Neuromyelitis Optica Spectrum Research Articles

Syndrome of inappropriate antidiuretic hormone secretion in patients with aquaporin-4 antibody.

The objective of this study was to analyze the frequency of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with positive aquaporin-4 (AQP4) antibodies and evaluate the relationship between SIADH and hypothalamic lesions in patients with NMO and NMO spectrum disorder (NMOSD). AQP4 antibodies were tested by an indirect immunofluorescence assay employing HEK-293 cells transfected with recombinant human AQP4. Clinical data of patients were analyzed retrospectively. In total, 192 patients with AQP4 antibodies were certified, of which 41 patients (21.4 %) were included in the present study. Six patients (14.6 %, 6/41) met the criteria of SIADH, of which hyponatremia was mild in one patient, and severe in five. Five patients experienced confusion or decreased consciousness. Four patients were diagnosed with NMO and two were diagnosed with recurrent optic neuritis. Magnetic resonance imaging showed 11 of 41 patients (26.8 %) had hypothalamic lesions. All patients with SIADH had hypothalamic abnormalities. Hyponatremia resolved in all patients after intravenous methylprednisolone and intravenous immunoglobulin therapy. SIADH is not rare in patients with NMO/NMOSD, especially in patients with lesions close to the hypothalamus.

The developmental history of study on neuromyelitis optica

In 19th century, neuromyelitis optica (NMO) indicated optic neuritis and myelitis with simultaneous onset of both sides. Later studies proposed that the onset of right or left side optic neuritis could be separated by weeks, months even years. The revolutionary discovery of aquaporin 4 (AQP4) antibody in 2004 by Vanda A Lennon challenged and changed the old concept of NMO. The concept of neuromyelitis optica spectrum disorders (NMOSDs) was proposed in 2007. Since then, a series of different terms have been proposed, including opticospinal multiple sclerosis (OSMS), NMOSDs, spectrum of NMO, expanded spectrum of NMO, etc. Through a summary of different concepts of NMO, this paper will make a comprehensive review on the evolution history of NMO study from 19th to 21st century, and the prospective targets of study will also be proposed. doi: 10.3969/j.issn.1672-6731.2014.09.002

Low levels of vitamin D in neuromyelitis optica spectrum disorder: association with disease disability.

Patients with autoimmune disorders often have low levels of 25-hydroxyvitamin D [25(OH)D3], which correlates with disability or disease activity. Vitamin D may play a role in neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), as an important factor involved in immunological pathways. We investigated the relationship between vitamin D levels and disease related disability and clinical activity in patients with NMOSD. Blood samples from 51 patients with NMOSD who were positive for anti-aquaporin4-antibody (AQP4-ab) and 204 healthy controls were collected for 25(OH)D3 measurement. Clinical parameters, including expanded disability status scale (EDSS) score, annualized relapse rate (ARR) and time of blood sampling relative to attack, were determined in patients with NMOSD. We found that 25(OH)D3 levels were significantly lower in patients with NMOSD compared to healthy controls. There was no difference between 25(OH)D3 levels in blood samples taken at relapse or remission, and no association between 25(OH)D3 levels and ARR, but there was an inverse correlation between 25(OH)D3 levels and EDSS scores in patients with NMOSD. It remains to be determined whether low vitamin D levels predispose to NMO and/or modify disease severity, or are secondary to neurological disability. In either case the results could also be of relevance to other neurological diseases such as multiple sclerosis as well as NMO.

Vomiting and Singultus As Presenting Signs and Symptoms of Neuromyelitis Optica Spectrum Disorder in a 14-Year-Old Boy

Background: Neuromyelitis optica (NMO) is a rare degenerative disorder of the central nervous system affecting mainly optic nerves and spinal cord. It often leads to devastating visual and motor disabilities with a 5-year mortality of 30%; so early recognition and treatment are important. Obligatory criteria for diagnosis are transverse myelitis and optic neuritis in the absence of defining criteria for multiple sclerosis and ADEM. Aquaporin-4-receptor antibody seropositivity is diagnostic as it has been detected exclusively in sera of patients with NMO and neuromyelitis spectrum disorders (NMOSD). In children, presentation may differ from adult onset NMO and is characterized by frequent brain involvement.

