Immune Mediated Myelopathies.11

REVIEW ARTICLE

Immune-Mediated
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Myelopathies
By Michael Levy, MD, PhD, FAAN
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ABSTRACT
OBJECTIVE: Immune-mediated myelopathies are conditions in which the
CITE AS:
CONTINUUM (MINNEAP MINN) immune system attacks the spinal cord. This article describes the
2024;30(1, SPINAL CORD distinguishing characteristics of immune-mediated myelopathies and
DISORDERS):180–198.
treatment strategies for patients affected by these disorders.
Address correspondence to
Dr Michael Levy, 65 LATEST DEVELOPMENTS:New biomarkers, such as aquaporin 4 and myelin
Landsdowne St, Lab 500,
Cambridge, MA 02139,
oligodendrocyte glycoprotein antibodies, in the blood and spinal fluid
MLEVY11@mgh.harvard.edu. have led to the identification of antigen-specific immune-mediated
myelopathies and approved therapies to prevent disease progression.
RELATIONSHIP DISCLOSURE:
Dr Levy has received personal
compensation in the range of ESSENTIAL POINTS: Thefirst step in the diagnosis of an immune-mediated
$500 to $4999 for serving as a myelopathy is confirming that the immune system is the cause of the attack
consultant for Mitsubishi
Tanabe Pharma America, Inc, by excluding non–immune-mediated causes. The second step is to narrow
and UCB, Inc, and as an editor, the differential diagnosis based on objective biomarkers such as serology
associate editor, or editorial
and MRI patterns. The third step is to treat the specific immune-mediated
advisory board member for
Elsevier; in the range of $5000 to myelopathy by using evidence-based medicine.
$9999 for serving as a
consultant for Sanofi and
serving on scientific advisory or
data safety monitoring boards INTRODUCTION
for Alexion Pharmaceuticals, Inc,
Genentech, Inc, and Horizon Immune-mediated myelopathies are conditions in which spinal cord dysfunction
Therapeutics plc; and in the results from damage caused by the immune system. The scope of this article is
range of $10,000 to $49,999 for limited to immune-mediated conditions outside of the context of an infection,
serving as an expert witness for
various law firms. The institution including multiple sclerosis (MS), antigen-specific autoimmune diseases,
of Dr Levy has received inflammatory myelitis, neurosarcoidosis, and paraneoplastic diseases. Infections
research support from the
National Institutes of Health (R01
in the spinal cord and the damage that occurs as a result of the infection plus
AI153068). the immune response are included in the article “Infectious Myelopathies” by
Anita M. Fletcher, MD, and Shamik Bhattacharyya, MD, FAAN,1 in this issue
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
of Continuum. Immune-mediated myelopathies are often included in the
USE DISCLOSURE: differential diagnosis of other disorders of the spinal cord, particularly those
Dr Levy discusses the use of included in the article “Vascular Myelopathies” by Ashutosh P. Jadhav, MD,
azathioprine, corticosteroids,
cyclophosphamide, infliximab, PhD, FAAN,2 and a detailed algorithm for diagnosing spinal cord disorders can
intravenous immunoglobulins be found in the article “Clinical Approach to Myelopathy Diagnosis” by Carlos A.
(IVIg), mycophenolate mofetil,
Pardo, MD,3 both of which can also be found in this issue of Continuum. CASE 8-1
and rituximab, none of which
are approved by the US Food is an example of a typical case of an immune-mediated myelopathy.
and Drug Administration for the
treatment of immune-mediated
myelopathies. GENERAL PRINCIPLES OF IMMUNE-MEDIATED MYELOPATHIES
The immune system can lead to nervous system dysfunction in two ways. First,
© 2024 American Academy the inflammatory process can disrupt the function of white matter tracts and
of Neurology. neuronal activity. Even when the tracts remain anatomically intact and
180 F E B R U A R Y 2 0 24
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

myelinated, saltatory conduction may be impaired because of changes in the
surrounding electrolyte balance, and synaptic transmission may be disrupted by
cytokines and antibodies. Second, inflammation can cause anatomic damage in
the spinal cord, ranging from demyelination to necrosis. In the first mechanism,
reversal of inflammation typically leads to rapid recovery of function whereas
when anatomic damage occurs recovery is delayed by a longer remyelinating
process.4
The immune-mediated myelopathies discussed in the article share many
features and can be difficult to distinguish without a thorough workup. In many
cases, the diagnosis is easier to make in retrospect because clues emerge from
both the acute attack and the recovery period. Clinical equipoise and empiric
treatment based on clinical judgment are common principles in the workup and
treatment of immune-mediated myelopathies in the real world.
A 46-year-old woman from Haiti with a history of Sjögren syndrome CASE 8-1
presented to the emergency department with sudden neck pain,
followed by arm and leg weakness over 24 hours. While in the emergency
department, she developed urinary retention requiring catheterization.
Her Sjögren syndrome history included dry eyes and a previous episode
of vision loss in her right eye that was ascribed to Sjögren optic neuritis.
She had been using hydroxychloroquine and occasionally corticosteroids
for flares of her Sjögren syndrome.
Her physical examination revealed a normal mental status. Her cranial
nerves were intact except for 20/200 visual acuity covering most of her
visual field in her right eye. She had 3/5 strength in her arms and 2/5
strength from her hips to her toes in both legs. Reflexes were reduced in
her arms, absent in her legs, and mute in her toes. Sensation was
markedly reduced to light touch in her legs with a sensory level at C5. She
was unable to ambulate.
MRI of her spinal cord showed a longitudinally extensive lesion from C1
to C5 with avid contrast enhancement at C2 and C3. Serologies were sent
for antinuclear antibodies (she was previously positive for Sjögren
syndrome antigens A and B), anti–aquaporin 4 (AQP4) antibodies,
anti–myelin oligodendrocyte glycoprotein (MOG) antibodies, and
anticardiolipin antibodies. Spinal fluid identified the presence of 120
white blood cells/mm3, 99% of which were lymphocytes, mildly elevated
protein and glucose, and negative Gram stain for bacteria.
This case highlights a typical presentation of an immune-mediated COMMENT

myelopathy. Evidence of inflammation in the spinal cord was confirmed by
both spinal fluid analysis and MRI. While awaiting serology results, she was
appropriately started on treatment with high-dose corticosteroids. After
her AQP4 antibody returned positive, she was diagnosed with
neuromyelitis optica spectrum disorder and escalated to therapy with
plasma exchange.
CONTINUUMJOURNAL.COM 181

