Review

The spectrum of neuromyelitis optica

Dean M Wingerchuk, Vanda A Lennon, Claudia F Lucchinetti, Sean J Pittock, Brian G Weinshenker

Neuromyelitis optica (also known as Devics disease) is an idiopathic, severe, demyelinating disease of the central
nervous system that preferentially aects the optic nerve and spinal cord. Neuromyelitis optica has a worldwide
distribution, poor prognosis, and has long been thought of as a variant of multiple sclerosis; however, clinical,
laboratory, immunological, and pathological characteristics that distinguish it from multiple sclerosis are now
recognised. The presence of a highly specic serum autoantibody marker (NMO-IgG) further dierentiates
neuromyelitis optica from multiple sclerosis and has helped to dene a neuromyelitis optica spectrum of disorders.
NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from
peripheral B cells cause the activation of complement, inammatory demyelination, and necrosis that is seen in
neuromyelitis optica. The knowledge gained from further assessment of the exact role of NMO-IgG in the
pathogenesis of neuromyelitis optica will provide a foundation for rational therapeutic trials for this rapidly
disabling disease.

Introduction
Inammatory demyelinating diseases of the central
nervous system occur throughout the world and are the
foremost reason for non-traumatic neurological disability
in young, white adults;1 multiple sclerosis is the most
common of these disorders. The diagnosis of multiple
sclerosis requires conrmation that the symptoms and
signs of CNS white-matter involvement are disseminated
in time and space, supportive evidence from magnetic
resonance imaging and cerebrospinal uid analysis, if
needed, and the exclusion of other diagnoses (table).2
Multiple sclerosis is not associated with a specic
biomarker, and although intrathecal synthesis of
oligoclonal IgGs is characteristic of multiple sclerosis, no
target antigen has been dened;3 therefore, any relapsing
idiopathic demyelinating disease of the central nervous
system has, until recently, been diagnosed as multiple
sclerosis.4
Neuromyelitis optica (Devics disease) is an
inammatory, demyelinating syndrome of the central
nervous system that is characterised by severe attacks of

optic neuritis and myelitis, which, unlike the attacks in

multiple sclerosis, commonly spare the brain in the early
stages.5 In developed nations, neuromyelitis optica
disproportionately strikes non-white populations, in
which multiple sclerosis is rare. Whether neuromyelitis
optica is a variant of multiple sclerosis or a separate
disease has been long debated: optic neuritis, myelitis,
and inammatory demyelination are features of both
disorders.68 The traditional concept of neuromyelitis
optica was that it is a monophasic disorder, in which
near-simultaneous bilateral optic neuritis and transverse
myelitis arise. Nowadays, neuromyelitis optica is
recognised as a discrete, relapsing, demyelinating
disease, with clinical, neuroimaging, and laboratory
ndings that can distinguish it from multiple sclerosis
(table).5,9 Moreover, the detection of neuromyelitis optica
immunoglobulin G (NMO-IgG), an autoantibody, in
the serum of patients with neuromyelitis optica,
distinguishes neuromyelitis optica from other
demyelinating disorders.10 NMO-IgG binds to
aquaporin 4,11 which is the main channel that regulates

Multiple sclerosis

Neuromyelitis optica

Denition

Central nervous system symptoms and signs that

indicate the involvement of the white-matter tracts
Evidence of dissemination in space and time on the
basis of clinical or MRI ndings
No better explanation

Transverse myelitis and optic neuritis

At least two of the following: brain MRI, non-diagnostic for multiple
sclerosis; spinal cord lesion extending over three or more vertebral
segments; or seropositive for NMO-IgG

Clinical onset and course

85% remitting-relapsing
15% primary-progressive
Not monophasic

Onset always with relapse

8090% relapsing course
1020% monophasic course

Median age of onset (years)

29

39

Sex (F:M)

2:1

9:1

Secondary progressive course

Common

Rare

MRI: brain

Periventricular white-matter lesions

Usually normal or non-specic white-matter lesions; 10% unique

hypothalamic, corpus callosal, periventricular, or brainstem lesions

MRI: spinal cord

Short-segment peripheral lesions

Longitudinally extensive (3 vertebral segments) central lesions

CSF white-blood-cell number

and dierential count

Mild pleocytosis
Mononuclear cells

Occasional prominent pleocytosis

Polymorphonuclear cells and mononuclear cells

CSF oligoclonal bands

85%

1530%

Lancet Neurol 2007; 6: 80515

Department of Neurology,
Mayo Clinic College of
Medicine, Scottsdale, AZ, USA
(DM Wingerchuk MD);
Departments of Neurology
(VA Lennon PhD,
CF Lucchinetti MD,
SJ Pittock MD,
BG Weinshenker MD),
Laboratory Medicine and
Pathology (SJ Pittock,
VA Lennon), and Immunology
(VA Lennon), Mayo Clinic
College of Medicine, Rochester,
MN, USA
Correspondence to:
Dean M Wingerchuk,
Department of Neurology,
Mayo Clinic College of Medicine,
13400 East Shea Boulevard,
Scottsdale, AZ 85259, USA
wingerchuk.dean@mayo.edu

