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The understanding of neuromyelitis optica spectrum disorder (NMOSD) has evolved substantially since its initial description over a century ago. The discovery in 2004 of a pathogenic autoantibody biomarker targeting aquaporin 4 IgG revolutionized diagnosis and therapeutic development. Although NMOSD resembles multiple sclerosis (MS), differences were identified and articulated in the late 1990s. New diagnostic criteria incorporating the biomarker as well as better understanding of the clinical and radiologic features of NMOSD now permit accurate diagnosis and differentiation from MS. Aquaporin 4 IgG–associated NMOSD is now regarded as an immune astrocytopathy with lytic and nonlytic effects on astrocytes. A second autoantibody, myelin oligodendrocyte glycoprotein IgG, which targets myelin rather than astrocytes, leads to an NMOSD syndrome with clinical and radiologic features that overlap but are distinct from those of aquaporin 4 IgG–associated NMOSD and MS. We review current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD.
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Learning Objectives: On completion of this article, you should be able to: (1) apply 2015 diagnostic criteria to diagnose neuromyelitis optica spectrum disorders in patients who are either seropositive or seronegative for aquaporin 4 antibodies; (2) summarize how the discovery of aquaporin 4 autoantibodies has advanced the understanding of the pathophysiology of neuromyelitis optica spectrum disorders; and (3) recognize principles of managing neuromyelitis optica spectrum disorders, in particular the importance of treatment to prevent attacks and the differences between agents that are effective in suppressing attacks of neuromyelitis optica vs attacks of multiple sclerosis.
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In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry. Dr Weinshenker receives royalties from RSR Ltd, the University of Oxford, and MVZ Labor PD Dr. Volkmann und Kollegen GbR re patent for NMO-IgG as a diagnostic test for NMO and related disorders. He serves as a member of an adjudication committee for clinical trials in NMO being conducted by MedImmune and Alexion Pharmaceutical companies. Dr Wingerchuk serves on an adjudication committee for a neuromyelitis optica clinical trial conducted by MedImmune, LLC. This study was supported in part by grants from Alexion Pharmaceuticals, Inc (D.M.W.) and Terumo BCT, Inc (D.M.W.).
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The definition of neuromyelitis optica (NMO) spectrum disorder (NMOSD) has evolved over the past 150 years since the initial description of a syndrome manifested by selective severe optic nerve and spinal cord inflammation
; the propensity and selectivity for optic nerve and spinal cord involvement has been a mystery. Although this condition resembled multiple sclerosis (MS), which is also characterized by acute self-limited attacks of optic neuritis and myelitis, differences between these conditions were articulated in the late 1990s, and subsequent diagnostic criteria permitted accurate clinical and radiologic distinction.
revolutionized diagnosis and continues to inform therapeutic development. Because a specific diagnosis could be made in the presence of the biomarker, exclusive targeting of the optic nerve and spinal cord were no longer the exclusive basis for diagnosis. Nonopticospinal clinical syndromes within (and rarely outside) the central nervous system (CNS) were recognized as compatible with the disease and even as hallmarks, the most characteristic of these being inflammation of the area postrema, manifested as intractable vomiting or hiccups.
Two schools of thought emerged regarding diagnosis and classification. One held that AQP4-IgG defined a specific syndrome, making molecular diagnosis (AQP4-IgG–associated disease) possible and, indeed, preferable to clinically based diagnosis (NMOSD).
The other held that the sensitivity and specificity of AQP4-IgG is not yet adequately established and that seronegative NMOSD cannot be adequately distinguished from seropositive NMOSD; accordingly, clinical criteria for NMOSD are still appropriate, AQP4-IgG being an important, but still supportive, diagnostic test.
Autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG) are now increasingly recognized as defining an overlapping clinical syndrome that often satisfies the clinical diagnosis of NMOSD.
Conversely, MOG IgG–associated NMOSD appears to target myelin and not astrocytes and does not lead to elevation of markers of astrocyte injury in the context of attacks.
Emerging understanding of the pathogenic antibodies is driving contemporary treatment and clinical research on NMOSD and has spawned several clinical trials targeting B cells and complement-mediated activation by AQP4-IgG. We discuss current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD.
Diagnosis of NMO/NMOSD
Historical Overview and Nosology
Case reports describing opticospinal syndromes compatible with NMOSD date back to 1804.
Eugene Devic and his student, Francis Gault, synthesized their experience with a case and review of the available literature in a report proposing that the described cases represented a distinct clinical entity, neuromyélite optique aiguë.
Their limited experience defined “Devic disease” over most of the next century; the diagnosis was usually made in a patient with a monophasic syndrome of severe, near-simultaneous optic neuritis and myelitis. However, relapsing cases and cases in which pathologic examination revealed involvement of the cerebrum and brain stem led some to question whether NMO differed from MS.
In the late 20th century, the advent of magnetic resonance imaging (MRI) documented that NMO-associated transverse myelitis was accompanied by longitudinally extensive spinal cord lesions (contiguous lesion extending over >3 vertebral segments) (Figure 1) and that brain MRI findings were usually normal.
Cerebrospinal fluid (CSF) analysis also revealed findings distinct from MS—specifically, the absence of oligoclonal bands and, in a minority of patients, a prominent, occasionally neutrophil-predominant pleocytosis during a relapse.
