Epidemiology of neuromyelitis optica in the United States: a multicenter analysis

BACKGROUND Rare diseases require integrated multicenter clinical networks to facilitate clinical research. Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSDs) are uncommon neuroinflammatory syndromes that are distinct from multiple sclerosis and associated with NMO-IgG, a serologic antibody against aquaporin 4. OBJECTIVE To develop a national multicenter NMO clinical consortium and report initial demographic, clinical, and radiographic features of a cohort of patients with NMO/NMOSD in the United States. DESIGN Review of medical records from patients undergoing evaluation during a 5-year period. We used uniform diagnostic criteria and clinical, laboratory, and neuroimaging definitions to describe the cohort. SETTING Three academic medical centers. PATIENTS One hundred eighty-seven patients with NMO/NMOSD. RESULTS Of the 187 patients included in the analysis, 86 had NMO-IgG-seropositive NMO; 40, NMO-IgG-seronegative NMO; and 61, NMO-IgG-seropositive NMOSD. Altogether, 29.4% of our patients were initially misdiagnosed with multiple sclerosis. The average age at onset of NMO/NMOSD was 41.1 years with a strong female predilection, similar to other autoimmune disorders. Nonwhite patients constituted 52.4% of the cohort. The hallmark of NMO and NMOSD is recurrent longitudinally extensive transverse myelitis, but patients with NMO tend to initially present with optic neuritis. CONCLUSIONS A national multicenter consortium to study NMO/NMOSD is feasible and facilitates accurate clinical diagnosis. This network establishes a foundation for determining disease prevalence, translational research, and clinical trials.     

血清抗核抗体在视神经脊髓炎谱系疾病和多发性硬化中的分布

目的 研究血清抗核抗体(ANAs)在视神经脊髓炎谱系疾病(NMOSDs)和多发性硬化(MS)中的分布.方法 收集2009-01-2011-03间在作者医院神经内科门诊和住院诊治并行血清ANAs筛查的NMOSDs患者74例,包括视神经脊髓炎(NMO)53例、复发长节段横贯性脊髓炎(rLETM)20例和复发性视神经炎(RON)1例,以及MS患者49例,统计其血清ANAs阳性率并进行分析.结果 NMOSDs患者血清ANAs阳性率为45.9%(34/74),其中ANA(本文中特指用间接免疫荧光法检测的抗核抗体)、抗dsDNA、抗着丝粒抗体(ACA)、抗SSA抗体、抗SSB抗体阳性率分别为36.5%(27/74)、5.4%(4/74)、1.4%(1/74)、27.0%(20/74)、9.5%(7/74),MS组仅1例ANAs阳性,阳性率为2.0%(1/49),两组间差异有统计学意义(P<0.01).血清ANAs诊断NMOSDs的灵敏度为45.9%,特异度达98.0%;NMO和rLETM患者血清ANAs阳性率分别为47.2%和40.0%,两者无统计学差异(P=0.635).结论 NMO和rLETM患者血清ANAs阳性率高于MS组,支持NMO和rLETM同属于NMOSDs的观点.ANAs有可能是NMOSDs和MS两组疾病的鉴别指标之一.     

Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica

Neuromyelitis optica (NMO) is a rare CNS inflammatory disorder that predominantly affects the optic nerves and spinal cord. Recent serological findings strongly suggest that NMO is a distinct disease rather than a subtype of multiple sclerosis. In NMO, serum antibodies, collectively known as NMO-IgG, characteristically bind to cerebral microvessels, pia mater and Virchow-Robin spaces. The main target antigen for this immunoreactivity has been identified as aquaporin-4 (AQP4). The antibodies are highly specific for NMO, and they are also found in patients with longitudinally extensive transverse myelitis without optic neuritis, which is thought to be a precursor to NMO in some cases. An antibody-mediated pathogenesis for NMO is supported by several observations, including the characteristics of the AQP4 antibodies, the distinct NMO pathology--which includes IgG and complement deposition and loss of AQP4 from spinal cord lesions--and emerging evidence of the beneficial effects of B-cell depletion and plasma exchange. Many aspects of the pathogenesis, however, remain unclear.     

