spinal reflex arcs results in reduced inhibition of postural muscles, causing
exaggerated flexion of the arms and extension of the legs that may be associated
with weakness, stiffness, cramps, pain, and clonus. In patients who have
significant weakness and spasticity, overtreatment of spasticity may lead to loss
of function, as the presence of spasticity may facilitate transfers or walking by
providing postural support . Initial treatment of spasticity should primarily focus
on stretching exercises. Stretches should be held for at least 30 to 60 seconds, and
patients should be counseled to stretch twice daily. If this strategy is insufficient
to control spasticity, treatment with baclofen, tizanidine, or gabapentin can be
considered.80 These medications are limited by the side effects of sedation and
exacerbation of weakness. In addition, tizanidine can cause elevation in liver
enzymes in 3% to 5% of patients. Baclofen is typically used in doses of 10 mg
2 times a day, increasing in 10 mg increments every 2 to 3 days to a maximum
total daily dose of 80 mg. Some patients may require a slower titration or lower
doses to avoid drowsiness and cognitive side effects.
Tizanidine is a useful alternative to baclofen, primarily in patients who
develop significant weakness when treated with baclofen. The sedating effects of
tizanidine tend to be greater than those of baclofen; therefore, titration is
performed at 1 mg to 2 mg per day starting at 2 mg each night, increasing to a
maximum total daily dose of 12 mg in three divided doses. Gabapentin is
typically used at a total daily dose of 300 mg to 3600 mg in three divided doses,
and titration is typically limited by the side effects of sedation toward the upper
end of the therapeutic range.
Patients with severe spasticity that is not responsive to first-line antispasticity
medications may benefit from treatment with diazepam or dantrolene.
Diazepam at total daily doses of up to 30 mg reduces spasticity to a similar degree
when compared to baclofen and tizanidine. The safety profile is similar to
baclofen, despite a greater degree of sedation in patients treated with diazepam.
Long-term safety is typically not assessed in clinical trials, and benzodiazepine
dependence is a concern in patients treated with diazepam. The average total
daily dose of diazepam required to treat spasticity is 15 mg.
Dantrolene decreases the release of calcium in skeletal muscle, reducing
spasticity and causing significant weakness. Dosing starts at 25 mg once a day,
increasing to a maximum total daily dose of 400 mg in four divided doses.
Treatment is limited by weakness and by side effects of gastrointestinal
symptoms, fatigue, sedation, and dizziness. The risk of hepatotoxicity requires
monitoring of liver function before and during therapy.80
In patients with severe spasticity that is not responsive to stretching or
medications, or in patients with focal spasticity, botulinum toxin injections can
be used for both upper limb and lower limb spasticity.81 Evidence has not shown
that any formulation of botulinum toxin is superior to another. Although
botulinum toxin has been demonstrated to be effective for reducing spasticity,
the impact of botulinum toxin injections on functional outcomes is mixed,

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suggesting that patient selection is crucial. In patients with generalized or KEY POINTS
bilateral lower limb spasticity, treatment with botulinum toxin injections may
● Commonly used aural
lead to functional loss due to weakness. In contrast, for patients with focal thermometers are often
spasticity, botulinum toxin injection may be a good first-line choice, as it allows inaccurate in the setting
them to avoid the side effects associated with baclofen, tizanidine, or gabapentin. of hypothermia, and
Despite considerable interest in the use of medical marijuana for the treatment identification of
hypothermia requires the
of MS, no cannabinoid is US Food and Drug Administration (FDA) approved for
use of a low-reading rectal
the treatment of MS-related spasticity. Two recent meta-analyses have thermometer.
concluded that oral cannabis extract, synthetic tetrahydrocannabinol (THC),
and nabiximols are probably effective at reducing patient-reported symptoms of ● Initial treatment of
spasticity in people with MS, but oral cannabis extract and synthetic THC were spasticity should primarily
focus on stretching exercises.
not found to be effective for reducing physician-administered measures of Stretches should be held
spasticity.82 Cannabinoids are generally well tolerated but are associated with an for 30 to 60 seconds, and
increased risk of psychosis and schizophrenia and so should be avoided in at-risk patients should be counseled
individuals.83–85 Additionally, cannabis use is associated with increased risk for to stretch twice daily.
myocardial infarction, hypertension, heart failure, and stroke.86,87 Variability in ● For patients who are
production and extraction procedures means that clinically significant nonambulatory with severe
batch-to-batch variability may occur when using oral cannabis extract. In spasticity that is not
addition, although oral cannabis extract is legal in some states, health insurance responsive to or intolerant
of other treatment
typically does not cover use of federally prohibited substances.
strategies, intrathecal
For patients who are nonambulatory with severe spasticity that is not baclofen is a useful strategy,
responsive to or intolerant of the above treatment strategies, intrathecal baclofen particularly for facilitating
is a useful strategy, particularly for facilitating toileting and cleaning. Greater toileting and cleaning.
intrathecal concentrations of baclofen can be achieved than when using systemic
therapy, without significant systemic side effects. The main side effects are
related to the implantation of the intrathecal catheter and pump mechanism.
Because of this, an intrathecal baclofen test should be performed before the
pump implantation to determine response and functional loss.74
Gait impairment in MS is typically multifactorial and contributed to by
spasticity, weakness, fatigue, and sensory dysfunction. The management of gait
impairment and associated weakness consists mainly of nonpharmacologic
interventions such as physical therapy; ankle-foot orthosis to reduce the impact
of footdrop; and other mobility aids such as canes, walkers, wheelchairs, and
scooters, along with addressing other comorbidities that can impact gait and
weakness. The main pharmacologic therapy to treat weakness in MS is
dalfampridine sustained release, which can improve walking ability in
approximately one-third of patients. Side effects include seizures and anxiety,
with seizures being more common in patients with renal impairment.88 Some
evidence from uncontrolled trials indicates that dalfampridine may also improve
upper limb function.89,90 A clinical response to dalfampridine can be evaluated
by performing a timed 25-foot walk test before and several weeks after starting
the medication. If the patient does not have a clinical response, it is reasonable to
discontinue the medication at that time.