Initial diagnostic criteria devised in 1999 required both transverse myelitis and optic neuritis but no other evidence of clinically manifest CNS disease.
The aforementioned MRI findings and prominent or neutrophilic CSF pleocytosis were supportive criteria in distinguishing NMO from MS.
Figure 1Neuroimaging patterns associated with neuromyelitis optica spectrum disorder (NMOSD). A, Axial T1-weighted magnetic resonance image shows signal abnormality involving the optic chiasm after intravenous gadolinium administration (arrow). B, Sagittal magnetic resonance image shows a longitudinally extensive transverse myelitis lesion that extends into the brain stem on T2-weighted imaging (arrow). C, On T1-weighted sagittal imaging, the lesion has central hypointensity and regions of surrounding gadolinium enhancement (arrow). D, Sagittal fluid-attenuated inversion recovery image showing a characterstic periepenymal lesion involving the dorsal pons and medulla (arrow). Spinal cord lesions in NMOSD typically involve the central gray matter, as seen on T2-weighted axial cord imaging (E) (arrow) and may also reveal “bright spotty lesions” associated with the disease (F) (arrow). G, Axial fluid-attenuated inversion recovery image showing periependymal brain involvement (arrows), H, Acute lesions may enhance on T1-weighted post–gadolinium imaging (arrows). I, Lesions oriented along the anterior-posterior axis of the corpus callosum or involving the splenium are also characteristic of NMOSD (arrows).
which are clinical and MRI findings associated with AQP4-IgG seropositivity. These disorders include limited forms of NMO (single or recurrent longitudinally extensive transverse myelitis [LETM] events or recurrent isolated optic neuritis), Asian optic-spinal MS,
Guthy-Jackson Charitable Foundation NMO International Clinical Consortium & Biorepository. MRI characteristics of neuromyelitis optica spectrum disorder: an international update.
The evolving definitions of NMO/NMOSD indicate that the disease is severe, usually follows a relapsing course, and rarely converts to a secondary progressive phenotype.
to account for the expanding array of clinical and MRI findings associated with AQP4-IgG and because the ability to diagnose NMOSD and distinguish it from MS was often possible at initial presentation, especially in AQP4-IgG–seropositive patients. Increasing evidence that MS disease-modifying therapies, including interferon beta, natalizumab, fingolimod, and alemtuzumab, aggravate NMOSD has made early diagnosis essential.
The IPND criteria incorporate both NMO and NMOSD as previously defined into a single entity and stratify patients on the basis of AQP4-IgG serostatus (eg, NMOSD with AQP4-IgG and NMOSD without AQP4-IgG). For patients with AQP4-IgG and no better alternative diagnosis, a single clinical event referable to 1 of 6 neuroanatomically defined CNS regions (optic nerve, spinal cord, area postrema, brain stem, diencephalon, or cerebrum) is sufficient for diagnosis. Novel features of the IPND criteria for NMOSD with AQP4-IgG include (1) a single clinical event is sufficient for diagnosis, (2) transverse myelitis attacks need not meet the LETM MRI criterion,
(3) “area postrema syndrome” of intractable nausea, vomiting, and/or hiccups (owing to a lesion in the dorsal medulla), which occurs at some point in up to 40% of patients,
is recognized as a hallmark syndrome with the same diagnostic specificity as optic neuritis and myelitis, and (4) identification of “NMO-typical” MRI lesions of the diencephalon (hypothalamus and thalamus) or cerebrum, which are more specific than the clinical syndromes with which they are associated.
Guthy-Jackson Charitable Foundation NMO International Clinical Consortium & Biorepository. MRI characteristics of neuromyelitis optica spectrum disorder: an international update.
Cell-based AQP4-IgG assay with conformationally preserved target is strongly recommended because of its greater sensitivity (∼75%) and specificity (95%-100%) than enzyme-linked immunosorbent assays.
2. Positive test for AQP4-IgG using best available detection method (cell-based assay strongly recommended)
3. Exclusion of alternative diagnoses
Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status
1. At least 2 core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:
a. At least 1 core clinical characteristic must be optic neuritis, acute myelitis with LETM, or area postrema syndrome
b. Dissemination in space (2 or more different core clinical characteristics)
c. Fulfillment of additional MRI requirements, as applicable
2. Negative test(s) for AQP4-IgG using best available detection method, or testing unavailable
3. Exclusion of alternative diagnoses
Core clinical characteristics
1. Optic neuritis
2. Acute myelitis
3. Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting
4. Acute brain stem syndrome
5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG status
1. Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific white matter lesions OR (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted gadolinium-enhancing lesion extending over >½ optic nerve length or involving optic chiasm
2. Acute myelitis: requires associated intramedullary MRI lesion extending over ≥3 contiguous segments (LETM) or ≥3 contiguous segments of focal spinal cord atrophy in patients with prior history compatible with acute myelitis
3. Area postrema syndrome: requires associated dorsal medulla/area postrema lesions
The IPND defined NMOSD without AQP4-IgG more stringently than seropositive disease because the differential diagnosis comprises other conditions including sarcoidosis, neoplasms, and a variety of paraneoplastic disorders. Diagnosis requires involvement of 2 or more of the 6 CNS regions, at least 1 of which must be from the 3 most common presentations: optic neuritis, transverse myelitis (LETM MRI lesion required), or area postrema syndrome (dorsal medulla MRI lesion required). Typically, 2 or more attacks are necessary to establish the diagnosis, but “classic” NMO (a single event of optic neuritis and LETM-associated myelitis) would qualify. Recurrent isolated episodes of optic neuritis or myelitis do not qualify in the absence of AQP4-IgG given the broad differential diagnosis of these syndromes. However, NMOSD cannot be excluded in this situation, and patients should be followed up for emergence of new indications of NMOSD or other competing diagnoses. The IPND identified clinical, MRI (Figure 1), or other characteristics favoring NMOSD that may be especially helpful in seronegative cases. For example, optic chiasm involvement,
“longitudinally extensive” lesions of greater than half of the optic nerve length, predominant involvement of the posterior optic nerve, and bilateral optic neuritis favor NMOSD as a cause. The IPND described a number of clinical and neuroimaging “red flags” of potential alternative diagnoses and provided guidance for serologic retesting in AQP4-IgG–seronegative patients, especially at the time of a breakthrough attack when AQP4-IgG titer may increase.
