Relapsing Neuromyelitis Optica Research Articles

Neuromyelitis Optica in Child: Diagnostic and Therapeutic Challenges

Neuromyelitis optica (NMO) is a rare syndrome of severe inflammatory demyelination of the central nervous system, causing attacks of optic neuritis and transverse myelitis. Although uncommon, attention should be given to the proper identification and management of the affected patients. We present a case of a 13-year-old girl with severe neuromyelitis optica. The patient's initial presentation consisted of encephalopathy and optic neuritis. Approximately 2 months later, coinciding with the weaning of steroid treatment, she presented with ascending paralysis and respiratory failure. She was seropositive for NMO-IgG. Treatment included intravenous immune globulin, steroids, plasmapheresis, and rituximab and was complemented with proper nutrition, vitamins, minerals, and intense rehabilitation. Two years after the initial presentation and one short relapse, the patient has made a remarkable recovery without neurologic deficit. This report underscores the difficulty in making the initial diagnosis, choosing the best treatment, and the need for more streamlined pediatric guidelines for diagnosis, treatment, and prevention of relapses of pediatric NMO.

Abnormal nerve conduction study findings indicating the existence of peripheral neuropathy in multiple sclerosis and neuromyelitis optica.

Objective. Chronic inflammatory demyelinating polyneuropathy (CIDP) has been reported in patients with multiple sclerosis (MS). However, there have been limited reports of peripheral neuropathy as a complication of neuromyelitis optica (NMO). In this paper, we showed the characteristics and differences between peripheral neuropathy as a complication of MS and NMO. Method. We analyzed a series of 58 MS and 28 NMO patients and evaluated nerve conduction studies (NCS) in 21 MS and 5 NMO patients. Results. Six of the 58 MS and 3 of the 28 NMO patients revealed abnormal NCS findings. Three (5.2%) of the 58 MS patients fulfilled the criteria for CIDP. One (3.6%) of the 28 NMO patients showed peripheral neuropathy at the same time of NMO relapse, although CIDP was not seen in NMO. The other 5 (3 MS and 2 NMO) patients were complicated with neuropathy caused by concomitant diabetes mellitus and Sjögren's syndrome. Conclusion. Frequency of abnormal NCS findings might exhibit no significant difference between MS and NMO, although the cause and pathophysiology of peripheral neuropathy were different in MS and in NMO. There might be a group of NMO who were affected simultaneously in the central and peripheral nervous tissues.

Neuromyelitis Optica

Neuromyelitis optica (NMO) is a disabling inflammatory condition that targets astrocytes in the optic nerves and spinal cord. Neuro-ophthalmologists must be particularly aware of this disorder because about half of patients present as isolated unilateral optic neuritis months or years before a disease-defining and often crippling bout of myelitis. NMO is easily confused with multiple sclerosis because it is characterized by relapses that lead to stepwise accrual of deficits. The best predictor of conversion from optic neuritis to clinical definite NMO is the presence of a serum antibody to aquaporin-4 called NMO-IgG. However, this test is currently only about 75% sensitive. Suspicion of NMO should be high in patients who present with vision of light perception or worse or who are left with acuity of 20/50 or worse after optic neuritis and in those with simultaneous bilateral optic neuritis or recurrent attacks. Acute NMO relapses are generally treated with high-dose intravenous steroids, with plasma exchange often used as a rescue therapy for those who do not respond. Preventative strategies against relapses currently use broad-spectrum or selective B-lymphocyte immune suppression, but their use is based on small, generally uncontrolled studies. Hopefully, the future will bring more sensitive tools for defining risk and predicting outcome, as well as more targeted and effective forms of therapy.

