Neuromyelitis Optica Spectrum Disorders It is critical to maintain a high index of suspicion for these conditions when evaluating a patient with demyelination to avoid delays in treatment. By Michael J. Bradshaw, MD and Dorlan Kimbrough, MD

Introduction be accompanied by color desaturation, a relative afferent Neuromyelitis optica (NMO) pupillary defect, and/or optic disc edema. Clinical features and NMO spectrum disorders that suggest NMOSD (or MOG antibody-associated disorder) (NMOSD) are clinical syn- include simultaneously bilateral ON and severe vision loss dromes traditionally defined (acuity 20/200 or worse).7,8 by the presence of myelitis and (ON). Aquaporin-4 (AQP4) is a water chan- Brainstem Syndromes nel that is heavily expressed on astrocyte foot processes in The area postrema (AP) is an emetic reflex center located the optic nerves, brainstem, and spinal cord. Antibodies to in the floor of the fourth ventricle that modulates a number AQP4 are directly pathogenic and serve as a highly specific of physiologic processes such as hiccups and emesis. The AP diagnostic biomarker for NMO, which is technically an auto- has been proposed as the initial site of entry for pathogenic immune astrocytopathy.1 They are detectable in 60% to 80% AQP4 antibodies because AP capillaries lack tight junctions of patients with NMOSD. Lesions that are positive for AQP4 and AP astrocytes express an abundance of AQP4.9 antibodies (AQP4+), which have a prominent perivascular Area postrema syndrome (APS) occurs commonly in complement deposition, are pathologically distinct from AQP4+ NMOSD consequent to inflammatory lesions in the lesions of multiple sclerosis (MS). Among patients with an AP.10 In contrast to ON or myelitis, AP lesions lack demy- NMOSD phenotype who are seronegative for antibodies to elination or necrosis, which may in part explain the nearly AQP4 (AQP4-), as many as 42% have detectable serum anti- universal complete remission of symptoms after an attack. bodies to myelin oligodendrocyte glycoprotein (MOG) (See Proposed APS diagnostic criteria include acute or subacute Box p 78).3 The prevalence of NMOSD is roughly 4 to 10 per nausea, vomiting, or hiccups lasting for at least 48 hours 100,000, with higher rates among those of African or Asian without response to treatment or evidence of other etiolo- descent; onset occurs throughout the lifespan and 5 to 10 gies (eg, hyponatremia, CNS structural lesions, and gastroin- times more often in women than men.4,5 testinal or migrainous phenomena).11 Dorsal medulla lesions on MRI can facilitate early diagnosis. An attack of APS may Clinical Manifestations serve as warning of an impending attack of ON or myelitis as Most patients with NMOSD have a relapsing course with most occurrences (58%-68%) precede inflammatory involve- attacks that have a temporal profile similar to a demyelinat- ment elsewhere.11 Other brainstem syndromes sometimes ing episode of MS. Relapses in patients with AQP4+ NMOSD encountered in patients with NMOSD include oculomotor are more likely to be severe and disabling compared with abnormalities, hearing loss, nuclear facial nerve palsy, ves- MS relapses. The cardinal clinical features of NMOSD tibular dysfunction, and other cranial nerve abnormalities.12 include episodes of optic neuritis, acute myelitis, and brain- stem syndromes. Other core clinical features that occur less Myelitis often include symptomatic narcolepsy, acute diencephalic Considered a hallmark of NMOSD, longitudinally extensive syndrome, or acute cerebral syndromes.6 (LETM) is defined as myelitis spanning at least 3 spinal segments. Neurologists should be aware that Optic Neuritis short-segment myelitis is also common in NMOSD; neglecting Inflammatory ON typically presents as acute to subacute to consider this is associated with delay in diagnosis and treat- monocular vision loss with impaired visual acuity that may ment.13 The anterolateral cord syndrome with prominent