The IPND also confirmed applicability of the 2015 criteria to pediatric cases but noted that a greater proportion of children present with cerebral syndromes and that LETM-associated myelitis is not as strongly associated with NMOSD in children as in adults.
Finally, the IPND concluded that Asian optic-spinal MS is, in most cases, the same disorder as NMOSD.
Further advances in the nosology of NMOSD will depend in part on determination of whether other pathogenic autoantibodies are detected in the 30% of patients with NMOSD who are AQP4-IgG seronegative. Myelin oligodendrocyte glycoprotein IgG–seropositive patients comprise about 25% of those patients. The clinical features of MOG-IgG–associated NMOSD overlap with those of AQP4-IgG–associated NMOSD, but there appear to be group differences in demographic and clinical features including a lesser predilection for women, disproportionately greater optic nerve involvement, lesser tendency for relapse, and predilection for caudal spinal cord myelitis.
Although initially suggested to be a condition that is less severe and less likely to recur, this variant does lead to frequent relapses and substantial disability in some patients, with a disproportionate number experiencing impaired optic nerve function.
in cooperation with the Neuromyelitis Optica Study Group (NEMOS) MOG-IgG in NMO and related disorders: a multicenter study of 50 patients; Part 3: Brainstem involvement - frequency, presentation and outcome.
in cooperation with the Neuromyelitis Optica Study Group (NEMOS) MOG-IgG in NMO and related disorders: a multicenter study of 50 patients; Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome.
in cooperation with the Neuromyelitis Optica Study Group (NEMOS) MOG-IgG in NMO and related disorders: a multicenter study of 50 patients; Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin.
in cooperation with the Neuromyelitis Optica Study Group (NEMOS) MOG-IgG in NMO and related disorders: a multicenter study of 50 patients; Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients.
Myelin oligodendrocyte glycoprotein IgG assays are not yet widely available.
Epidemiology of NMO
A number of factors should be considered when evaluating epidemiological studies of NMOSD. Contemporary appreciation of NMOSD spectrum and its distinction from its common mimic, MS, occurred over the past 2 decades. The widely accepted biomarker for NMOSD, AQP4-IgG, was first reported in 2004. Before that, NMOSD was rarely diagnosed except in patients with bilateral optic neuritis and myelitis occurring in quick succession who did not experience relapse; this subgroup accounts for a small minority of cases now diagnosed with NMOSD. Different clinical labels, including Devic disease and Asian (Japanese) opticospinal MS, were applied in different countries to patients currently recognized as having NMOSD; some, but not all, patients with these diagnoses had NMOSD. International acceptance of nomenclature and contemporary definition has recently been achieved
but likely will continue to evolve. Finally, NMOSD is likely a heterogeneous condition, exemplified by 2 clinically overlapping syndromes, AQP4-associated and MOG-IgG–associated NMOSD, which appear to differ in sex distribution and age at onset.
Middle-aged and elderly women are most commonly affected, the average age at onset being 40 years. Preadolescent children do not have a sex predilection, but after adolescence, women predominate and constitute 70% to 90% of affected individuals.
which were widely accepted as the international standard until 2015, report prevalence rates ranging from 0.54 per 100,000 (Cuba) to 4.4 per 100,000 (Denmark) (Table 2).
AQP4-IgG = aquaporin 4 IgG; NA = not available; NMO = neuromyelitis optica; NMOSD = neuromyelitis optica spectrum disorder; UK = United Kingdom; USA = United States.
Two studies used AQP4-IgG to screen for cases in all patients with inflammatory demyelinating disease of the CNS, whereas others used serology to confirm the diagnosis in clinically suspected cases.
Two studies used AQP4-IgG to screen for cases in all patients with inflammatory demyelinating disease of the CNS, whereas others used serology to confirm the diagnosis in clinically suspected cases.
NMO/NMOSD, which included both NMO defined by Wingerchuk et al19 2006 criteria and patients who were AQP4-IgG seropositive with at least one clinical syndrome compatible with NMOSD.
NMO/NMOSD, which included both NMO defined by Wingerchuk et al19 2006 criteria and patients who were AQP4-IgG seropositive with at least one clinical syndrome compatible with NMOSD.
