Correspondence *Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK

Email angela.vincent@molecular-medicine.oxford.ac.uk

Introduction

Neuromyelitis optica (NMO or Devic syndrome) was first described in the late 19^th century by Eugène Devic and others.^{1, 2, 3, 4} In Japan and other Asian countries, NMO is often called opticospinal multiple sclerosis (OSMS), and is more prevalent than typical multiple sclerosis (MS). Although NMO has been classified as a subtype of MS for many years, the disease is classically restricted to the optic nerves and spinal cord, and it is now clear that it has distinct clinical and pathological features. In particular, new histopathological and serological findings strongly suggest the involvement of the humoral immune system, and the detection of NMO-specific serum autoantibodies, collectively known as NMO-IgG, helps to distinguish NMO from MS.^{5, 6} The discovery of NMO-IgG, and the subsequent identification of aquaporin-4 (AQP4)—the most abundant water channel in the CNS—as its target antigen,^{6, 7, 8, 9} makes NMO the first inflammatory demyelinating disorder of the CNS to have a defined autoantigen, which enables diagnosis of the disease by use of a serological test. Moreover, the possibility that NMO is an autoantibody-mediated disease, analogous to myasthenia gravis and other autoimmune channelopathies, raises the likelihood of establishing therapeutic strategies aimed at the humoral arm of the immune system.

In this article, we will first review the clinical, serological and pathological characteristics of NMO. We will then discuss the evidence for an antibody-mediated mechanism in the pathogenesis of this disease.

Clinical features of neuromyelitis optica

NMO predominantly affects the optic nerves and spinal cord.^{1, 10, 11} Brain lesions can occur during the course of the disease, but they mostly remain clinically silent.¹² NMO usually begins with either myelitis or optic neuritis—Devic's classical syndrome of simultaneous bilateral optic neuritis and myelitis occurs in only 10% of cases.¹¹ Spinal cord symptoms in NMO range from mild sensory disturbances to complete transverse myelitis with tetraplegia or paraplegia, sensory impairments and bladder–bowel dysfunction. NMO usually follows a relapsing course without marked progression of disability between relapses, but in a minority of cases the disease course can be monophasic (15–23%)^{10, 13} or secondary chronic progressive (2%).¹⁴ Spontaneous remission of neurological dysfunction is rare in NMO in comparison with MS, and accumulation of irreversible deficits and rapid progression of disability are frequent. Studies on the natural course of NMO report progression to severe motor dysfunction (muscle strength 2 on the Medical Research Council scale) or substantial loss of visual function (<20/200) in one or both eyes, in 45% of cases. Respiratory failure caused by ascending cervical myelitis is the most frequent cause of death in patients with NMO.¹¹ Attacks tend to be particularly severe in patients with monophasic NMO, who often show simultaneous optic neuritis and myelitis. The 5-year survival rate was found to be 90% in this group.^{11, 15} Patients with relapsing NMO were reported to have a 5-year survival rate of 70%.¹¹

The median age at NMO onset is about 37 years,^{10, 13, 16, 17} although the disease can also occur during infancy¹⁸ or in the elderly.¹⁹ There is no sex bias among patients with a monophasic disease course,¹¹ but there is a marked female preponderance among patients with relapsing disease.

Imaging

In patients with NMO, T2-weighted MRI of the spinal cord (Figure 1A) usually shows widespread lesions extending over three or more vertebral segments. In acute stages of the disease, the spinal cord lesions might be accompanied by gadolinium enhancement (detectable days to months following relapse), swelling of the spinal cord, and necrosis.²⁰ Vertical extension of spinal cord lesions over three or more segments is the most important MRI marker of NMO.¹⁰ Owing to confluent spinal lesions, however, longitudinal T2 hyperintense areas might also occur in patients with MS in rare cases.^{6, 10, 21, 22} Conversely, short lesions might be found in patients with NMO when MRI is performed very early during a relapse or when the lesion is depicted in its atrophic residual stage.¹⁰ Diffusion tensor imaging shows increases in mean diffusivity and fractional anisotropy in spinal NMO lesions compared with MS lesions; these changes correlate with the extent of tissue damage, as well as with clinical disability.^{23, 24} Optical coherence tomography often detects axonal injury, indicated by a thinning of the retinal nerve fiber layer, in patients with NMO, but it does not discriminate well between NMO and MS.²⁵ By contrast, thickened vessel walls and narrow arterioles extending far into the periphery, which can be revealed by retinal photography or simple fundoscopy in patients with NMO, are largely absent in MS.²⁵

Figure 1 Diagnosis of neuromyelitis optica and longitudinally extensive transverse myelitis.

