Review Article

Autoimmune
Address correspondence
to Dr Sean J. Pittock, Mayo
Clinic, Department of
Neurology, 200 First Street
SW, Rochester, MN, 55905,
pittock.sean@mayo.edu.
Relationship Disclosure:
Myelopathies
Dr Pittock and the Mayo Eoin P. Flanagan, MBBCh; Vanda A. Lennon, MD, PhD;
Clinic have a financial
interest in technology Sean J. Pittock, MD
titled ‘‘Neuromyelitis
Optica Autoantibodies as a
Marker for Neoplasia.’’ In
accordance with the ABSTRACT
Bayh-Dole Act, that The differential diagnosis of inflammatory myelopathies is broad. Autoimmune mye-
technology has been
licensed to a commercial
lopathies represent a heterogeneous but significant portion of inflammatory mye-
entity (RSR, Ltd.). Neither lopathies. The discovery of serologic biomarkers of autoimmune myelopathies
Dr Pittock nor the Mayo (including aquaporin-4 and collapsin response-mediator protein-5 [CRMP-5] im-
Clinic has received any
royalties to date.
munoglobulin [Ig]Gs) supports the concept of an autoimmune attack targeting the
Dr Pittock is the principal spinal cord. Neuroimaging, in particular MRI, may reveal distinctive patterns of signal
investigator of grants from abnormality suggesting an autoimmune etiology, such as longitudinally extensive
Alexion Pharmaceuticals,
Inc., the Guthy-Jackson
transverse myelitis in neuromyelitis optica spectrum disorders or tract-specific changes
Charitable Foundation, in paraneoplastic disorders. IgG biomarkers of autoimmune myelopathies enable
and the NIH. Dr Lennon’s more precise disease classification and have the potential to direct a cancer search,
research is supported
by a grant from the
predict outcome, guide therapeutic decision making, and lead to future development
Guthy-Jackson Charitable of antigen-specific targeted therapies. The goal of initial immunotherapy is to reverse
Foundation. She receives or halt progression. Long-term immunotherapy aims to maintain remission and pre-
royalties on a patent
relating to aquaporin-4 as
vent relapse.
a target of pathogenic
autoantibodies in Continuum Lifelong Learning Neurol 2011;17(4):776–799.
neuromyelitis optica and
related disorders. She
receives no royalties from
the sale of any serologic
tests performed on a
service basis by Mayo
INTRODUCTION neural autoantibody that rarely responds
Medical Laboratories; The differential diagnosis of myelopathy to immunotherapy. This article provides
however, Mayo a practical overview of current knowl-
Collaborative Services, is broad (Tables 4-1 and 4-2). In this
Inc. receives revenue for article, autoimmune myelopathies will edge in the field and focuses on differ-
conducting these tests. ential diagnosis, diagnostic evaluation,
Dr Lennon is a named
be categorized as (1) having an acute or
inventor on two patent subacute onset of motor, sensory, or interpretation of serologic and radiologic
applications filed by the autonomic spinal cord dysfunction, con- biomarkers, therapeutic management,
Mayo Foundation for
medical education and sidered ‘‘autoimmune transverse myeli- and prognosis.
research relating to tis,’’ (2) having an insidious onset and
functional assays for AUTOIMMUNE TRANSVERSE
detecting aquaporin-4 and progressive course, or (3) having a mo-
neuromyelitis optica. tor neuron diseaseYlike presentation. MYELITIS
Dr Flanagan has nothing
to disclose. Each will be discussed separately. Weakness, sensory abnormalities (usually
Unlabeled Use of Examples of autoimmune transverse with a sensory level), and bowel or
Products/Investigational myelitis include aquaporin-4 (AQP4) bladder symptoms are the most frequent
Use Disclosure:
Drs Pittock, Lennon, and immunoglobulin (Ig)GYassociated longi- presenting findings of a transverse mye-
Flanagan discuss the tudinally extensive transverse myelitides litis. In autoimmune transverse myelitis,
unlabeled use of
immunotherapies to treat
classified as neuromyelitis optica spec- symptom onset typically occurs over
autoimmune myelopathies. trum disorders (NMOSDs). Some para- hours to days, and symptoms plateau
Copyright * 2011, neoplastic myelopathies begin more within days. Recovery typically begins
American Academy of
Neurology. All rights slowly but usually progress to early dis- after a few weeks, although it may be
reserved. ability. Autoimmune motor neuron dis- incomplete. By contrast, paraneoplastic
ease may be accompanied by a definable myelopathies frequently begin insidiously

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Differential Diagnosis of Acute Transverse Myelitis
TABLE 4-1
b Demyelinating Disorders TABLE 4-1
Parasitic
Multiple sclerosis Neurocysticercosis
Neuromyelitis optica Schistosoma
Acute disseminated Gnathostoma
encephalomyelitis
Angiostrongylus
Idiopathic
Toxocara
b Postvaccinial
Viral (human T-cell
Rabies lymphotropic virus and
HIV cause more chronic
Diphtheria-tetanus-polio
myelopathies)
Smallpox
Herpesvirus: herpes
Measles simplex virus,
varicella-zoster virus,
Mumps
cytomegalovirus,
Rubella human herpes virus
types 6 and 7,
Japanese B encephalitis Epstein-Barr virus
Pertussis Flaviviruses: Dengue
Influenza fever, Japanese B
encephalitis, St Louis
Hepatitis B
encephalitis, tickborne
b Infections encephalitis, West
Nile virus
Bacterial
Orthomyxovirus:
Spinal cord abscess Influenza A virus
(epidural or
Paramyxoviruses:
intraparenchymal)
Measles virus,
due to spread from
mumps virus
systemic infection
Picornaviruses:
Mycoplasma
Coxsackievirus types A
Borrelia burgdorferi and B, echoviruses,
Enterovirus 70 and 71,
Treponema pallidum
hepatitis A and C
Mycobacterium
Poliovirus types 1, 2,
tuberculosis
and 3
Actinomyces
b Other Inflammatory
Fungal Disorders
KEY POINTS
h Autoimmune
myelopathies may be
categorized as
having an acute or
subacute onset of
TABLE 4-1sclerosis
Systemic
motor, sensory, or
Neurosarcoidosis autonomic spinal
Behçet syndrome cord dysfunction
(‘‘autoimmune
b Vascular Disorders transverse myelitis’’);
having an insidious
Anterior and posterior
spinal artery infarction onset and
progressive course;
Arteriovenous fistula
or having a motor
Hematomyelia neuron diseaseYlike
(arteriovenous presentation.
malformation,
cavernoma, h Examples of
autoimmune
bleeding diathesis,
transverse myelitis
Osler-Weber-Rendu
include aquaporin-4
syndrome)
IgGYassociated
Fibrocartilaginous disk
longitudinally
embolism
extensive transverse
b Neoplastic myelitides classified
Primary intramedullary as neuromyelitis
optica spectrum
tumors (lymphoma,
ependymoma, disorders.
astrocytoma, and
hemangioblastoma)
or metastatic
intramedullary tumors
b Paraneoplastic (may
also cause chronic
myelopathy)
Lung and breast
carcinomas most
common
Amphiphysin and
collapsin
response-mediator
protein 5YIgG most
common autoantibody
associations

Blastomyces Systemic lupus

erythematosus
Coccidioides
Sjögren syndrome
Cryptococcus
Mixed connective tissue
Aspergillus disorder

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 Autoimmune Myelopathies

TABLE 4-2 Differential Diagnosis of Chronic Myelopathies

b Idiopathic Inflammatory TABLE 4-2

Spinocerebellar ataxias
Demyelinating Diseases
ALS
Primary progressive multiple sclerosis
b Vascular
b Autoimmune
Cerebral autosomal dominant
Paraneoplastic myelopathy arteriopathy with subcortical infarcts and
leukoencephalopathy
Other autoimmune myelopathy
Dural arteriovenous malformation/fistula
Autoimmune/paraneoplastic
motor neuron disorders b Compression/Structural
b Infectious Spondylosis
HIV myelopathy Tumor
Human T-cell lymphotropic Syrinx
virusYassociated myelopathy/
b Inflammatory
tropical spastic paraparesis
Sarcoidosis
Brucellosis
Vasculitis
Schistosomiasis
Behçet syndrome
Borrelia burgdorferi
Sjögren syndrome
b Hereditary/Degenerative
b Deficiency States
Hereditary spastic paraparesis
Vitamin B12
Friedreich ataxia
Copper
Adrenomyeloneuropathy
Modified from Marriott JJ, O’Connor PW. Differential diagnosis and diagnostic criteria for multiple sclerosis:
application and pitfalls. In: Lucchinetti CF, Hohlfeld R, eds. Blue books of neurology: multiple sclerosis 3.
Philadelphia: Saunders Elsevier, 2010:19Y42. Copyright * 2010, with permission from Elsevier.

and have a progressive course without a
recovery period. Subacute myelitis has a
broad differential diagnosis (Table 4-1),
but certain clinical features provide a clue
to an autoimmune pathogenesis. Auto-
immune myelopathies (both chronic and
acute), autoimmune motor neuron dis-
orders, and multiple sclerosis (MS) are
compared in Table 4-3. It is important to
rule out other causes of myelopathy be-
fore initiating immunotherapy because
of immunotherapy’s adverse effects.
Preceding or concurrent optic neuritis
suggests neuromyelitis optica (NMO).
Symptoms and signs of myelitis in NMO
are usually symmetric and severe. Para-
paresis, sensory loss below the level
of the lesion, and bowel or bladder
dysfunction occur, and MRI reveals a
longitudinally extensive signal abnormal-
ity (greater than 3 vertebral segments) in
the spinal cord (Figure 4-1A). Respira-
tory failure may result from a high
cervical cord lesion. Other clinical symp-
toms or signs that may support a diag-
nosis of an NMOSD in the setting of a
myelitis include cervical myelitis extend-
ing into the medulla or area postrema
involvement with nausea, hiccups, or in-
tractable vomiting, which is sometimes
the sole presentation.1,2
In contrast to NMO, MS has a predi-
lection for proprioceptive fibers, and its
clinical findings are asymmetric (eg, a
Brown-Séquard syndrome). Short, asym-
metric signal abnormalities on MRI are

