The spectrum of neuromyelitis optica

Transcription

1 The spectrum of neuromyelitis optica Dean M Wingerchuk, Vanda A Lennon, Claudia F Lucchinetti, Sean J Pittock, rian G Weinshenker Neuromyelitis optica (also known as Devic s disease) is an idiopathic, severe, demyelinating disease of the central nervous system that preferentially affects 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 specific serum autoantibody marker (NMO-IgG) further differentiates neuromyelitis optica from multiple sclerosis and has helped to define 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 cells cause the activation of complement, inflammatory 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 Inflammatory 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 confirmation that the symptoms and signs of CNS white-matter involvement are disseminated in time and space, supportive evidence from magnetic resonance imaging and cerebrospinal fluid analysis, if needed, and the exclusion of other diagnoses (table). 2 Multiple sclerosis is not associated with a specific biomarker, and although intrathecal synthesis of oligoclonal IgGs is characteristic of multiple sclerosis, no target antigen has been defined; 3 therefore, any relapsing idiopathic demyelinating disease of the central nervous system has, until recently, been diagnosed as multiple sclerosis. 4 Neuromyelitis optica (Devic s disease) is an inflammatory, 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 inflammatory demyelination are features of both disorders. 6 8 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 findings 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 Lancet Neurol 2007; 6: 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, G 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, East Shea oulevard, Scottsdale, AZ 85259, USA wingerchuk.dean@mayo.edu Definition Clinical onset and course Multiple sclerosis 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 findings No better explanation 85% remitting-relapsing 15% primary-progressive Not monophasic Neuromyelitis optica 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 Onset always with relapse 80 90% relapsing course 10 20% monophasic course Median age of onset (years) Sex (F:M) 2:1 9:1 Secondary progressive course Common Rare MRI: brain Periventricular white-matter lesions Usually normal or non-specific 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 differential count Mild pleocytosis Mononuclear cells CSF oligoclonal bands 85% 15 30% Table: Definitions and characteristics of multiple sclerosis and neuromyelitis optica Occasional prominent pleocytosis Polymorphonuclear cells and mononuclear cells Vol 6 September

2 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 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.. 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 C 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 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 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 during an acute attack of optic neuritis), in contrast to multiple sclerosis, or they show non-specific, 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 rain 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 neuromyelitisoptica-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 y 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-opticaspecific myelitis. y 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 sclerosis 30,31 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 Vol 6 September 2007

3 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 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 Afrorazilians (15% of cases of demyelinating disease), 25 West Indians (27%), 44,45 Japanese (20 30%), 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 razil. 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 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 The MHC class II allele DP1*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 DR1*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 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 y 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 patients 24 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 Vol 6 September

4 A C E 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 [LF-PAS] stain for myelin; 10X).. Extensive axonal injury, necrosis, and associated cavitation (ielschowsky 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-organspecific 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 serum samples that were screened for suspected paraneoplastic autoimmunity; neuromyelitis optica was subsequently verified in 12 of the 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 study 78 have confirmed that assays for anti-aquaporin-4 antibodies, on the basis of immunofluorescence or immunoprecipitation, are % specific for differentiating neuromyelitis optica or opticspinal multiple sclerosis from conventional multiple sclerosis. The inclusion of the autoantibody in the recently revised diagnostic criteria for neuromyelitis optica 9 (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-workers 11 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 HEK2 80 cells described by Lennon and co-workers 11 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 Vol 6 September 2007

5 A C LV Ch pl C D E D LV Ch pl F F E 3V Ch pl Figure 3: rain 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 (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 Vol 6 September 2007 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

6 A lood Activated Monocyte lood Monocyte LFA-1 ICAM-1 T VLA-4 VCAM-1 MMP-9 CD8 IgG pool NMO-IgG EOS N TCR CD4 CNS parenchyma MHC II APC MS antigen(s) CD8 T Monocyte CD8 MØ AQP4 CNS parenchyma AQP4 Complement activated AQP4 Astrocyte foot process EOS N MØ Monocyte Clonal expansion Demyelination and axonal injury Vascular hyalinisation Demyelination and axonal injury Necrosis Complement activated MAC MAC CSF CD4 OC CSF EOS N 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 lymphocytes (), 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 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 ), 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 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 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 astrocytes 86 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 Vol 6 September 2007