Neuromyelitis Optica Relapse Associated with Pregnancy: Similarities to Multiple Sclerosis (P06.184)

Objective: To determine whether relapses of neuromyelitis optica (NMO) are associated with pregnancy. Background The risk of multiple sclerosis (MS) relapse is known to decrease markedly during pregnancy, particularly in the third trimester, and increase again in the first 3 months postpartum. However, little is known about the influence of pregnancy on the clinical course of NMO. Design/Methods: We retrospectively studied pregnant patients with NMO seen at Tokyo Women9s University Hospital, Tohoku University Hospital, or Juntendo University Hospital and diagnosed according to AQP4 antibody-positive findings and the revised criteria. We analyzed disease onset and/or relapse associated with pregnancy and investigated each trimester during pregnancy (1st, DP1; 2nd, DP2; 3rd, DP3) and each trimester postpartum (1st, PP1; 2nd, PP2; 3rd, PP3; 4th and over, PP4). Results: Among total 51 pregnant women diagnosed with NMO, we extracted 14 NMO patients (mean age at disease onset, 30.4±8.5 years; mean age at pregnancy, 32.6±6.6 years; these mean ages were lower than those of the general age at onset for NMO [39 years]). Total number of relapses was 17 among our patients. For each period, the number of relapses was 3 for DP1, 2 for DP2, 1 for DP3, 5 for PP1, 3 for PP2, 1 for PP3, 1 for PP4, and 1 immediately after elective abortion. NMO appeared to be associated with pregnancy in 6 patients, and the time of disease onset was more frequently postpartum (n=6) than during pregnancy (n=2) in these patients. Almost all of these patients delivered healthy babies. Conclusions: Our results suggest that NMO patients of childbearing age need to be aware of the potential for disease exacerbation and may be at a higher risk of relapse/disease onset postpartum compared to during pregnancy. The influence of pregnancy on NMO might bear some resemblance to MS. Supported by: A Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan. Disclosure: Dr. Shimizu has received personal compensation for activities with Bayer Yakuhin, Biogen Idec Japan, Teijin Pharma, and Novartis. Dr. Shimizu has received royalty payments for the Quick Reference Guide for Management. Dr. Ohashi has received personal compensation for activities with Bayer Yakuhin, Biogen Idec Japan, Teijin Pharma, and Novartis Pharma. Dr. Maruyama has nothing to disclose. Dr. Nakashima has received personal compensation for activities with Bayer Schering, Novartis, and Biogen Idec. Dr. Nakashima has received research support from Mitsubishi Chemical Medience Corporation and the Ministry of Education, Science, and Technology of Japan. Dr. Yokoyama has personal compensation for activities with Bayer Yakuhin, Biogen Idec Japan, Mitsubishi Tanabe Pharma, Teijin Pharma, Asteras Pharma, Daiichi Sankyo, Cosmic Corporation, Takeda Pharma, and AstraZeneca Pharmaceuticals. Dr. Fujihara has received personal compensation for Bayer Schering Pharma, Biogen Idec, Merck Serono, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, and Asahi Kasei Kuraray Medical Co., Ltd. Dr. Fujihara has received personal compensation in an editorial capacity for Clinical and Experimental Neuroimmunology. Dr. Fujihara has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, Eisai Inc., and Kyowa Pharmaceuticals America, Inc. Dr. Uchiyama has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Otsuka, Novartis, Boehringer Ingelheim Pharmaceuticals, Inc., and Daiichi Sankyo.

Treatment of Neuromyelitis Optica with Intravenous Immunoglobulin: Report of 8 Patients (P04.141)

Objective: Report the effect of IV immunoglobulin (IVIG) as a rescue therapy for patients with relapsing neuromyelitis optica (NMO) that have failed adequate immunosuppression. Background Treatment of NMO is based on case series that evidence benefit with immunosuppressive drugs (prednisone, azathioprine, micophenolate and rituximab). Plasmapheresis is recommended for patients with severe relapses or that keep on relapsing while on immunosuppressants. Because plasmapheresis is not immediately available in some Brazilian hospitals, requires a central line and the blood derived products, we implemented a program to use IVIG as a rescue therapy for those that kept on relapsing after an adequate immunosuppressant course. Design/Methods: Evaluation 8 patients with NMO that fulfilled the Wingerchuk 2006 criteria, followed at UNIFESP, that first received prednisone (0.5-1mg/kg) and azathioprine (2-3mg/kg) for preventing relapses and further received pulse IV immunoglobulin (IVIG) 2g/kg in five days every three to four months up to 5 years as rescue therapy. Efficacy was evaluated comparing annualized relapse rate (ARR) and progression index (PI) before and after IVIG use. Results: There were seven women and one man with mean age of 30 years and mean disease duration of 7.6 years; five were positive for the NMO-IgG. Reasons for IVIG indication were either severe relapse not improving after 5g IV methylprednisolone, inefficacy to reduce ARR or EDSS worsening. Two to ten cycles of IVIG were implemented to these eight patients; mean ARR decreased from 1.8 (±1.6) to 0.1 (±0.2) and mean PI from 1.5 (±1.6) to 0.9 (±0.6). One patient died due to severe encephalitic and brainstem relapse. Conclusions: IVIG provided additional short and long-term benefits in patients with NMO that have failed immunosuppression or suffered a severe relapse. The study for its use as a rescue therapy in places where plasmapheresis is unavailable should be encouraged based on these 7 patients that presented a positive response. Disclosure: Dr. Bichuetti has nothing to disclose. Dr. Boulos has nothing to disclose. Dr. Shinosaki has nothing to disclose. Dr. Souza has nothing to disclose. Dr. Oliveira has nothing to disclose. Dr. Gabbai has nothing to disclose.

