-
Acute DisseminatedEncephalomyelitis,Transverse Myelitis,
andNeuromyelitis Optica
Dean M. Wingerchuk, MD, MSc, FRCP(C), FAAN;Brian G. Weinshenker,
MD, FRCP(C), FAAN
ABSTRACTPurpose of Review: This review defines current clinical
criteria for diagnosis,differential diagnosis, and clinical
evaluation of acute disseminated encephalomy-elitis, transverse
myelitis, and neuromyelitis optica, and summarizes principles
oftreatment.Recent Findings: Consensus criteria for transverse
myelitis and acute dissemi-nated encephalomyelitis have been
proposed. A specific biomarker, aquaporin-4autoantibody, has been
discovered for neuromyelitis optica that allows for early
andaccurate diagnosis even in the absence of cardinal findings of
optic neuritis andmyelitis.The antibody is pathogenic and is
facilitating an understanding of the pathophysiologyof
neuromyelitis optica and development of antigen-specific
treatments.Summary: Clinical and radiologic findings combined with
serologic findings maypermit classification of syndromes of
transverse myelitis and acute disseminatedencephalomyelitis in ways
that may predict risk of relapse, type of relapse, andprognosis.
Treatment, especially to prevent relapse, is dependent on the
specificdisease context in which syndromes such as transverse
myelitis occur.
Continuum (Minneap Minn) 2013;19(4):944967.
INTRODUCTION: SYNDROMEVERSUS DISEASEThe nosology of
demyelinating dis-eases of the CNS is complex. Multiplesclerosis
(MS) has been an umbrellaterm for recurrent inflammatory dis-ease
of the CNS after definable non-demyelinating mimics are
excluded.Acute disseminated encephalomyelitis(ADEM), transverse
myelitis, and neu-romyelitis optica (NMO) are inflamma-tory
conditions that have not beenwell distinguished from MS or
itspresenting syndromes (termed clini-cally isolated
[demyelinating] syn-dromes) but are linked by theirtendency to
relapse and remit and by
their inflammatory characteristics andoverlapping pathology.
Distinction between syndromesthat reflect localization (eg,
optic neu-ritis and transverse myelitis) and dis-ease entities (eg,
ADEM, MS, and NMO)is now feasible. Distinction is importantbecause
of the prognostic and treat-ment implications of different
diseaseentities. For example, transverse myeli-tis refers to a
syndrome of acute orsubacute myelopathy accompanied byindicators of
inflammation, either ra-diologically or based on spinal fluid.
Itmay occur as a stand-alone syndrome, acomponent of ADEM, a
relapse of MS orNMO, or a nondemyelinating syndrome
Address correspondence toDr Brian G. Weinshenker,Department of
Neurology,Mayo Clinic, 200 First St SW,Rochester, MN
55905,[email protected].
Relationship Disclosure:Dr Wingerchuk receivesresearch support
fromAlexion, Genentech,Genzyme Corporation,Guthy-Jackson
CharitableFoundation, and Terumo BCT,Inc. Dr Weinshenker serveson
the data and safetymonitoring board of BiogenIdec and Novartis and
servesas a consultant regardingneuromyelitis opticatherapeutics for
Asahi KaseiMedical Co, Ltd, ElanCorporation, and Novartis.Dr
Weinshenker receivesroyalties for licensedtechnology for the
diagnosisof neuromyelitis optica fromRSR Limited, and
receivesresearch funding fromGuthy-Jackson
CharitableFoundation.
Unlabeled Use ofProducts/InvestigationalUse Disclosure:
DrsWingerchuk and Weinshenkerdiscuss the unlabeled uses
ofcorticosteroids and plasmaexchange for the treatmentof acute
disseminatedencephalomyelitis, transversemyelitis, and
neuromyelitisoptica; IV immunoglobulinfor acute
disseminatedencephalomyelitis; andazathioprine,
mycophenolatemofetil, rituximab,mitoxantrone, methotrexate,and
eculizumab forneuromyelitis optica.
* 2013, American Academyof Neurology.
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Review Article
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such as an infectious myelitis or agranulomatous myelitis. If
due to her-pes virus infection, it is best treated withantiviral
treatment; if indicative of arelapse or harbinger of MS, an
MSimmunomodulatory treatment may beappropriate; if a relapse of
NMO, animmunosuppressive drug, such as aza-thioprine, would be
appropriate,whereas interferon-" or natalizumabmay actually be
deleterious. Noninfec-tious and noninflammatory disorders,such as
arteriovenous fistula, mayproduce syndromes suggestive oftransverse
myelitis but would requireentirely different treatment.
ADEM, as currently defined, is char-acterized by acute
encephalopathy butfrequently accompanied by optic neuri-tis or
transverse myelitis. NMO is thefirst inflammatory demyelinating
condi-tion to be defined, in part, by a bio-marker that is molding
our evolvingconcept of this condition (an auto-immune
aquaporinopathy) and ex-panding the spectrum of the diseaseto
include nonYoptic nerve and spinalcord syndromes and
MRI-detectedbrain lesions that, in the past, wouldhave excluded a
diagnosis of NMO.
Understanding of the distinction andinterrelationships of these
syndromeshas been facilitated by insights into thepathophysiology,
informed by the neu-ropathology, and illustrated by ad-vances in
NMO over the past decadeas outlined below.
ACUTE DISSEMINATEDENCEPHALOMYELITISAlthough a number of
definitions havebeen proposed for ADEM, it remains apoorly defined
syndrome of symptom-atic diffuse or multifocal CNS inflam-mation
that is typically, if not always, amonophasic illness. ADEM has
beenhistorically regarded as the clinicalcounterpart of the
experimental dis-ease experimental autoimmune en-
cephalomyelitis. ADEM is also knownas postvaccinal
encephalomyelitiswhen it follows vaccination. Accord-ingly, it is
believed to be induced byan immune reaction directed at
across-reacting myelin antigen. Itssomewhat unique pathology
ofperivenous sleeves of inflammationand demyelination has been
recog-nized for decades but has been re-cently rediscovered and
expanded.1
Pathologically, ADEM can be distin-guished from fulminant acute
MS,which is a major consideration in thedifferential diagnosis.
Acute MS isassociated with confluent demyelin-ation and prominent
macrophagesadmixed with reactive astrocytes.When cases are
identified based onpathologic features, these featuresseem to be
associated with some ofthe key clinical characteristics that
havebeen identified in consensus clinicaldiagnostic criteria (Table
3-12) to dis-tinguish ADEM from MSVin particular,encephalopathy.1
Pathology has re-cently been proposed as the refer-ence standard to
distinguish ADEMfrom fulminant MS, although this hasnot been widely
debated and cannotbe considered as generally accepted atthe present
time. Consensus criteria2
remain imperfect in distinguishing pa-tients who, in the course
of follow-up,will remain free of future relapses.Furthermore,
consensus criteria allowfor recurrent and even multiphasicADEM
episodes with criteria that mightdistinguish it from MS (ie, a
newepisode must also meet the criteriafor ADEM and not be those of
anattack of MSVsee Table 3-1). Contro-versy persists about whether
relapsesmay occur in ADEM and remain con-sistent with the diagnosis
of ADEM,especially in adult patients.
The key clinical features requiredfor a diagnosis of ADEM
includediffuse encephalopathy but may also
KEY POINTS
h Distinguishing betweensyndromes (eg, opticneuritis and
transversemyelitis) and diseaseentities (multiplesclerosis,
neuromyelitisoptica, and acutedisseminatedencephalomyelitis)is
vital. Demyelinatingsyndromes may be acomponent of
differentdiseases and mayhave vastly differentprognoses dependingon
the disease context(and may thereforerequire
differenttreatment).
h Although the proposedconsensus criteria foracute
disseminatedencephalomyelitisallows for recurrent ormultiphasic
formsof the disease, theexistence of relapsingforms
remainscontroversial. Acriterion standardfor distinguishingacute
disseminatedencephalomyelitisfrom multiple sclerosishas not been
widelyaccepted, althoughpathology has beenproposed.
