REVIEW

CURRENT
OPINION Treatment of neuromyelitis optica spectrum
disorders
Andrew R. Romeo and Benjamin M. Segal

Purpose of review
This review discusses concepts for diagnosing neuromyelitis optica spectrum disorders (NMOSD),
distinguishing NMOSD from other inflammatory diseases of the central nervous system, and highlights
recent and forthcoming data on acute and maintenance therapy of NMOSD.
Recent findings
The neurologic manifestations of NMOSD are heterogenous, extending beyond classic presentations of
optic neuritis and longitudinally extensive transverse myelitis. NMOSD may be comorbid with
rheumatologic diseases, such as systemic lupus erythematosus, but is recognized as a distinct entity. Recent
studies of acute treatment of NMOSD support early use of plasmapheresis. Relapse prevention is essential,
as relapses can be disabling and patients may have only partial recovery. Current practice generally
recommends at least 5 years of maintenance treatment. Recent randomized data demonstrates superiority
of rituximab over azathioprine. Phase 3 trials have recently been completed or are underway studying
novel therapies employing B-cell depletion, complement inhibition, and cell-based mechanisms (among
other mechanisms) for maintenance therapy of NMOSD.
Summary
NMOSD is a heterogeneous but well-defined clinical entity, distinct from other neurologic and systemic
inflammatory diseases, and treatment is poised for expansion.
Keywords
immunosuppressive agents, lupus erythematosus, myelitis, neuromyelitis optica, plasmapheresis, systemic

INTRODUCTION binding of AQP4-IgG to astrocytic end feet that abut

Neuromyelitis optica spectrum disorders (NMOSD) blood vessels [2]. The clinical manifestation of
encompass a group of syndromes typically charac- NMOSD reflects this pathogenic mechanism, as
terized by optic neuritis and/or acute myelitis, often AQP4 channels are concentrated in the optic nerve,
in association with serum IgG autoantibodies area postrema, and spinal cord [2].
directed against aquaporin-4 (AQP4-IgG), an astro- The clinical course is typically relapsing, as
cytic water channel [1,2]. As opposed to multiple opposed to progressive [5,6]. Approximately 4%
sclerosis (MS), the myelitis that occurs in NMOSD experience a monophasic course (based on one
tends to involve all three of the major neurological study of untreated patients in the United States)
pathways (motor, sensory, and autonomic) simulta- [7]. Patients often do not enjoy a full functional
neously. Furthermore, spinal cord lesions tend to be recovery following each relapse, but incur perma-
longitudinally extensive (spanning three or more nent deficits, making it imperative to treat acutely
vertebral segments), centrally located within the and introduce maintenance therapy promptly to
cord, and expansive [1]. Bilateral optic neuritis is reduce the risk of future attacks [5]. A confident
not uncommon. NMOSD may manifest as an area
postrema syndrome (intractable nausea, vomiting,
Department of Neurology, University of Michigan, Ann Arbor, Michigan,
and/or hiccups), an acute brainstem syndrome (ocu- USA
lomotor dysfunction and/or facial itching), narco- Correspondence to Andrew R. Romeo, MD, Department of Neurology,
lepsy, acute diencephalic clinical syndrome (e.g., University of Michigan, 1500 E. Medical Center Drive, Floor 1, Reception C,
hypothermia or hypersomnolence), or a symptom- Ann Arbor, MI 48109, USA. Tel: +1 734 232 0438;
atic cerebral syndrome [1,3,4]. The underlying e-mail: [email protected]
pathogenesis involves complement-mediated cyto- Curr Opin Rheumatol 2019, 31:250–255
toxicity of astrocytes, presumably triggered by the DOI:10.1097/BOR.0000000000000603

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 Neuromyelitis optica spectrum disorders Romeo and Segal

