It is also known that those patients with more bladder symptoms
or sexual dysfunction have lower quality of life compared with patients without these
107 The treatment approaches for sexual dysfunction and urinary
incontinence in MS are similar to those used when these symptoms occur as part of a
In a survey commissioned by the National MS Society, 64% of patients with MS
stated that they had some limitation to their walking ability and, therefore, limited
activities that involved walking.
58 Physical therapy and conditioning may be of some
59 Another approved treatment option is extended-release
dalfampridine. This agent blocks potassium channels and prevents repolarization of
the cell, thus prolonging action potentials and nerve impulse transmission in the
In clinical studies of extended-release dalfampridine, 57% of treated patients were
unable to decrease the amount of time it took them to walk 25 feet. The 43% who did
decrease their time were considered responders. On average, they improved their
speed to walk 25 feet by 25% (approximately 3 seconds faster).
be difficult to determine which patients respond well to extended-release
dalfampridine without conducting timed 25-foot walks.
Adverse effects associated with extended-release dalfampridine include urinary
tract infections, insomnia, dizziness, headache, and nausea. Seizures are a less
common adverse effect and are related to dose and use of immediate-release
dalfampridine. Therefore, this agent is contraindicated in patients with a history of
Between 30% and 90% of patients with MS report experiencing pain.
to MS is of two types: non-neurogenic and neurogenic. Non-neurogenic pain is often
related to paralysis, immobility, or spasticity; examples include tension-type
headache, low back pain, and limb pain associated with poor mobility or postural
110 Physical therapy, repositioning limbs, and typical analgesics may be
effective for treatment of non-neurogenic pain.
A number of painful neurogenic conditions have been described in association
111 Patients often describe neurogenic pain as having a burning,
aching, pricking, stabbing, or smarting quality.
112 Atypical analgesics are used for
neurogenic pain. For trigeminal neuralgia, carbamazepine and oxcarbazepine are
112 Baclofen, lamotrigine, gabapentin, topiramate, misoprostol,
pimozide, or tocainide may be helpful as second-line treatments.
options may provide relief if drug treatments are ineffective.
medicines and antidepressants are also commonly used for other types of neurogenic
Often described as the most disabling symptom by patients with MS, 74% experience
61 The reason that patients exhibit fatigue is not well understood; however,
hypotheses include direct effects of cytokines, axonal loss, or cortical
113 Conduction is impaired in demyelinated axons, and increases in
temperature may further worsen conduction.
113 However, fatigue may be caused or
worsened by other mechanisms such as sleep dysfunction, depression, or medication
Nonpharmacologic approaches are often the mainstay of therapy for fatigue and
may include interventions to improve sleep quality, treatment for depression when
present, improvements in diet, and increased physical activity.
behavioral therapy has been helpful for some patients.
63 Cooling therapy with jackets
worn over large areas of the body and magnetic therapy have demonstrated benefit in
115–117 Acupressure was shown to help women with fatigue in a small
Types of Neurogenic Pain Associated with Multiple Sclerosis
distribution of one or more branches of the trigeminal nerve.
Burning dysesthesia of the limbs and trunk
The only pharmacologic therapy for fatigue with proven benefit is amantadine;
however, the clinical trials for this agent have included small numbers of patients.
Sustained-release fampridine may be helpful in some patients.
used in two placebo-controlled studies, but neither trial showed significant
differences in response between modafinil and placebo.
Cognitive dysfunction may occur early in the course of the disease and has a negative
33 Among patients with CIS, 29% had cognitive impairment
at the time of presentation. The only predictor of cognitive impairment was the
123 Between 40% and 70% of MS patients eventually have
59 The most common problems are memory impairment,
slowed speed of information processing, decreased mental flexibility, and impaired
62 Cognitive dysfunction can also limit the ability of patients
with MS to understand discussion of disease and treatments.
discussions into various components (e.g., intended effects, adverse effects) helps
Nonpharmacologic interventions such as cognitive rehabilitation to develop the
use of intact cognitive skills to compensate for areas of poor cognitive performance
126 Treatment of MS with immunomodulatory drugs has shown
some benefit for cognitive impairments.
127 Additionally, small studies of
acetylcholinesterase inhibitors were promising.
128–130 However, trials of memantine,
amantadine, pemoline, and gingko biloba have all been negative.
