Management of Multiple REVIEW ARTICLE

Sclerosis Relapses

C O N T I N U UM AUDIO
I NT E R V I E W A V A I L AB L E
ONLINE
By Pavle Repovic, MD, PhD

ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of the clinical and
pathologic features of multiple sclerosis (MS) relapses and reviews
evidence-based approaches to their treatment.

RECENT FINDINGS: Despite the increasing number and potency of MS

Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVGBWJMQ4hzAOIEPec+tnd8yttf6WwR4ESC54bT5lULUS on 06/03/2019

treatments, relapses remain one of the more unpredictable and

disconcerting disease aspects for many patients with MS, making their
accurate recognition and treatment an essential component of good
clinical care. The expanding range of relapse treatments now includes oral
corticosteroids, comparable in efficacy to IV methylprednisolone at a
fraction of the cost. While this development improves access to prompt CITE AS:
CONTINUUM (MINNEAP MINN)
treatment, it also underscores the importance of recognizing mimics of MS 2019;25(3, MULTIPLE SCLEROSIS
relapses to reduce corticosteroid overuse and its attendant risks. AND OTHER CNS INFLAMMATORY
DISEASES):655–669.

SUMMARY: Like MS itself, MS relapse remains primarily a clinical diagnosis.

Address correspondence to Dr
The treatment options for MS relapse include corticosteroids, Pavle Repovic, MS Center,
adrenocorticotropic hormone (ACTH), plasma exchange, and rehabilitation, Swedish Neuroscience Institute,
1600 E Jefferson St, Ste A,
used singly or sequentially, with the goal of limiting the duration and impact Seattle, WA 98122,
of associated disability. Even when treated promptly and effectively, pavle.repovic@swedish.org.
clinical or subclinical sequelae of MS relapses frequently remain.
RELATIONSHIP DISCLOSURE:
Dr Repovic has served as a
consultant for Biogen; EMD
Serono, Inc; Genentech, Inc;
INTRODUCTION Sanofi Genzyme; and Teva

F
or the majority of patients with multiple sclerosis (MS), especially those Pharmaceutical Industries Ltd
and has received personal
early in the disease course, relapse is the most apparent and compensation for speaking
unpredictable manifestation of their disease. The diagnosis (and name) engagements from Biogen; EMD
Serono, Inc; Genentech, Inc;
of relapsing MS is principally based on this event, the prominence of and Teva Pharmaceutical
which belies our understanding of its etiology. MS relapse can be Industries Ltd. Dr Repovic
defined as “a monophasic clinical episode with patient-reported symptoms and receives research/grant
support from Alexion, the
objective findings typical of multiple sclerosis, reflecting a focal or multifocal National Institutes of Health
inflammatory demyelinating event in the CNS, developing acutely or subacutely, (5U10NS077309), Novartis AG,
with a duration of at least 24 hours, with or without recovery, and in the absence and Genentech, Inc.

of fever or infection.”1 Symptoms of MS relapse typically evolve over hours to UNLABELED USE OF
days, reaching a nadir in a matter of days, followed by a gradual and variable PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
recovery course over ensuing weeks to months. Both hyperacute and very
Dr Repovic reports no
gradual (eg, >12 weeks) presentations are uncommon and should prompt disclosure.
consideration of alternative etiologies.
Typical manifestations of MS relapses include optic neuritis, spinal cord © 2019 American Academy
syndromes, and brainstem syndromes (TABLE 4-12). Analysis of relapse of Neurology.

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MANAGEMENT OF MS RELAPSES

phenotypes in 14,696 MS patients showed that most relapses are

monosymptomatic (71%) and involve sensory (48%), pyramidal (34%), or visual
(20%) functional systems.3 The relapse phenotype may change over the course of
MS; early in the disease course, sensory, visual, and brainstem relapses are
relatively more common than pyramidal, bowel/bladder, or cerebellar relapses,
which are more common later in the disease course. A tendency exists for
relapses to recur in a previously affected system, although the timing and the
location of a relapse remain unpredictable.3
The frequency of MS relapses decreases with both age and time from
diagnosis. Female patients, on average, experience more relapses than males
throughout the course of the disease.4 Based on the placebo arms of clinical trials,
a typical patient with MS has 0.27 to 1.66 relapses per year (ie, one relapse
approximately every 7 months to 4 years).5 This relapse rate has decreased over
the past 30 years; this appears to be more likely because of a change in study
recruitment patterns rather than a change in the nature of MS.5 MS relapses are
most frequent in early spring and least frequent in the winter of each

TABLE 4-1 Manifestations of Multiple Sclerosis Relapsesa

Common Features of Multiple Less Common Features of Multiple Atypical Features Not Expected in
Sclerosis Relapse Sclerosis Relapse Multiple Sclerosis Relapse
Optic nerve