AN OCCULT DISEASE… AND ONE THAT CHANGED MY PRACTISE

Neuromyelitis optica (NMO) and NMO spectrum disorder are well characterized demyelinating neurological conditions with established but evolving diagnostic criteria. Antibody mediated inflammation underpins their aetiology, in particular relating to antibodies to the aquaporin-4 transmembrane channel. NMO forms an important differential diagnosis to multiple sclerosis, requires a different treatment strategy and is therefore important to discriminate. A middle-aged woman presented with an acute inflammatory encephalopathy with subsequent brainstem relapse. Aquaporin-4 antibodies were positive. Following routine examination, a breast lump, subsequently diagnosed as locally invasive adenocarcinoma of the breast, was diagnosed. This was surgically resected. Initially treatment with methylprednisolone, and a subsequent course of plasma exchange with adjuvant chemotherapy led to an exponential recovery; 18 months later repeat antibody titres were negative and the patient had a residual mild spastic quadraparesis and ataxia. This case complements an evolving data set of paraneoplastic NMO and highlights the need to consider underlying neoplasia when making this diagnosis. Specific treatment of such underlying pathology, alongside appropriate immunosuppressive treatments, remain key therapies in this context and can secure a sustained neurological recovery.

IVIG IN NMO REFRACTORY/INTOLERANT TO RITUXIMAB

Background Neuromyelitis optica (NMO) is typically a severe relapsing inflammatory disease of optic nerves and spinal cord. Prednisolone, Azathioprine, Mycophenolate and Methotrexate are commonly used first-line immunosuppressants, stepping up to Rituximab if relapses occur. Results We report 3 NMO/ NMO spectrum disorder patients who stabilised on maintenance IVIG. Case 1: A 26 year-old woman who had 11 relapses over 10 years despite multiple immunosuppressants (including Rituximab) has remained in remission for 23 months with IVIG. Case 2: A 47 year old woman with 6 relapses over 8 years despite immunosuppressants was started on Rituximab with good effect. But Rituximab had to be discontinued due to respiratory problems. After starting 6 weekly IVIG infusions she has had no further relapses after 2.8 years. Case 3: A 59 year old woman with Aquaporin-4 antibody positive NMO spectrum disorder (3 episodes of severe optic neuritis over 5 years) was intolerant to Azathioprine (leukopenia). As baseline CD 19 counts were near 0, Rituximab was not given and she was initiated on 6 weekly IVIG and remains relapse free after 11 months. Conclusions IVIG seems to be effective in preventing NMO relapses.

FREQUENCY OF BLADDER, BOWEL AND SEXUAL DYSFUNCTION IN NMO

BackgroundThe impairment of mobility due the severe myelitis in NMO is well known, but the effect on bladder, bowel and sexual function is not reported. We report the frequency of...

Antibodies, MRI and unusual clinical features of NMO

AbstractNeuromyelitis optica (NMO) is a rare disease including both optic neuritis and myelitis together or successively. Recently, a specific antibody named anti‐NMO has been discovered allowing a more precise diagnosis. This antibody is directed againbst abti‐AQP4 protein, a watter chanel protein. This discovery enlarged the spectrum of NMO to patients with recurrent optic neuritis and positive antibodies, now include in the NMO spectrum disorder (NMOSD). MRI frequently shows intense hypersignal of optic nerve and spinal cord with normal or atypical brain MRI for MS. NMO is frequently associated with other auto‐immune diseases such as Sjogren syndrome ou lupus. The outcome of the disease may be severe with blindness and para/tetraplegia implying that an intensive treatment should be propose as soon as the diagnosis has been made.