Neuromyelitis optica-IgG in idiopathic inflammatory demyelinating disorders amongst Hong Kong Chinese

Background:  Idiopathic inflammatory demyelinating disorders (IIDD) affect the central nervous system. In classical multiple sclerosis (CMS), brain, optic nerves [optic neuritis (ON)] and spinal cord [acute transverse myelitis (ATM)] are affected. In neuromyelitis optica (NMO), optic nerves and spinal cord are predominantly affected. NMO-IgG, an autoantibody targeting aquaporin-4, is a marker for NMO. We studied the frequency and clinical relevance of NMO-IgG seropositivity in IIDD patients.
Methods:  Neuromyelitis optica-IgG was detected by indirect immunofluorescence using primate cerebellum.
Results:  Neuromyelitis optica-IgG was detected in six of 10 NMO patients (60%), six of 10 idiopathic relapsing transverse myelitis (IRTM) patients (60%), two of nine idiopathic relapsing ON patients (22%), one of 11 patients (9%) having single ON attack, one of 30 CMS patients (3%), and none of patients having single ATM attack or controls. Comparing NMO-IgG seropositive ( n  = 12) with NMO-IgG seronegative ( n  = 8) patients having NMO or IRTM, NMO-IgG seropositivity was associated with a higher relapse rate in first 2 years, 1.5 and 0.6 attacks/year for seropositive and seronegative groups respectively ( P  = 0.006), and non-significant trend towards more severe ON and myelitis with poorer clinical outcome.
Conclusion:  Neuromyelitis optica -IgG facilitates diagnosis of NMO spectrum disorders. NMO-IgG seropositivity is associated with higher relapse rate in first 2 years.     

Neuromyelitis optica IgG status in acute partial transverse myelitis

BACKGROUND: Neuromyelitis optica (NMO) IgG is a specific marker for NMO. Furthermore, a high proportion of patients with longitudinally extensive transverse myelitis (characterized by spinal cord lesions extending 3 vertebral segments or more on magnetic resonance imaging) are seropositive for NMO-IgG and are considered to have a limited form of NMO. The NMO-IgG status in mild cases of acute partial transverse myelitis asociated with minimal magnetic resonance imaging abnormalities (spinal cord lesions <2 vertebral segments on magnetic resonance imaging) is unknown. OBJECTIVE: To investigate the NMO-IgG status of patients with acute partial transverse myelitis and a normal cerebral magnetic resonance image. DESIGN: Observational, retrospective consecutive case series with longitudinal follow-up. SETTING: Allegheny Multiple Sclerosis Treatment Center. PATIENTS: Three groups of patients were tested for NMO-IgG. Group 1 consisted of 22 patients with acute partial transverse myelitis, group 2 consisted of 4 patients with definite NMO (by 1999 criteria of Wingerchuk et al), and group 3 consisted of 6 patients with definite multiple sclerosis. MAIN OUTCOME MEASURE: NMO-IgG status. A commercially available assay for NMO antibodies was performed at the Mayo Clinic. Testing was performed during the convalescent stage of the illness. RESULTS: Of the 22 patients with acute partial transverse myelitis, only 1 was seropositive for NMO-IgG at presentation. This patient subsequently developed recurrent episodes of longitudinally extensive transverse myelitis that are typicaly seen in association with NMO-IgG. Three of the 4 patients meeting criteria for NMO were seropositive. None of the patients with multiple sclerosis had NMO-IgG detected. CONCLUSION: NMO-IgG is rarely encountered in patients with acute partial transverse myelitis, which is in sharp contrast to the high frequency of this antibody in patients with NMO and longitudinally extensive transverse myelitis.     

Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis

OBJECTIVE: We investigated whether neuromyelitis optica (NMO) IgG seropositivity at the initial presentation of longitudinally extensive transverse myelitis (LETM) predicts relapse of myelitis or development of optic neuritis. METHODS: Prospective study of patients with initial LETM who were tested for the presence of NMO-IgG. RESULTS: Eleven of 29 patients (37.9%) were seropositive after a first attack of LETM spanning three or more vertebral segments on magnetic resonance imaging. Of 23 patients followed up for 1 year, none of 14 who were seronegative experienced a relapse or developed optic neuritis. Of 9 seropositive patients, 5 developed a second event: 4 of 9 (44%) developed recurrent transverse myelitis and 1 of 9 (11%) developed optic neuritis (p = 0.004). INTERPRETATION: LETM represents an inaugural or limited form of NMO in a high proportion of patients. The 40% of patients who are seropositive for NMO-IgG are at high risk for relapse.     

Neuromyelitis optica spectrum disorder in a patient with systemic lupus erythematosus and anti-phospholipid antibody syndrome

Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system characterized by severe episodes of optic nerve and spinal cord inflammation. NMO-IgG (anti-aquaporin-4) has been recently described as a sensitive and specific marker for NMO. As there have been prior published reports of an association between NMO and systemic autoimmune diseases, the prognostic value of the antibody test in these cases is uncertain. We describe a 47-year old woman with recurrent transverse myelitis and a long-standing history of systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APLS). While she did not have a history of optic neuritis, serological testing for the NMO-IgG was positive when she was admitted for her second episode of transverse myelitis. Testing for the NMO-IgG in cases of isolated or recurrent transverse myelitis attributed to current SLE and APLS may help clarify the diagnosis of a distinct disease process likely to cause recurrent and severe disability, warranting more aggressive immunotherapy.     

New Insights into Neuromyelitis Optica

Neuromyelitis optica (NMO) is an idiopathic inflammatory disorder of the central nervous system (CNS) that preferentially affects the optic nerves and spinal cord. In Asia, NMO has long been considered a subtype of multiple sclerosis (MS). However, recent clinical, pathological, immunological, and imaging studies have suggested that NMO is distinct from MS. This reconsideration of NMO was initially prompted by the discovery of a specific antibody for NMO (NMO-IgG) in 2004. NMO-IgG is an autoantibody that targets aquaporin-4 (AQP4), the most abundant water channel in the CNS; hence, it was named anti-AQP4 antibody. Since it demonstrated reasonable sensitivity and high specificity, anti-AQP4 antibody was incorporated into new diagnostic criteria for NMO.The spectrum of NMO is now known to be wider than was previously recognized and includes a proportion of patients with recurrent, isolated, longitudinally extensive myelitis or optic neuritis, and longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease or with brain lesions typical of NMO. In this context, a new concept of "NMO spectrum disorders" was recently introduced. Furthermore, seropositivity for NMO-IgG predicts future relapses and is recognized as a prognostic marker for NMO spectrum disorders. Humoral immune mechanisms, including the activation of B-cells and the complement pathway, are considered to play important roles in NMO pathogenesis. This notion is supported by recent studies showing the potential pathogenic role of NMO-IgG as an initiator of NMO lesions. However, a demonstration of the involvement of NMO-IgG by the development of active immunization and passive transfer in animal models is still needed. This review focuses on the new concepts of NMO based on its pathophysiology and clinical characteristics. Potential management strategies for NMO in light of its pathomechanism are also discussed.     

Neuromyelitis optica: a new perspective

The traditional view of neuromyelitis optica (NMO) as a monophasic inflammatory disorder that affects both the optic nerves and the spinal cord is expanding. Over the last decade, a combination of clinical, radiological, pathological, and serological findings have resulted in evolving definitions of NMO and the appreciation that it likely constitutes a broader, more diverse spectrum of disease that is pathogenically distinct from multiple sclerosis. Neuromyelitis optica-immunoglobulin (Ig)G is the first antibody marker for any inflammatory central nervous system disorder, and is both sensitive and specific for NMO. Its target antigen, aquaporin-4, the most abundant water channel in the central nervous system, has opened up new research directions into demyelinating disorders of the central nervous system. The identification of NMO-IgG in patients with recurrent optic neuritis or longitudinally extensive myelitis and its ability to predict subsequent relapse support the concept of a spectrum of NMO disorders. Preliminary in vitro studies and recent immunopathological evidence support a role for NMO-IgG as the initiator of the NMO lesion. Definitive proof of pathogenesis is needed and will require the development of active immunization and passive transfer animal models, which will hopefully lead to more effective targeted therapies.     

