Neuromyelitis Optica Spectrum Disorder: Disease Course and Long-Term Visual Outcome

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that classically manifests as attacks of optic neuritis (ON) and transverse myelitis (TM). The prevalence, course, and severity of NMOSD vary considerably. Few studies report the neuro-ophthalmologic disease course and visual outcome.; We sought to describe the course and long-term visual outcome in a cohort of NMOSD patients treated in a single tertiary referral center.; The database was searched for all patients with NMOSD who were treated in our center from 2005 to 2014. Data collected included detailed visual outcome, grade of final visual disability, neuroimaging, and results of optical coherence tomography. Details on relapses, acute episodes, and maintenance therapies were recorded.; Of the 12 patients with NMOSD who were followed for a mean duration of 9.06 years, 10 (83%) were women. Mean age at presentation was 33.90 ± 16.94 years. Patients with acute attacks were treated with high-dose intravenous methylprednisolone and offered immunosuppressive maintenance. ON occurred in 18 eyes of 12 patients, with a cumulative total of 37 ON episodes. At the end of the follow-up period, no patient had become legally blind and only 1 patient had lost her driver's license. Pain associated with acute ON was common (83%), whereas optic disc edema was a rare finding in our patient cohort (6%).; In this retrospective series of 12 patients with NMOSD, followed for a mean of 9.06 years, acute-phase treatment was given within 8 days of relapse, followed by maintenance therapy. Functional visual outcome, as measured by the World Health Organization/International Classification of Diseases, Tenth Revision visual disability scale was better than reported in previous studies and driver's license was preserved in 11 of 12 patients. Pain accompanied 83% of ON attacks and may not aid differentiating multiple sclerosis from NMOSD-related ON.

Original Contribution Neuromyelitis Optica Spectrum Disorder: Disease Course and Long-Term Visual Outcome Judith Brody, MD, Mark A. Hellmann, MD, Romain Marignier, MD, Itay Lotan, MD, Hadas Stiebel-Kalish, MD Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that classically manifests as attacks of optic neuritis (ON) and transverse myelitis (TM). The prevalence, course, and severity of NMOSD vary considerably. Few studies report the neuroophthalmologic disease course and visual outcome. Objective: We sought to describe the course and long-term visual outcome in a cohort of NMOSD patients treated in a single tertiary referral center. Methods: The database was searched for all patients with NMOSD who were treated in our center from 2005 to 2014. Data collected included detailed visual outcome, grade of final visual disability, neuroimaging, and results of optical coherence tomography. Details on relapses, acute episodes, and maintenance therapies were recorded. Results: Of the 12 patients with NMOSD who were followed for a mean duration of 9.06 years, 10 (83%) were women. Mean age at presentation was 33.90 ± 16.94 years. Patients with acute attacks were treated with high-dose intravenous methylprednisolone and offered immunosuppressive maintenance. ON occurred in 18 eyes of 12 patients, with a cumulative total of 37 ON episodes. At the end of the follow-up period, no patient had become legally blind and only 1 patient had lost her driver's license. Pain associated with acute ON was common (83%), whereas optic disc edema was a rare finding in our patient cohort (6%). Conclusions: In this retrospective series of 12 patients with NMOSD, followed for a mean of 9.06 years, acute-phase treatment was given within 8 days of relapse, followed by Sackler School of Medicine (JB, MAH, IL, HS-K), Tel Aviv University, Tel Aviv, Israel; Neuro-Immunology Service and Department of Neurology (MAH, IL), Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; Service de Neurologie A (RM), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon-Bron, France; and Neuro-Ophthalmology Unit, Department of Ophthalmology (JB, HS-K), Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel. R. Marignier serves on the scientific advisory board for MedImmune and has received honoraria from Biogen Idec, MerckSerono, Novartis, and Sanofi-Genzyme. The other authors report no conflicts of interest. J. Brody and M. A. Hellmann contributed equally to the work. Address correspondence to Hadas Stiebel-Kalish, MD, NeuroOphthalmology Unit, Rabin Medical Center, Petah Tikva 49100, Israel; E-mail: [e-mail] 356 maintenance therapy. Functional visual outcome, as measured by the World Health Organization/International Classification of Diseases, Tenth Revision