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include other symptoms characteristicof an inflammatory
demyelinating dis-ease, such as optic neuritis or trans-verse
myelitis, including transversemyelitis associated with
longitudinallyextensive lesions. Clinical features mayinclude
seizures or coma; coma ishighly suggestive of ADEM in the
appropriate setting of extensive whitematter disease (Case 3-1).
MRI usuallyshows multiple lesions, although asingle large lesion is
still felt to becompatible in the consensus criteria.Usually,
cerebral lesions occur in bothcerebral hemispheres in ADEM.3
In-volvement of the deep gray matter is
TABLE 3-1 International Pediatric Multiple Sclerosis Study Group
Consensus Definitionsa
b Monophasic Acute Disseminated Encephalomyelitis (ADEM)
A first clinical event with a presumed inflammatory or
demyelinating cause
Acute or subacute onset that affects multifocal areas of the
CNS
Polysymptomatic and must include encephalopathy, including one
or more of the following:
Behavioral change (confusion, irritability)
Alteration in consciousness (lethargy, coma)
Postevent improvement clinically, on MRI, or both; residual
deficits permitted
No prior clinical episode consistent with demyelinating
event
No other etiologies apparent
New or fluctuating symptoms, signs, or MRI findings occurring
within 3 months of the inciting ADEMevent permissible
Brain MRI (T2-weighted) with focal or multifocal supratentorial
or infratentorial lesions, often large (1 to2 cm), predominantly
involving white matter, but frequently present in gray matter
(especially basalganglia or thalamus), without evidence of previous
destructive white matter changes; brain MRI showinga single large
lesion (1 to 2 cm), predominantly affecting white matter also
possible, although rare
Spinal cord MRI may have confluent intramedullary lesion(s) with
variable enhancement, in addition toabnormal brain MRI findings
specified previously
b Recurrent ADEM
Recurrence of the initial symptoms and signs of ADEM 3 or more
months after the first event
No new lesions based on history, examination, or
neuroimaging
Event does not occur while on corticosteroids and occurs at
least 1 month after completing therapy
MRI shows no new lesions; original lesions may have enlarged
No better explanation exists
b Multiphasic ADEM
New clinical event also meeting criteria for ADEM but involving
new anatomic areas of the CNS asconfirmed by history, neurologic
examination, and neuroimaging
Subsequent event must occur:
At least 3 months after the onset of the initial ADEM event
At least 1 month after completing steroid therapy
Subsequent event must be a polysymptomatic presentation,
including encephalopathy, with neurologicsymptoms or signs that
differ from the initial event (mental status changes may not differ
from theinitial event)
Brain MRI shows new areas of involvement and complete or partial
resolution of prior ADEM-associatedlesion
a Modified with permission from Krupp LB, et al; International
Pediatric MS Study Group, Neurology.2 B 2007, American Academyof
Neurology.
www.neurology.org/content/68/16_suppl_2/S7.short?sid=d000124e-c5a6-4744-a896-c2c5cfcc4545.
946 www.ContinuumJournal.com August 2013
ADEM, Transverse Myelitis, and NMO
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not uncommon and is more com-monly observed in ADEM than in
MS(Figure 3-2).4 Lesions may also bepresent in the optic nerves and
spinalcord. A key exclusionary criterion islack of clinical or
radiologic evidenceof prior CNS pathology that wouldindicate
previous inflammatory de-myelination. Typically, CSF pleocytosisis
present.
ADEM is more common in childrenthan adults, and diagnosis can
bemade with greater confidence whenit follows an acute infectious
illness orvaccination in a child or an adult. Abroad differential
diagnosis of acute
leukoencephalopathies exists that mayproduce similar features
(Table 3-2).5
Clinical and radiologic clues are im-portant in distinguishing
ADEM fromother mimics. Investigations should betargeted to specific
suspected compet-ing diagnoses based on demographic,neurologic, and
non-neurologic symp-tomatology and radiologic clues.
The diagnosis of ADEM remainsone of exclusion of other
competingdiagnoses and monitoring of treat-ment response and
clinical courseVinparticular, whether remission occursspontaneously
or after corticosteroidtreatment and whether relapse occurs.
Case 3-1A 30-year-old woman with no antecedent illness or
vaccination presented with headaches andmigratory numbness. Four
days later she reported nausea and was confused, asking the
samequestion repetitively. She developed gaitunsteadiness, followed
within a week byparaplegia and later by paresis of herarms.
Examination revealed that she wassomnolent but opened her eyes
aftervigorous stimulation. She had bilateralpapilledema, moderate
upper extremityparesis, and plegia of the lower
extremities.Bilateral Babinski signs and spasticity werepresent.
MRI scan of the brain showedextensive white matter lesions (Figure
3-1).CSF analysis revealed 30 white blood cells(WBC)/2L, primarily
mononuclear; elevatedprotein level of 200 mg/dL, and
negative/normal results for IgG index and oligoclonalbands. In
spite of high-dose corticosteroids,she continued to deteriorate and
developedmultiple new lesions of the cerebralhemispheres and
brainstem, as wellas a herniation syndrome. Pathologicanalysis
revealed evidence of perivenousdemyelination consistent with
acutedisseminated encephalomyelitis (ADEM).
Comment. This case illustrates howfulminant a course ADEM may
take in certainindividuals and how it may cause cerebralherniation.
FIGURE 3-1 T2-weighted axial brain image shows
multiple lesions of varying size scatteredthroughout the
subcortical and deep cerebralwhite matter.
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Relapse is a strong indicator that adiagnosis of ADEM was
incorrect, al-though, as noted above, pediatric con-sensus criteria
do not consider arelapse as a strict exclusionary charac-teristic.
The radiologic characteristicsof ADEM are nonspecific. In the
major-ity of patients, they are difficult todistinguish from those
seen in MS,although extensive and symmetric ce-
rebral, cerebellar, and basal gangliaabnormalities have been
reported. Se-rial follow-up in ADEM does not revealnew MRI
findings, but this observationcan only be made retrospectively.
CSFfindings are similarly nonspecific. Ele-vations of IgG index or
the presenceof oligoclonal bands are usually absent,or when
present, are transient. WhenADEM is strongly suspected and no
FIGURE 3-2 Acute disseminated encephalomyelitis in a child.
Fluid-attenuated inversion recovery (FLAIR) axialimages at the
level of basal ganglia and pons (A, C) and T1-gadolinium axial
images at the samelevels (B, D). Note the mostly symmetrical,
thalamic gray matter T2 hyperintensity with minimal
gadolinium enhancement as well as the bilateral, though
asymmetrical, middle cerebellar peduncle T2hyperintensity with
prominent gadolinium enhancement.
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ADEM, Transverse Myelitis, and NMO
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other competing diagnosis seemslikely or is detected after a
comprehen-sive evaluation, a therapeutic trial ofcorticosteroids
should be administered.Generally, the course of
corticosteroidsshould be initiated within a short time,typically
within a few days, becausepatients with ADEM are often very ill.In
patients with clinical deterioration inspite of treatment with
high-dose corti-costeroids, a brain biopsy should beconsidered,
which can evaluate for bothADEM and other diagnoses.