Unilateral optic neuritis; pain on eye
movement; partial and mainly central
visual blurring; normal disc or mild
disc swelling
Uveitis (mild, posterior); no pain; no light
perception; bilateral simultaneous optic
neuritis; moderate to severe disc
swelling with no hemorrhages
Progressive optic neuropathy; severe
continuous orbital pain; persistent
complete loss of vision; neuroretinitis
(optic disc swelling with macular star);
uveitis (severe, anterior)

Brainstem/cerebellum

Bilateral internuclear Unilateral internuclear ophthalmoplegia; Complete external ophthalmoplegia,

ophthalmoplegia; ataxia and
multidirectional nystagmus; sixth
nerve palsy; facial numbness
facial palsy, facial myokymia; one-and-
a-half syndrome; trigeminal neuralgia,
deafness
vertical gaze palsies; vascular territory
syndrome (eg, lateral medullary); third
nerve palsy; progressive trigeminal
sensory neuropathy; focal dystonia;
torticollis

Spinal cord

Partial myelopathy; Lhermitte sign;
deafferented hand; numbness;
urinary urgency, incontinence,
erectile dysfunction
Complete transverse myelitis;
paroxysmal tonic spasms;
radiculopathy, areflexia; segmental loss
of pain and temperature sensation;
partial Brown-Séquard syndrome; fecal
incontinence
Anterior spinal artery territory lesion;
cauda equina syndrome; sharp sensory
level to all modalities and localized
spinal pain; complete Brown-Séquard
syndrome; acute urinary retention

Cerebral hemispheres

Mild subcortical cognitive Epilepsy; hemianopia Encephalopathy (obtundation,

impairment; hemiparesis confusion, drowsiness); cortical
blindness

a
Modified from Miller DH, et al, Mult Scler.2 © 2008 SAGE Publications.

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hemisphere6 and correlate with not only the seasonal variation in vitamin D KEY POINTS
levels and sunlight exposure but also latitude.7,8
● Typical manifestations of
multiple sclerosis relapses
PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS RELAPSES include optic neuritis, spinal
On a cellular level, the shared pathologic substrate of MS relapses is impaired cord syndromes, and
axonal conduction resulting from the combined effects of demyelination, brainstem syndromes.
inflammation, and a variable degree of neuronal loss.9 Loss of myelin, either
● The shared pathologic
between the nodes of Ranvier or through the widening of a nodal gap, increases substrate of multiple
the electrical capacitance of an axon, requiring higher current to depolarize the sclerosis relapses is
node. At the same time, newly demyelinated axolemma offers greater surface impaired axonal conduction
area to disperse the available current. Combined, these effects of myelin loss lead resulting from the combined
effects of demyelination,
to axonal conduction block by increasing the nodal firing threshold and reducing inflammation, and variable
the current available to do so. In addition, proinflammatory cytokines (tumor degree of neuronal loss.
necrosis factor-a, interferon gamma) contribute to axonal block either through
direct action on ion channels or indirectly by promoting local synthesis of nitric ● Viral and bacterial
infections increase the risk
oxide, a potent conduction blocker.9 of multiple sclerosis
The immunopathologic events leading to MS relapse are only partially known. relapse.
Initial triggers of MS relapse have long been sought through association studies,
ruling out exercise and epidural anesthesia.10,11 To date, evidence suggests that
systemic infections, perceived stress, the postpartum trimester, and assisted
reproductive techniques are associated with increased risk of MS relapse.4 Viral
and bacterial infections increase the risk of MS relapse, presumably by eliciting
helper T cell type 1 (TH1) immune response, whereas parasitic infections, which
elicit helper T cell type 2 (TH2) response, do not.
Given the strong and consistent relationship between viral or bacterial
infections and MS relapses, strategies to prevent infections, including
vaccination, are reasonable and recommended. Inactivated vaccines are
considered safe in MS, and for some vaccines (against seasonal influenza,
tetanus, and hepatitis B), compelling evidence exists that they do not increase
the risk of MS relapse.12 Live attenuated vaccines, on the other hand, require
caution, especially for patients with MS on immunosuppressants, as the
attenuated virus may cause the disease it was meant to prevent. In addition, some
live attenuated vaccines (eg, yellow fever vaccine) may increase the risk of MS
relapse and require careful consideration of risks and benefits.13 Current
guidelines recommend routine vaccination against seasonal influenza using
standard-dose inactivated (but not live attenuated) vaccine.14 Until more safety
data are available, the high-dose inactivated seasonal influenza vaccine is not
recommended for patients with MS.15 The recently approved nonlive herpes
zoster vaccine may be safer than the live attenuated vaccine. Vaccination within
4 to 6 weeks of a disabling MS relapse is not recommended, unless the delay
would harm the patient (eg, tetanus vaccine after open wound).14
Whatever triggers a relapse, it is followed by the inflammatory phase,
characterized by the trafficking of autoreactive immune cells into the central
nervous system (CNS). This influx is facilitated by the breakdown of the
blood-brain barrier, the macroscopic correlate of which can be seen on MRI as
extravasation of gadolinium from the circulation into the CNS parenchyma.
Serial MRI scans show that gadolinium enhancement is a temporary feature of
most (but not all) new lesions, only observable for several weeks, after which the
blood-brain barrier is repaired and the lesion ceases to take up contrast.16
Magnetic resonance spectroscopy and histopathologic studies indicate that