visual disability scale was better than reported in previous studies and driver's license was preserved in 11 of 12 patients. Pain accompanied 83% of ON attacks and may not aid differentiating multiple sclerosis from NMOSD-related ON. Journal of Neuro-Ophthalmology 2016;36:356-362 doi: 10.1097/WNO.0000000000000403 © 2016 by North American Neuro-Ophthalmology Society N euromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that classically manifests as attacks of optic neuritis (ON) and transverse myelitis (TM). The most current diagnostic criteria, published in 2015 by the International Panel for NMO Diagnosis (1), defined a unified term of NMOSD, further stratified by serologic testing into NMOSD with or without aquaporin-4-IgG antibodies. Although this inflammatory disease of the central nervous system originally required attacks of ON and TM to fulfill the diagnostic criteria, other clinical manifestations have been recognized, including involvement of the medulla, brainstem, diencephalon, and cerebrum (2-4). Brainstem symptoms, including intractable hiccups and nausea, vomiting, diplopia, and pruritus may occur in up to 31% of NMOSD cases (4). Treatment of NMOSD is composed of 1) acute-phase therapy, given during an episode of TM, ON, or other clinical manifestation, and 2) maintenance therapy. Acutephase therapy options include high-dose intravenous methylprednisolone with or without plasma exchange depending on response. It has been suggested that when treatment is given as early as possible during an acute attack of ON, there is reduced loss of retinal nerve fiber layer (RNFL) (5,6). Maintenance therapy, administered after an acute episode, is aimed at decreasing the relapse rate. Two main outcomes have been used to assess the success and benefits of maintenance therapy: 1) the annualized relapse rate, and Brody et al: J Neuro-Ophthalmol 2016; 36: 356-362 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 2) time to first relapse after initiation of therapy (7). Azathioprine, low-dose corticosteroids, mycophenolate mofetil, and rituximab are commonly used for NMOSD maintenance (8,9). Other drugs have been suggested to reduce the annualized relapse rate including intravenous immunoglobulins, mitoxantrone and methotrexate (10-16). There also is evidence for reduction of relapses in highly active NMOSD with the use of complement (17) and interleukin-6 inhibitors (18). The prevalence, course, and severity of NMOSD vary considerably (19-22). For example, compared with Asians, Caucasians are more likely to experience motor disability, wheelchair dependence, or death, whereas Afro-Caribbean patients are more likely to suffer from visual disability (21). Brainstem manifestations are reportedly more prevalent in non-Caucasian populations. The aim of our study was to describe the disease course and detailed long-term visual outcome in a cohort of NMOSD patients from a single tertiary referral center in Israel. MATERIALS AND METHODS Following Institutional Review Board approval, we conducted a retrospective study involving all patients diagnosed with NMOSD who were treated at the Rabin Medical Center, Petach Tikva, Israel, from January 2005 to November 2014. All patients underwent complete neurologic and neuro-ophthalmologic evaluations. Patients were examined at least every 6 months and during each episode of ON by the same neuro-ophthalmologist (H.S.K.). Data collected included best-corrected visual acuity, automated visual field results (Humphrey 30-2; SITA-standard), and peripapillary RNFL measurements by optical coherence tomography (Cirrus; Carl Zeiss Meditec, Jena, Germany). Seropositivity for anti-AQP4 antibodies was determined using a first-generation assay or an enzyme-linked immunosorbent assay. In cases needing reconfirmation, both assays were used (23-25). All patients were admitted for acute-phase treatment consisting of 3-5 days of 1 g of intravenous methylprednisolone during acute episodes of ON or TM. An individualized escalating treatment approach was used, with high-dose intravenous methylprednisolone given to all patients during the acute episode and with optional addition of plasmapheresis or intravenous immunoglobulins, when vision and/or visual field failed to improve within 10-14 days. Patients presenting with a first episode of NMOSD ON were initially treated according to the Optic Neuritis Treatment Trial (ONTT) protocol; yet, if vision improved followed by deterioration after cessation of treatment, steroids were re-instituted until NMOSD and other autoimmune testing was completed. Following the acute episode, continued care with maintenance therapy was given according to a combination of patient preferences and tailored their general