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Management of Multiple Sclerosis Relapses.7
Management of Multiple Sclerosis Relapses.7
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
Downloaded from https://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3kFt6OSS8/9Lyo4JLBYIu5ZA+GufMmWxLxPd7D7jJH2U6SUVqVJjW3A== on 08/25/2020
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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.
CONTINUUMJOURNAL.COM 655
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 Uveitis (mild, posterior); no pain; no light Progressive optic neuropathy; severe
movement; partial and mainly central perception; bilateral simultaneous optic continuous orbital pain; persistent
visual blurring; normal disc or mild neuritis; moderate to severe disc complete loss of vision; neuroretinitis
disc swelling swelling with no hemorrhages (optic disc swelling with macular star);
uveitis (severe, anterior)
Brainstem/cerebellum
Spinal cord
Partial myelopathy; Lhermitte sign; Complete transverse myelitis; Anterior spinal artery territory lesion;
deafferented hand; numbness; paroxysmal tonic spasms; cauda equina syndrome; sharp sensory
urinary urgency, incontinence, radiculopathy, areflexia; segmental loss level to all modalities and localized
erectile dysfunction of pain and temperature sensation; spinal pain; complete Brown-Séquard
partial Brown-Séquard syndrome; fecal syndrome; acute urinary retention
incontinence
Cerebral hemispheres
a
Modified from Miller DH, et al, Mult Scler.2 © 2008 SAGE Publications.
CONTINUUMJOURNAL.COM 657
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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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.
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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TABLE 4-2 Some Common Adverse Effects Associated With the Use of
Corticosteroids and Mitigation Strategies
IV = intravenous.
a
In patients with history of prior adverse effect(s), mitigation strategies may be used prophylactically.
CONTINUUMJOURNAL.COM 663
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
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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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.
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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