Advances in Neuromyelitis Optica: Take Them to the Clinic

Bench to Bedside Advances in Neuromyelitis Optica: Take Them to the Clinic Marc H. Levin, MD, PhD T he accompanying article by Bennett and Owens (1) reviews wide-ranging scientific progress in elucidating the pathophysiology of neuromyelitis optica (NMO). This renaissance in NMO research was jump-started by the discovery of the autoantibody AQP4-IgG as a marker of the disease and the demonstration of its central pathogenic role. How do we best translate recent advances in the laboratory to enhance NMO diagnosis and treatment in the clinic? I recently treated a 60-year-old woman with typical features of acute demyelinating optic neuritis. Unilateral vision loss was accompanied by pain and exacerbated by eye movements. There was mild optic nerve head swelling, and magnetic resonance imaging showed focal optic nerve enhancement. The patient received 2 weeks of high-dose systemic corticosteroids, and visual function predictably returned toward baseline, with only mild loss of temporal retinal nerve fiber layer evident several months later. The Optic Neuritis Treatment Trial concluded that for typical optic neuritis, serologic workup for autoimmune and infectious causes is not indicated. Yet, now that we are armed with a sensitive and highly specific marker for NMO, should we be sending AQP4-IgG testing for all cases of isolated optic neuritis? In reviewing my patient's medical history, I learned that 40 years before, she had undergone thymectomy for acetylcholine receptor binding antibody-positive myasthenia gravis, which then went into remission. Like myasthenia, NMO is a B-cell-dependent autoimmune disease. Late onset of NMO has been described in myasthenics, possibly due to immune dysregulation from thymectomy (2). Given this autoimmune backdrop, I sent a serum AQP4-IgG, and indeed, it was positive. Interestingly, acetylcholine receptor antibody levels were elevated as well. One month after the patient was diagnosed with NMO spectrum disorder (NMOSD), she developed transverse myelitis. Now, on maintenance B-cell-depleting immunotherapy, she has not experienced any further opticospinal attacks. Some clinicians have advocated testing all patients with optic neuritis for AQP4-IgG. However, when applied to low-risk populations, this approach would actually proDepartment of Ophthalmology (MHL), Palo Alto Medical Foundation, Palo Alto, California. Address correspondence to Marc H. Levin, Department of Ophthalmology, Palo Alto Medical Foundation, 795 EL Camino Real, Jamplis Building, Level 2, Palo Alto, CA 94301; E-mail: [e-mail] 300 duce otherwise rare false-positive results (3). The diagnostic clarity afforded by live cell-based AQP4-IgG assays has helped us better define ethnicity-specific prevalence of NMO. In regions comprised mainly of Caucasians, such as North America and Europe, prevalence is low, an estimated 1%-2% that of multiple sclerosis (MS). In contrast, NMO is at least a 10-fold more common cause of demyelinating disorders in Afro-Caribbean and East Asian populations (4,5). A prudent approach is, therefore, to assay all optic neuritis patients from high-risk ethnicities and to reserve NMO testing in lower risk (white) patients for those exhibiting clinical "red flags." Features distinguishing NMO from other causes of demyelinating optic neuritis include more advanced age of presentation; especially severe vision loss (acuity worse than counting fingers at nadir); and bilateral simultaneous (adults only), unresolving, or recurrent attacks. As illustrated in the case above, any history of autoimmune disease should raise suspicion for NMO (6,7). Magnetic resonance imaging signal abnormalities warranting AQP4-IgG testing include involvement of long optic nerve segments, optic chiasm, hypothalamus, or brainstem (notably the area postrema). A remote history of both transverse myelitis and optic neuritis ought to prompt consideration of NMO. In fact, a number of my patients diagnosed with opticospinal MS before the discovery of AQP4-IgG have proven to be seropositive when tested for the first time after many years of clinical stability. If suspicion for NMO remains high, based on clinical or imaging characteristics, one could consider retesting a patient 3 to 6 months after a negative result. Seroconversion is most likely during acute attacks or during treatment-free intervals. The practical utility of following AQP4-IgG titers as a measure of treatment response or to predict clinical attacks remains questionable (3). One common misconception is that cerebrospinal fluid testing increases diagnostic yield in seronegative patients. Although intrathecal AQP4-IgG production does occur, most autoantibody derives from the periphery where it circulates at higher concentration (8). It is therefore extremely unlikely to be seronegative but cerebrospinal fluid positive for AQP4-IgG. Serum myelin oligodendrocyte autoantibody (MOGIgG) testing has been sought by clinicians with increasing Levin: J Neuro-Ophthalmol 2017; 37: 300-302 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside frequency following several recent publications reporting serum autoantibodies against MOG in a subset of AQP4IgG-seronegative NMO patients (2006 criteria). However, as Bennett and Owens explain, MOG-IgG positivity more likely defines a distinct, typically milder disorder with phenotypic overlap with NMO (9). As such, MOG-IgG positivity was not included among the updated and expanded 2015 criteria defining NMOSD. On a practical note, this test is not yet readily available outside of the research setting. When treating a patient with a suspected first NMO attack, one should not wait for the result of serum AQP4IgG testing. Intravenous methylprednisolone is the treatment for severe optic neuritis or transverse myelitis from all demyelinating causes, including NMO. During an NMO exacerbation, plasma exchange is then indicated after 3-5 days of corticosteroids in patients showing no signs of improvement (10). Efficacy of intravenous immunoglobulin in treating NMO flares is suggested by a limited body of clinical and laboratory data (11,12). Distinguishing NMO from MS, however, is critical when considering appropriate long-term maintenance therapy. A number of case reports have associated several MS platform medications-interferon beta, natalizumab, and fingolimod -with worsening NMO disease activity (13-15), and these medications should be avoided. Although supported only by case series and expert opinions, general immunosuppressants (azathioprine, mycophenolate mofetil) and B-cell-depleting agents (rituximab) are empirically used as standard prophylactic NMO therapies (16). Fortunately, the research highlighted by Bennett and Owens has provided a number of additional, more specific drug targets and a rationale for more rigorous clinical testing. Three major randomized control trials are well underway, attempting to repurpose monoclonal antibody inhibitors of key mediators in NMO immunopathogenesis: MEDI 551, which depletes CD19+ B cells (NCT02200770; Ref. 17), eculizumab, which prevents cleavage of C5, a component the classical complement system (NCT01892345; Ref. 18), and SA237, which blocks the IL-6 receptor to limit plasmablast antibody production (NCT02073279; Ref. 19). The next wave of potential therapeutics incorporates nonimmunosuppressive approaches, which are predicted to have superior side effect profiles. These include 1) antibodies that block the binding of AQP4-IgG to AQP4, the inciting event in NMO pathogenesis, 2) upregulators of membrane-bound complement inhibitors that could blunt complement-dependent cytotoxicity (20), and 3) small molecule remyelinating agents, which have the potential to limit secondary disabling axon damage (21,22). Confronting NMO with a newfound understanding, we can now provide our patients with accurate and timely diagnoses and anticipate an era with safe therapies that preserve optic nerve health and visual function. Levin: J Neuro-Ophthalmol 2017; 37: 300-302 REFERENCES 1. Bennett JL, Owens GP. Neuromyelitis Optica: Deciphering a Complex Immune-Mediated Astrocytopathy. J Neuroophthalmol. 2017;37:291-299. 2. Uzawa A, Mori M, Iwai Y, Kobayashi M, Hayakawa S, Kawaguchi N, Kuwabara S. Association of anti-aquaporin-4 antibody-positive neuromyelitis optica with myasthenia gravis. J Neurol Sci. 2009;298:105-107. 3. 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