Atypical presentations of neuromyelitis optica

Neuromyelitis optica (NMO) is an inflammatory disease of central nervous system classically characterized by acute, severe episodes of optic neuritis and longitudinally extensive transverse myelitis, usually with a relapsing course. The identification of an autoantibody exclusively detected in NMO patients against aquaporin-4 (AQP-4) has allowed identification of cases beyond the classical phenotype. Brain lesions, once thought as infrequent, can be observed in NMO patients, but lesions have different characteristics from the ones seen in multiple sclerosis. Additionally, some AQP-4 antibody positive patients may present with a variety of symptoms not being restricted to optic neuritis and acute myelitis during the first attack or in a relapse. Examples are not limited to, but may include patients only with brain and/or brainstem lesions, narcolepsy with hypothalamic lesions or patients with intractable hiccups, nausea and vomiting. The prompt identification of NMO patients with atypical presentations may benefit these patients with institution of early treatment to reduce disability and prevent further attacks.     

Rethinking neuromyelitis optica (Devic disease).

Neuromyelitis optica (NMO), or Devic disease, has been distinguished from multiple sclerosis (MS) by the presence of optic neuritis that is usually bilateral, simultaneous, and often severe, myelopathic findings accompanied by longitudinally extensive spinal cord imaging abnormalities, no brain imaging abnormalities typical of MS, and often rapid progression to debility and even death. Researchers at the Mayo Clinic have identified an immunoglobulin marker of NMO (the "NMO antibody") that binds selectively to the aquaphorin-4 water channel and may play a causative role. This marker has been found in Japanese patients with opticospinal MS, prompting the suggestion that NMO and Japanese opticospinal MS are the same disorder. The NMO antibody, which predicts frequent relapse of myelopathy and optic neuritis, is also found in patients with lupus erythematosus and Sj?gren syndrome who also have severe optic neuritis and longitudinally extensive myelitis. Because this antibody is also found in patients with optic neuritis and myelitis who have brain signal abnormalities atypical of MS, the diagnosis of NMO has been revised to allow inclusion of these brain imaging abnormalities. Proper distinction of NMO from MS is important because the two disorders may respond differently to immune modulatory therapy.     

NMO-IgG positive neuromyelitis optica in a patient with myasthenia gravis but no thymectomy

Here we report on a 44-year old woman presenting with both myasthenia gravis (MG) and neuromyelitis optica (NMO). MRI showed transverse myelitis extending from C2 to T4, multifocal demyelinating lesions in the supratentorial white matter, and left optic neuritis. Serological analysis demonstrated antibodies to acetylcholine receptors as well as NMO-IgG. To our knowledge, this is the first case of NMO-IgG positive NMO in a patient with MG but no history of thymectomy or immunosuppression.     

Detection of anti-aquaporin-4 antibodies in neuromyelitis optica: current status of the assays