IMMUNE-MEDIATED MYELOPATHIES
COMMON FEATURES OF IMMUNE-MEDIATED MYELOPATHIES

The clues that neurologists rely on in the workup of immune-mediated
myelopathies are broadly categorized into a history of present illness, including
the time course, CSF analysis, MRI, and serology. Although spinal fluid analysis is
not always readily available, MRI with contrast and serology are vital parts of the
workup for immune-mediated myelopathy and should always be included in the
workup if possible.
When the immune system causes spinal cord inflammation, it can be acute and
severe, such as the attacks associated with neuromyelitis optica spectrum disorder
(NMOSD). These attacks can progress rapidly to a nadir of complete paralysis

within a few hours. More commonly, immune-mediated attacks of the spinal cord
tend to occur over hours to days. In 2002, the Transverse Myelitis Consortium
Working Group5 defined the time course of idiopathic inflammatory myelitis as at
least 4 hours but not more than 21 days to nadir. The 4-hour time minimum is
intended to exclude vascular myelopathies, which can take minutes in arterial
strokes to hours for venous strokes. The 21-day limit was intended to distinguish
subacute and chronic conditions such as arteriovenous malformations, which can
evolve over months. Paraneoplastic diseases also typically present in a subacute to
chronic time course. The time from onset to nadir is included as a major clue in
each section below to help organize the differential diagnoses.
Other important features of immune-mediated myelopathies that should be
captured in the history of present illness are immune triggers, co-occurring
autoimmunity or cancer, and family history. Triggers commonly include infections
and vaccines. These triggers are not yet known to be specific to a particular vaccine
or infection or a particular central nervous system (CNS) antigen. In contrast,
molecular mimicry has been shown to be the mechanism responsible for acute
peripheral nerve demyelination in Guillain Barre syndrome following infection with
Campylobacter, for example.6 Thus, there may be an element of molecular mimicry
to many different antigens that all lead to a common downstream clinical
presentation of myelopathy. Another explanation is that the immune triggers may
be nonspecific stimulants to a broader immune response whereby the rogue element
that attacks the spinal cord is given a boost sufficient to induce a clinical attack. This
latter explanation is supported by the wide number of immune triggers that have
been associated with immune-mediated myelopathies.7
Co-occurring autoimmunity is a clue that a patient may be predisposed to an
immune-mediated myelopathy. A good example is a patient with known
systemic lupus erythematosus who presents with an acute myelopathic
syndrome. Systemic lupus erythematosus has significant overlap with NMOSD,
and patients with this disorder commonly test positive after a transverse myelitis
attack for the aquaporin 4 (AQP4) antibody associated with NMOSD.8,9 Sjögren
syndrome is also tied to NMOSD and inflammatory myelitis.10,11 A history of N-
methyl-D-aspartate (NMDA) receptor encephalitis is associated with a higher
risk of NMOSD and myelin oligodendrocyte glycoprotein (MOG) antibody
disease.12 Sarcoidosis in the lungs is strongly linked to neurosarcoidosis in the
brain and spinal cord.13 Even without a link, co-occurring autoimmunity raises
the level of suspicion that a myelopathy may be autoimmune. Similarly, a known
history of cancer, especially small cell lung cancer, breast cancer, and thymomas,
should prompt consideration of paraneoplastic conditions.14
Family history may be useful in specific scenarios. MS has more than 200
known genetic factors.15 If one identical twin has MS, the other twin has an
182 F E B R U A R Y 2 0 24

approximately 30% risk of also developing the same disorder.16 Mothers with KEY POINT
MS transmit an approximately 5% risk of developing MS to their children, and
● The four major clues in
fathers pass down an approximately 3% risk.17 MS presents with a myelitis the diagnosis of
attack in approximately 62% to 80% of cases; 80% of people with MS have a visible immune-mediated
lesion in their spinal cord at diagnosis.18,19 In 2018, a familial form of idiopathic myelopathies are the time
inflammatory myelitis was described as related to variants in the family of genes course of disease, spinal
fluid analysis, MRI features,