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weakness and spinothalamic tract deficits is a typical but not TABLE. DIAGNOSTIC CRITERIA FOR NMOSD exclusive pattern. IN ADULTS AQP4+ NMOSD Pregnancy a Relapse rates in women with NMOSD do not change Positive test for AQP4-IgG during pregnancy in contrast to women with MS, who Exclusion of alternate diagnoses 14 have a reduced relapse rate during pregnancy; relapse risk At least 1 of the following: increases during the first 3 months postpartum in both women with NMOSD and MS, however.15 The placenta Optic neuritis expresses AQP4, which may in part explain why preeclamp- Acute myelitis sia, intrauterine growth restriction, and miscarriage are more Area postrema syndrome common in women with NMOSD. Antibodies to AQP4 are transferred across the placenta but do not appear to be Acute brainstem syndrome pathogenic to the fetus. Symptomatic cerebral syndrome w/ NMOSD-typical brain lesion Symptomatic narcolepsy OR acute diencephalic clinical Children syndrome with NMOSD-typical diencephalic lesions. Although median age of onset is 30 to 40 years, 3% to 5% of patients with NMOSD present as children, which can be clini- AQP4- or AQP4 status unknown NMOSD cally challenging.16 The most common presenting features of Negative or inconclusive test for AQP4-IgGa NMOSD in children include visual, motor, and constitutional Exclusion of alternative diagnoses symptoms (ie, vomiting, fever, seizures). A single study report- ed a mean annualized relapse rate (ARR) of 0.6 in pediatric- At least 1 of the following : onset NMOSD compared with 1.0 in adult-onset NMOSD; Optic neuritis time to disability is longer in patients with pediatric-onset, Acute myelitis with LETM largely explained by the severity of a first episode of myelitis in adults. Time to first treatment was significantly longer in chil- Area postrema syndrome dren compared with adults (13.1 vs 3.4 years). Children with If only 1 of above present, then also 1 of following: acute disseminated (ADEM) frequently Acute brainstem syndrome have LETM, which also occurs in a substantial minority of chil- dren with MS and monophasic myelitis. As in adults, antibodies Symptomatic cerebral syndrome w/ NMOSD-typical brain lesion to AQP4 are a critical diagnostic biomarker.17 Symptomatic narcolepsy OR acute diencephalic clinical syn- drome WITH NMOSD-typical diencephalic lesions Coexisting Autoimmunity PLUS THE FOLLOWING MRI FINDINGS Systemic autoimmune disorders such as systemic Acute optic Brain MRI normal or with nonspecific erythematosus (SLE), antiphospholipid antibody syndrome, neuritis white matter lesions OR optic nerve and Sjögren’s syndrome often coexist with NMOSD. hyperintense lesion or T1 Gd+ lesion Clinical episodes concerning for APS, myelitis, or ON in extending over more than half the patients with systemic autoimmunity should prompt test- optic nerve or involving optic chiasm ing for serum AQP4 antibodies.18 Conversely, patients with NMOSD, especially if seronegative, should be asked about Acute myelitis Associated intramedullary lesion systemic symptoms and have a rheumatologic workup com- extending over 3 or more contigu- mensurate with the degree of clinical suspicion for Sjögren’s ous segments (LETM) OR focal spinal syndrome, SLE, and related conditions. cord atrophy over 3 or more contigu- ous segments and compatible history Diagnosis Area postrema Dorsal medulla/area postrema lesions The International Panel for NMO Diagnosis (IPND) updat- syndrome 10 ed diagnostic criteria for NMOSD are shown in the Table. Acute brainstem lesion Periependymal brainstem lesions + Laboratory Studies Abbreviations: AQP4, aquaporin-4; Gd , gadolinium positive; Serum samples rather than (CSF) should IgG, ; LETM, longitudinally extensive trans- verse myelitis; NMOSD, neuromyelitis optica spectrum disor- be used to test for AQP4 antibodies and cell-based assays (eg, a fluorescence-activated cell sorting or direct immunofluores- ders. cell-based assay preferred for AQP4 antibody testing

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Box: Myelin Oligodendrocyte Glycoprotein-Antibody Associated Disease