health status, individual contraindications, and health insurance restricBrody et al: J Neuro-Ophthalmol 2016; 36: 356-362 tions. All patients were followed jointly by the NeuroImmunology service and the same physician at the Neuro-Ophthalmology units at the Rabin Medical Center. Patients were instructed to contact us immediately if a relapse occurred, allowing for immediate renewed acutephase treatment on relapse, given without delay. To evaluate functional visual outcome, visual impairment was graded and categorized according to the World Health Organization/International Classification of Diseases, Tenth Revision (WHO/ICD-10) visual disability scale (mild; moderate; severe visual impairment, or blindness) (26,27) and note was made of any patient losing their driver's license due to impaired vision. Visual fields were described in accordance with the ONTT classification of visual field abnormalities (28). RESULTS Demographic and Clinical Characteristics Between 2005 and 2014, 12 patients with NMOSD and ON were evaluated in the Neurology or NeuroOphthalmology outpatient departments, of whom 10 (83%) were women. Mean patient age at presentation was 33.9 ± 16.94 years. Patients were followed for 48-202 months (mean, 9.06 ± 4.78 years). Table 1 details the clinical characteristics of inaugural events, as well as magnetic resonance imaging results for each of the 12 patients. AQP4 seropositivity was documented in all but 1 patient (Patient 4), who met the 2015 diagnostic criteria for NMOSD. One patient (Patient 10) had both NMOSD and systemic lupus erythematosus with antiphospholipid antibody syndrome and another patient (Patient 8) was diagnosed with both NMOSD and myasthenia gravis. Visual Outcomes Table 2 presents the visual acuity at nadir (worst documented vision during the most severe acute ON attack) and the visual outcomes for all 12 patients. Eighteen eyes of 12 patients developed 37 overt attacks of ON. Of the 12 eyes for which complete visual nadir data were available, 8 developed visual acuity of 20/320 or worse during attacks. Final visual acuity improved to 20/28 or better in all but 3 eyes and the perimetric mean deviation was worse than 210 dB in only 3 eyes. Optical coherence tomography at last follow-up was available in 10 of 12 patients. None of the patients became legally blind (acuity worse than or equal to 20/400). One patient (Patient 6) lost her driver's license because of visual loss; mild visual impairment was present in 11 of the 12 patients (92%) who had experienced clinical ON. Mean RNFL thickness in ON-affected eyes was 62.4 mm, compared with an average of 88.2 mm in unaffected eyes. Three eyes (left eye in Patients 2 and 8; right eye in Patient 3) had subnormal RNFL values of less than 80 mm. Yet none of these patients have a history of ON or 357 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. ON Attacks (n) RON Attacks (n) LON Attacks (n) M/F Age at Presentation (y) Initial Presentation F-U (mo) Clinical and Neuroimaging Findings 1 1 1 0 F 20.3 ON and TM 62 1 0 M 55.7 ON 134 2 0 2 M 68.0 TM 65 4 2* 1 2 F 33.6 ON and TM 49 5 2 1 1 F 15.8 ON 40 6 3 3 0 F 35.6 ON 178 7 4 1 3 F 8.3 TM 170 8 4 4 0 F 36.2 TM 202 9 4 3 1 F 32.1 ON 48 10 4* 2 3 F 19.1 ON 84 Clinical: RON + TM Cervical MRI: hyperintense T2 signal-C4-T1 Brain MRI at onset: normal Clinical: bilateral ON + TM Cervical and thoracic MRI: hyperintense T2 signal-C2-C7 and T4- D10 Brain MRI at onset: normal, enhancement right optic nerve Clinical: RON + TM Cervical MRI: hyperintense signal: C2-T1 Brain MRI at onset: small, nonspecific, bilateral periventricular white matter lesions, not fulfilling diagnostic criteria for MS Clinical: bilateral ON + TM Cervical and thoracic MRI: extensive hyperintense T2 signal enhancement and swelling Brain MRI at onset: normal Clinical: RON Cervical MRI: hyperintense T2 signal C2-C3 Brain MRI at onset: T2 hyperintensity-of the internal capsule, not fulfilling diagnostic criteria for MS Clinical: bilateral ON + TM Cervical MRI: hyperintense T2 signal: C2 Brain MRI at onset: bilateral, periventricular white matter lesions, the corpus callosum and medulla oblongata Clinical: recurrent LON Cervical MRI: longitudinal hyperintense T2 signal C7-D2 Brain MRI at onset: multiple hyperintense lesions of white and gray matter bilaterally Clinical: TM + RON Cervical MRI: hyperintense T2 signal-C2-C5 Brain MRI at onset: normal Clinical: bilateral ON Spinal MRI: patient refused Brain MRI at onset: diffuse swelling and enhancement of the left optic nerve, without other parenchymal abnormalities Clinical: RON + TM Cervical and thoracic MRI: hyperintense T2 signal and swelling: C2, C5, T1, T3, T6, T8 and T12 2 1 3 Patient No. Original Contribution 358 Brody et al: J