Table: Denitions and characteristics of multiple sclerosis and neuromyelitis optica

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Review

Panel 1: Neuromyelitis optica spectrum

Neuromyelitis optica
Limited forms of neuromyelitis optica
Idiopathic single or recurrent events of longitudinally extensive myelitis (3 vertebral
segment spinal cord lesion seen on MRI)
Optic neuritis: recurrent or simultaneous bilateral
Asian optic-spinal multiple sclerosis
Optic neuritis or longitudinally extensive myelitis associated with systemic autoimmune
disease
Optic neuritis or myelitis associated with brain lesions typical of neuromyelitis optica
(hypothalamic, corpus callosal, periventricular, or brainstem)

Figure 1: Spinal cord MRI in multiple sclerosis and neuromyelitis optica

A. Sagittal T2-weighted MRI of the cervical spinal cord shows typical dorsal, short-segment signal abnormalities
(arrows) characteristic of multiple sclerosis. B. Sagittal T2-weighted cervical spinal cord MRI from a patient with
acute myelitis and neuromyelitis optica shows a typical longitudinally extensive, expansile, centrally located cord
lesion that extends into the brainstem (arrows). C. On T1-weighted sagittal MRI sequences, such acute lesions
might be hypointense (arrows), which might indicate necrosis and cavitation, while showing enhancement with
intravenous gadolinium administration (arrowheads), indicative of active inammation.

water homoeostasis in the central nervous system.12

NMO-IgG is also detected in the serum of patients with
disorders related to neuromyelitis optica, including Asian
optic-spinal multiple sclerosis, recurrent myelitis
associated with longitudinally extensive spinal cord
lesions, recurrent isolated optic neuritis, and optic
neuritis or myelitis in the context of certain organ-specic
and non-organ-specic autoimmune diseases (panel 1).

Clinical features and denition

In 1894, Devic and Gault described the sine qua non
clinical characteristics of neuromyelitis optica: optic
neuritis and acute transverse myelitis. The patients
described by Devic and Gault had monophasic or
relapsing courses of neuromyelitis optica.13,14 Various
antecedents or coexisting infections, vaccinations, and
systemic autoimmune diseases have been linked to
neuromyelitis optica, but the cause of the disease is
unknown.6,8,15
The denition of neuromyelitis optica developed from
the recognition that attacks of optic neuritis are more
commonly unilateral than bilateral, and that attacks of
optic neuritis and myelitis usually occur sequentially
rather than simultaneously.5 The interval separating
disease-dening attacks of optic neuritis and myelitis can
be years or decades.5,16 Ocular pain with loss of vision,
and myelitis with severe symmetric paraplegia, sensory
loss below the lesion, and bladder dysfunction are typical
806

features of neuromyelitis optica. Cervical myelitis can

extend into the brainstem (gure 1), resulting in nausea,
hiccoughs, or acute neurogenic respiratory failure,5,1719
which is exceedingly rare in multiple sclerosis.1921 Other
symptoms typical of spinal cord demyelination that are
seen in both neuromyelitis optica and multiple sclerosis
include paroxysmal tonic spasms (recurrent, stereotypic
painful spasms of the limbs and trunk that last
2045 seconds) and Lhermittes symptom (spinal or limb
dysaesthesias caused by neck exion).5,17
MRI ndings of the brain at the onset of neuromyelitis
optica are typically normal (except for optic nerve
enhancement by intravenously administered gadolinium
during an acute attack of optic neuritis), in contrast to
multiple sclerosis, or they show non-specic, whitematter lesions that do not satisfy neuroimaging criteria
for the diagnosis of multiple sclerosis.5,16,22 An exception is
brainstem lesions, which can occur in isolation or as a
rostral extension of cervical myelitis.18,23,24 Brain lesions
that can be detected with MRI occur in 60% of patients
with neuromyelitis optica later in the course of the disease
(mean follow-upSD [6056 years]), but these lesions
are usually clinically silent.24 MRI ndings in the spinal
cord have great diagnostic utility. During neuromyelitisoptica-associated attacks of myelitis, lesions imaged with
T2-weighted MRI are longitudinally extensive, and
characteristically span three or more contiguous vertebral
segments (gure 1).5,22,25 By contrast, the myelitis attacks
typical of multiple sclerosis are asymmetric, and the
associated lesion seen with MRI rarely exceeds one or two
vertebral segments in length.26
Laboratory studies aid the distinction of neuromyelitis
optica from multiple sclerosis. Prominent CSF pleocytosis
(>5010 leucocytes/L) with a high proportion of
neutrophils is a characteristic of neuromyelitis-opticaspecic myelitis. By contrast, pleocytosis to this degree, or
a predominance of neutrophils in the CSF, is rare in typical
attacks of multiple sclerosis, in which CSF leucocyte
counts comprise mostly lymphocytes and are almost
always fewer than 5010/L.5,16,22,2729 Supernumerary
oligoclonal bands of IgG in the CSF, which signify
synthesis of intrathecal immunoglobulins, are detected in
85% of patients with multiple sclerosis30,31 but in only
1530% of patients with neuromyelitis optica.5,16,22,25,32
These clinical, MRI, serological, and other laboratory
features have been consistently found by several
independent groups,5,16,33 and are included in the revised
diagnostic criteria for neuromyelitis optica (table). The
revised criteria enable the inclusion of patients with
unilateral or sequential optic neuritis and myelitis and a
relapsing course; thereby the term neuromyelitis optica
can be applied to a broader clinical syndrome than the
one described by Devic.