Introduction ADEM-like presentation, 88% of both adults (7/8) and Myelin oligodendrocyte glycoprotein (MOG) is expressed on children (8/9) with persistent seropositivity had a relapsing the outermost surface of the myelin sheath and may func- course, compared with no children (0/4) and 25% of adults tion in cell adhesion, microtubule stability, and interactions (1/4) with transient seropositivity.5 with the immune system. Antibodies targeting MOG have Laboratory Studies been implicated in the rodent model of multiple sclerosis Approximately 40% of children with ADEM have at least (MS), experimental autoimmune encephalitis (EAE); identi- transient MOG antibodies11 and MOG-antibody seroposi- fied in a small percentage of patients with MS; and reported tivity was associated with fewer emotional and behavioral in patients with neuromyelitis optic spectrum disorders problems, higher CSF pleocytosis, more frequent LETM, and (NMOSD). Early studies were limited by the use of older higher relapse risk compared with patients with ADEM who techniques that did not use the MOG antigen in its human were seronegative for MOG antibodies.12 conformational, or native, state but with the use of cell-based assays in which cells express native-state MOG, presence Diagnostic recommendations published in 2018 recom- mended against testing for MOG antibodies in all patients of antibodies to MOG are a specific biomarker of a central 13 nervous system (CNS) immune-mediated disease that is with MS. The overall specificity of MOG antibody detec- distinct from MS and AQP4 antibody seropositive (AQP4+) tion using a cell-based assay is 98.5%, although the sensitiv- NMOSD.1 Pathologically, lesions in anti-MOG disease are ity is lower. Testing should be done on serum and not CSF. indistinguishable from type II MS lesions and antibodies to Analysis of CSF reveals lymphocytic pleocytosis in approxi- MOG isolated from patients are pathogenic when infused mately half of patients with MOG antibody-associated into the cerebrospinal fluid (CSF) of rodents, suggesting disease and only rarely oligoclonal bands or an elevated IgG index (5.7 and 7.3% respectively in one large study), in con- a pathogenic role of the antibody in at least some cases, 4 although this remains uncertain.2 trast to CSF findings typical of MS. There are few population-based epidemiologic studies of Treatment MOG antibody-associated disease. In contrast to MS and Treatment of MOG antibody-associated disease consists of NMOSD, the increased incidence in women vs men seems managing acute relapses and reducing risk of further relapses. lower. Acute relapses are treated with intravenous methylpredniso- lone (IVMP), plamapheresis (PLEX), and intravenous immu- Clinical Features noglobulins (IVIG), and most patients respond well, although The major clinical features of MOG antibody-associated early relapses tend to occur after treatment.14 We generally disease are optic neuritis (ON), myelitis, acute disseminating use IVMP as a first-line treatment, with PLEX promptly for encephalomyelitis (ADEM), and brainstem encephalitis with a patients who do not respond well to IVMP or who have 3,4 course typical of other inflammatory demyelinated diseases. responded best to PLEX in the past. Either treatment can be Patients can have either a monophasic or relapsing course; followed by IVIG with or without a prolonged oral predni- higher titers of MOG antibodies as well as persistent sero- sone taper to minimize the risk of early relapse.15,16 positivity over time predict a relapsing course.5,6 Identifying which patients to treat with long-term immuno- Often bilateral with disc edema and inflammation involving therapy is not straightforward because approximately half more than half the length of the optic nerve, ON is associ- of patients with MOG antibodies may have a monophasic + ated with better outcomes than in AQP4 NMOSD as is course. In a large cohort, 36% of patients relapsed after a myelitis, which occurs in approximately 50% of patients with median of 16 months. At 48 months, 47% of patients had 7-9 MOG antibody-associated disease. permanent neurologic disability.3 With repeat testing, most Neuroimaging patients remain seropositive for MOG antibodies but those Relapses of longitudinally extensive transverse myelitis who seroconvert to negative status appear to be at low risk (LETM) are rare in MOG antibody-associated disease whereas for relapse; patients with simultaneous ON or myelitis or AQP4+ NMOSD accounts for 90% of relapsing LETM.10 ADEM-like illness appear to be less likely to remain seroposi- Pontine and thalamic lesions of the brainstem are more likely tive over time.3,5 Repeat testing after 6 months is valuable for in MOG antibody-associated disease than AQP4+ NMOSD, prognostication. which more often manifests with area postrema syndrome Most clinicians use similar management strategies for 4 or medullary lesions. In a small study of patients with an patients with MOG antibody-associated disease as for those

