Course Of Neuromyelitis Optica Research Articles

T-cell responses to distinct AQP4 peptides in patients with neuromyelitis optica (NMO)

BackgroundAlthough antibodies to aquaporin-4(AQP4) are strongly associated with Neuromyelitis optica (NMO), the sole transfer of these antibodies is not sufficient to induce an NMO-like disease in experimental animals and T-cells and complement are also needed. Initial data indicating the presence of T-cell responses to AQP4 in patients with NMO, have beeen recently reported. ObjectiveTo evaluate the T-cell responses to specific AQP4 peptides/epitopes in patients with NMO and multiple sclerosis (MS). MethodsPeripheral blood mononuclear cells (PBMCs) were obtained from 14 patients fulfilling the criteria for definite NMO and the proliferation responses to one of 15 distinct pentadecapeptides of AQP4, spanning the whole protein (except of its transmembrane parts) were tested by a standard [H3]-thymidine uptake assay and compared with those of 9 healthy controls and 7 MS patients. A cytometric bead array assay (CBA) and flow cytometry were used to evaluate cytokine (IFNγ, IL17, IL2, IL4, IL5, IL10 and TNFα) and chemokine (CXCL8, CCL5, CXCL10, CXCL9, CCL2) secretion by PHA-stimulated PBMCs and AQP4-specific T-cell lines. ResultsFour main immunodominant epitopes of the AQP4 protein (p137–151, p222–236, p217–231 and the p269–283) were identified in the NMO group. The first two epitopes (assigned as peptides 3 and 9) showed the highest sensitivity (~60% positivity), whereas the latter two (assigned as peptides 8 and 11), the higher specificity. Longitudinal follow up of 5 patients revealed changes in the epitope-specificities during the course of NMO. T-cell lines specific for the AQP4 peptides, produced from NMO patients (but not healthy donors) secreted mainly IL-17 and IL-10 and less IFNγ. ConclusionsOur findings indicate that T-cells bearing characteristics of both Th1 and Th17 T-cells and targeting specific immunodominant epitopes of the AQP4 protein might be involved in the pathogenesis of NMO.

Natural course of neuromyelitis optica (NMO) in patients with no long-term treatment

Natural course of neuromyelitis optica (NMO) in patients with no long-term treatment

Factors Associated With the Time to Next Attack in Neuromyelitis Optica: Accelerated Failure Time Models With Random Effects

Background and ObjectiveNeuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system with a relapsing and remitting course. We aimed to identify factors associated with the time to next attack, including the effect of the natural disease course and the diverse treatment regimens, by applying a longitudinal statistical analysis to the individual attacks of each patient.MethodsIn total, 184 acute attacks among 58 patients with either NMO or NMO spectrum disorder with anti-aquaporin-4 antibody were assessed retrospectively. Patient demographics, clinical characteristics at each attack, and type of treatment during inter-attack periods were assessed. The dependent variable was defined as the time from each attack to the next attack (inter-attack interval). An exponential accelerated failure time model with shared gamma frailty was adapted for statistical analysis.ResultsA multivariable analysis revealed that the time from each attack to the next attack in NMO increased independently by 1.31 times (95% confidence interval (CI), 1.02–1.67; p = 0.035) with each additional cumulative attack experienced, by 5.34 times (95% CI, 1.57–18.13; p = 0.007) with combined azathioprine treatment and continued oral prednisolone, and by 4.26 times (95% CI, 1.09–16.61; p = 0.037) with rituximab treatment.ConclusionThe time to next attack in NMO can increase naturally in the later stages of the disease as the number of cumulative attacks increases. Nevertheless, both combined azathioprine treatment with continued oral prednisolone and rituximab treatment were also associated with a longer time to next attack, independently of the natural disease course of NMO.