Epidemiology
Neuromyelitis optica is up to nine times more prevalent
in women than it is in men (table).5,16,34,35 The median age
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Review

of onset (39 years) is older than the median age of onset

of multiple sclerosis (29 years);4 however, neuromyelitis
optica also occurs in children and elderly people.5,36,37
Despite over-representation of east Asians and other nonwhite populations worldwide, compared with multiple
sclerosis, most patients with neuromyelitis optica in the
developed world are white.5,16
Multiple sclerosis is virtually unreported in indigenous
Africans and native Americans and Canadians, and the
few occurrences of demyelinating disease in these
populations are consistent with neuromyelitis optica.3841
African-American patients with demyelinating disease
commonly have an aggressive optic-spinal syndrome,
suggestive of neuromyelitis optica. Furthermore, optic
neuritis in African-American patients can precede
neuromyelitis optica more frequently than it does in
white patients.42,43 In contrast to multiple sclerosis,
neuromyelitis optica is relatively common in non-whites
and populations with a minor European contribution to
their genetic composition, such as AfroBrazilians (15%
of cases of demyelinating disease),25 West Indians
(27%),44,45 Japanese (2030%),4649 and east Asians,
including Hong Kong Chinese (36%),50 Singaporeans
(48%),51 and Indians (1023%).52,53 There are few data
from Latin American countries other than Brazil.
Japanese investigators have long distinguished opticspinal multiple sclerosis, which is essentially identical
to neuromyelitis optica, from western multiple
sclerosis.47 The decreasing proportion of Japanese
people with multiple sclerosis who have optic-spinal
disease reported during the past 50 years might indicate
an increase in the relative frequency of western
multiple sclerosis but this change is not explained by
immigration of Europeans to Japan.47,48,54 Some
investigators have noted that the increased frequency
of multiple sclerosis in Japan after 1960 coincided with
the inuences of advanced-economy countries on food
and housing.54
There are reports of familial cases of neuromyelitis
optica but not multigenerational pedigrees: perhaps the
inheritance pattern is complex or the susceptibility alleles
have low penetrance.5557 The MHC class II allele
DPB1*0501 was associated with east Asian optic-spinal
multiple sclerosis but this allele is present in 60% of the
Japanese population.49 The MHC class II allele
DRB1*1501 is most strongly associated with multiple
sclerosis in developed countries and in patients of
Japanese ethnic origin with western multiple sclerosis;
however, this allele is not associated with east Asian
optic-spinal multiple sclerosis.47

Disease course and prognosis

8090% of patients with neuromyelitis optica have
relapsing episodes of optic neuritis and myelitis, rather
than a monophasic course.5,16,17 Relapse occurs within
1 year in 60% of patients and within 3 years in 90%.5
Monophasic neuromyelitis optica is dicult to diagnose
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because relapses can happen decades after the index

event; however, patients with nearly simultaneous
bilateral optic neuritis and myelitis are less likely to
relapse than patients who have index events that are
several weeks or months apart.17
Most relapses of neuromyelitis optica worsen over
several days and then slowly improve in the weeks or
months after the maximum clinical decit is reached.
However, recovery is usually incomplete, and most
patients follow a course of early incremental disability
due to frequent and severe relapses.5 Within 5 years of
disease onset, more than 50% of patients with relapsing
neuromyelitis optica are blind in one or both eyes or
require ambulatory help. Predictors of a worse prognosis
include the number of relapses in the rst 2 years of
disease activity, the severity of the rst attack, and,
possibly, also having systemic lupus erythematosus or a
related non-organ-specic autoimmune disorder or
autoantibodies.17,35 In 1999, before the broad spectrum of
neuromyelitis-optica-related disorders was appreciated,
the calculated 5-year survival rate for neuromyelitis optica
was 68%: all deaths were due to neurogenic respiratory
failure.5,17 By contrast, patients with multiple sclerosis
typically have mild attacks with good recovery; permanent
disability generally accrues during the later, secondary
progressive phase of multiple sclerosis.1 A secondary
progressive phase is rare in neuromyelitis optica; this is a
notable observation because it argues against the
hypothesis that secondary progression in demyelinating
diseases is primarily due to the frequency or severity of
inammatory relapses, both of which are greater in
neuromyelitis optica than multiple sclerosis.58

