Neuromyelitis Optica Spectrum Disorder Onset Research Articles

Blood-Brain Barrier Disruption in Neuroimmunological Disease.

The blood-brain barrier (BBB) acts as a structural and functional barrier for brain homeostasis. This review highlights the pathological contribution of BBB dysfunction to neuroimmunological diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), autoimmune encephalitis (AE), and paraneoplastic neurological syndrome (PNS). The transmigration of massive lymphocytes across the BBB caused by the activation of cell adhesion molecules is involved in the early phase of MS, and dysfunction of the cortical BBB is associated with the atrophy of gray matter in the late phase of MS. At the onset of NMOSD, increased permeability of the BBB causes the entry of circulating AQP4 autoantibodies into the central nervous system (CNS). Recent reports have shown the importance of glucose-regulated protein (GRP) autoantibodies as BBB-reactive autoantibodies in NMOSD, which induce antibody-mediated BBB dysfunction. BBB breakdown has also been observed in MOGAD, NPSLE, and AE with anti-NMDAR antibodies. Our recent report demonstrated the presence of GRP78 autoantibodies in patients with MOGAD and the molecular mechanism responsible for GRP78 autoantibody-mediated BBB impairment. Disruption of the BBB may explain the symptoms in the brain and cerebellum in the development of PNS, as it induces the entry of pathogenic autoantibodies or lymphocytes into the CNS through autoimmunity against tumors in the periphery. GRP78 autoantibodies were detected in paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome, and they were associated with cerebellar ataxia with anti-P/Q type voltage-gated calcium channel antibodies. This review reports that therapies affecting the BBB that are currently available for disease-modifying therapies for neuroimmunological diseases have the potential to prevent BBB damage.

The relationship between neuromyelitis optica spectrum disorder and autoimmune diseases.

There have been reports of neuromyelitis optica spectrum disorder (NMOSD) coexisting with connective tissue disorders. The objective of this study was to describe the characteristics of NMOSD coexisting with autoimmune diseases (AID). This retrospective study evaluated NMOSD patients with and without AID. The enrolled patients had at least one attack, with duration of more than 1 year. Data on the demographics, clinical features, and laboratory findings were assessed. The Poisson model was used to investigate the risk factors associated with the annualized relapse rate (ARR), whereas the Cox model was used to evaluate the risk factors for the first relapse. A total of 180 patients (154 women and 26 men) with NMOSD were identified: 45 had AID and 135 did not. Female patients had a higher prevalence of concomitant AID (p = 0.006) and a greater relapse rate within the first year. There were no statistically significant differences in the characteristics of patients. Kaplan-Meier analysis revealed that NMOSD patients with seropositive aquaporin 4 antibodies (AQP4-Ab; log-rank: p = 0.044), had a shorter time to relapse. Patients seropositive for AQP4-Ab (HR = 2.402, 95%CI = 1.092-5.283, p = 0.029) had a higher risk of suffering a first relapse, according to the Cox model. Patients with and without AID showed a similar declining tendency in terms of change in ARR throughout the first 5 years of the disease. The ARR was greater in the first year [incidence rate ratio (IRR) = 1.534, 95%CI = 1.111-2.118] and the first 2 years (IRR = 1.474, 95%CI = 1.056-2.058) in patients with coexisting AID diagnosis prior to the NMOSD onset. Patients with NMOSD with coexisting AID had similar characteristics when compared with those without AID. NMOSD patients with AID diagnosed before onset had a higher risk of relapse in the early stage of the disease.

Overlap syndrome of anti-aquaporin 4 positive neuromyelitis optica spectrum disorder and primary Sjögren's syndrome: a systematic review of individual patient data.