7 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. eing 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. rain 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 with multiple sclerosis, most magnetisation transfer and diffusion tensor MRI studies of patients with neuromyelitis optica have found abnormalities in healthylooking grey matter but normal findings or minimal changes in healthy-looking white matter 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). y 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 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 erythematosus 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 erythematosus 106 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/ss) 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 Vol 6 September

8 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 Maintenance immunosuppressive therapy is a generally accepted strategy for reducing relapses of neuromyelitis 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 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 rituximab 119 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, Vol 6 September 2007

9 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. GW 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 ayh Dole Act of 1980 and Mayo Foundation policy, VAL, GW, 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 $ 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 erlex, iogen Idec, Genentech, Genzyme Pharmaceuticals, GlaxoSmithKline, Merck, Serono, and Teva Neurosciences. W has received consulting fees from Genentech and grant support to Mayo Clinic from erlex, 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. References 1 Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker G. Multiple sclerosis. N Engl J Med 2000; 343: Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. Ann Neurol 2005; 58: Frohman EM, Racke MK, Raine CS. Multiple sclerosis the plaque and its pathogenesis. N Engl J Med 2006; 354: Kantarci OH, Weinshenker G. Natural history of multiple sclerosis. Neurol Clin 2005; 23: Wingerchuk DM, Hogancamp WF, O rien PC, Weinshenker G. The clinical course of neuromyelitis optica (Devic s syndrome). Neurology 1999; 53: Cree A, Goodin DS, Hauser SL. Neuromyelitis optica. Semin Neurol 2002; 22: de Seze J. Neuromyelitis optica. Arch Neurol 2003; 60: Weinshenker G. Neuromyelitis optica: what it is and what it might be. Lancet 2003; 361: Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker G. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66: Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364: Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin 4 water channel. J Exp Med 2005; 202: Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci 2003; 4: Devic E. Myélite aiguë compliquée de névrite optique. ull Med (Paris) 1894; 8: Gault F. De la neuromyélite optique aiguë. Lyon; Scolding N. Devic s disease and autoantibodies. Lancet Neurol 2005; 4: O Riordan JI, Gallagher HL, Thompson AJ, et al. Clinical, CSF, and MRI findings in Devic s neuromyelitis optica. J Neurol Neurosurg Psychiatry 1996; 60: Wingerchuk DM, Weinshenker G. Neuromyelitis optica: clinical predictors of a relapsing course and survival. Neurology 2003; 60: Misu T, Fujihara K, Nakashima I, Sato S, Itoyama Y. Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica. Neurology 2005; 65: Pittock SJ, Weinshenker G, Wijdicks EF. Mechanical ventilation and tracheostomy in multiple sclerosis. J Neurol Neurosurg Psychiatry 2004; 75: Howard RS, Wiles CM, Hirsch NP, Loh L, Spencer GT, Newsom- Davis J. Respiratory involvement in multiple sclerosis. rain 1992; 115: Kurtzke JF. Cinical manifestations of multiple sclerosis. In: Vinken PJ, ruyn GW, eds. Handbook of Clinical Neurology. Amsterdam: North-Holland; 1970: de Seze J, Stojkovic T, Ferriby D, et al. Devic s neuromyelitis optica: clinical, laboratory, MRI and outcome profile. J Neurol Sci 2002; 197: Chalumeau-Lemoine L, Chretien F, Gaelle Si Larbi A, et al. Devic disease with brainstem lesions. Arch Neurol 2006; 63: Pittock SJ, Lennon VA, Krecke K, Wingerchuk DM, Lucchinetti CF, Weinshenker G. rain abnormalities in neuromyelitis optica. Arch Neurol 2006; 63: Papais-Alvarenga RM, Miranda-Santos CM, Puccioni-Sohler M, et al. Optic neuromyelitis syndrome in razilian patients. J Neurol Neurosurg Psychiatry 2002; 73: ot JC, arkhof F, Polman CH, et al. Spinal cord abnormalities in recently diagnosed MS patients: added value of spinal MRI examination. Neurology 2004; 62: Mandler RN, Ahmed W, Dencoff JE. Devic s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 1998; 51: Milano E, Di Sapio A, Malucchi S, et al. Neuromyelitis optica: importance of cerebrospinal fluid examination during relapse. Neurol Sci 2003; 24: McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: Ebers GC, Paty DW. CSF electrophoresis in one thousand patients. Can J Neurol Sci 1980; 7: McLean N, Luxton RW, Thompson EJ. A study of immunoglobulin G in the cerebrospinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the Log IgG-index: a comparison and diagnostic applications. rain 1990; 113 : ergamaschi R, Tonietti S, Franciotta D, et al. Oligoclonal bands in Devic s neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations. Mult Scler 2004; 10: Mandler RN, Davis LE, Jeffery DR, Kornfeld M. Devic s neuromyelitis optica: a clinicopathological study of 8 patients. Ann Neurol 1993; 34: de Seze J, Lebrun C, Stojkovic T, Ferriby D, Chatel M, Vermersch P. Is Devic s neuromyelitis optica a separate disease? A comparative study with multiple sclerosis. Mult Scler 2003; 9: Ghezzi A, ergamaschi R, Martinelli V, et al. Clinical characteristics, course and prognosis of relapsing Devic s neuromyelitis optica. J Neurol 2004; 251: arbieri F, uscaino GA. Neuromyelitis optica in the elderly. Acta Neurol 1989; 11: Davis R, Thiele E, arnes P, Riviello JJ Jr. Neuromyelitis optica in childhood: case report with sequential MRI findings. J Child Neurol 1996; 11: Mirsattari SM, Johnston J, McKenna R, et al. Aboriginals with multiple sclerosis: HLA types and predominance of neuromyelitis optica. Neurology 2001; 56: Osuntokun O. The pattern of neurological illness in tropical Africa. Experience at Ibadan, Nigeria. J Neurol Sci 1971; 12: Cosnett JE. Multiple sclerosis and neuromyelitis optica. Case report and speculation. S Afr Med J 1981; 60: Modi G, Mochan A, Modi M, Saffer D. Demyelinating disorder of the central nervous system occurring in black South Africans. J Neurol Neurosurg Psychiatry 2001; 70: Phillips PH, Newman NJ, Lynn MJ. Optic neuritis in African Americans. Arch Neurol 1998; 55: Cree A, Khan O, ourdette D, et al. Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology 2004; 63: Cabre P, Heinzlef O, Merle H, et al. MS and neuromyelitis optica in Martinique (French West Indies). Neurology 2001; 56: Vernant JC, Cabre P, Smadja D, et al. Recurrent optic neuromyelitis with endocrinopathies: a new syndrome. Neurology 1997; 48: Vol 6 September