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MANAGEMENT OF MS RELAPSES

CASE 4-1 A 37-year-old woman with relapsing-remitting multiple sclerosis (MS)

presented with the subacute onset of bilateral blurred vision that began
3 weeks earlier and had gradually worsened. She reported no associated
temporal or retroorbital pain, change in color perception, diplopia, or any
other symptoms. The patient was concerned that her blurred vision could
be another episode of optic neuritis.
She had been diagnosed with MS 3 years earlier, based on a history of
partial transverse myelitis with supportive MRI findings of a gadolinium-
enhancing spinal cord lesion at the T5 level, along with two enhancing
and several nonenhancing T2-hyperintense brain lesions consistent with
demyelinating disease. She had been treated with dimethyl fumarate for
11 months but then had an episode of optic neuritis in her left eye. Repeat
brain MRI at that time detected several lesions, some with enhancement,
that had developed despite reported adherence to treatment. Her
disease-modifying therapy was changed to fingolimod at that time, with
good tolerability and no subsequent relapses or additional lesions on
surveillance MRIs. She was diagnosed with diabetes mellitus 6 months
before this presentation, but her medical history was otherwise
unremarkable.
On examination, her visual acuity was 20/25 in both eyes, with pinhole
correction, a change from her baseline 20/20 vision. No relative afferent
pupillary defect or color desaturation was apparent. Ophthalmoscopic
examination was unremarkable. However, on Amsler grid testing, she
reported distortion of lines in her left eye. She was referred for urgent
ophthalmologic evaluation for possible macular edema, a known, albeit
uncommon, adverse effect of fingolimod. The ophthalmologist’s report
received later that day reported normal findings. However, the patient
did not have optical coherence tomography at this visit; when she
returned for the test the following day, it demonstrated bilateral macular
thickening consistent with cystoid macular edema. Fingolimod was
discontinued, and her vision returned to normal within several weeks.

COMMENT Because this patient’s blurred vision developed over several weeks and
had no associated pain or change in color perception, it did not fit the
expected pattern of optic neuritis, prompting consideration of alternative
etiologies. Fingolimod-associated macular edema is uncommon (incidence
of 5 per 1000), but this patient’s risk may have been higher owing to her
recent diagnosis of diabetes mellitus. Discontinuation of fingolimod leads
to resolution of macular edema and associated symptoms in over 90% of
affected patients.21

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demyelination and axonal loss occur during this inflammatory phase of the KEY POINTS
relapse.9 Four distinct histologic patterns of lesions have been described, based
● Resolution of the
on the relative prevalence of macrophages and complement/antibody deposits inflammatory phase of a
and the presence or absence of oligodendrocyte apoptosis.17 multiple sclerosis relapse is
Resolution of the inflammatory phase of a relapse is followed by a reparative followed by a reparative
phase. During this reparative phase, the blood-brain barrier is repaired, MRI phase.
enhancement resolves, and surviving axons are remyelinated. As the myelin
● Even when symptoms are
sheath is regenerated and local inflammation subsides, axonal conduction is unequivocally multiple
restored, manifesting clinically as gradual return of neurologic function. Even in sclerosis–related, a
the absence of remyelination, axonal conduction block may be reversed within distinction needs to be
weeks through redistribution of sodium channels. Remyelination is variable made between a bona fide
multiple sclerosis relapse
among individuals and, while it generally declines with age, is not restricted only and a pseudorelapse.
to young patients or to a specific phase of MS.18 Reparative processes are slower
than the inflammatory phase and may take up to 12 months.19 ● Fluctuation of symptoms
in patients with multiple
sclerosis is attributed to
PSEUDORELAPSES variable efficiency of repair
Recognition of MS relapse can sometimes be challenging for several reasons. following a relapse.
First, patients may underreport or overreport their symptoms. In one survey, as
many as 28% of patients did not report their most recent relapse.20 Second,
clinicians may misattribute reported symptoms to MS, even if that is not the case
(CASE 4-1), or dismiss reported symptoms, especially in patients who tend to
overreport them. Finally, even when the symptoms are unequivocally
MS-related, a distinction needs to be made between a bona fide MS relapse and
a pseudorelapse.
Considering that relapse frequency is a primary outcome of many therapeutic
trials in MS, attempts have been made to define a “confirmed” relapse; however,
these algorithms often rely on expert panel and complex criteria that are
impractical in routine clinical practice. To date, no simple biomarker or
algorithm is available to confirm an MS relapse, and its diagnosis ultimately relies
on clinical judgment. To aid the clinician in this task, some common and less
common features of MS relapses, organized by functional system, are listed in
TABLE 4-1. This list is neither exhaustive nor absolute. Nevertheless, if atypical
features are present, they warrant a search for an alternative cause other than
MS. Common features of typical relapses could also be used to educate patients
with MS to reduce underreporting.
Fluctuation of symptoms in patients with MS is attributed to variable
efficiency of repair following a relapse. Repaired myelin sheath is almost always
thinner (having fewer folds) and with shorter internodal distances than native
myelin. In addition, axonal segments that are not remyelinated adapt via sodium
channel redistribution, resulting in more continuous (as opposed to normal
saltatory) conduction of action potentials. This microsaltatory conduction and
incomplete remyelination lead to slower axonal conduction that can be
quantified as increased latency of visual, somatosensory, or brainstem evoked
potentials. Conduction slowing in an optic nerve is responsible for the Pulfrich
phenomenon: an object oscillating in a vertical plane is perceived instead as
following an elliptical trajectory in a horizontal plane, or, more prosaically,
oncoming traffic is seen as veering toward the driver.9
Demyelinated and remyelinated neurons exhibit other electrophysiologic
aberrations that underpin some of the clinical symptoms in MS. These include
positive phenomena (such as spontaneous or movement-induced generation of

