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Available online 11 January 2014

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most NMO patients have autoantibodies against aquaporin-4 (AQP4) or NMO-IgG, dramatically changed our

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tral nervous system (CNS), predominately affecting the spinal cord and inance usually higher than observed in MS. The median age of onset is

studies reported NMOexico, 1.42.8 in the

Autoimmunity Reviews 13 (2014) 531533

Contents lists available at ScienceDirect

Autoimmuni

e lsoptic neuritis occurring even years apart [3]. In light of the identicationin 2004 of a serological marker for NMO the aquaporin-4 antibody

USA, and 4.4 in Denmark. In Japan, the NMO/MS ratio is higher than inwestern countries [6].(AQP4 Ab), or NMO-IgG, great progress has been made in the under-(MS), consisting of acutemyelitis and optic neuritis. Subsequently, a re-lapsing form of NMO was recognized, with episodes of myelitis and

especially in Asian countries. Population basedprevalence of 0.5 per 100,000 in Cuba, 1.0 in Moptic nerves.The syndrome was described rst by Allbutt in 1870 [1], but Devic,

who reviewed 16 cases in 1894, rst coined the term neuromyelitisoptica [2]. Based on his descriptions, NMO was then considered asevere monophasic disorder and rare variant of Multiple Sclerosis

also higher than MS, with a median of 3545 years [3]. The disorder ismainly sporadic, though familial cases have been reported in 3% insome cohorts [5].

Cases of NMO have been described throughout the world, althoughit is found to be more prevalent in areas of non-Caucasian populations,standing of pathobiology, clinical spectrumnow considered a distinct autoimmune disord

Corresponding author at: Department of NeuroloHashomer, Israel, afliated to the Sackler Faculty of Medic

E-mail address: jchapman@post.tau.ac.il (J. Chapman)

1568-9972/$ see front matter 2014 Elsevier B.V. All rihttp://dx.doi.org/10.1016/j.autrev.2014.01.034une disorder of the cen- NMO is more prevalent in women thanmen, with a female predom-Neuromyelitis optica (NMO), is an autoimm4. The role of NMO-IgG . . . . . .5. Diagnostic criteria . . . . . . .6. Conclusions . . . . . . . . . .References . . . . . . . . . . . . .

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532

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2. Epidemiology3. Clinical manifestations . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5311. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . .Keywords:Neuromyelitis opticaAutoimmune CNS diseasesNMO-IgG antibodiesAutoimmunityDiagnostic criteria

understanding of the disease. The nding of NMO-IgG revealed wider array of clinical presentations, includingpatients with recurrent ON of TM alone, now considered part of the NMO spectrum. Furthermore, symptomsother than optic-spinal involvement and the presence of brain lesions, do not exclude the diagnosis of NMO astraditionally accepted.We present an overview of the epidemiology, clinicalmanifestations and current diagnos-tic criteria for NMO and NMO spectrum disorders.

2014 Elsevier B.V. All rights reserved.

ContentsReview

Diagnosis and classication of neuromyeli

Tali Drori a, Joab Chapman a,b,a Department of Neurology, Sheba Medical Center, afliated to the Sackler Faculty of Medicineb The Zabludowicz Center for Autoimmune diseases, Sheba Medical Center, Tel Hashomer, Isra

a b s t r a c ta r t i c l e i n f o

Article history:Accepted 13 November 2013

Neuromyelitis optica (NMO)(ON) and transverse myelit

j ourna l homepage: www.and treatment. NMO iser [4].

gy, Sheba medical center, Teline, Tel Aviv University, Israel..

ghts reserved.optica (Devic's Syndrome)

Aviv University, Tel Hashomer, Israel

n autoimmune disorder, predominantly characterized by severe optic neuritisM). Historically considered a variant of Multiple sclerosis, the discovery thatty Reviews

ev ie r .com/ locate /aut rev3. Clinical manifestations

The hallmarks of NMO are optic neuritis, which is often bilaterally si-multaneous or sequential and longitudinally extensive transverse mye-litis. Symptoms include unilateral and bilateral loss of visual acuity,

severe paraplegia or tetraplegia, with a well dened sensory level andsphincter dysfunction and pain and tonic spasms of the trunk and ex-tremities [3]. Extension of the lesions to the brain stem may cause hic-cups, nausea and even respiratory failure [7]. Cases of hypothalamicpituitary axis dysfunction, manifesting as hyponatremia, hyperthermia,hypothyroidism and hyperprolactinemia has also been described [8], aswell as encephalopathymimicking posterior reversible encephalopathysyndrome (PRESS) [9].