(A) T2-weighted (left) and T1-weighted (right) sagittal MRI of the cervical spinal and upper thoracic cord in a patient with NMO, showing longitudinal extensive transverse myelitis with swelling, necrosis and linear gadolinium enhancement. Image kindly provided by Dr Anna Pichiecchio, Neurological Institute "C. Mondino", Pavia, Italy. (B) Typical immunofluorescence pattern found on formalin-fixed adult mouse brain tissue immunostained with NMO-IgG₁-positive serum. The staining pattern shows that the autoantigen is localized around the microvasculature. (C) Antibodies to AQP4 in NMO identified by an assay that employs EGFP-tagged AQP4 solubilized from transfected human embryonic kidney cells; results are expressed as fluorescence units immunoprecipitated by the sera.⁸⁹ (D) Immunocytochemistry showing activation of complement C3b deposits (red) on the surface of EGFP–AQP4-transfected human embryonic kidney cells incubated in serum from a patient with NMO. Abbreviations: AQP4, aquaporin-4; EGFP, enhanced green fluorescent protein; MS, multiple sclerosis; NMO, neuromyelitis optica.

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Classically, brain MRI is normal at onset of NMO, but brain or brainstem lesions do not preclude a diagnosis of NMO. In a recent study, nonspecific, non-MS-like lesions were found in 30 out of 60 patients with an NMO disease course of several years, whereas MS-like lesions—most of them clinically silent—were present in only 10% of cases.¹² Signal abnormalities in fluid-attenuated inversion recovery images in NMO tend to be less than 3 mm in diameter and do not show the perpendicular orientation typical of MS.²⁶ Interestingly, T1 brain lesions (thought to represent persistent axonal loss in MS) are mostly missing in NMO.²⁶ In a minority of cases, periventricular, and hypothalamic–diencephalic lesions are detectable.²⁷

Diagnosis of neuromyelitis optica

Immunological features of neuromyelitis optica

Aquaporin-4 localization and function

AQP4 is an osmosis-driven, bidirectional water channel that belongs to the subfamily of strict mammalian aquaporins, which are impermeable to anions and glycerol. The protein is expressed in two isoforms: M1-AQP4 (323 aa, 34 kDa) and M23-AQP4 (301 aa, 32 kDa). The protein monomers consist of six membrane-spanning -helices and two pore helices that determine the channel's selectivity for water molecules (Figure 2A). Both termini are located intracellularly.^{41, 42, 43, 44, 45} Like other aquaporins, AQP4 forms homotetramers with four water-permeable pores per tetramer. M23-AQP4 tetramers and M1-AQP4 tetramers can form mixed arrays on the cell surface, although the M1 tetramers tend to disturb the array formation thereby limiting the size of the arrays.

Figure 2 The structure and localization of aquaporin-4.

(A) Each AQP4 monomer consists of six membrane-spanning -helices with both termini located intracellularly. Water selectivity depends on two pore helices and their highly conserved Asn–Pro–Ala motifs. Like other aquaporins, AQP4 forms homotetramers (not shown). (B) Polarization of AQP4 within the astrocytic end-feet at the glial–pial interfaces of the subarachnoid space and the Virchow–Robin space, and the glial–endothelial interface of arteries and arterioles. Astrocytic processes, together with collagen fibers of the subpial space, form the glia limitans externa that seals the brain surface, and form a dense sheath around capillaries, thereby constituting an integral part of the blood–brain barrier. (C) AQP4 is connected to the dystrophin-associated protein complex, which connects the astrocytic cytoskeleton via ₁-syntrophin with the basal lamina and is mainly responsible for the polarization of AQP4 at the astrocyte end-feet. Abbreviations: AQP4, aquaporin-4; -DG, -dystroglycan; -DG, -dystroglycan; DP71, dystrophin variant DP71; PDZ, PDZ domain of ₁-syntrophin; SXV, Ser-X-Val domain of aquaporin-4; Syn, ₁-syntrophin. Permission for panel A obtained from Nature Publishing Group © Badaut J et al. (2002) J Cereb Blood Flow Metab 22: 367–378. Permission for panel C obtained from Nature Publishing Group © Amiry-Moghaddam M and Ottersen OP (2003) Nat Rev Neurosci 4: 991–1001.