Table 1. Neuromyelitis optica spectrum disorders

KEY POINTS
diagnostic criteria
 Clinical manifestations of neuromyelitis optica include Core clinical Optic neuritis
not only optic neuritis and myelitis, but area postrema characteristics Acute myelitis
syndrome, brainstem syndromes, diencephalic of NMOSD Area postrema syndrome
syndromes, and cerebral syndromes. Acute brainstem syndrome
Diencephalic syndrome
 NMOSD may be comorbid with SLE, Sjögren’s Cerebral syndrome
syndrome, or inflammatory diseases, but should be
Seropositive 1. One core clinical characteristic
recognized as a distinct entity, and NMOSD 2. Positive serum AQP4-IgG
treated accordingly. 3. Alternative diagnoses excluded
 Corticosteroids remain first line for treatment of Seronegative 1. At least two core clinical characteristics
NMOSD relapses, but the clinician should have a low NMOSD (simultaneous or separated in time), and
threshold to employ plasmapheresis. fulfilling the following
a. At least one core clinical characteristic
 In addition to traditional immunosuppressants and B-cell must be optic neuritis, LETM, or area
depletion, future maintenance treatments for NMOSD postrema syndrome
may include complement pathway inhibition, inhibition b. Two distinct clinical characteristics
of interleukin-6 signaling, and cell-based therapies. (separation in space)
c. Fulfilling MRI requirements as applicable
(see [1])
2. Negative serum AQP4-IgG using cell-based
assay, or testing not available
diagnosis is critical for proper treatment, particu- 3. Alternative diagnoses excluded
larly as certain disease-modifying agents used in MS
are untested or ineffective in NMOSD, and may even AQP4, aquaporin-4; LETM, longitudinally extensive transverse myelitis;
be detrimental (such as recombinant interferon- NMOSD, neuromyelitis optica spectrum disorders.
Adapted from Ref. [1].
beta) [8]. This review will focus on current consensus
criteria for the diagnosis of NMOSD, the overlap
between NMOSD and rheumatological conditions, classical syndrome, but with negative serum AQP4-
and recent clinical studies and trials of both acute IgG, the clinician should ensure that a cell-based
and maintenance therapies. flow cytometry or microscopy test was performed.
Cell-based assays and ELISA for AQP4-IgG are both
commercially available, but cell-based assays are
DIAGNOSIS more sensitive [10]. Antibodies against myelin oli-
The diagnostic criteria for NMOSD were updated by godendrocyte glycoprotein (MOG-IgG) have been
an international panel in 2015, prompted by the associated with monophasic as well as relapsing
realization that these disorders are more heteroge- neurological syndromes that resemble NMOSD,
neous than previously thought [1]. Separate criteria including optic neuritis and LETM, and account
were developed for NMOSD with AQP4-IgG and for at least a subset of patients meeting criteria for
NMOSD without AQP4-IgG (Table 1). In an individ-
&
seronegative NMOSD [11 ,12]. Indications for test-
ual with positive AQP4-IgG titers, the presence of ing for MOG-IgG have recently been proposed, but
one of the core clinical characteristics is sufficient to
&
will not be detailed in this article [11 ]. Many of the
make a diagnosis of NMOSD, assuming that alterna- same red flags which would prompt testing for
tive diagnoses (such as sarcoidosis, lymphoma, AQP4-IgG should prompt consideration of testing
syphilis, HIV, spinal cord ischemia, and dural arte- for MOG-IgG: LETM, relapsing optic neuritis, and
riovenous fistula, among others) have been simultaneous bilateral optic neuritis, among other
excluded. The criteria are more stringent in the presentations. Thus far, MOG-IgG and AQP4-IgG
absence of AQP4-IgG (or if the sero-status is have not been found to co-occur [13].
unknown); a patient must present with at least When possible, the diagnosis of NMOSD should
two of the core clinical characteristics, and at least be corroborated with MRI. Acute NOSD lesions are
one of these must be optic neuritis, longitudinally hyperintense on T2 sequences, with associated
extensive transverse myelitis (LETM), or area post- enhancement on T1-weighted sequences after
rema syndrome. The two core clinical characteristics administration of gadolinium; chronic lesions are
may present simultaneously or be separated in time. hyperintense on T2-weighted sequences, without
Again, alternative diagnoses must be excluded. associated enhancement postgdolinium, and may
Testing for AQP4-IgG should be performed on have associated atrophy (particularly spinal cord
serum, as it is more sensitive than cerebrospinal lesions) [1]. As alluded to above, spinal cord MRI
fluid analysis [9]. For a patient presenting with a lesions typically span three vertebral segments or

