Download Multiple Sclerosis — Part 4 - Audio

Volume 02, Issue 16
Multiple Sclerosis — Part 4
Editor
Aaron E. Miller, MD, FAAN
Professor of Neurology
Mount Sinai School of Medicine
Medical Director
Corinne Goldsmith Dickinson Center for
Multiple Sclerosis
Associate Editors
David C. Anderson, MD
Professor of Neurology
University of Minnesota Medical School
Senior Physician
Hennepin County Medical Center
S. Andrew Josephson, MD
Associate Professor of Neurology
Director, Neurohospitalist Program
Medical Director, Inpatient Neurology
UCSF School of Medicine
Ralph F. Józefowicz, MD, FAAN
Professor of Neurology and Medicine
Associate Chair for Education
Department of Neurology
University of Rochester School of
Medicine and Dentistry
August 21, 2013
Contents
Acute Disseminated Encephalomyelitis,
Transverse Myelitis, and Neuromyelitis Optica
——Brian G. Weinshenker, MD, FRCP(C), FAAN, Professor of
Neurology, Mayo Clinic, Rochester, MN
Unusual Symptoms and Syndromes in Multiple
Sclerosis
——Alexander D. Rae-Grant, MD, Staff Neurologist, Mellen Center for
Multiple Sclerosis, Cleveland Clinic, Cleveland, OH
Educational Objectives
The goal of this program is to improve the management of multiple sclerosis
(MS) and other demyelinating diseases. After hearing and assimilating this program, the clinician will be better able to:
1. Distinguish acute disseminated encephalomyelitis from MS.
2. Manage partial and complete transverse myelitis in the acute setting.
3. Diagnose neuromyelitis optica and decrease the risk of its recurrence.
4. Recognize less common neurologic phenomena associated with MS.
Daniel G. Larriviere, MD, JD, FAAN
Vice-chair, Department of Neurology
Ochsner Clinic Foundation
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all
Steven L. Lewis, MD, FAAN (Host)
faculty and members of the planning committee to disclose relevant financial relationProfessor and Associate Chair
ships within the past 12 months that might create any personal conflicts of interest. Any
Department of Neurological Sciences
identified conflicts were resolved to ensure that this educational activity promotes qualRush University Medical Center
ity in health care and not a proprietary business or commercial interest. For this program,
the following was disclosed: Dr. Weinshenker serves on the data and safety monitoring
board of Biogen Idec and Novartis and serves as a consultant regarding neuromyelitis optica therapeutics for Asahi Kasei Medical Co, Ltd, Elan Corporation, and Novartis; he receives royalties for licensed technology for the diagnosis of neuromyelitis optica from RSR Limited, and receives research
funding from Guthy-Jackson Charitable Foundation. Dr. Rae-Grant has served as a speaker for Avanir Pharmaceuticals, Inc, Biogen Idec, Novartis,
and Teva Neuroscience. Unlabeled Use of Products/Investigational Use Disclosure: Dr. Weinshenker discusses the unlabeled uses of corticosteroids
and plasma exchange for the treatment of acute disseminated encephalomyelitis, transverse myelitis, and neuromyelitis optica; IV immunoglobulin for
acute disseminated encephalomyelitis; and azathioprine, mycophenolate mofetil, and rituximab for neuromyelitis optica. Dr. Rae-Grant discusses the
unlabeled use of carbamazepine, phenytoin, and thiamine for the treatment of multiple sclerosis symptoms. To view disclosures of planning committee
members with relevant financial relationships, visit: audiodigest.org/continuumaudio/committee. All other members of the planning committee report
nothing to disclose.
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Designation: The Audio-Digest Foundation designates this enduring material for
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3 years from its date of publication.
Estimated time to complete this educational activity:
Review Educational Objectives and Faculty Disclosure 5 min
Take pretest 10 min
Listen to audio 1 hr
Review complete written summary
35 min
Take posttest 10 min
Continuum Audio pretests and posttests can be completed online at:
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Continuum Audio
Volume 02, Issue 16
August 21, 2013
Multiple Sclerosis — Part 4
Acute Disseminated Encephalomyelitis, Transverse
Myelitis, and Neuromyelitis Optica
Brian G. Weinshenker, MD, FRCP(C), FAAN,
Rochester, MN
Acute Disseminated Encephalomyelitis
Features: Inflammatory syndrome that affects white matter;
difficult to distinguish from multiple sclerosis (MS), especially in adults (but syndrome more common in children);
characterized by MRI changes indicating inflammatory
demyelination in white matter and encephalopathy with
behavioral or cognitive changes; focal manifestations
similar to those seen in MS, including myelitis, paraplegia, and optic neuritis.