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MANAGEMENT OF MS RELAPSES

CASE 4-2 A 58-year-old man with relapsing-remitting multiple sclerosis (MS)

presented with symptoms of worsening ambulation and falls. He had
been diagnosed with MS 12 years earlier, when he presented with
diplopia and a prior episode of right leg weakness as well as MRI
evidence of brain and spinal cord lesions. Despite treatment with
interferon beta followed by glatiramer acetate, he continued to have
relapses, so 7 years ago, he started treatment with natalizumab. Since
then, he had experienced no additional relapses or MRI lesions on
surveillance scans and had no evidence of antibodies to JC virus on
quarterly tests. For ambulatory problems, he had been treated with
dalfampridine.
In clinic, he reported more difficulty standing up from a seated position
and more difficulty ambulating for the previous 2 weeks. He had started
using a cane after his right leg had buckled and he fell at home 3 days
before. The episode reminded him of the symptoms he had 2 years
earlier, when he ran out of dalfampridine because of a change in
insurance.
On examination, his right hip flexion was measurably weaker than
previously, and his timed 25-foot walk was 6.7 seconds, worse than his
baseline of 5.4 to 5.8 seconds over the past year. He reported more
fatigue but denied any other focal symptoms. He also denied any fever,
symptoms of an infection, or change in mentation. Four weeks earlier, he
had started taking baclofen to help with leg spasticity. His most recent
natalizumab infusion was 3 weeks before this presentation.
Because of his treatment with natalizumab, an urgent MRI was
performed, which showed no new lesions or lesions suspicious for
progressive multifocal leukoencephalopathy. Laboratory tests showed
normal electrolytes and liver function; however, urinalysis was positive
for nitrites and leukocyte esterase. Urine culture grew more than 100,000
Escherichia coli colony-forming units per milliliter, resistant to
fluoroquinolones and trimethoprim-sulfamethoxazole but sensitive to
nitrofurantoin. He was treated with nitrofurantoin, with improvement in
leg weakness and ambulation over the next 2 weeks.

COMMENT This patient presented with recurrence of his prior neurologic symptom
(leg weakness) against the background of well-controlled MS relapses on
an effective disease-modifying therapy and in the setting of subclinical
infection. While potential causes of pseudorelapse were being
investigated, he underwent evaluation for progressive multifocal
leukoencephalopathy, as should any patient on natalizumab who is
experiencing new symptoms, regardless of his or her JC antibody status.
Another possible contributor to his symptoms could have been the
initiation of baclofen, as antispasticity agents may uncover existing
weakness by reducing the tone of affected muscle.

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electrical impulse, as seen with neck flexion in the Lhermitte sign) as well as KEY POINTS
negative phenomena (intermittent filtering or conduction block that follows a
● Uhthoff phenomenon
sustained train of impulses). The most prominent of the negative phenomena, refers to reoccurrence of a
the Uhthoff phenomenon, refers to reoccurrence of a neurologic deficit from an neurologic deficit from an
earlier relapse (eg, visual blurring in a patient with a history of optic neuritis) in earlier relapse in the setting
the setting of increased core body temperature, classically observed with of increased core body
temperature, classically
exercise. The rise in core body temperature, even by a few fractions of a degree,
observed with exercise.
elicits conduction block due to temperature-related prolongation of the refractory
(eg, nonexcitable) period of demyelinated axons. Although the Uhthoff ● Several clinical trials and
phenomenon typically manifests as recapitulation of neurologic deficit from two meta-analyses provide
prior relapse, occasionally it may unmask previously unknown neuronal injury22 evidence that high-dose
corticosteroids hasten
or manifest less focally as cognitive or ambulatory decline.23,24 Drowning, neurologic recovery after
scalding, and other accidents have been attributed to this phenomenon.9 multiple sclerosis relapse.
The Uhthoff phenomenon is typically short-lasting and reverses readily with
cooling as the axonal conduction block resolves. When the recrudescent
symptoms persist for longer periods of time, mimicking MS relapse, the event
is referred to as a pseudorelapse. Pseudorelapses typically affect the same body
part and symptom constellation as a historical relapse, although symptoms may
not be as intense. Pseudorelapses can be seen in diverse settings that lead to an
increase in core body temperature, most frequently with fever, overt or occult
infection (eg, urinary tract infection), menstrual period, or stress (CASE 4-2).
A pseudorelapse should always be considered when patients report symptoms
similar to past MS relapses. In the absence of obvious triggers, laboratory testing
(eg, urinalysis with culture if indicated, complete blood cell counts, serum
electrolytes, and liver function tests) can help uncover triggers of pseudorelapse,
as can assessment of recent changes in medications. In case of infections,
however, caution is warranted since a pseudorelapse may be followed by a bona
fide MS relapse.