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cence) should be used.10 Although testing is more sensitive when done prior to initiating immunotherapy, testing should not delay acute treatment. Because even cell-based assays have sensitivity of only 75% to 80%,19 it is prudent to repeat with NMOSDs, favoring azathioprine (AZA), mycopheno- testing after a few weeks or months if results were nega- late mofetil (MMF) and rituximab (RTX) (not necessarily tive and clinical suspicion is high. Patients with suspected in this order) over disease-modifying treatments (DMTs) NMOSD should also be tested for serum antibodies to used for patients with MS. A multinational study of 102 MOG. children with MOG antibody-associated disease found Analysis of CSF from patients with NMOSD shows normal that treatment with interferon β and to highly inflammatory profiles, the latter being more typi- did not improve the annualized relapse rate (ARR), where- cal during an episode of myelitis than ON. Pleocytosis (>50 as a significant reduction in ARR was seen with AZA (ARR: leukocytes/mcL), especially with neutrophilic or eosinophilic 1.84 to 1.0), MMF (ARR: 1.79 to 0.52) and RTX (ARR: 2.16 predominance, is useful for distinguishing NMOSD from to 0.51).15 We favor MMF or RTX,14,17 and research is need- MS, although, most often, both conditions have a lympho- ed to determine if either is more efficacious. When using cytic predominance. Oligoclonal bands (OCBs) are found MMF, it is important to provide additional immunother- in approximately 30% of patients with NMOSD, most often apy (eg, oral prednisone or IVIG) for 3 to 6 months while during an attack. In contrast, OCBs are present in more than titrating MMF and awaiting full efficacy. Further studies 85% of patients with MS and pleocytosis of more than 50 are needed to help guide prognostication and therapeutic leukocytes per mcL is rare in patients with MS.20 decision-making in MOG antibody-associated disease. Neuroimaging 1. Reindl M, Jarius S, Rostasy K, Berger T. Myelin oligodendrocyte glycoprotein antibodies: How clinically Neuroimaging features are useful for distinguishing useful are they? Curr Opin Neurol. 2017;30:295-301. among NMOSD, MS and MOG antibody-associated dis- 2. Spadaro M, Winklmeier S, Beltran E, et al. Pathogenicity of human antibodies against myelin oligodendro- 21 cyte glycoprotein. Ann Neurol. 2018;84:315-328. eases (Figure 1). 3. Jurynczyk M, Messina S, Woodhall MR, et al. Clinical presentation and prognosis in MOG-antibody disease: MRI. Inflammation involving more than half the length of a UK study. Brain. 2017;140:3128-3138. the optic nerve, simultaneous bilateral ON, or involvement 4. Cobo-Calvo A, Ruiz A, Maillart E, et al. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study. Neurology. 2018;90:e1858-e1869. of the optic chiasm suggest NMOSD, and lesion length cor- 22 5. Lopez-Chiriboga AS, Majed M, Fryer J, et al. Association of MOG-IgG serostatus with relapse after acute relates with visual prognosis. Myelitis in NMOSD tends to disseminated encephalomyelitis and proposed diagnostic criteria for MOG-IgG-associated disorders. JAMA involve central gray matter nonexclusively. Although LETM Neurol. 2018. is a hallmark manifestation of NMOSD, it has a broad dif- 6. Hennes EM, Baumann M, Schanda K, et al. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology. 2017;89:900-908. ferential diagnosis including but not limited to infection, 7. Mariotto S, Ferrari S, Monaco S, et al. Clinical spectrum and IgG subclass analysis of anti-myelin oligoden- neurosarcoidosis, and SLE. Neurosarcoidosis, for example, drocyte glycoprotein antibody-associated syndromes: a multicenter study. J Neurol. 2017;264:2420-2430. can produce LETM distinguishable from NMOSD by the 8. Chen JJ, Flanagan EP, Jitprapaikulsan J, et al. Myelin oligodendrocyte glycoprotein antibody (MOG- presence of constitutional symptoms, pulmonary or hilar IgG)-positive optic neuritis: clinical characteristics, radiologic clues and outcome. Am J Ophthalmol. 2018;195:8-15. adenopathy, hypoglycorrhachia, elevated angiotensin 9. Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and converting enzyme levels, and persistent subpial contrast myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71:276-283. enhancement. 10. Jitprapaikulsan J, Lopez Chiriboga AS, Flanagan EP, et al. Novel glial targets and recurrent longitudinally extensive transverse myelitis. JAMA Neurol. 2018;75:892-895. Corpus callosum lesions occur in 12% to 40% of patients 11. Brilot F, Dale RC, Selter RC, et al. Antibodies to native myelin oligodendrocyte glycoprotein in children with NMOSD and typically follow the ependymal lining; with inflammatory demyelinating disease. Ann Neurol. 2009;66:833-842. acute lesions are often edematous and heterogeneous, 12. Baumann M, Sahin K, Lechner C, et al. Clinical and neuroradiological differences of paediatric acute dis- creating a marbled pattern. The complete thickness of the seminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. J Neurol Neuroimmunol Psychiatry. 2015;86:265-272. splenium may be involved, termed the arch bridge pat- 13. Jarius S, Paul F, Aktas O, et al. MOG encephalomyelitis: international recommendations on diagnosis and tern. Extensive hemispheric white matter lesions may have antibody testing. J Neuroinflamm. 2018;15:134. a tumefactive appearance resembling Baló’s concentric 14. Narayan R, Simpson A, Fritsche K, et al. MOG antibody disease: A review of MOG antibody seropositive neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2018;25:66-72. sclerosis, ADEM or posterior reversible encephalopathy 15. Hacohen Y, Wong YY, Lechner C, et al. Disease course and treatment responses in children with relapsing syndrome (PRES). Such large or confluent lesions are more myelin oligodendrocyte glycoprotein antibody-associated disease. JAMA Neurol. 2018;75:478-487. common in children. Lesions surrounding the third ven- 16. Ramanathan S, Mohammad S, Tantsis E, et al. Clinical course, therapeutic responses and outcomes in tricle and cerebral aqueduct (including the hypothalamus, relapsing MOG antibody-associated demyelination. J Neurol Neuroimmunol Psychiatry. 2018;89:127-137. 17. Montcuquet A, Collongues N, Papeix C, et al. Effectiveness of mycophenolate mofetil as first-line ventral midbrain and near the circumventricular organs therapy in AQP4-IgG, MOG-IgG, and seronegative neuromyelitis optica spectrum disorders. Mult Scler. in the dorsal medulla) are typical of NMOSD. With gado- 2017;23:1377-1384. linium, lesions may appear poorly marginated, subtle, and patchy, termed a cloud-like enhancement pattern. Pencil-