The hallmark pathologic character-istic for ADEM is perivenous
demye-lination, typically distributed in sleevessurrounding areas
of perivascular in-flammation (Figure 3-3). This patho-logic
picture is distinct from MS,which features confluent
demyelination,prominent and confluent macrophageinfiltration, and
reactive astrocytes.1
Recently, a distinctive microglial acti-vation and aggregation
without corti-cal demyelination similar to that seenin MS has been
observed in patients
TABLE 3-2 Selected Acute Leukoencephalopathies That Mimic Acute
DisseminatedEncephalomyelitis and Investigations
Condition Index of Suspicion Initial TestsConfirmatoryTests
Neurosarcoidosis Extra-CNS disease Serum and CSF
angiotensin-converting enzyme level
CNS or non-CNSbiopsyPersisting enhancement
on brain MRI Brain and spinal cord MRIs withand without
contrast
Imaging for pulmonary disease
Vasculitis Extra-CNS disease Sedimentation rate CNS or
non-CNSbiopsyResidual infarcts Vasculitis panel
(myeloperoxidase,
proteinase 3)
Angiography
Progressive multifocalleukoencephalopathy
Immunosuppressedindividual
CSF PCR for JC virus CNS biopsy
Natalizumab treatmentMRI sometimes sequential
HIV infection
Gliomatosis cerebri History of brain tumor Brain MRI with and
withoutgadolinium
CNS biopsy
CNS lymphoma Prior immunosuppression CSF cytology CNS biopsy
Homogeneous, nodularenhancement
Multifocal tumor
Posterior reversibleencephalopathysyndrome
Risk factor (eg,hypertension, cyclosporine)
Brain MRI with and withoutgadolinium
Follow-up MRI
No gadoliniumenhancement
Imaging may change rapidly
Indistinct boundaries
Paraneoplastic disorder History of cancer Paraneoplastic
antibody CNS biopsy
Erdheim-Chester disease Bone pain X-ray of long bones CNS or
non-CNSbiopsyExophthalmos
Diabetes insipidus
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with ADEM, which was highly associ-ated with coma.1
The prognosis of ADEM is highlyvariable and depends in large
part onthe accuracy of the diagnosis, whichhas been poor in the
existing literaturebecause of the lack of a specific di-agnostic
test and the rarity with whichbiopsy is obtained to differentiate
fromfulminant MS or other acute leuko-encephalopathies. Therefore,
firmguidance for patients and their familiesregarding prognosis is
difficult. Ingeneral, the outcome in definite ADEMis favorable if
the course is not compli-cated by supervening complications(eg,
sequelae of status epilepticus),because demyelination and acute
axo-nal pathology is usually less severe thanother fulminant
inflammatory disor-ders such as Marburg variant MS (anacute,
monophasic form of MS thattypically leads to death from a
hernia-tion syndrome or brainstem dysfunc-tion within days or weeks
from onset).
No randomized clinical trials ofADEM have been conducted.
Thestandard of treatment based on em-pirical studies is high-dose
IV cortico-steroids, typically administered at 1 g/d(in children
10Y30 mg/kg/d) for 5 daysfollowed by a taper of oral prednisoneover
3 to 6 weeks. Plasma exchange iseffective in acute, severe
demyelinating
diseases of a variety of types, althoughvery limited experience
is available forADEM. IV immunoglobulin and otherimmunosuppressive
agents similarlyhave been supported in case reportsand small
series.6,7
TRANSVERSE MYELITISThe term transverse myelitis de-scribes a
heterogeneous collection ofacute and subacute infectious
andnoninfectious inflammatory spinalcord syndromes. Cases of
myelitiswere first described in the 19th cen-tury. Inflammatory
demyelination wasrecognized as the underlying pathol-ogy in fatal
postvaccinal encephalomy-elitis (smallpox and rabies vaccines)
inthe 1920s. The annual incidence ofpostinfectious or idiopathic
forms oftransverse myelitis is estimated to be1.3 to 8 cases per
million population.8
When MS myelitis is included, theannual incidence approaches 25
permillion. Modern diagnostic neuroim-aging, CSF analysis, and
laboratorytechniques enable a specific diagnosisand prognosis in
most cases of trans-verse myelitis.
The consensus inclusion criteriafor diagnosis of idiopathic
transversemyelitis is outlined in Table 3-3 andincludes the
clinical features commonto all potential etiologies of
myelitis.9
KEY POINT
h Acute disseminatedencephalomyelitis isassociated
withperivenous sleeves ofdemyelination andperivascular
inflammation,rather than confluentdemyelination andmacrophages
andreactive astrocytes, as inacute multiple sclerosis.
FIGURE 3-3 Representative brain biopsies illustrating the
observed patterns of demyelination that may be found in
patientswith clinically defined acute disseminated
encephalomyelitis. A, Perivenous sleeve of inflammation
anddemyelination (20); B, Three coalescing perivenous lesions (60);
C, Extensive region of confluentdemyelination with areas of
perivenous demyelination in the periplaque white matter (4). Luxol
fast bluemyelin stain and periodic acidYSchiff counterstain was
used for all three images.
Reprinted with permission from Young NP, et al Brain.1 B 2010,
Guarantors of Brain.
brain.oxfordjournals.org/content/133/2/333.long.
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ADEM, Transverse Myelitis, and NMO
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Most patients present with a combina-tion of sensory, motor, and
bladder-or bowel-related symptoms suggestiveof myelopathy.
Lhermitte sign (anelectrical or dysesthetic sensation inthe spine
or limbs, elicited by neckflexion) and paroxysmal tonic
spasms(repeated, brief [30- to 90-second],stereotypic attacks of
painful limb ortruncal muscle spasms, with or withoutsensory
symptoms, often triggered bylimb movement) are hallmarks of
de-myelinating disease and suggest thatthe myelitis syndrome may be
causedby MS or NMO.
Transverse myelitis is classified clin-ically based on whether
it is completeor incomplete, which may assist withdifferential
diagnosis.10 A completecord lesion, which manifests as arelatively
symmetric moderate or se-vere loss of motor and sensory mo-dalities
caudal to the level of thelesion, suggests a monophasic
disorder(infectious, parainfectious, or idiopath-ic transverse
myelitis) or relapsingNMO. In contrast, a partial myelitissyndrome
(ie, incomplete or patchyinvolvement of at least one spinalsegment
with mild to moderate weak-
ness and asymmetric or dissociatedsensory symptoms) is more
likely toherald MS with high risk for futurerelapses.11
Nonetheless, the clinicalpresentation may not be concordantwith
neuroimaging findings, which arelikely more reliable than clinical
man-ifestations in determining the underly-ing etiology. MS-related
myelitis isusually characterized by short-segment,peripheral cord
lesions, whereas NMOis strongly associated with a longitudi-nally
extensive transverse myelitis(LETM) lesion that extends
contiguouslyover three or more vertebral segments(seen best on
sagittal T2-weighted MRI)and usually affects the central
cord(Figure 3-4).12 However, other diseases(including infarction,
viral and otherinfections, syringomyelia, and sarcoid-osis) can
cause a long cord lesion inthe central cord that mimics LETM.13
The differential diagnosis of trans-verse myelitis is extensive
and summa-rized in Table 3-4. Figure 3-5 outlines asystematic
diagnostic approach, whichfocuses on establishing that the
mye-lopathy is inflammatory and thenidentifying a causative agent
or under-lying disease (Case 3-2).
KEY POINTS
h Transverse myelitis isclassified clinicallybased on whether it
iscomplete or incomplete,which may assist withdifferential
diagnosis.
h Neuromyelitis opticais strongly associatedwith a
longitudinallyextensive transversemyelitis lesion.