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AQP4 is found on all surfaces of astrocytes, but they occur at the highest concentration in the domains of the perivascular and peripial end-feet that are in direct contact with the basal lamina of the endothelium and pia mater, respectively (Figure 2B).⁴⁶ AQP4 has also been detected in ependymal-cell membranes, but not in neurons, oligodendrocytes or choroidal epithelial cells.⁴³ Recent data suggest that AQP4 is more prominently expressed within optic nerves, brainstem and gray matter of the spinal cord than in the supraventricular white matter, and this correlates with the preferred lesion sites in NMO.^{47, 48} The periventricular regions and the hypothalamus are also considered to be sites of high AQP4 expression. Outside the CNS, AQP4 is present in the distal collecting tubes of the kidney and parietal cells of the stomach. No appreciable renal or parietal cell dysfunction has been reported, however, in ₁-syntrophin-deficient (-Syn^-/-) mice, which show a selective loss of perivascular AQP4; these findings suggest redundancy of AQP4 in these tissues.⁴⁹

AQP4 is co-expressed with the potassium channel Kir4.1 (IRK10). The polarization of both channels within astrocytic foot processes and the high density of AQP4 are mediated mainly by agrin, a proteoglycan within the basal lamina that binds to the -dystroglycan component of the dystrophin–dystroglycan complex. This complex in turn anchors AQP4 to the plasma membrane via ₁-syntrophin (Figure 2C).⁵⁰ Intriguingly, these interactions are highly reminiscent of those that anchor acetylcholine receptors at the neuromuscular junction.⁵¹

Little is known about the consequences of disrupting AQP4 function. Astrocytes transport water, derived from glucose metabolism within neurons, to the perivascular space, from where it is further drained via the CSF and the lymphatic system. In -Syn^-/- mice, mild swelling of astrocytic end-feet has been reported, and the edema that usually occurs after hypo-osmotic stress or ischemia was reduced in comparison with control mice.⁵² By contrast, the severity of artificially induced seizures was increased, probably as a result of disturbed potassium clearance.⁵³

Disease mechanisms in neuromyelitis optica

The existence of a highly specific antibody in NMO and LETM strongly suggests that humoral immunity has a substantial role in these conditions. To explore the function of autoantibodies in NMO, it is important to consider the occurrences of other autoimmune diseases in patients with NMO and the associations of human leukocyte antigens (HLA) with this disease. The characteristics of the antibodies, the pathology and immunopathogenic mechanisms, treatment responses, and animal models of disease must also be considered. In this section, we will discuss some of the features that relate to the immunopathogenesis of NMO, as summarized under three main headings in Box 2. These features are reminiscent of considerations relevant to the pathogenesis of myasthenia gravis,⁵⁴ the prototypical antibody-mediated disease, but the conclusions have to take into account the probable location of AQP4 behind the BBB.

Immunopathology

Acute NMO lesions are dominated by edema and necrosis, whereas chronic lesions are characterized by gliosis and atrophy. Lesions usually extend over three or more vertebral segments and predominantly affect the central parts of the spinal cord. Spinal cavities can occur as a result of necrosis.^{61, 62} On histological examination, extensive demyelination and substantial axonal damage (e.g. swelling, spheroid formation and/or reduction of axonal density) can be detected.⁵ Both white and gray matter are involved. Signs of remyelination are rare. Inflammatory infiltrates mainly consist of cells of the macrophage–microglia lineage, along with neutrophil and eosinophil granulocytes; CD3⁺CD8⁺ T lymphocytes are seen infrequently. AQP4 is expressed predominantly around blood vessels, and, in NMO, the perivascular immunoglobulin and complement deposits that surround blood vessels are seen in a distinctive rim or rosette fashion (Figure 3A–C). This suggests that the AQP4-Abs can access and target their antigen.⁵ This localization is different from that described for type II MS lesions, in which the complement deposits are found at the lesion edge, spatially associated with oligodendrocytes, as well as within macrophages (Figure 3D).⁶³ As already described by Devic in 1895, signs of hyalinization and fibrotic thickening of vessel walls are found in NMO lesions, as is increased vessel density.^{2, 5, 64} Typical features of necrotizing vasculitis (e.g. fibrinoid necrosis and/or granulocyte infiltrates in vessel walls), however, are usually absent.⁵

Figure 3 Complement deposits at sites of aquaporin-4 loss in neuromyelitis optica but not in multiple sclerosis.

Neuromyelitis optica lesions are characterized by (A) a distinct perivascular rim or (B) a rosette or mesh pattern of complement C9neo deposition, which corresponds well to (C) perivascular aquaporin-4 (brown) expression in the healthy CNS. (D) By contrast, in type II multiple sclerosis lesions, complement deposits (C9neo, brown) are found within macrophages (arrowheads) and on oligodendrocytes at the lesion edge (not shown), but not around vessels (arrow). Permission obtained from Guarantors of Brain © Lucchinetti CF et al. (2002) Brain 125: 1450–1461 (A,B) and Roemer SF et al. © Roemer SF et al. (2007) Brain 130: 1194–1205 (C,D).