Distinguishing acute disseminated encephalomyelitis
(ADEM) from MS: High percentage of patients (especially adults) initially diagnosed with ADEM ultimately
develop additional symptoms, leading to diagnosis of
MS; no good biomarkers available; clinical findings —
encephalopathy; polysymptomatic presentation; MRI
findings — typically diffuse, but spectrum includes large
single lesions as well; involvement of gray matter (eg,
thalamus) more common in ADEM than in MS; CSF
findings — oligoclonal bands less common in samples
taken from patients with ADEM; when present, oligoclonal bands more likely to disappear in patients with
ADEM (whereas they persist in patients with MS);
prominent pleocytosis typical in ADEM but not particularly useful for distinguishing from MS.
Acute management: Standard treatment consists of IV
methylprednisolone; limited evidence that patients with
severe symptoms who do not respond to corticosteroids
benefit from plasma exchange; anecdotal reports of benefit associated with administration of IV immunoglobulin.
Prognosis: ADEM associated with low mortality rate; prognosis favorable in most patients, especially with aggressive management; patients who actually have fulminant
MS continue to have active disease requiring additional
immunotherapy (eg, cyclophosphamide, mitoxantrone).
Association with infection: Viral infection may precede
development of ADEM and MS; severe viral infection
followed shortly by onset of neurologic symptoms in a
child suggests ADEM, but history of viral infection typically does not distinguish ADEM from MS.
Pathology: MS — demyelination typically extensive and
confluent; ADEM — narrow sleeves of demyelination
surround venules; relative preservation of myelin may
explain better prognosis, compared to patients with MS.
Transverse Myelitis
Syndrome: Characterized by motor, sensory, and autonomic (ie, sphincter) problems; partial — findings localized to
one side of body or limited to motor or sensory (but not
both); complete — bilateral involvement, affecting motor
and sensory function.
MRI findings: Partial — asymmetric lesion on spinal cord,
typically peripheral and extending over no more than
three segments; complete — long spinal cord lesion, typically extending over multiple segments and affecting central gray matter.
Etiologies: Include MS, neuromyelitis optica (NMO), and
other conditions (inflammatory or noninflammatory);
transverse myelitis may be difficult to distinguish from
spinal cord infarcts and zoster myelitis (unless characteristic zoster lesions also present).
Assessment: Distinguishing myelitis from other causes of
myelopathy — in myelitis, nadir of deficit occurs ≈3 weeks
after presentation of symptoms; in other causes of myelopathy, symptoms may progress for months; myelopathy associated with broader differential diagnosis, which
excludes transverse myelitis and NMO; clinical symptomology — partial or complete; dorsal column lesions
typically not present in transverse myelitis; radiology —
important to rule out spinal cord compression; when long
spinal cord lesion present, differential diagnosis includes
NMO, idiopathic transverse myelitis and viral myelitis;
CSF findings — pleocytosis typically occurs in patients
with myelitis; prominent polymorphonuclear pleocytosis,
although uncommon, suggests myelitis associated with
NMO; other tests — polymerase chain reaction (for eg,
herpesvirus) often helpful in establishing diagnosis.
Management: Even without specific diagnosis, patients
with clinical and MRI findings compatible with transverse myelitis typically treated with IV methylprednisolone; plasma exchange suggested as second-line therapy.
Prognosis: Dependent on degree of clinical deficit; of patients with severe deficits, one-third has excellent recovery, one-third has persistent moderate deficits, and
one-third has poor outcomes; outcomes tend to be worse
in patients with NMO or myelitis associated with connective tissue disease.
Neuromyelitis Optica (NMO)
Characterization: Historical — early reports describe nonrelapsing bilateral optic neuritis and myelitis; mortality
associated with respiratory failure; patients with relapsing
demyelinating disease considered to have MS, not NMO;
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later recognized that relapsing optic neuritis and myelitis
could constitute NMO; contemporary — in 1990s, clinicians observed that patients with severe relapsing optic
neuritis and myelitis and normal findings on MRI often
had long lesions on spinal cord; later discovered that
most patients seropositive for autoantibody to aquaporin-4 (AQP4); long intervals may occur between relapses;
monophasic NMO defined as optic neuritis and myelitis
without additional symptoms.