Spasticity can be defined as an increased resistance of muscle to an externally
131 Approximately 60% of patients with MS exhibit spasticity, which
may worsen with other noxious stimuli such as a full bladder or colon, infection, or
131 Complications from spasticity may include pain, spasms,
reduced mobility, limited range of movement, contractures, fatigue, poor quality of
sleep, cardiopulmonary deconditioning, decubitus ulcers, and skin breakdown.
Nonpharmacologic therapies, such as repositioning physical therapy, stretching, or
splinting, may help with spasticity.
131 These efforts are usually most successful with
spasticity that is localized to one area of the body. Injection of intramuscular
botulinum toxin can also be beneficial for localized spasticity.
generalized to many areas of the body is best addressed with systemic therapy in
addition to nonpharmacologic treatments. Baclofen and tizanidine are first-line
therapies for spasticity. Gabapentin, benzodiazepines, and dantrolene are considered
In severe cases, intrathecal baclofen can be delivered via
infusion pump through a catheter into the intrathecal space.
studied with some success for patient-reported improvements in spasticity, but there
is little objective evidence for effect.
133 There is no FDA-approved indication
Psychiatric problems including depression, bipolar disorder, pseudobulbar affect
(emotional lability), and psychosis all occur at increased rates in MS patients
compared with the general population.
134–136 Depression can affect up to 50% of
63 Several clinical trials of depression treatment have been
conducted in patients with MS. In these, cognitive behavioral therapy has been shown
to be possibly effective, and fluoxetine and sertraline have been shown to have
Pseudobulbar affect occurs in approximately 10% of patients with MS and
involves frequent and inappropriate episodes of crying, laughing, or both, which may
be unrelated to underlying mood. The exact cause of pseudobulbar affect is not
known, but it may be caused by disruption of neural pathways from the brainstem and
cerebellum. Serotonin, dopamine, and glutamate also appear to be important in the
development of pseudobulbar affect. It is not isolated to patients with MS, but may
also occur in other neurologic disorders such as stroke. This disorder can be socially
stigmatizing and highly disabling.
When used together, dextromethorphan and quinidine have shown efficacy for
pseudobulbar affect, and a combination product is approved for this indication by the
FDA. Dextromethorphan is an agonist at σ-1 receptors, suppressing release of
excitatory neurotransmitters, and an antagonist at N-methyl-D-aspartate glutamate
138 Dextromethorphan is metabolized by cytochrome P-450 (CYP) 2D6 to
dextrorphan, which does not cross the blood–brain barrier. When a low dose of
quinidine, a CYP 2D6 inhibitor, is added, dextromethorphan serum concentrations
are increased 20-fold. In a 12-week study of 283 patients, a 49% improvement in
inappropriate emotional episodes was demonstrated.
Complementary and Alternative Medicine
Several clinical trials are ongoing to evaluate the therapeutic potential of vitamin D
supplementation in patients with MS.
In one study, 49 patients with MS were
randomly assigned to receive open-label vitamin D or no active treatment (control
group). The treatment group was given vitamin D to rapidly raise the serum 25-
hydroxyvitamin D concentrations, starting with 4,000 international units/day and
increasing to 40,000 international units/day during 28 weeks. In the second phase,
subjects were administered 10,000 international units/day for 12 weeks. There was a
reduction in annualized relapse rate and a higher proportion of relapse-free patients
in the vitamin D group compared with the control group.
20,000 international units/week of vitamin D or placebo to interferon β-1b. The
group given vitamin D had decreased brain lesions on MRI after 1 year of
143 One study did not find benefits.
144 The results of these trials should be
interpreted cautiously, however, because of their small numbers of patients. Vitamin
D cannot be taken with impunity, however. An Institute of Medicine reports cautions
against intake of more than 10,000 international units daily because of associations
with kidney and tissue damage. Elevated serum concentrations of vitamin D have
also been associated with hypercalcemia, anorexia, weight loss, polyuria, heart
arrhythmias, vascular and tissue calcification, increases in all-cause mortality, some
cancers, cardiovascular disease risk, fractures, and falls. Thus, the recommended
dietary allowance for adults is 600 IU/day with an upper intake limit of 4,000
QUESTION 1: C.B. is a 32-year-old woman of Finnish descent who presents to the neurology clinic with
and a temperature of 37.4°C. Review of systems
mg PO every morning, and levonorgestrel-releasing intrauterine system.
What risk factors, signs, and symptoms suggestive of MS are present in C.B.? How do her MRI and CSF
findings support or refute a diagnosis of MS?