Central nervous system (CNS) involvement can occur in primary Sjögren's syndrome (pSS) due to co-existing neuromyelitis optica spectrum disorder (NMOSD) which has a highly relapsing course requiring indefinite immunosuppression, and if not diagnosed early, damage accrual occurs over time leading to permanent disability and morbidity. In this review, we describe and outline the clinical course and outcomes of anti-aquaporin 4 (AQP4) antibody seropositive NMOSD with pSS overlap cases. To investigate the co-existence of AQP4 + NMOSD with pSS, we conducted a review of individual patient data from case reports and case series found in major databases. The study extracted clinico-demographic features, imaging and laboratory profiles, treatment approaches, and outcomes of these patients. Inclusion criteria for the review required patients to have positivity for anti-AQP4 or NMO-IgG autoantibodies in the blood and/or cerebrospinal fluid (CSF) and exhibit at least one manifestation of both pSS and NMOSD. In this overlap between AQP4 + NMOSD and pSS, 44 patients were included of whom 41 (93.2%) were females. The mean age of pSS onset was 44.8 ± 18.4years and NMOSD onset was 43.2 ± 19.8years. In 20 (45.5%) patients, NMOSD preceded pSS onset, 13 (29.5%) NMOSD occurred after pSS onset, and 11 (25%) patients had a simultaneous presentation. 31 (70.5%) patients experienced acute transverse myelitis, 21 (47.7%) optic neuritis, 14 (31.8%) cerebral syndrome, 10 (22.7%) acute brainstem syndrome, 5 (11.4%) area postrema syndrome, and 2 (4.5%) diencephalic clinical syndromes. For the treatment of acute phase, 40 (90.9%) patients received intravenous methylprednisolone, 15 (34.1%) received plasma exchange, and 10 (22.7%) received intravenous immunoglobulin; and for the induction/maintenance therapy, 16 (36.4%) patients received cyclophosphamide, 6 (13.6%) received rituximab, 16 (36.4%) received azathioprine, and 10 (22.7%) received mycophenolate mofetil. Disease course was monophasic in 2 (4.5%) and relapsing in 27 (61.4%) patients. At median (IQR) follow-up duration of 2.4 (6) years, 39 (88.6%) patients showed improvement, 3 (6.8%) showed stabilization and 2 (4.5%) showed worsening of their NMOSD manifestations. In this overlap syndrome of AQP4 + NMOSD and pSS, patients have a neurologically disabling disorder that can mimic neurological manifestations of pSS, frequently occurs prior to the onset of pSS, has a relapsing course, responds well to immunosuppressants, and necessitates indefinite treatment. Collaborative multicentre studies are needed to clarify the natural history and outcomes of this rare overlap syndrome.

Clinical characteristics of late-onset neuromyelitis optica spectrum disorder.

Anti-aquaporin-4 (AQP-4) immunoglobulin G (IgG) is a major autoimmune antibody that contributes to the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). NMOSD often presents as disability, severe sensory impairment, and sleep disorders, which can cause anxiety and depression and further affect the quality of life. The age of onset is a key factor influencing the prognosis of NMOSD. However, this result was based on studies involving only anti-aquaporin-4 (AQP4) immunoglobulin G (IgG)-seropositive NMOSD patients or studies using the 2006 NMOSD diagnosis criteria. Therefore, further study of the age of onset of NMOSD is valuable. This study aimed to describe the clinical and magnetic resonance imaging (MRI) differences between early-onset neuromyelitis optica spectrum disorder (EO-NMOSD) and late-onset (LO)-NMOSD patients. Fifty patients were enrolled, their anti-AQP4-IgG titers were measured, and brain and spinal cord MRIs were obtained. Additionally, several questionnaires related to disease severity, anxiety, depression, cognition, sleep, pain, and fatigue were collected. Higher AQP4-IgG seropositivity, higher AQP4-IgG titer, frequency of thoracic myelitis, and white matter hyperintensities (WMH), as well as greater severity of disability, greater severity of sleep disorders, higher anxiety, poorer cognitive function, and higher clinical dementia rating (CDR)-community affairs scores were observed in late-onset (LO)-NMOSD patients than those in early-onset (EO)-NMOSD. AQP4-IgG titer positively correlated with age, annual relapse rate, Expanded Disability Status Scale (EDSS) sensory scores, Activity of Daily Living Scale (ADL) scores, and Pittsburgh Sleep Quality Index (PSQI) scores. The EDSS-sensory scores positively correlated with age, relapse time, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, PSQI, ADL, and CDR. WMH was positively correlated with age, EDSS-sensory scores, PSQI scores, and CDR scores and negatively correlated with the California Verbal Learning Test scores. LO-NMOSD patients have worse prognoses than those of EO-NMOSD patients. Higher AQP4-IgG titers, more WMHs, thoracic myelitis, and severe sensory symptoms are associated with cognition, depression, anxiety, and sleep disorders.