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TABLE 4-3 Comparison of Multiple Sclerosis, Neuromyelitis Optica, Acute Disseminated
Encephalomyelitis, and Paraneoplastic Myelopathies and Autoimmune/Paraneoplastic
Motor Neuron Disease

Autoimmune/
Acute Paraneoplastic
Multiple Neuromyelitis Disseminated Paraneoplastic Motor Neuron
Characteristic Sclerosis Optica Encephalomyelitis Myelopathy Disease
Antecedent Variable Variable Typical No No
infection or
immunization
Median age 29 39 Children to 62 Variable
of onset (years) young adults
Sex (F:M) 2:1 3-9:1 Similar Similar Slight female
predominance
Frequency Common Intermediate Intermediate Rare Extremely rare
Epidemiology Whites Disproportionately Any Unknown Unknown
Asians and
Africans
Myelitis Subacute, Subacute, Subacute, Insidious Mixed upper and
presentation asymmetric symmetric multifocal with lower motor
encephalitis neuron; ALS or
primary lateral
sclerosis
presentation
Course 85% relapsing 85% relapsing Monophasic Chronic Chronic
progressive (may progressive
mimic primary
progressive
multiple sclerosis)
Impairment Mild to Moderate to Mild to moderate Severe (most Severe (but
moderate severe after wheelchair progression may
after attack attack dependent be more benign
within 2 years) than ALS)
CSF G50 x 106/L 950 x 106/L 950 x 106/L WBCs G50 x 106/L Unknown, some
WBCs; WBCs, often (lymphocytes); WBCs, elevated reports of
OCBs 85% neutrophilic OCBs usually protein often elevated protein
predominant; absent marked;
OCBs in 30% OCBs 30%
Spine MRI Short lesions; Long lesion Variable Symmetric Normal
usually (93 vertebral tract-specific/gray
periphery of segments); matterYspecific
cord; variable central lesion on enhancement;
enhancement axial; variable can be normal
enhancement
Cancer None Rarely None Most commonly Most frequently
associations breast and lung breast and lung
carcinomas carcinomas and
lymphoma
continued on next page

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 Autoimmune Myelopathies

TABLE 4-3 Continued

Autoimmune/
Acute Paraneoplastic
Multiple Neuromyelitis Disseminated Paraneoplastic Motor Neuron
Characteristic Sclerosis Optica Encephalomyelitis Myelopathy Disease
Neural None Neuromyelitis None Collapsin Variable
autoantibody optica IgG response-mediator
associations protein-5 and
amphiphysin IgGs
most common
Brain MRI Periventricular Hypothalamic, Subcortical, may Normal Normal
white matter periventricular, involve deep gray
lesions particularly matter
third/fourth
ventricle;
cloudlike
enhancement
Chronic Interferon Azathioprine, None Cancer treatment, Cancer treatment,
treatment beta, steroids, steroids, IVIg, steroids, IVIg,
glatiramer mycophenolate plasmapheresis, cyclophosphamide,
acetate, mofetil, cyclophosphamide, azathioprine,
natalizumab rituximab azathioprine, mycophenolate
in severe cases mycophenolate mofetil
mofetil
Prognosis Majority Moderate to Good; monophasic Poor; most Poor response to
ambulatory severe disability wheelchair treatment; may
after 20 years over time; most dependent within have slower
patients disabled 2 to 5 years progression
after 5 years than ALS
WBCs = white blood cells; OCBs = oligoclonal bands; Ig = immunoglobulin.

characteristic of MS in the spinal cord. artery infarction and usually irreversible

Other clinical features of cervical myel-
opathy that may suggest but are not
exclusive to MS include useless hand
syndrome (from severe proprioceptive
loss in an upper extremity), Uhthoff
phenomenon (heat-induced worsening
of neurologic symptoms), Lhermitte
sign (electric shockYlike sensation radi-
ating down the spine and into the limbs
during neck flexion), and McArdle sign
(increased pyramidal weakness with neck
flexion). Tonic spasms (recurrent stereo-
typic painful spasms of the limbs and
trunk that typically last 20 to 45 seconds)
are more common with NMO than MS.3
Hyperacute onset and sparing of the
dorsal columns suggest anterior spinal
deficits (Figure 4-1B). Recent or inter-
current infection, fever, meningismus,
rash, or an immunocompromised state
may suggest an infectious etiology.
Myelitis in a patient with an underlying
malignancy may suggest a compres-
sive etiology from metastatic disease or
a paraneoplastic cause. A history of
erythema nodosum, lymphadenop-
athy, or anterior uveitis suggests sar-
coidosis; this disorder involves the
neurologic system in 5% to 16% of
cases and the spinal cord in approxi-
mately 1% (Figure 4-1E).4 A recent
viral illness or vaccination raises the
possibility of acute disseminated ence-
phalomyelitis (ADEM), which has been

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FIGURE 4-1 Differential diagnosis of a longitudinally extensive lesion on MRI of the spine. Arrows demonstrate
abnormalities. A, AQP4-IgGYpositive neuromyelitis optica patient: T2-weighted signal abnormality
extends at least five vertebral segments on sagittal images (A1) and localizes to the central cord on axial
images. A2, B, patient with anterior spinal artery infarction: spinal cord swelling and T2-weighted signal abnormality on
sagittal image (B1) with restricted diffusion (B2) and sparing of the dorsal columns (B3). C, patient with arteriovenous
fistula: T2-weighted signal abnormality extends at least six vertebral segments on sagittal image (C1) throughout
the central cord (C2). Note the flow voids (yellow arrows) on both sagittal and axial (C2) images. D, patient with
paraneoplastic myelopathy: T2 signal abnormality in the thoracic spinal cord (D1) preferentially involves the dorsal
columns (D2). E, patient with neurosarcoidosis: T2 signal abnormality extends at least four thoracic vertebral segments on
sagittal image (E1) with enhancement after gadolinium on sagittal (E2) and axial images (E3).

associated with many types of infec-
tions or vaccines (Table 4-1). The
potential role of infections and vacci-
nations as a trigger for a first attack of
NMO or MS remains unproven.
Aquaporin-4 Autoimmunity
and Transverse Myelitis
The neuromyelitis optica spectrum
concept. NMOSDs are a group of
inflammatory demyelinating CNS disor-
ders unified by a common target auto-
antigen, the AQP4 water channel. AQP4
is the most abundant CNS water chan-
nel. It is highly concentrated on astro-
cytic foot processes at the blood-brain
barrier. NMO is characterized by recur-
rent attacks of optic neuritis and longi-
tudinally extensive transverse myelitis
(LETM). Recovery after an acute episode
is usually incomplete, and disability after
attacks accumulates more rapidly than in
MS. AQP4 autoimmunity is recognized
as having neurologic manifestations that
extend beyond the optic nerve and
spinal cord.5 Patients seropositive for
AQP4-IgG may have disease confined to
the spinal cord and either a single epi-
sode or recurrent LETM. NMOSDs also
can occur in a paraneoplastic context,
most commonly with breast cancer, but
neoplasms recorded with NMO include
carcinomas of the lung and cervix,
thymoma, and lymphoma.6
Pathogenic potential of aquaporin-4–
immunoglobulin G. In addition to
serving as a serum biomarker, the
AQP4-specific autoantibody NMO-IgG
is an effector of the neuropathology
of NMO. In vitro, NMO-IgG binds to
the extracellular domain of AQP4 and

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 Autoimmune Myelopathies

reversibly downregulates its plasma
membrane expression (Figure 4-2A);7
(2) initiates robust activation of comple-
ment (when available), leading to rapid
loss of the target membrane’s integrity
(Figure 4-2B);7 and translocates the
major CNS glutamate transporter, the
excitatory amino acid transporter 2
(EAAT2) from the astrocyte surface to
the endolysosomal pathway,8 reducing
Na+-dependent glutamate uptake and
increasing extracellular glutamate con-
centration (Figure 4-2C). Astrocytes are
relatively tolerant of elevated glutamate,
but neurons and oligodendrocytes are
highly vulnerable to glutamate excito-
toxicity. These events plausibly explain
multiple downstream events, such as
the grossly necrotic central spinal cord
gray matter lesions and demyelination.
Finally, NMO-IgG alters AQP4 polar-
ized expression and increases perme-
ability of a human blood-brain barrier
endothelium/astrocyte barrier.9
Immunopathology of neuromyelitis
optica spectrum disorders in spinal cord.
Pathologic evaluation of active NMO
spinal cord lesions (Figure 4-3C to
Figure 4-3I)10 has demonstrated paren-
chymatous edema with infiltration by
mononuclear cells (lymphocytes, plasma
cells, and macrophages) and polymor-
phonuclear cells (neutrophils and eosino-
phils). Deposits of IgG (Figure 4-3D) and
the membrane attack complex of com-
plement (Figure 4-3E) are present in a

FIGURE 4-2 Functional effects of NMO-IgG binding to the extracellular domain of AQP4 in
living cell membranes. A, downregulation of AQP4 in transfected Human
Embryonic Kidney (HEK) 293 cells after exposure to NMO serum. Cells exposed to
control human IgG retain plasma membrane AQP4 as a linear pattern. Reorganization and
internalization of AQP4 occurs after treatment with NMO patient serum (scale bar, 20 Hm).
B, complement is activated by NMO-IgG binding to AQP4-expressing HEK293 cells. AQP4 is
tagged with green fluorescent protein. Nontransfected cells are gray. In the presence of control
serum or NMO serum and heat-inactivated complement, green cells remain in the monolayer.
Cells expressing AQP4 are selectively killed when active complement is present with NMO serum
but not with control serum. This is indicated by rounding up and floating of green cells (arrows).
C, glutamate uptake by cultured astrocytes is reduced after exposure to NMO patient serum.
Nonexposed cells (black bar) and cells exposed to control human serum (gray bar) take up
radiolabeled glutamate at approximately 3000 counts/min. Glutamate uptake is reduced by
approximately 50% in cells exposed to NMO serum (white bar).
Panels A and B reprinted from Hinson SR, Pittock SJ, Lucchinetti CF, et al. Pathogenic potential of IgG binding to water
channel extracellular domain in neuromyelitis optica. Neurology 2007;69(24):2221Y2231. Copyright B 2007, with
permission from AAN Enterprises, Inc. All rights reserved.

