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Show Neuromyelitis Optica Mark J. Morrow, MD, Dean Wingerchuk, MD, MSc, FRCP(C) Abstract: Neuromyelitis optica (NMO) is a disabling inflam-matory condition that targets astrocytes in the optic nerves and spinal cord. Neuro-ophthalmologists must be particularly aware of this disorder because about half of patients present as isolated unilateral optic neuritis months or years before a disease-defining and often crippling bout of myelitis. NMO is easily confused with multiple sclerosis because it is charac-terized by relapses that lead to stepwise accrual of deficits. The best predictor of conversion from optic neuritis to clinical definite NMO is the presence of a serum antibody to aquaporin-4 called NMO-IgG. However, this test is currently only about 75% sensitive. Suspicion of NMO should be high in patients who present with vision of light perception or worse or who are left with acuity of 20/50 or worse after optic neuritis and in those with simultaneous bilateral optic neuritis or recurrent attacks. Acute NMO relapses are generally treated with high-dose intravenous steroids, with plasma exchange often used as a rescue therapy for those who do not respond. Preventative strategies against relapses currently use broad-spectrum or selective B-lymphocyte immune suppression, but their use is based on small, generally uncontrolled studies. Hopefully, the future will bring more sensitive tools for defining risk and predicting outcome, as well as more targeted and effective forms of therapy. Journal of Neuro-Ophthalmology 2012;32:154-166 doi: 10.1097/WNO.0b013e31825662f1 © 2012 by North American Neuro-Ophthalmology Society Neuromyelitis optica (NMO, Devic disease) is a multi-focal central nervous system (CNS) demyelinating illness in which severe inflammatory attacks on the optic nerves and spinal cord predominate. Until recently, some considered NMO to be a variant of multiple sclerosis (MS). The discovery of a highly specific serum autoantibody (NMO-IgG) in 2004, however, helped prove that NMO is a distinct pathophysiologic condition. NMO-IgG is now known to target aquaporin-4 (AQP4), an astrocyte water channel that is widely distributed within the CNS. This insight has spurred a tremendous surge of interest in clinical and scientific aspects of NMO. Its most common neuro-ophthalmic presentation is unilateral optic neuritis, which often results in severe residual visual loss. No feature has yet been shown to fully distinguish optic nerve involvement in NMO from that in MS. Current clinical challenges include deciding which optic neuritis patients to screen for the NMO-IgG antibody and how to manage those with positive results. At present, there is no reliable method to predict poor outcome in patients at risk for developing NMO, nor any high-level evidence-based preventative regimen. ILLUSTRATIVE CASE A 54-year-old Laotian woman presented with bilateral upper and lower extremity weakness and numbness. Between ages 47 and 52 years, she experienced 4 attacks of unilateral optic neuritis (3 in right eye and 1 in left eye). These were treated with steroids, but recovery was limited, leaving her no light perception in the right eye and 20/20 in the left eye with bilateral optic atrophy. Brain MRI was unremarkable. Spinal cord MRI showed a 3-segment T2-intense lesion from C2 to C5. NMO-IgG antibody was positive. Comment One or more bouts of optic neuritis may precede a disease-defining attack of myelitis by months or years in NMO. PATHOGENESIS Myelin-bearing oligodendrocytes are the primary inflamma-tory target in MS, but astrocytes are lost first in NMO (1). AQP4, the predominant CNS water channel, localizes to astrocyte foot processes at the blood-brain barrier (2). It appears to be critical in maintaining water homeostasis in Department of Neurology (MJM), Harbor-UCLA Medical Center, Torrance, California; and the Department of Neurology (DW), Mayo Clinic Scottsdale. Disclosures: Dr. M. J. Morrow has received research support from Novartis and Biogen-Idec and has served as speaker/consultant for Biogen-Idec, EMD Serono, Teva Neuroscience, the American College of Physicians, and the National Multiple Sclerosis Society. Dr. D. Wingerchuk has received research support from Alexion, Genzyme, Genentech, and the Guthy-Jackson Charitable Foundation. Address correspondence to Mark J. Morrow, MD, Department of Neurology, Harbor-UCLA Medical Center, 1000 W Carson Street, Box 492, Torrance, CA 90509; E-mail: mmorrow@labiomed.org 154 Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166 State-of-the-Art Review Section Editors: Grant T. Liu, MD Randy H. Kardon, MD, PhD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. settings of physiologic stress. AQP4 heterotetramers assemble into orthogonal array particles that are probably the main binding target of the NMO-IgG antibody. Differential expression of these isoforms may explain greater occurrence of NMO lesions in the optic nerve and spinal cord than elsewhere (3). Antibodies to AQP4 may enter the CNS across permeable portions of the blood-brain barrier, where they would immediately encounter astrocytes and could trigger cell-dependent cytotoxicity (4). Acute NMO lesions in patients show loss of AQP4 (5,6), in contrast to a frequent increase in AQP4 expression in acute MS lesions (6,7). Demyelination may occur as a secondary event in NMO because myelin is mainly found adjacent to AQP4-rich para-nodal regions (4). NMO lesions show vasculocentric deposi-tion of immunoglobulin and complement (5,6). Histopathologic findings of NMO-associated optic neuritis include infiltration with lymphocytes, macrophages, and monocytes and venular inflammation (8,9). Long-term sequelae include cavitation and necrosis, vascular endothe-lial proliferation, glial proliferation or loss, and demyelin-ation in the optic nerve and chiasm (8-10). Loss of the retinal nerve fiber layer (RNFL) and disappearance of retinal ganglion cell bodies attest to retrograde degeneration after axonal loss in the optic nerve (9). Green and Cree (11) have reported visible retinal vascular changes in NMO eyes, in-cluding arteriolar narrowing and "frosting." This suggests that retinal ischemic or inflammatory damage might at times contribute to visual loss. However, Kerrison et al (9) did not find active retinal inflammation concurrent with NMO-associated optic neuritis in two cases. Putative animal models have been created by adminis-tering NMO-IgG. Passive transfer of the antibody produces central lesions if it is injected directly into the CNS with complement (12) or when it is infused peripherally after first interrupting the blood-brain barrier (13-15). Although these early models have not replicated spontaneous NMO, they do recapitulate most of its key pathologic features and present the opportunity to develop new therapies. GENERAL CLINICAL CHARACTERISTICS The case report by Devic (16) and subsequent case series by his student Gault (17) solidified the term neuromyelitis optica over a century ago, describing a monophasic disorder with optic neuritis and transverse myelitis of simultaneous onset. Many experts considered NMO to be a variant of MS. Over the past 15 years, however, a different pattern of NMO has emerged, along with its unequivocal distinction as a clinical and pathophysiologic entity. Most importantly, it was recognized that NMO follows a relapsing rather than monophasic course in over 70% of cases (Table 1) (18,19). NMO series from around the world have suggested consistent demographics that largely parallel MS. Women are much more commonly affected than men, with female to male ratios of at least 3:1. Median age of onset is generally in the mid 30s, with a very wide range. Earlier reports of NMO in children focused on the classic mono-phasic condition, which is often preceded by a viral illness and has a benign course (20). More recent pediatric case series, however, chiefly describe relapsing disease with median ages of onset of 10-14 years and strong female predominance (21-24). In a large French cohort, 10% of all patients with NMO were younger than 18 years (22). The authors have personally seen cases with onset as young as 4 years and as old as 85. Population-based studies of NMO from the French West Indies, Cuba, Denmark, and Japan indicate preva-lence rates between 0.3 and 4.4 per 100,000 people and annual incidence rates of 0.05-0.4 cases per 100,000 person-years (25-28). The reported proportion of definite TABLE 1. Comparison of clinical features of MS and NMO MS NMO Initial clinical course 85% relapsing-remitting 80%-90% relapsing-remitting 15% primary progressive 10%-20% monophasic Secondary progressive course Often Rare Brain MRI lesions Periventricular, subcortical (Barkhof criteria) If seen, symmetrical hypothalamic, brainstem Resemble MS in about 10% Spinal cord MRI lesions 1-2 segments long .3 segments acutely (can resolve or shrink) CSF WBCs during relapses ,50/mm3, all mononuclear Often .50/mm3, polymorphonuclear component CSF oligoclonal bands About 85% 15%-30% Systemic autoimmune disease Occasional Common Severity of relapses Usually mild to moderate Usually moderate to severe Recovery from relapses Usually fair to good Usually fair to poor Response to interferons Usually helpful Can worsen disease CSF, cerebrospinal fluid; WBCs, white blood cells. Adapted from Wingerchuk et al (57). Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166 155 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. NMO among adults and children with inflammatory de-myelinating diseases (including MS) varies widely, with a range of 1%-22% in a group of recent studies (21,28- 32). The authors' experiences suggest a value toward the lower end of this range for their clinic populations in the United States. NMO appears to account for a greater pro-portion of CNS demyelinating disease in non-Caucasians, including African Americans, Hispanics, Afro-Brazilians, black Africans, Asians, and Native Americans. A high per-centage of Japanese patients thought to have MS have pre-dominant involvement of the optic nerves and spinal cord, often termed "opticospinal MS." A masked assessment showed that more than half of patients with this condition were seropositive for the NMO-IgG antibody, suggesting NMO as the correct diagnosis (33,34). Familial NMO is rare, accounting for no more than 3% of established cases (35). Its existence, however, suggests that genetic factors may play a role in disease susceptibility. Human leukocyte anti-gens associated with increased NMO risk include DPB1*0501 in Asians and DRB1*0301 in Caucasians (36,37). Analysis of AQP4 gene single-nucleotide polymor-phisms did not detect variations associated with general NMO susceptibility (38). NMO-related disability accrues almost exclusively from incomplete recovery of relapses. A secondary progressive course is common in MS but rare in NMO (39). Patients with monophasic NMO tend to have worse initial attacks than those with relapsing disease but better long-term prog-nosis. Individual attacks tend to be more severe and leave more residual deficits than in MS. In one series, half of patients with NMO had severe visual impairment in at least 1 eye or required ambulatory aids within 5 years of onset (40). A small group of patients with NMO have a more favorable course (41). Relapsing NMO tends to progress more slowly in children than in adults, with lower annual-ized relapse rates (22). Higher initial rates of relapse with more severe residua predict early death (42). Key features help to differentiate relapsing NMO and MS and are similar in adults and children. Roughly half of patients present with isolated optic neuritis; approximately 20% of these attacks are bilateral (18,22-24,43-45). The remaining half usually present as isolated myelitis with numbness, tingling, or weakness of the arms, legs, or trunk that develops over hours to days. Myelitis is often associated with bowel or bladder dysfunction. In about 10% of patients with NMO, concurrent optic nerve and spinal cord involvement characterizes the initial attack. During acute attacks of MS, cerebrospinal fluid (CSF) typically contains fewer than 50 white blood cells per cubic millimeter, mostly lymphocytes. In contrast, NMO attacks often produce dra-matic CSF pleocytosis with significant numbers of neutro-phils or eosinophils. Oligoclonal bands are found in the CSF of about 85% of MS patients but 30% or fewer of those with NMO (46). Although many patients with NMO have brain MRI abnormalities, these are usually mild and nonspecific (47). Up to 10% of antibody-positive, clinically definite patients with NMO have MRI abnormalities con-sistent with MS (Fig. 1A). Others have lesions in unique locations like the hypothalamus and caudal medulla (see below). Spinal cord MRI features of MS and NMO often differ significantly. Acute MS-associated cord lesions are usually one vertebral segment long, but NMO lesions are FIG. 1. MRI in an NMO-IgG-positive 32-year-old woman. NMO presented as simultaneous bilateral visual loss and mye-lopathy at age 4, with recurrence at age 7 that left the patient totally blind bilaterally with severe myelopathy. A. Axial FLAIR MRI of the brain reveals periventricular lesions resembling MS. B. Sagittal short T1-inversion recovery (STIR) MRI shows longitudinally extensive signal change along the length of the cervical cord (between the arrows). MS, multiple sclerosis; NMO, neuromyelitis optica. 