C.B. has several epidemiologic factors associated with MS (see Table 57-1): She
is 32 years old, consistent with onset between the ages of 20 and 50 years; she is
female—women are 2 to 3 times more likely to develop MS than men—and she is of
northern European ancestry, which also increases her risk of MS. Her symptoms and
physical examination findings are consistent with a demyelinating event in the pons
area of the brainstem. On MRI, C.B. has two active (gadolinium-enhancing) lesions
in this area. This finding on the MRI is abnormal, and gadolinium-enhancing lesions
are found commonly in patients with MS. Additionally, her CSF examination on
lumbar puncture shows the presence of oligoclonal bands and an increased rate of
IgG synthesis. These findings are also consistent with a diagnosis of MS. Although
the combined evidence from her history, examination, and CSF and MRI studies
make the eventual diagnosis of MS very likely, they do not demonstrate dissemination
in space and time. To show dissemination in time, an additional clinical event or
another MRI showing a new lesion would be necessary. To show dissemination in
space, another clinical event affecting another part of the body or another MRI
showing lesions in a different area of the brain would be necessary.
time, C.B. would be diagnosed as having CIS.
CASE 57-1, QUESTION 2: Should C.B. begin treatment at this time? If so, what treatment(s) would be
Most of the interferon β preparations, glatiramer acetate, and teriflunomide have
demonstrated reduced development of MS if taken after the identification of CIS
It should be noted that the subcutaneous administration of
interferon β-1a for CIS was less frequent than the usual treatment regimen of 3 times
149 This may account for the lower response rate seen in the trial with that
regimen compared with the other treatments in Table 57-5.
educated on the risk of developing clinically definite MS, and she should begin
therapy with one of these therapies. There is no evidence on which to base the choice
of therapy; commonly the prescriber will have a preference based on discussion with
CASE 57-1, QUESTION 3: C.B. is started on glatiramer acetate 20 mg subcutaneously daily. How should
treatment? How can she help alleviate or avoid these adverse effects? What monitoring is required?
Glatiramer acetate is supplied as a single-use, prefilled syringe. In general, the
recommended administration techniques are similar to those used for other
subcutaneously administered products, and the important counseling points are
summarized in Table 57-6. The administration technique is slightly different for the
intramuscular injection. There are product-specific differences in dose preparation
for which it is important to consult the product information. C.B. should be instructed
Glatiramer acetate is initiated at a dose of 20 mg subcutaneously daily. No dosage
titration is required. However, for interferon β products, a product-specific titration
schedule is recommended to minimize flu-like symptoms.
Injection site reactions with glatiramer acetate
include hemorrhage, hypersensitivity, inflammation, mass, pain, edema, and atrophy
at the injection sites. Rarely, necrosis at the injection site can develop. Lipoatrophy
may be seen in up to 45% of patients with longer-term use.
reactions may be reduced by applying warm compresses or ice to the injection site
before injection, warming the medication to room temperature before injection, and
ensuring that the needle completely penetrates the skin during injection.
Symptoms of post-injection systemic reactions include facial flushing, chest tightness,
dyspnea, palpitations, tachycardia, and anxiety.
151 Approximately 16% of patients
experience this reaction. When this reaction occurs, its onset is within seconds to
minutes after injection, and it may last up to 30 minutes.
recommended for post-injection systemic reactions to glatiramer acetate.
Development of Clinically Definite Multiple Sclerosis with Therapy Compared to
Development of Clinically Definite
146 Interferon β-1a 30 mcg IM weekly 20 38
147 Interferon β-1a 22 mcg subcutaneously weekly 34 45
148 Interferon β-1b 250 mcg subcutaneously every
149 Glatiramer acetate 20 mg subcutaneously daily 25 43
150 Teriflunomide 7 mg PO daily
IM, intramuscular; MS, multiple sclerosis; PO, orally.
Patient Counseling Points for Interferon β and Glatiramer Acetate
site or needle tip to other surfaces or with fingers.
For intramuscular injection—front of thigh, side of thigh, upper arm.
Rotate between injection sites to avoid overuse of any one site.
For subcutaneous injection—pinch up a fold of skin between index finger and thumb for the injection.
For intramuscular injection—stretch the skin between index finger and thumb for the injection.
Insert the needle at a 90 degrees angle to the skin.