that control vesicle and exosome handling.20 There are a few patient families with
and serology.
NMOSD21 but as yet no reports of hereditary MOG antibody disease.
The blood-brain barrier (and blood-spine barrier) maintains an
immune-privileged zone in the CNS. Typically, only select immune cells are
permitted to traffic in and out; these include monocytes and T cells. No more
than 5 white blood cells/mm3 of CSF is expected in healthy lumbar puncture
samples. More than 5 white blood cells/mm3 indicates that a pathologic process is
occurring or has recently occurred. In some nonimmune myelopathies, including
trauma and vascular myelopathy, a mild pleocytosis (>5 white blood cells/mm3)
has been observed.22-24 Myelopathies with more than 100 white blood cells/mm3
must be considered to have an immune-mediated or infectious etiology until
proven otherwise.25 Immune cell counts and other CSF characteristics are useful
clues in distinguishing among the causes of immune-mediated myelopathies
described in more detail in the individual sections that follow.
MRI can be useful in distinguishing immune-mediated myelopathies from
other etiologies. Immune-mediated lesions in the spinal cord are expected to
enhance with gadolinium during the acute phase of an attack. In
immune-mediated myelopathies, enhancement on MRI indicates that the lesion
is actively inflamed, which is an important treatment consideration.
Nonenhancing lesions can also be immune mediated, especially early or late in
the course of an attack and when associated with pleocytosis on CSF analysis.26
The length and location of a lesion within the spinal cord provide additional
clues. For example, short lesions, which also tend to localize to white matter
tracts, are characteristically seen in MS. Long lesions are generally observed in
NMOSD and vascular myelopathies.27 Vascular myelopathies may localize by
vascular territory: a lesion covering the anterior two-thirds of the spinal cord is
consistent with a stroke of the anterior spinal artery.22 Neurosarcoidosis lesions
usually appear nodular on MRI and maintain a border with the meninges,
occasionally demonstrating the trident sign.28
Finally, positive serologies can be useful in diagnosis. The specificity of a
positive serum AQP4 antibody test is nearly 100% if performed with a cell-based
assay. The high specificity of this test allows any immune-mediated myelopathy
case, regardless of the clinical history; lesion length, location, or enhancement
pattern on MRI; or spinal fluid characteristics, to be considered for a diagnosis of
NMOSD. There is a very high bar for excluding NMOSD in the context of a
positive AQP4 antibody test.29 The MOG antibody cell-based assay is highly
specific when the titer is greater than 1:100; lower titers may be associated with
false positives, particularly in the context of MS.30,31 Other useful serologic
markers are described in more detail in the later sections.
MULTIPLE SCLEROSIS
A typical presentation of an MS attack in the spinal cord is a week of numbness or
heaviness in one leg. Most people with MS who develop these symptoms already
have a diagnosis of MS, and the presumption is that the symptoms are the result

of a new immune-mediated myelopathy.18 Red flags in the history include a

severe presentation such as paralysis or a rapid progression occurring over hours.
Fever and other systemic symptoms may indicate the symptoms may be caused
by an older lesion rather than a new attack.32 Such presentations, referred to as
pseudorelapses, are stereotypical and can be familiar to the patient. Neurologic
symptoms during pseudorelapses are thought to be caused by the loss of
compensation or reduced neurologic reserve and should resolve with the

treatment of the underlying systemic problem.32
The workup of a myelopathy in a person with established MS would not
necessarily require imaging or testing unless there is some uncertainty about the
MS diagnosis or if the symptoms are particularly severe or fluctuating. On MRI, a
lesion in a person with MS is usually small (around 1 cm), focal, and localized to
the white matter tracts such as the posterior columns of the spinal cord.27
Enhancement of the lesion indicates that the attack is recent.33 If the MRI is not
consistent with an MS attack, further workup may be indicated.
Approximately 50% of cases of acute inflammatory myelitis are caused by
MS.34 In these cases, the workup commonly shows a small, focal lesion in the
spinal cord in the context of typical ovoid periventricular lesions in the brain.
CSF is positive for oligoclonal bands in more than 87% of cases,35 and serology for
AQP4 and MOG antibodies should be negative. Because spinal cord lesions
contribute to much of the disability over the lifetime of a person with MS,
aggressive disease-modifying treatment has been advocated for these patients.36
There is no consensus on the need for treatment of an acute MS attack in the
spinal cord. Data from long-term observational studies in MS suggest that
patients with attacks in the CNS may recover faster with corticosteroid
treatment; however, in the long term, there may be little to no benefit from
corticosteroids.37 It is not clear if these data can be extrapolated to lesions in the
spinal cord. Studies show a long-term benefit to acute treatment of MS attacks in
the spinal cord starting with corticosteroids and, when needed, escalating to
plasma exchange.38 Generally, severe attacks are treated whereas mild attacks
can be observed depending on the individual presentation.
NEUROMYELITIS OPTICA SPECTRUM DISORDER

NMOSD is a rare autoimmune disease in which the immune system targets the
AQP4 water channel. Although this channel is present throughout the body, the
immune attacks occur only in the CNS, primarily in the optic nerves and spinal
cord. Accepted clinical criteria for the diagnosis of NMOSD in the presence of a
positive AQP4 antibody test requires only a single attack of the spinal cord, optic
nerve, or brainstem.39 The typical presentation of an NMOSD attack of the spinal
cord is clinically severe because of the associated necrotic inflammation. NMOSD
in the spinal cord presents with severe weakness or paralysis of limbs, loss of
sensation, and loss of bowel and bladder control. Because the lesions are large,
most patients present with both weakness and numbness in multiple limbs.
Progression over 4 to 48 hours is common, but evolution can occur over 2 to
4 weeks because myelopathies may not be recognized early by patients and their
doctors. The earlier an NMOSD attack of the spinal cord is diagnosed and treated,
the better the outcomes are for the patient.40,41
The damage caused by NMOSD rarely heals completely, and most patients are
left with residual symptoms. These include persistent weakness and sensory
dysfunction but also neuropathic pain and spasticity. Fluctuation in some or all
184 F E B R U A R Y 2 0 24

these symptoms is very common in NMOSD and can sometimes feel like a KEY POINTS
relapse to the patient because of the intensity.42 In these situations, MRI is useful
● Neuromyelitis optica
to exclude inflammation (seen as contrast enhancement on MRI). spectrum disorder is
Lesions in NMOSD are usually not subtle on MRI. They are typically associated with a positive
longitudinally extensive, defined as spanning at least 3 vertebral segments, as serologic test for the
shown in CASE 8-1 and FIGURE 8-1.43 Axially, lesions are large and extend across aquaporin 4 antibody.
white and gray matter, often involving both sides of the spinal cord at several
● Spinal cord injury after
levels. In the acute stage, these lesions are expected to enhance although the attacks of neuromyelitis
extent of enhancement is usually shorter than the T2-hyperintense lesion. Even optica spectrum disorder is
after treatment, NMOSD lesions remain visible as a T2-hyperintense scar on MRI usually severe, and recovery
for many years. T2-hyperintense lesions associated with T1 hypointensities and is often poor.
atrophy indicate permanent damage to the spinal cord.44