Neuromyelitis optica and pregnancy

Less than a hundred cases of pregnancies in women with neuromyelitis optica (NMO) have been published in the world. The aim of the present study was to add the Brazilian experience to this subject. Cases of women with NMO who became pregnant, or who developed NMO soon after pregnancy, were included. Retrospective analysis of medical data from these patients was carried out by the neurologist responsible for the case. Seventeen cases of pregnancies (16 full-term pregnancies, one miscarriage) were identified. The relapse rate of demyelinating events in the first trimester after pregnancy was significantly higher than at any other time. Disability progression was significantly worse 1 year after delivery. Pregnancy negatively influenced the disease course of NMO in these women. These results are similar to those of other authors, although the total number of cases so far described is still small. Obstetricians must be aware of the potential complications of a pregnancy in a woman who has NMO.

Modifications of longitudinally extensive transverse myelitis and brainstem lesions in the course of neuromyelitis optica (NMO): a population-based, descriptive study

BackgroundNeuromyelitis optica (NMO) includes transverse myelitis, optic neuritis and brain lesions. Recent studies have indicated that the brainstem is an important site of attack in NMO. Longitudinally extensive transverse myelitis (LETM) is an important component of the clinical diagnosis of NMO. The frequency of brainstem and LETM lesions, changes over time of LETM and the clinical consequences in the course of NMO have only been sparsely studied.MethodsThe study was a population-based retrospective case series with clinical and magnetic resonance imaging (MRI) follow-up of 35 patients with definite NMO and a relapsing-remitting course.ResultsBrainstem lesions were observed in 25 patients, 18 in medulla oblongata (11 in area postrema). Lesions in the pons, mesencephalon and diencephalon occurred in 10, 7 and 7 patients, respectively. Lesions were symptomatic in medulla oblongata and pons, asymptomatic in mesencephalon and diencephalon. Brainstem lesions were observed significantly more often in anti-aquaporin-4 (AQP-4) antibody positive than in seronegative patients (p < 0.002).LETM was demonstrated by MRI of the spinal cord in 30/36 patients, 23/30 of whom had follow-up MRI of the spinal cord. Recurrent LETM was observed in five patients. In nine patients the LETM changed into multiple lesions during remission or treatment. Spinal cord atrophy was observed in 12/23 (52%) patients, correlating to Expanded Disability Status Scale (r = 0.88, p < 0.001).ConclusionsNMO patients had frequent occurrence of brainstem lesions and LETM. Brainstem lesions were associated with anti-AQP4 antibody positivity. LETM lesions differentiated over time and the outcome included relapses, fragmentation and atrophy. Correlation was observed between spinal cord atrophy and neurological disability.

Interleukin 6 Receptor Blockade in Patients With Neuromyelitis Optica Nonresponsive to Anti-CD20 Therapy

To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). Retrospective case series. Neurology department at a tertiary referral center. Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy. Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4-positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. Interleukin 6 receptor-blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.

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.

Neuromyelitis optica and pregnancy

The purpose of our study was to assess the influence of pregnancy on the course of neuromyelitis optica (NMO) and the impact of epidural analgesia and breastfeeding on its activity in the postpartum period. We performed a retrospective study of patients with NMO diagnosed according to Wingerchuk criteria. We noted the number of relapses during the year before pregnancy (BP), during pregnancy (first trimester, second trimester, third trimester), and the year after (Y + 1: first trimester, second trimester [PP2], and third and fourth trimesters postpartum). Epidural analgesia and breastfeeding were recorded. Disability was evaluated with the Kurtzke Expanded Disability Status Scale (EDSS). The annualized relapse rate (ARR) was calculated. We identified 124 patients (85 female) in the French NOMADMUS cohort on November 1, 2010. A total of 20 women (including 25 pregnancies) were informative with complete files. Comparisons between the ARR of each period and BP (1.0 ± 0.09) only showed an increased tendency for PP2 (0.8 ± 0.06, p = 0.07). Epidural analgesia and breastfeeding had no influence on the course of NMO. The EDSS score increased from 1.5 ± 1.7 BP to 2.6 ± 1.9 Y + 1 (p = 0.027). This study shows that pregnancy influences the activity of NMO, a finding that justifies close medical monitoring. We found no evidence to suggest that either epidural analgesia or breastfeeding has an aggravating effect on NMO.

