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 Devic’s disease) is an idiopathic, severe, demyelinating disease of the central Lancet Neurol 2007; 6: 805–15
nervous system that preferentially affects the optic nerve and spinal cord. Neuromyelitis optica has a worldwide Department of Neurology,
distribution, poor prognosis, and has long been thought of as a variant of multiple sclerosis; however, clinical, Mayo Clinic College of
Medicine, Scottsdale, AZ, USA
laboratory, immunological, and pathological characteristics that distinguish it from multiple sclerosis are now
(DM Wingerchuk MD);
recognised. The presence of a highly specific serum autoantibody marker (NMO-IgG) further differentiates Departments of Neurology
neuromyelitis optica from multiple sclerosis and has helped to define a neuromyelitis optica spectrum of disorders. (VA Lennon PhD,
NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from CF Lucchinetti MD,
SJ Pittock MD,
peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in
BG Weinshenker MD),
neuromyelitis optica. The knowledge gained from further assessment of the exact role of NMO-IgG in the Laboratory Medicine and
pathogenesis of neuromyelitis optica will provide a foundation for rational therapeutic trials for this rapidly Pathology (SJ Pittock,
disabling disease. VA Lennon), and Immunology
(VA Lennon), Mayo Clinic
College of Medicine, Rochester,
Introduction optic neuritis and myelitis, which, unlike the attacks in MN, USA
Inflammatory demyelinating diseases of the central multiple sclerosis, commonly spare the brain in the early Correspondence to:
nervous system occur throughout the world and are the stages.5 In developed nations, neuromyelitis optica Dean M Wingerchuk,
foremost reason for non-traumatic neurological disability disproportionately strikes non-white populations, in Department of Neurology,
Mayo Clinic College of Medicine,
in young, white adults;1 multiple sclerosis is the most which multiple sclerosis is rare. Whether neuromyelitis
13400 East Shea Boulevard,
common of these disorders. The diagnosis of multiple optica is a variant of multiple sclerosis or a separate Scottsdale, AZ 85259, USA
sclerosis requires confirmation that the symptoms and disease has been long debated: optic neuritis, myelitis, wingerchuk.dean@mayo.edu
signs of CNS white-matter involvement are disseminated and inflammatory demyelination are features of both
in time and space, supportive evidence from magnetic disorders.6–8 The traditional concept of neuromyelitis
resonance imaging and cerebrospinal fluid analysis, if optica was that it is a monophasic disorder, in which
needed, and the exclusion of other diagnoses (table).2 near-simultaneous bilateral optic neuritis and transverse
Multiple sclerosis is not associated with a specific myelitis arise. Nowadays, neuromyelitis optica is
biomarker, and although intrathecal synthesis of recognised as a discrete, relapsing, demyelinating
oligoclonal IgGs is characteristic of multiple sclerosis, no disease, with clinical, neuroimaging, and laboratory
target antigen has been defined;3 therefore, any relapsing findings that can distinguish it from multiple sclerosis
idiopathic demyelinating disease of the central nervous (table).5,9 Moreover, the detection of neuromyelitis optica
system has, until recently, been diagnosed as multiple immunoglobulin G (NMO-IgG), an autoantibody, in
sclerosis.4 the serum of patients with neuromyelitis optica,
Neuromyelitis optica (Devic’s disease) is an distinguishes neuromyelitis optica from other
inflammatory, demyelinating syndrome of the central demyelinating disorders.10 NMO-IgG binds to
nervous system that is characterised by severe attacks of aquaporin 4,11 which is the main channel that regulates

Multiple sclerosis Neuromyelitis optica

Definition
Clinical onset and course
Median age of onset (years)
Sex (F:M)
Secondary progressive course
MRI: brain
MRI: spinal cord
CSF white-blood-cell number
and differential count
CSF oligoclonal bands
Central nervous system symptoms and signs that Transverse myelitis and optic neuritis
indicate the involvement of the white-matter tracts At least two of the following: brain MRI, non-diagnostic for multiple
Evidence of dissemination in space and time on the sclerosis; spinal cord lesion extending over three or more vertebral
basis of clinical or MRI findings segments; or seropositive for NMO-IgG
No better explanation
85% remitting-relapsing Onset always with relapse
15% primary-progressive 80–90% relapsing course
Not monophasic 10–20% monophasic course
29 39
2:1 9:1
Common Rare
Periventricular white-matter lesions Usually normal or non-specific white-matter lesions; 10% unique
hypothalamic, corpus callosal, periventricular, or brainstem lesions
Short-segment peripheral lesions Longitudinally extensive (≥3 vertebral segments) central lesions
Mild pleocytosis Occasional prominent pleocytosis
Mononuclear cells Polymorphonuclear cells and mononuclear cells
85% 15–30%