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Clinical therapeutics and hematologic complications

more in length, involve central grey as well as white Antiphospholipid syndrome has been associ-
matter, and may be associated with swelling. In ated with both ischemic myelopathy and inflamma-
contrast, MS cord lesions generally span one vertebral tory myelitis. A Mayo Clinic retrospective study of
segment or less, are confined to white matter tracts 24 cases of LETM with antiphospholipid or b2-gly-
(particularly the dorsal columns), and are not associ- coprotein antibodies detected AQP4-IgG in nearly
ated with significant swelling. These distinctions are half of the study participants (and did not find
not absolute, as up to 14% of spinal cord lesions in AQP4-IgG in control cases with antiphospholipid
&&
individuals with seropositive NMOSD are not longi- antibodies but without LETM) [20 ].
tudinally extensive, and initially distinct MS lesions The pathogenesis of CNS involvement in
can become confluent and span multiple segments as patients with Sjögren’s syndrome is somewhat con-
they accumulate [1,14]. Features of orbital MRI that troversial, and likely heterogeneous. Although
are suggestive of NMOSD include bilateral optic patients with Sjögren’s syndrome may have anti-
nerve involvement, posterior nerve predominance, bodies against other aquaporin isoforms, it appears
and involvement of the optic chiasm [1]. only those patients with clinical diagnoses of
NMOSD have AQP4-IgG [21,22]. Some Sjögren’s
syndrome patients with CNS demyelinating syn-
NMOSD AND RHEUMATOLOGICAL dromes meet diagnostic criteria for MS.
CONDITIONS
NMOSD may be comorbid with other autoimmune
syndromes, such as systemic lupus erythematosus ACUTE TREATMENT
(SLE) or Sjögren’s syndrome [1,15]. Optic neuritis NMOSD relapses have significant potential to result
has also been associated with SLE, rheumatoid arthri- in permanent disability, distinct from MS relapses or
tis, and Sjögren’s syndrome [16]. In a multicenter idiopathic acute transverse myelitis [5]. Whereas
retrospective study of patients with NMO (2006 con- relapse severity may govern the need for acute treat-
sensus diagnostic criteria) or seropositive NMOSD, ment in MS, all NMOSD relapses should be treated
approximately 60% of patients had a positive anti- acutely. A common approach to treatment of
nuclear antibody (ANA) (titer greater than 1:40), with NMOSD relapse begins with corticosteroid pulses
approximately 28% of patients exhibiting ANA titer (e.g., methylprednisolone 1000 mg intravenous
at least 1:320 [7]. Approximately 26 and 11% of the daily for 3–5 days). If the initial response to steroids
patients tested positive for Sjögren’s-syndrome- is inadequate, then plasmapheresis should be con-
related antigen A (SS-A) and Sjögren’s-syndrome- sidered. A recent multicenter retrospective found
related antigen B (SS-B), respectively [7]. A recent that using apheresis therapy as a first-line treatment
Brazilian cohort of NMO patients found lower rates of relapse, or initiating apheresis within days of
&
of ANA, antiSS-A, and antiSS-B seropositivity [17]. relapse onset, predicted full recovery [23 ]. There
Birnbaum et al. [18] described two clinical syn- was no difference in efficacy when comparing
dromes of lupus myelitis: ‘gray matter myelitis’ therapeutic plasma exchange (PLEX) with immu-
(‘flaccidity and hyporeflexia’) and ‘white matter noadsorption. An independent, single-center retro-
myelitis’ (‘spasticity and hyperreflexia’). Patients spective analysis of patients with syndromes
with gray myelitis had significantly higher mean reminiscent of NMOSD found that the probability
Systemic Lupus Erythematosus Disease Activity of complete recovery from relapse decreased as the
Index and erythrocyte sedimentation rate. Relapses time interval between relapse onset and PLEX
&
were more common with white matter myelitis. increased [24 ]. The authors concluded that the first
Over half of the patients with white matter myelitis, five days after relapse onset are a critical period to
but none with grey matter myelitis, had a history of initiate PLEX, and that waiting to initiate PLEX after
optic neuritis. Most of the white matter myelitis failure of response to corticosteroids ‘could be dele-
patients (80%) satisfied 2006 diagnostic criteria terious.’ A smaller retrospective from a Chinese
for neuromyelitis optica; four of seven patients with center found an association between earlier initia-
white matter myelitis were seropositive for AQP4- tion of PLEX and favorable recovery, in patients
IgG. Myelitis was most often longitudinally exten- deemed refractory to intravenous corticosteroids
&
sive in both groups. A recent systematic review and/or intravenous immunoglobulin [25 ]. Though
(which included the Birnbaum cohort), corrobo- there are inherent limitations in the designs of each
rated the overlap between NMOSD and white matter of these retrospective studies, collectively they
&&
lupus myelitis [19 ]. In our opinion, cases of myeli- endorse a low threshold to initiate PLEX.
tis and/or optic neuritis that occur in the setting of A number of novel biological agents are being
SLE, which meet criteria for NMOSD, should be investigated for the treatment of acute NMOSD
treated as NMOSD. episodes. In a Phase 1b trial, a C1-esterase inhibitor