Two studies used AQP4-IgG to screen for cases in all patients with inflammatory demyelinating disease of the CNS, whereas others used serology to confirm the diagnosis in clinically suspected cases.
NMO/NMOSD, which included both NMO defined by Wingerchuk et al19 2006 criteria and patients who were AQP4-IgG seropositive with at least one clinical syndrome compatible with NMOSD.
NMO/NMOSD, which included both NMO defined by Wingerchuk et al19 2006 criteria and patients who were AQP4-IgG seropositive with at least one clinical syndrome compatible with NMOSD.
a AQP4-IgG = aquaporin 4 IgG; NA = not available; NMO = neuromyelitis optica; NMOSD = neuromyelitis optica spectrum disorder; UK = United Kingdom; USA = United States.
c Two studies used AQP4-IgG to screen for cases in all patients with inflammatory demyelinating disease of the CNS, whereas others used serology to confirm the diagnosis in clinically suspected cases.
d NMO/NMOSD, which included both NMO defined by Wingerchuk et al
A seroprevalence study from Olmsted County, Minnesota, and Martinique that systematically tested all individuals with suspected inflammatory demyelinating disease for AQP4-IgG found the prevalence in Martinique to be 3-fold higher than previously reported (10 per 100,000) and 2.5-fold more common than in Olmsted County (3.9 per 100,000).
In both geographic regions, blacks were overrepresented compared with expected rates, and the prevalence in the black and white populations did not differ between the 2 geographic regions, suggesting that ethnicity is a key determinant of prevalence.
and will be discussed subsequently (see “Genetic Factors” section). Environmental factors have largely been unexplored, and no studies of NMOSD in migrants compared the populations from which they arose to address whether risk is mutable, although as noted, the prevalence of similarly defined NMOSD does not seem to vary considerably on the basis of geography. Myelin oligodendrocyte glycoprotein IgG–associated NMOSD occurs more frequently in men and in younger individuals than AQP4-IgG–associated NMOSD.
Most patients with NMOSD have AQP4-targeting, polyclonal IgG1 autoantibodies capable of modulating AQP4 from the cell surface in vitro and inducing complement-mediated lysis of target cells in the presence of complement.
suggest that NMOSD is an antibody-mediated aquaporinopathy. Myelin oligodendrocyte glycoprotein IgG is detected in approximately 25% of AQP4-IgG–seronegative individuals, can induce pathology in mice,
Any theories of pathogenesis must explain the following key observations: (1) selectivity for the optic nerve and spinal cord, and, to a lesser but still notable degree, for the area postrema and other circumventricular organs of the brain; (2) evidence of perivascular inflammation accompanied by evidence of complement activation
Recent research yields some answers about many of these phenomena and offers rationale to current and future treatment strategies for NMO (Table 3 and Figure 2). Recent advances are reviewed in the following sections, concentrating on AQP4-IgG–seropositive NMOSD.
Table 3NMO Treatment Strategies Based on Mechanism of Disease
Pathogenic step
Treatment strategy
Treatment
Current status
T-cell activation
Immunosuppression
Various (corticosteroids, azathioprine, mycophenolate)
Current maintstay of therapy
Immune tolerance
Various (vaccination to antigen, autoreactive T cells or dendritic cells; oral tolerization; induction of Treg or Breg cells)
In development
TH17 polarization
mAb to cytokines involved in TH17 polarization or to TH17 surface markers
Various
In development
B cell/plasmablast
Anti–B-cell mAb
Anti–CD20 mAb (rituximab) Anti–CD19 mAb
Current mainstay of therapy Phase 3 clinical trial
Inhibition of B-cell survival
Anti–IL-6 receptor mAb: tocilizumab SA237
Phase 1 clinical trials Phase 3 clinical trials
Blood-brain barrier permeability
Vascular endothelial growth factor inhibition
Bevacizumab
Phase 1 clinical trial
AQP4-IgG
Bulk removal
Plasma exchange
Current mainstay of therapy
Protective inactive AQP4-reactive antibody or generation thereof
Generation of human anti–AQP4 mAb with Fc modifications incapable of complement activation or cell-mediated cytotoxicity
Preclinical work in tissue slice and animal models
Complement-mediated cyototoxicity
Inhibition of complement pathways
Eculizumab C1 esterase inhibitor
Phase 1 trial completed; phase 3 study in progress Phase 1 trial completed
Neutrophil cytotoxicity
Inhibition of neutrophil function/products
Sivelestat
Preclinical work in tissue slice and animal models
Eosinophil cytotoxicity
Inhibition of eosinophil function/products
Cetirizine
Preclinical work and phase 1 clinical trial
AQP4-IgG = aquaporin 4 IgG; Breg = regulatory B cell; IL-6 = interleukin 6; mAb = monoclonal antibody; TH17 = helper T-cell subtype 17; Treg = regulatory T cell.