TREATMENT OF MULTIPLE SCLEROSIS RELAPSE

The majority of MS relapses are followed by some degree of spontaneous
recovery even without dedicated treatment. The dynamics of MS relapses
combined with their diverse phenotypes have made it challenging to distinguish
the additive effect of any given treatment to the natural course of recovery.
A number of clinical trials have attempted to address this conundrum, leading to
the current evidence that supports the use of corticosteroids, adrenocorticotropic
hormone (ACTH), and plasma exchange for MS relapse. Unfortunately, these
trials also suggest that while treatments hasten the recovery from a relapse in the
short term, they may not alter the long-term outcome in terms of our current
measures of neurologic disability. Nevertheless, the treatment of MS relapses
remains valuable in that it alleviates suffering, since the full impact of a relapse,
including emotional and financial costs to patients and their social networks, goes
well beyond the measures of neurologic function.

Corticosteroids
Corticosteroids are the principal treatment modality for MS relapses. Since their
earliest published use in MS in 1951,25 numerous studies have addressed the
effects of corticosteroids on MS. As a result, considerable variability remains
regarding the dose, type, and duration of corticosteroid regimens used for MS
relapses. Several clinical trials and two meta-analyses provide evidence that

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MANAGEMENT OF MS RELAPSES

high-dose corticosteroids hasten the neurologic recovery after MS relapse. In one

meta-analysis, compared to placebo, patients treated with high-dose steroids
improved by 0.76 points on the Expanded Disability Status Scale (EDSS) 5 to
7 days after treatment and by 0.85 points 2 to 4 weeks later.26 In another
meta-analysis, high-dose steroids reduced the odds of no improvement 5 weeks
after treatment to 0.2 compared to placebo.27 High-dose steroid treatment
was defined as at least 500 mg methylprednisolone or equivalent, given daily
for at least 3 days. One commonly used steroid regimen is 1000 mg daily IV
methylprednisolone for 3 to 5 days.28
Unless the relapse is very severe and leads to hospitalization, IV corticosteroids
can be administered at home or in an outpatient setting, with similar efficacy.29
Methylprednisolone, approved for medical use in 1951, is relatively inexpensive,
although the cost of its IV administration remains significant, about $2400 for a
3-day course on outpatient basis, according to a 2016 analysis.30
Oral steroids are less expensive, somewhat more convenient, and no less
effective than IV steroids for the treatment of MS relapses. Five clinical trials and
their meta-analysis, comprising 215 patients, provided initial evidence that oral
and IV steroids offer similar benefits.31 However, because of methodologic flaws
in some of the studies, these conclusions were regarded as tentative by some
specialists, awaiting confirmation from a larger, sufficiently powered
double-blind randomized clinical trial. The COPOUSEP (Oral Versus
Intravenous High-dose Methylprednisolone for Treatment of Relapses in

TABLE 4-2 Some Common Adverse Effects Associated With the Use of
Corticosteroids and Mitigation Strategies

Adverse Effect Mitigation Strategya

Flushing Reduce the rate of steroid infusion (if IV)

Insomnia Zolpidem 5 mg (female) or 5–10 mg (male) oral, lorazepam

0.5 mg oral, or doxepin 25 mg oral

Anxiety, agitation, or Lorazepam 0.5 mg oral

euphoria

Gastrointestinal pain/ Over-the-counter indigestion aids, omeprazole 20 mg oral

indigestion

Nausea/vomiting Metoclopramide 25 mg oral, ondansetron 4 mg oral

Elevated blood pressure Low-salt diet, adjustment of antihypertensive medication

Hyperglycemia Insulin sliding scale

Hypokalemia Potassium chloride 1000 mg oral if low potassium on basic

metabolic profile, or if patient on acetazolamide or taking
potassium-wasting diuretic

Edema Hydrochlorothiazide 12.5–25 mg oral

Metallic taste (dysgeusia) Breath mints

IV = intravenous.
a
In patients with history of prior adverse effect(s), mitigation strategies may be used prophylactically.