Neuro-Ophthalmol 2016; 36: 356-362 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Demographic and clinical characteristics of patients with NMOSD and ON Brody et al: J Neuro-Ophthalmol 2016; 36: 356-362 Patient No. ON Attacks (n) RON Attacks (n) LON Attacks (n) M/F Age at Presentation (y) Initial Presentation F-U (mo) 11 5 2 3 F 38.7 ON 131 12 5 3 2 F 43.8 ON 142 Clinical and Neuroimaging Findings Brain MRI at onset: small, nonspecific periventricular white matter lesions, splenium and left pons. Enhancement of prechiasmatic optic nerve Clinical: bilateral ON + TM Cervical MRI: hyperintense T2 lesions: C2, D5 Brain MRI at onset: cerebellar and lentiform nucleus T2 hyperintense lesions, not fulfilling diagnostic criteria for MS Clinical: Recurrent bilateral ON and brainstem symptoms Spinal MRI: patient refused Brain MRI at onset: right frontal white matter lesion, not fulfilling diagnostic criteria for MS *Two patients had simultaneous bilateral ON. Therefore, the summation of right and left episodes exceeds the total number of attacks per patient. F, female; F-U, follow-up; LON, left optic neuritis; M, male; ON, optic neuritis; RON, right optic neuritis; TM, transverse myelitis; MRI, magnetic resonance imaging; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder. TABLE 2. Outcomes of patients with NMOSD and ON Patient No. Visual Acuity at Nadir of Most Severe Attack Final Visual Acuity Final Contrast Sensitivity Final Visual Field Pattern Final Mean Deviation (dB) Final Average RNFL (mm) WHO/ICD-10 Visual Disability Scale OD OS OD OS OD OS OD OS OD OS OD OS OU 20/30 - ◊ - 20/66 NLP - - CF - - - ◊ ◊ CF 20/400 HM ◊ NLP ◊ 20/360 HM 20/40 20/480 20/25 20/22 20/22 20/20 20/32 20/22 20/20 20/20 20/20 20/20 20/20 20/32 20/20 20/25 20/28 20/20 20/20P 20/63 NLP 20/20 20/20 20/22 20/20 20/25 - - 1.65 - - 1.65 2.10 1.65 - 1.65 1.65 1.05 - - 1.20 - - 1.65 - 1.80 - 1.65 1.65 1.65 C C NL NL Q H NL PPR C C PR 3Q NL SD H NL C NL - NL C NL NL Alt 25.23 23.90 20.38 22.28 24.02 29.36 +1.11 22.80 - 29.62 23.31 217.99 22.28 27.30 211.08 29.50 24.56 23.52 - 21.91 - 27.56 21.42 211.12 - 53 76 - 104 50 97 56 76 56 49 45 - 78 52 - 70 98 - 77 68 61 53 46 Mild Mild Mild Normal Mild Moderate* Mild Normal Mild Mild Mild Mild *Patient 6 had a final visual acuity of 20/22 in her right eye, and would have qualified as mild WHO visual impairment but her visual fields prevented her from reinstating her driver's license. -, Unavailable; ◊, unaffected eye without ON; 3Q, 3 quadrants; Alt, altitudinal; C, central scotoma; CF, count fingers; H, hemianopia; M, hand motion; NL, normal; NLP, no light perception; NMOSD, neuromyelitis optica spectrum disorder; NS, nasal step; OD, right eye; OS, left eye; OU, both eyes; PPR, partial peripheral rim; PR, peripheral rim; Q, Quadrant; RNFL, retinal nerve fiber layer; SD, superior depression; WHO/ICD-10, World Health Organization/International Classification of Diseases, Tenth Revision. Original Contribution 1 2 3 4 5 6 7 8 9 10 11 12 359 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Original Contribution had detectable abnormalities of optic nerve function (decreased visual acuity, afferent pupillary defect, visual field defect, optic disc pallor). Presentation and Management Seven patients presented with ON, 9 with TM, and 2 with simultaneous ON and TM. Twelve patients experienced ON at some point, with a cumulative total of 37 ON attacks. The number of ON attacks of each patient is detailed in Table 1. All patients, except 1 patient (Patient 6), received pulse intravenous methylprednisolone within 8 days of every ON attack (mean time from symptom development to treatment, 2.7 days). One patient (Patient 12) refused acute treatment, and another patient required acute treatment with both intravenous immunoglobulin and plasma exchange in addition to corticosteroids. Two of these 36 ON attacks presented with mild disc edema (without hemorrhage) in the affected eye, whereas pain or retrobulbar discomfort accompanied ON in 83% of NMOSD patients. On diagnosis of NMOSD, patients were given detailed information regarding prognosis and maintenance therapy options. Ten patients elected to receive maintenance therapy, including azathioprine (4 patients), rituximab (2 patients), daily low-dose corticosteroids (8 patients), intravenous immunoglobulin (2 patients), methotrexate (1 patient), cyclophosphamide (2 patients), and mycophenolate mofetil (1 patient). Maintenance treatment was given within a mean of 2 months of AQP4-antibody positivity confirmation and within 5 months of presentation, except in the 2 cases of a 1-year delayed diagnosis. These 2 patients (Patients 7 and 12) were initially treated with multiple sclerosis (MS) therapy and subsequently