Steadily push down on the plunger until all of the medicine is injected.
Pull needle straight out of skin and dispose of it in a hard-walled plastic container.
Adverse effects are fairly common with interferon β; they include leukopenia
(36%–86%), injection site reaction (6%–92%) and necrosis (3%–6%), flulike
symptoms (49%–57%), breakthrough menstrual bleeding (28%), and increased liver
79–82,156 Depression and suicide are seen in patients treated
with the β interferons; however, it is difficult to distinguish the independent
contribution of interferon from any possible concomitant effects of MS itself.
Flu-like reactions include the symptoms of fever, chills, myalgia, malaise, and
sweating, and they occur in about half of patients who are initiated on an interferon
78 Symptoms usually begin 3 to 6 hours after administration and last approximately
24 hours. Female patients and those with lower body mass index may have more
156 Most patients find that these symptoms decrease with
time, with only 10% of patients reporting flu-like symptoms after 1 year of therapy.
Helpful tips for patients to reduce flu-like symptoms include administering the
injections at night to sleep through the time of peak symptoms, taking ibuprofen or
acetaminophen before and every 4 to 6 hours as needed after the injection, and
gradual titration to full dose.
Injection site reactions vary from 92% with some subcutaneous preparations of
interferon β to 6% with the intramuscular preparation.
similar to those seen with glatiramer acetate except that lipoatrophy is not seen with
interferon β. Women appear to be more likely to experience injection site reactions
156 Strategies to reduce injection site reactions include injecting the drug in
areas with more subcutaneous fat (abdomen or buttocks), rotating injection sites,
using an auto-injection device, icing the site after injection, and using a vitamin K
Patient Characteristics and Other Factors Associated with Reduced Adherence
to β Interferons or Glatiramer Acetate
Secondary-progressive multiple sclerosis Younger age
Female sex Cognitive impairment
Depression Perceived lack of efficacy
Unrealistic expectations Adverse effects
Lifestyle or economic instability Lack of family or other support
General monitoring recommendations for both interferon β and glatiramer acetate
include observation of injection sites for infection, necrosis, and atrophy.
Specifically for the β interferons, complete blood counts and liver function tests are
79–82 The frequency of monitoring is not specified in product literature, but
a reasonable approach would be at baseline and 1 to 3 months after initiation and
then every 6 to 12 months during continuation of therapy. Additionally, patients
should be monitored for signs or symptoms of depression. Therefore, the specific
counseling and monitoring plan needed for C.B. is instruction in self-injection
technique for the subcutaneous injection and discussion of injection site reactions,
including their prevention and monitoring, and post-injection systemic reactions. C.B.
should also be counseled regarding the value of ongoing clinical monitoring (for
efficacy, injection site reactions, and post-injection reactions) during glatiramer
might C.B.’s neurologist deal with this adherence problem?
Adherence is often poor with self-injection of interferons and glatiramer acetate;
over 2 to 5 years, only 60% to 76% of patients adhere to therapy.
characteristics and other factors that have been associated with poor adherence are
In one study, self-efficacy and belief that the medicine
would have benefit were strong predictors of adherence, whereas cognitive
difficulties, occurrence of adverse effects, depression, more disability, and poor
quality of life predicted nonadherence.
169 Adherent patients have a lower risk of
relapses, fewer emergency department visits, and fewer hospitalizations.
For C.B., it appears that she has perceived lack of efficacy for the glatiramer
acetate; however, other factors associated with nonadherence should be sought and
discussed with her. For an individual patient, it is impossible to know what the
course of disease would be without treatment; thus, many patients believe that the
medicine is not having a positive impact. Particularly for a patient with CIS who
does not have ongoing symptoms, embarking on a lifelong therapy can be challenging.
Additionally, there is no immediate feedback to the patient that the medication is
having an effect, in contrast to some other diseases such as diabetes in which a
fingerstick blood glucose measurement provides positive reinforcement.
evidence suggests that patients would prefer not to take a treatment that causes
significant adverse effects until the symptoms experienced from their MS are
worse than the perceived adverse effects.
171 Strategies that may improve adherence
include establishing a good patient–healthcare provider relationship, patient
education and periodic reinforcement, management of adverse effects, involving care
partners, and treating depression.
CASE 57-1, QUESTION 5: After re-education and frank discussion, C.B.’s adherence improves, and she
the MRI scan. Does this new information change her diagnosis and treatment?