Exploring the association of reproductive history with the development and course of neuromyelitis optica spectrum disorder

women of childbearing age are at higher risk for developing Neuromyelitis Optica Spectrum Disorder (NMOSD). Post-onset pregnancy is believed to affect and be affected by NMOSD. This study aimed to assess the effect of pregnancy on the development and course of NMOSD. All women from the patient registry of the neurology outpatient clinic in Tehran, Iran, who were diagnosed with NMOSD without any comorbidity were enrolled in this survey. Retrospectively, the participants' reproductive history was collected, and the association of pregnancy-related factors with the age of onset, attack rate, and disability status was sought. The age at first attack was significantly higher in patients with prior pregnancy (P<0.001). To eliminate the immortal time bias, the researchers assessed the effect of pregnancy as a time-varying exposure in the time-dependent Cox model, which indicated that pregnancy did not alter the time of developing NMOSD (Hazard Ratio=0.91, P=0.741). However, more than one-fourth of patients with pregnancy before NMOSD onset had their first attack within the year of delivery. In addition, younger age at disease onset was accompanied by a shorter interval between the first pregnancy and first attack (Spearman's rho=0.826, P<0.001). NMOSD onset or prognosis seemed not to be affected by pregnancy before the disease onset. However, in women with early disease onset, pregnancy might be a trigger for the development of NMOSD.

P 4 The impact of low affinity immunoglobulin gamma Fc region receptor III-A gene polymorphisms in neuromyelitis optica spectrum disorder and implications for treatment outcomes: results from the N-MOmentum study

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an autoantibody-mediated CNS disease. The rs396991 F176V polymorphism of the low-affinity IgG Fc region receptor III-A (FCGR3A) gene affects IgG binding affinity. The V allele is linked to poor outcomes in antibody-mediated autoimmune diseases but enhanced response to monoclonal antibody therapies. Characterize the relationship between rs396991 polymorphism, NMOSD disease activity and treatment response in N–MOmentum trial participants. Material and method: N-MOmentum had a randomized controlled period (RCP; inebilizumab 300 mg or placebo on days 1 and 15) of up to 28 weeks, followed by an open-label period (OLP). 142 participants (104 randomized to inebilizumab, 38 to placebo) consented for polymorphism genotyping via TaqMan qPCR assay. Results: Historical annualized attack rates (AAR) and change in Expanded Disability Status Scale (EDSS) scores from NMOSD onset to enrolment were nominally higher in rs396991 V allele participants (V; V/V or V/F genotype; n=74) than in F/F allele participants (F/F; n=68): mean (±SEM) AAR: V, 1.0 (0.8–1.3); F/F, 0.7 (0.5–0.9); EDSS score change: V, 0.6 (0.5–0.7); F/F, 0.4 (0.3–0.5). In the placebo group, the rates of attacks, new/enlarged T2 MRI lesions and NMOSD-related hospitalizations were higher in V allele (n=22) than in F/F allele participants (n=16), but not statistically significant: mean (±SEM) AAR: V, 1.3 (0.9–1.7); F/F, 0.8 (0.5–1.2); new T2 lesions: V, 4.5 (2.6–6.3); F/F, 2.1 (1.0–3.1); hospitalizations: V, 0.5 (0.2–0.8); F/F, 0.2 (0.0–0.4). At end of RCP, V-allele carriers randomized to inebilizumab (n=52) had greater median (IQR) B-cell, plasma-cell and Ig depletion than F/F homozygotes (n=52): B cells; V, 0.6 (0.1–3.2) vs F/F, 1.3 (0.5–4.2) cells/µl; plasma cells: V, 0.04 (0.02–0.2) vs F/F, 0.05 (0.03–0.2) fold change from control mean; Ig: V, 1050 (867–1284) vs F/F, 1238 (1076–1455) Ig/µl. V allele carriers also had lower attack rates and new/enlarged T2 lesions than F/F homozygotes but differences were not statistically significant: mean (±SEM): AAR: V, 0.1 (0.1–0.2); F/F, 0.3 (0.2–0.4); new T2 lesions: V, 1.4 (0.9–1.8); F/F, 1.7 (1.2–2.2). By dose 4 in the OLP, there was little difference between the subgroups in clinical metrics or B-cell depletion. Conclusion: V allele carriers may have increased NMOSD disease activity but may have greater early pharmacodynamic response to inebilizumab compared with those with the wild F/F genotype.