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A B E F

C D

Figure 1. A: Axial fluid-attenuated inversion recovery (FLAIR) MRI of a patient with AQP4+ NMOSD and area postrema syndrome demonstrating T2 hyperintensity in the dorsal medulla (image courtesy of Dr. Divyanshu Dubey). B: Axial FLAIR MRI from a patient with AQP4+ NMOSD demonstrating an “arch bridge” lesion in the splenium of the corpus callosum (arrow; Image courtesy of Dr. Carlos Sollero). C: Coronal T1 postgadolinium MRI in a patient with AQP4+ NMOSD demonstrating an enhancing linear brainstem lesion in the right cerebral peduncle. D: Sagittal FLAIR MRI from a patient with AQP4+ NMOSD demonstrating a marbled lesion in the corpus callosum following the ependymal lining (arrow). E: Cervical spine sagittal STIR MRI of a patient with AQP4+ NMOSD with longitudinally extensive myelitis including F: an area of contrast enhancement on T1 MRI post-gadolinium.

thin enhancement of lateral ventricle ependymal surface has Studies with OCT have also demonstrated that retinal damage been described, as have well-marginated nodular or menin- in NMOSD can occur independently of ON attacks, raising the geal areas of enhancement.17 possibility that neurodegeneration may contribute to disabil- Most lesions seen on MRI in patients with NMOSD are ity, in addition to the relapse-driven disability most commonly not typical of MS, and only 10% to 20% of patients who attributed to AQP4+ NMOSD.25,26 have brain lesions will meet Barkhof criteria for MS.17 In common practice across multiple centers, classic MS brain Treatment lesions (eg, Dawson’s fingers or subcortical u-fiber lesions) Treatment of Acute Relapses appear useful in distinguishing MS from NMOSD and MOG Because most disability in NMOSD accumulates as a direct antibody-associated disease.23,24 The sensitivity and specificity consequence of relapses that typically leave substantial residual of lesions for distinguishing between MS and NMOSD at dis- disability, a relapse can be considered an emergency, calling ease onset was 79.8% and 87.5%, respectively in a study.24 for prompt neurologic examination and evaluation for occult Optical Coherence Tomography. Widely used to characterize infection to identify pseudorelapses. Vision loss may be the structural injury to the retina in demyelinating diseases (par- only early predictor of true relapse.27 Emergent spinal MRI may ticularly MS), optical coherence tomography (OCT) has shown be necessary for patients with new or changing symptoms and that ON episodes in patients with NMOSD cause a greater a prior episode of myelitis, particularly when signs and symp- degree of retinal damage than in patients with MS (Figure 2).25 toms are not clearly localizable to a new lesion. High clinical

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A authors, advocate for early PLEX rather than using it only as a rescue therapy for patients who are not improving with IVMP. A retrospective study demonstrated improved outcomes when patients were treated with PLEX early in the course of an exacerbation.28 Probability of complete recovery decreased from 50% with PLEX immediately (day 0), to 1% to 5% after day 20, emphasizing the importance of early treatment. In another study, 51% of patients treated with IVMP and PLEX at day 5 after presentation recovered to prerelapse Expanded Disability Status Scale (EDSS) baseline compared with only 16.6% of patients who received IVMP only.29 Retrospective analysis of 871 patients having NMOSD attacks found the addition of PLEX to IVMP improved responder rates and that first-line PLEX was superior to IVMP for myelitis.30 Immediate B initiation of