Immunopathology
Demyelination in neuromyelitis optica extends across
multiple sections of the spinal cord, and the necrosis and
cavitation aect the grey matter and the white matter in
spinal cord and optic nerve lesions.33,59,60 Unlike in
multiple sclerosis, eosinophils and neutrophils are
commonly found in the inammatory inltrates of active
lesions of neuromyelitis optica,38,60 and the penetrating
spinal vessels are frequently thickened and hyalinised.33,60,61
Post-mortem studies conrm that brain lesions visualised
on MRI in neuromyelitis optica patients24 have the same
immunohistochemical characteristics as spinal cord
lesions.62,63
Immunoglobulin and complement components are
deposited in a characteristic vasculocentric rim and rosette
pattern in active neuromyelitis optica lesions (gure 2).60
Immune complexes are also deposited along myelin
sheaths and within macrophages in pattern II of the four
immunopathologically dened subsets of multiple
sclerosis.64 Active neuromyelitis optica lesions are distinctly
dierent because their vasculocentric distribution of
immune complexes corresponds to the normal expression
of aquaporin 4 in the endfeet of astrocytes.65,66 Similar
lesions are seen in east Asian optic-spinal multiple
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Figure 2: Pathological and immunopathological ndings in neuromyelitis optica

A. Extensive demyelination of the grey matter and white matter at the level of the thoracic cord (Luxol fast blue-periodic acid Schi [LFB-PAS] stain for myelin; 10X).
B. Extensive axonal injury, necrosis, and associated cavitation (Bielschowsky silver impregnation; 10X). C and D. The inammatory inltrate contains perivascular and
parenchymal eosinophils and granulocytes (100X). E. Prominent vasculocentric complement activation, in a characteristic rosette and rim pattern surrounding
thickened blood vessels (immunocytochemistry for C9neo antigen [red]; 200X). F. Higher magnication (1000X) of rosette pattern of immunoglobulin deposition
(immunocytochemistry for IgG). G. Rosette pattern of C9neo antigen in a similar distribution around the same vessels as in panel F. All images were from a spinal cord
lesion from a 52 year old woman who died from active neuromyelitis optica associated with a longitudinally extensive spinal cord lesion extending from C3 to T8.

sclerosis, which further supports this disorder and

neuromyelitis optica being a single clinical entity.67 In
contrast to multiple sclerosis lesions, in which aquaporin 4
immunoreactivity is increased, aquaporin 4 is absent in
neuromyelitis optica lesions.65,68,69 A further new type of
lesion in neuromyelitis optica, seen in the spinal cord and
medullary tegmentum and extending into the area
postrema,65 shows loss of aquaporin 4 with inammation
and oedema, but neither demyelination nor necrosis.

Autoantibodies against aquaporin 4

An early clue to the role of autoimmunity in neuromyelitis
optica was the association with autoimmune diseases
such as thyroiditis, systemic lupus erythematosus, or
Sjgrens syndrome in 1040% of patients.5,16 Anti-nuclear
autoantibodies were detected in the serum of about
50% of patients with neuromyelitis optica.5,16,70 Non-organspecic autoantibodies (particularly anti-Ro) are seen
more frequently in the serum of patients with recurrent
transverse myelitis or relapsing neuromyelitis optica
(77%) than in those with monophasic disease (33%).71
Lennon and colleagues reported a serum autoantibody,
NMO-IgG, the presence of which was 73% sensitive and
91% specic for clinically dened neuromyelitis optica.10
NMO-IgG was not found in autoimmune disorders that
had no manifestations of neuromyelitis optica.70,72 NMOIgG was detected, incidentally, in 14 of 85 000 serum
samples that were screened for suspected paraneoplastic
autoimmunity; neuromyelitis optica was subsequently
veried in 12 of the 14.10 In a study from Japan, NMO-IgG
808

was found in the serum of 12 of 19 patients who were

diagnosed with the optic-spinal form of multiple sclerosis,
and in 2 of 13 patients with conventional multiple
sclerosis. However further imaging assessment of the
two seropositive patients with conventional multiple
sclerosis showed evidence of longitudinally extensive
transverse myelitis or a clinical course consistent with
optic-spinal multiple sclerosis.73 Recent data from groups
in Spain,74 the UK,75 France,76 Turkey,77 and a European
collaborative study78 have conrmed that assays for
anti-aquaporin-4 antibodies, on the basis of immunouorescence or immunoprecipitation, are 91100%
specic for dierentiating neuromyelitis optica or opticspinal multiple sclerosis from conventional multiple
sclerosis. The inclusion of the autoantibody in the
recently revised diagnostic criteria for neuromyelitis
optica9 (table) and support for the existence of a spectrum
of disorders related to neuromyelitis optica (panel) was
justied on the basis of these ndings. Two independent
groups have since reported experience with the assay
introduced by Lennon and co-workers11 using recombinant
human aquaporin 4 as the antigen.79,80 Takahashi and
co-workers reported that with 1:4 dilutions of patient
serum, the immunouorescence assay of transfected
HEK280 cells described by Lennon and co-workers11 was
91% sensitive and 100% specic for neuromyelitis optica,
with clinical diagnosis as the reference standard.80
However, even with the most sensitive assays, 1025% of
patients clinically diagnosed with neuromyelitis optica
are seronegative for NMO-IgG. Whether the lack of
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Review