Newly diagnosed neuromyelitis optica spectrum disorders following vaccination: Case report and systematic review

The pathogenesis of neuromyelitis optica spectrum disorder (NMOSD) has been vigorously illustrated, but triggers of the disease remain unclear. Viral infection and vaccination have been observed to precede certain cases of NMOSD. Amidst the Coronavirus disease 2019 (COVID-19) pandemic, mass vaccination takes place across the globe. We report two cases of newly diagnosed NMOSD following COVID-19 vaccination and systematically review previous reports. Searching of Ovid MEDLINE and EMBASE databases was done using predefined search terms related to NMOSD and vaccination. Duplicates were removed. Newly diagnosed NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis criteria with symptoms presenting between 2-30 days after vaccination were included. Data on age, sex, comorbidity, vaccine name, type, and dose number, duration from vaccination to symptom onset, clinical phenotype(s), MRI findings, CSF profiles, severity of attack, initial and maintenance treatment, number of relapses after vaccination, and clinical outcomes were extracted using a standardized table and compared. Ten cases of postvaccination NMOSD were identified. Patients aged between 15-46 years old. Nine patients (90%) presented with transverse myelitis and 3 (30%) with optic neuritis. The mean duration from vaccination to clinical onset was 8.2 days (median 9 days). Five patients (50%) tested positive for aquaporin 4 (AQP4) antibody. One patient had a family history of NMOSD. Three-fourths of AQP4-IgG seropositive patients with myelopathy had short transverse myelitis. The reported vaccines included CoronaVac, ChAdOx1 nCoV-19, yellow fever, quadrivalent influenza, H1N1 influenza, quadrivalent human papillomavirus, Japanese encephalitis, rabies, and recombinant hepatitis B virus together with tetanus-diphtheria-pertussis vaccines. All patients received high-dose steroids for initial treatment and 2 received additional therapeutic plasma exchange. Maintenance therapy was given in 4 patients. Five patients (50%) experienced no subsequent relapses within the follow-up period ranging between 3-34 months. Almost all patients returned to baseline functional status. The temporal relationship between vaccination and onset of symptoms suggests that vaccine might be a trigger of NMOSD. Genetic predisposition could be a risk factor for postvaccination NMOSD as there are evidences of family history and presence of an associated HLA allele. The prevalence of short-segment transverse myelitis seems to be higher than in typical cases of NMOSD, but the natural history is otherwise similar. All patients received acute treatment with high-dose corticosteroids, most with excellent response. Long-term immunomodulation therapy should be initiated for relapse prevention. Limitations of this study are lack of some relevant data, precision of temporal relationship, and the small number of reports. Postvaccination NMOSD is a rare condition that can occur with various types of vaccines. The short temporal relationship between vaccination and onset of NMOSD and the history of NMOSD in one patient's sibling indicate that vaccine might be a trigger for genetically predisposed individuals.

New BBB Model Reveals That IL-6 Blockade Suppressed the BBB Disorder, Preventing Onset of NMOSD.