Reduced serum uric acid levels in neuromyelitis optica: serum uric acid levels are reduced during relapses in NMO

Uric acid (UA), a product of purine metabolism, is known to be reduced in patients with various neurological disorders including multiple sclerosis (MS). However, it has still remained unclear whether there is a close relationship between UA and neuromyelitis optica (NMO). The aim of this study was to investigate the association between serum UA levels and disease activity in NMO. Retrospective analysis was made of blood samples during relapses (n=48) and during stable disease (n=49) from 20 patients with NMO. As controls, 59 blood samples during relapses from 39 patients with MS and 90 samples from healthy subjects were obtained. Spine magnetic resonance images (MRIs) performed during relapses (n=24) in NMO were analysed. The results indicated that UA levels during relapses in NMO were significantly lower compared to healthy subjects (P<0.01), but not different from those during relapses in MS, and that reduced UA levels during relapses in NMO were normalized during stable disease. However, UA levels during relapses were not correlated with Gd enhancement in spine MRI. UA levels are associated with clinical disease status in patients with NMO. Further investigations are recommended to elucidate the role of UA as a biomarker of disease activity in NMO.

Failure of Natalizumab to Prevent Relapses in Neuromyelitis Optica

To describe first experiences with the integrin inhibitor natalizumab, given to patients with suspected relapsing-remitting multiple sclerosis (MS) who were later diagnosed with aquaporin 4-positive neuromyelitis optica (NMO). Retrospective case series. Neurology departments at tertiary referral centers in Germany. Patients with NMO who tested positive for antibodies to aquaporin 4. Treatment with natalizumab. Relapses and accumulation of disability. We identified 5 patients (4 female; median age, 45 years) who were initially diagnosed with MS and treated with natalizumab before diagnosis of NMO was established. Natalizumab was given as escalation therapy after failure of first- or second-line immunomodulatory therapies for MS. During natalizumab therapy (median duration, 8 infusions; range, 2-11 infusions), all 5 patients displayed persisting disease activity; a total of 9 relapses occurred (median duration to relapse, 120 days; range, 45-230 days) after the start of treatment. Four patients had an accumulation of disability and 1 patient died 2 months after cessation of natalizumab treatment. Our results suggest that natalizumab fails to control disease activity in patients with NMO. Neuromyelitis optica should be considered as a differential diagnosis in patients with suspected MS who are unresponsive to natalizumab therapy.