Figure 2Pathophysiology of aquaporin (AQP4) IgG–associated neuromyelitis optica spectrum disorder and therapeutic strategies. Aquaporin 4 peptides are recognized by T cells, which then are polarized to a helper T-cell subtype 17 (TH17) phenotype and provide help to B cells that are activated by conformationally intact AQP4 proteins. These B cells then differentiate into plasmablasts that secrete AQP4-IgG; this process occurs outside the central nervous system (top half of figure). Aquaporin 4 IgG circulates in the blood and enters the central nervous system (bottom half of figure), where it interacts with AQP4 proteins, encoded on chromosome 18, and is expressed on astrocyte endfeet that abut blood vessels and the pia mater and lead to complement activation by classic pathway of C1q binding. Aquaporin 4 supramolecular aggregates consisting of the M23 isoform decorated on their periphery by M1 isoform are particularly prone to C1q binding and complement activation when they interact with AQP4-IgG. Aquaporin 4 binding may lead to lytic damage due to complement activation or may lead to activation of astrocytes and an inflammatory milieu due to NF-κB signaling. Intervention strategies or drugs that are being considered or are in current use are shown in red font where they are thought to act in the pathophysiology of neuromyelitis optica spectrum disorder. APC = antigen presenting cell; IL-6= interleukin 6; IL-6R = interleukin 6 receptor; M1, M23 = dominant isoforms of AQP4; mAb = monoclonal antibody; EAAT2 = excitatory amino acid transporter 2; MHC-1 = major histocompatibility complex 1 protein; TcR = T-cell receptor.
Neuromyelitis optica is generally a sporadic disease, although familial cases have been reported and constitute at least 3% of cases, a frequency higher than expected by chance given its rarity; current data regarding familial segregation is most consistent with non-Mendelian polygenic inheritance.
There is no, or perhaps a negative, association with HLA-DRB1*1501, the allele most strongly and consistently associated with MS, with which NMOSD was commonly confused.
Furthermore, a single study evaluating 35 non–major histocompatibility complex MS susceptibility loci in 110 patients with NMOSD compared with 332 controls found no association of these alleles with NMOSD.
These data further support the current hypothesis that MS and NMOSD are distinct entities. Neuromyelitis optica spectrum disorder is associated with HLA-DRB1*03, an allele also associated with other autoimmune conditions including systemic lupus erythematosus (SLE).
In Brazil, NMOSD has stronger association with African and weaker association with European ancestry genes than MS, although European ancestry genes predominate in both conditions.
Two studies examining AQP4 polymorphisms have not convincingly confirmed any association with NMOSD, although a rare allelic variant seemed to segregate with susceptibility in one pedigree.
Limited numbers of positive associations of candidate genes have yet to be confirmed.
Autoimmunity
Neuromyelitis optica is commonly associated with other systemic autoimmune diseases. Multiple, often high-titer, autoantibodies associated with autoimmune disease are even more commonly detected in those without clinical illness. The most frequent coassociations are with thyroid autoimmunity, SLE, and Sjögren syndrome (SS). However, a general increase in autoantibodies, including AQP4-IgG in patients with systemic autoimmunity, does not explain the association with SLE and SS. Individuals with SLE and SS but without symptoms of myelitis and optic neuritis are consistently seronegative for AQP4-IgG.
An important clinical correlate to consider is whether a given symptom or imaging abnormality is a direct result of NMOSD or related to comorbidity. The excess of autoimmune disease in patients with NMOSD remains unexplained, although a variety of autoimmune diseases may occur in individuals with allelic variants that affect immune tolerance. A recent report of a patient with coexisting Aicardi-Goutières syndrome and NMOSD suggests that conditions impairing immune function may lead to a milieu favoring development of NMOSD.
These cancers may initiate the humoral autoimmune process leading to NMOSD, although the specificity of paraneoplastic AQP4 expression for NMOSD remains to be established.
Other
Limited studies have addressed other predisposing factors. One study found no clear association of smoking or markers of previous Epstein-Barr virus exposure in patients with NMOSD.
South Japan Multiple Sclerosis Genetics Consortium Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status.
A retrospective study reported that patients with recurrent spinal cord inflammatory disease, 61% of whom were seropositive for AQP4-IgG, had lower vitamin D levels than those with monophasic disease.
Immunopathogenesis
T Cells
Aquaporin 4 IgG is an IgG1 antibody. IgG1 synthesis is dependent on T-cell help. Peripheral T cells exhibit antigen-specific reactivity to AQP4. Aquaporin 4 antigenic stimulation polarizes the immune system toward a helper T-cell subtype 17 repertoire.
The immunodominant peptide located at the N-terminus of AQP4 is 90% homologous with a 10–amino acid sequence of a Clostridium perfringens adenosine triphosphate–binding cassette transporter permease.
A recent study found an overabundance of C perfringens in the microbiome of patients with NMOSD compared with healthy controls, although other organisms were also overrepresented.
Human aquaporin 4281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03:01: relevance for diagnosing and monitoring patients with neuromyelitis optica.
The presence of a pathogenic autoantibody and the demonstrated efficacy of rituximab, albeit not in a definitive, controlled study, highlight the importance of B cells. The main subpopulation of cells responsible for AQP4-IgG production is plasmablasts. An expanded population of CD27highCD38highCD180− CD19 B cells, with properties of plasmablasts, has been identified in NMOSD; this subpopulation is the primary source of AQP4-IgG.
Cytokine activation may provide insight into the nature of contributing immune cell subsets and other clues to pathogenesis; analysis of cytokine elevation in NMOSD has suggested involvement of helper T-cell subtype 17 pathway activation. Interleukin 6 has been consistently overexpressed in NMOSD and is associated with disease activity; as noted, it may promote B-cell survival among other pathogenic mechanisms. B-cell activating factor is also overexpressed in NMO.