Background and ObjectivesTo evaluate the pathophysiology of neuromyelitis optica spectrum disorder (NMOSD) and the therapeutic mechanism and levels of interleukin-6 (IL-6) blockade (satralizumab), especially with respect to blood-brain barrier (BBB) disruption with the new in vitro and ex vivo human BBB models and in vivo model.MethodsWe constructed new static in vitro and flow-based ex vivo models for evaluating continued barrier function, leukocyte transmigration, and intracerebral transferability of neuromyelitis optica-immunoglobulin G (NMO-IgG) and satralizumab across the BBB using the newly established triple coculture system that are specialized to closely mimic endothelial cell contact of pericytes and endfeet of astrocytes. In the in vivo study, we assessed the effects of an anti–IL-6 receptor antibody for mice (MR16-1) on in vivo BBB disruption in mice with experimental autoimmune encephalomyelitis in which IL-6 concentration in the spinal cord dramatically increases.ResultsIn vitro and ex vivo experiments demonstrated that NMO-IgG increased intracerebral transferability of satralizumab and NMO-IgG and that satralizumab suppressed the NMO-IgG–induced transmigration of T cells and barrier dysfunction. In the in vivo study, the blockade of IL-6 signaling suppressed the migration of T cells into the spinal cord and prevented the increased BBB permeability.DiscussionThese results suggest that (1) our triple-cultured in vitro and in ex vivo BBB models are ideal for evaluating barrier function, leukocyte transmigration, and intracerebral transferability; (2) NMO-IgG increased the intracerebral transferability of NMO-IgG via decreasing barrier function and induced secretion of IL-6 from astrocytes causing more dysfunction of the barrier and disrupting controlled cellular infiltration; and (3) satralizumab, which can pass through the BBB in the presence of NMO-IgG, suppresses the BBB dysfunction and the infiltration of inflammatory cells, leading to prevention of onset of NMOSD.

Neuromyelitis Optica Spectrum Disorder and Uveitis

ABSTRACT Background Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare disease marked by CNS demyelination with a predilection for the optic nerve and spinal cord often resulting in severe vision loss. We aimed to characterize uveitis occurring in the setting of NMOSD. Methods Retrospective chart review Results Of 572 NMOSD patients, 1% were found to have uveitis with a relative risk of 6.2 (95% confidence interval 3–14, p < .001) compared to the general population. The mean age of uveitis onset was 50 years, and that of NMOSD onset was 52 years. Bilateral anterior uveitis was the most common subtype and most patients were treated with rituximab for their NMOSD. A uveitis attack preceded onset of demyelination attacks in 67% of patients. Eyes without optic neuritis had a mean visual acuity at last follow-up of 20/22. Conclusion Uveitis is a rare complication of NMOSD, bilateral anterior uveitis was the most common subtype.

Pregnancy in Patients With AQP4-Ab, MOG-Ab, or Double-Negative Neuromyelitis Optica Disorder.

To analyze the effects of pregnancy on neuromyelitis optica spectrum disorder (NMOSD) according to patients' serostatus and immunosuppressive therapy (IST). We performed a retrospective multicenter international study on patients with NMOSD. Patients were tested for aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). Informative pregnancies were reported when NMOSD onset occurred before or during pregnancy or up to 12 months postpartum. The mean annualized relapse rate (ARR) was calculated for the 12 months before conception, for each trimester of pregnancy, and postpartum. Events such as miscarriage, abortion, and preeclampsia were reported. IST was considered if taken in the 3 months before or during pregnancy. We included 89 pregnancies (46 with AQP4-Ab, 30 with MOG-Ab, and 13 without either Ab) in 58 patients with NMOSD. Compared to the prepregnancy period, the ARR was lower during pregnancy in each serostatus group and higher during the postpartum period in patients with AQP4-Ab (p < 0.01). Forty-eight percent (n = 31) of pregnancies occurred during IST and these patients presented fewer relapses during pregnancy and the 12 months postpartum than untreated patients (26% vs 53%, p = 0.04). Miscarriages occurred in 10 (11%) pregnancies, and were mainly in patients with AQP4-Ab (with or without IST) and a previous history of miscarriage. Preeclampsia was reported in 2 (2%) patients who were AQP4-Ab-positive. We found a rebound in the ARR during the first postpartum trimester that was higher than the prepregnancy period only in AQP4-Ab-positive patients. Taking IST just before or during pregnancy reduces the risk of relapses in these conditions.