BACKGROUND: Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease that predominantly affects the optic nerve and spinal cord. Since the discovery of a specific serum marker for NMO in 2004, and its subsequent identification as an antibody to aquaporin-4 (AQP-4), various methods have been developed to test for the antibodies in patients sera. OBJECTIVE: To assess the principal methods used to measure AQP-4 antibodies in patients sera, describe their contribution to neuromyelitis spectrum disease and examine their value in the early detection of disease. METHODS: We compared the published data on each assay and used the relapsing NMO cohort as a uniform patient group for direct assay comparison. RESULTS: The indirect immunofluorescence assay, a cellbased assay (CBA) and a fluorescence-based immunoprecipitation assay have broadly similar high sensitivities (86%, 91% and 83%) in the relapsing cohort, but the indirect immunofluorescence has a lower specificity (91%) compared with the other two (both 100% specific). CONCLUSIONS: The indirect immunofluorescence assay for NMO-IgG allows the detection of antibodies in routine screening, but the CBA for AQP-4 antibodies is the most sensitive. The fluoroimmunoprecipitation assay is a potentially high-throughput test for identifying positive sera and for serial estimations of antibody levels, but in its present form is slightly less sensitive. Overall, these assays are proving very useful in helping to diagnose those patients with longitudinally extensive transverse myelitis or recurrent optic neuritis who are likely to have relapsing NMO, including patients with myelopathy and Sjogrens syndrome, but it appears to be less often positive in patients with monophasic NMO.     

The emerging relationship between neuromyelitis optica and systemic rheumatologic autoimmune disease

Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) are associated with autoantibodies that target aquaporin-4 and, in many cases, multiple other autoantibodies, including antinuclear antibody and antibodies to extractable nuclear antigens. The clinical syndromes that define NMO and NMOSD, especially longitudinally extensive transverse myelitis and optic neuritis, can also occur in the context of established rheumatologic diseases such as systemic lupus erythematosus and Sj?gren syndrome and other organ-specific autoimmune diseases. These observations raise questions fundamental to both clinical practice and etiologic research. For example, they could suggest that NMO is one manifestation of a genetic tendency toward humoral autoimmunity. Alternatively, they might indicate that NMO is a central nervous system complication of a multisystem rheumatologic disease. We describe the historical background of this controversy, summarize the current evidence that addresses NMO-systemic autoimmunity relationships, and discuss the practical implications for clinical management.     

Revised diagnostic criteria for neuromyelitis optica (NMO)

We analyzed neuromyelitis optica (NMO) IgG in the serum or CSF samples from 46 patients with suspected NMO (28) and limited forms of NMO (18). One hundred and fifteen samples from multiple sclerosis (MS) patients were included as controls. The final clinical diagnosis after follow-up was 16 NMO, 12 MS, 11 transverse myelitis (TM) and seven recurrent optic neuritis (RON). NMO-IgG was detected in 62.5% of NMO, 50% of the recurrent longitudinally extensive TM, 14.3% of the RON but in none of the MS patients. The authors then compared the newly revised diagnostic criteria for NMO with the criteria published in 1999, in the 28 patients with suspected NMO. The revised criteria had higher specificity, and positive and negative predictive value (83.3% vs. 25%; 87.5% vs. 62.5; 83.3% vs. 75%), but slightly lower sensitivity (87.5% vs. 93.7%). Our study confirms NMO-IgG as a highly specific marker of NMO, and the usefulness of the revised diagnostic criteria in predicting a diagnosis of NMO.     

Neuromyelitis optica

Neuromyelitis optica (NMO), otherwise known as Devic's disease, is an idiopathic, severe, inflammatory disorder that preferentially affects the optic nerves and spinal cord. Clinical, laboratory and immunopathological evidence suggests that NMO is a humorally mediated disease distinct from MS. A spinal cord lesion extending contiguously over three or more vertebral segments is characteristic of NMO and, in combination with a cranial magnetic resonance imaging scan that does not meet radiological criteria for MS, is over 94% sensitive and 96% specific for NMO diagnosis. The serum autoantibody marker, neuromyelitis optica-immunoglobulin G (NMO-IgG), appears specific for NMO and suggests that the disease spectrum includes cases of recurrent longitudinally extensive transverse myelitis and Japanese opticospinal MS. Its target antigen is the water channel aquaporin-4, suggesting that NMO may represent a novel autoimmune channelopathy. Relapsing NMO has a poor prognosis; therapy, typically with immunosuppression, is necessary as early as possible in the disease course to prevent attack-related disability.     

Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS) with a poor prognosis in terms of the optic-spinal function. Recently, a serum autoantibody (NMO-IgG) binding to the blood-brain barrier region was detected exclusively in patients with NMO and its high risk group. We treated six NMO-IgG-positive patients (all female; age 21-67 years old, median 41; three with optic neuritis and three with myelitis) who were unresponsive to high-dose intravenous methylprednisolone (HIMP), with plasma exchange (PE) (three to five exchanges, 2-3 L each). Three of the patients (one with optic neuritis and two with myelitis) showed definite functional improvement following PE. The clinical improvement started to appear after one or two exchanges, while there was little or no improvement in the other three patients. Such quick clinical responses to PE suggest a pathogenetic role of humoral immune factors in NMO, although delayed responses to the corticosteroid therapy might have contributed to the therapeutic efficacy, in part. Further clinical and in vitro studies are needed to determine whether the removal of NMO-IgG is directly relevant to the therapeutic efficacy. PE may hasten the functional recovery from corticosteroid-resistant relapses in some NMO-IgG-positive patients with NMO.     

Neuromyelitis optica: atipic clinic presentation

We present a patient with neuromyelitis optica who exhibited longitudinally extensive transverse myelitis and aquaporin-4 IgG positivity. Patient did not have optic neuritis clinically, but we detected it with examination of visual evoked potentials (prolonged P100 wave latans), subclinically. We argue that neuromyelitis optica may also be considered in elderly patients with isolated involvement of the longitudinally extensive transverse myelitis, and visually evoked potential evaluation is important to determine of subclinic optic neuritis and anti-AQP-4 is also important to support to determination.     

Espectro de neuromielitis óptica: ¿seropositivo para la anticuaporina es una entidad diferente de los pacientes que son seronegativos? Una perspectiva de Colombia

IntroductionNeuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterised by attacks of optic neuritis and longitudinally extensive transverse myelitis. The discovery of anti–aquaporin-4 (anti-AQP4) antibodies and specific brain MRI findings as diagnostic biomarkers have enabled the recognition of a broader and more detailed clinical phenotype, known as neuromyelitis optica spectrum disorder (NMOSD).ObjectiveThis study aimed to determine the demographic and clinical characteristics of patients with NMO/NMOSD with and without seropositivity for anti-AQP4 antibodies, in 2 quaternary-level hospitals in Bogotá.MethodsOur study included patients > 18 years of age and diagnosed with NMO/NMOSD and for whom imaging and serology results were available, assessed between 2013 and 2017 at the neurology departments of hospitals providing highly complex care. Demographic, clinical, and imaging data were gathered and compared in patients with and without seropositivity for anti-AQP4 antibodies.ResultsThe sample included 35 patients with NMO/NMOSD; the median age of onset was 46.5 years (P25-P75, 34.2-54.0); most patients had sensory (n = 25) and motor manifestations (n = 26), and a concomitant autoimmune disease was identified in 6. Twenty patients were seropositive for anti-AQP4 antibodies. Only age and presence of optic nerve involvement showed statistically significant differences between groups (p = .03).ConclusionsClinical, imaging, and laboratory variables showed no major differences between patients with and without anti-AQP4 antibodies, with the exception of age of onset and presence of optic nerve involvement (uni- or bilateral); these factors should be studied in greater detail in larger populations.     

Brain magnetic resonance imaging findings in acute relapses of neuromyelitis optica spectrum disorders

We studied cranial magnetic resonance imaging (MRI) lesions in three women with acute attacks of recurrent longitudinally extensive transverse myelitis (r-LETM), recurrent-optic neuritis (r-ON) and r-LETM-CNS. Neuromyelitis Optica -immunoglobulin (IgG) antibody was positive in all cases. Brain MRI (1.5 Tesla) was performed according to protocol from consortium MS centre. We described the cranial lesions in brain MRI of acute relapses. These lesions were different from MS, most had an asymptomatic course which disappeared with time, protocol from consortium of MS centre criteria for brain MRI and seropositivity of NMO-IgG are useful tools for differentiate acute lesions of NMO/MS.