https://orcid.org/0000-0003-0544-8296
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is characterized by chronic inflammation of the central nervous system (CNS), particularly the optic nerves and spinal cord. Although it displays some clinical features similar to multiple sclerosis (MS), the etiology and treatment are distinct, and therefore accurate diagnosis is essential. Autoantibodies targeting the water channel protein aquaporin-4 (AQP4) and the myelin sheath protein myelin oligodendrocyte glycoprotein are the major antigen-specific serological biomarkers known to date, with destruction of astrocytes as the primary mode of CNS damage in AQP4-positive disease.
This mini-review summarizes the pathobiology, clinical features, and current methods of serological testing used to assess NMOSD and differentiate this disorder from MS. A brief summary of emerging therapies is also presented.
NMOSD can be distinguished from MS through a combination of clinical findings, imaging investigations, and serological analysis. Seronegative cases are particularly difficult to diagnose and can pose a challenge to clinicians. As knowledge deepens, new therapies and biomarkers are expected to improve treatment of this rare debilitating disease.
Neuromyelitis optica spectrum disorder is a rare neurological illness with some similar features to multiple sclerosis. This review aims to inform readers about the major characteristics of the disease, as well as the laboratory tests that contribute to diagnosis. The most current knowledge in the field is presented.
Introduction
Neuromyelitis optica spectrum disorder (NMOSD) is characterized by inflammatory attacks on the central nervous system (CNS), particularly the optic nerves and spinal cord (1). First described by Eugene Devic and Fernand Gault in 1894 (2), NMO was originally called Devic’s syndrome and was considered a variant of multiple sclerosis (MS) (3). Unlike MS, NMOSD is generally characterized by recurrent acute attacks, with ensuing disabilities related to relapses (1, 4). Acute attacks result from astrocyte damage and secondary demyelination, mediated by the immune system and can lead to paralysis, transverse myelitis, other neuropathological conditions, or even death (5). Other characteristic features include severe visual impairment due to optic neuritis (unilateral or bilateral) and unexplained nausea/vomiting or hiccups due to area postrema syndrome (3, 5, 6). NMOSD patients often deteriorate quickly and reach their clinical nadir within a few weeks of symptom onset (6). Although many people recover some function over the following weeks, patients are commonly left with residual disability including vision loss, incontinence, sensorimotor problems, or erectile dysfunction (1, 3, 4).
Treatments for NMOSD include high-dose corticosteroids (e.g., methylprednisolone; first line) and plasma exchange (second line) (1, 3). Relapse prevention is critically important and long-term immunosuppressive therapies (e.g., rituximab; azathioprine) are used to prevent cumulative sequelae and to minimize disability. Unlike MS, disease-modifying drugs such as natalizumab and interferon-ß are not helpful for NMOSD and may even aggravate symptoms (5). New monoclonal antibody therapies (discussed in the Emerging Treatments section of the review) are beginning to supplant traditional therapies. Regardless, NMOSD is still incurable although significant research is ongoing.
NMOSD is rare, with an estimated incidence of 0.5 to 10 individuals per 100 000 people (7–11). Like other autoimmune conditions, NMOSD is most prevalent in women who comprise between 3 to 9 times more cases than men (12). Usually sporadic (not genetic) (1), NMOSD affects a disproportionate number of people of African or Southeast Asian descent (13) with a mean age of incidence of 32 to 45 years (14), although cases in children and older adults are also documented. In contrast, MS is most common in white individuals with a lower average age of onset of approximately 30 years (3).
Etiology
Like MS, NMOSD is an inflammatory disorder of the CNS, but it has a distinct etiology. Most commonly, autoantibodies to the water-selective channel protein aquaporin-4 (AQP4) are involved. AQP4 is predominantly expressed in CNS astrocytes (particularly at the blood–brain barrier) and ependymal cells, as well as in the retina and inner ear (15). AQP4- positive NMOSD is marked by destruction of astrocytes by the humoral immune system (1) in contrast to MS, which is primarily a demyelinating disease. AQP4-IgG (also called “NMO-IgG”) immunoglobulins bind to AQP4 (the third extracellular loop is thought to be the major epitope) (16). While the exact mechanism is not entirely delineated, the patient’s adaptive immune system produces interleukin 6 (IL-6) and blood–brain barrier permeability increases through the downregulation of AQP4 surface expression. Subsequently, complement is activated which promotes tissue infiltration by leukocytes, which damages or kills astrocytes (5, 17). As a result, astrocytes can no longer support the surrounding cells, which include neurons and oligodendrocytes. Most commonly, demyelinating lesions and necrosis occur in NMOSD (18); however, other types of lesions can be formed by granulocytic inflammation and oligodendrocyte apoptosis (19). Repeated attacks of NMOSD exacerbate these lesions, leading to nerve degeneration as well as neural cavitation and gliosis (1). Altogether, a key distinguishing feature is that demyelination in NMOSD is a secondary effect of astrocyte damage whereas in MS, demyelination is a primary feature (3).
