The spectrum of neuromyelitis optica - Orphanet · PDF fileThe spectrum of neuromyelitis optica Dean M Wingerchuk, Vanda A Lennon, Claudia F Lucchinetti, Sean J Pittock, Brian G Weinshenker

http://neurology.thelancet.com Vol 6 September 2007 805

Review

The spectrum of neuromyelitis opticaDean 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 nervous system that preferentially aff ects 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 specifi c serum autoantibody marker (NMO-IgG) further diff erentiates neuromyelitis optica from multiple sclerosis and has helped to defi ne a neuromyelitis optica spectrum of disorders. NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, infl ammatory 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.

IntroductionInfl ammatory 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 confi rmation that the symptoms and signs of CNS white-matter involvement are disseminated in time and space, supportive evidence from magnetic resonance imaging and cerebrospinal fl uid analysis, if needed, and the exclusion of other diagnoses (table).2 Multiple sclerosis is not associated with a specifi c biomarker, and although intrathecal synthesis of oligoclonal IgGs is characteristic of multiple sclerosis, no target antigen has been defi ned;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 infl ammatory, 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 infl ammatory 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 fi ndings that can distinguish it from multiple sclerosis (table).5,9 Moreover, the detection of neuromyelitis optica immunoglobulin G (NMO-IgG), an autoantibody, in the serum of patients with neuromyelitis optica, distinguishes neuromyelitis optica from other demyelinating disorders.10 NMO-IgG binds to aquaporin 4,11 which is the main channel that regulates

Lancet Neurol 2007; 6: 805–15

Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ, USA (DM Wingerchuk MD); Departments of Neurology (VA Lennon PhD, CF Lucchinetti MD, SJ Pittock MD, BG Weinshenker MD), Laboratory Medicine and Pathology (SJ Pittock, VA Lennon), and Immunology (VA Lennon), Mayo Clinic College of Medicine, Rochester, MN, USA

Correspondence to:Dean M Wingerchuk, Department of Neurology, Mayo Clinic College of Medicine, 13400 East Shea Boulevard, Scottsdale, AZ 85259, [email protected]

Multiple sclerosis Neuromyelitis optica

Defi nition Central nervous system symptoms and signs that indicate the involvement of the white-matter tractsEvidence of dissemination in space and time on the basis of clinical or MRI fi ndingsNo better explanation

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

Clinical onset and course 85% remitting-relapsing15% primary-progressiveNot monophasic

Onset always with relapse80–90% relapsing course10–20% monophasic course

Median age of onset (years) 29 39

Sex (F:M) 2:1 9:1

Secondary progressive course Common Rare

MRI: brain Periventricular white-matter lesions Usually normal or non-specifi c 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 diff erential count

Mild pleocytosisMononuclear cells

Occasional prominent pleocytosisPolymorphonuclear cells and mononuclear cells

CSF oligoclonal bands 85% 15–30%

Table: Defi nitions and characteristics of multiple sclerosis and neuromyelitis optica

Reprinted with permission from Elsevier (The Lancet Neurology, 2007, 6:805-15)LANCET NEUROLOGYHomepage at www.lancet.com

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

Review

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-specifi c and non-organ-specifi c autoimmune diseases (panel 1).

Clinical features and defi nitionIn 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 defi nition 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-defi ning 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

features of neuromyelitis optica. Cervical myelitis can extend into the brainstem (fi gure 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 fl exion).5,17

MRI fi ndings of the brain at the onset of neuromyelitis optica are typically normal (except for optic nerve enhancement by intravenously administered gadolinium during an acute attack of optic neuritis), in contrast to multiple sclerosis, or they show non-specifi c, 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 fi ndings 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 (fi gure 1).5,22,25 By contrast, the myelitis attacks typical of multiple sclerosis are asymmetric, and the associated lesion seen with MRI rarely exceeds one or two vertebral segments in length.26

Laboratory studies aid the distinction of neuromyelitis optica from multiple sclerosis. Prominent CSF pleocytosis (>50×10⁶ leucocytes/L) with a high proportion of neutrophils is a characteristic of neuromyelitis-optica-specifi c 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.

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

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 bilateralAsian optic-spinal multiple sclerosisOptic neuritis or longitudinally extensive myelitis associated with systemic autoimmune diseaseOptic neuritis or myelitis associated with brain lesions typical of neuromyelitis optica (hypothalamic, corpus callosal, periventricular, or brainstem)

BA C

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 infl ammation.



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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 infl uences 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 prognosis80–90% 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 diffi cult 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 defi cit 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 fi rst 2 years of disease activity, the severity of the fi rst attack, and, possibly, also having systemic lupus erythematosus or a related non-organ-specifi c 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 infl ammatory relapses, both of which are greater in neuromyelitis optica than multiple sclerosis.58

ImmunopathologyDemyelination in neuromyelitis optica extends across multiple sections of the spinal cord, and the necrosis and cavitation aff ect 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 infl ammatory infi ltrates of active lesions of neuromyelitis optica,38,60 and the penetrating spinal vessels are frequently thickened and hyalinised.33,60,61 Post-mortem studies confi rm 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 (fi gure 2).60 Immune complexes are also deposited along myelin sheaths and within macrophages in pattern II of the four immunopathologically defi ned subsets of multiple sclerosis.64 Active neuromyelitis optica lesions are distinctly diff erent 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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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 infl ammation and oedema, but neither demyelination nor necrosis.

