Autoimmunity Reviews 13 (2014) 531533

Contents lists available at ScienceDirect

Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Review

Diagnosis and classication of neuromyelitis optica (Devic's Syndrome)

Tali Drori a, Joab Chapman a,b,
a
b

Department of Neurology, Sheba Medical Center, afliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
The Zabludowicz Center for Autoimmune diseases, Sheba Medical Center, Tel Hashomer, Israel

a r t i c l e

i n f o

a b s t r a c t

Article history:
Accepted 13 November 2013
Available online 11 January 2014

Neuromyelitis optica (NMO) is an autoimmune disorder, predominantly characterized by severe optic neuritis
(ON) and transverse myelitis (TM). Historically considered a variant of Multiple sclerosis, the discovery that
most NMO patients have autoantibodies against aquaporin-4 (AQP4) or NMO-IgG, dramatically changed our
understanding of the disease. The nding of NMO-IgG revealed wider array of clinical presentations, including
patients with recurrent ON of TM alone, now considered part of the NMO spectrum. Furthermore, symptoms
other than optic-spinal involvement and the presence of brain lesions, do not exclude the diagnosis of NMO as
traditionally accepted. We present an overview of the epidemiology, clinical manifestations and current diagnostic criteria for NMO and NMO spectrum disorders.
2014 Elsevier B.V. All rights reserved.

Keywords:
Neuromyelitis optica
Autoimmune CNS diseases
NMO-IgG antibodies
Autoimmunity
Diagnostic criteria

Contents
1.
Introduction . . . . .
2.
Epidemiology . . . .
3.
Clinical manifestations
4.
The role of NMO-IgG .
5.
Diagnostic criteria . .
6.
Conclusions . . . . .
References . . . . . . . .

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

.
.
.
.
.
.
.

531
531
531
532
532
532
532

1. Introduction

2. Epidemiology

Neuromyelitis optica (NMO), is an autoimmune disorder of the central nervous system (CNS), predominately affecting the spinal cord and
optic nerves.
The syndrome was described rst by Allbutt in 1870 [1], but Devic,
who reviewed 16 cases in 1894, rst coined the term neuromyelitis
optica [2]. Based on his descriptions, NMO was then considered a
severe monophasic disorder and rare variant of Multiple Sclerosis
(MS), consisting of acute myelitis and optic neuritis. Subsequently, a relapsing form of NMO was recognized, with episodes of myelitis and
optic neuritis occurring even years apart [3]. In light of the identication
in 2004 of a serological marker for NMO the aquaporin-4 antibody
(AQP4 Ab), or NMO-IgG, great progress has been made in the understanding of pathobiology, clinical spectrum and treatment. NMO is
now considered a distinct autoimmune disorder [4].

NMO is more prevalent in women than men, with a female predominance usually higher than observed in MS. The median age of onset is
also higher than MS, with a median of 3545 years [3]. The disorder is
mainly sporadic, though familial cases have been reported in 3% in
some cohorts [5].
Cases of NMO have been described throughout the world, although
it is found to be more prevalent in areas of non-Caucasian populations,
especially in Asian countries. Population based studies reported NMO
prevalence of 0.5 per 100,000 in Cuba, 1.0 in Mexico, 1.42.8 in the
USA, and 4.4 in Denmark. In Japan, the NMO/MS ratio is higher than in
western countries [6].

Corresponding author at: Department of Neurology, Sheba medical center, Tel

Hashomer, Israel, afliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel.
E-mail address: jchapman@post.tau.ac.il (J. Chapman).
1568-9972/$ see front matter 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.autrev.2014.01.034

3. Clinical manifestations
The hallmarks of NMO are optic neuritis, which is often bilaterally simultaneous or sequential and longitudinally extensive transverse myelitis. Symptoms include unilateral and bilateral loss of visual acuity,

532

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

severe paraplegia or tetraplegia, with a well dened sensory level and

sphincter dysfunction and pain and tonic spasms of the trunk and extremities [3]. Extension of the lesions to the brain stem may cause hiccups, nausea and even respiratory failure [7]. Cases of hypothalamic
pituitary axis dysfunction, manifesting as hyponatremia, hyperthermia,
hypothyroidism and hyperprolactinemia has also been described [8], as
well as encephalopathy mimicking posterior reversible encephalopathy
syndrome (PRESS) [9].
Clinical attacks generally progress over days, with varying degrees of
recovery within months. Most patients endure some residual disability,
which increases with recurring attacks [3]. NMO has a generally poor
prognosis and response to therapy compared with MS.
4. The role of NMO-IgG
Signicant breakthrough in the research of NMO was made by Lennon et al. in 2004, when they described a circulating IgG auto-antibody
(NMO-IgG) in patients with neuromyelitis optica, that was absent in
those with multiple sclerosis. The sensitivity and specicity of the
NMO-IgG in identifying NMO in their series was 73% and 91%, respectively [10].
A year later, its target was identied as the astrocyte water channel
protein aquaporin 4 (AQP4) [4]. AQP4 is expressed strongly in astrocytes in the brain, spinal cord and optic nerve, but also in epithelial
cells outside the CNS, such as stomach and kidney [11]. Pathological
changes attributed to NMO occur mostly in the spinal cord and optic
nerve, and to a lesser extent in the brain [12]. Pathogenesis occurs by
complement-mediated astrocyte damage, cascading to leukocyte inltration, oligodendrocyte death and neuronal cell damage [13]. The result is necrosis of major CNS cell types, explaining the poor recovery
and major neurological decits.
5. Diagnostic criteria
Due to poorer prognosis than MS and different treatment approaches, early diagnosis of NMO is essential. In 1999, Wingerchuk
et al [3] proposed diagnostic criteria with three absolute requirements:
optic neuritis, acute myelitis and the lack of symptoms involving other
CNS regions. Diagnosis requires all absolute criterion and one major
supportive criteria or two minor supportive criteria (Table 1).
However, these criteria failed to capture patients with symptoms
other than opticspinal involvement or whose clinical course was
compatible with NMO, but brain MRI lesions met the criteria for MS.
On the other hand, patients diagnosed initially as NMO based on an initial negative brain MRI, may later fulll the criteria for MS [14]. Revised
criteria for the diagnosis of NMO were published in 2006 [14], incorporating the then recently discovered antibody NMO-IgG. The objective
was to include a biomarker that would increase diagnostic certainty