Antigen Expression
Aquaporin 4 is expressed predominantly on astrocytes of the CNS, principally on the astrocyte foot process where it is molecularly linked to the dystrophin complex that directly abuts the endothelial cells and comprises the glia limitans at the pial surface. This localization explains, in large part, the “vasculocentric” nature of the pathology and the colocalization of AQP4-IgG binding with abluminal surface markers such as laminin rather than with factor VIII, an endothelial marker.
Aquaporin 4 is physically linked with excitatory amino acid transporter 2. Binding and complement activation result in markedly reduced immunoreactivity in NMOSD lesions, which may impair glutamate clearance. Aquaporin 4 is expressed as the tetramer of 2 dominant isoforms transcribed from the same gene, which differ by 22 amino acids at the N-terminus that are present in M1 but absent in M23. Aquaporin 4 tetramers are further assembled into supramolecular aggregates of large size identified by freeze-fracture electron microscopy. The molecular interactions between the isoforms that lead to supramolecular aggregation have been characterized. Binding of AQP4-IgG requires supramolecular aggregation.
Although the level of AQP4 expression was similar in a single case in nonlesional tissue compared with controls, the optic nerve and spinal cord differ greatly in levels of expression of both isoforms and the degree of supramolecular aggregation, providing a plausible explanation for selective targeting of optic nerves and spinal cord by AQP4-IgG.
Furthermore, low levels of expression and colocalization of complement-inhibitory proteins with AQP4 in the CNS may predispose the CNS to AQP4-IgG–mediated pathology compared with non-CNS tissues.
The principal effector mechanism for NMO attacks is complement-mediated inflammation and its downstream consequences including generation of chemoattractants and secondary neutrophils and eosinophil toxicity.
Extensive loss of immunoreactive AQP4 may occur without demyelination and may suggest lesion reversibility. Widespread reactive astrocytic changes of unclear clinical importance occur in the brain but could contribute to cognitive dysfunction in NMOSD as reported by some investigators.
Because NMOSD attacks require aggressive treatment and appropriate preventive therapy, early accurate diagnosis is important. Although several randomized controlled trials of preventive therapies are in progress, current treatment decisions are based primarily on data from uncontrolled retrospective and prospective observational studies. At present, no compelling data indicate that treatment decisions differ in NMOSD on the basis of AQP4-IgG serologic status.
Immune-Directed Therapy
Acute attacks are treated with intravenous corticosteroids (eg, methylprednisolone, 1000 mg daily for 5 consecutive days). A series of 5 to 7 plasma exchange procedures serves as rescue therapy for severe, corticosteroid-unresponsive attacks.
A recent retrospective study suggests that plasma exchange may be more efficacious as primary therapy for an acute attack than corticosteroids, but this theory requires further study.
Similarly, the effectiveness and role of intravenous immunoglobulin or cell-depleting therapies require more study.
Long-term relapse prevention therapy is recommended for all AQP4-IgG–seropositive patients and for AQP4-IgG–seronegative patients with established relapsing disease.
When diagnostic uncertainty exists between NMOSD and MS, especially in AQP4-IgG–seronegative patients, we recommend an NMOSD-suitable immunosuppressive strategy, which will be effective for both conditions. Contemporary treatment approaches (Table 4) all involve immunosuppression, but no regimen has been proved to be superior given the absence of completed randomized, placebo-controlled trials that either establish the magnitude of benefit for any single agent or provide head-to-head comparisons of 2 or more therapies.
The most commonly used treatments include the oral drugs azathioprine and mycophenolate mofetil (MMF) and the intravenous anti-CD20 monoclonal antibody rituximab. Retrospective and limited prospective cohort data suggest that these immunosuppressive therapies result in relapse-free rates of 25% to 66% during variable follow-up durations.
Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK.
In the absence of evidence from controlled trials and therapeutic biomarkers, the choice of initial therapy depends on availability, comorbidities, and disease course. Some retrospective case series suggest that azathioprine is less effective than the other 2 drugs,
although similar-quality evidence suggests that regardless of which initial therapy is selected, most patients can achieve remission with 1 of the first 2 drugs they try.
Azathioprine is inexpensive and widely available, but adherence rates are low and thiopurine methyltransferase deficiency is a relative contraindication. Full biological activity of azathioprine and MMF is delayed by 4 to 6 months after initiation, necessitating concomitant “bridge” therapy with oral prednisone. Rituximab is more expensive, but first-line use in one cohort was associated with an 84% relapse-free rate after a mean of 28 months of therapy.
Rituximab has several advantages, including easily tracked adherence and rapid onset of action, as it results in B-cell depletion within 2 weeks of course completion. Other reportedly beneficial approaches include long-term oral low-dose corticosteroids,
all of which are relatively accessible in developed nations.
