MULTIPLE SCLEROSIS 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 optic neuritis (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 transverse myelitis (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 76 PRACTICAL NEUROLOGY FEBRUARY 2019 MULTIPLE SCLEROSIS 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 encephalomyelitis (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 lupus 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 cerebrospinal fluid (CSF) should IgG, immunoglobulin G; 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 FEBRUARY 2019 PRACTICAL NEUROLOGY 77 MULTIPLE SCLEROSIS 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