When is neuromyelitis optica diagnosed after disease onset?

To diagnose neuromyelitis optica (NMO), the 2006 NMO diagnostic criteria is commonly used. However, adequate studies about the time course of NMO according to the criteria have been lacking. The aim of the study was to identify the interval between disease onset and diagnosis of NMO, as well as the clinical characteristics and time course, according to the 2006 NMO diagnostic criteria in Japanese patients with NMO. Clinical progression and time course of 43 Japanese patients with NMO who fulfilled the 2006 NMO diagnostic criteria with mean disease duration of 14.2 years were investigated retrospectively. The initial inflammatory event was myelitis in 44.2% (long extensive transverse myelitis [LETM] in 14.3%), optic neuritis in 41.9%, and concurrent myelitis and optic neuritis in 9.3% of the patients. The presence of LETM and anti-aquaporin-4 antibody seropositivity by the end of the observation period was found in 85.7 and 93.0% of the patients, respectively. Among the patients whose medical information were sufficiently available, the median intervals between NMO onset and the time until development of both optic neuritis and myelitis, LETM, or fulfillment of the 2006 NMO criteria were 16.5, 35.1, and 27.8 months, respectively. The development of diagnostic method at an early stage of NMO may be needed in order to initiate early treatment.

Glatiramer acetate could be a hypothetical therapeutic agent for neuromyelitis optica

Neuromyelitis optica (NMO) is characterized by concurrence of optic neuritis and transverse myelitis, which is typically associated with a spinal cord lesion extending three or more vertebral segments. NMO is an inflammatory, demyelinating central nervous system disorder, and although it has a relapsing course in more than 90% of patients, it differs from multiple sclerosis in that it is more severe, usually spares the brain, and is associated with a longitudinally extensive lesion on spinal cord magnetic resonance imaging (MRI). Furthermore, NMO is associated with a highly specific serum marker called anti-aquaporin-4 antibody, which is believed to have a central pathogenetic role in NMO. Treatment with B-cell specific monoclonal antibody (rituximab) and plasma exchanges appears to reduce the severity and frequency of attacks in NMO, and therefore, B-cell autoimmunity as well as a humoral mechanism may be involved in the pathogenesis of NMO. Glatiramer acetate (GA; also known as Copaxone, COP-1) is a synthetic copolymer of a pool of peptides composed of random sequences of four amino acids: glutamine, lysine, alanine, and tyrosine. GA-specific T-helper 1- (Th1) and 2-type (Th2) cells produce brain-derived neurotrophic factor (BDNF), which may affect neuronal survival and myelin repair. GA treatment also leads to sustained augmentation of BDNF, neurotrophin (NT)-3, and NT-4 expression in various brain regions as demonstrated by histological analysis of immunostained brain sections and BDNF elevation after GA treatment on both protein and mRNA levels. GA-Th2 activation may also have a neuroprotective role in the course of NMO. Furthermore, B cells from GA-treated mice suppress experimental autoimmune encephalomyelitis. The pathogenesis of NMO is largely unknown. However, there is some evidence that B-cell autoimmunity, activation of eosinophils, and B-cell activating factor play important roles, based on neurotrophic factors, neuroprotection, anti-inflammation, and B-cell modulation, GA is thus a hypothetic potential treatment agent for NMO.