10 46 Fukazawa T, Yamasaki K, Ito H, et al. oth the HLA-CP1 and DR1 alleles correlate with risk for multiple sclerosis in Japanese: clinical phenotypes and gender as important factors. Tissue Antigens 2000; 55: Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol 2003; 2: Nakashima I, Fujihara K, Takase S, Itoyama Y. Decrease in multiple sclerosis with acute transverse myelitis in Japan. Tohoku J Exp Med 1999; 188: Yamasaki K, Horiuchi I, Minohara M, et al. HLA-DP1*0501- associated opticospinal multiple sclerosis: clinical, neuroimaging and immunogenetic studies. rain 1999; 122: Lau KK, Wong LK, Li LS, Chan YW, Li HL, Wong V. Epidemiological study of multiple sclerosis in Hong Kong Chinese: questionnaire survey. Hong Kong Med J 2002; 8: Das A, Puvanendran K. A retrospective review of patients with clinically definite multiple sclerosis. Ann Acad Med Singapore 1998; 27: Chopra JS, Radhakrishnan K, Sawhney, Pal SR, anerjee AK. Multiple sclerosis in North-West India. Acta Neurol Scand 1980; 62: Gangopadhyay G, Das SK, Sarda P, et al. Clinical profile of multiple sclerosis in engal. Neurol India 1999; 47: Kira J, Yamasaki K, Horiuchi I, Ohyagi Y, Taniwaki T, Kawano Y. Changes in the clinical phenotypes of multiple sclerosis during the past 50 years in Japan. J Neurol Sci 1999; 166: Ch ien LT, Medeiros MO, elluomini JJ, Lemmi H, Whitaker JN. Neuromyelitis optica (Devic s syndrome) in two sisters. Clin Electroencephalogr 1982; 13: McAlpine D. Familial neuromyelitis optica: its occurrence in identical twins. rain 1938; 61: Yamakawa K, Kuroda H, Fujihara K, et al. Familial neuromyelitis optica (Devic s syndrome) with late onset in Japan. Neurology 2000; 55: Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA, Weinshenker G. A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 2007; 68: Cloys DE, Netsky MG. Neuromyelitis Optica. Amsterdam: North- Holland; Lucchinetti CF, Mandler RN, McGavern D, et al. A role for humoral mechanisms in the pathogenesis of Devic s neuromyelitis optica. rain 2002; 125: Lefkowitz D, Angelo JN. Neuromyelitis optica with unusual vascular changes. Arch Neurol 1984; 41: Nakamura M, Endo M, Murakami K, Konno H, Fujihara K, Itoyama Y. An autopsied case of neuromyelitis optica with a large cavitary cerebral lesion. Mult Scler 2005; 11: Jacobs D, Roemer S, Weinshenker, et al. The pathology of brain involvement in neuromyelitis optica spectrum disorder. Mult Scler 2006; 12: S Lucchinetti C, ruck W, Parisi J, Scheithauer, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000; 47: Roemer SF, Parisi JE, Lennon VA, et al. Pattern specific loss of aquaporin 4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. rain 2007; 130: Misu T, Fujihara K, Kakita A, et al. Loss of aquaporin 4 in lesions in neuromyelitis optica: distinction from multiple sclerosis. rain 2007; 130: Misu T, Kakita A, Fujihara K, et al. A comparative neuropathological analysis of Japanese cases of neuromyelitis optica and multiple sclerosis. Neurology 2005; 64: A Misu T, Fujihara K, Nakamura M, et al. Loss of aquaporin 4 in active perivascular lesions in neuromyelitis optica: a case report. Tohoku J Exp Med 2006; 209: Sinclair C, Kirk J, Herron, Fitzgerald U, McQuaid S. Absence of aquaporin 4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normalappearing white matter. Acta Neuropathol 2007; 113: Pittock SJ, Lennon VA, Wingerchuk DM, Homburger HA, Lucchinetti CF, Weinshenker G. The prevalence of non-organspecific autoantibodies and NMO-IgG in neuromyelitis optica (NMO) and related disorders. Neurology 2006; 66: A Hummers LK, Krishnan C, Casciola-Rosen L, et al. Recurrent transverse myelitis associates with anti-ro (SSA) autoantibodies. Neurology 2004; 62: Pittock SJ, Lennon VA, De Seze J, et al. Neuromyelitis optica spectrum disorders and non-organ-specific autoimmunity. Arch Neurol (in press). 