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nonrelapse (53%) and had a rate of UTI (23%) similar to those
with nonrelapse (34%).
Treatment of Acute Attacks
Most acute attacks (relapses) are treated with glucocorticoids.
Steroid treatment appears to accelerate the recovery from an
attack, improving outcome assessed at 4 to 5 weeks. However,
steroid treatment does not appear to alter the long-term
outcome of the attack or reduce the long-term risk of further
attacks.
25-27
A typical course of steroid consists of 3 to 7 days
of either intravenous (IV) (500-1000 mg of
methylprednisolone daily) or oral steroid (626-1250 mg of oral
prednisone). There does not appear to be any significant
benefit for IV over oral route of administration. The potential
side effects of short courses of high-dose steroids are familiar
to emergency practitioners and include psychiatric
disturbances, gastrointestinal symptoms, increased
susceptibility to infection, and hyperglycemia in diabetics.
Adrenocorticotropic hormone (ACTH), which stimulates
adrenal production of glucocorticoids, is occasionally used for
patients who cannot tolerate or do not respond to direct
administration of corticosteroids. Some investigators have
suggested that there may be additional anti-inflammatory and
immunomodulatory effect of ACTH mediated through
melanocortin pathways.
Several very small trials have suggested that plasmapheresis
might improve the short-term resolution of acute attacks. The
American Academy of Neurology recommends consideration
of plasmapheresis as a second-line therapy for patients whose
relapse does not respond to steroid.
Disease-Modifying Agents
Several immunomodulatory agents have been demonstrated to
slow the rate of clinical relapse and the rate of accumulation of
MRI brain lesions in patients with RRMS. Most of these
therapies are started as soon as a patient receives a diagnosis
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of MS and are continued indefinitely unless side effects
become intolerable. Many are unique to MS treatment and
relatively unfamiliar to ED clinicians. Progression of clinical
or radiographic disease may cause clinicians to change to a
different agent.
28,29
Treatment of the progressive forms of MS (primary and
secondary) has proved more challenging. Ocrelizumab has
been shown to slow disability progression in PPMS, and
siponimod may be beneficial in the secondary-progressive
phase.
Injectable Therapies
Interferon Beta-1b (Betaseron)
Interferon beta-1b (Betaseron) is a cytokine that modulates
immune responsiveness by a variety of mechanisms and was
the first disease modifying therapy approved for treatment of
MS. It is administered by self-injection every other day. A
pegylated form of interferon beta-1a (Plegridy) is now
available that can be given every other week. Side effects of
interferons include injection-site reactions, infections and
necrosis, and flu-like symptoms. There is a high prevalence of
asymptomatic liver function test (LFT) elevations and possibly
an association with leukopenia.
Glatiramer Acetate (Copaxone)
Glatiramer acetate (Copaxone) is a mixture of random
polymers of four amino acids, designed to be antigenically
similar to myelin basic protein; it appears to compete with
myelin antigens for presentation to T cells and induce T helper
and T suppressor cells to modulate immune response.
Glatiramer acetate is given by subcutaneous injection three
times per week. Side effects include injection-site reactions,
transient flushing, as well as occasional chest pain, dyspnea,
and palpitations.
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Infusion Therapies
Natalizumab (Tysabri)
Natalizumab (Tysabri) is a recombinant monoclonal antibody
against alpha4 integrin. The integrins are a family of celladhesion molecules; alpha4 integrin, which is expressed on the
surface of inflammatory lymphocytes and monocytes,
modulates adhesion to endothelium and migration of
leukocytes into the brain. It is usually given as an infusion
every 4 weeks. The most important side effect of natalizumab
is development of PML, a potentially fatal neurological
disease caused by reactivation of the JC virus. Risk factors for
natalizumab-induced PML include previous
immunosuppression, presence of anti-JC virus antibody, and
duration of treatment. Any patient given natalizumab
presenting with new neurological symptoms, especially
confusion, change in behavior, aphasia, or hemiparesis should
have an evaluation by the neurology service that includes MRI
and possibly lumbar puncture to assess JC virus DNA titer.
30
Alemtuzumab (Campath, Lemtrada)
Alemtuzumab (Campath, Lemtrada) is a humanized
monoclonal antibody (also used to treat chronic lymphocytic
leukemia and T cell lymphoma) against the cell-surface
molecule CD52, which causes the depletion of CD52-positive
immune cells such as T lymphocytes, natural killer cells, and
monocytes. Treatment is given as a course of infusions on five
consecutive days, followed a year later by a course of three
daily infusions. Immediate infusion reactions include
headache, nausea, rash, and fever. Longer-term complications
include susceptibility to viral infections such as herpes
simplex and zoster and autoimmune disorders such as thyroid
dysfunction and immune thrombocytopenia.
31
Ocrelizumab (Ocrevus)
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Ocrelizumab (Ocrevus) is a recombinant human monoclonal
antibody against CD20, a cell-surface marker found on B
lymphocytes. Adverse reactions include immediate infusion
reactions; its use is contraindicated in patients with active
hepatitis B infection because of virus reactivation seen in
patients treated with other CD20 antibodies such as rituximab.
32
Oral Therapies
Dimethyl Fumarate (Tecfidera)
Dimethyl fumarate (Tecfidera) is an organic compound
recently found to have efficacy in MS. It has antiinflammatory and immunomodulatory properties. Common
adverse effects include flushing and gastrointestinal
complaints, as well as decreased lymphocyte counts.