Current diagnostic criteria: Requires optic neuritis, myelitis, and two of the following three findings: (1) positive
test for AQP4 autoantibodies, (2) spinal cord lesion extending over ≥3 segments, and/or (3) normal findings on
brain MRI at initial presentation (but brain lesions may
develop later in disease process).
NMO spectrum disorder: Patients have recurrent episodes
of transverse myelitis or optic neuritis and are seropositive for antibody to AQP4; also includes patients with
medullary lesions in the area postrema, associated with
intractable nausea and vomiting (initial presentation in
≈20% of patients with NMO).
Pathophysiology of NMO: Evidence that AQP4 is primary
effector — (1) patients (including those with severe clinical deficits) respond well to plasma exchange; (2) location
of AQP4 proteins (in astrocyte foot processes that abut
blood vessels) consistent with perivascular inflammation;
(3) brain lesions in NMO seem to occur selectively in
areas with high immunoreactivity for AQP4; (4) in vitro
studies show that, in setting of AQP4 expression, presence of AQP4 antibody and complement result in activation of complement and cell death; (5) passive transfer of
immunoglobulin produces pathology similar to that seen
in NMO; T-cell involvement — IgG1 antibodies, including AQP4 autoantibody, requires recognition by T-cells,
but specific mechanism unknown.
Necrosis: Complement seems to mediate pathology in
necrotizing lesions; different effector mechanisms probably operate in non-necrotizing brain lesions.
Demyelination: Paroxysmal tonic spasms result from
cross-talk between demyelinated axons; mechanism
of demyelination may involve loss of glutamate transporter EAAT2; astrocyte foot processes (site of AQP4
proteins) abut nodes of Ranvier; emerging evidence that
nodes of Ranvier may be important sites for initiating
demyelination.
Diagnosis: Clinical indicators — optic neuritis; myelitis;
intractable nausea and vomiting; narcolepsy (rare); hypersomnolence and encephalopathy, typically associated
with low levels of hypocretin in CSF; demography —
NMO more common in black and Hispanic populations
but should not be excluded in other populations; MRI indicators — long lesion on spinal cord; normal brain MRI
supports diagnosis of NMO; AQP4 antibody assay — sen-
August 21, 2013
sitivity 70%; highly specific, but false-positives occur occasionally; assay typically performed with serum (lower
sensitivity using CSF); useful to retest seronegative patients with clinical signs and symptoms consistent with
NMO.
Management: Acute — IV methylprednisolone; plasma
exchange if patient unresponsive to corticosteroids; preventing recurrence — interferon-β and natalizumab ineffective (possibly associated with harm); best evidence for
efficacy with azathioprine, mycophenolate mofetil, and
rituximab; no comparative efficacy studies available, but
these agents appear to reduce frequency of recurrence by
80%; important to prevent recurrence because attacks often devastating.
Prognosis: Early diagnosis and management has resulted in
significantly improved prognosis; many patients experience no relapses for 5 to 10 years; most disability associated with NMO results from acute attacks, so preventing
attacks greatly improves outcomes.
Comorbid autoimmune disease: Present in ≈25% of patients with NMO; Sjögren syndrome and lupus common;
myasthenia gravis may develop before or (less commonly) after NMO; conditions presumed to co-occur rather
than having shared etiology.
Unusual Symptoms and Syndromes in
Multiple Sclerosis
Alexander D. Rae-Grant, MD, Cleveland, OH
Lhermitte sign: Flexion of neck results in electrical sensation (lasting seconds) in limbs or other body parts; less
commonly triggered by neck extension or other movements; relatively common symptom early in MS, and
generally does not persist for long periods; positive sign
typically correlates with presence of lesions on cervical
segments of spinal cord (typically dorsal); also occurs in
other diseases affecting cervical spine; mechanism — sensation probably results from demyelinated nerve fibers
being pulled across each other, resulting in a short circuit;
active inflammation not required.
Pulfrich phenomenon: Occurs in patients with history of
optic neuritis or other condition affecting only one eye;
results from disparity in visual acuity between eyes; when
observing moving objects, patient perceives them as moving in strange ways (eg, objects “jump at them”); simulation — effect can be simulated in individuals with normal
vision by covering one eye with light-attenuating filter.