BLADDER DYSFUNCTION
Neurogenic bladder dysfunction is common in patients with MS and is associated
with pontine and spinal cord lesions. Urinary symptoms are broadly categorized
into failure to store (urinary frequency), failure to empty (urinary retention), or a
combination of both. In contrast to other neurologic disorders affecting the spinal
cord, such as spina bifida, upper urinary tract disorders in MS are rare, possibly

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MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES

because of the slowly progressive nature of the disease. Consequently, a more

symptom-based approach may be employed than that used in other causes of
neurogenic bladder dysfunction due to spinal injury. Features that should
prompt early referral to urology services are outlined in TABLE 9-3.91 A suggested
algorithm for the evaluation and management of neurogenic bladder
dysfunction is outlined in FIGURE 9-3.
In patients presenting with urinary symptoms, a urinalysis and postvoid
residual ultrasound of the bladder should be performed. Patients should be
counseled regarding conservative strategies, including fluid restriction at night;
scheduled voiding; and avoidance of bladder irritants such as caffeine, tobacco,
alcohol, carbonated beverages (including sparkling water), chili peppers, citrus
fruits, and vitamin C supplements. Treatment of comorbid conditions that can
exacerbate bladder dysfunction, including obesity and constipation, may also
be beneficial. If this is ineffective, patients with a postvoid residual volume of
less than 100 mL may be treated with anticholinergic medications such as
oxybutynin, trospium, or darifenacin.

Intravesical Botulinum Toxin

Patients with neurogenic detrusor overactivity who do not respond to first-line
treatment with anticholinergic medications can be considered for a variety of
second-line options, including intravesical botulinum toxin injection. This is
generally well tolerated and reduces urinary incontinence while increasing
quality of life. The main side effect of this treatment is urinary retention, which
can occur in approximately 50% of patients. Despite the efficacy of treatment and
persistence of effect with repeated doses, patients with MS tend not to continue
with long-term therapy, possibly because of progression of the disease.92

Catheterization
Patients with a postvoid residual volume of more than 100 mL should be
offered intermittent self-catheterization. Indwelling catheters are associated
with a greater risk of urinary tract infections, genital erosions, and bladder
stone formation than intermittent catheterization. Indwelling catheters are
typically considered in patients who are unable to perform intermittent

TABLE 9-3 Red Flags That Should Initiate an Early Referral to Urology Servicesa

◆ Presence of hydronephrosis
◆ Renal impairment
◆ Recurrent urinary tract infections
◆ Hematuria
◆ Suspicion of concomitant urologic pathology (eg, prostate enlargement)
◆ Stress urinary incontinence
◆ Loin and/or pelvic pain
◆ Symptoms refractory to first-line treatment

a
Reprinted from Tornic J, Panicker JN, Curr Neurol Neurosci Rep.91 © 2018 The Authors.