Neuromyelitis optica spectrum disorders.

Since the discovery of aquaporin 4-IgG, a sensitive and highly specific biomarker of neuromyelitis optica (NMO), a wide range of syndromes have been recognized as being associated with this condition. This observation has led to new proposed terminology for the entire disorder, NMO spectrum disorders (NMOSD). The discovery of a pathogenic autoantibody and its target antigen has also facilitated basic research into the immunopathogenesis of the disease. Key advances include establishment of passive transfer animal models demonstrating the pathogenic potential of the autoantibody and confirming an important role of complement suggested by immunopathology of NMO brain lesions and of B-cell subsets, plasmablasts in particular. These discoveries have led to phase 1 clinical trials of targeted immunotherapy with potential for improved efficacy and less toxicity than current empiric immunosuppressant medications used to treat NMOSD. Randomized clinical trials are beginning to assess the efficacy and safety of a variety of immunotherapies in NMOSD. Therapeutic options are likely to increase, and improved outcomes in NMOSD patients are anticipated.

Neuromyelitis optica spectrum disorders associated with other autoimmune diseases

Neuromyelitis optica (NMO) is an inflammatory demyelinating autoimmune disease with severe, tremendously incapacitating, consequences in the patient's health and wellbeing. Until 2004, NMO was considered a restricted type of multiple sclerosis but in the same year an auto-antibody reacting against aquaporin-4 (NMO-IgG) was found to be related with NMO and it was considered the main etiologic agent of this disease. Its detection is very sensitive and specific allowing an early diagnosis and a better treatment and prognosis. With this tool, a spectrum of diseases including other autoimmune diseases was found to have NMO-IgG antibodies and a new classification named NMO spectrum disorders was created. In this review, we sum up the developments in this field associated with other autoimmune diseases. We approach the latest discoveries in the diagnosis like the new biomarkers that will possibly be used in the close future or the developments in the neuroimaging techniques. We reviewed the literature and synthesized case reports of NMO patients with concurrent autoimmune diseases and the information from useful larger studies. Finally, we summarize the commonly used treatments in NMO and we try to specify the best treatment for NMO with simultaneous autoimmune disease. This review updates the information about this issue and raises the awareness of rheumatologists for these severe diseases.

Longitudinally extensive transverse myelitis.

Longitudinally extensive transverse myelitis (LETM) is a frequently devastating clinical syndrome which has come into focus for its association with neuromyelitis optica (NMO). Recent advances in the diagnosis of NMO have led to very sensitive and specific tests and advances in therapy for this disorder. LETM is not pathognomonic of NMO, therefore it is important to investigate for other causes of myelopathy in these patients. This review aims to discuss recent advances in NMO diagnosis and treatment, and to discuss the differential diagnosis in patients presenting with LETM. Fluorescence-activated cell sorting and cell binding assays for NMO-IgG are the most sensitive for detecting NMO spectrum disorders. Patients who have a clinical presentation of NMO, who have been tested with older ELISA or immunofluorescence assay and been found to be negative, should be retested with a fluorescence-activated cell sorting assay when available, particularly in the presence of recurrent LETM. Novel therapeutic strategies for LETM in the context of NMO include eculizumab, which could be considered in patients with active disease who have failed azathioprine and rituximab. Thorough investigation of patients with LETM who are negative for NMO-IgG may lead to an alternate cause for myelopathy. LETM is a heterogeneous condition. Novel treatment strategies are available for NMO, but other causes need to be excluded in NMO-IgG-seronegative patients.

Predictors of recurrence following an initial episode of transverse myelitis.