With these new MRI lesions, the “separation in space and time” criteria for the
diagnosis of MS have been met. Thus, C.B. now would be diagnosed with MS. Given
her history, it would appear that she has relapsing-remitting MS. To guide the
clinician in choosing the most efficacious therapy, there are data from several
clinical trials that directly compare first-line therapies (Table 57-8).
the data available, it appears that interferon β-1a intramuscularly once weekly is less
effective than the other first-line treatments. Otherwise, the medicines are roughly
equivalent for treatment of relapsing-remitting MS. A recently proposed treatment
algorithm suggests that patients who present with relapsing-remitting MS should
receive dimethyl fumarate, glatiramer acetate, interferon β, or teriflunomide as a
first-line therapy. Should disease activity be detected, patients could rotate to another
first-line therapy or move to a second-line therapy of natalizumab, fingolimod, or
Clinical Trials Directly Comparing Active Treatments
172 Interferon β-1b 250 mcg subcutaneously
every other day vs. interferon β-1a 30 mcg
Compared with interferon β-1a-treated
patients, more interferon β-1b-treated
patients were relapse-free (51% vs. 36%),
there were fewer mean relapses (0.38%
vs. 0.5%), and fewer patients progressing 1
point on the EDSS (13% vs. 30%) after 2
173 Interferon β-1a subcutaneously 44 mcg 3
times weekly vs. interferon β-1a 30 mcg
Compared with interferon β-1a IM-treated
patients, interferon β-1a subcutaneously
treated patients had fewer mean relapses
(0.29% vs. 0.4%) and fewer lesions on
174 Interferon β-1a 44 mcg subcutaneously 3
times weekly vs. glatiramer acetate 20 mg
No significant differences in time to first
175 Interferon β-1b 250 mcg subcutaneous
every other day vs. interferon β-1b 500
mcg subcutaneous every other day vs.
glatiramer acetate 20 mg subcutaneous
No differences in relapse rate, EDSS
CONFIRM89 Dimethyl fumarate 240 mg PO twice daily
vs. dimethyl fumarate 240 mg PO 3 times
daily vs. glatiramer acetate 20 mg
subcutaneous daily vs. placebo
Compared to placebo, all active therapies
reduced annualized relapse rates (0.22,
0.20, 0.29 vs. 0.40), EDSS progression, and
MRI lesions. No differences between
dimethyl fumarate 240 mg twice daily and
glatiramer for any outcome except for one
176 Teriflunomide 7 mg PO daily vs.
teriflunomide 14 mg PO daily vs. interferon
β-1a 44 mcg subcutaneous 3 times weekly
No differences in relapse rate, treatment
76 Alemtuzumab 12 mg IV daily for 5 days,
then 12 mg IV daily for 3 days 12 months
later vs. interferon β-1a 44 mcg
More patients taking alemtuzumab were
relapse-free (78%) at 2 years than the
interferon group (59%). Fewer patients
taking alemtuzumab had disease
177 Alemtuzumab 12 mg IV daily for 5 days,
then 12 mg IV daily for 3 days 12 months
later vs. interferon β-1a 44 mcg
More patients taking alemtuzumab were
relapse-free (65.4%) at 2 years than the
interferon group (46.7%). Fewer patients
taking alemtuzumab had disease
progression (12.71% vs. 21.13%). Fewer
patients taking alemtuzumab had new MRI
with dimethyl fumarate delayed-release 120 mg PO twice daily for 7 days, then 240 mg PO twice daily
thereafter. What counseling should she receive regarding the adverse effects of this medication?
Dimethyl fumarate commonly causes flushing and gastrointestinal (GI) adverse
effects; it has been formulated as a delayed-release product to help with these
problems. Flushing occurs in about 30% to 38% of patients taking dimethyl fumarate
179 The GI adverse effects include diarrhea 13%, nausea 11%, and
179 Taking doses with food helps decrease both of these
types of adverse effects. In a small study specifically examining flushing and GI
effects, the incidence of flushing was much higher, up to 98% in some groups, but
decreased somewhat with continued use. Each event lasted between 1 to 2 hours.
Aspirin 325 mg taken 30 minutes prior to the dose decreases the incidence of flushing
by about 14%. The subjects also had much higher incidences of GI effects, between
79% and 81%, falling to 53% to 61% during the second month of use. GI event onset
was a median time of 2 weeks. Aspirin had no effect on GI symptoms.
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