Autoantibodies against aquaporin 4An 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-specifi c 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% specifi c for clinically defi ned 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 verifi ed 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 confi rmed that assays for anti-aquaporin-4 antibodies, on the basis of immuno-fl uorescence or immunoprecipitation, are 91–100% specifi c for diff erentiating 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 justifi ed on the basis of these fi ndings. Two independent groups have since reported experience with the assay introduced by Lennon and co-workers11 using recombinant human aquaporin 4 as the antigen.79,80 Takahashi and co-workers reported that with 1:4 dilutions of patient serum, the immunofl uorescence assay of transfected HEK280 cells described by Lennon and co-workers11 was 91% sensitive and 100% specifi c 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

CA

DB

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Figure 2: Pathological and immunopathological fi ndings in neuromyelitis opticaA. 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 infl ammatory infi ltrate 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 magnifi cation (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.



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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 diff erent 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 (fi gure 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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Figure 3: Brain lesions typical of neuromyelitis optica localise at the sites where aquaporin 4 expression are normally highestRepresentative 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 fl uid-attenuated inversion recovery (FLAIR), T2-weighted signal or after being given gadolinium. Patient 1: image A (sagittal) and image B (axial) have FLAIR signal abnormality around the 3rd ventricle, with extension into the hypothalamus. Patient 2 (image C; coronal, post-contrast T1-weighted image) has subependymal enhancement along the frontal horns bilaterally and in the adjacent white matter. The immunofl uorescence 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). Immunofl uorescence 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.



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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 (fi gure 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 infi ltrate 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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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 infl ammation 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 proinfl ammatory cascade that results leads to demyelination and axonal injury through divergent mechanisms, including cytotoxic CD8-positive T lymphocytes and macrophages (MØ). Clonal proliferation of infi ltrating 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 infi ltration 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 infl ux 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.



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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 (fi gure 4).

Revised diagnostic criteria for neuromyelitis opticaDiagnostic 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 fi rst present with a clinically isolated syndrome (eg, optic neuritis or myelitis).87 However, these criteria did not include patients who have brain lesions on MRI (usually asymptomatic) but a disease course that is otherwise indicative of neuromyelitis optica. Conversely, patients who present with optic neuritis, partial myelitis that is not longitudinally extensive, and an initial MRI that shows no brain lesions are commonly misclassifi ed 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% specifi c for neuromyelitis optica. However, the presence of at least two of three laboratory fi ndings—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% specifi c 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 diff erentiation of neuromyelitis optica from multiple sclerosis in most instances, when the clinical fi ndings were inconclusive.

Brain involvementNon-specifi c cerebral lesions seen with MRI are common at the onset of neuromyelitis optica. Furthermore, new brain lesions that are non-specifi c 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 fulfi l 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 (fi gure 3).24,73,83,84 The white-matter lesions are sometimes symptomatic and specifi c 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 diff usion tensor MRI studies of patients with neuromyelitis optica have found abnormalities in healthy-looking grey matter but normal fi ndings or minimal changes in healthy-looking white matter.91–93 These fi ndings suggest either retrograde neural degeneration or selective or more severe lesioning of grey matter, which is a site of high aquaporin 4 expression.

Disorders related to neuromyelitis opticaRetrospective 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 fi rst event of longitudinally extensive transverse myelitis, 11 were NMO-IgG seropositive.99 Within 1 year, 6 of the 11 seropositive patients had a relapse of myelitis (indicative of recurrent transverse myelitis) or developed optic neuritis (indicative of neuromyelitis optica). By contrast, no patient who was seronegative for NMO-IgG relapsed in a follow-up of 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 diseaseTransverse 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



Review

are likely to occur in patients with systemic lupus erythematosus or Sjögren’s syndrome who are seropositive for NMO-IgG, which signifi es the coexistence of two autoimmune diseases, rather than a secondary vasculitic complication of the systemic disorder.70,72

Asian optic-spinal multiple sclerosisNeuromyelitis 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 infi ltration 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 classifi cation 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

TreatmentIntravenous corticosteroid therapy is commonly the initial treatment for acute attacks of optic neuritis or myelitis. Patients who did not respond promptly to corticosteroid treatment benefi ted 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 benefi cial for patients with acute, severe vision loss who have optic neuritis that is refractory to corticosteroid therapy.113

No controlled therapeutic trials have specifi cally 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 effi cacy of these drugs for treatment of neuromyelitis optica.114–116

Maintenance immunosuppressive therapy is a generally accepted strategy for reducing relapses of neuromyelitis

optica.114 The fi ndings 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.

ConclusionThe heterogeneity of idiopathic infl ammatory 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 identifi ed 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 eff ector 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 defi ne 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

ContributorsDMW selected most references, determined the structure of the review, prepared the initial draft of the review, and designed fi gures 1 and 4. All authors participated in revising the manuscript, suggested additional references, and took principal responsibility for revisions and corrections of sections in their major areas of expertise. VAL compiled the section on immunobiological features of NMO-IgG and aquaporin 4,

Search strategy and selection criteria

References for this review were identifi ed 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 identifi ed articles through searches of their own fi les and by reviewing original papers published in English, translations of relevant papers published in French and Spanish, and abstracts published in Japanese.



Review

and revised fi gure 4. CFL compiled the section on immunopathology and provided all the images for fi gure 2. SJP compiled the imaging section and designed fi gure 3. BGW compiled the sections on epidemiology and made fi nal revisions to the fi gures. All authors have seen and approved the fi nal version.

Confl icts of interestThe 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-specifi c autoantibodies. The intellectual property is licensed to a commercial entity for the development of a simple, antigen-specifi c 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 off ers the test as an indirect immunofl uorescence assay to aid the diagnosis of neuromyelitis optica but the authors do not benefi t 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 confl ict of interest.

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

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The spectrum of neuromyelitis optica - Orphanet · PDF fileThe spectrum of neuromyelitis optica Dean M Wingerchuk, Vanda A Lennon, Claudia F Lucchinetti, Sean J Pittock, Brian G Weinshenker