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Neuromyelitis Optica

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  Neuromyelitis Optica Mark J. Morrow, MD, Dean Wingerchuk, MD, MSc, FRCP(C) Abstract:  Neuromyelitis optica (NMO) is a disabling in 󿬂 am-matory condition that targets astrocytes in the optic nervesand spinal cord. Neuro-ophthalmologists must be particularly aware of this disorder because about half of patients presentas isolated unilateral optic neuritis months or years before adisease-de 󿬁 ning and often crippling bout of myelitis. NMO iseasily confused with multiple sclerosis because it is charac-terized by relapses that lead to stepwise accrual of de 󿬁 cits.The best predictor of conversion from optic neuritis to clinicalde 󿬁 nite NMO is the presence of a serum antibody toaquaporin-4 called NMO-IgG. However, this test is currently only about 75% sensitive. Suspicion of NMO should be highin patients who present with vision of light perception or worseor who are left with acuity of 20/50 or worse after opticneuritis and in those with simultaneous bilateral opticneuritis or recurrent attacks. Acute NMO relapses aregenerally treated with high-dose intravenous steroids, withplasma exchange often used as a rescue therapy for thosewho do not respond. Preventative strategies against relapsescurrently use broad-spectrum or selective B-lymphocyteimmune suppression, but their use is based on small,generally uncontrolled studies. Hopefully, the future will bringmore sensitive tools for de 󿬁 ning risk and predicting outcome,as well as more targeted and effective forms of therapy. Journal of Neuro-Ophthalmology 2012;32:154 – 166doi: 10.1097/WNO.0b013e31825662f1© 2012 by North American Neuro-Ophthalmology Society N  euromyelitis optica (NMO, Devic disease) is a multi-focal central nervous system (CNS) demyelinating illness in which severe in 󿬂 ammatory attacks on the opticnerves and spinal cord predominate. Until recently, someconsidered NMO to be a variant of multiple sclerosis (MS).The discovery of a highly speci 󿬁 c serum autoantibody (NMO-IgG) in 2004, however, helped prove that NMOis 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. Thisinsight has spurred a tremendous surge of interest in clinicaland scienti 󿬁 c aspects of NMO. Its most common neuro-ophthalmic presentation is unilateral optic neuritis, whichoften results in severe residual visual loss. No feature has yetbeen shown to fully distinguish optic nerve involvement inNMO from that in MS. Current clinical challenges includedeciding which optic neuritis patients to screen for theNMO-IgG antibody and how to manage those with positiveresults. At present, there is no reliable method to predictpoor 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 ages47 and 52 years, she experienced 4 attacks of unilateral opticneuritis (3 in right eye and 1 in left eye). These were treated  with steroids, but recovery was limited, leaving her no lightperception in the right eye and 20/20 in the left eye withbilateral optic atrophy. Brain MRI was unremarkable. Spinalcord MRI showed a 3-segment T2-intense lesion from C2 toC5. NMO-IgG antibody was positive. Comment  One or more bouts of optic neuritis may precede a disease-de 󿬁 ning attack of myelitis by months or years in NMO. PATHOGENESIS Myelin-bearing oligodendrocytes are the primary in 󿬂 amma-tory target in MS, but astrocytes are lost  󿬁 rst in NMO (1). AQP4, the predominant CNS water channel, localizes toastrocyte foot processes at the blood  – brain barrier (2). Itappears to be critical in maintaining water homeostasis in Department of Neurology (MJM), Harbor-UCLA Medical Center,Torrance, California; and the Department of Neurology (DW), MayoClinic Scottsdale.Disclosures: Dr. M. J. Morrow has received research support fromNovartis and Biogen-Idec and has served as speaker/consultant for Biogen-Idec, EMD Serono, Teva Neuroscience, the AmericanCollege 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, MDRandy H. Kardon, MD, PhD Copyright © North American Neuro- O  phthalmology Society.   Unauthorized reproduction of this article is prohibited.    