Panel C courtesy of Shannon R. Hinson, PhD, Mayo Clinic, Rochester, Minnesota.

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 KEY POINTS
h Longitudinally extensive
lesions (greater than 3
vertebral segments) on
T2-weighted MRI are
characteristic of
neuromyelitis optica
spectrum disorder.
h AQP4-IgG
seropositivity is
detectable in one-third
to one-half of all
patients with
longitudinally extensive
transverse myelitis and
predicts a high risk
for relapse.
h Spinal cord lesions
in adult patients
with multiple
sclerosisYassociated
myelitis are short
and asymmetric and
are rarely, if ever,
FIGURE 4-3 NMO-IgG and immunopathology. A, B, immunofluorescence pattern of NMO-IgG
bound to mouse CNS tissues and kidney (x 20). A, prominent staining of longitudinally extensive.
microvessel and pia (around large unstained vessel [V]) in cerebellar cortex
(molecular layer [ML], granular layer [GL], and midbrain [MB]). B, selective staining of h The length of a
distal-collecting tubules in renal medulla. C-F, images showing acute NMO. C, spinal cord, classic spinal cord lesion
actively demyelinating NMO lesion is cavitary and involves both gray and white matter; peripheral depends on the
myelin is spared (Luxol fast blueYperiodic acid-Schiff [LFBYPA-S] x 1.25). D, E, complement
(D, arrow) and Ig (E, arrow) are deposited around penetrating vessels in a rosette pattern (AQP4 timing of the MRI
immunoreactivity x 60). G, acute active MS lesions. AQP4 immunoreactivity is enhanced around because the signal
vessels and in the cytoplasm of reactive astrocytes (x 60). H, I, novel lesion of acute NMO in spinal abnormality may
cord. Complete AQP4 loss in the white matter (H); note residual AQP4 immunoreactivity in gray
matter (x 10) and preservation of myelin (I) and tissue integrity (LFBYPA-S x 10). resolve or become
shorter with time.
Reprinted with permission from Pittock SJ. Neuromyelitis optica: a new perspective. Semin Neurol 2008;28(1):95Y104.

characteristic vasculocentric ‘‘rim and DIAGNOSTIC EVALUATION OF

rosette’’ pattern that corresponds to
the high density of AQP4 in astrocytic
end-feet. Immunohistologic study of the
spinal cord in NMO reveals a unique
pattern of AQP4 loss that is inde-
pendent of demyelination stage, le-
sion site, or degree of tissue necrosis
(Figure 4-3F).11 AQP4 loss is accompa-
nied by a striking loss of the major CNS
EAAT2,8 which is confined to astrocytes.
These changes precede demyelination.
In contrast to NMO lesions, AQP4 and
EAAT2 are upregulated in early MS le-
sions (Figure 4-3G).11,12
AUTOIMMUNE TRANSVERSE
MYELITIS
Spinal Cord MRI
The spinal cord MRI pattern is very useful
for distinguishing different types of inflam-
matory and autoimmune myelopathy.
Long lesions. Longitudinally extensive
lesions (greater than 3 vertebral seg-
ments) on T2-weighted MRI are charac-
teristic of NMOSDs (Figure 4-1A). Axial
lesions usually involve both gray and
white matter. AQP4-IgG seropositivity is
detectable in one-third to one-half of all
patients with LETM and predicts a high

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 Autoimmune Myelopathies

longitudinally extensive lesions favor the

NMO-IgG predicts relapse after
FIGURE 4-4
longitudinally extensive transverse
myelitis. Kaplan-Meier survival
analysis stratified by serologic status for NMO-IgG,
considering two end points: recurrent transverse myelitis
(TM; closed circles) and optic neuritis (ON; open circles).
At 1 year, five of nine patients for whom clinical
information was available experienced either event,
whereas zero of 14 seronegative individuals experienced
a subsequent event (P=.004, Fisher exact test).
Reprinted with permission from Weinshenker BG, Wingerchuk DM, Vukusic
S, et al. Neuromyelitis optica IgG predicts relapse after longitudinally
extensive transverse myelitis. Ann Neurol 2006;59(3):566Y569.
risk for relapse (Figure 4-4).13 In con-
trast, NMO-IgG is rarely found in acute
‘‘short segment’’ partial transverse myeli-
tis. Only one of 22 patients with acute par-
tial (short segment) transverse myelitis
reported by Scott and colleagues was se-
ropositive for AQP4-IgG.14 Recurrent
episodes of LETM typical of NMOSDs
subsequently developed in the single se-
ropositive patient.14 In adult patients,
diagnosis of an NMOSD. Spinal cord le-
sions in adult patients with MS-associated
myelitis are short and asymmetric and are
rarely, if ever, longitudinally extensive. By
contrast, up to 14% of pediatric patients
with MS have longitudinally extensive spi-
nal cord lesions.15 Therefore, LETM is not
as predictive of an NMOSD in children.
The length of the lesion depends on the
timing of the MRI because the signal ab-
normality may resolve or become shorter
with time. It is also important to remem-
ber that a longitudinally extensive lesion
can occur with other disorders, such as
anterior spinal artery infarction, dural ar-
teriovenous fistula, sarcoidosis, and para-
neoplastic myelopathy (Figure 4-1).
Serologic testing for AQP4-IgG is justified
for all patients with a longitudinally ex-
tensive lesion because seropositivity pre-
dicts relapse and warrants maintenance
immunosuppression (Case 4-1).
Short lesions. Short lesions (fewer
than three vertebral segments), espe-
cially those in the periphery of the
spinal cord, are typical of MS. In pa-
tients with a first attack of transverse
myelitis (clinically isolated syndrome
[CIS]), the brain MRI and CSF findings
both aid in predicting the likelihood of
developing MS and assist in therapeutic
decision making (Figure 4-5).

Case 4-1
A 58-year-old right-handed woman presented with subacute onset of left hand clumsiness and right-side
sensory loss in the leg and torso that developed over 5 days and progressed. She had no prior history of
neurologic problems. Her past medical history was significant for atrial fibrillation and osteoporosis, and
she had a family history of presumed multiple sclerosis, which had developed in a brother at age 29.
Neurologic examination revealed moderate left arm and leg weakness in an upper motor neuron pattern.
She had mild spasticity and hyperreflexia on the left and a left Babinski sign. She required a cane. Pinprick
sensation was decreased in the right leg and vibration sensation was absent in the left. The cervical spinal
cord MRI demonstrated a longitudinally extensive T2 hyperintense lesion with patchy enhancement after
gadolinium administration. CSF abnormalities included elevated leukocyte numbers (10, mixed monocytes
and lymphocytes) and elevated protein (92 mg/dL); glucose was normal and no supernumerary oligoclonal
bands were present. Serologic testing revealed strongly positive antinuclear antibody (positive for
double-stranded DNA, SSA/anti-Ro, and lupus anticoagulant) and AQP4-IgG (end point dilution 61,440).
continued on page 785

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 Continued from page 784
Comment. The patient presented with a longitudinally extensive transverse myelitis and AQP4-IgG
seropositivity. This constellation of findings supports the diagnosis of a neuromyelitis optica spectrum
disorder. The patient was treated initially with IV methylprednisolone 1 g/d for 5 days, but she did not
improve. Plasma exchange was then initiated (half- to full-volume exchange every other day for a total
of seven exchanges). She improved to the point of ambulating independently without a cane. Because
of the high risk of relapse, azathioprine therapy was begun (100 mg/d; thiopurine methyltransferase
level was normal). Carbamazepine was given for tonic spasms that developed after initial hospitalization.
Regular monitoring of blood counts and liver function was initiated. Mycophenolate mofetil (500 mg
2 times a day) was substituted for azathioprine because of a significant rise in alanine aminotransferase
and aspartate aminotransferase. A second attack of longitudinally extensive transverse myelitis developed
2 months later. Mycophenolate mofetil was increased to 1000 mg 2 times a day. At last follow-up,
4 years later, no further relapses had occurred.
Detection of AQP4-IgG in serum at the first attack of longitudinally extensive transverse myelitis
predicts a high risk of recurrence or development of optic neuritis. Initiation of immunosuppressant
therapy is appropriate to prevent further attacks.

FIGURE 4-5 An evidence-based approach to the management of clinically isolated syndromes.

Blue arrows reflect reasonable evidence, and red arrows reflect areas of controversy.
ON = optic neuritis; LETM = longitudinally extensive transverse myelitis; TM = transverse myelitis;
NMO = neuromyelitis optica; MS = multiple sclerosis; IgG = immunoglobulin G; Gd = gadolinium;
PP = patient preference; CR = complete recovery; IR = incomplete recovery; OCB = oligoclonal band.
Modified with permission from Abou Zeid NE, Pittock SJ. Clinically isolated syndromes. In: Lucchinetti CF, Hohlfeld R, eds. Blue books
of neurology: multiple sclerosis 3. Philadelphia: Saunders Elsevier, 2010:206Y218. Copyright * 2010, with permission from Elsevier.