Spinal fluid analysis is not usually required in the workup for NMOSD because
a longitudinally extensive NMOSD lesion and a positive AQP4 antibody are
sufficient to make the diagnosis. In cases in which spinal fluid has been analyzed,
acute attacks show significant pleocytosis with greater than 50 white blood cells/
mm3, which are predominantly lymphocytes but also granulocytes including
eosinophils.45 The high number of immune cells often prompts a workup for
infectious diseases, which may be useful but should not delay treatment for
NMOSD. Oligoclonal bands are rare in NMOSD; however, one study detected a
single monoclonal band unique to CSF in 18% of patients with NMOSD.8 AQP4
antibody testing is not routinely done with spinal fluid because the serum titer is
usually 250 to 400 times higher and the number of mismatches between spinal
fluid and serum is low.46
The specificity of the cell-based AQP4 antibody test is nearly 100%.29 That
means that any person who tests positive must be considered for a diagnosis of
NMOSD. Rare cases in which a false-positive AQP4 antibody test has been
reported are mostly related to low titers with enzyme-linked immunosorbent
FIGURE 8-1
Longitudinally extensive myelitis. A, Sagittal T2-weighted spine MRI shows a longitudinal
cord hyperintensity (arrows) from C1 to C5. B, Sagittal precontrast T1-weighted MRI shows a
T1 hypointense region (arrows) in the same area. C, Sagittal postcontrast T1-weighted MRI
shows an avid area of enhancement (arrows) at C2 and C3.

assay (ELISA).47 Some cases of double-positive AQP4 and MOG have been
reported as well.48 Antibody titers in the cell-based assay do not predict the
prognosis of the disease course.49 Because NMOSD is lifelong, once a person tests
positive and a diagnosis is confirmed, repeat testing is not necessary.
All NMOSD attacks should be treated without exception. An untreated attack
will typically lead to permanent neurologic disability.50 The treatment should
begin with high-dose corticosteroids for 3 to 5 days, and in most cases,

therapeutic plasma exchange is indicated and helpful particularly when no
clinical benefit is achieved with corticosteroid alone.50 Other treatments such as
IV immunoglobulin (IVIg) and cyclophosphamide have shown benefit in small

studies.51,52 Despite prompt and appropriate treatment, most NMOSD attacks in
the spinal cord leave residual damage, and persistent deficits are common.
During the recovery process, neuropathic pain occurs in more than 60% of
patients and can severely limit rehabilitation.53 Neuropathic pain usually requires
combined medical and nonmedical treatment approaches that serve to reduce,
but not eliminate, the pain, which may subside over time.54 Similarly, muscle
spasms in previously weakened muscles are common during recovery.
Treatment with muscle relaxants may help but can exacerbate weakness.
Given poor outcomes after NMO attacks, preventive treatment is key to
improving long-term outcomes. All AQP4 antibody–positive patients with
NMOSD should be on preventive medications to avoid future attacks. Although
relapses may still occur on preventive therapy, immunosuppressive medications
can reduce the severity of breakthrough attacks.55 Three preventive therapies for
NMOSD are US Food and Drug Administration (FDA) approved: eculizumab,
satralizumab, and inebilizumab.
Eculizumab is a terminal C5 complement inhibitor that was shown to reduce
the risk of relapse by 94% over background immunosuppressive therapy for
AQP4 antibody–seropositive patients with NMOSD56 It is infused intravenously
every 2 weeks and causes very few side effects other than headache and occasional
upper respiratory infection. However, inhibiting complement increases the risk of
infection with encapsulated organisms, specifically Neisseria meningitidis. In
addition to vaccination against Neisseria, prophylactic antibiotics may be required.
Satralizumab is an interleukin-6 receptor blocker that was shown to reduce the
risk of relapse in AQP4 antibody–seropositive patients with NMOSD by 79%.57 It
is not approved for the treatment of seronegative NMOSD because of a lack of
demonstrated efficacy. The drug is injected subcutaneously once per month and
has very few side effects except for injection site reaction and occasional
laboratory abnormalities, including neutropenia and elevated lipids in
approximately 10% of patients.
Inebilizumab is a CD19 monoclonal antibody that depletes B cells along with
plasmablasts and some short-lived plasma cells. It was shown to reduce the risk of
relapse by 77% in AQP4 antibody–seropositive patients.58 It is not approved for
the treatment of seronegative NMOSD because of insufficient data in that
population. The drug is infused intravenously every 6 months and is very well
tolerated compared with rituximab. Before the approval of inebilizumab,
rituximab was widely used off-label because it was first suggested to be beneficial
in observational case series.59 In Japan, a trial of rituximab (the RIN-1 study)
demonstrated that 1000 mg of rituximab 2 times a year and low-dose
corticosteroids was superior to low-dose corticosteroids alone in preventing
relapses in AQP4 seropositive NMOSD, leading to approval in that country.60
186 F E B R U A R Y 2 0 24

MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY DISEASE KEY POINTS
MOG antibody disease is a relatively newly recognized clinical entity that overlaps
● In patients with
both NMOSD and MS but is also emerging as an autoimmune disease with neuromyelitis optica
distinctive features. MOG is expressed on the outer surface of the myelin sheath spectrum disorder,
and is only found in the CNS.61 Immunity to MOG has long been known to cause preventive treatment with
an inflammatory CNS disease in rodents and other animals, but the recognition immunosuppressive
medications is key to
that MOG immunity causes disease in humans was hampered by poor specificity
preventing attack-related
of early MOG antibody assays.62 Since 2015 with the improvement of the test, neurologic disability.
MOG antibody disease is now defined as an autoimmune disease with monophasic
or relapsing inflammatory attacks of the CNS.63 In children, the most common ● Among children with
clinical presentations are acute disseminated encephalomyelitis (ADEM) and demyelinating disease,
myelin oligodendrocyte
optic neuritis.64 In adults, optic neuritis accounts for more than half of attacks with glycoprotein (MOG)
inflammatory myelitis occurring in about 18% of patients.65 Myelitis may be the antibody disease is
initial event in MOG antibody disease, presenting with bladder retention, leg especially prevalent and
weakness, and sensory changes in the pelvis and legs when associated with a low commonly presents with
acute disseminated
thoracic lesion.66 Myelopathies associated with MOG antibody disease can occur encephalomyelitis (ADEM).
throughout the spinal cord and can be mild, moderate, or severe. Some cases of
MOG antibody disease present identically to NMOSD in severity of initial onset ● Spinal cord attacks in
whereas other cases are mild and more similar to MS. In addition to myelitis, MOG antibody disease can
present with severe
MOG antibody disease can cause an aseptic meningitis presentation with typical
symptoms and disability, but
features including headache and neck stiffness.66 patients generally recover
Some features of MOG antibody disease are more obvious in retrospect. If the well over time.
initial attack resembles NMOSD, the antibody tests for AQP4 and MOG are
critical to making the correct diagnosis quickly. However, with hindsight,
clinicians can distinguish MOG and NMOSD by the degree of recovery. Recovery
from NMOSD attacks is often limited as described earlier, but patients who have
MOG attacks tend to recover well.67 It is not unusual for a patient with MOG
antibody disease to be hospitalized for complete paralysis due to a thoracic
myelitis and return to the clinic in 3 to 6 months with the ability to walk again,
often unassisted.
In patients with a known history of MOG antibody disease, a new myelitis
attack is suspected when new symptoms are associated with changes on
neurologic examination that persist for more than a day. MRI of the spinal cord
typically confirms the relapse with the presence of a new or enhancing lesion.68
Lesions can be either longitudinally extensive (FIGURE 8-2) or focal and can
involve both gray and white matter tracts. A distinctive MRI finding in MOG
antibody disease is that recovery after myelitis tends to normalize the spinal
cord lesion so that old lesions may not be visualized on subsequent scans. This
has led to the notion that MOG antibody disease may be the cause of “MRI-
negative myelitis” in which patients with suspected inflammatory myelitis do
not have a lesion on MRI.69
Although the most common cause of inflammatory myelitis in the US
population is MS, consideration of NMOSD and MOG is particularly relevant
when the brain is radiographically spared on MRI. Given the ease of antibody
testing and the widely different treatment plans among NMOSD, MS, and MOG
antibody disease, there is a consensus that AQP4 and MOG antibodies should be
tested in all initial cases of inflammatory myelitis.
Oligoclonal bands are rare in MOG antibody disease.62 In cases where MOG
antibody disease and MS are both high on the differential diagnosis, a positive
oligoclonal band test can help push the diagnosis toward MS. Similar to CSF

findings during acute attacks in

NMOSD, MOG attacks can
present with marked pleocytosis
(>50 white blood cells/mm3),
predominantly lymphocytes.70
Such white blood cell elevations
are rare in MS.

The MOG antibody test was
improved in 2015 to minimize the
false positive tests that plagued the

assay since it was originally
published in 1999.71 The new assay
uses a cell-based approach with
the full-length extracellular
FIGURE 8-2 portion of MOG rather than an
Myelin oligodendrocyte glycoprotein (MOG) ELISA using MOG peptides. In
antibody–seropositive optic neuritis. This axial addition, the detection of human
postcontrast T1-weighted brain MRI shows avid
contrast enhancement extending a little more
MOG antibodies with this method
than half the length of the optic nerve (arrows) screens out IgM antibodies, which
primarily in the anterior portion and sparing are commonly found in healthy
the chiasm. people. In some laboratories, only
IgG1 antibodies to MOG are
considered positive for this assay
whereas in others the IgG is considered positive if above a specific titer. Titer
appears to be important in MOG antibody disease in two ways. First, a high titer
bolsters specificity with levels of 1:1000 or greater being 100% specific.30,31
Lower MOG antibody levels should prompt consideration of other conditions,
including MS. Second, MOG antibody titers can be tracked over time because
those whose MOG antibody assays normalize have a lower risk of
subsequent relapse.72
There are no approved therapies for MOG antibody disease, either for acute
relapse or for preventive use. Treatment of relapses seems to respond to high
doses of corticosteroids.73 Patients typically receive 3 to 5 days of high-dose IV
steroids followed by a 2- to 3-month taper. The taper ensures continued
anti-inflammatory effect but also prevents a steroid-withdrawal relapse to which
patients with MOG antibody disease are prone. New data also suggest that IVIg
may be effective in suppressing acute inflammation and can spare the associated
toxicity of 2 to 3 months of steroid treatment.
Preventively, many patients with MOG antibody disease are administered
IVIg every 4 weeks. Depending on the dose, the risk of relapse can be reduced
60% to 80%.74 Aseptic meningitis and blood clots are potential side effects of
IVIg, but they can be mitigated by using a subcutaneous route.75 Mycophenolate
mofetil and azathioprine have been used in the treatment of MOG antibody
disease, especially in children, with generally good outcomes.76
Two medications are being developed for preventive uses in MOG antibody
disease. Rozanolixizumab is a neonatal Fc receptor (FcRn) monoclonal antibody
that blocks the ability of FcRn to prevent intravascular antibodies from being
destroyed and recycled.77 A phase 3, randomized, placebo-controlled trial is
underway to test the ability of rozanolixizumab to prevent relapses in MOG
antibody disease. A phase 3, randomized, placebo-controlled trial of
188 F E B R U A R Y 2 0 24

satralizumab, which is already approved for NMOSD (see above), is also KEY POINTS
underway to test its ability to prevent relapses in MOG antibody disease.78
● The criteria for MOG
Both trials are expected to report results in 2025 to 2026. antibody disease depends
on the MOG antibody titer
OTHER ANTIBODY-ASSOCIATED AUTOIMMUNE DISEASES level; high-titer positive
Rare cases of immune-mediated myelopathies occur in the context of other MOG antibody tests confer a
diagnosis of MOG antibody