TABLE 3-3 Diagnostic Criteria for Transverse Myelitisa
b Development of sensory, motor, or autonomic dysfunction
attributable to thespinal cord.
b Bilateral signs and/or symptoms (although not necessarily
symmetric).
b Clearly defined sensory level.
b Exclusion of extra-axial compressive etiology by MRI.
b Inflammation within the spinal cord demonstrated by CSF
pleocytosis orelevated IgG index or gadolinium enhancement. If none
of the inflammatorycriteria is met at symptom onset, repeat MRI and
lumbar puncture evaluationbetween 2 and 7 days later.
b Progression to nadir between 4 hours and 21 days following the
onset ofsymptoms.
a Modified with permission from Transverse Myelitis Consortium
Working Group, Neurology.9
B 2002, American Academy of Neurology.
www.neurology.org/content/59/4/499.short?sid=68d5cae0-275d-41e5-9a2b-9834280d8f5d.
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TABLE 3-4 Concise Differential Diagnosis and Evaluationfor
Transverse Myelitisa
Etiology Diagnostic Tests
Infection Blood serology
CSF culture, serologies, PCR
Chest radiograph; other imaging as indicated
Systemic autoimmune/inflammatory disease
Clinical examination findings
Serologic studies
Chest and joint radiographs
Other tests and/or imaging directed by historyand
examination
Paraneoplastic Chest radiography, CT, and/or body imaging
Comprehensive serum and CSF paraneoplasticantibody panel
Acquired CNS demyelinatingdisease (multiple
sclerosis/neuromyelitis optica)
Brain MRI with gadolinium
CSF examination for cell count/differential,oligoclonal bands,
and IgG index
Visual evoked potentials
Postinfectious orpostvaccinal
Clear, recent history of infection or vaccination
Serologic confirmation of recent infection
Exclusion of other causesa Data from Frohman EM, Wingerchuk DM,
N Engl J Med.10 www.nejm.org/doi/full/10.1056/NEJMcp1001112.
FIGURE 3-4 Spinal cord MRI in multiple sclerosis (MS) and
neuromyelitis optica. A, Sagittal T2-weighted MRI of the
cervicalspinal cord demonstrates typical dorsal, short-segment
signal abnormalities (arrows) characteristicof MS. B, In contrast,
patients with acute myelitis in the setting of neuromyelitis optica
typically have
longitudinally extensive, expansile, centrally located cord
lesions that may extend into the brainstem (arrows)
(sagittalT2-weighted cervical spinal cord MRI). C, On T1-weighted
sagittal MRI sequences, such acute lesions may be
hypointense(arrows), suggesting necrosis and cavitation, while
exhibiting enhancement with IV gadolinium administration
(arrowheads),indicative of active inflammation.
Reprinted from Wingerchuk DM, et al, Lancet Neurol.12 B 2007,
with permission from Elsevier.
www.thelancet.com/journals/laneur/article/PIIS1474-4422(07)70216-8/fulltext.
952 www.ContinuumJournal.com August 2013
ADEM, Transverse Myelitis, and NMO
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FIGURE 3-5 Diagnostic algorithm for acute myelopathies and
myelitis. A systematic approach to the evaluation ofacute
myelopathy syndromes allows for diagnosis of transverse myelitis
and its etiology.
MS = multiple sclerosis; NMO-IgG = neuromyelitis
opticaYimmunoglobulin G;TM = transverse myelitis.
Reprinted from Frohman EM, Wingerchuk DM, N Engl J Med.10 B
2010, with permission from Massachusetts MedicalSoceity.
www.nejm.org/doi/full/10.1056/NEJMcp1001112.
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Neuroimaging characteristics arecritical for diagnosis.
Identification ofan intramedullary cord lesion, espe-cially if it
exhibits postgadoliniumenhancement, is very helpful in sup-
porting a diagnosis of myelitis. Asdiscussed above, the lesion
pattern(short peripheral lesions versus longi-tudinally extensive
central lesions) of-fers substantial diagnostic guidance. In
Case 3-2A 52-year-old woman with a history of vitiligo and
hypothyroidism experiencedprogressive truncal and bilateral lower
extremity numbness over 9 days. She lostthe ability to walk and
developed urinary retention at day 14. Examinationrevealed
moderately severe paraparesis, a T8 sensory level, and
repetitive,involuntary, painful right lower extremity spasms each
lasting 30 to 40 seconds.MRI (Figure 3-6) revealed an active
longitudinally extensive transverse myelitis(LETM) lesion. Brain
MRI was normal, CSF showed a lymphocytic pleocytosis(44 white blood
cells/2L) but normal IgG index and no oligoclonal bands.Laboratory
testing revealed vitamin B12 deficiency (level 169 ng/L) with
positiveparietal cell antibodies, positive antinuclear antibody
(1:160), and positiveneuromyelitis optica (NMO)YIgG (aquaporin-4
antibody). Her spasms resolvedwithin 6 hours of receiving 200 mg
oral carbamazepine. She made a completeneurologic recovery after
corticosteroid infusions and vitamin B12 replacement.She was also
treated with mycophenolate mofetil with no evidence of recurrentCNS
disease 3 years later.
Comment. This case illustrates a first-ever attack of LETM;
aquaporin-4seropositivity denotes an NMO spectrum disorder with
high risk for relapse andneed for immunosuppression. The paroxysmal
tonic spasms are common inLETM and usually respond well to
carbamazepine therapy. The vitamin B12deficiency and positive
antinuclear antibody reflect coexisting systemicautoimmunity in the
context of NMO.
FIGURE 3-6 Sagittal thoracic spine MRI shows a longitudinally
extensive transverse myelitislesion (A, T2-weighted sequence) and
gadolinium enhancement (B, T1-weightedsequence).
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the setting of partial myelitis, detectionof brain MRI lesions
characteristic forMS (eg, periventricular, juxtacortical,or
posterior fossa lesions) stronglypredicts future conversion to MS.
Re-vised MS diagnostic criteria permit adiagnosis of MS in the
presence of acombination of gadolinium-enhancingand nonenhancing
white matter le-sions.14 Detection of CSF pleocytosissupports an
inflammatory etiology,and other tests on CSF, includingserology and
PCR, may establish aspecific inflammatory or infectiouscause. CSF
oligoclonal bands are anindependent predictive factor for
laterconversion to MS.15 No clinical, bio-logical, or MRI factor at
onset ispredictive of long-term disability. Labo-ratory studies for
viral, rickettsial, andother infectious diseases; serologic
test-ing; and selected cultures obtained atpresentation may be
informative underspecific circumstances. Autoimmuneserology should
be obtained, especiallyto detect aquaporin-4 (AQP4) anti-bodies
(also known as NMO-IgG)associated with NMO.11 Some non-infectious
inflammatory disorders re-quire systemic evaluation, such as
bodyimaging (eg, for sarcoidosis) or para-neoplastic antibody panel
for myelitisrelated to occult malignancy. Spinalcord biopsy should
be reserved forsituations in which there is concern fora
neoplastic, vasculitic, or other disor-der that has evaded
diagnosis and inwhich no other site presents a likelyinformative
biopsy target. Attentionhas recently been drawn to the sub-stantial
risk of further neurologic defi-cit complicating spinal cord biopsy
thatcan be eliminated by a positive testfor AQP4 antibodies in many
patientswith NMO.16
Up to half of myelitis events arepreceded or accompanied by an
identi-fiable viral illness, a clinical prodromesuggestive of
infection (eg, upper re-
spiratory tract syndrome or fever), ora vaccination. Because a
systemic in-fection or vaccination may trigger in-flammatory
neurologic events inpatients with underlying diseases suchas MS or
NMO, comprehensive diag-nostic evaluation is still indicated
be-fore concluding that the infection orvaccination is the primary
cause of themyelitis. A presumed diagnosis ofmonophasic
parainfectious, postinfec-tious, or postvaccinal transverse
myeli-tis may be appropriate when theworkup is negative,
recognizing itsinherent limitations. In one-third toone-half of
transverse myelitis cases, anextensive neurologic and medical
inves-tigation reveals no underlying cause ordisease, and the term
idiopathic trans-verse myelitis is applied. Patients inthis
category generally have a low riskof either recurrent myelitis or
otherdisorders such as MS or NMO.