Treatment of Neuromyelitis Optica

Neuromyelitis optica (NMO) or Devic's disease is an inflammatory neurologic disease characterized by severe optic neuritis and transverse myelitis. Other features of NMO include female preponderance, higher onset age, severe functional disability, longitudinally extensive spinal cord lesions (longer than 3 vertebral segments), and oligoclonal IgG bands negativity. Brain lesions are not uncommon in NMO. The relation between NMO and multiple sclerosis (MS) has long been a matter of controversy, but since the discovery of anti-aquaporin 4 (AQP4) antibody (NMO-IgG), an NMO-specific autoantibody, the clinical, MRI, and laboratory features that distinguish NMO from MS have been clarified. Anti-AQP4 antibody binds to the extracellular domain of AQP4, which is highly expressed in endfeet of astrocytes. Recent neuropathological studies, analysis of CSF-GFAP levels during relapse and experimental studies strongly suggest that NMO is an anti-AQP4 antibody-mediated astrocytopathic disease and that T cell-mediated CNS inflammation is necessary to develop NMO. Also, IL-6 is remarkably elevated in the CSF and appears to regulate plasmablasts to produce anti-AQP4 antibody. Therefore, from the therapeutic point of view, depletion of anti-AQP4 antibody, suppression of T cell response to trigger relapse and anti-IL-6 therapy seem to be pivotal. High-dose intravenous methylprednisolone is the first-line therapy for acute exacerbations of NMO. But plasma exchange should be started soon if corticosteroid is not efficacious. If untreated, AQP4 antibody-positive patients are highly likely to experience relapses within a year. Thus, immunosuppressive therapy (corticosteroids, immunosuppressants, rituximab) should be initiated without delay. Preliminary results suggest that eculizumab, an anti-C5 monoclonal antibody, can also prevent relapse in NMO, Meanwhile, interferon-beta, a first-line disease modifying drug of MS, is not effective in NMO. Symptomatic therapy for pain, paresthesia, spasticity, dysuria and constipation which commonly occur in the chronic stage of NMO is also important to improve patients' quality of life.

Elderly-Onset Neuromyelitis Optica which Developed after the Diagnosis of Prostate Adenocarcinoma and Relapsed after a 23-Valent Pneumococcal Polysaccharide Vaccination

We report a case of elderly-onset neuromyelitis optica (NMO) positive for the anti-aquaporin-4 (AQP-4) antibody; symptoms developed after the diagnosis of prostate adenocarcinoma and relapsed after a 23-valent pneumococcal polysaccharide vaccination. We suggest that activation of CD4-positive T cells and secretion of interferon-gamma induced by adenocarcinoma and complement activation induced by vaccination are responsible for the onset and relapse of NMO, even if a patient is positive for the anti-AQP-4 antibody. This case supports the previous experimental finding that the anti-AQP-4 antibody does not cause NMO-like lesions when injected alone, but does so after the induction of T cell-mediated experimental autoimmune encephalomyelitis or when co-injected with human complement.

The Diagnostic and Prognostic Value of Neurofilament Heavy Chain Levels in Immune-Mediated Optic Neuropathies

Background. Loss of visual function differs between immune-mediated optic neuropathies and is related to axonal loss in the optic nerve. This study investigated the diagnostic and prognostic value of a biomarker for neurodegeneration, the neurofilament heavy chain (NfH) in three immune-mediated optic neuropathies. Methods. A prospective, longitudinal study including patients with optic neuritis due to multiple sclerosis (MSON, n = 20), chronic relapsing inflammatory optic neuritis (CRION, n = 19), neuromyelitis optica (NMO, n = 9), and healthy controls (n = 28). Serum NfH-SMI35 levels were quantified by ELISA. Findings. Serum NfH-SMI35 levels were highest in patients with NMO (mean 0.79 ± 1.51 ng/mL) compared to patients with CRION (0.13 ± 0.16 ng/mL, P = 0.007), MSON (0.09 ± 0.09, P = 0.008), and healthy controls (0.01 ± 0.02 ng/mL, P = 0.001). High serum NfH-SMI35 levels were related to poor visual outcome. Conclusions. Blood NfH-SMI35 levels are of moderate diagnostic and more important prognostic value in immune-mediated optic neuropathies. We speculate that longitudinal blood NfH levels may help to identify particular disabling events in relapsing conditions.

Successful treatment of a woman with relapsing neuromyelitis optica by interferon beta

Neuromyelitis optica (NMO) is an antibody-mediated disease with the target antigen being the water channel aquaporin-4 (AQP4). More than 90% of NMO patients have relapse. Optimal treatments to prevent recurrence have not been established. Previous reports suggest that interferon beta (IFNB) has not been effective in NMO. However, we present a case of NMO with positive anti-myelin oligodendrocyte glycoprotein (MOG)(27-38) IgG and anti-AQP4 IgG treated with IFNB-1a successfully. The effect of IFNB on NMO and the role of anti-MOG antibodies in NMO deserve further study.