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 Autoimmune Myelopathies
KEY POINTS
h Approximately 10%
of patients have
‘‘neuromyelitis
opticaYtypical’’ brain
lesions, which involve
regions of high
AQP4 expression
around the lateral, third,
and fourth ventricles
and the hypothalamus.
h For patients with
short-segment cord
lesions (partial myelitis),
the presence of two or
more white matter
lesions on brain MRI
predicts an 88% risk of
developing multiple
sclerosis after 14 years,
compared to a 19% risk
if the MRI is normal.
h The detection of the
AQP4Yspecific
autoantibody NMO-IgG
is both a sensitive
(60% to 80%) and
highly specific
(greater than 90%)
marker for
neuromyelitis optica.
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Brain MRI
MRI of the brain is helpful in evaluat-
ing suspected autoimmune transverse
myelitis, especially in distinguishing
between MS and NMOSD, and should
be performed in all cases. In 60% of
NMO cases, the brain MRI reveals non-
specific white matter changes during the
course of the disease. These lesions are
typically silent clinically and do not meet
criteria for MS. However, approximately
10% of patients have ‘‘NMO-typical’’
brain lesions, which involve regions of
high AQP4 expression around the lat-
eral, third, and fourth ventricles and the
hypothalamus,16 with cervical cord
lesions extending to the medulla, the
floor of the fourth ventricle, and the
area postrema.1 Brain lesions enhancing
in a ‘‘cloudlike’’ pattern after gadoli-
nium (multiple areas of patchy en-
hancement with blurred margins in
adjacent regions) have also been de-
scribed as characteristic of NMOSD.17
Brain scanning by MRI is also helpful
in predicting the likelihood of develop-
ing MS after a CIS of transverse myelitis.
The presence of two or more white
matter lesions on brain MRI predicts an
88% risk of developing MS after 14
years, compared to a 19% risk if the
MRI is normal.18 In ADEM, MRI of the
head shows patchy, poorly marginated
areas of T2 hyperintensity that are
usually large, asymmetric, and involve
the deep gray matter (thalamus and
basal ganglia). Gadolinium enhance-
ment may be present in all lesions that
are theoretically of similar age. In neu-
rosarcoidosis, MRI abnormalities are
typically most abundant at the base of
the brain, with meningeal involvement
and focal or diffuse thickening of the
meninges that typically enhance with
gadolinium.19
CSF Evaluation
CSF examination is most helpful to
exclude infectious causes of myelitis
and to distinguish other inflamma-
tory causes of myelopathy (Table 4-3).
Pleocytosis (ranging from 50 to 1000 x
106 leukocytes/L) with a neutrophilic
or eosinophilic predominance is typical
of NMO; supernumerary oligoclonal
bands are less frequent (15% to 30%)
than in MS (85%).20 CSF findings in
ADEM include elevated protein and
leukocytosis that is more severe than
in MS. Oligoclonal bands are rare in
ADEM and, when present, are usually
transient.
Glial fibrillary acidic protein (GFAP),
a major component of astrocytic cyto-
plasmic intermediate filaments, is ele-
vated in CSF several thousand times
higher than in MS as an early event
in the acute phase of LETM associ-
ated with an NMOSD.21,22 GFAP lev-
els also are considerably higher in
LETM than in spinal infarct and ADEM
and correlate strongly with attack sev-
erity and length of the spinal cord le-
sion by MRI. Thus, the CSF GFAP level
is potentially useful as a biomarker in
evaluating the acute phase of LETM.
The marked elevations in NMOSD
implicate astrocytic damage as a pri-
mary event.
Autoantibodies
The detection of the AQP4-specific auto-
antibody NMO-IgG is both a sensitive
(60% to 80%) and highly specific
(greater than 90%) marker for NMO.23
By indirect immunofluorescence assay,
NMO-IgG yields a characteristic immu-
nohistochemical staining pattern in CNS
tissues (Figure 4-3A), binding to the
abluminal surface of penetrating blood
vessels, pia, subpial and Virchow-Robin
spaces, and white matter. It also binds
to the distal collecting tubules in kid-
ney (Figure 4-3B) and basolateral mem-
branes of gastric parietal cells. Higher
sensitivities are yielded by cell-binding
assays24 and optimized ELISA assays
(P. Waters, PhD, unpublished data,
August 2011
2011) compared with tissue-based im-
munofluorescence assays.
AQP4-IgG seropositivity is a compo-
nent of the revised diagnostic criteria for
NMO (Table 4-4) and should be tested
in all patients with a single or recurrent
episode of LETM.
The detection of other neural-specific
antibodies in serum or CSF also aids the
diagnosis of an autoimmune neurologic
disorder and may direct a focused search
for cancer. Paraneoplastic autoimmune
myelopathies (discussed later in this
article) generally have a subacute or
insidious presentation and progressive
course instead of presenting as an acute
transverse myelitis.
Diagnostic clues and tests that aid
the diagnosis of myelitis associated
with systemic autoimmunity are de-
tailed in Table 4-5. Patients known to
have systemic lupus erythematosus (SLE)
or Sjögren syndrome may have a mye-
lopathy attributable to that autoim-
TABLE 4-4 Diagnostic Criteria
for Neuromyelitis
Optica
b Transverse Myelitis and Optic
Neuritis
b At Least Two of the Following
Features:
Brain MRI nondiagnostic for
multiple sclerosis
MRI spinal cord lesion extending Q
three vertebral segments
Neuromyelitis
opticaYimmunoglobulin G
seropositivity
Adapted with permission from Wingerchuk DM,
Lennon VA, Pittock SJ, et al. Revised diagnostic
criteria for neuromyelitis optica. Neurology
2006;66(10):1485Y1489. Copyright B 2006,
AAN Enterprises, Inc. All rights reserved.
mune disease. It has been recently
recognized that transverse myelitis
occurring in a patient with a history of

TABLE 4-5 Myelopathies/Myelitis Associated With Systemic

Autoimmune Disease

Autoimmune
Disease Clues to Diagnosis Supportive Diagnostic Tests
Systemic lupus Photo-sensitive rash, inflammatory Serology: antinuclear antibody, antiYdouble-
erythematosus arthritis, serositis (pleural or stranded DNA, and others
pericardial effusion) Complete blood count: anemia, leukopenia,
thrombocytopenia
Urine: microscopic hematuria,
hypocomplementemia
Imaging: joint x-rays
Sjögren syndrome Dry eyes, dry mouth Schirmer test, SSA (Ro) and SSB (La)
antibodies, salivary gland/conjunctival
biopsy showing lymphocytic infiltration
Antiphospholipid Livido reticularis, recurrent miscarriages, Serology: antiphospholipid and anticardiolipin
antibody syndrome arterial or venous thromboses antibodies, coagulation studies
Systemic sclerosis/ Skin thickening and calcinosis, nail bed infarcts, Serology: anti-Scl-70 or anticentromere
scleroderma telangiectasias, Raynaud phenomenon, antibodies
gastroesophageal reflux disease
Behçet disease Mediterranean/Middle Eastern descent, oral ulcers, Ophthalmic examination, gynecologic
genital ulcers, erythema nodosum, anterior uveitis examination, pathergy test
Modified with permisssion from Frohman EM, Wingerchuk DM. Clinical practice. Transverse myelitis. N Engl J Med 2010;363(6):564Y572. Copyright * 2010,
Massachusetts Medical Society. All rights reserved.

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 Autoimmune Myelopathies

KEY POINTS
h Myelitis in the
setting of systemic
lupus erythematosus,
Sjögren syndrome, or
related manifestations of
nonYorgan-specific
autoimmunity most
often represents a
neuromyelitis optica
spectrum disorder
coexisting with a
second autoimmune
condition.
h IV corticosteroid
therapy is the
first-line treatment
for acute attacks of
autoimmune
myelopathies.
SLE or Sjögren syndrome is likely to be
accompanied by AQP4-IgG (Case 4-2).
This autoantibody is not found in
patients who have SLE or Sjögren
syndrome without myelopathy. The con-
clusion is that myelitis in the setting of
SLE, Sjögren syndrome, or related man-
ifestations of nonYorgan-specific au-
toimmunity most often represents an
NMOSD coexisting with a second auto-
immune condition.25
TREATMENT OF AUTOIMMUNE
TRANSVERSE MYELITIS
The treatment of autoimmune trans-
verse myelitis can be divided into three
parts: (1) acute treatment, (2) attack pre-
vention, and (3) symptomatic treatment.
Symptomatic treatment is beyond the
scope of this article.
Acute Treatment
IV corticosteroid therapy is the first-line
treatment for acute attacks of autoim-
mune myelopathies (usually methylpred-
nisolone 1 g/d for 5 days). In refractory
cases, plasmapheresis is sometimes ben-
eficial (usually every other day for 2
weeks.) The strategy is similar for myeli-
tis associated with either an NMOSD or
MS.26 Some evidence suggests that plas-
mapheresis may be indicated as supple-
mentary therapy for all patients with a
severe attack of NMO, particularly those
at risk for respiratory compromise.27 For
refractory cases of ADEM, IVIg is an
alternative to plasma exchange.28 For a
detailed discussion of the acute treat-
ment of transverse myelitis, see the
article ‘‘Treatment of Acute Transverse
Myelitis and Its Early Complications.’’
Attack Prevention
Neuromyelitis optica and neuromyeli-
tis optica spectrum disorders. Evidence
supporting immunosuppressant thera-
pies for attack prevention in NMOSD is
limited to small retrospective case series,

Case 4-2
A 50-year-old woman presented for evaluation of a complex neurologic
syndrome. Eight years earlier she had been evaluated for a constellation of
symptoms including dry eyes and dry mouth. The medical records documented
antinuclear antibodies, including Ro (SSA) and La (SSB) antibodies,
double-stranded DNA antibodies, a positive lupus anticoagulant, and
hypocomplementemia. Sjögren syndrome and possible systemic lupus
erythematosus were diagnosed. Six months after the diagnosis, she had an
episode of right optic neuritis that recurred 6 months later, and 2 years later
she experienced an episode of transverse myelitis. The CSF had no detectable
oligoclonal bands. MRI of the spine revealed a longitudinally extensive
lesion at C2 to C4 with gadolinium enhancement. This was considered to be
a direct complication of her systemic lupus erythematosus/Sjögren syndrome.
At her current presentation she had symmetric upper motor neuron pattern
weakness in the lower extremities, brisk deep tendon reflexes throughout,
and bilateral Babinski signs. NMO-IgG was detected in the serum, and a clinical
diagnosis of neuromyelitis optica (NMO) was made. Azathioprine therapy was
started and the patient was referred for follow-up.
Comment. Longitudinally extensive transverse myelitis in a patient with
Sjögren syndrome or systemic lupus erythematosus should raise suspicion
for NMO, and an NMO-IgG evaluation should be performed. Seropositivity
supports an NMO spectrum disorder coexisting with the rheumatologic
diagnosis as the likely cause of myelitis rather than the systemic
autoimmune disease itself.