Table 4Commonly Used Treatment Options for NMOSD Attack Prevention
Drug
Target dose
Route
Pretreatment tests and monitoring
Adverse effects
Comment
First-line therapies
Azathioprine
2.5-3.0 mg/kg daily
Oral
Pretreatment: Avoid if TMPT deficient. CBC with differential and LFTs During treatment: Monthly CBC and LFTs for 6 mo, then twice yearly. Reduce dose if WBC <3.0 × 109/L or ANC <1.0 × 109/L
Latency to full biological effect is 4-6 mo; therefore, immunosuppressive bridge required, typically with oral prednisone (see entry for prednisone in this Table). Drug effect can be demonstrated through increase of MCV by >5 points from baseline
Mycophenolate mofetil
750-1500 mg twice a day
Oral
Pretreatment: CBC with differential and LFTs. During treatment: Monthly CBC and LFTs for 6 mo, then twice yearly. Reduce dose if WBC <3.0 × 109/L or ANC <1.0 × 109 /L.
Gastrointestinal symptoms, excessive bone marrow suppression, teratogenicity
Latency to full biological effect is 4-6 mo; therefore, immunosuppressive bridge required, typically with oral prednisone (see below)
Prednisone
30-60 mg/d initial dose
Oral
Pretreatment: Fasting blood sugar During treatment: Periodic check of fasting blood sugar, electrolytes, blood pressure
Hyperglycemia, hypertension, gastric irritation, fluid retention/weight gain
Stable dose of at least 30 mg/d used until azathioprine or mycophenolate fully effective; then taper gradually over 6 mo
Rituximab
Typical course: 1000 mg given twice, 14 d apart. Each 2-treatment course may be administered (1) every 6 mo or (2) based on reemergence of CD19+ B cells
IV
Pretreatment: CBC with differential, LFTs, hepatitis B serology During treatment: CBC with differential, LFTs before each course. Monthly flow cytometry for CD19+ cells if redosing based on cell depletion. Check immunoglobulins annually
Infusion reactions, hepatitis B reactivation, skin reactions
With first course, consider use of oral prednisone, 30 mg/d, starting before treatment and continuing until 2-4 wk after second infusion. To plan retreatment based on B-cell depletion, monitor CD19+ counts with flow cytometry monthly. Initiate next course when CD19+ count ≥1% of total lymphocytes
Second-line or later therapeutic options
Methotrexate
15-25 mg weekly
Oral
Pretreatment: CBC with differential and LFTs During treatment: Monthly CBC and LFTs for 6 mo, then LFTs quarterly
Hepatotoxicity, teratogenic
Supplement with folate, 1 mg/d, during therapy; avoid nonsteroidal anti-inflammatory drugs
Tocilizumab
8 mg/kg every 4 wk
IV
Pretreatment: CBC with differential, LFTs, TB testing During treatment: CBC with differential and LFTs every 4-8 wk for 3 mo and then quarterly; blood pressure
Infection, especially TB, fungal, and opportunistic; infusion reactions, hepatotoxicity, hypertension
Do not initiate therapy in patients with ANC below 2 × 109/L, platelet count below 100 × 109/L, or ALT or AST above 1.5 times ULN. Do not combine with rituximab
Mitoxantrone
12 mg/m2 every 3 mo; maximum cumulative dose 140 mg/m2
IV
Pretreatment: CBC with differential, LFTs During treatment: CBC with differential, LFTs Echocardiography before each course; discontinue drug if left ventricular ejection fraction <50% or declines by >10% from baseline. Monitor echocardiography annually after treatment completed
Cardiotoxicity related to cumulative dose, treatment-related acute leukemia, excessive bone marrow suppression
Recommended as later-line therapy (after failure of 2 or more other treatments) because of risks of cardiomyopathy and leukemia
ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood cell count; IV = intravenous; LFTs = liver function tests; MCV = mean corpuscular volume; NMOSD = neuromyelitis optica spectrum disorder; TB = tuberculosis; TPMT = thiopurine methyltransferase; ULN = upper limit of normal; WBC = white blood cell.
In a prospective open-label trial, 14 patients received intravenous eculizumab, a monoclonal antibody that targets C5, the terminal component of complement.
At 12 months, 12 of the 14 patients remained relapse free, and 5 experienced relapse after eculizumab withdrawal. Eculizumab is 1 of 3 therapies currently being studied in NMOSD randomized controlled trials.
The other 2 are inebilizumab, an anti-CD19 monoclonal antibody also known as MEDI-551, and SA237, an anti–IL-6 receptor monoclonal antibody. Inebilizumab is a B-cell depletion agent with a potential advantage over rituximab because of its ability to deplete plasmablasts. SA237 is similar to tocilizumab and is of interest because of the identified role of IL-6 in NMOSD pathogenesis.
Once NMOSD diagnosis is confirmed and preventive treatment initiated, disease monitoring consists mainly of detecting breakthrough attacks, laboratory surveillance for safety, and adherence monitoring. The goal of preventive immunotherapy is absence of attacks; because NMOSD rarely converts to a secondary progressive course, prolonged relapse-free remissions should be associated with neurologic stability or improvement. There are no validated therapeutic biomarkers for NMOSD, but a recent report that fragment c gamma receptor 3A allelic variants may predict lack of rituximab response shows potential for individualized therapy.
Treatment outcomes with rituximab in 100 patients with neuromyelitis optica: influence of FCGR3A polymorphisms on the therapeutic response to rituximab.
Aquaporin 4 IgG titers may increase in the periattack period but may not predict attacks. Similarly, although serum AQP4-IgG sometimes becomes undetectable with immunosuppression, this outcome does not necessarily indicate clinical response. When breakthrough attacks occur despite apparently adequate immunosuppression, switching to a drug with a different mechanism of action is recommended. Combination therapy (eg, rituximab plus MMF) is an option, but published data are limited. Repurposing of available therapies such as intravenous immunoglobulin and the granulocyte inhibitors sivelestat and cetirizine deserves further examination.