Diffusion tensor imaging characterization of occult brain damage in relapsing neuromyelitis optica using 3.0T magnetic resonance imaging techniques

Studies of relapsing neuromyelitis optica (RNMO) using advanced MRI techniques are limited compared with those done on multiple sclerosis (MS). The present study used diffusion tensor imaging (DTI) to investigate whether occult brain damage exists in RNMO patients. DTI scans using a 3.0T MRI scanner were performed in 24 clinically confirmed RNMO patients whose conventional brain MRI results were normal, and also in 24 age- and sex-matched healthy control subjects. DTI data were processed to generate fractional anisotropy (FA) and mean diffusivity (MD) maps, and region of interest (ROI) analyses were performed to obtain these parameters in white matter (including medulla oblongata, cerebral peduncle, optic radiation, genu of corpus callosum, splenium of corpus callosum, and internal capsule) and gray matter (including thalamus and putamen). Regional measures from patients at stable and acute phases were compared with healthy controls. Both acute and stable NMO patients had a higher average FA in ROIs of the thalamus and putamen. Acute NMO patients had significantly higher average MDs than controls in the genu of corpus callosum and optic radiation, and significantly lower average MDs in the medulla oblongata. Stable NMO patients had increased MDs in the genu of corpus callosum and optic radiation, but lower MDs in the medulla oblongata, internal capsule and thalamus. The DTI findings confirm the presence of occult tissue damage in normal-appearance white and gray matter, especially deep gray matter, in RNMO patients. This study adds further to the evidence that DTI is suitable as a tool for characterizing subtle brain tissue damage.

Systemic Lupus Erythematosus (SLE) Complicated by Neuromyelitis Optica: Case Series from a Tertiary Paediatric Rheumatology Centre

Objective: To identify the presence of Neuromyelitis optica (NMO) in juvenile SLE patients.Background: NMO is a rare autoimmune demyelinating disease of the central nervous system, manifesting with transverse myelitis involving three or more continuous spinal segments and optic neuritis in the presence of NMO-IgG antibodies.Methods: Retrospective study of SLE patients with CNS symptoms, diagnosed from 2000 to2010 and review of clinical data, laboratory and MRI findings.Setting: A tertiary referral centre for juvenile SLE.Results: A total of 210 SLE patients were indentified, 39 of which had manifestations of potential CNS involvement and underwent CNS imaging including the spinal cord. Three were indentified with probable NMO, which was confirmed in two (0.9%). Both patients were adolescent females of Caucasian origin. In one patient NMO was the first manifestation of SLE. In the other NMO developed three years following diagnosis of SLE. They both presented with deterioration of visual acuity, localized spinal tenderness and malaise. NMO was confirmed based on MRI findings and the presence of raised Aquaporin-4-IgG-antibodies. NMO had a relapsing course and interestingly NMO relapses coincided with SLE disease flare-up, both of which responded to treatment simultaneously.Discussion: SLE is a multisystemic autoimmune disease and 25% of patients develop CNS involvement. While NMO has been described in adult patients with SLE, these cases derive specifically from a paediatric population. We believe that SLE and NMO are parts of the same disease spectrum. When this condition is noticed in patients with refractory, long standing SLE, prognosis is guarded.