settings of physiologic stress. AQP4 heterotetramers assembleinto orthogonal array particles that are probably the mainbinding target of the NMO-IgG antibody. Differentialexpression of these isoforms may explain greater occurrenceof NMO lesions in the optic nerve and spinal cord thanelsewhere (3). Antibodies to AQP4 may enter the CNS acrosspermeable portions of the blood  – brain barrier, where they  would immediately encounter astrocytes and could trigger cell-dependent cytotoxicity (4). Acute NMO lesions inpatients 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 NMObecause 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  󿬁 ndings of NMO-associated opticneuritis include in 󿬁 ltration with lymphocytes, macrophages,and monocytes and venular in 󿬂 ammation (8,9). Long-termsequelae 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 theretinal nerve  󿬁 ber layer (RNFL) and disappearance of retinalganglion cell bodies attest to retrograde degeneration after axonal loss in the optic nerve (9). Green and Cree (11) havereported visible retinal vascular changes in NMO eyes, in-cluding arteriolar narrowing and   “ frosting. ”  This suggeststhat retinal ischemic or in 󿬂 ammatory damage might attimes contribute to visual loss. However, Kerrison et al(9) did not  󿬁 nd active retinal in 󿬂 ammation concurrent withNMO-associated optic neuritis in two cases.Putative animal models have been created by adminis-tering NMO-IgG. Passive transfer of the antibody producescentral lesions if it is injected directly into the CNS withcomplement (12) or when it is infused peripherally after  󿬁 rst interrupting the blood  – brain barrier (13 – 15). Althoughthese 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) solidi 󿬁 ed the term  neuromyelitis optica   over a century ago, describing a monophasic disorder  with optic neuritis and transverse myelitis of simultaneousonset. 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 distinctionas a clinical and pathophysiologic entity. Most importantly,it was recognized that NMO follows a relapsing rather thanmonophasic course in over 70% of cases (Table 1) (18,19).NMO series from around the world have suggested consistent demographics that largely parallel MS. Womenare much more commonly affected than men, with femaleto male ratios of at least 3:1. Median age of onset isgenerally 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 illnessand has a benign course (20). More recent pediatric caseseries, however, chie 󿬂 y describe relapsing disease withmedian ages of onset of 10 – 14 years and strong femalepredominance (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 100,000person-years (25 – 28). The reported proportion of de 󿬁 nite TABLE 1.  Comparison of clinical features of MS and NMO MS NMOInitial clinical course 85% relapsing – remitting 80% – 90% relapsing – remitting15% primary progressive 10% – 20% monophasicSecondary progressive course Often RareBrain MRI lesions Periventricular, subcortical(Barkhof criteria)If seen, symmetrical hypothalamic, brainstemResemble MS in about 10%Spinal cord MRI lesions 1 – 2 segments long  . 3 segments acutely (can resolve or shrink)CSF WBCs during relapses  , 50/mm 3 , all mononuclear Often . 50/mm 3 , polymorphonuclear componentCSF oligoclonal bands About 85% 15% – 30%Systemic autoimmunediseaseOccasional CommonSeverity of relapses Usually mild to moderate Usually moderate to severeRecovery from relapses Usually fair to good Usually fair to poor Response to interferons Usually helpful Can worsen disease CSF, cerebrospinal  󿬂 uid; 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- O  phthalmology Society.   Unauthorized reproduction of this article is prohibited.    NMO among adults and children with in 󿬂 ammatory de-myelinating diseases (including MS) varies widely, witha range of 1% – 22% in a group of recent studies (21,28 – 32). The authors ’  experiences suggest a value toward thelower end of this range for their clinic populations in theUnited 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 assessmentshowed 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 israre, 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 includeDPB1*0501 in Asians and DRB1*0301 in Caucasians(36,37). Analysis of   AQP4   gene single-nucleotide polymor-phisms did not detect variations associated with generalNMO susceptibility (38).NMO-related disability accrues almost exclusively fromincomplete recovery of relapses. A secondary progressivecourse is common in MS but rare in NMO (39). Patients with monophasic NMO tend to have worse initial attacksthan those with relapsing disease but better long-term prog-nosis. Individual attacks tend to be more severe and leavemore residual de 󿬁 cits than in MS. In one series, half of patients with NMO had severe visual impairment in at least1 eye or required ambulatory aids within 5 years of onset(40). A small group of patients with NMO have a morefavorable course (41). Relapsing NMO tends to progressmore slowly in children than in adults, with lower annual-ized relapse rates (22). Higher initial rates of relapse withmore 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). Theremaining half usually present as isolated myelitis