Several novel therapeutic approaches have been identified because of the known key pathogenic role of AQP4-IgG. Restoring immune tolerance is an attractive and potentially feasible goal based on recent advances in other autoimmune diseases. Direct influence on AQP4 antibody-antigen binding can be achieved in multiple ways. A nonpathogenic monoclonal anti-AQP4 antibody, aquaporumab, binds to AQP4, thereby blocking pathogenic AQP4-IgG binding.
We anticipate that further heterogeneity will be recognized in NMOSD. Currently recognized heterogeneity in NMOSD includes clinical cases mediated by AQP4-IgG and others by antibodies with myelin-directed rather than astrocyte-directed targets. Also, the variable nature of pathology apparently induced by AQP4-IgG interaction with its target can vary from activation of transcriptional pathways to modulation of AQP4 from the cell surface to complement-mediated cell lysis and downstream effects of complement cascade activation. We anticipate increasing reliance on antibody detection for diagnosis. It remains unclear whether antibody detection will eventually supplant reliance on clinical and radiologic findings for diagnosis.
However, at the present time, it is impossible to exclude NMOSD in seronegative patients. Future studies must validate the new diagnostic criteria, especially for seropositive patients, and long-term follow-up will be needed to determine that mimics of NMOSD are not being misdiagnosed.
Major improvements in the course of NMOSD have been achieved over the past decade by early recognition and differentiation from MS (and subsequent avoidance of treatments directed at preventing MS attacks, which are often ineffective and even potentially harmful). The effectiveness of current therapy, although not assessed by randomized trials, is generally good to excellent for most patients. However, immunosuppression is associated with infections and other risks and is incompletely effective. For occasional patients, it is not very effective at all. The prospects of antigen-specific therapeutics (eg, aquaporumab) and antigen-specific tolerization are tantalizing. However, they pose many challenges including delivery of therapeutics to AQP4 channels on the astrocyte foot process in a timely manner when treating attacks and in a durable fashion when striving to prevent attacks. An immediate challenge is the search for biomarkers to assess disease activity and the need for therapy and conversely determine when long-term immunosuppressive treatment is no longer necessary.
Conclusion
New diagnostic criteria have expanded the spectrum of NMOSD to include patients with recurrent myelitis only, recurrent optic neuritis only, and with certain brain syndromes. Neuromyelitis optica spectrum disorder remains a clinical diagnosis that requires a compatible clinical syndrome. In AQP4-IgG–seropositive patients, only a single clinical event is required. Neither optic neuritis nor myelitis, both requisite syndromes for a confident diagnosis until 2015, is now obligatory. Neuromyelitis optica spectrum disorder diagnosis is also possible in AQP4-IgG–seronegative cases, but such patients are likely heterogeneous. Emerging data suggest that another pathogenic antibody, MOG-IgG, defines a subset of patients with overlapping but different group demographic and clinical characteristics; the prognosis in this subgroup is poorly defined. Treatment for NMOSD has not yet been rigorously established on the basis of clinical trials, but considerable retrospective and uncontrolled prospective experience suggests that patients with NMOSD do not respond to many different MS treatments, and some of these treatments may even be harmful. Multiple studies, albeit uncontrolled, suggest that azathioprine, MMF, or rituximab are effective in reducing the frequency of attacks.
Guthy-Jackson Charitable Foundation NMO International Clinical Consortium & Biorepository. MRI characteristics of neuromyelitis optica spectrum disorder: an international update.
in cooperation with the Neuromyelitis Optica Study Group (NEMOS)
MOG-IgG in NMO and related disorders: a multicenter study of 50 patients; Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome.
in cooperation with the Neuromyelitis Optica Study Group (NEMOS)
MOG-IgG in NMO and related disorders: a multicenter study of 50 patients; Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin.
in cooperation with the Neuromyelitis Optica Study Group (NEMOS)
MOG-IgG in NMO and related disorders: a multicenter study of 50 patients; Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients.
Human aquaporin 4281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03:01: relevance for diagnosing and monitoring patients with neuromyelitis optica.
Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK.
Treatment outcomes with rituximab in 100 patients with neuromyelitis optica: influence of FCGR3A polymorphisms on the therapeutic response to rituximab.
Grant Support: This study was supported in part by grants from Alexion Pharmaceuticals, Inc (D.M.W.) and Terumo BCT, Inc (D.M.W.).
Potential Competing Interests: Dr Weinshenker receives royalties from RSR Ltd, the University of Oxford, and MVZ Labor PD Dr. Volkmann und Kollegen GbR re patent for NMO-IgG as a diagnostic test for NMO and related disorders. He serves as a member of an adjudication committee for clinical trials in NMO being conducted by MedImmune and Alexion Pharmaceutical companies. Dr Wingerchuk serves on an adjudication committee for a neuromyelitis optica clinical trial conducted by MedImmune, LLC.
Individual reprints of this article and a bound reprint of the entire Symposium on Neurosciences will be available for purchase from our website www.mayoclinicproceedings.org.
The Symposium on Neurosciences will continue in an upcoming issue.
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