Severe Gastroparesis in Neuromyelitis Optica: Response to Corticosteroids

Purpose: Introduction: Gastroparesis has been rarely associated with demyelinating lesions involving the medulla. We describe a case of severe gastroparesis associated with neuromyelitis optica (Devic's disease) involving the medulla. The patient was refractory to all antiemetics and prokinetics. Her gastrointestinal and neurological symptoms responded rapidly and dramatically to corticosteroids. Case Report: A 41 year old female with a history of optic neuritis presented with severe nausea, vomiting, and intractable hiccups of 2 months duration. She lost 40 lbs. Physical examination was unremarkable other than signs of recent weight loss. Laboratory evaluation was normal for complete blood count, comprehensive metabolic panel, and thyroid function. Negative evaluation included upper endoscopy, small bowel follow through x-ray, CT scan of the abdomen and gallbladder ultrasound. Hepatobiliary scan showed no gallbladder emptying, consistent with gallbladder dyskinesia. Gastric emptying scan revealed markedly delayed emptying with a half-time emptying of 532 minutes (normal < 90 minutes), consistent with severe gastroparesis. She did not respond to proton pump inhibitors, metoclopramide, erythromycin, domperidone, ondansetron, scopolamine, prochlorperazine, promethazine, or baclofen. She then developed ataxia and diploplia, and was found to have nystagmus, upgoing toes and clonus. An MRI of her brain revealed demyelinating lesions of the medulla. NMO antibody was positive, consistent with neruomyelitis optica (Devic's disease). She was given methylprednisolone 1 g twice daily for 3 days. Her neurological and gastrointestinal symptoms resolved within days. Subsequent relapse of her demyelinating lesions involving the spine, but not the medulla, was not associated with gastrointestinal symptoms. Discussion: Demyelinating lesions involving the medulla can be associated with various gastrointestinal manifestations since the medulla houses the dorsal motor nucleus of the vagus nerve. Our patient had severe gastroparesis, nausea, vomiting, hiccups and gallbladder dyskinesia, due to interference with the vomiting center of the brainstem and vagal motor innervation of the stomach and gallbladder. She was refractory to antiemetics and prokinetics, but responded dramatically to corticosteroids. The fact that relapses of neuromyelitis optica not involving the medulla were not associated with gastrointestinal symptoms, indicates that the symptoms were due to medullary involvement, not the disease itself. Gastroenterologists should be aware of this association and its prompt response to corticosteroids.

Lack of Response to Monoclonal Antibody Therapy in Neuromyelitis Optica

The report by Matiello et al regarding a relapse of neuromyelitis optica (NMO) after autologous hematopoietic stem cell transplantation highlights the need to further understand the role of the immune system in this disease.1 Immunosuppressive therapeutics targeting B- and T-cells are utilized to prevent disabling relapses in NMO.2 Rituximab is a monoclonal anti-CD20 antibody that is reported to be effective in NMO.3 Alemtuzumab is a monoclonal anti-CD52 antibody with preliminary phase II data in multiple sclerosis, but not in NMO.4 We describe a patient with 20 relapses in 5 years despite sequential treatment with four immunomodulatory therapeutics in combination with corticosteroids and plasma exchange (PLEX) for relapses. She appeared to paradoxically worsen with profound weakness after B cell depletion with rituximab and developed tumefactive cerebral lesions after alemtuzumab.

Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica

In neuromyelitis optica (NMO), B-cell autoimmunity to aquaporin-4 (AQP4) has been shown to be essential. However, the role of T cells remains ambiguous. Here, we first showed an increase in CD69+ activated T cells in PBMCs during NMO relapses. Next, T-cell responses to AQP4 and myelin peptides were studied in 12 NM0 patients, 10 multiple sclerosis (MS) patients and 10 healthy subjects (HS). Four hours after adding 1 of 28 overlapping AQP4 peptides, a mixture of AQP4 peptides (AQP4-M) or one of six distinct myelin peptides to 2-day cultured PBMC, CD69 expression on CD4+ T cells was examined. Data were analyzed by paired t-test, frequency of samples with 3-fold increase of CD69 on CD4+ cells (fSI3) and mean stimulation index (mSI). The T-cell response to AQP4-M was significantly increased in NMO (fSI3 = 10/12, mSI = 5.50), with AQP4 (11-30) and AQP4 (91-110) representing the two major epitopes (AQP4 (11-30), fSI3 = 11/12, mSI = 16.0 and AQP4 (91-110), fSI3 = 11/12, mSI = 13.0). Significant but less extensive responses to these two epitopes were also observed in MS and HS. Significant reactivities against AQP4 (21-40), AQP4 (61-80), AQP4 (101-120), AQP4 (171-190) and AQP4 (211-230) were exclusively found in NMO. In addition, responses to AQP4 (81-100) were higher and more frequently detected in NMO, without reaching statistical significance. Interestingly, among the six myelin peptides studied, proteolipid protein (95-116) induced a significant T-cell response in NMO (fSI3 = 7/12, mSI = 4.60). Our study suggests that cellular as well as humoral responses to AQP4 are necessary for NMO development and that the immune response to myelin protein may contribute to disease pathogenesis.