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Periventricular hypothalamic lesions affecting the area postrema (with or without associated endocrinopathies) have recently been described in some AQP4-Ab-positive patients.^{12, 27} These areas are not only characterized by a high density of astrocytes and strong AQP4 expression, but might also function as an interface between the immune system and the brain.⁶⁵ Like other circumventricular organs, the area postrema lacks a BBB and has, accordingly, been implicated in antibody and immune-cell trafficking in conditions such as experimental autoimmune encephalomyelitis, a rodent model of MS.⁶⁶ Moreover, the periventricular organs have been implicated in regulation of osmolarity and cerebral blood flow.^{47, 67}

Loss of aquaporin-4

A marked loss of AQP4 immunoreactivity within spinal cord lesions in patients with NMO, independent of disease stage, has recently been demonstrated (Figure 4A).^{47, 48, 72} Importantly, foci of AQP4 loss in NMO corresponded well to the sites of perivascular immunoglobulin and complement activation,⁴⁷ in contrast to MS in which AQP4 loss is restricted to inactive plaques (Figure 4B–D). In MS, AQP4 expression is increased in the center of actively demyelinating or remyelinating lesions, as well as in the white matter surrounding such lesions (Figure 4B–C).^{47, 73}

Figure 4 Aquaporin-4 expression in neuromyelitis optica and multiple sclerosis.

All images show spinal cord lesions. (A) In neuromyelitis optica, a marked and stage-independent loss of AQP4 (brown) is found within spinal cord lesions, although it is retained in the periplaque white matter. (B,C,D) AQP4 immunoreactivity (brown) is stage-dependent in multiple sclerosis. In the case of active demyelinating lesions (B), AQP4 expression is increased in the adjacent cortical gray matter (arrow) and periplaque white matter. In active remyelinating lesions (C), there is diffusely increased expression in both the center of the lesion and the periplaque region. In chronic inactive lesions (D), there is complete loss of AQP4. Abbreviations: AQP4, aquaporin-4; PPWM, periplaque white matter. Permission obtained from Roemer SF et al. © Roemer SF et al. (2007) Brain 130: 1194–1205.

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In the same study, the authors described two histological types of NMO lesion: a demyelinating cavitary type predominant in the spinal cord and optic nerves (type A), and a highly inflammatory type without demyelination or axonal pathology found in the brainstem and the spinal cord (type B).⁴⁷ In view of the finding that brainstem lesions often remain clinically silent in NMO and are reversible in some patients, as demonstrated by MRI, the authors speculate that type B lesions might reflect reversible functional impairment of astrocytic water flux caused by IgG-mediated blocking of AQP4. These findings were confirmed by a study from Japan, which described relatively preserved myelinated fibers in acute inflammatory, actively demyelinating and even chronic active NMO lesions.⁴⁸ The preservation of myelin despite a complete loss of AQP4 immunoreactivity in some NMO lesions (contrasting with the marked loss of myelin proteins and increased AQP4 expression in MS) suggests that demyelination might be secondary to astrocyte damage in NMO (Figure 5A,B).

Figure 5 Aquaporin-4 loss seems to be primary rather than secondary to astrocyte loss in neuromyelitis optica.

(A) Myelin (blue) is relatively preserved in some neuromyelitis optica lesions despite (B) marked AQP4 loss, which suggests that demyelination is secondary to AQP4 loss. Moreover, (C) the reactive-astrocyte marker glial fibrillary acidic protein (brown) is expressed despite AQP4 loss (D) in some lesions, which suggests that AQP4 loss occurs before astrocyte death in neuromyelitis optica. Abbreviation: AQP4, aquaporin-4. Permission obtained from Roemer SF et al. © Roemer SF et al. (2007) Brain 130: 1194–1205.

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One study reported that the loss of AQP4 immunoreactivity in spinal cord lesions was paralleled by a loss of GFAP in some NMO lesions from an early stage of the disease.⁴⁸ This observation further distinguishes NMO from MS lesions, which are characterized by strong reactive astrogliosis and, consequently, increased GFAP expression.^{48, 74, 75} The limited extent of astrogliosis in NMO is consistent with the proposed immune attack against astrocytes, as well as with recent findings that indicate a role for AQP4-Ab in astroglial migration.⁷⁶ Interestingly, Roemer and colleagues observed normal GFAP staining in type B lesions; this strengthens the case for AQP4 loss in these lesions preceding astrocyte loss (Figure 5C,D).⁴⁷

Overall, there is circumstantial evidence for an autoimmune pathology with loss of AQP4 in NMO lesions, along with associated immune-complex deposition, but the pathogenic mechanisms that underly tissue edema and necrosis and lead to irreversible loss of function are not clear.

