Journal of Neuro-Ophthalmology, June 2012, Volume 32, Issue 2

MS and NMO - Partners No More

MS and NMO: Partners No More Steven L. Galetta, MD Multiple sclerosis (MS) and neuromyelitis optica (NMO) are recurring inflammatory disorders of the central nervous system. Although the exact pathogenesis of MS and NMO is uncertain, an autoimmune process directed at glial antigens appears to be a key ingredient. Several lines of evidence support that these 2 entities are separate but closely allied disorders. Some inflammatory lesions asso-ciated with MS are composed of macrophages, T cells, B cells, and microglial cells (1, 2). In a number of patients, the pathology appears to be antibody and complement driven, resulting in demyelination and axonal injury (1). Whereas MS may have myelin as its primary target, the immune response in NMO appears to be directed against the astrocyte (3, 4). The pathology of NMO is characterized by necro-tizing injury, neutrophils, hyalinized blood vessels, and antibodies that fix complement and are directed against aquaporin 4 (AQP4), a dominant water channel densely expressed on astrocyte foot processes (3,4). In this issue of the Journal, we have 4 articles that attempt to separate further the clinical and diagnostic features of NMO and MS (5-8). Morrow and Wingerchuk (5) provide a wonderful state-of- the-art review of NMO, Kezuka et al (6) show that the presence of the NMO and myelin oligo-dendrocyte glycoprotein (MOG) antibodies may help predict visual outcome, and Fernandes et al (7) find that the visual fields of patients with NMO rarely return to normal compared to those patients with typical optic neuritis. Finally, Romero et al (8) report a patient with homonymous hemimacular thinning noted on optic coherence tomography as a manifestation of optic tract injury in NMO. The findings of Fernandes et al (7) show that visual field abnormalities are worse in NMO patients following a single episode of optic neuritis. The authors found that only 5% of patient eyes with NMO regained a normal visual field after an attack of optic neuritis compared with nearly 50% who had typical optic neuritis. These findings supplement the long-standing data that visual acuity is worse in NMO and it is consistent with the observation that there is more profound retinal nerve fiber layer loss in this disorder when compared with MS (9). It is disheartening that over a 10-year time frame, 50%- 60% of patients with NMO will be legally blind in one eye as opposed to the routine optic neuritis patient who has a risk of legal blindness in the 3% range (10-12). In one study of patients with severe visual loss (,20/200 acuity), 32% of patients were found to harbor the NMO antibody, and in another study, the antibody was detected in 20% of patients with recurrent optic neuritis (13, 14). From the point of view of visual functions, the diagnosis of NMO is strongly suggested when the visual loss from optic neuritis is severe, bilateral, or recurrent or the recovery is poor. The difference in prognosis and treatment response of patients with NMO has lead some to conclude that it is worth getting an NMO titer on every patient with optic neuritis. Although the yield (about 5%) may be low (15), it is becoming harder to argue against routine testing for NMO if the result can have such important prog-nostic and therapeutic implications including the potential to worsen with interferon therapy (16). As Morrow and Wingerchuk (5) emphasize, relapse rates are higher in NMO compared with MS and disability milestones are achieved at a more rapid pace. At the very least, knowledge of the antibody status could prompt aggressive treatment if a subsequent attack ensues. The distinction of these 2 entities is critical because of the relatively poor visual prognosis of NMO and the differential response of these conditions to immunomodulatory therapy. It has become increasingly evident that interferon beta products may have a deleterious effect on the relapse rate of NMO, suggesting that the immunologic differences of these disorders have therapeutic implications (17, 18). For disease prevention, the present consensus is that patients with NMO should be treated with immunosuppressive agents such as azathioprine and mycophenolate mofetil or the anti-CD20 Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania. The author reports no conflicts of interest. Address correspondence to Steven L. Galetta, MD, Department of Neurology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; E-mail: [e-mail] Galetta: J Neuro-Ophthalmol 2012; 32: 99-101 99 Editorial Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. agent rituxamab (19-23). Nonetheless, we are hampered in making definitive statements about the treatment of NMO because, to date, we have only case studies without concur-rent control patients. Furthermore, a small number of patients with NMO do incredibly well with decades separat-ing their episodes even