apheresis (within 2 days of symptom onset) was associated with a 40% rate of complete response compared with 3.2% when started at 6 days after symptom onset, again emphasizing the importance of early PLEX.31 Strong predictors of a complete response were the use of apheresis as first-line therapy, time from onset of attack to start of therapy in days, presence of antibodies to AQP4, and monofocal attack. There was no significant difference between PLEX and immunoad- sorption. Figure 2. A: Axial T1 fat-saturated post-gadolinium MRI in a Intravenous Immunoglobulins. Data on the use of intrave- patient with AQP4+ NMOSD demonstrates bilateral optic neuritis nous immunoglobulin (IVIG) in patients with NMO relapses over more than 50% of the optic nerves (arrows). B: Optical remain limited, although small studies suggest that IVIG coherence tomography taken 1 year after bilateral optic neuritis may be effective in preventing relapses.32,33 demonstrates thinning of the right and left retinal nerve fiber layers (right 62 µm, left 54 µm; normal thickness on OCT is more Relapse Prevention than 80 µm; OCT images contributed by Dr. Sara Qureshi). We recommend prompt initiation of long-term immu- nosuppression once a diagnosis of NMOSD is made.34 No suspicion, aggressive acute treatment, and prompt initiation of randomized clinical trial investigating preventative therapy preventative immunotherapy are critical. in NMOSD has had final results published to date, there- Given our understanding of the pathophysiology of fore treatment is based on open-label prospective and NMOSD, our practice is to administer intravenous methyl- retrospective studies. Given the available data, we prefer prednisolone (IVMP) and plasma exchange (PLEX) as first-line rituximab (RTX) for most patients with NMOSD. If there acute therapy as quickly as possible for most patients with are contraindications to RTX, we typically use mycopheno- NMOSD when the clinical presentation is consistent with an late mofetil (MMF). exacerbation, especially those with AQP4+ NMOSD. To date, the best-studied immunotherapies for NMOSD Corticosteroids. Acute exacerbations of NMOSD are initially include RTX, MMF, and azathioprine (AZA). Treatment with treated with IVMP, typically 1 g daily for 3 to 5 days. Some cli- RTX or MMF, and to a lesser degree, AZA, is associated with nicians include an oral prednisone taper starting at up to 1 mg a decrease in relapse rates in patients with NMOSD; retro- per kg per day (usually 15-30 mg/day) and decreasing gradu- spective studies suggest that relapse risk is significantly higher ally over several weeks depending on individual factors such with AZA compared with MMF or RTX.35,36 Treatment with as timing of disease modifying therapy, patient comorbidities, RTX decreased relapse rate by up to 88%, with 2 of 3 patients and tolerance of oral glucocorticoids. Long-term oral gluco- achieving complete remission during a 10-year study period, corticoids are associated with significant toxicity and are often whereas MMF reduced relapse rates by 87.4% with a 36% avoided in favor of steroid-sparing immunotherapy. failure rate and AZA reduced relapse rates by 72% with a 53% Apheresis therapy (plasma exchange or immunoadsorption). failure rate even when used concurrently with prednisone.35 A Because antibodies to AQP4 activate the complement cascade retrospective review of 116 patients found predictors of poor leading to demyelination and necrosis with loss of astrocytes, response to AZA or MMF included pretreatment history of axons, and oligodendrocytes, many clinicians, including the severe attack and younger age. Among 40 patients with a poor