Frequency of comorbidities in Neuromyelitis Optica spectrum disorder

Comorbidity may influence clinical aspects of neuromyelitis optica spectrum disorder (NMOSD). We estimated the prevalence of comorbidities to assess their association with outcomes. This retrospective study assessed records of NMOSD patients from 2008 to 2019, categorizing comorbidities into three groups: somatic, psychiatric and autoimmune. Severity of disease was evaluated by the Expanded Disability Status Scale, progression index (PI) and annualized relapse rate. The frequency of comorbidities was compared between anti-aquaporin 4 antibody (AQP4-IgG) seropositive and seronegative patients. A total of 67 NMOSD patients were enrolled. Thirty-five (52.2%) patients reported at least one comorbidity. In total, 44 comorbidities were found, of which 24 occurred prior to NMOSD onset: 29 somatic, 13 psychiatric and 2 autoimmune entities. The most common comorbidities were anxiety disorders 7/67 (10.4%), followed by migraine 6/67 (8.9%) major depression disorder 6/67 (8.9%), iron deficiency anemia 8/54 (14.8%), and non-autoimmune hypothyroidism 4/67 (6.0%). Psychiatric comorbidities associated with PI in unadjusted (OR=0.538, 95% CI=0.141, 0.935, P=0.009) and adjusted models (OR=0.386, 95% CI=0.022, 0.751, P=0.038). A significantly higher frequency of psychiatric comorbidities was observed in the AQP4-IgG positive patients (P=0.031). Half of the patients had comorbidities, suggesting screening for comorbidity as part of NMOSD care. The psychiatric comorbidities hadimpact on clinical outcome.

Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial

Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200mg/2weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. NCT01892345 (ClinicalTrials.gov).

Outcome of pregnancies after onset of the neuromyelitis optica spectrum disorder.

Data on the pregnancy outcome of neuromyelitis optica spectrum disorder (NMOSD) remain limited, especially for woman who had received immunosuppressive treatment before becoming pregnant. The aim was to evaluate the outcome of pregnancy amongst patients with NMOSD who attempted to become pregnant after NMOSD onset and to identify risk factors that predict pregnancy-related attack. Medical records from 29 patients who attempted to become pregnant after NMOSD onset were retrospectively evaluated and the patients were interviewed for pregnancy outcomes. Pregnancy-related attack was defined as an attack that occurred during pregnancy or within 1year of delivery. Amongst the 29 patients, 26 had 33 pregnancies after NMOSD symptom onset. The 33 pregnancies after NMOSD onset resulted in 24 live births (healthy neonates except one with low birth weight), six miscarriages and three elective abortions. Pregnancy-related attack occurred in nine (75%) of 12 pregnancies before initiation of immunosuppressive therapy, but in only five (24%) of 21 pregnancies after initiation of immunosuppressive therapy (P=0.009). Multivariable analysis indicated that pregnancy-related attack was negatively associated with pregnancy after initiation of rituximab (odds ratio 0.048, 95% confidence interval 0.004-0.546). Successful pregnancy without maternal and neonatal complications may be feasible in patients with NMOSD. Rituximab treatment before pregnancy might help to prevent pregnancy-related attack in patients with NMOSD.

Disability and Therapeutic Response in Paediatric Neuromyelitis Optica Spectrum Disorder: A Case Series from Iran.

The characteristics ofpaediatric neuromyelitis optica spectrum disorder (NMOSD) may indicate the degree of disability and identify factors that predict the response to treatment. Among 114 NMOSD patients in an acquired demyelinating syndromes registry at the Sina Hospital, in Tehran, Iran, 10 paediatric NMOSD patients with longitudinal follow-up from 2005 to 2016 were retrospectively identified. The median time between disease onset and diagnosis was 18 months (range 1-108 months). All patients had a relapsing course, which resulted in disability in six with severe visual impairment and functional blindness in one and impaired ambulation in five patients during follow-up. Azathioprine (AZA) was first drug of choice for prophylaxis, but in five patients new attacks occurred and therapy was switched to rituximab (RTX) with no further relapses after median two years (range 1-3 y) follow-up. Paediatric onset of NMOSD was associated with severe attacks and poor response in 50 % of cases to AZA, RTX seemed to decrease the relapse rate.