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single case reports, and a single open-
label trial. In contrast to MS, disability in
NMO accrues incrementally with re-
peated attacks. Thus, early initiation of
immunotherapy is predicted to have a
significant impact on the natural history
of NMO. The current mainstays of treat-
ment are oral azathioprine (2 mg/kg
to 3 mg/kg) or mycophenolate mofetil
(1000 mg 2 times a day) in combination
with low-dose prednisolone (10 mg to
20 mg daily). Rituximab, a monoclonal
antibody targeting CD20+ B cells, is
usually reserved for patients who con-
tinue to have attacks on this therapy,
although some neurologists use ritux-
imab as first-line therapy.29 Cyclophos-
phamide is another therapeutic option.
It has been reported to be beneficial
for patients with both SLE and LETM
and for patients with NMO.30,31 Natural
history studies of NMO report that 5
years after NMO onset 42% of patients
require a gait aid (Expanded Disability
Status Scale of greater than 6) and half
are blind in one or both eyes. Predic-
tors of a poor prognosis include multi-
ple attacks in the first 2 years and a
severe initial attack.32,33 Prior to rec-
ognition of the broader NMOSDs, the
5-year survival rate of NMO was calcu-
lated to be 68%.34 Most deaths are
caused by respiratory compromise as-
sociated with cervical myelitis. It ap-
pears that the natural history of this
disease has been improved by early
diagnosis of an NMOSD and early initia-
tion of ‘‘attack prevention’’ therapies
(justified by early detection of AQP4-IgG
seropositivity at presentation of a CIS
of optic neuritis or transverse myelitis).
Potential future therapies include inhib-
itors of complement activation. A trial
assessing the efficacy of eculizumab (a
monoclonal antibody that inhibits com-
plement) is currently underway.
Multiple sclerosis and other inflam-
matory myelopathies. Most disability in
MS is related to disease progression
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KEY POINT
rather than sequelae of attacks. Immu- h Disability in
nomodulatory medications (such as gla- neuromyelitis
tiramer acetate, interferon beta, and optica accrues
natalizumab) reduce the likelihood of incrementally with
clinical relapses by 30% to 60%, but evi- repeated attacks;
dence for preventing disability is lack- therefore, early
ing.35 For patients whose first clinical initiation of
attack is transverse myelitis, Figure 4-5 immunotherapy is
outlines an evidence-based medicine ap- predicted to have a
proach. Detailed discussion of MS treat- significant impact on
the natural history.
ment is beyond the scope of this article.
ADEM is usually a monophasic disease
not requiring long-term treatment. Rec-
ommended therapy for neurosarcoidosis
involving the spinal cord includes initial
high-dose IV corticosteroids followed by a
slow taper of oral steroids. Relapse during
steroid taper is common, and patients
may need long-term maintenance with
low-dose prednisone (15 mg to 20 mg/d).
Other immunosuppressants, reserved
for refractory or steroid-intolerant cases
(eg, methotrexate, mycophenolate mo-
fetil, azathioprine, cyclophosphamide,
and cyclosporine), have varying de-
grees of success. Infliximab, a chimeric
monoclonal antibody targeting tumor
necrosis factor ", has been reported to
be efficacious for treatment of refrac-
tory neurosarcoidosis.36
Chronic immunosuppressant treat-
ments: side effects and monitoring.
Long-term use of prednisone is compli-
cated by weight gain, insomnia, skin
thinning, bruising, cataracts, hyperglyce-
mia, hypertension, Cushing syndrome,
infections, osteoporosis, and avascular
necrosis of the hip. Rapid withdrawal of
steroids after long-term administration
can precipitate an addisonian crisis.
Patients should receive daily oral supple-
ments of calcium (1200 mg) and vita-
min D (1200 IU), and bisphosphonate
therapy should be considered if osteopo-
rosis is present or develops during steroid
therapy. Prednisone doses greater than
20 mg/d necessitate prophylaxis for
Pneumocystis jiroveci (trimethoprim/
sulfamethoxazole, one double-strength
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 Autoimmune Myelopathies
KEY POINTS
h The presentation
of paraneoplastic
and many
nonYcancer-associated
autoimmune
myelopathies is
insidious or subacute,
and the course is
progressive.
h Paraneoplastic
myelopathies often
have a characteristic
MRI pattern of
longitudinally
extensive T2 signal
changes that are
tract specific or gray
matter specific and
may enhance
symmetrically
with gadolinium.
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tablet daily). A proton pump inhibitor
may be indicated if the patient has
peptic ulcer symptoms, and regular
monitoring for diabetes, hypertension,
and cataracts is advised.
Long-term steroid-sparing immunosup-
pressant therapies are also associated with
multiple side effects. Prior to beginning
azathioprine, thiopurine methyltransferase
enzyme activity should be checked. Pa-
tients with low activity are susceptible to
severe side effects, including rash, bone
marrow suppression, and hepatotoxicity.
Adverse effects of mycophenolate mofetil
include diarrhea, hypertension, hepatox-
icity, and bone marrow suppression. Both
mycophenolate and azathioprine are asso-
ciated with an increased risk of hemato-
logic malignancies. Use of mycophenolate
mofetil has been limited by its cost. Pa-
tients taking cyclophosphamide are en-
couraged to drink liberal amounts of fluid,
and mesna should be prescribed to reduce
the risk of hemorrhagic cystitis. Other side
effects of cyclophosphamide include
nausea and vomiting, alopecia, infertil-
ity, and bone marrow suppression. Close
monitoring of blood counts and renal and
liver function is required for patients
receiving mycophenolate, azathioprine,
or cyclophosphamide. Blood tests are
recommended weekly for 1 month, every
other week for 1 month, and monthly
thereafter. Rituximab therapy holds risk
for infusion reactions and reactivation of
infections like JC virus (agent of progres-
sive multifocal leukoencephalopathy).
CHRONIC PROGRESSIVE
(PARANEOPLASTIC)
AUTOIMMUNE MYELOPATHIES
The differential diagnosis of chronic
myelopathies is broad (Table 4-2). The
presentation of paraneoplastic and many
nonYcancer-associated autoimmune
myelopathies is insidious or subacute,
and the course is progressive. Paraneo-
plastic myelopathies are more common
in elderly patients and occur most
frequently in the setting of a multifocal
neurologic syndrome that includes ence-
phalopathy, peripheral neuropathy, and
cerebellar dysfunction. Isolated spinal
cord involvement without other neuro-
logic findings is rare. Isolated paraneo-
plastic myelopathy is misdiagnosed as
primary progressive MS in 25% of cases,
and in most cases the neurologic symp-
toms precede the detection of cancer.37
Clinical signs of myelopathy are usually
symmetric. Numerous neural autoanti-
bodies are recognized as markers of auto-
immune myelopathies, of which some
are more predictive of cancer than others
(Table 4-6). The diagnosis of paraneo-
plastic myelopathy is not excluded by
failure to detect a neural autoantibody
(Case 4-3). Breast and lung cancers are
the most frequent oncologic associations.
DIAGNOSTIC EVALUATION OF
CHRONIC PROGRESSIVE
(PARANEOPLASTIC)
AUTOIMMUNE MYELOPATHIES
Spine MRI
MRI of the spine is useful as the initial
diagnostic step to exclude a compressive
cause for the myelopathy. Magnetic
resonance angiography may also be
indicated to exclude a dural arteriove-
nous fistula. Paraneoplastic myelopathies
often have very characteristic MRI pat-
terns (Cases 4-3 and 4-4; Figure 4-1D)
of longitudinally extensive T2 signal
changes that are tract specific or gray
matter specific and may enhance sym-
metrically with gadolinium.37 The axial
image may show tract-specific T2 hyper-
intensity or gadolinium enhancement
with an ‘‘owl eye’’ appearance. Despite
this characteristic appearance, in 50% of
cases the spine MRI is normal.
CSF Findings
A lymphocyte-predominant pleocytosis
(usually less than 100) is found in CSF in
60% of patients with paraneoplastic
August 2011
 KEY POINT

TABLE 4-6 Paraneoplastic Autoantibodies Associated With Myelopathy h Neural-specific

autoantibodies predict
Frequency of cancer rather than a
Myelopathy Most Frequent Cancer specific neurologic
Association Associations syndrome.
Strong association with
cancer (970%)
Amphiphysin-IgG 24% Breast and small cell lung
CRMP-5-IgG 16% Small cell lung, thymoma
ANNA-1 (anti-Hu) 11% Small cell lung
ANNA-2 (anti-Ri) 18% Breast or lung
ANNA-3 18% Lung
PCA-1 (anti-Yo) 5% Ovary, breast, fallopian tube
PCA-2 10% Lung
Ma1 (anti-Ma) 4% Lung, gastrointestinal tract,
breast, germ cell, non-Hodgkin
lymphoma
Ma2 (anti-Ta) 3% Germ cell
Weak association with
cancer (G30%)
AQP4 (NMO)-IgG 2%–3% Breast, lung, thymoma
Calcium channel (N unknown Breast and lung
and P/Q types)
Voltage-gated 1% Lung, breast
potassium channel
complex
IgG = immunoglobulin G; CRMP-5 = collapsin response-mediator protein-5; ANNA-1 = antineuronal
nuclear antibody, type 1; ANNA-2 = antineuronal nuclear antibody, type 2; ANNA-3 = antineuronal
nuclear antibody, type 3; PCA-1 = Purkinje cell antibody, type 1; PCA-2 = Purkinje cell antibody, type 2;
AQP4 = aquaporin-4; NMO = neuromyelitis optica.