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Patients With Multiple Sclerosis) trial, published in 2015, provided this KEY POINTS
evidence.32 This multicenter trial enrolled 199 patients who were randomly
● Oral steroids are less
assigned to receive 1000 mg methylprednisolone daily for 3 days, either IV or expensive, somewhat more
orally (as 10 tablets of 100 mg methylprednisolone, a tablet strength that is not convenient, and no less
available in the United States). Steroid treatment was initiated within 15 days of effective than IV steroids for
symptom onset (average 7 days). The primary objective of this study was to the treatment of multiple
sclerosis relapses.
compare the proportion of patients who improved by day 28 without additional
steroid treatment. Eighty-one percent of oral and 80% of IV subjects met this ● Given the considerable
end point, offering the strongest evidence of noninferiority between these frequency of steroid side
two routes of steroid administration. The extent of improvement, time to effects, a proactive
improvement, need for additional treatment, and proportion of patients who approach to minimize their
impact on patients is
fully recovered at 28 days or 6 months were no different between oral and IV recommended.
groups. The proportion of patients who subsequently experienced a relapse
within 6 months also did not differ between the two routes of administration.
Oral steroids were tolerated as well as IV steroids, except for insomnia, which
was more common with oral steroids (77% compared to 64%), leading to the
recommendation that steroid tablets be taken in the morning rather than in the
evening. This study did not use imaging-based outcomes, but an earlier study of
49 patients showed that oral and IV steroids have equivalent effects on MRI
outcomes in MS relapses.33 Another study of 55 patients with optic neuritis
compared bioequivalent doses of 1000 mg IV methylprednisolone and 1250 mg
oral prednisone and reached much the same conclusions with regard to recovery
of visual acuity and visual evoked potentials.34
In the United States, the convenience of oral corticosteroids is somewhat
offset by the number of tablets patients must take to reach doses comparable to
those used in the studies discussed above. With the currently available
formulations, this translates into a daily regimen of 25 tablets of 50 mg
prednisone or 32 tablets of 6 mg dexamethasone.
Following a pulse of high-dose corticosteroids, a tapering dose is not necessary in
most cases. Early trials used steroid taper after high-dose treatment to avoid acute
adrenal insufficiency or to prolong the anti-inflammatory effect. Subsequent
research has shown that this taper is not necessary after a brief (3- to 5-day) course
of high-dose steroids, since such a brief steroid pulse does not significantly suppress
the hypothalamic-pituitary-adrenal axis,35 nor does taper contribute to recovery.36
Common side effects of high-dose steroids are listed in TABLE 4-2. Almost all
patients exposed to high-dose steroids experience at least one of these side
effects. In one survey, the most common steroid-related adverse effects were
metallic taste, facial flushing, and gastrointestinal disturbance. One-third of
adverse effects were deemed severe by patients and impacted their activities of
daily living. More side effects were seen with longer (5-day) steroid courses than
with shorter (3-day) steroid courses. CNS-related adverse effects were twice as
common among patients with higher disability and higher burden of disease.37
Given the considerable frequency of steroid side effects, some trials have
taken a proactive approach to minimize the impact of side effects on patients. In
the COPOUSEP study, for example, sucralfate and omeprazole were universally
administered,32 possibly explaining fewer reports of gastrointestinal symptoms
compared to the study by Jongen and colleagues37 (44% versus 53%). These and
other mitigation strategies are outlined in TABLE 4-2. Uncommon but serious side
effects of corticosteroids include avascular bone necrosis, pancreatitis, hepatitis,
and psychosis.

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MANAGEMENT OF MS RELAPSES

Adrenocorticotropic Hormone
A preparation of purified ACTH in gelatin that provides a prolonged release after
IM injection was approved for use in MS based on the results of the United States
Cooperative Study, conducted from 1965 to 1968.38 This was a double-blind
study that randomly assigned 197 patients within 8 weeks of a relapse to either
placebo or ACTH gel for 2 weeks. Patients with advanced MS and those who were
recently treated with ACTH or corticosteroids were excluded. ACTH gel was
administered as IM injection at a tapering dose (40 U 2 times a day for 7 days,
followed by 20 U 2 times a day for 4 days and 20 U daily for 3 days). Patients were
evaluated weekly for 4 weeks. Compared to placebo, a greater proportion of
the ACTH-treated group showed improvement at weekly assessments during
weeks 1 to 3 after relapse; by week 4, however, the difference was not statistically
significant.38 The benefit seemed to be limited to patients who had no
improvement of relapse symptoms before entering the study.
ACTH gel is contraindicated in patients with osteoporosis, a history of peptic
ulcer disease, or chronic heart failure and in those allergic to porcine proteins.
The immunogenic potential of ACTH gel is also recognized, with antibodies
formed either to the ACTH itself or other proteins in the preparation.39
Compared to corticosteroids, ACTH use in MS relapses is not well defined.
Assertions that ACTH gel is better tolerated than corticosteroids have not been
substantiated by clinical trials to date.27,40 It also remains unknown whether
ACTH effects on MS relapses extend beyond corticosteroid induction via its
melanocortin receptor–mediated actions or whether ACTH may improve the
recovery of patients with incomplete response to corticosteroids. Several clinical
trials are currently under way to evaluate these uses of ACTH. ACTH is used less
frequently than methylprednisolone as an initial treatment for MS relapses
because of the unpredictable rise in serum cortisol and inconvenience of IM
injections. The staggering rise in the cost of this treatment has also limited its use.
The price of a single vial of ACTH gel in the United States increased from $40 in
2001 to $34,000 in 2014, resulting in over half a billion dollars of Medicare spending
in 2015 (or $162,371 per patient), although not all of it in patients with MS.41