156 Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. typically 3 or more segments long (Fig. 1B). Acute NMO lesions tend to be centrally located within the cord, cause cord expansion, and enhance with gadolinium. Nonacute spinal cord MRI can be misleading because elongated NMO lesions can shrink into smaller spots that are typical of MS (Fig. 2). The first report of the NMO-IgG antibody, using an indirect immunofluoresence assay, found it to be 73% sensitive and 91% specific for distinguishing clinically defined NMO from MS (33). These data have been con-firmed in widespread patient populations, although anti-body positivity has ranged as low as 50% depending on the specific test used. An enzyme-linked immunosorbent assay is now commercially available. The highest sensitiv-ities, about 75%, are attained with assays that detect IgG binding to cells expressing recombinant AQP4 (48). CSF AQP4 antibodies have been detected in some seronegative patients (49). Widely accepted clinical and laboratory crite-ria were developed for NMO in 1999 (18) and then updated in 2006 with incorporation of antibody status (Table 2) (50). The discovery of the pathogenic antibody has allowed for recognition of a wider array of clinical and radiologic characteristics associated with NMO. Certain brain MRI lesions that would be atypical for MS have proven to be common in NMO. These aggregate in regions with a high density of AQP4 and include caudal medullary lesions that present with hiccups and nausea and diencephalic lesions that cause somnolence and endocrine disturbances (Figs. 2, 3) (51-53). Large cerebral white matter lesions suggesting tumefactive MS (54) or posterior reversible encephalopathy syndrome (55) (PRES) may also occur in NMO (Fig. 4). Patients with features of NMO often have serologic or clinical evidence of systemic lupus erythemato-sus, Sjogren syndrome, or other autoimmune conditions (56). Because these patients are commonly seropositive for NMO-IgG, it is likely that their systemic autoimmune con-dition is coincidental rather than causative. Patients with isolated optic neuritis or myelitis and a positive NMO-IgG antibody are currently described as having "NMO spectrum disorder" (57). This at-risk state might be considered comparable to clinically isolated syn-drome in patients who have had a single episode consistent with demyelination and brainMRI abnormalities suggestive of MS. In one study of patients presenting with transverse my-elitis, 55% of those who were seropositive developed recurrent myelitis or NMO-defining optic neuritis within a year (58). No seronegative patient had such an event. Given the high risk for future attacks with serious residua, detection of NMO-IgG may allow for early initiation of preventative therapy. NEURO-OPHTHALMIC CONSEQUENCES OF NMO Optic neuritis is a required element for clinically definite NMO according to widely accepted criteria (Table 2) (50). It is the initial clinical manifestation in about half of patients (18,43-45). Reported lags between initial optic neuritis and a disease-defining attack of myelitis averaged about 2 years in 5 large series of patients, with ranges from a few months to decades (18,19,45,59,60). Recurrent attacks of optic neuritis may occur before or after myelitis and lead to a stepwise loss in visual function. Table 3 sum-marizes visual outcomes in several large NMO series. The Optic Neuritis Treatment Trial (ONTT) provides compar-ative data in a cohort in whom over half were eventually diagnosed with MS (61). Current NMO criteria were not in place during the ONTT, and it is not known how many patients actually converted to NMO rather than MS; only 1 patient was known to have NMO with certainty (62,63). FIG. 2. T2 sagittal MRI demonstrates NMO-typical caudal medullary lesion (upper arrow) along rostral continuation of central spinal canal. Such lesions may cause nausea, vomiting, hiccups, lower cranial nerve palsies, and nystag-mus. Lower arrows show residua of cord lesions at C4-C5 and T5, now less than 3 segments in length. NMO, neuro-myelitis optica. TABLE 2. Diagnostic criteria for NMO Required (at least 1 attack of each of the following) Optic neuritis Transverse myelitis Supportive (at least 2 of the following 3) Brain MRI: normal or lesions not meeting criteria for MS Spinal cord MRI: lesion extending continuously over 3 or more vertebral segments NMO-IgG seropositivity NMO, neuromyelitis optica. Adapted from Wingerchuk et al (50). Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166 157 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Entry demographics for the ONTT were similar to most current NMO and MS series, with a 3:1 female predomi-nance and mean age of 32 years. Differences between NMO and the ONTT populations can be appreciated in the prevalence of severe visual loss. In the ONTT, 36% of eyes showed nadir visual acuity of 20/200 or worse and 7% of eyes were light perception or no light perception (61,64). In contrast, NMO eyes are initially 20/200 or worse in up to 80% of optic neuritis cases and no light perception in over 30% (18,44,60,65). Long-term out-come discrepancies are even more striking. In patients with NMO for at least 5 years, about half have vision of 20/200 or worse in at least 1 eye and about 20% have this level of impairment in both eyes (18,44,45,59). About 30% of patients are left with visual acuity of #20/200 after their first bout of optic neuritis (44,45). In contrast to NMO, 15-year follow-up in the ONTT yielded only about 4% of patients with acuity of 20/200 or less in one eye and fewer than 2% with this level of loss in both eyes (66). Median acuity was 20/20 after 15 years in the ONTT (66), compared to means of 20/32 to 20/50 at about 10 years in NMO (45,59). Other than visual acuity, most series have not included information on initial characteristics that might help to distinguish optic neuritis in NMO from MS. In the ONTT, eye pain and optic disk edema were reported in 92% and 35% of patients, respectively (61). Two retrospec-tive series of NMO-associated optic neuritis reported initial eye pain in 27% (44) and 67% (67). Another series noted optic disk edema (papillitis) in 5% of cases of optic neuritis associated with NMO but only 10% of cases associated with MS, a much lower value than the ONTT (59). In patients with NMO, asymptomatic disk edema can occur when the fellow eye shows symptomatic papillitis (68). Visual field analysis reveals localized peripheral defects more frequently in optic neuritis associated with NMO than with MS, but there is considerable overlap (69). Both conditions cause predominantly central impairment (69,70). Simultaneous bilateral optic neuritis was thought to be sufficiently atypical that it was an exclusion criterion for the ONTT. In a series of 472 MS patients reviewed by Burman et al (71), only 0.4% presented with bilateral optic neuritis as their first neurologic attack compared to 20% presenting with unilateral optic neuritis. Simultaneous bilateral optic neuritis occurred at some point in the course of only 2% of their MS cohort and comprised 4% of all optic neuritis attacks. In contrast, acute, isolated, bilateral optic neuritis FIG. 3. Axial brain MRI shows symmetric hypothalamic lesion typical of NMO surrounding the inferior aspect of third ventricle (arrows). A. FLAIR image. B. Gadolinium-enhanced T1 image. Lesions in this location can cause somnolence, polyphagia, and endocrinopathy. NMO, neuromyelitis optica. FIG. 4. Coronal FLAIR image reveals a chronic cavitary left temporal lesion in a patient with NMO spectrum disorder (arrow). Such lesions often appear tumefactive acutely, with ring enhancement, edema, and mass effect similar to MS. MS, multiple sclerosis; NMO, neuromyelitis optica. 158 Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 3. Synopsis of 8 large series of visual outcome in NMO compared with Optic Neuritis Treatment Trial final data First Author Year Subjects (n) Mean Disease Duration, Last Examination, y Mean/Median Age Onset, y Female, % Relapsing Course, % Simultaneous Bilateral ON as Initial Visual Event, % Isolated ON as Presenting Problem (Uni- or Bilateral) VA at Peak in Affected Eye VA at Follow-up O'Riordan (19) 1996 12 5 35 92 83 83 42 N/A 83% #CF at least 1 eye Wingerchuk (18) 1999 71 10.6 36 72 68 11 52 37% NLP 48% #20/200 at least 1 eye de Seze (65) 2002 13 8.6 37 77 100 85 15 58% #20/200 54% #20/200 at least 1 eye Ghezzi (43) 2004 46 8.8 40 80 100 20 57 N/A N/A Merle (59) 2007 30 9.6 30 93 100 13 77 N/A 70% #20/200 at least 1 eye Rivera (60) 2008 24 5.8 36 71 68 3 23 80% #20/200 91% #20/200 at least 1 eye Papais-Alvarenga (44) 2008 60 8 N/A 90 100 18 53 78% #20/200 63% #20/200; 23% NLP, at least 1 eye Collongues (45) 2010 125 10 35 75 73 N/A 37 N/A 45% #20/200 at least 1 eye Optic Neuritis Study Group (66) 2008 294 .15 32 77 50 N/A 100 36% #20/200 3% #20/200 at least 1 eye Four NMO trials were selective for relapsing disease only, whereas others included patients with monophasic illness. CF, count fingers; N/A, not applicable; NLP, no light perception; NMO, neuromyelitis optica; ON, optic neuritis; VA, visual acuity. Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166 159 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. was the initial presentation of NMO in 11%-20% of patients in several larger series (18,27,44,59). Concurrent bilateral attacks account for about 20% of all NMO-related optic neuritis in relapsing cases and are even more common in monophasic disease. Recurrent optic neuritis may be another harbinger of NMO. Pirko et al (72) reported 72 patients with recurrent optic neuritis occurring before any other neurologic manifestations. Of these, 8 (11%) converted to NMO, 20 (28%) converted to MS, and 44 (61%) did not develop signs of either condition over a mean follow-up of approximately 9 years. Patients who developed NMO showed a higher female to male ratio and more frequent and severe attacks of optic neuritis than those who converted to MS or to neither condition. Recurrent optic neuritis that is destined to become definite NMO seems distinct from the condition described as chronic relapsing inflammatory optic neuropathy (CRION) by Kidd et al (73). Similarities be-tween NMO and CRION include severe recurrent visual loss and predominance in young women. In CRION, both eyes are usually involved within 1 month of onset and dem-onstrate optic disk edema. In contrast to NMO, patients with CRION appear exquisitely sensitive to steroids, improv-ing rapidly with treatment and relapsing within weeks after steroids are tapered. One report showed positive NMO-IgG antibodies in only 1/19 CRION patients (74). NMO may involve the optic chiasm and tracts, giving rise to bitemporal or homonymous hemianopic visual field defects (75-77). Chiasmal and tract involvement may be seen on MRI (18,78) and has been identified pathologically (8,10,52,67). Atypical cerebral white matter lesions, such as those of PRES, may cause retrogeniculate visual loss (55). Eye movements may also be affected in NMO, usually in association with brainstem lesions. Reported abnormalities include upbeating, downbeating, or mixed horizontal-torsional nystagmus (78); wall-eyed bilateral internuclear ophthalmoplegia (79); and opsoclonus (78). Diplopia is one of the most common brainstem symptoms of NMO (80). Oscillopsia has been described without identifiably abnormal eye movements (81). ANCILLARY TESTING In patients presenting with a single attack of optic neuritis and no neurologic history, the prevalence of NMO-IgG positivity has been reported to be 3%-5% (74,82), rising into the 10%-20% range in patients with recurrent attacks (82,83). Two reports examined antibody status in patients presenting with optic neuritis, most recurrent, with follow-up averaging over 2 years (82,83). A subsequent attack of myelitis consistent with NMO occurred in 10 of 20 (50%) of those with positive antibodies but only in 1 of 82 sero-negative patients (1%). Even after a decade, however, not all seropositive patients with recurrent optic neuritis will have suffered myelitis (84). Which optic neuritis patients should be tested for NMO-IgG? (85,86). In support of widespread screening is the observation that attacks of NMO are particularly disabling. Relapse rates are about twice those of MS, and disability thresholds are reached much faster (45,87). Against wide-spread screening is the relative infrequency of NMO in patients presenting with uncomplicated optic neuritis, the cost of the test, and uncertainty regarding the best course of therapy in at-risk individuals. Most would recommend antibody testing in those with bilateral visual symptoms, recurrent optic neuritis, poor visual outcomes, or concur-rent autoimmune disease, assuming that they lack typical changes of MS on MRI (Table 4). Because at least 25% of patients with clinically defined NMO are seronegative, one should maintain a high index of suspicion and consider long-term immunosuppression in patients with recurrent severe bouts of unexplained optic neuropathy (88). Retest-ing seronegative NMO suspects is worthwhile, especially during a recurrent attack when antibody levels typically rise. Immunosuppression or recent plasma exchange may reduce NMO-IgG levels, yielding a false-negative result. A recent report suggests that elevation of serum glial fibrillary acidic protein, an astrocyte component, may distinguish isolated optic neuritis in NMO from MS (89). Anatomic and physiologic testing shows both symptom-atic and subclinical