Repeated Treatment With Rituximab Based on the Assessment of Peripheral Circulating Memory B Cells in Patients With Relapsing Neuromyelitis Optica Over 2 Years

To evaluate the efficacy and safety of repeated rituximab treatment based on the assessment of peripheral circulating memory B cells over 24 months in patients with relapsing neuromyelitis optica (NMO). Prospective open-label study. Institutional referral center for multiple sclerosis. Patients Thirty patients with relapsing NMO or NMO spectrum disorder. Intervention Treatment protocol of rituximab consisted of an induction therapy (375 mg/m² once weekly for 4 weeks or 1000 mg infused twice, with a 2-week interval between the infusions) followed by maintenance therapy. The maintenance therapy was repeated treatment with rituximab (375 mg/m², once) whenever the frequency of reemerging CD27+ memory B cells was more than 0.05% in peripheral blood mononuclear cells by flow cytometric analysis. Annualized relapse rate, disability (Expanded Disability Status Scale score), anti-aquaporin 4 antibody level, and safety of rituximab treatment. Of 30 patients, 28 showed a marked reduction in relapse rate while taking rituximab over 24 months. The relapse rate was reduced significantly, by 88%, and 70% of patients became relapse-free over 24 months. Disability either improved or stabilized in 97% of patients. Anti-aquaporin 4 antibody levels declined significantly following treatment with rituximab, consistent with the clinical response and the effect on CD27+ memory B cells. Repeated treatment with rituximab was generally well tolerated, and no clinically relevant adverse event leading to discontinuation of treatment was observed. Repeated treatment with rituximab appeared to produce consistent and sustained efficacy over 24 months with good tolerability in patients with NMO.

Increased memory Th17 cells in patients with neuromyelitis optica and multiple sclerosis

ObjectTo investigate the clinical relevance of memory Th17 cells in patients with neuromyelitis optica (NMO) or multiple sclerosis (MS). Patients and methodsThe proportion of peripheral memory Th17 cells was determined by flow cytometry. Sera IL-17A and IL-23 levels were detected by ELISA kits. ResultsMemory Th17 proportion and IL-17A level were much higher in patients with NMO or MS and were related to clinical features. After high-dose intravenous methylprednisolone (IVMP) therapy, memory Th17 proportion and IL-17A and IL-23 levels were decreased. ConclusionsMemory Th17 is related to the development and relapse of NMO and MS, and IVMP can inhibit memory Th17.

Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica

Neuromyelitis optica (NMO) is an inflammatory disease affecting the optic nerve and spinal cord, in which autoantibodies against aquaporin 4 (AQP4) water channel protein probably play a pathogenic role. Here we show that a B-cell subpopulation, exhibiting the CD19(int)CD27(high)CD38(high)CD180(-) phenotype, is selectively increased in the peripheral blood of NMO patients and that anti-AQP4 antibodies (AQP4-Abs) are mainly produced by these cells in the blood of these patients. These B cells showed the morphological as well as the phenotypical characteristics of plasmablasts (PB) and were further expanded during NMO relapse. We also demonstrate that interleukin 6 (IL-6), shown to be increased in NMO, enhanced the survival of PB as well as their AQP4-Ab secretion, whereas the blockade of IL-6 receptor (IL-6R) signaling by anti-IL-6R antibody reduced the survival of PB in vitro. These results indicate that the IL-6-dependent B-cell subpopulation is involved in the pathogenesis of NMO, thereby providing a therapeutic strategy for targeting IL-6R signaling.

Relapse of Neuromyelitis Optica Spectrum Disorder Associated with Intravenous Lidocaine

Lidocaine unmasks silent symptoms and eases neuropathic pain in multiple sclerosis patients; however, the effects of lidocaine in neuromyelitis optica have never been reported. We describe the case of a 59-year-old Japanese woman with neuromyelitis optica spectrum disorder who developed optic neuritis 1 day after intravenous lidocaine injection for treating allodynia. Her symptom seemed to result from a relapse of neuromyelitis optica induced by lidocaine administration, and not because of the transient effects of intravenous lidocaine administration. The possibility that lidocaine administration results in relapse of neuromyelitis optica due to its immunomodulating effects cannot be ruled out.