Management: If phenomenon causes distress or impaired
function, it may be reduced by using a density filter (on
glasses or contact lens) on unaffected eye.
Uhthoff phenomenon: Occurs in ≈25% of patients with
history of optic neuritis; patient reports blurred vision
upon exercise or increased body temperature; also may
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occur in eg, heightened emotional settings or during menstruation; mechanism — blurred vision does not represent
injury (important to reassure patient); electrical phenomenon results from reduced effectiveness of neural transmission through demyelinated fibers, especially when
temperature increases.
Management: Reassure patient that phenomenon does not
represent injury or new flare; if triggered by heat or exercise, counsel patient to reduce core body temperature
(eg, by drinking icy beverage) or cool eyes with gel ice
pack before exercising.
Useless hand of Oppenheim: Patients report loss of function in hand or arm, but motor strength appears normal;
phenomenon typically related to sensory deficit (eg, impaired sense of position or vibration) and often correlated
to presence of demyelinating plaques on cervical segments of spinal cord (dorsal).
Transient paroxysmal neurologic events: Neurologic
symptoms that last seconds to minutes and may occur
many times each day; often occur early in MS (may be
presenting symptom); symptoms include numbness, tingling, visual disturbances, weakness, imbalance (potentially resulting in falls), and dysarthria; symptoms may
occur in combinations, stereotypic for each patient; etiology — symptoms typically occur in setting of acute exacerbation but also may occur without inflammation (exact
mechanism unknown); in setting of acute relapse, additional neurologic signs and symptoms typically occur;
phenomena do not constitute epileptic event.
Examples: Tonic spasms — tonic (often painful) tightening of limbs; symptom correlates with corticospinal
tract deficit; paroxysmal dysarthria — sudden onset of
slurred speech or inability to speak.
Thermoregulatory disorders in MS: Associated with lesions in anterior hypothalamus; phenomenon typically
occurs later in disease process.
Hypothermia: Patients may report feeling better when
mildly hypothermic (≈35°C [95°F] to 36°C [96.8°F]);
more severe hypothermia (≥31°C [87.8°F]) often associated with exacerbation of symptoms or episode of
decreased responsiveness (occasionally coma); management — anecdotal reports of improvement with
August 21, 2013
high-dose IV thiamine and, in one case, worsening of
symptoms when thiamine withheld and again improving when thiamine subsequently resumed; pathophysiology possibly similar to that seen with Wernicke
encephalopathy.
Hyperthermia: Unexplained episodes of hyperthermia;
less common than hypothermia; reports of symptom exacerbation during eg, hot bath, after which symptoms
persist; prevention — preventive cooling measures more
important before intense exercise and in heat-sensitive
patients.
Epilepsy and MS: Prevalence of epilepsy higher in patients
with MS (3% to 4%) than in general population; some
evidence of increased risk in patients with more progressive forms of MS; mechanism — MS can affect cortex,
but cortical lesions difficult to see on standard MRI (because of composition of cortical tissue); newer techniques
improve yield, but visualization remains suboptimal; focal lesions shown to correlate with epilepsy focus.
Management: Antiepilepsy agents — selection based in
part on type of seizure (focal vs generalized); carbamazepine associated with exacerbations in MS symptoms;
animal studies suggest that phenytoin may increase rate
of demyelination.
Sleep events in MS: 95% of patients with MS report significant fatigue; in some patients, nonrestorative sleep responsible for fatigue.
Syndromes: Common conditions include restless legs
syndrome, syndrome of periodic limb movements, and
obstructive sleep apnea; less commonly, REM sleep behavior disorder; rare conditions include narcolepsy and
Kleine-Levin syndrome; narcolepsy — more common in
teens; may be caused by hypocretin deficiency related to
MS lesions of hypothalamus; Kleine-Levin syndrome —
typically presents during adolescence; characterized by
excessive sleep and odd behaviors persisting for days
to weeks.
Diagnosis and management: Important to inquire about
sleep and, when possible, interview sleep partner; review medications; screen for sleep-related disorders and
for depression; refer for sleep study when indicated.
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Suggested Reading
Acute Disseminated Encephalomyelitis, Transverse Myelitis, and Neuromyelitis Optica
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple
sclerosis. Lancet 2004;364(9451):2106–2112.