withnumbness, 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 acuteattacks of MS, cerebrospinal  󿬂 uid (CSF) typically containsfewer than 50 white blood cells per cubic millimeter, mostly lymphocytes. In contrast, NMO attacks often produce dra-matic CSF pleocytosis with signi 󿬁 cant numbers of neutro-phils or eosinophils. Oligoclonal bands are found in theCSF of about 85% of MS patients but 30% or fewer of those with NMO (46). Although many patients with NMOhave brain MRI abnormalities, these are usually mild and nonspeci 󿬁 c (47). Up to 10% of antibody-positive, clinically de 󿬁 nite patients with NMO have MRI abnormalities con-sistent with MS (Fig. 1A). Others have lesions in uniquelocations like the hypothalamus and caudal medulla (seebelow). Spinal cord MRI features of MS and NMO oftendiffer signi 󿬁 cantly. Acute MS-associated cord lesions areusually 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 FLAIRMRI of the brain reveals periventricular lesions resembling MS.  B . Sagittal short T1-inversion recovery (STIR) MRI showslongitudinally 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- O  phthalmology Society.   Unauthorized reproduction of this article is prohibited.    typically 3 or more segments long (Fig. 1B). Acute NMOlesions tend to be centrally located within the cord, causecord expansion, and enhance with gadolinium. Nonacutespinal cord MRI can be misleading because elongated NMO lesions can shrink into smaller spots that are typicalof MS (Fig. 2).The  󿬁 rst report of the NMO-IgG antibody, using anindirect immuno 󿬂 uoresence assay, found it to be 73%sensitive and 91% speci 󿬁 c for distinguishing clinically de 󿬁 ned NMO from MS (33). These data have been con- 󿬁 rmed in widespread patient populations, although anti-body positivity has ranged as low as 50% depending onthe speci 󿬁 c test used. An enzyme-linked immunosorbentassay is now commercially available. The highest sensitiv-ities, about 75%, are attained with assays that detect IgGbinding to cells expressing recombinant AQP4 (48). CSF AQP4 antibodies have been detected in some seronegativepatients (49). Widely accepted clinical and laboratory crite-ria were developed for NMO in 1999 (18) and thenupdated 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 radiologiccharacteristics associated with NMO. Certain brain MRIlesions that would be atypical for MS have proven to becommon in NMO. These aggregate in regions with a highdensity of AQP4 and include caudal medullary lesionsthat present with hiccups and nausea and diencephaliclesions that cause somnolence and endocrine disturbances(Figs. 2, 3) (51 – 53). Large cerebral white matter lesionssuggesting tumefactive MS (54) or posterior reversibleencephalopathy syndrome (55) (PRES) may also occur inNMO (Fig. 4). Patients with features of NMO often haveserologic 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 ashaving   “ NMO spectrum disorder  ”  (57). This at-risk statemight be considered comparable to clinically isolated syn-drome 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 my-elitis, 55% of those who were seropositive developed recurrentmyelitis or NMO-de 󿬁 ning optic neuritis within a year (58).No seronegative patient had such an event. Given the highrisk for future attacks with serious residua, detection of NMO-IgG may allow for early initiation of preventative therapy. NEURO-OPHTHALMIC CONSEQUENCESOF NMO Optic neuritis is a required element for clinically de 󿬁 niteNMO 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 opticneuritis and a disease-de 󿬁 ning attack of myelitis averaged about 2 years in 5 large series of patients, with ranges froma few months to decades (18,19,45,59,60). Recurrentattacks of optic neuritis may occur before or after myelitisand lead to a stepwise loss in visual function. Table 3 sum-marizes visual outcomes in several large NMO series. TheOptic 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 inplace during the ONTT, and it is not known how many patients actually converted to NMO rather than MS; only 1patient was known to have NMO with certainty (62,63). FIG. 2.  T2 sagittal MRI demonstrates NMO-typical caudalmedullary 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 – C5and 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 neuritisTransverse myelitisSupportive (at least 2 of the following 3)Brain MRI: normal or lesions not meeting criteria for MSSpinal cord MRI: lesion extending continuously over 3 or more vertebral segmentsNMO-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- O  phthalmology Society.   Unauthorized reproduction of this article is prohibited.  
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