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response to oral agents, 29 were changed to RTX, and among with that seen in unexposed mothers.15 Although RTX those, only 10% had a poor response to RTX.37 crosses the placenta after gestational weeks 16 to 20 and Adequate RTX dose is important in order to maintain remis- depletes fetal B cells, miscarriage and congenital malforma- sion. Although the optimal dosing regimen has yet to be deter- tion rates in children exposed prenatally are similar to that mined, we agree with dosing protocols tailored to an individ- seen in the general population and B-cell depletion was ual’s rate of immune reconstitution. A target B-cell (CD19+ associated with serious infection in only 1 of 153 offspring and CD20+) count less than 0.05% of total lymphocytes in in a study.42 Given the relative safety of RTX, patients can the first 2 years and less than 0.1% thereafter can be consid- be treated with RTX well before planned conception (eg, ered.38 Some practices are monitoring the number of CD27+ a few months) and again in the early postpartum period. cells in isolation as there is evidence that these are a marker Monthly IVIG has also been used, although there is less for the return of disease activity.39 Because RTX can produce data regarding efficacy.32,33 hypogammaglobulinemia which may be associated with sig- nificant infections, we monitor immunoglobulin levels prior Treatment in Children to initiation and maintenance doses of RTX.40 Patients must Treatment of pediatric NMOSD is largely similar to treat- also be counseled regarding the risk of infusion reactions ment in adults,43 although pediatric patients treated with and infections. No studies of (an anti-CD20 RTX often require more frequent dosing as their B cells tend monoclonal antibody approved for treating relapsing and to reconstitute more rapidly than in adults. primary progressive MS) for NMOSD have been reported. Medications to Avoid in NMOSD Breakthrough Disease Several studies have suggested inefficacy or worsening of If a relapse is confirmed while on immunotherapy, NMOSD associated with the use of some disease modifying it is important to determine if the medication is being agents used to treat MS, including interferon β,44 natali- optimally dosed. For RTX, B-cell reconstitution should zumab,45 and .46 Therefore, we avoid these agents be investigated and dosing adjusted to optimize sup- for NMOSD. pression of memory B cells. Based on clinical experience, we consider PLEX just prior to RTX infusions for patients Future Directions with appropriately suppressed memory B cells who have a Since 2014, clinical trials for several agents with potential to breakthrough relapse. Ongoing clinical trials will likely pro- treat patients with NMOSD have been launched, including vide additional options for such patients. For patients on tocilizumab, satralizumab, eculizumab, and inebilizumab.47 MMF, the lymphocyte count can be targeted to less than 1,500 per mcL and dose increased up to the maximum dose Tocilizumab of 3 g per day if necessary. Two open-label trials of tocilizumab, an interleukin-6 (IL‑6) receptor antagonist, demonstrated a reduction in Treatment During Pregnancy relapse rates in patients with AQP4+ NMOSD as adjunctive Risks of withholding acute treatment, including irreversible treatment or monotherapy.48,49 In one of these, 7 patients paralysis and blindness for the mother must be weighed care- had an ARR reduction from 2.9 (despite background immu- fully against risks of treating relapses during pregnancy. Lower notherapy, including AZA or corticosteroids) to 0.4 with the infant head circumference and birth weight have been report- addition of tocilizumab.49 In the other, 8 patients who were ed with corticosteroid exposure during pregnancy. Although refractory to RTX treatment had an ARR reduction from historical data suggested corticosteroid exposure increased 4.0 to 0.4 after treatment with tocilizumab.48 There was risks of cleft lip or palate, more recent studies have not repro- significant reduction in neuropathic pain for patients who duced this and suggest that the risk, if any, is very small.41 received tocilizumab in both studies. Plasma exchange has been administered safely for pregnant women with NMOSD relapse at various gestational stages.15 Satralizumab For preventative therapy, methotrexate and cyclophos- Based on the success of tocilizumab, which requires dos- phamide are contraindicated during pregnancy, whereas ing every 1-2 weeks, satralizumab (SA237) was developed. AZA and RTX appear to have better safety profiles.15 It is a humanized recycling monoclonal antibody targeting Although listed by the Food and Drug Administration the IL-6 receptor with extended dosing frequency of once (FDA) as pregnancy class D, in 3,124 women exposed to per month or longer. Preliminary results from a randomized, AZA during pregnancy, there was no increased risk of international, double blind phase 3 trial of satralizumab as preterm birth, low birth weight, miscarriage, birth defects, adjunctive therapy showed satralizumab reduced the risk of major congenital malformations or neoplasia compared relapse by 62% in patients with NMOSD (n = 83); those who

