Journal of Neuro-Ophthalmology:
MS and NMO: Partners No More
Steven L., Galetta MD
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania.
Address correspondence to Steven L. Galetta, MD, Department of Neurology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; E-mail: email@example.com
The author reports no conflicts of interest.
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 associated 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 necrotizing 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 oligodendrocyte 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 prognostic 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 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 concurrent control patients. Furthermore, a small number of patients with NMO do incredibly well with decades separating their episodes even without treatment. Geographical differences 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 frequency 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 antibodies 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 neurologic 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 MOG− 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. Biomarkers 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 isolated 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 methods 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)!
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© 2012 Lippincott Williams & Wilkins, Inc.
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