SECOND-LINE THERAPY
While some degree of recovery follows most MS relapses, full recovery to
baseline is less common. Analysis of relapses from the placebo arms of several
trials showed that 2 months after a relapse, 42% patients had residual worsening
of 0.5 points or more on the EDSS scale.42 In trials of ACTH or corticosteroids
for MS relapses, about one-fourth of MS relapses did not improve by the end of
the trial.32,38,43 Severity of relapse and older age correlate with less recovery after
MS relapses treated with corticosteroids.44 Higher nonfasting blood glucose
levels during steroid treatment were recently reported as another negative
predictor of recovery, but this finding awaits validation.45 Amelioration of
neurologic deficits was seen as early as 5 to 7 days after treatment with
methylprednisolone or ACTH,27,38 and most studies to date have defined lack of
improvement by 2 weeks as indication for additional treatment.43,46
Second-line treatment options include repetition of corticosteroid treatment
(sometimes using a different dose, route, or type of steroid), ACTH, plasma
exchange, or, outside the United States, immunoadsorption. Among these
options, clinical evidence47 best supports the use of plasma exchange, based on
several retrospective studies, subgroup analysis of a randomized clinical trial,48

664 JUNE 2019

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and a randomized clinical trial specifically addressing its use when relapses fail to KEY POINTS
improve with steroids.46 This trial enrolled 22 patients (12 with MS, 10 with other
● Compared to
inflammatory demyelinating diseases) who remained severely impaired, with corticosteroids,
paraplegia, hemiplegia, or quadriplegia despite high-dose corticosteroid adrenocorticotropic
treatment. Patients were randomly assigned in a crossover design to undergo hormone use in multiple
plasma exchange (seven exchanges every other day) or sham treatment. After sclerosis relapses is not
well defined.
14 days, plasma exchange led to significant improvement in 42% of the cases,
compared to only 5% with sham treatment.46 A retrospective review of ● Second-line treatment
steroid-unresponsive demyelinating episodes treated by plasma exchange options for multiple
identified predictors of response to this treatment: male gender, preserved or sclerosis relapse include
brisk deep tendon reflexes, and initiation of exchange within 60 days of repetition of corticosteroid
treatment (sometimes using
relapse.49 Analysis based on description of four histopathologic patterns of MS a different dose, route, or
lesions17 suggests that pattern II lesions (characterized by antibodies and type of steroid),
complement) showed the best response to plasma exchange, followed by pattern I adrenocorticotropic
lesions (T-cell/macrophage predominance), whereas pattern III lesions (distal hormone, and plasma
exchange.
oligodendrogliopathy) showed no improvement after plasma exchange.50 The
clinical utility of these findings, however, remains limited until these patterns ● In one study, plasma
can be reliably distinguished without invasive sampling (biopsy). Plasma exchange led to significant
exchange can be performed via peripheral access most of the time. Scheduling improvement in 42% of
patients who remained
exchanges every other day reduces, but does not eliminate, the risk of
severely impaired after
hypotension. Anemia, heparin-induced thrombocytopenia, and paresthesia relapses treated with
have been reported with plasma exchange. high-dose corticosteroids,
The benefits of plasma exchange notwithstanding, it should be noted that if a compared to only 5% with
sham treatment.
patient fails to respond to the initial course of corticosteroids, a second course of
steroids or ACTH is sometimes pursued, although clinical evidence is not yet available ● The decision whether to
to justify this strategy. This may be because of patient convenience, moderate (rather treat or monitor a multiple
than severe) relapse-related impairment, or limited access to plasma exchange.43 sclerosis relapse should be
made jointly between a
patient and a clinician,
REHABILITATION considering the impact
While rehabilitation is broadly perceived as beneficial in MS, few formal of both the relapse and
attempts have been made to determine the added benefit of this intervention in the proposed treatment
the management of MS relapses. In one randomized (but not blinded) trial, on a patient.
patients received IV steroids either with or without multidisciplinary therapy
consisting of physical therapy, occupational therapy, and other rehabilitation
modalities. Both therapists and the patients reported better neurologic recovery
up to 3 months later with multidisciplinary therapy as compared to the patients
who received steroids alone.51 Whether patients should rest while receiving
steroids or engage in rehabilitation at the same time remains unknown and is the
subject of at least one ongoing clinical trial.