Treatment of transverse myelitis de-pends on its etiology.10,11
Acute treat-ment of noninfectious myelitis includesa trial of IV
methylprednisolone (ie,1 g/d for 3 to 5 days), with an optionaloral
prednisone taper afterwards. Se-vere attacks that do not respond
wellto corticosteroids may improve with acourse of plasma exchange
(five toseven exchanges over 10 to 14 days).11
The need for plasma exchange wouldbe more common with NMO,
post-infectious, or idiopathic myelitis thanwith MS.
Immunomodulatory or immu-nosuppressive therapy is only indicatedif
the cause of myelitis poses significantrisk of relapse. MS
disease-modifyingtherapy is indicated after a single epi-sode of
myelitis in which MS is thelikely cause. AQP4 antibodyYpositiveLETM
is highly likely to relapse early(approximate 60% risk at 1 year),
andimmunosuppressive therapy is recom-mended (see section on NMO
treat-ment). Diagnosis of specific infections,connective tissue
diseases, vascular
KEY POINTS
h Spinal cord biopsyshould be reserved forsituations in which
thereis concern for a disorderrequiring pathologicdiagnosis,
especially ifprogressive neurologicdysfunction continuesdespite
therapy and noother site presents alikely informative
biopsytarget.
h Because a systemicinfection orvaccination maytrigger
inflammatoryneurologic events inpatients with underlyingdiseases
such asmultiple sclerosis orneuromyelitis
optica,comprehensivediagnostic evaluationis still indicated
beforeconcluding that theinfection or vaccinationis the primary
cause ofthe myelitis.
h Severe myelitis attacksthat do not respondwell to
corticosteroidsmay improve with acourse of plasmaexchange.
h Aquaporin-antibodyYpositive longitudinallyextensive
transversemyelitis is highlylikely to relapse early(approximately
60%risk at 1 year), andimmunosuppressivetherapy isrecommended.
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causes, or paraneoplastic disease mayrequire interventions such
as antiviralor other antimicrobial therapies, immu-nosuppression,
or detection and re-moval of the underlying malignancy,as
appropriate.
The prognosis for a patient toregain function after transverse
myeli-tis is highly dependent on its etiology.Partial cord
syndromes seen in MS aretypically mild to moderate in severityand
plateau after days to 2 to 4 weeks,and patients typically recover
well,although achievement of final recov-ery may take several
months. Patientswith complete cord syndromes mayalso recover, but
these syndromes aremore likely to result in substantialresidual
neurologic deficits. Overall,50% to 70% of patients achieve at
leastpartial recovery and ability to walk withor without
assistance. Neurologicfollow-up is required, particularly forthose
patients judged to be at high riskfor recurrent CNS disease.
NEUROMYELITIS OPTICAHistorical PerspectiveNMO was originally
recognized as aclinical syndrome characterized bybilateral optic
neuritis and severemyelitis that occurred in quick succes-sion.
Although recognized by severalauthors in the late 19th
century,Devics description of a single casewith neuropathologic
analysis and athesis by his student, Gault, capturedthe most
attention and led Acchiotteto propose the eponym Devic
dis-ease.17,18 The similarities betweenMS and NMO have been
recognized,and the potential differences were amatter of debate
until the 21st cen-tury. In general, most pre-1990
reportsemphasized the nonrelapsing natureof NMO and its tendency to
sparethe brain as key features differentiat-ing it from MS. Around
the same time,reports from Asia, especially Japan,described a
condition called optico-spinal MS, which had a higher fre-quency
compared to classic MS.Opticospinal MS, like its conven-tional MS
counterpart, was describedas a relapsing disorder, but was
differ-entiated from MS by virtue of itsfrequent and severe attacks
specifical-ly targeting the optic nerve and spinalcord and by
infrequent detection ofCSF oligoclonal bands. At that time,the key
differentiating feature be-tween opticospinal MS and NMO wasthe
temporal course: monophasic forNMO and relapsing for
opticospinalMS. In the late 20th century, severalgroups recognized
that the majority ofpatients with severe optic nerve andspinal cord
selective demyelinatingdisease in western countries typicallyhad a
relapsing course, blurring thedistinction between NMO and
opti-cospinal MS. Diagnostic criteria forNMO were proposed,
emphasizingspecific clinical, MRI, and CSF featuresthat appeared to
distinguish NMO
TABLE 3-5 Diagnostic Criteriafor NeuromyelitisOpticaa
b Optic Neuritis
b Acute Myelitis
b At Least Two of the ThreeSupportive Criteria Below:
Contiguous spinal cord MRIlesion extending over threeor more
vertebral segments(reliably assessed in thecontext of an acute
myelitis)
Brain MRI not meeting diagnosticcriteria for multiple
sclerosis
Neuromyelitis opticaYIgGseropositive status
a Adapted from Wingerchuk DM, et al,Neurology.22 B 2006,
American Academyof Neurology.
www.neurology.org/content/66/10/1485.short?sid=
c5435b8d-ac14-439a-9754-e244754ec58f.
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from MS. A landmark observation in2004 reported a high frequency
of aspecific autoantibody in both westernNMO and typical Japanese
opti-cospinal MS. One year later, theNMO autoantibody was found to
bespecific for AQP4.19 Later immuno-pathologic studies and passive
transferexperiments provided strong evi-dence for the pathogenic
nature ofthis autoantibody.20 At the presenttime, no clear
distinguishing charac-teristics between Asian opticospinalMS and
relapsing NMO have beendocumented.
Definitions and ClassificationThe most widely accepted
diagnosticcriteria were those proposed by in-vestigators at Mayo
Clinic originallyin 199921 and then revised in 2006(Table 3-5).22
The 1999 criteriapredated the novel biomarker. Fur-thermore, the
1999 criteria provedinsufficiently rigorous to distinguishNMO from
some cases of MS withnormal brain MRI scan at presentation.The
revised criteria in 2006 weresimplified and modified to include
anindependent criterion of AQP4 auto-antibody seropositivity,
although itsdetection was not required becauseof its imperfect
sensitivity. Respectinghistorical tradition and clinical
obser-vations at that time, those criteriarequire both optic
neuritis and trans-verse myelitis for diagnosis. At approx-imately
the same time, a variety ofclinical observations emerged in
pa-tients with otherwise definite NMOand in some patients who had
limitedsymptoms of NMO. These observa-tions suggested that an even
broaderspectrum of syndromes existed underthe NMO designation, such
as intrac-table vomiting and lesions (bothsymptomatic and
asymptomatic) ofthe circumventricular organs. These syn-dromes
sometimes preceded other,
more typical symptoms of NMO andwere associated with
AQP4-specificautoantibodies. Patients with NMOtypically present
with isolated trans-verse myelitis or unilateral optic neuri-tis.
They are frequently, if not usually,seropositive at initial
presentation. Toembrace these patients under a moregeneral rubric,
the term neuromyelitisoptica spectrum disorders was pro-posed to
comprise a group of patientswho probably had the same
biologicaldisorder even though they did notsatisfy the strict 2006
criteria.12 Aninternational panel is currently deter-mining the
syndromes that warrantinclusion under this rubric. Several ofthe
brain syndromes seem to be unitedby their tendency to target AQP4,
whichis identified either by MRI lesionsin AQP4-rich areas or
selective loss ofAQP4 demonstrated on brain biopsytissue.