Table: Definitions 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)
A B C during an acute attack of optic neuritis), in contrast to
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 inflammation.
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-specific
and non-organ-specific autoimmune diseases (panel 1).
Clinical features and definition
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 definition 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-defining 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 (figure 1), resulting in nausea,
hiccoughs, or acute neurogenic respiratory failure,5,17–19
which is exceedingly rare in multiple sclerosis.19–21 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
20–45 seconds) and Lhermitte’s symptom (spinal or limb
dysaesthesias caused by neck flexion).5,17
MRI findings of the brain at the onset of neuromyelitis
optica are typically normal (except for optic nerve
enhancement by intravenously administered gadolinium
multiple sclerosis, or they show non-specific, white-
matter 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-up±SD [6·0±5·6 years]), but these lesions
are usually clinically silent.24 MRI findings in the spinal
cord have great diagnostic utility. During neuromyelitis-
optica-associated attacks of myelitis, lesions imaged with
T2-weighted MRI are longitudinally extensive, and
characteristically span three or more contiguous vertebral
segments (figure 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
(>50×10⁶ leucocytes/L) with a high proportion of
neutrophils is a characteristic of neuromyelitis-optica-
specific 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 50×10⁶/L.5,16,22,27–29 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
15–30% 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
http://neurology.thelancet.com Vol 6 September 2007

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 non-
white 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.38–41
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 (20–30%),46–49 and east Asians,
including Hong Kong Chinese (36%),50 Singaporeans
(48%),51 and Indians (10–23%).52,53 There are few data
from Latin American countries other than Brazil.
Japanese investigators have long distinguished optic-
spinal 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 influences 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.55–57 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
80–90% 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 difficult to diagnose
http://neurology.thelancet.com Vol 6 September 2007
Review
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 deficit 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 first 2 years of
disease activity, the severity of the first attack, and,
possibly, also having systemic lupus erythematosus or a
related non-organ-specific 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
inflammatory 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 affect 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 inflammatory infiltrates of active
lesions of neuromyelitis optica,38,60 and the penetrating
spinal vessels are frequently thickened and hyalinised.33,60,61
Post-mortem studies confirm 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 (figure 2).60
Immune complexes are also deposited along myelin
sheaths and within macrophages in pattern II of the four
immunopathologically defined subsets of multiple
sclerosis.64 Active neuromyelitis optica lesions are distinctly
different 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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A C E

B D
F G

Figure 2: Pathological and immunopathological findings 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 Schiff [LFB-PAS] stain for myelin; 10X).
B. Extensive axonal injury, necrosis, and associated cavitation (Bielschowsky silver impregnation; 10X). C and D. The inflammatory infiltrate 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 magnification (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 inflammation
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
Sjögren’s syndrome in 10–40% of patients.5,16 Anti-nuclear
autoantibodies were detected in the serum of about
50% of patients with neuromyelitis optica.5,16,70 Non-organ-
specific 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% specific for clinically defined neuromyelitis optica.10
NMO-IgG was not found in autoimmune disorders that
had no manifestations of neuromyelitis optica.70,72 NMO-
IgG was detected, incidentally, in 14 of 85 000 serum
samples that were screened for suspected paraneoplastic
autoimmunity; neuromyelitis optica was subsequently
verified in 12 of the 14.10 In a study from Japan, NMO-IgG
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 confirmed that assays for
anti-aquaporin-4 antibodies, on the basis of immuno-
fluorescence or immunoprecipitation, are 91–100%
specific for differentiating neuromyelitis optica or optic-
spinal 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
justified on the basis of these findings. 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 immunofluorescence assay of transfected
HEK280 cells described by Lennon and co-workers11 was
91% sensitive and 100% specific for neuromyelitis optica,
with clinical diagnosis as the reference standard.80
However, even with the most sensitive assays, 10–25% of
patients clinically diagnosed with neuromyelitis optica
are seronegative for NMO-IgG. Whether the lack of

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 Review

A C

LV
Ch pl

C D
B

LV
D Ch pl
B
E
F

F E

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 fluid-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 immunofluorescence 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). Immunofluorescence 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 different 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 (figure 3)
of NMO-IgG is characteristic diagnostically. In the CNS,
NMO-IgG binds selectively to the abluminal face of
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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A B
Blood Monocyte Blood Monocyte
Activated
T B IgG pool
LFA-1 VLA-4 NMO-IgG EOS
B
CD8
MMP-9 N
ICAM-1 VCAM-1

MHC II Complement
Monocyte activated Monocyte
APC
TCR CD8 B
T AQP4 AQP4 EOS
B
CD4 AQP4 N
MS B
antigen(s) Astrocyte
CD8
CNS MØ CNS foot MØ
parenchyma parenchyma process