myelopathies, and CSF protein is ele- panies many paraneoplastic neural

vated in over 90% of cases.37
Neural Autoantibodies
Comprehensive serologic testing for
paraneoplastic autoantibodies should
be performed in patients who are
known to have cancer, cancer risk fac-
tors, or characteristic MRI findings of
longitudinally extensive changes con-
fined to tracts or gray matter. Neural-
specific autoantibodies predict cancer
rather than a specific neurologic syn-
drome; myelopathy commonly accom-
autoantibodies (Table 4-6).38 Neural
autoantibodies recognized most fre-
quently with paraneoplastic myelitis
include those directed against collapsin
response-mediator protein-5 (CRMP-5)-
IgG and amphiphysin-IgG. The immu-
nostaining patterns characteristic of each
are shown in Figure 4-8. Several other
IgG markers of autoimmune myelopathy
are not as strongly associated with can-
cer. For example, cancer less frequently
accompanies voltage-gated potassium
channel (VGKC) complex antibodies39

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 Autoimmune Myelopathies

Case 4-3
A 57-year-old man with a 45 pack-year
history of smoking presented with slowly
progressive gait difficulty. He required a
walker for ambulation 18 months after
symptom onset. Neurologic examination
revealed an upper motor neuron pattern of
weakness in both lower extremities with
hyperreflexia at the knees and ankles and
bilateral Babinski signs. MRI of the entire spine
revealed longitudinally extensive T2 signal
abnormality that enhanced symmetrically in
the distribution of the lateral columns (Figure 4-6).
CSF analysis revealed elevated protein (91 mg/dL)
and a lymphocyte-predominant pleocytosis
(29 nucleated cells). The tract-specific changes
on MRI raised suspicion for a paraneoplastic FIGURE 4-6 Tract-specific MRI signal abnormalities in
paraneoplastic myelopathy. Thoracic spine
myelopathy. CT scan of the chest, abdomen, and MRI demonstrates longitudinally extensive T2
signal hyperintensity on sagittal T2 image (A, arrows); after IV
pelvis demonstrated a left renal mass. Biopsy injection of gadolinium, the lesion enhances (B, arrows) in a
confirmed a renal cell carcinoma. No neural tract-specific pattern involving the lateral columns (C, arrows).
autoantibodies were detected on comprehensive
paraneoplastic evaluation. Despite nephrectomy, neurologic impairment progressed, and he was
wheelchair dependent 6 months later. With prednisone therapy he improved to ambulation with a
walker, and with continued oral prednisone he was able to avoid the need for a wheelchair until
6 years later.
Comment. Tract-specific T2 signal changes with or without associated enhancement by gadolinium
are a hallmark of paraneoplastic myelopathies. The radiologic findings described here led to the
detection of an unsuspected renal cell carcinoma. This case demonstrates that the diagnosis of
paraneoplastic myelopathy does not require detection of a paraneoplastic autoantibody.

or CRMP-5-IgG detected by recombi- at peptides derived from the targeted

nant Western blot analysis but not by
immunohistochemical staining.40
Neural autoantibodies that predict
cancer most strongly recognize intra-
cellular onconeural proteins. Those
expressed in the nucleus include the
neuronal Hu, nova, and astrocytic SOX 1
proteins (antigens of antineuronal nu-
clear antibody (ANNA)-1, ANNA-2, and
antiglial neuronal nuclear antibody IgGs,
respectively) and those in the cyto-
plasm include cdr2 (antigen of Purkinje
cell antibody, type 1 [anti-Yo]), CRMP-5,
and amphiphysin. None of these auto-
antibodies is likely to be pathogenic
because the antigens are intracellular,
but the IgGs are markers of a concomi-
tant cytotoxic T-cell response directed
neurons and glia. Peptides derived from
these intracellular onconeural proteins
are displayed on major histocompatibility
complex (MHC) class 1 molecules that
are upregulated in a pro-inflammatory
cytokine environment and thus accessi-
ble to peptide-specific CD8+ cytotoxic
T cells initially activated by tumor anti-
gens. Neurons and glia expressing these
peptides on surface MHC class 1 mole-
cules are unintended targets of the T-cell
response.
In contrast, autoantibodies targeting
neuronal and glial plasma membrane pro-
teins (eg, VGKC complex proteins or
AQP4) have the potential to be patho-
genic to those cells if they access the
intrathecal compartment. Autoantibodies

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 Case 4-4
A 69-year-old man presented with a lump in his left axilla. Biopsy revealed metastatic melanoma. Two
months later he had right arm weakness, and a hemorrhagic metastatic melanoma lesion was found
in the left frontal lobe. After treatment with gamma knife and whole-brain radiation, the right-sided
weakness gradually improved. Eleven months after initial presentation, slowly progressive weakness
and stiffness
developed in the
lower extremities,
and the patient
was wheelchair
dependent within
6 weeks. Severe
low back pain
accompanied this
decline, but he had
no bowel or bladder
dysfunction. The
local physician
attributed the
problem to arthritis.
Neurologic evaluation
revealed spastic
paraparesis with
Tract-specific MRI signal abnormalities in paraneoplastic myelopathy. Thoracic spine
diffuse hyperreflexia FIGURE 4-7 MRI demonstrates longitudinally extensive T2 signal hyperintensity in the central
of lower extremities cord on sagittal image (A, arrows); after IV injection of gadolinium, the lesion enhances
and bilateral Babinski (B, arrows) in a tract-specific pattern involving the lateral columns (C, arrows).
signs. Sensory
examination was normal. MRI of the thoracic spine demonstrated moderate cord swelling and T2 signal
hyperintensity involving the cord from the T6 through T11 vertebral levels; sagittal and axial images revealed
symmetric gadolinium enhancement in the lateral columns (Figure 4-7). CSF analysis showed 38 nucleated
cells (97% lymphocytes), elevated protein (107 mg/dL [normal range less than 45 mg/dL]), and normal
glucose. Autoimmune serology revealed amphiphysin-IgG in serum and CSF. CT scans of the chest revealed
no evidence of malignancy. The patient was treated with prednisone. Repeated MRI of the spine
demonstrated improvement. The patient reported subjective clinical improvement but remained
wheelchair dependent at follow-up 8 months later.
Comment. Tract-specific signal changes on spinal MRI scans, particularly those that enhance
symmetrically with gadolinium, suggest paraneoplastic myelopathy. Disability develops early and is
severe. When improvement occurs after treatment, it is usually minor. Most patients become
wheelchair dependent.

targeting plasma membrane proteins NMOSD), whereas T cellYdepleting

are less strongly associated with cancer.
The immunopathogenic mechanisms
underlying autoimmune myelopathies
have implications for treatment. Anti-
body-depleting therapies such as plasma-
pheresis, azathioprine, and rituximab are
anticipated to be more effective in treat-
ing IgG-mediated myelopathies (eg,
agents such as cyclophosphamide appear
to be more effective for treating paraneo-
plastic disorders mediated by cytotoxic
T cells targeting intracellular antigens.
The Detection of Cancer
When evaluating patients with a sus-
pected autoimmune myelopathy, it is

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 Autoimmune Myelopathies

important to assess for known risk factors (and thromboembolic phenomena) is

for cancer. History of smoking or past
history or family history of cancer is
pertinent. Symptoms and signs custom-
arily associated with cancer (eg, weight
loss, systemic symptoms, or mass) are
generally lacking. A hypercoagulable state
particularly common with CRMP-5 auto-
immunity41 but could be related to
immobility imposed by the neurologic
syndrome. Patients with tract-specific or
gray matterYspecific changes on MRI or
cancer risk factors require close scrutiny
for cancer because in most cases the
neurologic symptoms of paraneoplastic
myelopathy precede the diagnosis of
cancer.37 Detection of an informative
paraneoplastic autoantibody profile in
serum or CSF is most helpful in directing
the search for cancer (Table 4-6). CT
scans of the chest, abdomen, and pelvis
are routinely performed, but if these are
negative in a seropositive patient or
when other cancer risk factors are noted,
PET-CT increases imaging sensitivity for
cancer detection.42 Sex-specific tests such
as pelvic ultrasound and mammogram
for women and testicular ultrasound
for men should also be performed. Re-
peated imaging should be considered
in follow-up when initial cancer screen-
ing is negative, especially in patients
with paraneoplastic autoantibodies that
are highly predictive of malignancy.