NMO is currently classified as beingeither monophasic (nearly
simulta-neous bilateral optic neuritis and my-elitis with no
subsequent relapses) orrelapsing (usually, but not
always,presenting with unilateral optic neuri-tis or myelitis,
followed by relapsesthat can include either optic neuritisor
myelitis, or less frequently cerebralinvolvement). These subtypes
seem todiffer in important ways; the relapsingform is more commonly
associatedwith AQP4 autoantibodies and alsoaffects women and older
individualsmore commonly than the monophasicform.23 Some have
suggested that themuch less common monophasic formmay be a limited
form of ADEM.Familial cases have been reported butconstitute fewer
than 5% of cases.24
PathophysiologyNMO has been suspected to haveunique pathogenesis
and to be avasculocentric disease based on im-munopathologic
studies reported in
KEY POINTS
h The term neuromyelitisoptica spectrumdisorders includes
aseries of well-describedclinical and radiologicsyndromes
associatedwith aquaporin-4seropositivity.
h After an initialclinical presentationof a
neuromyelitisopticaYtypical clinicalsyndrome such asintractable
vomitingand hiccup, isolatedlongitudinally extensivetransverse
myelitis, oroptic neuritis, detectionof
aquaporin-4autoantibodiespredicts a high risk ofsubsequent
attacks.
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the early 2000s.25 The presence ofperivascular immunoglobulin
and acti-vated complement suggested ahumoral-mediated injury to an
antigenexpressed on or near microvessels.With the discovery of a
specific autoan-tibody, advances rapidly led to theidentification
of AQP4-specific anti-bodies that target extracellular domainsof
this protein. This targeting is partic-ularly avid when the protein
forms largeaggregates, as occurs when a certainlong AQP4 isoform
called M23 isexpressed. Although no active immuni-zation model has
yet been reported,numerous investigators have been ableto use
different passive transfer strate-gies when the blood-brain barrier
isdirectly bypassed (ie, by intracerebralinjection) or opened
either by concom-itant induction of T-cellYmediated ex-perimental
allergic encephalomyelitis26
or by injection of complete Freund ad-juvant.27 Lesions produced
by passivetransfer have many of the characteristicimmunopathologic
findings of NMO.AQP4-specific autoantibodies are ofIgG1 isotype and
are therefore believedto be dependent on T-cell help. Avariety of
studies support the impor-tance of T-helper 17 (Th17) cells in
thiscondition, including similar pathology(frequent neutrophilic
infiltration) toTh17-polarized experimental
allergicencephalomyelitis,28 elevated serumand CSF levels of
interleukin 6 (IL-6)29
(which is a potent inducer of Th17differentiation), elevated
levels of IL-17in CSF of NMO patients, and thepredilection of an
immunodominantresidue of AQP4 to induce a Th17-polarized
response.30
Clinical FeaturesThe dominant manifestations in mostpatients are
optic neuritis and myelitis.In a recent series of seropositive
pa-tients, the frequencies of specific pre-sentations were as
follows: 41% optic
neuritis, 43% myelitis, 5% brain orbrainstem presentations in
isolation,4% optic neuritis and simultaneousmyelitis, and 7% mixed
presentations(eg, optic neuritis and brain).31 Opticneuritis and
myelitis may be difficult todistinguish from those that occur inMS,
and are variable in severity. Typi-cally, the clinical
manifestations aremore severe than those in MS. Trans-verse
myelitis in NMO may be partial(ie, unilateral, motor, or sensory)
orcomplete (ie, bilateral, motor, and sen-sory); by contrast,
transverse myelitisdue to MS is rarely complete. Radio-logically,
the manifestations overlap,although lesions tend to be
consider-ably longer, especially in the spinalcord. A lesion length
of three or morespinal segments is widely accepted toeffectively
distinguish NMO from MS.Some NMO exacerbations may not beassociated
with long spinal cord le-sions, particularly in patients
receivingimmunosuppressive treatment.
NonYoptic nerve and spinal cordsymptoms include the following,
ingeneral order of frequency:
1. Intractable vomiting and/or hiccuptypically associated with
lesionsin the area postrema, either incontiguity with a myelitis
lesion oras an isolated lesion (Case 3-3)Vthis occurs in
approximately 20% to30% of cases and can be the firstmanifestation
of the disease32
2. Symptomatic forms of narcolepsy orstates of altered
consciousnessassociated with hypothalamic lesionsand reduced CSF
hypocretin levels33
3. Encephalopathy associated withdiffuse white matter CNS
lesionsthat may appear similar to ADEM
Other uncommon presentations orcomplications include posterior
re-versible encephalopathy syndrome(PRES) and hyponatremia during
at-tacks of NMO.
KEY POINT
h Patients withneuromyelitis opticawith concomitantsystemic
lupuserythematosus orhigh-titer antinuclearautoantibodies havebeen
commonly labeledas having lupus myelitisin the past and are
nowincreasingly acceptedas having concomitantneuromyelitis optica
andsystemic autoimmunedisease.
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NMO is commonly associated withother autoimmune diseases,
especiallysystemic lupus erythematosus andSjogren syndrome.34
Myastheniagravis occurs more commonly thanexpected in NMO.35 The
associationwith systemic autoimmunity has led toconfusion in the
past. Patients whohave NMO with concomitant systemiclupus
erythematosus or high-titer anti-
nuclear autoantibodies have been com-monly labeled as having
lupus myelitisin the past and are now increasinglyaccepted as
having concomitant NMOand systemic autoimmune disease.
Differential DiagnosisThe differential diagnosis is largelythat
of optic neuritis and of myelitisas most patients present with one
of
Case 3-3A 34-year-old man presented with recurrent vomiting that
remained unexplained after thoroughgastroenterologic evaluation.
The vomiting subsided but was shortly followed by imbalance and
legweakness. A lesion was detected in his cervical spinal cord
extending from the medulla through C6 onT2-weighted sequences, and
focal gadolinium enhancement was evident in the medulla, as well
assome subpial/leptomeningeal enhancement (Figure 3-7). He improved
after corticosteroid treatment.CSF revealed 12 white blood
cells/2L, absent oligoclonal bands, and a total protein level of 80
mg/dL.He had multiple recurrent events of myelitis over the ensuing
months, all associated withlongitudinally extensive spinal cord
lesions. Episodes of myelitis were prevented by
azathioprinetreatment, but stopping azathioprine was followed by
recurrent episodes of myelitis. He respondedsatisfactorily to
treatment with corticosteroids after each attack. Repeated tests
for aquaporin-4autoantibodies in serum and testing of CSF on one
occasion yielded negative results. Chest x-rayand serum
angiotensin-converting enzyme were normal.
Comment. This case illustrates that recurrent attacks of
longitudinally extensive myelitis, especiallywhen preceded by
intractable vomiting (a signature syndrome of neuromyelitis optica
[NMO]),may lead to a working diagnosis of NMO spectrum disorder;
this is true even when there has beenno history of optic neuritis.
Similarly, recurrent optic neuritis alone may be an indicator of
NMOsyndrome when NMO-IgG is detected; the proportion of cases with
recurrent optic neuritis that areseropositive for NMO-IgG is lower
than cases of recurrent myelitis. Often NMO-IgG may be negativein
cases of clinically definite NMO; depending on the specific assay
used, the seronegative rate inhighly suspect cases is between 30%
and 50%.
FIGURE 3-7 Cervical spinal cord MRI. Sagittal imaging reveals a
longitudinally extensive transverse myelitis lesion(A, T2-weighted
sequence) associated with cord swelling (B, T1-weighted sequence)
and focal gadoliniumenhancement (C, T1-weighted sequence).