without treatment. Geographical dif-ferences may also play a role as certain populations appear to have a more favorable prognosis. The frequency of positive NMO antibodies is in the 50% range in European studies. In the United States, the Mayo Clinic group found a sensitivity of 73%, and investigators in southern Japan reported a fre-quency of 27% in optospinal MS patients (24-26). The variable visual prognosis of NMO and the relatively large number of patients with negative titers suggest that there are other antibodies or pathogenetic factors to be discovered. There is increasing evidence that certain proteins such as MOG, proteolipid protein, myelin basic protein, and AQP4 may all induce inflammatory central nervous system changes (27-32). The NMO antibody has high specificity and variable sensitivity depending on population being studied. Its discovery has not only aided in distinguishing NMO from MS but also helped to define the features that characterize NMO. On the other hand, MOG protein has been more variably associated with MS and optic neuritis (27-32). This protein is located in the outer myelin sheath and might be subject to autoimmune attack, particularly by T cells. Several studies have demonstrated the MOG anti-bodies in the serum and cerebrospinal fluid of MS patients, but it is unclear if these antibodies are responsible for the demyelination associated with this disorder (27-32). MOG antibodies have been found in patients with other neuro-logic disorders and healthy controls (29). Nonetheless, the high concentration of the MOG protein in the optic nerve suggests that it may play a role in the development of optic neuritis. The study of Kezuka et al (6) shows that these antibodies may help predict the visual outcome of patients with optic neuritis (6). The authors found that when patients harbored either NMO IgG or MOG antibody, their prognosis for visual recovery was poor compared with those that lacked both antibodies. However, the presence of the NMO antibody seemed to be the main determinant of poor visual prognosis as there was no statistical difference in outcome between the MOG2 and MOG+ patients when the NMO antibody was absent. If upheld by further study, this may be an important observation and may guide how aggressive one is about treatment from disease onset. Bio-markers may help guide treatment and explain why certain individuals do relatively well with this disorder, whereas others have devastating visual consequences. To date, the role of MOG antibodies in the pathogenesis and predicting disease course remains unsettled (27-33). It was initially reported that these antibodies could separate various forms of MS or even predict the conversion of the clinically iso-lated syndrome to MS (28), but many of these findings have not been replicated (27-31). Most inflammatory optic neuropathies have overlapping clinical features including those associated with MS and NMO. The delineation of the underlying molecular and inflammatory mechanisms may provide us with new meth-ods to characterize and treat these disorders. For example, the discovery that an antibody directed against aquaporin-4 drives the pathologic changes of NMO permits creation of molecules that neutralize its effect. Hopefully, the next wave of excitement will come from the development of targeted therapies (34, 35)! REFERENCES 1. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47:707-717. 2. Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17:210-218. 3. Roemer SF, Parisi JE, Lennon VA, Benarroch EE, Lassmann H, Bruck W, Mandler RN, Weinshenker BG, Pittock SJ, Wingerchuk DM, Lucchinetti CF. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain. 2007;130:1194-1205. 4. Fujihara K. Neuromyelitis optica and astrocytic damage in its pathogenesis. J Neurol Sci. 2011;306:183-187. 5. Morrow MJ, Wingerchuk D. Neuromyelitis optica. J Neuroophthalmol. 2012;32:154-166. 6. Kezuka T, Usui Y, Yamakawa N, Matsunaga Y, Matsuda R, Masuda M, Utsumi H, Tanaka K, Goto H. Relationship between NMO-antibody and anti-MOG antibody in optic neuritis. J Neuroophthalmol. 2012;32:107-110. 7. Fernandes D, Ramos RP, Falcochio C, Apóstolos-Pereira S, Callegaro D, Monteiro MLR. Comparison of visual acuity and automated perimetry findings in patients with neuromyelitis optica or multiple sclerosis after single or multiple attacks of optic neuritis. J Neuroophthalmol. 2012;32:102-106. 8. Romero RS, Gutierrez I, Wang E, Reder ET, Bhatti T, Bernard JT, Javed A. Homonymous hemimacular thinning: a unique presentation of optic tract injury in neuromyelitis optica. J Neuroophthalmol. 2012;XX:XX-XX. 9. Ratchford JN, Quigg ME, Conger A, Frohman T, Frohman E, Balcer LJ, Calabresi PA, Kerr DA. Optical coherence tomography helps differentiate neuromyelitis optica and MS optic neuropathies. Neurology. 2009;73:302-308. 10. Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology. 1999;53:1107-1114. 