Immunohistochemical pattern of IgG bound TREATMENT OF CHRONIC

FIGURE 4-8
to amphiphysin-IgG and CRMP-5 in PROGRESSIVE
mouse tissues. A, amphiphysin-IgG. Binding of IgG in a (PARANEOPLASTIC)
patient’s serum (at 1:120 dilution) to formalin-fixed substrate
of mouse cerebellum, midbrain, gut mucosa and smooth AUTOIMMUNE MYELOPATHIES
muscle, and kidney. Intense synaptic pattern of
immunofluorescence staining of the cerebellar cortical Treatment of chronic progressive auto-
molecular layer (ML), granular cell layer (GL, synaptic patches immune myelopathies requires a mul-
render a cobblestone pattern), and midbrain (MB). Purkinje tidisciplinary approach and involves
neurons are unstained. Enteric neural elements are stained
throughout the smooth muscle layer (SM). The kidney (K) and close collaboration among the neurolo-
mucosa (M) are unstained. B, CRMP-5-IgG. Binding of IgG in a gist, oncologist, surgeon, and physical
patient’s serum (at 1:240 dilution) to formalin-fixed sections
of mouse cerebellar cortex (B1) and gut wall (B2) detected by medicine/rehabilitation physician. Treat-
indirect immunofluorescence and immunoperoxidase ment can be divided into three steps.
staining. The pattern demonstrates pale green CRMP-5
immunoreactivity (B1) in the cerebellum’s synaptic regions First, if the cancer has been identified,
(granular layer [GL] and molecular layer [ML]) with sparing of it should be treated. Second, immuno-
Purkinje neuron bodies and cerebellar white matter (WM).
Immunostaining in the myenteric plexus (MP) is seen as a therapies aimed at improving neuro-
fluffy snowball pattern (B2); mucosal (M) and kidney (K) logic function should be started. If
epithelia are not stained. reversing the neurologic impairment
Panel A reprinted with permission from Pittock SJ, Lucchinetti CF, Parisi JE, et al. is not possible, the objective should be
Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol
2005;58(1):96Y107. to maintain stability and halt progres-
sion. Finally, the neurologic symptoms

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should be treated and complications
should be prevented.
Oncologic Treatment
The initial step in treating paraneoplastic
myelopathy is aimed at eradicating or
reducing the burden of any identified
cancer using combinations of surgery,
radiation, and chemotherapy.
Chronic Immunosuppressant
Treatment
The second step in treating paraneo-
plastic myelopathy involves immuno-
therapy to reverse or halt progression
of the neurologic impairment. Be-
cause of the rarity of paraneoplastic
myelopathy, no randomized con-
trolled trials have been conducted to
evaluate treatments. Case reports have
suggested improvement with corticoste-
roids,43 IVIg, and cyclophosphamide.44
Steroids in combination with myco-
phenolate mofetil, azathioprine, or
cyclophosphamide have also been as-
sociated with improvement in a recent
case series.37 For patients whose can-
cer is detected after myelopathy on-
set, cyclophosphamide may be a good
choice because of its dual action as a
cancer chemotherapeutic and immuno-
suppressant agent.
A nonYevidence-based treatment al-
gorithm has been suggested for auto-
immune dementia.45 In our experience,
a similar approach is useful for treating
paraneoplastic myelopathies. The most
important question is whether neuro-
logic impairment can be reversed or
halted by immunotherapy. The physi-
cian should ask, ‘‘What is the maximal
reversibility attainable with immuno-
therapy?’’ We advocate a trial of IV
methylprednisolone at a dose of 1 g/d
for 3 days, then once weekly for 6
weeks. IVIg is an alternative consider-
ation for patients intolerant of steroids.
If improvement occurs and needs to be
maintained, immunotherapy should be
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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
continued. In our experience, most pa- h Treatment of
tients have little objective evidence of paraneoplastic
improvement. In these cases, the goal myelopathy includes
of continued immunotherapy is to halt treatment of the
neurologic symptom progression and cancer, if identified;
maintain stability. A steroid-sparing immunotherapies
agent such as mycophenolate mofetil aimed at stabilizing or
or azathioprine with or without oral improving neurologic
prednisone is sometimes efficacious. function; and treatment
For patients with presumed cytotoxic of neurologic symptoms
and prevention
T cellYmediated myelopathy, cyclo-
of complications.
phosphamide (monthly IV or daily oral)
may be the most appropriate therapy to
maintain stability.
Symptomatic Treatment and
Prevention of Complications
Symptomatic treatment and the pre-
vention of complications are an essen-
tial part of the management strategy
in patients with chronic progressive
myelopathies. Treatment may have a
profound impact on quality of life, and
avoiding complications may prevent
morbidity or premature death. Further
discussion on symptomatic treatments
and the prevention of complications is
beyond the scope of this article.
PROGNOSIS OF CHRONIC
PROGRESSIVE (PARANEOPLASTIC)
AUTOIMMUNE MYELOPATHIES
Paraneoplastic myelopathy follows a
chronic progressive course similar to
that of primary progressive MS, which
is a common misdiagnosis. The out-
come after treatment is generally poor.
Few patients show clinical improve-
ment, and improvement in those who
do show it is usually not sustained.
Treatment may confer some stability
(Case 4-3) and delay progression to a
wheelchair. The prognosis is poor,
however, and morbidity is high. A
recent study reported that 50% of
treated patients are expected to be
wheelchair dependent 16 months after
symptom onset (Case 4-4).37
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 Autoimmune Myelopathies

AUTOIMMUNE/PARANEOPLASTIC series dating to the early 1960s have

MOTOR NEURON DISORDERS
Patients rarely present with symptoms
and signs of motor neuron disease or
ALS as a manifestation of an auto-
immune myelopathy (usually paraneo-
plastic). Several case reports and case
described patients with motor neuron
disease occurring in a paraneoplastic
context, particularly with lung, breast,
kidney, ovary, and hematologic malig-
nancies.46Y52 The existence of paraneo-
plastic motor neuron disease as a clinical

FIGURE 4-9 NonYevidence-based diagnostic algorithm for evaluation of a patient with a suspected autoimmune
myelopathy.
IgG = immunoglobulin G; AVF = arteriovenous fistula; NMO = neuromyelitis optica; PPMS = primary progressive multiple
sclerosis; MS = multiple sclerosis.