LV
Ch pl

D
E

LV
Ch pl

B
F

3V
Ch pl

Figure 3: Brain lesions typical of neuromyelitis optica localise at the sites where aquaporin 4 expression are normally highest
Representative MRI of three patients who are seropositive for NMO-IgG. The images show lesions in periependymal regions of the brain; these sites are enriched with
aquaporin 4 (white dots on centre picture of midline sagittal section). In centre picture dashed black lines show the anatomical level of MRI in the diagram; arrows
show abnormality on uid-attenuated inversion recovery (FLAIR), T2-weighted signal or after being given gadolinium. Patient 1: image A (sagittal) and image B
(axial) have FLAIR signal abnormality around the 3rd ventricle, with extension into the hypothalamus. Patient 2 (image C; coronal, post-contrast T1-weighted image)
has subependymal enhancement along the frontal horns bilaterally and in the adjacent white matter. The immunouorescence photomicrograph linked to image C
shows the binding pattern of the serum IgG from a patient with neuromyelitis optica in a mouse brain (400X). Intense immunoreactivity of basolateral ependymal
cell membranes lining the lateral ventricle (LV) and extending into the subependymal astrocytic mesh coincides with aquaporin 4 immunoreactivity; the choroid
plexus (Ch pl) is unstained. Patient 3 has contiguous signal abnormality throughout the periventricular tissues: diencephalon (image D; axial T2-weighted), third
ventricle (image E; axial, FLAIR), and 4th ventricle (image F; axial FLAIR). Immunouorescence photomicrograph linked to image E shows the binding pattern of the
serum IgG from a patient with neuromyelitis optica in a mouse brain (400X), with intense staining of periventricular tissues (3rd ventricle, 3V); choroid plexus (Ch pl)
is unstained. Image C is courtesy of Allen Aksamit, Mayo Clinic College of Medicine.

NMO-IgG in these patients is indicative of inadequate

clinical diagnostic criteria, suboptimal assay sensitivity,
or it represents a closely related autoimmune disorder
that targets a dierent autoantigen in the glia limitans
(the outermost layer of CNS tissue in the brain delimited
by astrocyte foot processes) is not clear.
The immunohistochemical-staining pattern (gure 3)
of NMO-IgG is characteristic diagnostically. In the CNS,
NMO-IgG binds selectively to the abluminal face of
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microvessels, pia, subpia, and Virchow-Robin sheaths,10

paralleling the sites of immune complex deposition in
the spinal cord lesions of neuromyelitis optica.60 In the
renal medulla, NMO-IgG binds to distal collecting
tubules, and in the gastric mucosa it binds to basolateral
membranes of parietal epithelial cells. These sites of
enriched NMO-IgG immunoreactivity outside the central
nervous system59 were the initial clue that aquaporin 4 was
the autoantigen in neuromyelitis optica.11
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B
Monocyte

Blood
Activated
T
LFA-1

Monocyte

Blood
IgG pool

B
VLA-4

EOS

NMO-IgG
CD8

VCAM-1

ICAM-1

MHC II

CD4

Complement
activated

Monocyte

APC

TCR

CD8

Monocyte

AQP4

AQP4

EOS

AQP4
MS
antigen(s)