Diagnosis
NMOSD can be challenging to diagnose as it shares many features with MS (3). Timely and accurate diagnosis is imperative to improve patient outcomes. A detailed patient history and neurological/physical examination are crucial, as is contrast MRI of the brain, optic nerves, and spinal cord to observe the characteristic CNS inflammation and lesions. Proper diagnosis is challenged by the fact that approximately 25% of AQP4-IgG–positive NMOSD patients also have another autoimmune disease including myasthenia gravis, systemic lupus erythematosus, Sjögren syndrome, psoriatic arthritis, or coeliac disease (20).
Serologic testing is most helpful in confirming NMOSD diagnosis and, ideally, should be performed during an attack and before immunotherapy is initiated. The diagnostic criteria for NMOSD were revised in 2015 to allow for diagnosis of NMOSD after a first attack with positive AQP4 serology and a typical clinical syndrome (21). AQP4-IgG is present in up to 70% to 90% of NMOSD patients and is highly specific for the disease (11, 22, 23). At least 2 typical clinical characteristics, with at least 1 meeting MRI criteria, are required if AQP4-IgG serology is negative or unknown (21). In seronegative NMOSD, the female-to-male ratio is not as high, and patients may not respond to the same therapies as with AQP4+ disease. Autoantibodies against myelin oligodendrocyte glycoprotein, which characterized myelin oligodendrocyte glycoprotein (MOG) antibody disease, are associated with some seronegative cases with the NMOSD clinical phenotype and are found on the oligodendrocyte surface and CNS myelin. They are present in approximately 40% of AQP4-IgG seronegative NMOSD patients and imply distinct underlying pathophysiology with a primary demyelinating process (24). Less is known about MOG antibody disease–positive cases, but relapses are generally associated with better recovery than AQP4-IgG+ disease (3).
Serological Assays
Different assays can be used to detect and quantify AQP4-IgG with varying sensitivity and specificity. Indirect immunofluorescence methods (Fig. 1) vary in sensitivity (58%–75%) and specificity (85%–99%) depending on the assay used, while live cell-based assays tend to perform slightly better (sensitivity 74%–83%; specificity 100%) (26). If a patient is seronegative but NMOSD is still suspected, some data show that a repeated test 3 to 6 months later may produce positive results (26), especially if tested at the time of a recurrent attack. Moreover, patients are more likely to receive false-negative results while undergoing immunosuppressant treatment or plasma exchange or during remission. There are some studies comparing the various advantages and disadvantages as well as the sensitivity and specificity of various commercial assays for both AQP4 IgG (27) and MOG IgG (27).
![Indirect immunofluorescence cell-based assays for anti-AQP4 IgG in NMO disease. Positivity for AQP4-IgG is shown at increasing semiquantitative titers (reported as +1 to +4 by the Euroimmun fixed transfected cell BIOCHIP assay) (25). The pattern produced is a flat, smooth to fine granular fluorescence in cytoplasm, in part with fluorescence of the cell membrane and only slightly stained cell nuclei. Both serum and CSF samples may be used for analysis. [Images taken at St. Joseph’s Health Centre immunology laboratory].](https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/jalm/7/1/10.1093_jalm_jfab150/2/m_jfab150f1.jpeg?Expires=1712725499&Signature=sVx8debBJJhER4wSHCPc9wTrrrQhJ-i-U9-GQwuRPFOBVSaldVnuzDRe~9eUeoZSu85fZRncg0L0Cs8cjbfjtga7aPqStOmfY5jtugvC0UaagvjSeKuHco06O2ezyNxYhMSYLrdIPKwF90JbqdrFwH-vkBW8DryVpYVGHC-ZkJDleKrvEmlCXaMi8Rp0SfAfnA9uTlCXjJ5zgTf~wKB1Amv-cWImZO2ZIB6biq7GDPRpRRxxKSHaJXbMeVu-MHcCw~jVw1kp2eT2kSgT0025nTIeIoMruomOLNX2AbM5mgrIKHWH0lWahZt1~2QTuphLtLuL67Mao0mBwpQWRN2PLA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Indirect immunofluorescence cell-based assays for anti-AQP4 IgG in NMO disease. Positivity for AQP4-IgG is shown at increasing semiquantitative titers (reported as +1 to +4 by the Euroimmun fixed transfected cell BIOCHIP assay) (25). The pattern produced is a flat, smooth to fine granular fluorescence in cytoplasm, in part with fluorescence of the cell membrane and only slightly stained cell nuclei. Both serum and CSF samples may be used for analysis. [Images taken at St. Joseph’s Health Centre immunology laboratory].
