Guideline sources The following summarized guidelines for the evaluation and management of neuromyelitis optica spectrum disorder (NMOSD) are prepared by our editorial team based on guidelines from the American College of Rheumatology (ACR 2023), the European League Against Rheumatism (EULAR 2022), the American College of Radiology (ACR 2021), the Latin American Consensus Group on Neuromyelitis Optica Spectrum Disorder (LACG-NMOSD 2020), the French Society of Multiple Sclerosis (SFSEP/OFSEP/NOMADMUS 2018), the Neuromyelitis Optica Study Group (NEMOS 2013), and the European Federation of Neurological Societies (EFNS 2010). 1 2 3 4 5 6 7 Guidelines 1. Screening and diagnosis Diagnosis: https://web.pathway.md/diseases/recF6PpqGbrUiikaO 1/8 6/30/23, 1:19 AM Neuromyelitis optica spectrum disorder Pathway Diagnosis: As per LACG-NMOSD 2020 guidelines, diagnose NMOSD in the presence of clinical involvement in at least 1 of the 6 CNS regions: optic nerve, spinal cord, area postrema of the dorsal medulla, brainstem, diencephalon, or cerebrum. E Show 2 more As per EFNS 2010 guidelines, recognize that: the predominant course of neuromyelitis optica is characterized by recurrent severe attacks of myelitis and/or uni- or bilateral optic neuritis with incomplete recovery and is up to 10 times more prevalent in women than in men age of onset, the late 30s, is approximately 10 years later than the age of onset in multiple sclerosis, but neuromyelitis optica may also occur in children and elderly people optic neuritis with severe visual loss and in rapid succession may be indicative of neuromyelitis optica optic atrophy is more pronounced than in multiple sclerosis and may form cavitation complete transverse myelitis is typical for neuromyelitis optica, and partial transverse myelitis syndromes are more indicative of multiple sclerosis expansion of the spinal cord lesion may lead to brainstem symptoms and life-threatening complications. E 2. Classification and risk stratification Prognosis: Recognize that the presence of anti-AQP-4 antibodies at disease onset in patients with NMOSD predicts worse medium/long-term disability. E Recognize that the number of relapses and their severity in patients with NMOSD during the first 2 years predicts medium/long-term disability (5-10 years). E 3. Diagnostic investigations Aquaporin-4 antibodies: As per LACG-NMOSD 2020 guidelines, obtain testing for serum anti-AQP-4 antibodies in patients with suspected NMOSD. E Show 6 more As per EFNS 2010 guidelines, obtain testing for serum neuromyelitis optica-IgG/AQP-4 antibodies in the evaluation of neuromyelitis optica and NMOSDs. E Myelin oligodendrocyte glycoprotein antibodies: obtain testing for anti-myelin oligodendrocyte glycoprotein antibodies in AQP-4 antibody-negative (tested via cell-based assay) patients with suspected NMOSD. E Show 2 more Magnetic resonance imaging: https://web.pathway.md/diseases/recF6PpqGbrUiikaO 2/8 6/30/23, 1:19 AM Neuromyelitis optica spectrum disorder Pathway As per ACR 2021 guidelines, obtain spinal cord MRI as initial imaging in patients with acute onset myelopathy. B As per LACG-NMOSD 2020 guidelines, use a standardized MRI protocol for diagnosis and follow-up of neuromyelitis optica. E Show 2 more As per EFNS 2010 guidelines, obtain brain and spinal cord MRI to assess the appearance of spinal cord lesions and display gadolinium enhancement of the optic nerve and both symptomatic and asymptomatic brain lesions for the diagnosis of neuromyelitis optica. E Pretreatment evaluation: As per EULAR 2022 guidelines, screen for HBV infection in all patients eligible for treatment with conventional synthetic, biological, or targeted synthetic DMARDs, immunosuppressants, or corticosteroids (according to dose and duration). B Show 3 more As per NOMADMUS 2018 guidelines, obtain the following evaluations before initiating rituximab: CBC lymphocyte subset counts (including CD19+, CD3+, CD4+ and CD8+ cells) SPEP immunoglobulin subset amounts (IgG, IgA, IgM, IgG subclasses) human immunodeficiency virus, HBV, HCV, and VZV serology tests -hCG (for females of childbearing age) CXR. E Show 2 more As per NEMOS 2013 guidelines, inform patients about the risks of side effects before initiating immunosuppressive therapies, such as malignancy, infertility, cytotoxicity and myelotoxicity, infections including progressive multifocal leukoencephalopathy, vaccination issues, and the need for contraception. E 4. Diagnostic procedures Cerebrospinal fluid analysis: As per LACG-NMOSD 2020 guidelines: Perform lumbar puncture with an evaluation of WBC count, protein levels, and oligoclonal bands in CSF to evaluate differential diagnoses in