CNS
parenchyma

CD8

MMP-9

CNS
parenchyma

Astrocyte
foot
process

Clonal expansion
Demyelination
and axonal
injury

B
Vascular
hyalinisation

Complement
activated

CSF

MAC

CD4

CSF

Demyelination
and axonal
injury

Necrosis

MAC

EOS
N

OCB

Figure 4: Comparative immunopathological hypotheses for multiple sclerosis and neuromyelitis optica
In multiple sclerosis (panel A), peripherally activated T lymphocytes interact with endothelial cells, as an early event that leads to CNS inammation and clinical
exacerbations. Tethering and rolling of T lymphocytes along the endothelium results in binding of the 4 integrins (LFA-1, VLA-4) with their endothelial receptors
(VCAM-1, ICAM-1 [blue arrows]) and selectins (not shown), which initiates endothelial adhesion extravasation into the CNS parenchyma (cell movement is shown by
red arrows). Migration across the bloodbrain barrier is increased by release of proteinases such as MMP-9. CD4-positive T cells are reactivated after interaction of
their T-cell receptor with an unknown antigen presented in the CNS by class II major histocompatibility class (MHC) molecules on antigen-presenting cells (APC). The
intraparenchymal secretion of cytokines and chemokines leads to chemoattraction of other circulating leucocytes, including B lymphocytes (B), monocytes, and
CD8-positive T lymphocytes. The proinammatory cascade that results leads to demyelination and axonal injury through divergent mechanisms, including cytotoxic
CD8-positive T lymphocytes and macrophages (M). Clonal proliferation of inltrating B lymphocytes results in local antibody production which might augment
complement activation and axonal injury. Analysis of CSF from patients with multiple sclerosis typically detects small concentrations of lymphocytes and oligoclonal
IgG products. In neuromyelitis optica (panel B), the immunising event is not known; however, the peripheral immunoglobulin pool (blue) contains NMO-IgG (red).
These immunoglobulins have limited access to the CNS parenchyma, either through endothelial transcytosis or at areas of relative bloodbrain barrier permeability or
injury. The astrocytic foot processthe astrocyte terminus that is one constituent of the bloodbrain barrierwhich is bound to the basal lamina of the endothelium
makes the extracellular domain of aquaporin 4 channels accessible to any NMO-IgG entering this region. Increased permeability of the bloodbrain barrier caused by
complement activation would explain the massive inltration of leucocytes, including polymorphonuclear cells (eosinophils [EOS] and neutrophils [N]), detected in
the CSF in large numbers in the acute phase of neuromyelitis optica. The combined complement-mediated injury and cellular inux causes demyelination, severe
neuronal injury, and necrosis. Cytolytic injury by assembly of the membrane attack complex (MAC) of complement explains the irregular thickening and hyalinisation
of penetrating vessels in neuromyelitis optica lesions. Clonal expansion of B cells in the CNS is presumably uncommon, as indicated by the low prevalence of
oligoclonal IgG bands in CSF. Abbreviations: LFA-1=lymphocyte function-associated antigen 1; VLA-4=very late activation antigen 4; VCAM-1=vascular cell adhesion
molecule 1; ICAM-1=intercellular adhesion molecule 1; MMP-9=matrix metalloproteinase 9; TCR=T-cell receptor; AQP4=aquaporin 4.

The apparently normal renal function in neuromyelitis

optica might indicate the minor contribution of
aquaporin 4 to water homoeostasis in the nephron, in
contrast to its role as the most abundant water channel
in the central nervous system.81,82 Remarkably, aquaporin 4
is not present in myelin or oligodendrocytes.12 The areas
of the central nervous system that have higher
concentrations of aquaporin 4 coincide with the sites of
distinctive brain abnormality, seen on MRI in 10% of
patients with neuromyelitis optica (gure 3).24,83,84
The IgG oligoclonal bands that are frequently seen in
the CSF of patients with multiple sclerosis are thought
810

to be produced by antigen-activated B cells that inltrate

the central nervous system.85 IgG bands are threefold
less frequent in neuromyelitis optica.8 The limited
access of circulating IgG to the extracapillary space in
the central nervous system would only permit interaction
of NMO-IgG with aquaporin 4 at the glia limitans. The
interaction could, in turn, activate complement produced
locally by astrocytes86 or cross-link aquaporin 4, thereby
perturbing water homoeostasis in the central nervous
system.11 In-vitro studies have found that serum IgG
from patients with neuromyelitis optica binds to the
extracellular domain of live cells transfected with
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aquaporin 4 and initiates activation of the complement

cascade and down-regulation of surface aquaporin 4
through endocytosis (Hinson S, unpublished data).
Current concepts and hypotheses concerning the
pathogenesis of neuromyelitis optica and multiple
sclerosis are divergent (gure 4).

Revised diagnostic criteria for neuromyelitis

optica
Diagnostic criteria before 2006 have helped the distinction
of neuromyelitis optica from multiple sclerosis in people
in disparate geographic regions and ethnic groups,25,34,35
and in patients who rst present with a clinically isolated
syndrome (eg, optic neuritis or myelitis).87 However,
these criteria did not include patients who have brain
lesions on MRI (usually asymptomatic) but a disease
course that is otherwise indicative of neuromyelitis
optica. Conversely, patients who present with optic
neuritis, partial myelitis that is not longitudinally
extensive, and an initial MRI that shows no brain lesions
are commonly misclassied as having neuromyelitis
optica rather than multiple sclerosis. We investigated
these limitations in a study of 96 patients with
neuromyelitis optica and 33 patients with multiple
sclerosis. Being seropositive for NMO-IgG was 76%
sensitive and 94% specic for neuromyelitis optica.
However, the presence of at least two of three laboratory
ndingslongitudinally extensive cord lesion, a brain
MRI that is non-diagnostic for multiple sclerosis at
presentation, or NMO-IgG seropositivitywas 99%
sensitive and 90% specic for neuromyelitis optica.9 The
revised diagnostic criteria were validated in an
independent study of Spanish and Italian patients;88 in
this study, the revised criteria enabled dierentiation of
neuromyelitis optica from multiple sclerosis in most
instances, when the clinical ndings were inconclusive.