Clinical attacks generally progress over days,with varying degrees ofrecovery within months. Most patients endure some residual disability,which increases with recurring attacks [3]. NMO has a generally poorprognosis and response to therapy compared with MS.

4. The role of NMO-IgG

Signicant breakthrough in the research of NMO was made by Len-

[5] Matiello M, Kim HJ, Kim W, et al. Familial neuromyelitis optica. Neurology2010;75:3105.

[6] Uzawa A, Mori M, Kuwabara S. Neuromyelitis optica: concept, immunology andtreatment. J clinical neurosci 2013. http://dx.doi.org/10.1016/j.jocn.2012.12.022.

[7] Misu T, Fujihara K, Nakashima L, Sato S, Itoyama Y. Intractable hiccup and nauseawith periaqueductal lesions in neuromyelitis optica. Neurology 2005;65:147982.

[8] Poppe AY, Lapierre Y, Melancon D, et al. Neuromyelitis optica with hypothalamicinvolvement. Multiple sclerosis 2005;76:61721.

[9] Maganda SM, Matiello M, Pittock SJ, et al. Posterior reversible encephalopathysyndrome in neuromyelitis optica spectrum disorders. Neurology 2009;72:7127.

[10] Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neu-romyelitis optica: distinction form multiple sclerosis. Lancet 2004;364:210612.

[11] Verkman AS. Aquaporins in clinical medicine. Annu Rev Med 2012;63:30316.[12] Papadopoulos M, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol

532 T. Drori, J. Chapman / Autoimmunity Reviews 13 (2014) 531533non et al. in 2004, when they described a circulating IgG auto-antibody(NMO-IgG) in patients with neuromyelitis optica, that was absent inthose with multiple sclerosis. The sensitivity and specicity of theNMO-IgG in identifying NMO in their series was 73% and 91%, respec-tively [10].

A year later, its target was identied as the astrocyte water channelprotein aquaporin 4 (AQP4) [4]. AQP4 is expressed strongly in astro-cytes in the brain, spinal cord and optic nerve, but also in epithelialcells outside the CNS, such as stomach and kidney [11]. Pathologicalchanges attributed to NMO occur mostly in the spinal cord and opticnerve, and to a lesser extent in the brain [12]. Pathogenesis occurs bycomplement-mediated astrocyte damage, cascading to leukocyte inl-tration, oligodendrocyte death and neuronal cell damage [13]. The re-sult is necrosis of major CNS cell types, explaining the poor recoveryand major neurological decits.

5. Diagnostic criteria

Due to poorer prognosis than MS and different treatment ap-proaches, early diagnosis of NMO is essential. In 1999, Wingerchuket al [3] proposed diagnostic criteria with three absolute requirements:optic neuritis, acute myelitis and the lack of symptoms involving otherCNS regions. Diagnosis requires all absolute criterion and one majorsupportive criteria or two minor supportive criteria (Table 1).

However, these criteria failed to capture patients with symptomsother than opticspinal involvement or whose clinical course wascompatible with NMO, but brain MRI lesions met the criteria for MS.On the other hand, patients diagnosed initially as NMO based on an ini-tial negative brain MRI, may later fulll the criteria for MS [14]. Revisedcriteria for the diagnosis of NMOwere published in 2006 [14], incorpo-rating the then recently discovered antibody NMO-IgG. The objectivewas to include a biomarker that would increase diagnostic certainty

Table 1Diagnostic criteria for NMO, Wingerchuk et al. 1999.

Diagnosis requires all absolute criteria and onemajor supportive criterion or twominorsupportive criteria.

Absolute criteria:Optic neuritisAcute myelitisNo evidence of clinical disease outside of the optic nerve and spinal cord

Major supportive criteria:1. Brain MRI at disease onset does not fulll MS imaging criteria2. Spinal cord MRI shows a lesion extending over 3 vertebral segments3. CSF is signicant for 50 WBC/mm3 or 5 neutrophils/mm3

Minor supportive criteria:1. Bilateral optic neuritis2. Severe optic neuritis with visual acuity worse than 20/200 in at least one eye3. Severe, xed, attack related weakness in one or more limbs.and denition of the NMO spectrum. The proposed criteria dened def-inite NMO as consisting of optic neuritis and acute myelitis, with two ofthree additionally supportive criteria, consisting of longitudinally exten-sive spinal cord lesions, brain MRI not meeting the diagnosis of MS andseropositive NMO (Table 2). The criteria were innovative in removingthe restriction on CNS involvement beyond the optic nerves and spinalcord and emphasizing the specicity of spinal cord lesions and NMO-IgG seropositivity.

