Neuromyelitis optica (NMO, Devic disease) is a multifocal 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.
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.
One or more bouts of optic neuritis may precede a disease-defining attack of myelitis by months or years in NMO.
Myelin-bearing oligodendrocytes are the primary inflammatory 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 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 paranodal regions (4). NMO lesions show vasculocentric deposition 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 endothelial proliferation, glial proliferation or loss, and demyelination 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, including 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 administering 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 monophasic 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 prevalence 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 NMO among adults and children with inflammatory demyelinating 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 proportion of CNS demyelinating disease in non-Caucasians, including African Americans, Hispanics, Afro-Brazilians, black Africans, Asians, and Native Americans. A high percentage of Japanese patients thought to have MS have predominant 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 antigens associated with increased NMO risk include DPB1*0501 in Asians and DRB1*0301 in Caucasians (36,37). Analysis of AQP4 gene single-nucleotide polymorphisms 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 prognosis. 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 annualized 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 dramatic CSF pleocytosis with significant numbers of neutrophils 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 consistent 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 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 confirmed in widespread patient populations, although antibody positivity has ranged as low as 50% depending on the specific test used. An enzyme-linked immunosorbent assay is now commercially available. The highest sensitivities, 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 criteria 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 erythematosus, Sjogren syndrome, or other autoimmune conditions (56). Because these patients are commonly seropositive for NMO-IgG, it is likely that their systemic autoimmune condition 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 syndrome in patients who have had a single episode consistent with demyelination and brain MRI abnormalities suggestive of MS. In one study of patients presenting with transverse myelitis, 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 summarizes visual outcomes in several large NMO series. The Optic Neuritis Treatment Trial (ONTT) provides comparative 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). Entry demographics for the ONTT were similar to most current NMO and MS series, with a 3:1 female predominance 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 outcome 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 retrospective 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 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 between 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 demonstrate optic disk edema. In contrast to NMO, patients with CRION appear exquisitely sensitive to steroids, improving 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).
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 seronegative 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 widespread 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 concurrent 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). Retesting 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 symptomatic 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 μm in NMO versus 10–20 μm in MS (Fig. 5, Table 5) (11,90–93). Ratchford et al (91) estimated that a first attack of NMO-associated optic neuritis reduces mean RNFL thickness by 31 μm, with each subsequent attack subtracting another 10 μm. RNFL thinning is more evenly distributed around the peripapillary circumference in NMO than in MS, where it often selectively involves the temporal quadrant (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 without 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 thickness has been correlated with high- and low-contrast visual acuity, contrast sensitivity, visual fields, and overall disability (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 thickness below which visual loss occurs is similar in NMO (93) and MS (98) at about 70 μm.
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, including 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 optic chiasm and tracts (102). Spinal MRI occasionally shows small cord lesions in NMO-IgG–positive patients with isolated optic nerve disease (100).
Acute and disease-modifying treatment for NMO is limited by an absence of randomized controlled trials (103). Corticosteroids, 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 inadequately 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 immunomodulatory drugs such as beta interferon. However, interferons and other MS therapies like natalizumab and fingolimod may actually aggravate NMO (106–108). The most appropriate 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 mycophenolate 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 prednisone 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 infusions approximately every 6 months). In the absence of comparative controlled trials, it remains unclear which treatment 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).
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 seronegative; 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. There is no high-level evidence-based guidance on how aggressively to start treatment, how long to continue after the last clinical relapse, or which drugs provide the best combination of efficacy and long-term safety. A better understanding of the mechanisms by which NMO causes CNS injury will hasten development of novel targeted therapies.
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