deficits in eyes of patients with NMO. Compared to MS, eyes with NMO-associated optic neuritis show more severe RNFL loss on optical coherence tomography. Average thickness reductions are 30-40 mm in NMO versus 10-20 mm in MS (Fig. 5, Table 5) (11,90- 93). Ratchford et al (91) estimated that a first attack of TABLE 4. Suggested criteria for testing NMO-IgG in isolated optic neuritis Clinical Visual acuity at nadir of LP or NLP Visual acuity after recovery of 20/50 or worse Symptomatic bilateral visual loss Recurrent optic neuritis Mild symptoms or findings of myelopathy Systemic autoimmune disease Ancillary Brain MRI not consistent with MS Mean OCT-RNFL thickness of ,70 mm Severe, bilateral, or recurrent visual loss are more common in NMO than in MS. Subtle evidence of spinal cord dysfunction may be present in patients without clear history of myelitis. Many patients with NMO have concurrent systemic autoimmune disease. These clinical findings should raise suspicion, especially when they are not accompanied by brain MRI changes typical of MS. OCT meas-ures of mean RNFL thickness could also be used to discriminate between MS and NMO; a final value of ,70 microns measured 3 or more months after onset is uncommon in idiopathic or MS-associated optic neuritis. LP, light perception; MS, multiple sclerosis; NLP, no light per-ception; NMO, neuromyelitis optica; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer. 160 Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. NMO-associated optic neuritis reduces mean RNFL thick-ness by 31 mm, with each subsequent attack subtracting another 10 mm. RNFL thinning is more evenly distributed around the peripapillary circumference in NMO than in MS, where it often selectively involves the temporal quad-rant (11,90,92-94). Syc et al (95) identified thinning of the inner plexiform-ganglion cell layer complex in the maculas of NMO eyes compared with controls, even in those with-out a history of optic neuritis. Subclinical RNFL loss has been observed in NMO eyes by some authors (90), but not others (91,95). Bouyon et al (96) reported progressive RNFL thinning in patients with NMO without an interval history of optic neuritis, suggesting a noninflammatory component of axonal loss as seen in MS (97). RNFL thick-ness has been correlated with high- and low-contrast visual acuity, contrast sensitivity, visual fields, and overall disabil-ity (Expanded Disability Status Scale [EDSS] score) in NMO, as it has in MS (11,90,91,94). Some have found that RNFL thickness is lower in NMO than in MS, even after adjusting for poorer visual acuity in the former (11,92). However, the "break point" of mean RNFL thick-ness below which visual loss occurs is similar in NMO (93) and MS (98) at about 70 mm. Visual evoked potentials (VEP) are typically absent or delayed in NMO eyes that have suffered optic neuritis, although they occasionally may show reduced amplitude alone (19,59,99). Subclinical abnormalities may also be seen. In a group of patients with myelitis and positive NMO-IgG antibodies but no history of optic neuritis, 4 of 8 had abnormal VEP (100). Conventional MRI shows typical changes of acute optic neuritis with NMO, includ-ing optic nerve enlargement, increased T2 signal, and enhancement (Fig. 6) (101). These changes are often more extensive than in MS, frequently bilateral and involving the FIG. 5. Peripapillary RNFL thickness plots from spectral-domain OCT in a 63-year-old woman with 17-year history of NMO and at least 4 episodes of optic neuritis. Visual acuity was 20/70, right eye, and NLP, left eye. A and C. Graphs of patient's data (dark black trace) over 360° circumference. B and D. Mean data in each sector. A and B. Right eye. C and D. Left eye. Both eyes show severe diffuse loss, with mean values of 53 mm, right eye, and 37 mm, left eye. All quadrants are thinned at P , 0.01 (red sectors) or P , 0.05 (yellow) level compared with normal. In contrast, MS eyes usually show mean RNFL thickness of 70 mm or more, and thinning often involves only the temporal quadrant. G, global (overall) mean; I, inferior; MS, multiple sclerosis; N, nasal; NLP, no light perception; NMO, neuromyelitis optica; N:T, nasal to temporal ratio; OCT, optical coherence tomography; PMB, papillomacular bundle; S, superior; T, temporal. TABLE 5. Summary of OCT comparison studies First Author Year Mean RNFL Controls, mm Mean RNFL MS-ON eyes, mm Mean RNFL NMO-ON eyes, mm Differences in Quadrant Values, NMO vs MS Merle (90) 2008 106 84 65 Ytemporal and