73 Nakashima I, Fujihara K, Miyazawa I, et al. Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG. J Neurol Neurosurg Psychiatry 2006; 77: Zuliani L, Lopez de Munain A, Ruiz Martinez J, Olascoaga J, Graus F, Saiz A. NMO-IgG antibodies in neuromyelitis optica: a report of 2 cases. Neurologia 2006; 21: Littleton ET, Jacob A, oggild M, Palace J. An audit of the diagnostic usefulness of the NMO-IgG assay for neuromyelitis optica. Mult Scler 2006; 12: S Marignier R, De Seze J, Durand-Dubief F, et al. NMO-IgG: a French experience. Mult Scler 2006; 12: S4. 77 Akman-Demir G. Probably NMO-IgG in Turkish patients with Devic s disease and multiple sclerosis. Mult Scler 2006; 12: S Jarius S, Franciotta D, ergamaschi R, et al. NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007; 68: Matsuoka T, Matsushita T, Kawano Y, et al. Heterogeneity of aquaporin 4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese. rain 2007; 130: Takahashi T, Fujihara K, Nakashima I, et al. Anti- aquaporin 4 antibody is involved in the pathogenesis of NMO: a study on antibody titer. rain 2007; 130: Agre P, Kozono D. Aquaporin water channels: molecular mechanisms for human diseases. FES Lett 2003; 555: Nielsen S, Nagelhus EA, Amiry-Moghaddam M, ourque C, Agre P, Ottersen OP. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin 4 in rat brain. J Neurosci 1997; 17: Pittock SJ, Weinshenker G, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006; 63: Poppe AY, Lapierre Y, Melancon D, et al. Neuromyelitis optica with hypothalamic involvement. Mult Scler 2005; 11: Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: Morgan P, Gasque P. Expression of complement in the brain: role in health and disease. Immunol Today 1996: 17: Rubiera M, Rio J, Tintore M, et al. Neuromyelitis optica diagnosis in clinically isolated syndromes suggestive of multiple sclerosis. Neurology 2006; 66: Saiz A, Zuliani L, lanco Y, et al, for the Spanish-Italian NMO study group. Revised diagnostic criteria for neuromyelitis optica (NMO). Application in a series of suspected patients. J Neurol 2007; published online April 2. DOI: /s arkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. rain 1997; 120: Yamasaki K, Horiuchi I, Minohara M, et al. Hyperprolactinemia in optico-spinal multiple sclerosis. Intern Med 2000; 39: Filippi M, Rocca MA, Moiola L, et al. MRI and magnetization transfer imaging changes in the brain and cervical cord of patients with Devic s neuromyelitis optica. Neurology 1999; 53: Rocca MA, Agosta F, Mezzapesa DM, et al. Magnetization transfer and diffusion tensor MRI show gray matter damage in neuromyelitis optica. Neurology 2004; 62: Yu CS, Lin FC, Li KC, et al. Diffusion tensor imaging in the assessment of normal-appearing brain tissue damage in relapsing neuromyelitis optica. AJNR Am J Neuroradiol 2006; 27: Chan KH, Tsang KL, Fong GC, Cheung RT, Ho SL. Idiopathic severe recurrent transverse myelitis: a restricted variant of neuromyelitis optica. Clin Neurol Neurosurg 2005; 107: Katz JD, Ropper AH. Progressive necrotic myelopathy: clinical course in 9 patients. Arch Neurol 2000; 57: Kidd D, urton, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy (CRION). rain 2003; 126: Pirko I, lauwet LK, Lesnick TG, Weinshenker G. The natural history of recurrent optic neuritis. Arch Neurol 2004; 61: Vol 6 September 2007