Table 1
Diagnostic criteria for NMO, Wingerchuk et al. 1999.
Diagnosis requires all absolute criteria and one major supportive criterion or two minor
supportive criteria.
Absolute criteria:
Optic neuritis
Acute myelitis
No 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 criteria
2. Spinal cord MRI shows a lesion extending over 3 vertebral segments
3. CSF is signicant for 50 WBC/mm3 or 5 neutrophils/mm3
Minor supportive criteria:
1. Bilateral optic neuritis
2. Severe optic neuritis with visual acuity worse than 20/200 in at least one eye
3. Severe, xed, attack related weakness in one or more limbs.

Table 2
Revised diagnostic criteria for NMO, Wingerchuk et al. 2006.
Denite NMO:
Optic neuritis
Acute myelitis
At least two of three supportive criteria:
1. Contiguous spinal cord MRI lesion extending over 3 vertebral segments
2. Brain MRI not meeting diagnostic criteria for multiple sclerosis
3. NMO-IgG seropositive status.

and denition of the NMO spectrum. The proposed criteria dened definite NMO as consisting of optic neuritis and acute myelitis, with two of
three additionally supportive criteria, consisting of longitudinally extensive spinal cord lesions, brain MRI not meeting the diagnosis of MS and
seropositive NMO (Table 2). The criteria were innovative in removing
the restriction on CNS involvement beyond the optic nerves and spinal
cord and emphasizing the specicity of spinal cord lesions and NMOIgG seropositivity.
The discovery of the NMO-IgG antibody broadened the clinical spectrum of NMO to include patients who have only optic neuritis or transverse myelitis (neuromyelitis optica spectrum disorders [NMOSDs]),
thus preventing a misdiagnosis of MS [15]. NMOSDs may be considered
as an early or limited manifestation of NMO, guiding treatment
accordingly.
NMO-IgG seropositivity also predicts relapse and conversion to
NMO in patients with recurrent optic neuritis [16] and a single attack
of longitudinally extensive transverse myelitis [17].
The question of seronegative NMO raises further debate. Reports
show that seropositive NMO differs from seronegative disease both clinically and epidemiologically, reecting strong predominance in women,
frequent association with other autoimmune disorders, more frequent
and severe attacks and higher spinal cord lesion load [18]. Whether seronegative disease represents optico-spinal MS, or reects pathogenic
diversity in NMO, such as seronegative myasthenia gravis, it is still
unknown [19].
6. Conclusions
Our understanding of NMO has rapidly changed over the passing decade. From a monophasic to an MS-like disease, we've come to acknowledge a severe, relapsing antibody-mediated autoimmune disorder.
Great heterogeneity still exists in this rare disease, making further
debate on advancing diagnostic criteria relevant in guiding future
treatment.
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). Neurology
1999;53:110718.
[4] Lennon VA, Kryzer TJ, Pittock SJ, Verkma AS, Hinson SR. IgG marker of optic spinal
multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med
2005;202:4737.
[5] Matiello M, Kim HJ, Kim W, et al. Familial neuromyelitis optica. Neurology
2010;75:3105.
[6] Uzawa A, Mori M, Kuwabara S. Neuromyelitis optica: concept, immunology and
treatment. 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 nausea
with periaqueductal lesions in neuromyelitis optica. Neurology 2005;65:147982.
[8] Poppe AY, Lapierre Y, Melancon D, et al. Neuromyelitis optica with hypothalamic
involvement. Multiple sclerosis 2005;76:61721.
[9] Maganda SM, Matiello M, Pittock SJ, et al. Posterior reversible encephalopathy
syndrome in neuromyelitis optica spectrum disorders. Neurology 2009;72:7127.
[10] Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis 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
2012;11:53544.

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

[13] Retelade J, Verkman AS. Neuromyelitis optica: aquaporin-4 based pathogenesis
mechanisms and new therapies. Int J Biochem Cell Biol 2012;44:151930.
[14] Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:14859.
[15] Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:80515.
[16] Matiello M, Lennon VS, Jacob A, et al. NMO-IgG predicts the outcome of recurrent
optic neuritis. Neurology 2008;70:2197200.

533

[17] Weinshenker BG, Wingerchuk DM, Vukusic S, et al. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol
2006;59:5669.
[18] Jacob A, Mckeon A, Nakashima I, et al. Current concept of neuromyelitis
optica (NMO) and NMO spectrum disorders. J Neurol Neurosurg Psychiatry
2013;84:92230.
[19] Akmar-Demir G, Tuzun E, Waters P, et al. Prognostic implications of aquaporin-4
antibody status in neuromyelitis optica patients. J Neurol 2011;258:46470.