Summary: evidence supporting a role for aquaporin-4 antibodies

Box 2 and Table 1 summarize some of the data relating to the pathogenesis of NMO compared with MS. Our current knowledge regarding AQP4-Ab fits well into the concept of NMO as a humorally mediated autoimmune disease. Many of the serum reactivities of unknown pathogenic importance associated with neurological conditions—particularly paraneoplastic disorders—are directed against intracellular targets, but AQP4 is located on the plasma membrane, and is, therefore, directly accessible to antibodies. The loss of AQP4 within spinal cord lesions, a finding that distinguishes NMO from MS,^{47, 72, 88} strongly suggests that the antibodies can target their antigen in vivo. A primary response against AQP4, as opposed to a secondary loss of AQP4 through astrocyte damage, is also favored both by the finding that GFAP is relatively preserved in some lesions, and by the lack of AQP4 loss in the periplaque white matter,⁴⁷ although the channel might be lost in other regions owing to tissue necrosis.⁴⁸ Importantly, foci of AQP4 loss were demonstrated to coincide with sites of intense vasculocentric immune-complex deposition, further supporting a possible role for AQP4-Ab as the initiator of NMO lesions. It is noteworthy that the MRI lesions typical of NMO correlate well with the normal distribution of AQP4.^{27, 47, 48}

Table 1 Comparison of immunopathological features of neuromyelitis optica and multiple sclerosis.

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Further lines of evidence that AQP4-Ab could be involved in NMO pathogenesis come from a recent study that reported a positive correlation between AQP4-Ab titers during relapse and longitudinal extension of spinal cord lesions (and possibly between AQP4-Ab titers and severity of optic nerve and brain involvement). In addition, observations from this study show that AQP4-Ab titers seem to correlate with clinical improvement and stabilization.⁴⁰

Many questions remain unresolved. For instance, intralesional immunoglobulin deposits, as demonstrated by immunohistochemistry, consist mainly of IgM, whereas AQP4-Ab seems to be largely of the IgG class (both in serum and in CSF).^{71, 89} Moreover, it is not well understood why the antibody causes tissue damage in the CNS but not in the kidneys, the stomach or other organs in which the BBB would not provide any protection. Similarly, it is unknown why inflammation in NMO is restricted mainly to the optic nerves and spinal cord, despite AQP4 being expressed throughout the entire CNS. Differential accessibility of AQP4 in vivo, and regional differences in the spatial distribution and density of the AQP4 epitopes that determine cross-linking and complement activation (as seen in other autoimmune diseases),⁹⁰ might explain this discrepancy.^{7, 47, 48} The lack of substantial disease in AQP4-deficient mice suggests that AQP4 is redundant, and that NMO reflects the resulting inflammation rather than loss of AQP4 function. Finally, the presence of high AQP4-Ab titers during remission in some patients with NMO renders it unlikely that the presence of AQP4-Ab is sufficient to cause clinical disease; additional prerequisites (e.g. disturbance of the BBB and/or T-cell involvement) might be required.

Seronegative neuromyelitis optica

Some patients are negative for NMO-IgG or AQP4-Ab even when the most sensitive assays are used, and attempts to identify novel antigens are in progress.⁹¹ The sensitivity of some assays could probably be improved further, although the use of human AQP4 expressed at a high concentration in cell lines, as by Takahashi et al.⁴⁰ and by ourselves,⁸⁹ is likely to be optimal for detection of the antibodies. It will be equally important to test samples taken during relapse and before treatment, as these are more likely to test positive for the antibodies.⁸⁹

Conclusions and future prospects

The recent observation of a distinct immunopathology in patients with NMO and the subsequent detection of AQP4-Ab as a unique serological biomarker have substantially advanced our understanding of NMO, and have raised the possibility of making a clearer distinction at early disease stages between patients with NMO and patients with spinal cord and optic nerve demyelination associated with MS or other diseases. Longitudinal AQP4 antibody measurements will establish the relationship between antibody levels and clinical status. More-detailed immunopathology, and active immunization and passive transfer experiments, will be needed to help elucidate the precise role of AQP4-Ab in NMO.

Acknowledgments

The work of S Jarius was supported by a fellowship from the European Neurological Society. The authors are very grateful to Professor Margaret Esiri for helpful comments on the manuscript, and to Dr Isabel Leite and Dr Saiju Jacob for allowing us to show unpublished data.

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Subject areas under which this article appears: Neuroimmunology and neuroinflammation