ADDITIONAL CONSIDERATIONS
Because most MS relapses are followed by some degree of spontaneous recovery,
it is acceptable to monitor (rather than treat) some milder relapses. The decision
whether to treat or monitor a relapse should be made jointly between a patient
and a clinician, considering the impact of both the relapse and the proposed
treatment on a patient. Compared to controls, patients who were educated about
the role of corticosteroids in relapse treatment tended to treat fewer relapses,
preferred oral to IV steroids, and perceived higher levels of autonomy.52
Whether actively treated or not, MS relapses should always entail a discussion
of adherence to disease-modifying therapy. MRI may also be considered to

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MANAGEMENT OF MS RELAPSES

evaluate for evidence of additional subclinical disease activity. For most

disease-modifying therapies, a combination of breakthrough relapses and
MRI lesions is a poor prognostic factor and may argue for a change to a more
effective disease-modifying therapy. For some disease-modifying therapies
(eg, beta interferons, natalizumab), laboratory testing for antidrug antibodies
can inform this decision for the patient and clinician (CASE 4-3). If plasma
exchange is used, a disease-modifying therapy susceptible to removal by

CASE 4-3 A 28-year-old woman presented with new onset of double vision and
unsteadiness that she noticed upon waking. Her examination revealed
incomplete left ptosis, diagonal diplopia, impaired coordination of
her right arm and leg, and gait ataxia. Brain MRI showed an enhancing
left medullary lesion along with 12 supratentorial nonenhancing
T2-hyperintense lesions in periventricular and juxtacortical locations,
leading to the diagnosis of relapsing-remitting multiple sclerosis.
Because of gait instability, she was admitted for a course of IV
methylprednisolone (1000 mg daily for 5 days). By the fifth day of
admission, some of her deficits improved, but she developed new
dysarthria and weakness of her right arm and leg. Repeat brain MRI
showed resolution of enhancement in the medullary lesion but also new
left parasagittal midbrain and cerebral peduncle lesions. Seven cycles of
plasma exchange were performed. Her symptoms began improving after
the third exchange, and she was discharged to an acute rehabilitation
facility. Recovery from this relapse was slow, and 1 year later she still had
residual gait ataxia and trace diplopia.
Disease-modifying therapy with IV natalizumab (300 mg every 4 weeks)
was initiated. Seventeen months later, she experienced a relapse
manifesting as numbness that developed in her right hand and spread
over the next 3 days to involve her right arm up to the shoulder. Brain MRI
showed four nonenhancing lesions that were new compared to an MRI
from 7 months prior; spinal cord MRI showed an enhancing lesion at the
C4 level. Treatment with IV methylprednisolone (1000 mg daily for 3 days)
led to full resolution of her symptoms within 2 weeks. On further testing,
the patient was found to have antinatalizumab antibodies, prompting a
change of her disease-modifying therapy.

COMMENT This patient’s initial severe relapse did not respond to treatment with IV
methylprednisolone, prompting escalation of therapy to plasma exchange.
However, her subsequent relapse did respond to steroids, indicating that
steroid responsiveness may vary from relapse to relapse. When a patient
relapses while on disease-modifying therapy, the clinician should assess
adherence and, if relevant, biological resistance to the disease-modifying
therapy. In this case, the detection of antidrug antibodies allowed for a
timely change in treatment. Although most patients with antibodies to
natalizumab have infusion reactions, this patient had tolerated her
infusions without any incident.

666 JUNE 2019

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plasma exchange (eg, natalizumab) may need to be administered earlier than
routinely scheduled.
Clinicians treating MS relapses during pregnancy should be familiar with the
risks of corticosteroids and avoid their use during the first trimester, as they
increase the risk of cleft palate.53
Breast-feeding mothers can minimize exposure of the infant by not
breast-feeding for 8 hours after IV methylprednisolone; this period may be
longer if high-dose oral steroids are used.54,55 Patients with a documented allergy
or intolerance to one corticosteroid may benefit from a different type of steroid
as cross-reactivity is rare56 or from the use of ACTH instead. Of note, a true
allergy to corticosteroids is less common than pseudoallergic reactions due to
rapid IV infusion (eg, flushing, hypotension, bradycardia). A history of serious
behavioral problems (eg, psychosis) or metabolic dysregulation (eg, severe
hyperglycemia) triggered by prior steroid treatment justifies inpatient admission
for monitoring and management of these anticipated adverse events.

CONCLUSION
The goal of MS relapse treatment is to reduce the impact of relapse on the patient.
Current treatment consists of corticosteroids, ACTH, plasma exchange, and
rehabilitation, used singly or sequentially. Education of patients about cardinal
features of MS relapses, treatment options, and expected outcomes is an integral
component of relapse management. Recognition of pseudorelapses is also
important to limit unnecessary treatment.

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