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were AQP4+ (n = 53) had a 79% risk reduction and who Conclusions were AQP4- (n = 30) had a 34% risk reduction.50 The diagnostic criteria for NMOSD were updated in 2015 and account for both patients who are AQP4 seropositive Eculizumab and seronegative. Treatment recommendations have been Eculizumab is a monoclonal antibody that inhibits largely based on retrospective studies and expert clini- activation of C5 complement protein, thereby disrupt- cal experience with data supporting RTX, MMF, or AZA. ing the complement cascade. In an open-label pilot study, Ongoing clinical trials may offer more evidence for using 12 of 14 patients with AQP4+ NMOSD (6 who had failed new therapies in the near future. It is critical that neurolo- prior immunotherapy) had no attacks and 2 had possible gists encountering patients with suspected demyelinating minor single attacks while being treated with eculizumab disorders consider NMOSD in the differential diagnosis, for 48 weeks. After the trial, when returned to alternative thereby avoiding delays in recognition and treatment. n immunotherapy (AZA, RTX, MMF, or prednisone), 5 had 1. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple a relapse in the subsequent year. Hemolytic complement sclerosis. Lancet. 2004;364:2106-2112. activity dropped from a mean of 88.5% to 0.4% after 6 weeks 2. Zekeridou A, Lennon VA. Aquaporin-4 autoimmunity. Neurol Neuroimmunol Neuroinflamm. 2015;2:e110. 51 3. Hamid SHM, Whittam D, Mutch K, et al. What proportion of AQP4-IgG-negative NMO spectrum disorder patients are MOG- of treatment and remained suppressed during the study. IgG positive? A cross sectional study of 132 patients. J Neurol. 2017;264:2088-2094. An open-label phase 3 double-blind placebo-controlled 4. Flanagan EP, Cabre P, Weinshenker BG, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. 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A double-masked, placebo-controlled study with open label period to evaluate MEDI-551 in neuromyelitis optica and neuromyelitis optica spectrum disorders (NCT02200770). FEBRUARY 2019 PRACTICAL NEUROLOGY 83 MULTIPLE SCLEROSIS

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Michael J. Bradshaw, MD Assistant Professor of Neurology Multiple Sclerosis and Autoimmune Neurology Chicago Medical School Rosalind Franklin University of Medicine and Science Billings Clinic Billings, MT

Dorlan Kimbrough, MD Department of Neurology Brigham and Women’s Hospital Boston, MA

Disclosures MJB serves on the editorial board of Continuum: Lifelong Learning in Neurology. The authors have no financial relationships relevant to this content to disclose.

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