766 JUNE 2019

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 self-catheterization because of KEY POINTS
upper limb dysfunction, for
● In contrast to other
example, or in patients for neurologic disorders
whom spasticity makes affecting the spinal cord,
intermittent self-catheterization such as spina bifida, upper
challenging to perform. The urinary tract disorders in
multiple sclerosis are rare,
suprapubic route is preferable
possibly because of the
for ease of care, comfort, and slowly progressive nature of
fewer complications. Silicone the disease.
catheters are associated with less
susceptibility for encrustation ● In patients with multiple
sclerosis presenting with
and allergy than latex catheters. urinary symptoms, a
urinalysis and postvoid
residual ultrasound of the
Neuromodulation bladder should be
Percutaneous93 and performed.
transcutaneous94 tibial nerve
stimulation have been shown ● Indwelling catheters are
associated with a greater
to have short-term benefits on risk of urinary tract
urinary symptoms for patients infections, genital erosions,
with an overactive bladder and bladder stone formation
secondary to MS and may also than intermittent
catheterization.
have a positive effect on fecal
incontinence.95 Several ● Percutaneous and
treatment paradigms have been transcutaneous tibial nerve
studied, with a typical paradigm stimulation have been
for percutaneous tibial nerve shown to have short-term
benefits on urinary
stimulation consisting of symptoms for patients with
stimulating the nerve through a overactive bladder
fine gauge needle using a fixed secondary to multiple
frequency electrical signal once sclerosis and may also have
FIGURE 9-3 a positive effect on fecal
weekly for 30 minutes over an incontinence.
Suggested algorithm for evaluation and
management of urinary symptoms in a patient with 8- to 12-week period. Tibial
multiple sclerosis. nerve stimulation does not
KUB = kidney ureter bladder; UTI = urinary tract infection. increase bladder volume and,
a
Additional assessment and quantification with quality of
life and symptom questionnaires.
therefore, does not lead to an
b
By ultrasound scan or in-out catheterization. increased rate of requiring
c
Alpha1-blockers in selected cases. intermittent self-catheterization.
Reprinted from Tornic J, Panicker JN, Curr Neurol
Transcutaneous stimulation has
Neurosci Rep.91 © 2018 The Authors.
the additional benefit that it can
be performed by the patient or
caregiver at home. Both techniques are minimally invasive, and the absence of a
permanently implanted device means that no safety concerns exist regarding
future MRI scans.

Surgical Options
Surgical interventions can be considered in patients for whom conservative
treatments have failed, although this is becoming increasingly uncommon
because of the availability of less-invasive options. Procedures such as
continent/incontinent urinary diversion for debilitating urgency and frequency

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MANAGEMENT OF MS SYMPTOMS AND COMORBIDITIES
KEY POINT
● Sexual dysfunction
affects up to 90% of patients
with multiple sclerosis
during the course of
the disease.
768
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
and external sphincter/bladder neck incision for urinary retention could be
considered in carefully selected patients who have exhausted other options.
SEXUAL DYSFUNCTION
Sexual dysfunction affects up to 90% of patients with MS during the course of
the disease. Men primarily report erectile dysfunction and ejaculatory
disorders; medications and other medical issues can also contribute to these
symptoms. Sexual dysfunction in men is associated with other indicators of
spinal cord dysfunction, such as leg weakness, bladder dysfunction, and
higher EDSS scores. In women, the most common symptoms are anorgasmia,
reduced vaginal lubrication, and reduced libido. In contrast to men, sexual
dysfunction in women is not associated with higher EDSS scores and is
primarily associated with fatigue. Conservative measures to improve sexual
function in both men and women include defining sexual activity more
broadly than penile-vaginal intercourse (eg, massage, petting, kissing,
flirting, mutual sensual pleasuring). Patients should be encouraged to pursue
sexual activity when energy levels are highest. If physical disability is
contributing to sexual dysfunction, the use of cushions (eg, wedge or pillow)
for positioning may be helpful. Additional time and communication may be
required to prepare for sexual activity, and patients should take breaks during
sexual activity as needed. The use of lubricants, moisturizers, and vibrators
should be encouraged as appropriate.
After offending medications have been removed, phosphodiesterase
inhibitors are the first-line medical treatment of erectile dysfunction. Erectile
dysfunction that is resistant to treatment with phosphodiesterase inhibitors may
respond to use of a constriction band or ring placed at the base of the penis. Other
options that can be tried include a vacuum erection device used in combination
with a constriction band or ring, intraurethral alprostadil suppositories, or penile
injection of vasoactive medications.
Identification of sexual dysfunction may be facilitated by a screening tool. For
men, this can be as simple as a single question about erectile dysfunction.96 For
both men and women, a single screening question, “Do you have any sexual
problems or concerns?” can be used.97
CONCLUSION
The symptoms of MS are myriad, and comorbidities are common. Identification
and management of MS-related symptoms and comorbidities can lead to
improved outcomes, improved quality of life, and reduced disease activity. The
use of brief patient-reported screening tools at or before the point of care can
facilitate identification of symptoms and comorbidities that may be amenable
to intervention.
USEFUL WEBSITE
PATIENT HEALTH QUESTIONNAIRE (PHQ) SCREENERS
The PHQ screeners website offers free, public
domain access to the PHQ family of screening tools
(PHQ, PHQ-4, PHQ-7, PHQ-9, PHQ-15, Brief PHQ, and
PHQ-SADS) and the Generalized Anxiety Disorder
7-Item Scale (GAD-7).
phqscreeners.com
JUNE 2019
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