11 98 Okai AF, Muppidi S, agla R, Leist TP. Progressive necrotizing myelopathy: part of the spectrum of neuromyelitis optica? Neurol Res 2006; 28: Weinshenker G, Wingerchuk DM, Vukusic S, et al. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006; 59: Chan AY, Liu DT. Devic s syndrome in systemic lupus erythematosus and probable antiphospholipid syndrome. Rheumatology 2006; 45: Lehnhardt FG, Impekoven P, Rubbert A, et al. Recurrent longitudinal myelitis as primary manifestation of SLE. Neurology 2004; 63: Krishnan AV, Halmagyi GM. Acute transverse myelitis in SLE. Neurology 2004; 62: Giorgi D, alacco Gabrieli C, onomo L. The association of optic neuropathy with transverse myelitis in systemic lupus erythematosus. Rheumatology 1999; 38: Mochizuki A, Hayashi A, Hisahara S, Shoji S. Steroid-responsive Devic s variant in Sjogren s syndrome. Neurology 2000; 54: Yamamoto T, Ito S, Hattori T. Acute longitudinal myelitis as the initial manifestation of Sjogren s syndrome. J Neurol Neurosurg Psychiatry 2006; 77: Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: Vitali C, ombardieri S, Jonsson R, et al. Classification criteria for Sjögren s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61: Misu T, Fujihara K, Nakashima I, et al. Pure optic-spinal form of multiple sclerosis in Japan. rain 2002; 125: Weinshenker G, Wingerchuk DM, Nakashima I, Fujihara K, Lennon VA. OSMS is NMO, but not MS: proven clinically and pathologically. Lancet Neurol 2006; 5: Weinshenker G, O rien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999; 46: Watanabe S, Nakashima I, Misu T, et al. Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica. Mult Scler 2007; 13: Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, Weinshenker G. Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology 2002; 58: Ruprecht K, Klinker E, Dintelmann T, Rieckmann P, Gold R. Plasma exchange for severe optic neuritis: treatment of 10 patients. Neurology 2004; 63: Wingerchuk DM, Weinshenker G. Neuromyelitis optica. Curr Treat Options Neurol 2005; 7: Papeix C, Vidal JS, de Seze J, et al. Immunosuppressive therapy is more effective than interferon in neuromyelitis optica. Mult Scler 2007; 13: Warabi Y, Matsumoto Y, Hayashi H. Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J Neurol Sci 2007; 252: Weinstock-Guttman, Ramanathan M, Lincoff N, et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease). Arch Neurol 2006; 63: akker J, Metz L. Devic s neuromyelitis optica treated with intravenous gamma globulin (IVIG). Can J Neurol Sci 2004; 31: Cree A, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 2005; 64: Kerr DA. The lumping and splitting of inflammatory CNS diseases. Neurology 2006; 66: Vol 6 September