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entity has been questioned in three
studies that found (1) no heightened
prevalence of cancer in a population-
based cohort of patients with motor
neuron disease,53 (2) no clinical differ-
ences among patients with ALS with
and without cancer,54 and (3) no neu-
ral autoantibodies in patients with mo-
tor neuron disease.55 However, recent
case reports have described associa-
tions with paraneoplastic autoantibodies
(eg, ANNA-1 [anti-Hu] or Purkinje cell an-
tibody, type 1 [anti-Yo]).49,56 Two inde-
pendent groups have reported a 3% to
4% frequency of a predominantly mo-
tor neuron diseaseYlike presentation
among ANNA-1 (anti-Hu) seropositive
patients.57,58 A paucity of reported data
exists for the neurologic outcome of can-
cer treatment or immunotherapy in pa-
tients with presumed paraneoplastic
motor neuron disorders.48,49,59 The clini-
cal, laboratory, and therapeutic re-
sponses of patients with presumed
paraneoplastic/autoimmune motor neu-
ron disease need further documentation.
CONCLUSIONS
Autoimmune myelopathies represent a
significant and increasingly recognized
proportion of inflammatory myelopa-
thies, even without consideration of
NMOSDs. Patients may present with an
acute transverse myelitis, a chronic pro-
gressive myelopathy, or a motor neuronY
like disorder. Comprehensive clinical,
radiologic, serologic, and CSF evaluations
aid the diagnosis and may direct a cancer
search. We suggest a diagnostic algorithm
that may be helpful to all physicians,
particularly neurologists (Figure 4-9).
Treatment of acute autoimmune trans-
verse myelitis should be directed pri-
marily at reversing functional deficits and
preventing relapse. For patients with a
chronic progressive autoimmune myel-
opathy, the main objective of immuno-
therapy should be to halt progression.
Continuum Lifelong Learning Neurol 2011;17(4):776–799
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Prognosis varies depending on the
underlying cause, but NMO and para-
neoplastic myelopathies typically have a
worse prognosis than MS, ADEM, or
other causes of inflammatory myelop-
athy. Recent identification of specific
antigenic targets (such as AQP4 and
CRMP-5) as pertinent targets of auto-
immune myelopathies may lead to more
specific therapies and better outcomes.
ACKNOWLEDGMENT
We would like to thank Dr Brian
Weinshenker for providing Cases 4-1
and 4-2 and Andrew McKeon for
providing the images for Figure 4-1C.
REFERENCES
1. Apiwattanakul M, Popescu BF, Matiello M,
et al. Intractable vomiting as the initial
presentation of neuromyelitis optica. Ann
Neurol 2010;68(5):757Y761.
2. Misu T, Fujihara K, Nakashima I, et al.
Intractable hiccup and nausea with
periaqueductal lesions in neuromyelitis
optica. Neurology 2005;65(9):1479Y1482.
3. Usmani N, Bedi G, Brown AD, et al. Association
of paroxysmal dystonia with neuromyelitis
optica (NMO). Ann Neurol 2010;68(suppl 14):
S58. [Abstract].
4. Cohen-Aubart F, Galanaud D, Grabli D, et al.
Spinal cord sarcoidosis: clinical and
laboratory profile and outcome of 31
patients in a case-control study. Medicine
(Baltimore) 2010;89(2):133Y140.
5. Wingerchuk DM, Lennon VA, Lucchinetti CF,
et al. The spectrum of neuromyelitis optica.
Lancet Neurol 2007;6(9):805Y815.
6. Pittock SJ, Lennon VA. Aquaporin-4
autoantibodies in a paraneoplastic context.
Arch Neurol 2008;65(5):629Y632.
7. Hinson SR, Pittock SJ, Lucchinetti CF, et al.
Pathogenic potential of IgG binding to
water channel extracellular domain in
neuromyelitis optica. Neurology 2007;69(24):
2221Y2231.
8. Hinson SR, Roemer SF, Lucchinetti CF, et al.
Aquaporin-4-binding autoantibodies in
patients with neuromyelitis optica impair
glutamate transport by down-regulating
EAAT2. J Exp Med 2008;205(11):2473Y2481.
9. Vincent T, Saikali P, Cayrol R, et al.
Functional consequences of neuromyelitis
www.aan.com/continuum 797
 Autoimmune Myelopathies
optica-IgG astrocyte interactions on
blood-brain barrier permeability and
granulocyte recruitment. J Immunol 2008;
181(8):5730Y5737.
10. Lucchinetti CF, Mandler RN, McGavern D,
et al. A role for humoral mechanisms
in the pathogenesis of Devic’s neuromyelitis
optica. Brain 2002;125(pt 7):1450Y1461.
11. Roemer SF, Parisi JE, Lennon VA, et al.
Pattern-specific loss of aquaporin-4
immunoreactivity distinguishes neuromyelitis
optica from multiple sclerosis. Brain 2007;
130(pt 5):1194Y1205.
12. Vallejo-Illarramendi A, Domercq M,
Pérez-Cerdá F, et al. Increased expression
and function of glutamate transporters in
multiple sclerosis. Neurobiol Dis 2006;21(1):
154Y164.
13. Weinshenker BG, Wingerchuk DM, Vukusic S,
et al. Neuromyelitis optica IgG predicts
relapse after longitudinally extensive
transverse myelitis. Ann Neurol 2006;59(3):
566Y569.
14. Scott TF, Kassab SL, Pittock SJ. Neuromyelitis
optica IgG status in acute partial transverse
myelitis. Arch Neurol 2006;63(10):1398Y1400.
15. Banwell B, Tenembaum S, Lennon VA, et al.
Neuromyelitis optica-IgG in childhood
inflammatory demyelinating CNS disorders.
Neurology 2008;70(5):344Y352.
16. Pittock SJ, Weinshenker BG, Lucchinetti CF,
et al. Neuromyelitis optica brain lesions
localized at sites of high aquaporin 4
expression. Arch Neurol 2006;63(7):964Y968.
17. Ito S, Mori M, Makino T, et al. ‘‘Cloud-like
enhancement’’ is a magnetic resonance
imaging abnormality specific to neuromyelitis
optica. Ann Neurol 2009;66(3):425Y428.
18. Brex PA, Ciccarelli O, O’Riordan JI, et al.
A longitudinal study of abnormalities on
MRI and disability from multiple sclerosis.
N Engl J Med 2002;346(3):158Y164.
19. Pickuth D, Heywang-Köbrunner SH.
Neurosarcoidosis: evaluation with MRI.
J Neuroradiol 2000;27(3):185Y188.
20. Zaffaroni M. Cerebrospinal fluid findings in
Devic’s neuromyelitis optica. Neurol Sci
2004;25(suppl 4):S368YS370.
21. Misu T, Takano R, Fujihara K, et al. Marked
increase in cerebrospinal fluid glial fibrillar
acidic protein in neuromyelitis optica:
an astrocytic damage marker. J Neurol
Neurosurg Psychiatry 2009;80(5):575Y577.
22. Takano R, Misu T, Takahashi T, et al. Astrocytic
damage is far more severe than demyelination
in NMO: a clinical CSF biomarker study.
Neurology 2010;75(3):208Y216.
798 www.aan.com/continuum
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
23. Lennon VA, Wingerchuk DM, Kryzer TJ, et al.
A serum autoantibody marker of
neuromyelitis optica: distinction from multiple
sclerosis. Lancet 2004;364(9451):2106Y2112.
24. Waters P, Jarius S, Littleton E, et al.
Aquaporin-4 antibodies in neuromyelitis
optica and longitudinally extensive
transverse myelitis. Arch Neurol
2008;65(7):913Y919.
25. Pittock SJ, Lennon VA, de Seze J, et al.
Neuromyelitis optica and non organ-specific
autoimmunity. Arch Neurol 2008;65(1):78Y83.
26. Weinshenker BG, O’Brien PC, Petterson TM,
et al. A randomized trial of plasma exchange
in acute central nervous system inflammatory
demyelinating disease. Ann Neurol 1999;
46(6):878Y886.
27. Bonnan M, Valentino R, Olindo S, et al.
Plasma exchange in severe spinal attacks
associated with neuromyelitis optica
spectrum disorder. Mult Scler 2009;15(4):
487Y492.
28. Tenembaum S, Chitnis T, Ness J, et al. Acute
disseminated encephalomyelitis. Neurology
2007;68(16 suppl 2):S23YS36.
29. Jacob A, Weinshenker BG, Violich I, et al.
Treatment of neuromyelitis optica with
rituximab: retrospective analysis of 25
patients. Arch Neurol 2008;65(11):1443Y1448.
30. Espinosa G, Mendizábal A, Minguez S, et al.
Transverse myelitis affecting more than 4
spinal segments associated with systemic
lupus erythematosus: clinical, immunological,
and radiological characteristics of 22
patients. Semin Arthritis Rheum 2010;39(4):
246Y256.
31. Mok CC, To CH, Mak A, Poon WL.
Immunoablative cyclophosphamide for
refractory lupus-related neuromyelitis optica.
J Rheumatol 2008;35(1):172Y174.
32. Ghezzi A, Bergamaschi R, Martinelli V, et al.
Clinical characteristics, course and prognosis
of relapsing Devic’s Neuromyelitis Optica.
J Neurol 2004;251(1):47Y52.
33. Wingerchuk DM, Weinshenker BG.
Neuromyelitis optica: clinical predictors of a
relapsing course and survival. Neurology
2003;60(5):848Y853.
34. Wingerchuk DM, Hogancamp WF, O’Brien
PC, Weinshenker BG. The clinical course of
neuromyelitis optica (Devic’s syndrome).
Neurology 1999;53(5):1107Y1114.
35. Abou Zeid NE, Pittock SJ. Clinically isolated
syndromes. In: Lucchinetti CF, Hohlfeld R,
eds. Blue books of neurology: multiple
Sclerosis 3. Philadelphia: Saunders Elsevier,
2010:206Y218.
August 2011
36. Santos E, Shaunak S, Renowden S, et al.
Treatment of refractory neurosarcoidosis
with Infliximab. J Neurol Neurosurg
Psychiatry 2010;81(3):241Y246.
37. Flanagan EP, McKeon A, Lennon VA, et al.
Paraneoplastic isolated myelopathy: clinical
course and neuroimaging clues. Neurology
2011;76(24):2089Y2095.
38. Pittock SJ, Kryzer TJ, Lennon VA.
Paraneoplastic antibodies coexist and
predict cancer, not neurological syndrome.
Ann Neurol 2004;56(5):715Y719.
39. Tan KM, Lennon VA, Klein CJ, et al. Clinical
spectrum of voltage-gated potassium
channel autoimmunity. Neurology 2008;
70(20):1883Y1890.
40. Keegan BM, Pittock SJ, Lennon VA.
Autoimmune myelopathy associated with
collapsin response-mediator protein-5
immunoglobulin G. Ann Neurol 2008;63(4):
531Y534.
41. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5
neuronal autoantibody: marker of lung
cancer and thymoma-related autoimmunity.
Ann Neurol 2001;49(2):146Y154.
42. McKeon A, Apiwattanakul M, Lachance DH,
et al. Positron emission tomography-computed
tomography in paraneoplastic neurologic
disorders: systematic analysis and review. Arch
Neurol 2010;67(3):322Y329.
43. Rajabally YA, Qaddoura B, Abbott RJ.
Steroid-responsive paraneoplastic
demyelinating neuropathy and myelopathy
associated with breast carcinoma. J Clin
Neuromuscul Dis 2008;10(2):65Y69.
44. Leypoldt F, Eichhorn P, Saager C, et al.
Successful immunosuppressive treatment and
long-term follow-up of anti-Ri-associated
paraneoplastic myelitis. J Neurol Neurosurg
Psychiatry 2006;77(10):1199Y1200.
45. McKeon A, Lennon VA, Pittock SJ.
Immunotherapy-responsive dementias and
encephalopathies. Continuum Lifelong
Learning Neurol 2010;16(2):80Y101.
46. O’Doherty DS. The amyotrophic lateral
sclerosis syndrome (an exercise in differential
diagnosis). Dis Nerv Syst 1961;22:305Y312.
47. Brain L, Croft PB, Wilkinson M. Motor
neurone disease as a manifestation of
neoplasm (with a note on the course of
classical motor neurone disease). Brain 1965;
88(3):479Y500.
Continuum Lifelong Learning Neurol 2011;17(4):776–799
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
48. Evans BK, Fagan C, Arnold T, et al.
Paraneoplastic motor neuron disease and
renal cell carcinoma: improvement after
nephrectomy. Neurology 1990;40(6):
960Y962.
49. Forsyth PA, Dalmau J, Graus F, et al. Motor
neuron syndromes in cancer patients. Ann
Neurol 1997;41(6):722Y730.
50. Gordon PH, Rowland LP, Younger DS, et al.
Lymphoproliferative disorders and motor
neuron disease: an update. Neurology
1997;48(6):1671Y1678.
51. Ferracci F, Fassetta G, Butler MH, et al. A
novel antineuronal antibody in a motor
neuron syndrome associated with breast
cancer. Neurology 1999;53(4):852Y855.
52. Sadot E, Carluer L, Corcia P, et al. Breast
cancer and motor neuron disease: clinical
study of seven cases. Amyotroph Lateral
Scler 2007;8(5):288Y291.
53. Chiò A, Brignolio F, Meineri P, et al. Motor
neuron disease and malignancies: results of
a population-based study. J Neurol 1988;
235(6):374Y375.
54. Vigliani MC, Polo P, Chiò A, et al. Patients
with amyotrophic lateral sclerosis and cancer
do not differ clinically from patients with
sporadic amyotrophic lateral sclerosis.
J Neurol 2000;247(10):778Y782.
55. Stich O, Kleer B, Rauer S. Absence of
paraneoplastic antineuronal antibodies in
sera of 145 patients with motor neuron
disease. J Neurol Neurosurg Psychiatry 2007;
78(8):883Y885.
56. Khwaja S, Sripathi N, Ahmad BK, et al.
Paraneoplastic motor neuron disease with
type 1 Purkinje cell antibodies. Muscle
Nerve 1998;21(7):943Y945.
57. Graus F, Keime-Guibert F, Reñe R, et al.
Anti-Hu-associated paraneoplastic
encephalomyelitis: analysis of 200 patients.
Brain 2001;124(pt 6):1138Y1148.
58. Lucchinetti CF, Kimmel DW, Lennon VA.
Paraneoplastic and oncologic profiles
of patients seropositive for type 1
antineuronal nuclear autoantibodies.
Neurology 1998;50(3):652Y657.
59. Mitchell DM, Olczak SA. Remission of
a syndrome indistinguishable from motor
neurone disease after resection of
bronchial carcinoma. Br Med J 1979;2(6183):
176Y177.
www.aan.com/continuum 799