Neuromyelitis optica and NMO-IgG in European pediatric patients

Neuromyelitis optica (NMO) is currently considered a severe relapsing CNS demyelinating disorder that is associated with aquaporin-4 immunoglobulin G (NMO-IgG) while in earlier reports of NMO in childhood it has been described as a benign and monophasic disorder. This study was performed to analyze the prevalence and the clinical course of NMO in a European pediatric cohort of patients with demyelinating CNS disorders. A cohort study was performed evaluating 118 pediatric patients presenting at the Center for Multiple Sclerosis in Childhood and Adolescents, Göttingen, Germany, with demyelinating CNS disorders between 2000 and 2009. In all patients, NMO-IgG status was determined. The majority of patients (94%) were diagnosed with remitting recurrent multiple sclerosis. Six patients fulfilled the clinical criteria for NMO but only 1 was seropositive for NMO-IgG. This patient had a severe relapsing course in contrast to the seronegative patients who showed a mild and in the majority of cases monophasic course. The diagnostic criteria clearly distinguished the patients with NMO from patients with other demyelinating CNS disorders. In the European pediatric population, NMO is very rare and in the majority of patients not associated with NMO-IgG. These seronegative cases have a benign and predominantly monophasic course and therefore do not need the immunosuppressant therapy that is recommended for NMO in the recent literature.

Neuromyelitis optica in France

There have been few epidemiologic studies on neuromyelitis optica (NMO) and none used the recent 2006 diagnostic criteria. Here we describe the clinical, laboratory, MRI, and disability course of NMO in a French cohort of 125 patients. We performed an observational, retrospective, multicenter study. Data were collected from September 2007 through August 2008, corresponding to the endpoint of the study. We identified 125 patients fulfilling the 2006 NMO criteria. Selection was made using hospital files and a specific clinical questionnaire for NMO. Mean age at onset was 34.5 years (range 4-66) with a mean disease duration of 10 +/- 7.8 years at the endpoint. The patients were mainly (87%) Caucasian, with a female:male ratio of 3:1. In 90% of cases, the association of optic neuritis, longitudinal extensive myelitis, and a Paty-negative initial brain MRI was sufficient to fulfill the supportive criteria. Eighty-eight percent of patients were treated with immunosuppressive therapies. Median delay from onset to Expanded Disability Status Scale (EDSS) score 4 was 7 years; score 6, 10 years; and score 7, 21 years. The first episode of myelitis was immediately followed by an EDSS score > or = 4 in 37.3% of cases, and a severe residual visual loss was observed in 22% of patients after the first episode of optic neuritis. Multivariate analysis did not reveal any predictors of a poor evolution other than a high number of MRI brain lesions at diagnosis, which were predictive of a residual visual acuity < or = 1/10. Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment.

Retinal Peripapillary Nerve Fiber Layer Thickness in Neuromyelitis Optica

To measure the thickness of retinal peripapillary nerve fibers throughout the course of neuromyelitis optica (NMO). This study was of a cross-sectional design, examining the thickness of the retinal peripapillary nerve fiber layer by optical coherence tomography, in patients with NMO (n = 15; 30 eyes), patients with multiple sclerosis (MS; n = 15; 30 eyes), and a control group (n = 23; 46 eyes). The thicknesses were acquired according to protocol with the fast RNFL (Retinal Nerve Fiber Layer) procedure. The study of visual function includes for each eye a determination of refraction, measurement of visual acuity, measurement of contrast vision, an analysis of color vision, and a frequency-doubling technology perimetry (FDTP). The main outcome measurements were the thickness of the retinal peripapillary nerve fibers, visual acuity, and scores of contrast vision. The average thickness of retinal peripapillary nerve fibers was respectively in the NMO, MS, and control group: 65.44 +/- 24.19, 83.85 +/- 24.12, and 106.24 +/- 12.46 microm (P = 0.01). The average thickness of retinal peripapillary nerve fibers correlated to visual acuity, the scores of contrast vision, the scores of FDTP, and the number of episodes per patient (r = -0.58, P = 0.03). This is the first study to produce measurements of the thickness of retinal peripapillary nerve fibers during optic neuropathies of NMO. The optic neuropathies of NMO are also accompanied by an acute and chronic axonal loss, as clearly illustrated by the OCT.