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these syndromes. Once other ophthal-mic disorders such as acute
glaucomaor retinal venous occlusion have beenexcluded, the major
entities to be con-sidered in the differential diagnosis ofoptic
neuritis are ischemic optic neu-ropathy (sometimes associated
withgiant cell arteritis), toxic and metabolicamblyopia,
compressive lesions of theoptic nerve, sarcoidosis, and
otherinfiltrative disorders of the optic nerve.The entities to be
considered in thedifferential diagnosis of acute longitu-dinally
extensive myelitis are spinalcord infarction, viral
myelopathies,postinfectious inflammatory transversemyelitis (which
is clinically and radio-logically indistinguishable from trans-
verse myelitis in NMO), intrinsic tumorsof the spinal cord
(which rarely presentacutely), and other inflammatory
andparaneoplastic disorders.
Occasional patients present withsimultaneous optic neuritis and
myeli-tis, in which case the differentialdiagnosis is more limited.
Rare pa-tients have independent causes foroptic neuropathy and
myelopathy syn-dromes (eg, ischemic optic neuropa-thy and a viral
myelitis). Conditionsother than NMO that result in bothinflammatory
optic neuropathy andmyelopathy include other CNS demy-elinating
syndromes (MS, ADEM), sar-coidosis, paraneoplastic disorders
(ie,syndromes associated with collapsing
KEY POINTS
h A broad range of brainlesions have beendescribed in
associationwith neuromyelitisoptica and aquaporin-4antibodies.
h Aquaporin-4 antibodytesting is approximately70% sensitive and
morethan 90% specific forneuromyelitis optica.
TABLE 3-6 Diagnostic Utility of Characteristics of Neuromyelitis
Optica
Characteristic Findings in Neuromyelitis OpticaRelative
DiagnosticUtility
Race/ethnicity NMO affects any race/ethnicity but accountsfor a
smaller proportion (approximately 1% to 2%)of cases of CNS
demyelinating disease in white patientsas compared to other groups
(eg, 30% or more ofAfrican, Asian, and American Indian
patients)
++
Gender Predilection for women (80% in NMO versus 65%in MS)
+
Attack severity Optic neuritis and transverse myelitis attacks
are moresevere than in MS
++
Attack characteristics Paroxysmal tonic spasms ++
Greater risk for neurogenic respiratory failure fromacute,
ascending cervical transverse myelitis in NMOcompared with MS
++
Attack residual Greater residual impairment than in MS attacks
++
Brain MRI Normal or nonspecific findings not meeting MS
MRIcriteria
+++
Hypothalamic lesions ++++
Spinal cord MRI T2-weighted lesion extending contiguously over
atleast three vertebral segments
++++
CSF cell count anddifferential
950 white blood cells/2L; neutrophil predominance +++
CSF immunoglobulinstudies
Negative IgG index and absence of unique oligoclonalbands
+
NMO-IgG Seropositive ++++
NMO = neuromyelitis optica; MS = multiple sclerosis.
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ADEM, Transverse Myelitis, and NMO
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response mediator protein-5 [CRMP-5],which can include optic
neuritis andmyelitis), and rarely CNS malignancy.
The potential overlap with systemiclupus
erythematosusYassociated opticneuritis andmyelitis was discussed
above,and most such cases probably reflectcoexistent NMO rather
than a causativerole of systemic lupus erythematosus.
Clinical, radiologic, and other labo-ratory characteristics that
should beused in differentiating MS from NMOare outlined in Table
3-6.
Diagnostic MethodsBeyond recognition of clinical syn-dromes
associated with NMO andexclusion of competing diagnoses,the main
contributors to NMO diag-nosis are brain and spinal cord MRIand
serologic assessment.
Neuroimaging. At or near clinicalonset, brain MRI in roughly 90%
ofpatients is either normal or revealsonly nonspecific white matter
lesionsthat do not fulfill MS criteria.21 Serialimaging reveals new
asymptomaticbrain lesions in more than 60% ofpatients, but the
pattern usually re-mains subcortical and nonspecific. Infact, the
MRI pattern is typically notdistinguishable from those caused
bysmall vessel cerebrovascular disease.36
In the context of acute optic neuritis,increased T2 signal and
gadoliniumenhancement of the affected opticnerve or chiasm may be
seen andsometimes is longitudinally extensive.The discovery of AQP4
antibodies hasallowed recognition of a broader spec-trum of brain
MRI lesions in thedisease (Figure 3-8). Cerebral whitematter
lesions include large, confluentsubcortical lesions, sometimes
withcloudlike gadolinium enhancementor transient lesions
reminiscent ofPRES.37 Corpus callosum lesions tendto be
block-shaped rather thanthe perpendicular Dawson fingers
typical of MS. Diencephalic andperiaqueductal lesions are also
typicalin NMO. Lesions may occur in the areapostrema within the
dorsal medulla,particularly in patients with bouts ofnausea,
vomiting, or hiccups.
Detection of a LETM lesion onspinal cord T2-weighted sagittal
MRIis a common and very specific neuro-imaging finding for NMO. In
the acutephase, the lesion usually exhibits gad-olinium
enhancement, and on preYgadolinium T1-weighted imaging mayappear
hypointense. Acute cervical cordlesions sometimes ascend into the
brain-stem. After several weeks or months,LETM lesions may
disappear or resolveinto several small, patchy lesions thatcan
bemistaken for smaller MS plaques.
Serology. The detection of serumAQP4 antibodies is approximately
70%sensitive and more than 90% specificfor NMO.19 In the setting of
opticneuritis, LETM, or both, the presenceof AQP4 antibodies
provides strongevidence for the diagnosis of NMO ora NMO spectrum
disorder and in-dicates high risk for recurrent opticneuritis or
myelitis. The likelihood of apositive result diminishes if the
pa-tient is already receiving immunosup-pressive therapy or after
plasmaexchange. Antibody levels may rise inassociation with disease
activity. There-fore, it is reasonable to retest a previ-ously
seronegative patient during a newrelapse. Rare patients who have
beenrepeatedly seronegative have had AQP4antibody detected in
CSF.38
Several immunologic assays havebeen developed for
AQP4-antibodydetection. The original test was anindirect
immunofluorescence assay.19
At present, the most widely availabletest is an enzyme-linked
immunosor-bent assay (ELISA), and laboratoriesmay report either
dichotomous results(ie, positive or negative) or a quanti-tative
titer. Other assay methods
KEY POINTS
h Permanent neurologicdisability fromneuromyelitis optica
isalmost all attack-related(secondary progressiveneuromyelitis
optica israre); therefore,attack-preventionstrategies are thekey to
preservationof function.
h Standard multiplesclerosis therapiessuch as
interferon-",natalizumab, orfingolimod may worsenneuromyelitis
optica. If itis unclear whether apatient has neuromyelitisoptica or
multiplesclerosis, animmunosuppressivetreatment strategytypically
used forneuromyelitis opticashould be consideredto avoid
inadvertentdisease aggravation.
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FIGURE 3-8 Brain lesions in patients with neuromyelitis optica
(NMO) and NMO spectrumdisorders. Panels A, B, and C show cerebral
hemispheric white matter lesions; panelsD, E, and F show
diencephalic lesions; panels G, H, and I show brainstem
lesions.
Extensive bihemispheric subcortical nonenhancing white matter
fluid-attenuated inversion recovery(FLAIR) signal abnormality (A).
Large confluent FLAIR signal abnormality in the right parietal area
(B)with diffuse gadolinium enhancement (C). Images from one patient
show FLAIR abnormality in thehypothalamus (F, arrow) and right
cerebral peduncle (H, arrow). FLAIR signal abnormality in
thethalamus (E, arrow), hypothalamus, and optic chiasm extending
into the superior cerebellarpeduncle and the floor of the fourth
ventricle. Images from a patient with a confluent
nonenhancingsignal abnormality from the anterosuperior
thalamus-hypothalamus (D, arrow) to the optic tractsbehind the
chiasm to the superior surface of the mesencephalon extending to
the periaqueductalarea (right to left) to the superior cerebellar
peduncles, and the pontine tegmentum (I, arrows).Extension of
T2-weighted MRI signal abnormality into the medulla (G, arrow).