known autoantibodies. Most notably, glial fibrillary acidic protein (GFAP)
disease.
encephalomyelitis is among the more common of these rare conditions.79
GFAP encephalomyelitis is a monophasic immune-mediated attack on the ● Seronegative relapsing
astrocyte protein GFAP, which typically presents as an acute encephalitis, inflammatory myelitis likely
meningoencephalitis, or encephalomyelitis. Like for other forms of autoimmune includes a mix of different
conditions that have yet to
myelitis, treatment of GFAP encephalomyelitis starts with high-dose IV be specifically defined.
corticosteroids and a prolonged oral taper; plasma exchange may be helpful
when corticosteroids are insufficient.79 Although outcomes are generally good
after treatment, patients with spinal cord involvement may have residual
myelopathic symptoms.
Other autoantibodies that have been reported in association with myelitis
include anti-glutamic acid decarboxylase (GAD),80 antiglycine receptor in the
context of progressive encephalomyelitis with rigidity and myoclonus,81,82 and
antiamphiphysin antibodies.83,84
SERONEGATIVE RELAPSING INFLAMMATORY MYELITIS

With improvements in the cell-based assays for AQP4, MOG, and paraneoplastic
antibodies, new cases of seronegative relapsing transverse myelitis are becoming
more rare. A select number of cases remain seronegative despite repeated testing
in the setting of recurrent inflammatory attacks of the spinal cord. This might
reflect the limited sensitivity of these assays, incorrect diagnosis, or other
autoantibodies that may have not been discovered.
Among other causes of myelopathy, neurosarcoidosis, discussed later in this
article, and vascular myelopathies should be given special consideration. For more
information about vascular myelopathy, refer to the article “Vascular Myelopathies”
by Ashutosh P. Jadhav, MD, PhD, FAAN,2 in this issue of Continuum.
There is a consensus that a single event of seronegative inflammatory myelitis
does not necessarily predict a relapsing disease course.85 However, a spatially and
temporally distinct second attack is a good indication that the disease is relapsing.
Even if persistently seronegative, the trend in the field is to offer preventive
medication to prevent a third attack. Additionally, if patients relapse despite an
adequate trial of an appropriate medication, they are usually switched to a
different mechanism of treatment. For example, if a patient with a history of
seronegative relapsing inflammatory myelitis has a new inflammatory lesion in
the spinal cord while B cell counts are zero following treatment with rituximab,
the presumption is that B cell depletion is not going to be an effective preventive
therapy for the patient.
The clinical presentation of seronegative inflammatory myelitis ranges from
NMOSD to MS in severity, location, and chronicity. Although it might be
easy to categorize seronegative inflammatory myelitis as part of MS, patients
with seronegative inflammatory myelitis usually have been spared brain disease
both clinically and radiologically. They also have no oligoclonal bands in the
CSF and thus do not easily meet the criteria for MS. There has been a tendency
to pigeonhole these patients into “NMOSD-like” versus “MOG antibody

disease–like” categories based on their MRI patterns and responses to

treatments. Patients with lesions that remain bright on T2-weighted MRI long
after an attack and who seem to respond clinically to B cell therapies are
considered to have an “NMOSD-like” presentation whereas those whose spinal
cord lesions recover well over time and do not respond well to B cell therapies
may be labeled as having an “MOG antibody disease–like” presentation. In
addition to B cell–depletion therapies, other patients with an “NMOSD-like”

presentation may respond to interleukin 6 blockers such as tocilizumab.
“MOG antibody disease–like” therapy includes IVIg. Patients may opt for
a broad immunosuppressive approach such as mycophenolate mofetil or

azathioprine.
MONOPHASIC IDIOPATHIC INFLAMMATORY MYELITIS

Monophasic idiopathic inflammatory myelitis refers to a single inflammatory
attack of the spinal cord that is not the result of MS, NMOSD, or MOG antibody
disease. Originally coined in 1948,86 the term transverse myelitis was used to define
an inflammatory attack of the spinal cord that presented with bilateral symptoms
due to disease across a transverse section of the spinal cord and corresponding
dermatomal distribution. In 2002, the bilateral requirement was incorporated
into the Transverse Myelitis Working Group’s formalized criteria for the
diagnosis of inflammatory myelitis, which, although now somewhat outdated,
attempted to distinguish inflammatory from noninflammatory etiologies.5 MRI
visualization of lesions negated the bilateral requirement that was previously
helpful to spinal cord localization.
Triggers for inflammatory myelitis have historically included vaccines and
infections of many different kinds.87 The COVID-19 pandemic provided a unique
situation in which to study immunologic triggers because testing was widely
available and infections were documented. Also, large populations received the
vaccine essentially at the same time. In one of the most closely watched trials of
one COVID-19 vaccine, the first COVID-19 vaccine trial to be published, three
people developed inflammatory myelitis during the study, only one of which was
determined to be caused by the vaccine.88 In addition to vaccines, infections may
also trigger attacks. For example, there are a similar number of case reports of
inflammatory myelitis following COVID-19 infection as there are following
COVID-19 vaccination, both of which were low frequency in the
general population.89,90
MRI lesions of idiopathic inflammatory myelitis vary in size and location.
Longitudinally extensive lesions are more commonly associated with NMOSD
and MOG than with idiopathic inflammatory myelitis, which tends to span less
than three vertebral lengths.42 Transverse myelitis does not preferentially target
gray versus white matter tracts as MS does. Gadolinium enhancement is
associated with active inflammation in inflammatory myelitis although, in some
cases of severe inflammatory myelitis, persistent enhancement is seen
throughout recovery. Over time, inflammatory myelitis lesion scars transition to
a residual nonenhancing T2 hyperintensity.
Spinal fluid analysis may be used in place of MRI contrast enhancement to
confirm the presence of an inflammatory process. The presence of pleocytosis is
not exclusive to immune-mediated myeloapthies; many nonimmune
myelopathies can cause damage to the spinal cord, which recruits an immune
cellular response. However, a higher number of cells, particularly greater than
190 F E B R U A R Y 2 0 24