patients with clinically suspected NMOSD with non-typical brain or spinal cord MRI lesions suggestive of multiple sclerosis. E Do not rule out the diagnosis of NMOSD in the presence of oligoclonal bands in CSF. D As per EFNS 2010 guidelines: Consider testing for anti-AQP-4 antibodies in the CSF in highly suspicious AQP-4 seronegative neuromyelitis optica and NMOSDs. E https://web.pathway.md/diseases/recF6PpqGbrUiikaO 3/8 6/30/23, 1:19 AM Neuromyelitis optica spectrum disorder Pathway Recognize that lymphomononuclear pleocytosis > 50 cells/ L, the occasional presence of neutrophils/eosinophils, and the lack of oligoclonal bands may be indicative of, but not specific for, neuromyelitis optica and NMOSDs. E 5. Medical management Setting of care: evaluate patients with suspected NMOSD in a center with experience in diagnosing demyelinating diseases, to ensure an earlier and more precise diagnosis and adequate treatment. E First-line therapy: As per LACG-NMOSD 2020 guidelines, initiate early immunosuppressant therapy with any of the following agents to reduce disease activity and prevent NMOSD attacks. Situation Guidance 2-3 mg/kg/day divided into 2-3 doses per day Azathioprine At a target dose of 2-3 g/day divided into 2 doses per day Mycophenolate mofetil IV infusion at doses of 375 mg/m of BSA, administered once weekly for 4 weeks, or IV 1,000 mg with re-treatment at 14 days Rituximab Consider administering maintenance rituximab 1,000 mg with re-treatment at 14 days or one infusion of 1,000 mg or one infusion of 375 mg/m repeated every 6 months. (Expert opinion). E Show 2 more As per NEMOS 2013 guidelines: Initiate azathioprine or rituximab as first-line therapy in patients with neuromyelitis optica or AQP-4 antibody-positive NMOSDs. E Consider initiating IVIG as first-line therapy in patients with contraindications to immunosuppressive therapies. Decide on initiating therapy in AQP-4 antibody-negative patients with NMOSDs depending on the severity and remission of the first relapse and the clinical course. E As per EFNS 2010 guidelines, consider initiating one of the following options as first-line therapy in patients with NMOSD: azathioprine plus prednisolone: azathioprine PO 2.5-3 mg/kg/day plus prednisolone PO 1 mg/kg/day, tapered when azathioprine becomes effective (after 2-3 months) https://web.pathway.md/diseases/recF6PpqGbrUiikaO 4/8 6/30/23, 1:19 AM Neuromyelitis optica spectrum disorder Pathway rituximab: option 1: i.v. 375 mg/m weekly for 4 weeks (lymphoma protocol); option 2: 1,000 mg infused twice, with a 2-week interval between the infusions (rheumatoid arthritis protocol); options 1 and 2: re-infusion after 6-12 months. E Second-line therapy: As per LACG-NMOSD 2020 guidelines, administer low-dose oral corticosteroids (5-10 mg of prednisolone or its equivalent) for a prolonged period in combination with mycophenolate mofetil/azathioprine in patients with suboptimal treatment response. E Show 2 more As per NEMOS 2013 guidelines, consider switching from azathioprine to rituximab, or vice versa, or to mycophenolate mofetil, methotrexate, or mitoxantrone in case of side effects or poor response. E Show 2 more As per EFNS 2010 guidelines, consider initiating one of the following options as second-line therapy in patients with NMOSD: Situation Guidance Cyclophosphamide IV 7-25 mg/kg every month over a period of 6 months, especially in case of association with SLE/Sj gren's syndrome Cyclophosphamide Mitoxantrone IV 12 mg/m monthly for 6 months, followed by 12 mg/m every 3 months for 9 months Mitoxantrone Mycophenolate mofetil PO 1-3 g/day. E Mycophenolate mofetil Considerations for rituximab therapy: do not leave any therapeutic window between the end of the relapse treatment and the initiation of rituximab. Switch from a previous immunosuppressant to rituximab (if switching) without delay after azathioprine or mycophenolate mofetil. Ensure that neutrophil count is > 1, 500/mm to initiate rituximab after cyclophosphamide or mitoxantrone infusion. Use the 1 g 2 weeks apart protocol for the treatment induction. D Show 6 more 6. Specific circumstances Pregnant patients: As per LACG-NMOSD 2020 guidelines, continue immunosuppressive therapy with azathioprine or rituximab during pregnancy in patients with a history of NMOSD attacks within the past 3 years. E Show 2 more https://web.pathway.md/diseases/recF6PpqGbrUiikaO 5/8 6/30/23, 1:19 AM Neuromyelitis optica spectrum disorder Pathway As per NOMADMUS 2018 guidelines, advise female patients with NMOSDs with childbearing potential to use effective contraceptive methods during and 6 months after treatment with rituximab. E Show 2 more 7. Preventative