Reprinted with permission from Pittock SJ, et al, Arch Neurol.36
B 2006, American Medical Association.
archneur.jamanetwork.com/article.aspx?articleid=790890.
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ADEM, Transverse Myelitis, and NMO
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include immunoprecipitation and cell-based assays, the latter of
which in-volves cells that express human AQP4.In a blinded, direct
comparison ofthese methods, all assays had strongspecificity, but
the cell-based assaysdemonstrated the highest sensitivityand may
eventually become the refer-ence standard.39
Pathologic examination. The vastmajority of NMO cases can be
identifiedusing clinical criteria, MRI, and serologictesting. Some
perplexing cases haveundergone spinal cord or brain biopsyor come
to autopsy, revealing immuno-pathologic differences between NMOand
MS. In particular, NMO is asso-ciated with vasculocentric
depositionof immunoglobulin and complement.
Lesions may reveal eosinophils withina vigorous cellular
infiltrate. More-over, in actively demyelinating NMOlesions, AQP4
is depleted, whereas inMS, similarly active plaques revealAQP4
upregulation (Figure 3-9).40,41
The authors do not generally advocatebiopsy for NMO diagnosis,
but in un-usual situations, such as seronegativepatients with
progressive leukoen-cephalopathy or extensive,
treatment-unresponsive cord lesions, biopsy maybe considered.
PrognosisNMO is generally a more severedisease than MS.
Individual attacksare more likely to result in a perma-nent
neurologic deficit. In one study,
FIGURE 3-9 Comparison of aquaporin-4 (AQP4) immunoreactivity
(IR) in active neuromyelitisoptica (A, B) and multiple sclerosis
(C, D) optic nerve lesions. A, Activedemyelination with macrophages
containing myelin oligodendrocyte
glycoprotein (MOG)Yimmunoreactive myelin debris (arrowheads),
adjacent to periplaque whitematter (asterisk). B, AQP4 is lost in
the active lesion but retained in the periplaque white
matter(asterisk). C, Active demyelination with macrophages
containing proteolipidprotein-immunoreactive myelin debris
(arrowheads), adjacent to periplaque white matter(asterisk). D,
AQP4 IR is increased in both the active lesion and periplaque white
matter (asterisk).Immunohistochemistry: A, MOG; B, D, AQP4; C,
proteolipid protein.
Reprinted with permission from Roemer SF, et al, Brain.40 B
2007, Guarantors of Brain.
brain.oxfordjournals.org/content/130/5/1194.long.
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50% of NMO patients were blind in atleast one eye or required
ambulatoryassistance within 5 years of diseaseonset.42 Unlike
typical MS, in whichmost disability accrues during a sec-ondary
progressive disease phase,NMO disability occurs as a result
ofindividual attacks, and gradually pro-gressive disability like
that seen insecondary progressive MS is rare.43
The expansion of the NMO spectrumhas probably uncovered milder
andmore heterogeneous cases. Recently,French investigators asked
whetherbenign NMO exists by evaluatingoutcomes of 175 patients with
NMOover 10 years.44 Although mild disabil-ity was noted in about
12% of thesepatients (compared with 22% of MSpatients over that
time frame), severalof them experienced a disabling attackbefore
year 15. Therefore, all NMOpatients should be considered at riskof
disabling attacks. Together with therarity of a secondary
progressive NMOcourse, this attack-related threat em-phasizes the
importance of attack-prevention strategies to prevent
disability.
TreatmentTreatment of NMO is evolving becauseof collective
longitudinal experience inlarge care centers and advances
inunderstanding disease pathobiology.There are no randomized
controlledtrials for NMO therapies.
Acute attacks are typically treatedwith corticosteroids and, if
necessary,rescue plasma exchange as outlined inthe discussion of
transverse myelitis.Relapse prevention strategies aremeantto reduce
or eliminate the effects ofpathogenic AQP4 antibodies,
eitherdirectly or indirectly. The importanceof accurate diagnosis
has been height-ened recently because of a number ofreports
indicating that the standard MStherapy interferon-" aggravates
NMO.45
Furthermore, worsening of NMO has
been reported with other MS therapiessuch as natalizumab and,
less convinc-ingly, fingolimod.46,47 Therefore, insituations where
the diagnosis remainsuncertain between NMO and MS, theauthors favor
starting with an NMOimmunosuppression strategy becauseit is likely
to provide benefit in treatingeither disease, and the
subsequentclinical course will usually reveal thecorrect
diagnosis.
General immunosuppression strat-egies. Patients with established
relaps-ing NMO and those deemed to be athigh risk for relapse (eg,
patients withseropositive NMO spectrum disordersuch as those with
first-ever LETM oroptic neuritis) require long-term
im-munosuppressive therapy.12,48 Themost common approaches to
immu-nosuppression include oral drugs (eg,azathioprine or
mycophenolate mofetil)or parenteral drugs (eg, rituximab).
Inretrospective series, these agents appearto reduce relapse rates
by 30% to 70%,but no controlled or comparative stud-ies have
confidently established themagnitude of treatment effect.
Azathio-prine and mycophenolate have delayedonset of action and
typically requirebridge therapy for 4 to 6months, usuallywith oral
prednisone (40 to 60 mg/d).Rituximab (1000 mg/d twice, 2
weeksapart, with retreatment approximatelyevery 6 months) is fully
active withinabout 2 weeks but is substantially moreexpensive. In
some countries,mitoxantrone, methotrexate, or chronicoral
prednisone represent the mainstayof preventive therapy; a consensus
sum-mary review of the use of these therapieswas recently
published.48
Regardless of which drug is selected,the goal of therapy is
elimination ofacute relapses by optimizing drug dos-age,
retreatment frequencies, and com-pliance. Patient compliance can
bemonitored unequivocally for rituximabbut only indirectly for
azathioprine (ie,
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ADEM, Transverse Myelitis, and NMO
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CasillasResaltado
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elevation in mean corpuscular volume).The key outcome evaluation
is theoccurrence of breakthrough attacks.Unfortunately, no
predictive or thera-peutic biomarkers in NMO have beenvalidated.
Repeat neuroimaging willusually not yield
treatment-changinginformation. AQP4 antibody titer tendsto decrease
with immunosuppression,but this is not consistently associatedwith
clinical course.
Rapid advances in our understandingof immunopathogenic
mechanisms inNMO are informing therapeutic strate-gies.49 A recent
open-label study ofeculizumab, a monoclonal antibodythat affects
cleavage of complement,showed a marked reduction in on-study attack
rate and resumption ofattacks in some patients after the drugwas
discontinued.50 Inference fromhuman immunopathology and
animal-model data suggests potential roles fortherapies aimed at
interrupting B-cell,T-cell, complement, or cytokine func-tion.
Moreover, particularly interestingstrategies are now being
developed tointerfere with AQP4 antibody structureor antigen
binding. Aquaporumab is anonpathogenic recombinant antibodythat
competes with anti-AQP4 for anti-gen binding.51 In cell cultures
and ina passive-transfer animal model, aqua-porumab eliminated
complement-mediated and cell-mediated cytotoxicityinduced by AQP4
antibody. Small-molecule screening has identified aseries of
compounds that can alsointerfere with antibody binding. Someof
these agents, including antivirals,flavonoids, and berbamine
alkaloids,are available for testing.52 Selectivedeglycosylation of
the AQP4 antibodyheavy chain mitigates its pathogeniceffects and
may convert it to anaquaporumablike blocking antibody.53
Antigen-specific treatment strategiesare some distance from
clinical usebut illustrate rapid application of
emerging pathophysiologic informationtoward therapy.
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