50 white blood cells/mm3, should be worked up for a primary immune- KEY POINTS
mediated myelopathy.
● Broad-spectrum
Treatment for idiopathic inflammatory myelitis begins with suppression of the immunosuppression can be
inflammatory process by using high-dose corticosteroids. Escalated therapy to useful in preventing relapses
therapeutic plasma exchange or cyclophosphamide or both should be considered of seronegative relapsing
when the response to steroids is poor.91 Once the inflammation subsides, the inflammatory myelitis.
recovery can take 6 to 18 months or more depending on the extent of damage.

● Monophasic idiopathic
Recovery is rarely complete, and patients are frequently left with some degree of inflammatory myelitis is a
weakness, numbness, and neuropathic pain. The one-third prognosis rule was one-time immunologic event
published in the early 1980s based on an observational case series in which about that leads to spinal cord
one-third of patients recovered well, one-third made some recovery back to injury.
walking with assistance, and one-third had a poor outcome.92 With modernized ● A link between
and more intensive immunosuppressive therapy initiated as early as possible in the inflammatory myelitis and
course of the condition, the expectation is that patients will have better recoveries. vaccines has been
Even in patients who do not make meaningful recoveries, initiating treatment speculated but not
confirmed.
for idiopathic inflammatory myelitis appears to blunt the progressive decline in
neurologic function. Nearly all studies in transverse myelitis using various forms ● Neurosarcoidosis in the
of immunosuppression show that the nadir of disease is reached just before spinal cord should be
treatment is started. This pattern suggests that, without treatment, some patients suspected in cases with MRI
lesions that are persistently
would have continued to progress in their disease course. Some patients present
enhancing over a long
too late for treatment. If the inflammation has already subsided naturally as period.
indicated by stable neurologic deficits, nonenhancing lesion on MRI, and no
pleocytosis on CSF analysis, there is a reduced expectation that ● Steroids are often
immunosuppressive therapy would be helpful. sufficient to treat
neurosarcoidosis of the
After inflammation subsides and recovery begins, physical therapy is spinal cord, but newer
important to optimizing long-term neurologic function.93 treatments, such as anti–
tumor necrosis factor
NEUROSARCOIDOSIS medications, are available.
Neurosarcoidosis is a granulomatous inflammatory disease that affects the CNS.
● The differential diagnosis
In the spine, non-necrotizing epithelioid granulomas slowly grow into the CNS of immune-mediated
parenchyma from the spinal meninges triggering a lymphocytic inflammatory myelopathies can be
reaction leading to a subacute or chronic myelopathy.94 In the basal meninges, narrowed by workup that
uses imaging, serology,
neurosarcoidosis can cause cranial neuropathies in addition to headaches and
spinal fluid analysis, and
papilledema due to increased intracranial pressure depending on where the sometimes histopathology.
granulomas grow. Ninety percent of cases of neurosarcoidosis occur in the
context of systemic sarcoidosis, usually in the lung, but it is frequently the
neurologic symptoms that prompt the workup.95
The clinical presentations of neurosarcoidosis depend on the location of the
granulomatous inflammation, but in most cases, the progression of decline is
subacute or chronic, occurring over weeks to months. Because granulomas
usually grow into the cord from the meninges, white matter tracts are affected
more commonly than gray matter, leading to long tract signs that affect motor
and sensory function below the level of the lesion.
The gold standard for diagnosis is biopsy of the CNS lesion with demonstration
of a noncaseating granuloma, which is usually surrounded by a ring of fibroblasts
mixed with lymphocytes. In most cases, workup of neurosarcoidosis identifies
other granulomas, such as in the lung and spleen, that are easier to biopsy than
in the CNS; positive findings confer a diagnosis of probable neurosarcoidosis.
When neurosarcoidosis is diagnosed on clinical grounds without biopsy
confirmation, it is considered possible neurosarcoidosis.96 Clinical grounds to

make a diagnosis depend on the rest of the workup by MRI, positron emission
tomography (PET), and CSF and blood testing.
On MRI, neurosarcoid lesions are avidly enhancing with gadolinium, and they
almost always attach to the meninges in the basal cisterns or spinal column.97
In the axial plane, the pattern resembles a trident because of confluent central
canal and dorsal subpial enhancement. They are nodular in appearance and can
include a longitudinally extensive T2-hyperintense halo depending on how

inflamed the granuloma is. Even after the start of the treatment, neurosarcoid
lesions distinguish themselves from other causes of immune-mediated
myelopathies in that they remain persistently contrast enhancing for at least