measures Routine immunizations: As per ACR 2023 guidelines, consider offering high-dose or adjuvanted influenza vaccination, rather than regular-dose influenza vaccination, in 18-65 years old patients on immunosuppressive medications. C Show 15 more As per NOMADMUS 2018 guidelines, update the vaccination schedule, in particular vaccination against measles, and offer pneumococcal vaccination before initiating rituximab. E Initiate rituximab after the first pneumococcal vaccine injection. E Show 2 more Anti-infective prophylaxis: As per EULAR 2022 guidelines, consider administering prophylaxis against P. jirovecii pneumonia in patients initiating high-dose corticosteroids, especially in combination with immunosuppressants and depending on the risk-benefit ratio. C As per NOMADMUS 2018 guidelines, consider administering prophylaxis against P. jirovecii in patients with a CD4 cell count < 200/mm . E Show 2 more 8. Follow-up and surveillance Assessment of treatment response: classify patients with NMOSD as having suboptimal treatment response when presenting with relapse after 6 months of therapy within 5 years of starting treatment with azathioprine at a target dose of 2.5-3.0 mg/kg/day adjusted to the total lymphocyte count (< 600-1, 000/ L) and a MCV increase of at least 5 points from the baseline. E Show 4 more Management of relapse: As per LACG-NMOSD 2020 guidelines, administer early IV methylprednisolone 1 g daily for 3-5 days for the management of acute relapses. Taper the course of oral corticosteroids slowly for 2- 8 weeks, depending on the severity of the attack. E Show 3 more As per EFNS 2010 guidelines: Consider administering high-dose corticosteroids (methylprednisolone 1 g for 3-5 consecutive days) as first-line therapy, followed by an oral prednisolone taper, for the treatment of relapses. E https://web.pathway.md/diseases/recF6PpqGbrUiikaO 6/8 6/30/23, 1:19 AM Neuromyelitis optica spectrum disorder Pathway Escalate therapy early with plasmapheresis in patients with corticosteroid-unresponsive relapses. Consider administering a repeated course of high-dose corticosteroids before escalation therapy. E Clinical findings Symptoms Past medical history Dysesthesia Anti-NMDA receptor encephalitis Erectile dysfunction Antiphospholipid syndrome Eye pain Celiac disease Facial numbness Myasthenia gravis Hiccups Optic neuritis Nausea Paraneoplastic syndrome Paresthesia Rheumatoid arthritis Urinary retention SLE Vision loss Sj gren's disease Vomiting Transverse myelitis Neurological exam Ocular exam Ataxia Papilledema Hemiparesis Relative afferent pupillary defect Visual field defect visual acuity Lhermitte's phenomenon Uhthoff's phenomenon Serological findings Lab findings anti-AQP-4 antibodies CSF GFAP CSF lactate Cytological findings CSF WBC count Likelihood Ratios Pertinent positives The following findings increase the probability of neuromyelitis optica spectrum disorder in adults. 7 Finding LR+ Value Positive anti-AQP-4 antibodies 8.1 Pertinent negatives https://web.pathway.md/diseases/recF6PpqGbrUiikaO 7/8 6/30/23, 1:19 AM Neuromyelitis optica spectrum disorder Pathway The following findings decrease the probability of neuromyelitis optica spectrum disorder in adults. 7 Finding LR- Value Negative anti-AQP-4 antibodies 0.3 References 1. Edgar Carnero Contentti, Juan Ignacio Rojas, Edgardo Cristiano et al. Latin American consensus recommendations for management and treatment of neuromyelitis optica spectrum disorders in clinical practice. Mult Scler Relat Disord. 2020 Oct;45 102428. Open 2. Corinna Trebst, Sven Jarius, Achim Berthele et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group NEMOS . J Neurol. 2014 Jan;261 1 1 16. Open 3. J Sellner, M Boggild, M Clanet et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol. 2010 Aug;17 8 1019 32. Open 4. J Ciron, B Audoin, B Bourre et al. Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders. Rev Neurol Paris). 2018 Apr;174 4 255 264. Open 5. Anne R Bass, Eliza Chakravarty, Elie A Akl et al. 2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2023 Jan 4. Online ahead of print. Open 6. George E Fragoulis, Elena Nikiphorou, Mrinalini Dey et al. 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2022 Nov 3;ard-2022 223335. Open 7. Expert Panel on Neurological Imaging, Vikas Agarwal, Lubdha M Shah et al. ACR Appropriateness Criteria Myelopathy: 2021 Update. J Am Coll Radiol. 2021 May;18 5S S73 S82. Open 8. Lennon VA, Wingerchuk DM, Kryzer TJ et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004 Dec 11 17;364 9451 2106 12. Open 9. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. 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