inferior Ratchford (91) 2009 102 88 64 N/A Naismith (92) 2009 N/A 77 55 Ysuperior, inferior, and nasal Green (11) 2009 N/A 82 59 N/A; Yall quadrants vs normal Nakamura (93) 2010 N/A 84 64 Ysuperior and inferior Mean RNFL thickness in normal controls vs eyes with history of optic neuritis in MS and NMO. Right column summarizes comparisons between mean data in 4 testing quadrants in NMO and MS eyes. Values are about 20 mm lower in NMO eyes than in MS, consistently less than 70 mm. Values in individual quadrants, especially inferior, are often lower in NMO than in MS. MS affects the temporal quadrant predominantly. N/A, not applicable; NMO, neuromyelitis optica; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer. Morrow and Wingerchuk: J Neuro-Ophthalmol 2012; 32: 154-166 161 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. optic chiasm and tracts (102). Spinal MRI occasionally shows small cord lesions in NMO-IgG-positive patients with isolated optic nerve disease (100). Treatment Acute and disease-modifying treatment for NMO is limited by an absence of randomized controlled trials (103). Cortico-steroids, typically intravenous methylprednisolone 1 g daily for 5 consecutive days, represent first-line therapy for NMO attacks. Nakamura et al (93) suggested a neuroprotective effect of high-dose steroids when they are given within the first 2-3 days after onset of NMO-associated optic neuritis, but not later. Many severe NMO attacks respond inade-quately to corticosteroid treatment. Plasma exchange improves clinical outcomes for steroid-unresponsive relapses, including optic neuritis (104,105). Intravenous immune globulin is sometimes tried for acute NMO attacks, but efficacy data are limited. Relapse prevention is the key to preserving neurologic function in NMO. Some patients with NMO have been diagnosed with MS initially and treated with immunomod-ulatory drugs such as beta interferon. However, interferons and other MS therapies like natalizumab and fingolimod may actually aggravate NMO (106-108). The most appro-priate treatment approach in NMO is immunosuppression that is effective against antibody-mediated diseases. Current options include azathioprine, mycophenolate mofetil, rituximab, mitoxantrone, cyclophosphamide, methotrexate, intravenous immunoglobulin, and prednisone (103). Of these, azathioprine (109,110), mycophenolate (111), and rituximab (112,113) are probably the most commonly used for long-term prophylaxis. Azathioprine and mycophe-nolate are oral drugs that are generally well tolerated but not fully effective for 4-6 months. With these, adding a "bridge therapy" that has more rapid onset is advisable; oral pred-nisone is usually used and can be tapered when full effect of the long-term drug is expected. Rituximab is a monoclonal antibody that targets CD20, destroying B lymphocytes but not plasma cells. Its advantages include rapid onset of action (full activity within 2 weeks) and infrequent dosing (2 infu-sions approximately every 6 months). In the absence of comparative controlled trials, it remains unclear which treat-ment is superior. It is likely that no single drug is the best for every patient with NMO. Improved understanding of NMO pathophysiology is facilitating development of new therapies. Eculizumab, a monoclonal antibody that targets the terminal component of complement, is being evaluated for relapse prevention (114). Strategies aimed at blocking the binding of NMO-IgG to AQP4 are also being exploited. Aquaporumab is a highly selective, nonpathogenic, AQP4-binding antibody that prevents cytotoxicity in animal models and cell cultures (115). A variety of small molecules have also been identified as potential binding inhibitors (116). For example, sivelestat inhibits neutrophil elastase and reduces lesions in an animal model resembling NMO (117). FUTURE DIRECTIONS An essential first step in reducing the consequences of NMO is early recognition of at-risk patients. This requires careful assessment of those with optic neuritis or myelitis and judicious testing for the NMO-IgG antibody. Many patients who go on to have definite NMO are persistently seroneg-ative; new methods will have to be found to detect the disorder and, better yet, to predict its outcome. Along with such biomarkers must come information about the best course of preventative therapy. Current strategies of broad-spectrum or selective B cell immunosuppression carry significant long-term risk. 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