Teriflunomide (Aubagio)
Teriflunomide (Aubagio) is an inhibitor of pyrimidine
synthesis that has immunomodulatory effects via reduced
proliferation of activated T and B lymphocytes. Adverse
effects include gastrointestinal complaints, hair thinning, and
elevation of LFTs. Leflunomide, a compound metabolized to
teriflunomide, is associated with embryo lethality and
teratogenesis in animal testing; although there is no evidence
of fetal harm in babies born to mothers taking teriflunomide, it
is considered contraindicated in patients who are pregnant or
trying to conceive.
Fingolimod (Gilenya)
Fingolimod (Gilenya) is a sphingosine-1-phosphate receptor
modulator, which causes lymphocytes to be sequestered in
lymph nodes. Common adverse effects include headache,
cough, diarrhea, back pain, leukopenia, and elevated liver
enzymes. There have also been reports of dose-dependent
bradyarrhythmias, atrioventricular block, and QT prolongation
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associated with its use. This is commonly seen with first-dose
administration. Use of fingolimod with other drugs that can
cause QT interval prolongation such as escitalopram should be
avoided.
Goals of Emergency Department
Evaluation
For patients with a possible first attack of MS, a thorough ED
evaluation, including MRI, is important. Neurology
consultation and hospital admission appear to markedly
increase the rate of early diagnosis for these patients. An
accurate diagnosis will allow them to begin disease-modifying
treatment early, perhaps delaying or preventing later disability.
For patients with established MS and new symptoms, the goal
of ED evaluation is more ambiguous. As the Mount Sinai
study showed, ED evaluation of these patients often focuses
on distinguishing true from pseudorelapse, usually with MRI
as the deciding factor. Most patients with presumed relapse are
then admitted.
Both components of this approach are flawed. The
determination of a true relapse effectively means a decision to
consider steroids, which are the only commonly used
treatment for relapses. However, steroids do not alter the
eventual outcome of a relapse; they only speed up the eventual
resolution of symptoms. This means that the diagnosis of a
relapse is not critical for the patient’s long-term well-being and
the use of advanced MRI must be weighed against the costs in
time, money, and use of a limited resource.
There is good reason to question the need to admit all patients
with relapses. Evidence suggests that high-dose oral steroid is
as effective as IV steroid. 27 If a patient’s acute symptoms are
not severe or disabling, a basic medical evaluation shows no
serious infection, and the patient has good outpatient
neurological follow-up, there is no reason that the patient with
relapse needs to be admitted. Even when IV steroid is selected,
patients may be able to receive the treatment as an outpatient.
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The Cleveland Clinic authors proposed an evaluation
algorithm for MS in which most patients avoid the ED
entirely. Patients should be instructed to contact their
neurologist before presenting to the hospital. Those who
appear medically stable and are able to care for themselves
should be managed outside of the hospital, with a prompt
outpatient visit to screen for infection and oral or outpatient IV
steroid for suspected relapse. Patients with new neurological
symptoms should receive imaging only if their symptoms are
severe.
21
Although this protocol is reasonable, it assumes the existence
of resources that might not be present in most hospitals, such
as easy telephone access to a neurologist, prompt outpatient
follow-up, and an MS team able to provide outpatient IV
steroids. In the absence of such resources, many symptomatic
patients will come to the ED and many patients will be
admitted for IV steroids.
Conclusion
Multiple sclerosis is a complex neurological disorder whose
diagnosis and management present many challenges for EM
clinicians. A better understanding of the natural history and
complications of MS, as well as the many therapies used for
the disease, can help clinicians provide the best care for these
patients.
Key Points
The role that acute relapses play in the long-term accumulation
of disability in patients with MS remains unclear.
Steroids given for acute attacks speed up resolution of
symptoms but do not affect long-term disability. Oral steroids
appear to be as effective as IV ones.
In a patient with known MS and new or worsened symptoms,
the most important goals are excluding significant infection or
other acute medical condition, assessing the functional
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severity of the symptoms, and assuring that the patient has
good outpatient neurological follow-up.
Patients with mild symptoms, no evidence of severe infection,
and good follow-up can generally be treated as outpatients.
The decision to start steroids for a suspected relapse should
ideally be made in collaboration with the patient’s neurologist
or the neurology consultant. For patients with mild symptoms,
the potential side effects may outweigh the symptomatic
benefit.
Patients with severe acute symptoms, significant acute medical
illness, poor follow-up, or limited ability to care for
themselves because of advanced disease may require
admission.
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C H A P T E R 8
Visual Dysfunction in
Multiple Sclerosis
Doria M. Gold Janet C. Rucker Steven Galetta
Introduction
Multiple sclerosis (MS) is the most common and familiar
disease in a class of inflammatory demyelinating disorders that
cause myelin inflammation and destruction and neuronal and
axonal loss. 1 Visual symptoms occur in 50% to 80% of
patients with MS at some point in the disease course and are a
significant source of disability. 2 Visual loss is frequently the
initial disease manifestation, with 20% of patients presenting
with idiopathic demyelinating optic neuritis.
1,3
Effects on the
visual system can be divided into disorders of the afferent
visual system, including the optic nerves and intracranial
visual pathways, and the efferent visual system of eye
movement control.
Afferent Visual Disturbances
Optic Neuritis
Idiopathic demyelinating optic neuritis is the most common
optic neuropathy under the age of 40 years. It may occur as an
initial clinically isolated demyelinating event in the absence of
a diagnosis of MS or in a patient with an established diagnosis
of MS (Case 1). Typical presentation is vision loss in one eye
that progresses over 1 to 2 weeks and is accompanied by eye
pain that is typically worse with eye movement. 4 Bilateral
simultaneous optic neuritis can occur, especially in children,
5
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