Clonal expansion
Demyelination B B B
and axonal Demyelination
Vascular and axonal
injury hyalinisation Necrosis
injury
B B B B B B

Complement
activated MAC MAC

EOS
CSF CD4 CSF B 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 inflammation and clinical
exacerbations. Tethering and rolling of T lymphocytes along the endothelium results in binding of the α4 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 blood–brain 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 proinflammatory cascade that results leads to demyelination and axonal injury through divergent mechanisms, including cytotoxic
CD8-positive T lymphocytes and macrophages (MØ). Clonal proliferation of infiltrating 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 blood–brain barrier permeability or
injury. The astrocytic foot process—the astrocyte terminus that is one constituent of the blood–brain barrier—which 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 blood–brain barrier caused by
complement activation would explain the massive infiltration 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 influx 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 (figure 3).24,83,84
The IgG oligoclonal bands that are frequently seen in
the CSF of patients with multiple sclerosis are thought
to be produced by antigen-activated B cells that infiltrate
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 (figure 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 first 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 misclassified 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% specific for neuromyelitis optica.
However, the presence of at least two of three laboratory
findings—longitudinally extensive cord lesion, a brain
MRI that is non-diagnostic for multiple sclerosis at
presentation, or NMO-IgG seropositivity—was 99%
sensitive and 90% specific 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 differentiation of
neuromyelitis optica from multiple sclerosis in most
instances, when the clinical findings were inconclusive.
Brain involvement
Non-specific cerebral lesions seen with MRI are common
at the onset of neuromyelitis optica. Furthermore, new
brain lesions that are non-specific 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 fulfil 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
(figure 3).24,73,83,84 The white-matter lesions are sometimes
symptomatic and specific 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
Review
with multiple sclerosis, most magnetisation transfer and
diffusion tensor MRI studies of patients with
neuromyelitis optica have found abnormalities in healthy-
looking grey matter but normal findings or minimal
changes in healthy-looking white matter.91–93 These
findings 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 25–60% of patients with
longitudinally extensive myelitis, including some with
necrotic myelopathy, and in patients with recurrent optic
neuritis.5,10,73–78,94–98 In a prospective study of 29 patients
with a first 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 1–7 years. The presence of
serum NMO-IgG and the evidence of brain involvement
support the existence of a continuum of neuromyelitis-
optica-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
erythematosus100–103 and Sjögren’s 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 Sjögren’s 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 Sjögren’s 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 Sjögren’s syndrome
but did not have optic neuritis or myelitis were NMO-
IgG seronegative. Furthermore, the seroprevalence of
NMO-IgG in patients with symptoms of neuromyelitis
optica and a clinical diagnosis of systemic lupus
erythematosus or Sjögren’s 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 Sjögren’s syndrome who are
seropositive for NMO-IgG, which signifies 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 infiltration
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 classification 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 benefited from seven treatments
of plasmapheresis (1·0 to 1·5 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
beneficial for patients with acute, severe vision loss who
have optic neuritis that is refractory to corticosteroid
therapy.113
No controlled therapeutic trials have specifically
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 efficacy of these
drugs for treatment of neuromyelitis optica.114–116
Maintenance immunosuppressive therapy is a generally
accepted strategy for reducing relapses of neuromyelitis
812
Search strategy and selection criteria
References for this review were identified by searches of Ovid
Medline from 1966 to June, 2007 with the terms
“neuromyelitis optica”, “Devic’s syndrome”, “Devic’s disease”,
“opticospinal”, and “multiple sclerosis”. The authors also
identified articles through searches of their own files 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 findings of small observational studies
suggest that azathioprine (typically 2·5–3·0 mg/kg/day)
in combination with oral prednisone (~1·0 mg/kg/day)
reduces the frequency of attacks.27 The results of
observational reports of 1–8 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 inflammatory
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 identified 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 effector 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 define 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 Eugène
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 figures 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

and revised figure 4. CFL compiled the section on immunopathology
and provided all the images for figure 2. SJP compiled the imaging
section and designed figure 3. BGW compiled the sections on
epidemiology and made final revisions to the figures. All authors have
seen and approved the final version.
Conflicts of interest
The authors disclose that, in accordance with the Bayh–Dole Act of 1980
and Mayo Foundation policy, VAL, BGW, and CFL stand to receive
royalties for commercial assays to detect of aquaporin 4-specific
autoantibodies. The intellectual property is licensed to a commercial
entity for the development of a simple, antigen-specific 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 offers the test as an indirect immunofluorescence
assay to aid the diagnosis of neuromyelitis optica but the authors do not
benefit 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 conflict of interest.
Acknowledgements
VAL wishes to acknowledge the assistance of Shannon Hinson and grant
support from the Ralph Wilson Medical Research Foundation.
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