The discovery of the NMO-IgG antibody broadened the clinical spec-trum of NMO to include patients who have only optic neuritis or trans-verse myelitis (neuromyelitis optica spectrum disorders [NMOSDs]),thus preventing a misdiagnosis of MS [15]. NMOSDs may be consideredas an early or limited manifestation of NMO, guiding treatmentaccordingly.

NMO-IgG seropositivity also predicts relapse and conversion toNMO in patients with recurrent optic neuritis [16] and a single attackof longitudinally extensive transverse myelitis [17].

The question of seronegative NMO raises further debate. Reportsshow that seropositive NMOdiffers from seronegative disease both clin-ically and epidemiologically, reecting strong predominance inwomen,frequent association with other autoimmune disorders, more frequentand severe attacks and higher spinal cord lesion load [18]. Whether se-ronegative disease represents optico-spinal MS, or reects pathogenicdiversity in NMO, such as seronegative myasthenia gravis, it is stillunknown [19].

6. Conclusions

Our understanding of NMOhas rapidly changed over the passing de-cade. Fromamonophasic to anMS-like disease, we've come to acknowl-edge a severe, relapsing antibody-mediated autoimmune disorder.Great heterogeneity still exists in this rare disease, making furtherdebate on advancing diagnostic criteria relevant in guiding futuretreatment.

References

[1] Allbutt TC. On the ophthalmoscopic signs of spinal disease. Lancet 1870;1:768.[2] Devic E. Myelite subaigue compliquee de neurite opticqoe. Bull Med 1894;8:10334.[3] Wingerchuk DM, Hogancamp WF, Hogancamp WF, Obrien PC, Weinshenker BG.

The clinical course of neuromyelitis optica (Devic's syndrome). Neurology1999;53:110718.

[4] Lennon VA, Kryzer TJ, Pittock SJ, Verkma AS, Hinson SR. IgG marker of optic spinalmultiple sclerosis binds to the aquaporin-4 water channel. J Exp Med2005;202:4737.

Table 2Revised diagnostic criteria for NMO, Wingerchuk et al. 2006.

Denite NMO:

Optic neuritisAcute myelitis

At least two of three supportive criteria:1. Contiguous spinal cord MRI lesion extending over 3 vertebral segments2. Brain MRI not meeting diagnostic criteria for multiple sclerosis3. NMO-IgG seropositive status.2012;11:53544.

[13] Retelade J, Verkman AS. Neuromyelitis optica: aquaporin-4 based pathogenesismechanisms and new therapies. Int J Biochem Cell Biol 2012;44:151930.

[14] Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised di-agnostic criteria for neuromyelitis optica. Neurology 2006;66:14859.

[15] Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spec-trum of neuromyelitis optica. Lancet Neurol 2007;6:80515.

[16] Matiello M, Lennon VS, Jacob A, et al. NMO-IgG predicts the outcome of recurrentoptic neuritis. Neurology 2008;70:2197200.

[17] Weinshenker BG, Wingerchuk DM, Vukusic S, et al. Neuromyelitis optica IgG pre-dicts relapse after longitudinally extensive transverse myelitis. Ann Neurol2006;59:5669.

[18] Jacob A, Mckeon A, Nakashima I, et al. Current concept of neuromyelitisoptica (NMO) and NMO spectrum disorders. J Neurol Neurosurg Psychiatry2013;84:92230.

[19] Akmar-Demir G, Tuzun E, Waters P, et al. Prognostic implications of aquaporin-4antibody status in neuromyelitis optica patients. J Neurol 2011;258:46470.

533T. Drori, J. Chapman / Autoimmunity Reviews 13 (2014) 531533

Diagnosis and classification of neuromyelitis optica (Devic's Syndrome)1. Introduction2. Epidemiology3. Clinical manifestations4. The role of NMO-IgG5. Diagnostic criteria6. ConclusionsReferences