Brain involvement
Non-specic cerebral lesions seen with MRI are common
at the onset of neuromyelitis optica. Furthermore, new
brain lesions that are non-specic for neuromyelitis
optica develop in 60% of patients after the diagnosis of
neuromyelitis optica, and the immunohistopathological
characteristics of the brain lesions in these patients are
typical of those seen in the spinal cord of patients with
neuromyelitis optica.5,24,65,73,83 Over time, brain lesions that
meet MRI criteria for multiple sclerosis develop in
10% of patients who otherwise full the criteria for the
diagnosis of neuromyelitis optica.24,89 Another 10% of
patients have white-matter lesions in the periependymal
regions that are enriched in aquaporin 4, including the
hypothalamus and the periaqueductal brainstem
(gure 3).24,73,83,84 The white-matter lesions are sometimes
symptomatic and specic for neuromyelitis optica, and
could plausibly account for the non-autoimmune
endocrinopathies reported in association with
neuromyelitis optica.45,90 In contrast to studies of patients
http://neurology.thelancet.com Vol 6 September 2007

with multiple sclerosis, most magnetisation transfer and

diusion tensor MRI studies of patients with
neuromyelitis optica have found abnormalities in healthylooking grey matter but normal ndings or minimal
changes in healthy-looking white matter.9193 These
ndings suggest either retrograde neural degeneration
or selective or more severe lesioning of grey matter,
which is a site of high aquaporin 4 expression.

Disorders related to neuromyelitis optica

Retrospective and prospective studies have found
NMO-IgG in the serum of 2560% of patients with
longitudinally extensive myelitis, including some with
necrotic myelopathy, and in patients with recurrent optic
neuritis.5,10,7378,9498 In a prospective study of 29 patients
with a rst event of longitudinally extensive transverse
myelitis, 11 were NMO-IgG seropositive.99 Within 1 year,
6 of the 11 seropositive patients had a relapse of myelitis
(indicative of recurrent transverse myelitis) or developed
optic neuritis (indicative of neuromyelitis optica). By
contrast, no patient who was seronegative for NMO-IgG
relapsed in a follow-up of 17 years. The presence of
serum NMO-IgG and the evidence of brain involvement
support the existence of a continuum of neuromyelitisoptica-related disorders that range from a limited event
of longitudinally extensive myelitis (or optic neuritis) to
relapsing neuromyelitis optica with symptomatic brain
lesions.

Neuromyelitis optica and systemic autoimmune disease

Transverse myelitis, optic neuritis, relapsing myelitis, or
neuromyelitis optica can occur in the context of
autoimmune diseases, particularly systemic lupus
erythematosus100103 and Sjgrens syndrome.104,105 The
detection of antinuclear autoantibodies (particularly
those that react to extractable nuclear antigen) in a patient
with optic neuritis or myelitis normally leads to the
diagnosis of lupoid myelitis or a vasculitic neurological
complication of Sjgrens syndrome. However,
antinuclear autoantibodies are also common in patients
with neuromyelitis optica who do not have clinical
evidence of a systemic autoimmune disease.5,16 In a group
of 78 patients with neuromyelitis optica, of whom 3%
met the international criteria for the diagnosis of systemic
lupus erythematosus106 or Sjgrens syndrome,107 and 78%
were seropositive for NMO-IgG,72 we detected antinuclear
antibody in 53% and antibodies to extractable nuclear
antigens (primarily anti-Ro/SSA and anti-La/SSB) in
17%.70,72 Patients who met the diagnostic criteria for
systemic lupus erythematosus or Sjgrens syndrome
but did not have optic neuritis or myelitis were NMOIgG seronegative. Furthermore, the seroprevalence of
NMO-IgG in patients with symptoms of neuromyelitis
optica and a clinical diagnosis of systemic lupus
erythematosus or Sjgrens syndrome is the same as the
occurrence of NMO-IgG in typical neuromyelitis
optica.70,72 Therefore, transverse myelitis or optic neuritis
811

Review

are likely to occur in patients with systemic lupus

erythematosus or Sjgrens syndrome who are
seropositive for NMO-IgG, which signies the coexistence
of two autoimmune diseases, rather than a secondary
vasculitic complication of the systemic disorder.70,72

Asian optic-spinal multiple sclerosis

Neuromyelitis optica and Asian optic-spinal multiple
sclerosis have similar neuroimaging, serological, and
immunopathological characteristics.67,73,108,109 Moreover,
NMO-IgG was detected in 7 of 12 Japanese patients
diagnosed with optic-spinal multiple sclerosis by blinded
Japanese neurologists.10 The idea that neuromyelitis
optica and Asian optic-spinal multiple sclerosis are the
same disease is supported by the perivascular inltration
of eosinophils and the rosette pattern of immunoglobulin
and complement detection in pathological specimens
from both groups.60,67 The debate continues with regard
to the clinical classication of patients with optic neuritis,
myelitis associated with longitudinally extensive cord
lesions and brain MRI lesions (usually clinically silent).
In Japan, such patients are diagnosed with multiple
sclerosis, but in North America and Europe, these
patients are diagnosed with neuromyelitis optica.79