Objective:This study sought to identify factors that increased the risk of recurrence after an initial transverse myelitis (TM) presentation.Methods:Retrospective cohort study of 192 patients initially presenting with TM of unknown etiology. Patients diagnosed with multiple sclerosis during the first myelitis episode were excluded. Demographic and laboratory data were analyzed for associations with recurrence.Results:One hundred ten of 192 patients (57%) eventually developed recurrent symptoms: 69 (63%) neuromyelitis optica (NMO) or NMO spectrum disorder, 34 (31%) non-NMO recurrent TM, and 7 (6%) systemic autoimmune disease. Multiple independent risk factors for recurrence were identified: African American race (risk ratio 1.60, p < 0.001, 95% confidence interval 1.26–2.03; similarly noted hereafter), female sex (1.88, p = 0.007, 1.19–2.98), longitudinally extensive myelitis at onset (1.34, p = 0.036, 1.01–1.78), Sjogren syndrome antigen A (1.89, p = 0.003, 1.44–2.48), vitamin D insufficiency (4.00, p < 0.001, 1.60–10.0), antinuclear antibody titer ≥1:160 (1.69, p = 0.006, 1.23–2.32), and the presence of inflammatory markers (e.g., immunoglobulin G index) in the CSF (2.14, p < 0.001, 1.44–3.17).Conclusions:Sex, race, and serologic biomarkers warrant consideration when assessing risk of TM recurrence. Male sex and Caucasian American race were independently associated with risk of monophasic idiopathic TM. Recurrence risk in female and African American patients appears driven by a greater likelihood of developing NMO or NMO spectrum disorder.

Purified human C1-esterase inhibitor is safe in acute relapses of neuromyelitis optica.

Objective:To minimize complement-mediated damage in acute relapses of neuromyelitis optica (NMO) by adding treatment with a complement inhibitor, purified C1-esterase inhibitor, to the current standard of care (high-dose glucocorticoids).Method:We conducted an open-label phase 1b safety and proof-of-concept trial in 10 patients with NMO–immunoglobulin G seropositive NMO or NMO spectrum disease (NMOSD) who presented with acute transverse myelitis and/or optic neuritis. In addition to treating with 1 g of daily IV methylprednisolone, we infused 2,000 units of C1-esterase inhibitor daily for 3 days, beginning on day 1 of hospitalization. The primary outcome measure was safety, and the secondary efficacy measure was change in Expanded Disability Status Scale (EDSS) scores.Results:Ten patients with NMO/NMOSD were enrolled, 7 of whom presented with acute transverse myelitis and 3 with acute optic neuritis. C1-esterase inhibitor proved to be safe in all 10 patients, with no serious adverse events recorded. There were no thromboembolic events or related lab abnormalities in any of the subjects. EDSS scores dropped from a median of 4.5 on admission to 4.0 on discharge and then down to 2.5 on 30-day follow-up. All but 1 patient returned to preattack EDSS or better and only 2 patients required escalation to plasmapheresis.Conclusions:C1-esterase inhibitor is a safe add-on therapy for patients with NMO/NMOSD presenting with acute transverse myelitis and optic neuritis. Preliminary evidence suggests a promising benefit with C1-esterase inhibitor in reducing neurologic damage and improving outcomes. A placebo-controlled trial is necessary to confirm these findings.Classification of evidence:This study provides Class IV evidence that for patients with NMO with acute transverse myelitis or optic neuritis, C1-esterase inhibitor is safe and improves disability.

Spotlight on the April 15 Issue

Seven patients with anti-aquaporin-4 antibody–positive neuromyelitis optica (NMO) or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment. This study showed that monthly IV injections of tocilizumab, an anti–interleukin-6 receptor antibody, reduced relapses, neurogenic pain, and fatigue in patients with NMO. See p. 1302 From editorialists Rose-John & Gold: “Given the expression pattern of IL-6, targeting the bioactivity of this cytokine is a rational therapeutic approach for the treatment of autoimmune diseases.” See p. 1294 Combining advanced structural and functional imaging …