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 Neuromyelitis optica spectrum disorders Romeo and Segal

(which prevents activation of the complement sys- P ¼ 0.028). There was no significant difference in
tem) was found to be a well-tolerated adjunctive the rate of side-effects, though one patient in the
therapy to intravenous corticosteroids for AQP4-IgG rituximab group had a severe allergic reaction.
seropositive NMOSD patients presenting with acute A large prospective open-label observational
myelitis or optic neuritis [26]. Bevacizumab, a study of azathioprine and mycophenolate mofetil
monoclonal IgG against vascular endothelial in NMOSD patients in China found no significant
growth factor that ostensibly stabilizes the blood– difference in relapse rates. However, more patients
brain barrier, has also been shown to be well toler- on azathioprine discontinued or switched therapy
ated as an add-on to intravenous corticosteroids in because of adverse effects, including leukopenia,
relapses of NMOSD or presumed NMOSD, in a phase hepatotoxicity, hair loss, and nausea/vomiting
&
1b trial [27]. Ublituximab, a B-cell depleting mono- [37 ].
clonal antibody that targets the cell surface mole- Granulocytes are thought to contribute to the
cule CD20, is currently under study as an add-on to inflammatory cascade in NMOSD lesions. Cetirizine
steroids for acute treatment of NMOSD relapse is a second-generation antihistamine, purported to
(NCT02276963). Each of these novel acute treat- stabilize eosinophils. Cetirizine was well tolerated as
ments will need to be studied in randomized trials an add on to typical NMOSD maintenance therapy
to assess efficacy. in a recent open-label pilot study, but a controlled
study will be necessary to demonstrate efficacy [38].
Anecdotally, NMOSD patients have been treated
MAINTENANCE TREATMENT with MS disease modifying therapies, sometimes
Relapse prevention is essential, as relapses can be inadvertently when the spectrum was still being
disabling and patients may have only partial recov- defined. Extrapolating from uncontrolled case
ery. Current practice generally recommends at least reports and series, fingolimod, alemtuzumab, and
5 years of maintenance treatment [28]. To date there dimethyl fumarate are suspected to be (at least)
&
are no published randomized placebo-controlled ineffective in NMOSD [39 ,40]. Interferon-b has
trials for maintenance treatment of NMOSD, been reported to actually exacerbate NMO [8].
though multiple trials are currently underway. Natalizumab is a monoclonal antibody against the
Empiric maintenance regimens have included adhesion molecule, a4-integrin, effective for treat-
mycophenolate mofetil, azathioprine, rituximab, ment of relapsing MS and Crohn’s disease [41,42]. It
& &
and chronic corticosteroids [29,30 ,31 ,32,33,34]. curtails the migration of lymphocytes from the blood
Our practice has favored rituximab for maintenance stream into solid tissues. A recent study identified
treatment. So far no distinctions have been made four natalizumab-treated patients (initially misdiag-