worsened. Maintenance treatment choice was based on a combination of patient preference, insurance coverage, and the clinical course. DISCUSSION Our results with prompt treatment NMOSD of patients with visual involvement are more favorable compared with previous reports (29-31). One explanation could be the difference in ethnic background. People of AfroCaribbean and Asian background reportedly suffer worse visual outcomes (19-22), whereas in our study, the ethnic groups consisted of patients of both Arab and Jewish ethnicity. A poorer visual outcome has been reported in previous European retrospective cohorts (31,32). However, 2 factors may contribute to this difference. The report by Collongues et al (32) merged the Wingerchuk 1999 and the Wingerchuk 2006 inclusion criteria, possibly excluding patients with milder illness who would fulfill the updated 2015 NMOSD criteria. A second factor was that these cohorts included a proportion of patients initially diagnosed with MS. Consequently, these misdiagnosed patients may have been mistreated until NMOSD was recognized. Merle 360 et al (33), in describing 37 patients with NMOSD meeting the Wingerchuk 2006 criteria, found that 42% of eyes of patients with NMO had a visual acuity worse than 20/200. Yet, in this report, in addition to using older inclusion criteria, visual acuity assessments were available for 92 of 125 patients, 31.5% of whom developed severe final visual loss of less than 20/200. Support for early, tailored, escalating treatment for acute ON in NMOSD improving outcomes can be found in a large case series by Kleiter et al (34), who analyzed 871 attacks of NMOSD. The authors found that clinical remission was more likely to occur following early initiation of acute-phase treatment. This series however details neurological scale outcomes and rates of complete remission but does provide details of visual outcomes. Patients with NMOSD ON were mostly steroid responsive, but in 2 cases when vision and/or visual field failed to improve, plasmapheresis or intravenous immunoglobulin treatment were added. No patient in our cohort became legally blind and only 1 patient lost her driver's license. Interestingly, the patient who lost her driver's license was initially thought to have MS, and was referred to our center after her second ON attack. It was only then that the correct diagnosis was established. To assess visual outcome in NMOSD, we used the United Kingdom driving standards for vision and the WHO/ICD-10 visual disability scale, both of which better describe functional outcomes than scales that sum the deficit from both eyes (35). Pain in our cohort accompanied 83% of ON attacks compared with 92% in the Optic Neuritis Treatment Trial (36) and may not aid differentiating NMOSD-related ON from that of MS. The prevalence of disc edema during acute ON attack was found to be 6% in our patients compared with 35.3% observed in the ONTT (36). At least 2 explanations have been proposed for the difference between prevalence of optic disc edema in ON related to NMOSD from that in MS (37,38). One may be the propensity for ON in NMOSD to affect more posterior parts of the optic nerve. Another possible explanation is the existence of 2 very different histopathological lesions in NMO: one with demyelination, severe axonal loss and necrosis, and a second NMO lesion characterized by vacuolated myelin in the absence of demyelination, granulocytic inflammation, and limited axonal injury with potential for reversibility. The average RNFL was thinner in NMOSD ONaffected eyes (62.4 mm) than in unaffected eyes (88.2 mm). These results confirm the findings of Bichuetti et al (5), who concluded that RNFL thinning is considered a useful adjunct for imaging the sequalae of ON in NMOSD follow-up. In addition, in 3 eyes, diminished RNFL thickness was detected in patients who did not report an attack of ON in that eye. This suggests that patients with NMOSD may experience subclinical episodes of ON. Possibly, the Brody et al: J Neuro-Ophthalmol 2016; 36: 356-362 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution visual prognosis in NMOSD with prompt treatment may be better than previously reported. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: H. Stiebel-Kalish and R. Marignier; b. Acquisition of data: J. Brody, M. A. Hellmann, and I. Lotan; c. Analysis and interpretation of data: J. Brody, M. A. Hellmann, R. Marignier, I. Lotan, and H. Stiebel-Kalish. Category 2: a. Drafting the manuscript: J. Brody, M. A. Hellmann, R. Marignier, I. Lotan, and H. Stiebel-Kalish; b. Revising it for intellectual content: J. Brody, M. A. Hellmann, R. Marignier, I. Lotan, and H. Stiebel-Kalish. 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