AQP4-IgG testing should be considered in patients with isolated transverse myelitis, severe optic neuritis, or longitudinally extensive transverse myelitis; in patients with severe optic neuritis with poor recovery; or in patients with unexplainable and intractable nausea or vomiting. However, due to the potential for false positives (particularly when tested by enzyme-linked immunosorbent assay methods), it is often inadvisable to test patients with clinical presentation, MRI findings, and cerebrospinal fluid (CSF) abnormalities that are characteristic of MS (e.g., oligoclonal banding).
CSF analysis can also be helpful in diagnosing NMOSD although its retrieval by spinal tap is much more invasive than drawing serum. Pleocytosis (increased cell count) of monocytes and lymphocytes is frequently observed, with a cell count greater than 50 cells/µL observed in 14% to 79% of patients (28, 29). Pleocytosis is rarely observed in MS, which can facilitate diagnosis (30). Increased protein levels are also common and are present in 46% to 75% of cases (29, 31). Levels of neurofilament light chain and glial fibrillary acidic protein are also much higher in CSF samples from NMOSD patients compared to those with MS or other CNS conditions during acute attacks (18, 32). It is very rare for AQP4-IgG positivity to be observed exclusively in CSF (low sensitivity and specificity), so paired testing is often not necessary (33, 34), making serum the optimal and most cost-effective specimen for testing. It is probable that most AQP4-IgG is concentrated in peripheral lymphoid tissues so it is more easily detectable in serum.
Emerging Treatments
New monoclonal antibody therapies are now available for both AQP-4 seropositive and seronegative NMOSD. Eculizumab is a humanized monoclonal antibody targeting the complement protein C5 to inhibit the formation of the C5b-induced membrane attack complex. It effectively reduced risk of relapse in randomized trials of AQP4-positive patients (25). Another monoclonal antibody, satralizumab, binds IL-6 receptors to suppress IL-6–mediated inflammatory pathways. This drug also reduced time to relapse in NMOSD, both as monotherapy and as an add-on therapy to a baseline treatment regimen (34). Another IL-6 receptor antagonist, tocilizumab, has also demonstrated a reduction in NMO disease activity and relapse rate (35). Through a mechanism of binding to CD19 on the surface of B cells to deplete lymphocyte production, the humanized monoclonal inebilizumab has shown efficacy in reducing attacks (25). Finally, B-cell depletion by rituximab (which targets C20) showed a significant reduction in relapse rate compared to other standard conventional therapies (36).
Conclusion
Recurrent, acute attacks with progressive deterioration and high mortality rates in NMOSD highlight the fundamental need to improve diagnosis and, by extension, patient outcomes. More research is urgently needed to address this devastating and currently incurable disease. Specifically, novel biomarkers and greater laboratory medicine expertise will be highly useful in diagnosing, monitoring, or even predicting the course of disease.
Nonstandard Abbreviations: NMOSD, neuromyelitis optica spectrum disorder; CNS, central nervous system; MS, multiple sclerosis; AQP4, aquaporin-4; IL-6, interleukin 6; MOG IgG, myelin oligodendrocyte glycoprotein.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.
Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: D. Rotstein, Alexion, Biogen, EMD Serono, Novartis, Roche, Sanofi Aventis. Stock Ownership: None declared. Honoraria:D. Rotstein, Alexion, Biogen, Novartis, Roche. Research Funding: D. Rotstein, Multiple Sclerosis Society of Canada, Consortium of Multiple Sclerosis Centers, Roche Canada. Expert Testimony: None declared. Patents: None declared.