between seronegative and seropositive NMOSD nosed with MS) who met diagnostic criteria for sero-
&
patients in regards to treatment. A multinational, positive NMOSD [43 ]. The same research group
multicenter retrospective analysis found no differ- previously reported five cases of NMOSD patients
ence between seropositive and seronegative initially misdiagnosed with MS and treated with
NMOSD patients in their responsiveness to rituxi- natalizumab [44]. Taken together, all nine patients
&
mab or mycophenolate mofetil [35 ]. Comparative continued to have relapses while on natalizumab.
studies to help guide initial treatment choice or A number of novel therapies have been sug-
sequencing are limited. Our discussion will focus gested or are currently under study for treatment
on recent note-worthy studies of maintenance of NMOSD. Eculizumab is a monoclonal antibody
therapies as well as on-going inquiries and future against terminal complement component 5 (C5); it
directions. has been approved for treatment of paroxysmal
Rituximab and azathioprine were compared nocturnal hemoglobinuria and atypical hemolytic
head-to-head in an open-label randomized trial, uremic syndrome. An open-label pilot study of
which included seropositive and seronegative eculizumab in NMOSD demonstrated safety, and
&&
NMOSD patients [36 ]. The primary outcome was 12 of 14 patients remained relapse-free after
annualized relapse rate (ARR) at 12 months. Despite 12 months [45]. Most of these patients had failed
randomization, the rituximab group had a signifi- standard NMOSD maintenance therapies prior to
cantly higher mean Expanded Disability Status Scale enrollment. A double-blind, placebo-controlled trial
and mean ARR at baseline compared with the aza- of eculizumab has completed and results have not
thioprine group. The rituximab group had a signifi- yet been reported (NCT01892345). A double-blind,
cantly greater decline in ARR from baseline to placebo-controlled trial of MEDI-551, a monoclonal
12 months (1.09 vs. 0.49, P < 0.001), and a signifi- antibody against the B-cell/plasmablast marker
cantly greater proportion of relapse-free patients CD19 is currently underway (NCT02200770) [46].
(65 vs. 41.3% with intention to treat analysis, Tocilizumab is a monoclonal antibody against

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Clinical therapeutics and hematologic complications

interleukin-6 receptor, approved for treatment of Conflicts of interest

rheumatoid arthritis; retrospective data in NMOSD As a fellow A.R.R. was an EDSS rater for the MEDI-551
showed potential benefit [47]. An open-label trial trial (NCT02200770), which is discussed in this article.
of tocilizumab in NMOSD has completed B.M.S. receives an investigator-initiated grant sponsored
(NCT03062579), but the results have yet to be pub- by Genentech, the manufacturer of rituximab, a therapy
lished. A randomized trial comparing tocilizumab mentioned in this article.
and azathioprine is ongoing (NCT03350633). Satra-
lizumab is also a monoclonal antibody against inter-
leukin-6 receptor, and is the subject of randomized REFERENCES AND RECOMMENDED
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