Misu T, Fujihara K, Kakita A, et al. Loss of aquaporin 4 in lesions in neuromyelitis optica: distinction from multiple sclerosis.
Brain 2007;130(pt 5):1224–1234.
Wingerchuk DM, Weinshenker BG. Acute disseminated encephalomyelitis, transverse myelitis, and neuromyelitis optica.
Continuum (Minneap Minn) 2013;19(4).
Unusual Symptoms and Syndromes in Multiple Sclerosis
Chitnis T. Unusual symptoms and syndromes in multiple sclerosis. Continuum (Minneap Minn) 2013;19(4).
Test on Next Page
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Volume 02, Issue 16
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Multiple Sclerosis — Part 4
Complete pretest before listening and posttest after listening. To test online, go to www.audiodigest.org/onlinetesting
1. Which of the following features is most useful for distinguishing between acute disseminated encephalomyelitis (ADEM) and
multiple sclerosis (MS)?
(A) diffuse encephalopathy **
(C) oligoclonal bands on CSF analysis
(B) history of viral infection
(D) pleocytosis present in CSF
2. Which of the following statements best describes the pattern of demyelination that occurs in ADEM?
(A) extensive confluent lesions restricted to the brain
(B) longitudinally extensive lesions of the spinal cord
(C) narrow sleeves of perivenous lesions in the CNS **
(D) periventricular and juxtacortical lesions
3. A 30-year-old woman diagnosed with partial transverse myelitis does not respond to IV methylprednisolone. Which of the following
treatments should be used as second-line therapy?
(A) interferon-β
(C) plasma exchange **
(B) IV immunoglobulin
(D) rituximab
4. Which of the following findings is most specific to neuromyelitis optica (NMO)?
(A) autoantibodies to aquaporin-4 membrane protein **
(B) hypothalamic lesions
(C) nausea and vomiting
(D) spinal cord lesion extending over two or more segments
5. A 52-year-old woman experienced progressive truncal and bilateral lower extremity numbness over 9 days. Upon history and
examination, evidence suggests a previous optic neuritis and a current episode of myelitis. MRI reveals an active longitudinally
extensive transverse myelitis lesion. Brain MRI is normal. She is seropositive for aquaporin-4 antibodies. The presentation and
findings are most consistent with which of the following conditions?
(A) ADEM
(C) neuromyelitis optica (NMO) **
(B) multiple sclerosis
(D) Partial transverse myelitis
6. Which of the following statements best describes the approach to long-term management of NMO?
(A) because attacks of NMO can be devastating, use of an effective preventive agent is very important **
(B) comparative efficacy studies clearly show that rituximab therapy is associated with the lowest rate of relapse
(C) interferon beta-β and natalizumab are considered first-line therapies for preventing recurrence of NMO
(D) IV methylprednisolone, administered during acute relapses, is sufficient for preventing most disability associated with
NMO
7. Within 2 years after being diagnosed with MS, a 24-year-old man reports experiencing electrical sensations down his spine and
along the length of his arms upon neck flexion. This is known as:
(A) Lhermitte sign **
(C) Spurling sign
(B) Pulfrich phenomenon
(D) Uhthoff phenomenon
8. Uhthoff phenomenon can sometimes be prevented by:
(A) avoiding hypothermia
(B) reducing temperature of the eyes and/or the body core before exercising **
(C) treatment with interferon-β or natalizumab
(D) using a light-attenuating filter over the affected eye
9. Which of the following phenomena is most typically associated with the presence of demyelinating plaques on cervical segments
of the dorsal spinal cord?
(A) paroxysmal dysarthria
(C) Uhthoff phenomenon
(B) Pulfrich phenomenon
(D) useless hand of Oppenheim **
10. For which of the following antiepileptic drugs is there some evidence to suggest that they should be avoided in patients with
comorbid epilepsy and MS?
(A) carbamazepine and phenytoin **
(C) lamotrigine and zonisamide
(B) clonazepam and phenobarbital
(D) levetiracetam and topiramate
Answers to the previous issue of Continuum Audio (Volume 02, Issue 15): 1-A, 2-C, 3-B, 4-B, 5-B, 6-D, 7-A, 8-B, 9-C, 10-A
C 2013 American Academy of Neurology P 2013 Audio-Digest Foundation • ISSN 2168-2666 • www.audiodigest.org
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