Neuromyelitis Optica Spectrum with Autoantibodies Against Myelin-Oligodendrocyte Glycoprotein Have Distinct Clinical Features and Prognosis from Seronegative Patients (S63.006)

Neuromyelitis Optica Spectrum with Autoantibodies Against Myelin-Oligodendrocyte Glycoprotein Have Distinct Clinical Features and Prognosis from Seronegative Patients (S63.006)

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

Background: Azathioprine (AZA) is a common immunosuppressive drug used for relapse prevention in neuromyelitis optica (NMO). Objectives: The objective of this paper is to assess efficacy, tolerability and retention of AZA in a large NMO cohort. Methods: We conducted a retrospective review of medical records of 103 aquaporin-4 antibody-positive NMO and NMO spectrum disorder (NMOSD) patients treated with AZA. Results: This is the largest reported cohort of AQP4-Ab positive patients treated with AZA. Eighty-nine per cent (n = 92) had reduction in median annualised relapse rates from 1.5 (IQR 0.6–4.0) to 0 (IQR 0–0.27, p < 0.00005) with treatment. Sixty-one per cent (n = 63) remained relapse free at a median follow-up of 18 months. Neurological function improved or stabilised in 78%. At last follow-up, treatment was discontinued in 46% (n = 47). Of these, 62% (n = 29) were because of side effects, 19% (n = 9) because of death, 15% (n = 7) because of ongoing disease activity, and 2% (n = 1) because of pregnancy. Using Kaplan-Meyer curves, we estimate that 73%, 58%, 47% and 33% of patients will remain on AZA for longer than one, three, five and 10 years, respectively, after initiation of treatment. Conclusions: AZA is a modestly effective treatment for NMO. However, many patients discontinue AZA over time and this seems to reflect poor tolerability more than lack of efficacy.

Efficacy of the anti–IL-6 receptor antibody tocilizumab in neuromyelitis optica

Objective:To evaluate the safety and efficacy of a humanized anti–interleukin-6 receptor antibody, tocilizumab (TCZ), in patients with neuromyelitis optica (NMO).Methods:Seven patients with anti–aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment. They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year. We evaluated the annualized relapse rate, the Expanded Disability Status Scale score, and numerical rating scales for neurogenic pain and fatigue. Serum levels of anti-AQP4-Ab were measured with AQP4-transfected cells.Results:Six females and one male with NMO were enrolled. After a year of TCZ treatment, the annualized relapse rate decreased from 2.9 ± 1.1 to 0.4 ± 0.8 (p < 0.005). The Expanded Disability Status Scale score, neuropathic pain, and general fatigue also declined significantly. The ameliorating effects on intractable pain exceeded expectations.Conclusion:Interleukin-6 receptor blockade is a promising therapeutic option for NMO.Classification of evidence:This study provides Class IV evidence that in patients with NMO, TCZ reduces relapse rate, neuropathic pain, and fatigue.

Antineutrophil Cytoplasmic Antibodies in Patients with Idiopathic Inflammatory-Demyelinating Diseases

Objective: We assessed the clinical significance of antineutrophil cytoplasm antibodies (ANCA) in patients with idiopathic inflammatory-demyelinating disease (IIDD). Methods: A consecutive cohort of 269 subjects with IIDD and 595 controls was analyzed retrospectively. Results: Among all subjects, ANCA positivity rates were low [9.5% in a perinuclear pattern (pANCA) and 2.3% in a cytoplasmic pattern (cANCA)]. One of the 117 patients with multiple sclerosis (MS) had cANCA and 2 had pANCA. Ten patients with neuromyelitis optica (NMO; 13.9%) had pANCA and 3 (4.2%) had cANCA. Four patients with recurrent longitudinal extensive transverse myelitis (RLETM; 19.0%) had pANCA and 1 (4.8%) had cANCA. In monophasic TM, 22.9% were pANCA seropositive. Among patients with brainstem syndromes, 14.3% were pANCA seropositive. Patients with NMO, RLETM or monophasic TM had higher pANCA levels than patients with MS. There was a positive association between spinal cord (SC) lesions and ANCA, and especially between longitudinal extensive transverse myelitis and ANCA. Among anti-aquaporin 4 antibody-positive patients, ANCA-positive patients (n = 16) were older and had higher Expanded Disability Status Scale scores, more antinuclear antibodies, longer SC lesions and fewer brain abnormalities than the ANCA-negative patients (n = 68). In the NMO subgroup, ANCA-positive patients were older and had more antinuclear antibodies and longer SC lesions than ANCA-negative patients. Conclusion: Among the IIDDs, we found a higher occurrence of ANCA in patients with NMO spectrum disorders than in patients with MS. Therefore, ANCA is another interesting marker of autoimmunity in IIDD patients, especially those with anti-aquaporin 4 antibody.

Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin‐4 channelopathies

AbstractWater channels are a recognized “novel” target for central nervous system, inflammatory, autoimmune, demyelinating diseases, and represent an evolving spectrum of disorders termed neuromyelitis optica (NMO) spectrum disorders (SD). These disorders should now be considered under the umbrella term “autoimmune aquaporin‐4 channelopathy”. NMOSD represent the first multiple sclerosis (MS)‐like disease for which a specific antigen has been identified – the astrocytic water channel aquaporin‐4 (AQP4). MS lacks a distinguishing biomarker. This discovery represents a seismic shift from historic emphasis on the oligodendrocyte and myelin to the astrocyte. The NMO of today represents a relapsing spectrum of disease, not necessarily restricted to the optic nerves and spinal cord, that is different from the monophasic disorder in which near simultaneous bilateral optic neuritis and transverse myelitis occur, as was originally described by Devic. Recent clinical, radiological and pathological findings have documented brain involvement in NMO spectrum disorders, particularly in children. Most patients with NMOSD have brain abnormalities on magnetic resonance imaging, and these are consistent with MS in up to 10% of patients. Others have lesions in areas that highly express AQP4 including the circumventricular organs accounting for intractable nausea and vomiting, and the syndrome of inappropriate antidiuresis as presenting symptoms or heralds of relapse. Diencephalic involvement might explain recently recognized sleep disorders and endocrinopathies. Continued progress in our understanding of the immunobiology of AQP4 autoimmunity necessitates continuing revision of the clinical diagnostic criteria for NMO spectrum disorders. As the clinical spectrum broadens, the importance of highly specific assays that detect pathogenic AQP4‐immunoglobulin G targeting extracellular epitopes of AQP4 cannot be overemphasized.

Comparison of Relapse and Treatment Failure Rates Among Patients With Neuromyelitis Optica

Neuromyelitis optica (NMO) is an inflammatory disease of the optic nerves and spinal cord that leads to blindness and paralysis. Effective immunosuppression is the standard of care for relapse prevention. To compare the relapse and treatment failure rates among patients receiving the 3 most common forms of immunosuppression for NMO: azathioprine, mycophenolate mofetil, and rituximab. We performed a retrospective, multicenter analysis of relapses in 90 patients with NMO and NMO spectrum disorder treated with azathioprine, mycophenolate, and/or rituximab at the Mayo Clinic and the Johns Hopkins Hospital during the past 10 years. Annualized relapse rates. Rituximab reduced the relapse rate up to 88.2%, with 2 in 3 patients achieving complete remission. Mycophenolate reduced the relapse rate by up to 87.4%, with a 36% failure rate. Azathioprine reduced the relapse rate by 72.1% but had a 53% failure rate despite concurrent use of prednisone. Initial treatment with rituximab, mycophenolate, and, to a lesser degree, azathioprine significantly reduces relapse rates in NMO and NMO spectrum disorder patients. Patients for whom initial treatment fails often achieve remission when treatment is switched from one to another of these drugs.