Antibody to aquaporin-4 in the long-term course of neuromyelitis optica

Neuromyelitis optica (NMO) is a severe inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the spinal cord and optic nerves. Recently, a highly specific serum reactivity to CNS microvessels, subpia and Virchow–Robin spaces was described in patients with NMO [called NMO–IgG (NMO–immunoglobulin G)]. Subsequently, aquaporin-4 (AQP4), the most abundant water channel in the CNS, was identified as its target antigen. Strong support for a pathogenic role of the antibody would come from studies demonstrating a correlation between AQP4-Ab (AQP4-antibody) titres and the clinical course of disease. In this study, we determined AQP4-Ab serum levels in 96 samples from eight NMO–IgG positive patients (median follow-up 62 months) in a newly developed fluorescence-based immunoprecipitation assay employing recombinant human AQP4. We found that AQP4-Ab serum levels correlate with clinical disease activity, with relapses being preceded by an up to 3-fold increase in AQP4-Ab titres, which was not paralleled by a rise in other serum autoantibodies in one patient. Moreover, AQP4-Ab titres were found to correlate with CD19 cell counts during therapy with rituximab. Treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels and relapse rates. Our results demonstrate a strong relationship between AQP4-Abs and clinical state, and support the hypothesis that these antibodies are involved in the pathogenesis of NMO.

Evidence for humoral autoimmunity in neuromyelitis optica

Neuromyelitis optica (NMO) is an idiopathic central nervous system (CNS) demyelinating syndrome that may be distinguished from typical multiple sclerosis (MS). Although the cause of the disorder is not known, several lines of evidence suggest that the fundamental immunological process is driven by humoral mechanisms. These observations include the frequent coexistence of systemic autoimmune disease or positive serum autoantibodies with NMO, immunopathologic studies that demonstrate prominent complement activation and immunoglobulin deposition and the discovery of the serum autoantibody NMO-IgG, a potential NMO biomarker that targets aquaporin-4. Furthermore, clinical experience suggests that plasmapheresis and immunosuppressive therapies are beneficial for treatment and prevention of acute attacks but that standard MS immunomodulatory drugs may not alter the course of NMO. This evidence is reviewed in the context of its implications for future laboratory and clinical research in NMO.

A patient with a benign course of neuromyelitis optica (Devic’s syndrome) over 12 years

A patient with a benign course of neuromyelitis optica (Devic’s syndrome) over 12 years

Magnetization transfer and diffusion tensor MRI show gray matter damage in neuromyelitis optica.

Using magnetization transfer (MT) and diffusion tensor (DT) MRI, the authors assessed the extent of tissue damage of the brain normal-appearing white and gray matter (NAGM) in patients with neuromyelitis optica (NMO). Compared to healthy controls, patients with NMO showed reduced MT ratio and increased mean diffusivity of the NAGM. This challenges the classic notion of a sparing of the brain tissue in the course of NMO.

The clinical course of neuromyelitis optica (Devic's syndrome).

To evaluate the spectrum of neuromyelitis optica (NMO), including characteristics of the index events (optic neuritis [ON]) and myelitis), neuroimaging, CSF, and serologic studies, and to evaluate the long-term course. Review of 71 patients with NMO evaluated at the Mayo Clinic between 1950 and 1997. NMO was either monophasic or relapsing. Patients with a monophasic course (n = 23) usually presented with rapidly sequential index events (median 5 days) with moderate recovery. Most with a relapsing course (n = 48) had an extended interval between index events (median 166 days) followed within 3 years by clusters of severe relapses isolated to the optic nerves and spinal cord. Most relapsing patients developed severe disability in a stepwise manner, and one-third died because of respiratory failure. Features of NMO distinct from "typical" MS included >50 cells/mm3 in CSF (often polymorphonuclear), normal initial brain MRI, and lesions extending over three or more vertebral segments on spinal cord MRI. Clinical, laboratory, and imaging features generally distinguish neuromyelitis optica from MS. Patients with relapsing optic neuritis and myelitis may have neuromyelitis optica rather than MS. Patients with a relapsing course of neuromyelitis optica have a poor prognosis and frequently develop respiratory failure during attacks of cervical myelitis.