11. Merle H, Olindo S, Bonnan M, Donnio A, Riches P, Smadja D, Cabre P. Natural history of the visual impairment of relapsing neuromyelitis optica. Ophthalmology. 2007;114:810-815. 12. Optic Neuritis Study Group. Visual function 15 years after optic neuritis: a final follow-up report from the Optic Neuritis Treatment Trial. Ophthalmology. 2008;115:1079-1082. 13. Lai C, Tian G, Takahashi T, Liu W, Yang L, Zhang X. Neuromyelitis optica antibodies in patients with severe optic neuritis in China. J Neuroophthalmol. 2011;31:16-19. 14. Matiello M, Lennon VA, Jacob A, Pittock SJ, Lucchinelti CF, Wingerchuk DM, Weinshenker BG. NMO-IgG predicts the outcome of recurrent optic neuritis. Neurology. 2008;70:2197-2200. 15. Jarius S, Frederikson J, Waters P, Paul F, Akman-Demic G, Marignier R, Franciotta D, Ruprecht K, Kuenz B, Rommer P, Kristoferitsch W, Wildemann B, Vincent A. Frequency and prognostic impact of antibodies to aquaporin-4 in patients with optic neuritis. J Neurol Sci. 2010;298:158-162. 16. Galetta SL, Cornblath WT. Should most patients with optic neuritis be tested for neuromyelitis optica antibodies and 100 Galetta: J Neuro-Ophthalmol 2012; 32: 99-101 Editorial Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. should this affect their treatment? J Neuroophthalmol. 2010;30:376-379. 17. Warabi Y, Matsumoto Y, Hayashi H. Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J Neurol Sci. 2007;252:257-261. 18. Shimizu J, Hatanaka Y, Hasegawa M, Iwata A, Sugimoto I, Date H, Goto J, Shimizu T, Takatsu M, Sakurai Y, Nakase H, Uesaka Y, Hashida H, Hashimoto K, Komiya T, Tsuji S. IFN beta-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology. 2010;75:1423-1427. 19. Mandler RN, Ahmed W, Dencoff JE. Devic's neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology. 1998;51:1219-1220. 20. Jacob A, Matiello M, Weinshenker BG, Wingerchule DM, Lucchinelti C, Shuster E, Carter J, Keegan BM, Katarci OH, Pittock SJ. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol. 2009;66:1128-1133. 21. Cree BA, Lamb S, Morgan K, Chen A, Waubant F, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005;64:1270-1272. 22. Jacob A, Weinshenker BG, Violich I, McLinskey N, Krupp L, Fox RJ, Wingerchuk DM, Boggild M, Constantinescu CS, Miller A, Dc Angelis T, Mateillo M, Cree BA. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol. 2008;65:1443-1448. 23. Costanzi C, Matiello M, Lucchinetti CF, Weinshenker BG, Pittock SJ, Mandrekar J, Thapa P, McKeon A. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011;77:659-666. 24. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364:2106-2112. 25. Kira J. Neuromyelitis optica and Asian phenotype of multiple sclerosis. Ann N Y Acad Sci. 2008;1142:58-71. 26. Collongues NR, Marignier R, Ze phir H, Zephir H, Papieux C, Blanc F, Ritleng C, Tehikuiladze M, Outterycho O, Vukusic S, Fleury M, Fontaine B, Brassat D, Clanet M, Milh M, Pelletier J, Audoin B, Ruet A, Lebrun-Frenay C, Thouvenot E, Camo W, Debouverie M, Creange A, Moreau T, Labauge P, Castelnovo C, Edan G, Le Page E, Defer G, Barosso B, Heinzlef O, Gout O, Rodriguez D, Wiertlewski S, Laplaud D, Borgel F, Tournaire P, Grimaud J, Brochet B, Vermesch P, Confavreux C, de Seze J. Neuromyelitis optica in France: a multicenter study of 125 patients. Neurology. 2010;74:736-742. 27. Zhou D, Srivastava R, Nessler S, Grummel V, Sommer N, Bruck W, Hartung HP, Stadelmann C, Hemmer B. Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc Natl Acad Sci U S A. 2006;50:19057-19062. 28. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med. 2003;349:139-145. 29. Lampasona V, Franciotta D, Furlan R, Zanaboni S, Fazio R, Bonifacio E, Comi G, Martino G. Similar low frequency of anti- MOG IgG and IgM in MS patients and healthy subjects. Neurology. 2004;62:2092-2094. 30. Di Pauli F, Mader S, Rostasy K, Schanda K, Bajer-Kornek B, Ehling R, Deisenhammer F, Reindl M, Berger T. Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases. Clin Immunol. 2011;138:247-254. 31. Mantegazza R, Crisaldini P, Bernasconi O, Baggi F, Pedotti R, Piccini I, Mascoli N, LaMantia L, Antozzi C, Simonchini O, Cornelio F, Milanese C. Anti MOG autoantibodies in Italian multiple sclerosis patients: specificity, sensitivity and clinical association. Int Immunol. 2004;16:559-565. 32. Olsson T. Roles of anti MOG antibodies in demyelination diseases. Nat Rev Neurol. 2011;7:248-249. 33. Reindl M, Khalil M, Berger T. Antibodies as biological markers for pathophysiological processes in MS. J Neuroimmunol. 2006;180:50-62. 34. Tradtrantip L, Zhang H, Anderson MO, Saadoun S, Phuan PW, Papadopoulos MC, Bennett JL, Verkman AS. Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica. FASEB J. 2012 Feb 8 (epub ahead of print). 35. Tradtrantip L, Zhang H, Saadoun S, Phuan PW, Lam C, Papadopoulos M, Bennett JL, Verkman AS. Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol. 2012;71:314-322. Galetta: J Neuro-Ophthalmol 2012; 32: 99-101 101 Editorial Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.