Treatment
Intravenous corticosteroid therapy is commonly the
initial treatment for acute attacks of optic neuritis or
myelitis. Patients who did not respond promptly to
corticosteroid treatment beneted from seven treatments
of plasmapheresis (10 to 15 plasma volume per
exchange) over a period of 2 weeks in a randomised,
controlled, crossover trial of patients with acute, severe
demyelinating disease, which included patients with
neuromyelitis optica and acute transverse myelitis.110 In a
recent observational series of 6 patients with neuromyelitis
optica, a similar (50%) clinical response rate was reported
when plasmapheresis was used to treat patients with
attacks that were refractory to corticosteroid treatment.111
Early initiation of plasmapheresis is recommended,
particularly for patients with neuromyelitis optica with
severe cervical myelitis, who are at high risk for
neurogenic respiratory failure.5,112 Plasmapheresis is also
benecial for patients with acute, severe vision loss who
have optic neuritis that is refractory to corticosteroid
therapy.113
No controlled therapeutic trials have specically
investigated neuromyelitis optica.114 Until recently, most
patients with neuromyelitis optica were diagnosed with
progressive severe multiple sclerosis and treated with
immunomodulatory therapies that are approved for
reducing the frequency of relapse in multiple sclerosis
(eg, interferon beta and glatiramer acetate). However
clinical observations do not support the ecacy of these
drugs for treatment of neuromyelitis optica.114116
Maintenance immunosuppressive therapy is a generally
accepted strategy for reducing relapses of neuromyelitis
812

Search strategy and selection criteria

References for this review were identied by searches of Ovid
Medline from 1966 to June, 2007 with the terms
neuromyelitis optica, Devics syndrome, Devics disease,
opticospinal, and multiple sclerosis. The authors also
identied articles through searches of their own les and by
reviewing original papers published in English, translations of
relevant papers published in French and Spanish, and
abstracts published in Japanese.

optica.114 The ndings of small observational studies

suggest that azathioprine (typically 2530 mg/kg/day)
in combination with oral prednisone (~10 mg/kg/day)
reduces the frequency of attacks.27 The results of
observational reports of 18 patients suggest that
mitoxantrone,117 intravenous immunoglobulin,118 and
rituximab119 can induce clinical remission of neuromyelitis
optica in patients who are treatment-naive or who
continue to relapse despite other attempts at
immunosuppression.

Conclusion
The heterogeneity of idiopathic inammatory
demyelinating diseases of the central nervous system is
one of the main factors that confound epidemiological,
genetic, and therapeutic studies of multiple sclerosis.
Neuromyelitis optica is a homogeneous disorder that can
be identied from within this group of demyelinating
diseases by a combination of clinical, neuroimaging,
serological, and pathological characteristics.120 The use of
these characteristics to distinguish neuromyelitis optica
from multiple sclerosis has considerable implications for
clinical practice and is important for preserving the
validity of therapeutic trials for multiple sclerosis by not
enrolling patients with neuromyelitis optica.
An eector role of NMO-IgG in the pathogenesis of
neuromyelitis optica has not yet been proven. Nevertheless,
the discovery of this antibody and its new class of
autoantigen is a valuable tool to dene an extended
spectrum of neuromyelitis-optica-related disorders.
Research must now investigate the potential pathogenicity
of NMO-IgG, the role of aquaporin 4 as the inducer and
target of this autoimmune attack, and the design of
treatment trials on the basis of detailed knowledge of the
pathogenesis of neuromyelitis optica. Two questions
about neuromyelitis optica that were posed by Eugne
Devic at the end of the 19th century are now closer to
being answered: Why such a peculiar localisation? and
What is the intimate nature of the process?13
Contributors
DMW selected most references, determined the structure of the review,
prepared the initial draft of the review, and designed gures 1 and 4. All
authors participated in revising the manuscript, suggested additional
references, and took principal responsibility for revisions and
corrections of sections in their major areas of expertise. VAL compiled
the section on immunobiological features of NMO-IgG and aquaporin 4,

http://neurology.thelancet.com Vol 6 September 2007

Review

and revised gure 4. CFL compiled the section on immunopathology

and provided all the images for gure 2. SJP compiled the imaging
section and designed gure 3. BGW compiled the sections on
epidemiology and made nal revisions to the gures. All authors have
seen and approved the nal version.

20

Conicts of interest
The authors disclose that, in accordance with the BayhDole Act of 1980
and Mayo Foundation policy, VAL, BGW, and CFL stand to receive
royalties for commercial assays to detect of aquaporin 4-specic
autoantibodies. The intellectual property is licensed to a commercial
entity for the development of a simple, antigen-specic assay, to be made
available worldwide for patient care. The test will not be exclusive to
Mayo Clinic. Until now, the authors have received less than $10 000 in
royalties. Mayo Clinic oers the test as an indirect immunouorescence
assay to aid the diagnosis of neuromyelitis optica but the authors do not
benet personally from the performance of the test. DMW has received
consulting fees from Genentech, and research or educational grant
support to Mayo Clinic from Berlex, Biogen Idec, Genentech, Genzyme
Pharmaceuticals, GlaxoSmithKline, Merck, Serono, and Teva
Neurosciences. BW has received consulting fees from Genentech and
grant support to Mayo Clinic from Berlex, Genzyme Pharmaceuticals,
and Serono. SJP has no conict of interest.

22

Acknowledgements
VAL wishes to acknowledge the assistance of Shannon Hinson and grant
support from the Ralph Wilson Medical Research Foundation.
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