6 weeks, and often more than that.98 They tend to shrink in size over time with
ongoing immunosuppressive treatments and eventually disappear.
In the initial workup, fludeoxyglucose (FDG)-PET is useful in two ways.
First, FDG avidity of the spinal cord lesion supports the diagnosis of
neurosarcoidosis and the decision to pursue a spine biopsy.99 Usually, a biopsy
of the meninges is sufficient to find a granuloma, and the spinal cord can be
spared. Second, even when the spinal cord lesion is avid, scans of the chest and
abdomen often identify an avid lesion in the lungs or spleen that would provide
for an easier biopsy target than the spine or brain.
Spinal fluid analysis usually demonstrates a mix of pleocytosis and low
glucose. Neurosarcoidosis is distinctive among immune-mediated
(noninfectious) causes of myelopathy in causing glucose levels in the low range
of 20 mg/dL to 40 mg/dL (reference range, 60 mg/dL to 100 mg/dL).94 CSF
angiotensin-converting enzyme, produced by macrophages within the
granuloma, is a relatively specific finding in neurosarcoidosis but has low
sensitivity.100 Blood testing for angiotensin-converting enzyme has a lower
specificity than the CSF and is generally not recommended in the workup for
neurosarcoidosis. Soluble interleukin 2 released by activated T cells has been
proposed recently as a marker for sarcoidosis with a sensitivity and specificity
of 88% and 85% in biopsy-proven cases.101,102 However, when tested in the CSF
for neurosarcoidosis, soluble interleukin 2 was not specific except to help
exclude MS.103
Although mild cases of systemic sarcoidosis may not require treatment,
neurosarcoidosis is almost always treated to reverse neurologic symptoms and
prevent progression. Severe or acute cases of myelopathy should be treated with
high doses of corticosteroids, similar to the treatment for inflammatory myelitis,
although the expectation in neurosarcoidosis is that immunosuppressive
treatment for several months or even years may be necessary to achieve full
remission.94 Corticosteroids can be converted to lower oral doses, but in the long
term, the required doses of corticosteroids may cause significant side
effects.94,104 Steroid-sparing agents, such as mycophenolate and methotrexate,
may be added to permit lower doses of steroids. Infliximab, a tumor necrosis
factor inhibitor, is effective and safe in neurosarcoidosis, even in cases that are
not responsive to corticosteroids.105 More recently, JAK/STAT inhibitors have
been shown to be useful in systemic sarcoidosis.106
PARANEOPLASTIC DISEASE
Paraneoplastic myelopathy should be suspected in any patient with myelopathy
in the setting of cancer. The most common cancer associated with paraneoplastic
myelopathy is small cell lung cancer, and associated autoantibodies are usually
192 F E B R U A R Y 2 0 24

anti-Hu, collapsin response mediator protein-5 (CRMP5), or amphiphysin
antibodies.107
Myelopathy can be the initial presentation leading to the diagnosis of cancer.
In patients older than 55 who present with myelopathy, vascular and
paraneoplastic myelopathy should be considered the differential diagnosis,
especially with a weeks- to months-long history of unintended weight loss, night
sweats, or both. MRI features that favor paraneoplastic myelopathy include

longitudinally extensive lesions that appear to track along the white matter in the
spinal cord, brainstem, or brain, which is called tractopathy.108 Another MRI
feature of paraneoplastic myelopathy is necrotic destruction with contrast

enhancement and T1 hypointensity.109 Necrotizing myelopathy in paraneoplastic
disease is a poor prognostic sign.110 Some cases of aggressive paraneoplastic
myelopathy can overlap with AQP4-seropositive NMOSD.111,112
Detection of serologic antibodies to Hu, CRMP5, or amphiphysin should
prompt a cancer workup, including imaging of the chest and abdomen by CT,
PET, or both. Treatment is directed at the underlying cancer, which is usually
immunosuppressive as well. Even when the cancer is treatable, neurologic
damage may be permanent, particularly in the cerebellum and spinal cord.
CONCLUSION
Immune-mediated myelopathies share a common mechanism of immune
dysfunction that targets the spinal cord. There are many other causes of
myelopathy that can mimic immune-mediated myelopathies. In distinguishing
among the several specific causes of immune-mediated myelopathies, a workup
that includes objective data in the form of serology, imaging, spinal fluid analysis,
and, in some cases, histopathology is helpful in narrowing the differential
diagnosis. Newly approved and emerging therapies are available for specific
immune-mediated myelopathies, with more in development.
ACKNOWLEDGMENT
This work was supported by a grant from the National Institutes of Health
(R01 AI153068).
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This case highlights a typical presentation of an immune-mediated COMMENT

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COMMON FEATURES OF IMMUNE-MEDIATED MYELOPATHIES

(NMOSD). These attacks can progress rapidly to a nadir of complete paralysis

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fluid analysis, MRI features,

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of a new immune-mediated myelopathy.18 Red flags in the history include a

compensation or reduced neurologic reserve and should resolve with the

NEUROMYELITIS OPTICA SPECTRUM DISORDER

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atrophy indicate permanent damage to the spinal cord.44

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begin with high-dose corticosteroids for 3 to 5 days, and in most cases,

IV immunoglobulin (IVIg) and cyclophosphamide have shown benefit in small

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findings during acute attacks in

are rare in MS.

false positive tests that plagued the

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diagnosis of MOG antibody

SERONEGATIVE RELAPSING INFLAMMATORY MYELITIS

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disease–like” categories based on their MRI patterns and responses to

addition to B cell–depletion therapies, other patients with an “NMOSD-like”

a broad immunosuppressive approach such as mycophenolate mofetil or

MONOPHASIC IDIOPATHIC INFLAMMATORY MYELITIS

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recovery can take 6 to 18 months or more depending on the extent of damage.

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include a longitudinally extensive T2-hyperintense halo depending on how

myelopathies in that they remain persistently contrast enhancing for at least

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sweats, or both. MRI features that favor paraneoplastic myelopathy include

feature of paraneoplastic myelopathy is necrotic destruction with contrast

1 Fletcher A, Bhattacharyya S. Infectious 5 Transverse Myelitis Consortium Working Group.

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overlapping cases. Autoimmun Rev 2011;10(3):

Neuromyelitis optica and non organ-specific doi:10.1016/0003-9993(94)90032-9

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spinal cord: distribution across vertebral levels Neuroinflammation 2014;1(1):e11. doi:10.1212/

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efficacy of rituximab in neuromyelitis optica

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myelitis: a retrospective study. 966-971. doi:10.1212/wnl.31.8.966

81 Hutchinson M, Waters P, McHugh J, et al. (Minneap Minn) 2011;17(4):816-830. doi:10.1212/

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

111 Cai G, He D, Chu L, et al. Paraneoplastic

central nervous system. F1000Research 2020;9: doi:10.3109/00207454.2015.1054481

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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