Neuromyelitis optica spectrum disorder and menstruation

Gender issues and the female preponderance in neuromyelitis optica spectrum disorder (NMOSD) have been investigated before, yet the interplay between NMOSD and menstrual characteristics has remained unknown. Thus, the aim was to compare menstrual cycle patterns and their symptoms in NMOSD patients and healthy women. This cross-sectional study was conducted during 2015-2016 in Isfahan, Iran, and included female patients aged>14years with a diagnosis of NMOSD and healthy subjects as controls. Data regarding age at menarche, menstrual characteristics, history of premenstrual syndrome (PMS) and possible perimenstrual symptoms were collected. Also, NMOSD patients were asked to report changes in their menstrual cycles after onset of the disorder. The final study population included 32 NMOSD and 33 healthy controls. These groups did not differ regarding their demographics (P>0.05), and age at menarche in the NMOSD and control groups was 13.31±1.49 years and 13.48±1.44 years, respectively (P=0.637). The controls experienced PMS more frequently (78.8% vs. 40.6% in the NMOSD patients; P=0.03), with no significant differences in other menstrual features between groups (P>0.05). However, changes in menstruation after NMOSD onset were reported by 43.8% of patients, with an increase in menstrual irregularities from 15.6% to 43.7% (P=0.012); other menstrual characteristics did not differ after disease onset (P>0.05). Menstruation do not differ between healthy controls and NMOSD patients before the onset of disease whereas, after its onset, those affected experienced more irregularities in their menstrual cycles. This may be an effect of NMOSD and its underlying disorders on menstruation and suggests that further interventions may be required for affected women.

Comprehensive analysis of patients with neuromyelitis optica spectrum disorder (NMOSD) combined with chronic hepatitis B (CHB) infection and seropositive for anti-aquaporin-4 antibody.

Previous research indicated the association between hepatitis B virus (HBV) infection/vaccination and the onset of demyelinating diseases. However, most of these studies were single case reports, and comprehensive data are still scarce. Here we present a comprehensive analysis of 10 patients with neuromyelitis optica spectrum disorder (NMOSD) combined with chronic hepatitis B (CHB) infection and seropositive for anti-aquaporin-4 antibody (AQP4-Ab). Demographic, clinical, laboratory, neuroimaging, outcome, and follow-up data of the 10 patients were retrospectively analyzed. The median age at the onset of NMOSD was 35 years (range 25-43). Nine patients were female (90%). All patients were positive for HBsAg and had been diagnosed with CHB earlier than with NMOSD. One patient had an autoimmune disease. All patients had normal thyroid function. Paresthesia and visual impairment were the most common clinical symptoms. The cerebrospinal fluid (CSF) parameters (protein and glucose) were normal in 10 cases, whereas slightly higher CSF white blood cell count was detected in 3 patients. The brain and spinal cord magnetic resonance imaging findings were abnormal in 8 patients. All patients were treated with hormone and immunosuppressive therapy, and anti-HBV agents. Patients with detectable serum HBV DNA were more prone to liver damage after receiving high doses of corticosteroids. In 8 patients, the symptoms improved before they were discharged. Two patients with optic neuritis (ON) maintained the symptoms. A month later, 1/8 patient had recurrence of symptoms, and one ON patient progressed to NMO. Overall, the characteristics of NMOSD patients with CHB and seropositive for AQP4-Ab are usually nonspecific. Abnormal liver function test results in NMOSD patients should be a warning of possible CHB infection, and the treatment should be modified accordingly.

Neuromyelitis optica spectrum disorder (NMOSD) seropositive for AQP4-IGG more than 3 years before NMOSD onset

Neuromyelitis optica spectrum disorder (NMOSD) seropositive for AQP4-IGG more than 3 years before NMOSD onset

Effectiveness and safety of immunosuppressive therapy in neuromyelitis optica spectrum disorder during pregnancy

To evaluate the effectiveness and safety of immunosuppressive therapy in neuromyelitis optica spectrum disorder (NMOSD) during pregnancy. Sixteen NMOSD patients who had at least one pregnancy after NMOSD onset were enrolled. The patients were divided into two groups according to whether they received immunosuppressive therapy during pregnancy. The annual relapse rate (ARR) before pregnancy (BP); during the first (DP1), second (DP2), and third trimesters (DP3); first trimester postpartum (PP1); and second trimester postpartum (PP2) were calculated. The Expanded Disability Status Scale (EDSS) was used to evaluate the degree of disability. Pregnancy outcomes were recorded and the children were followed up and their health condition was evaluated. In the group taking prednisone alone or in combination with azathioprine as immunosuppressive therapies, there was no difference among ARRs of each period (DP1, DP2, DP3, PP1, PP2) and BP. Compared with EDSS BP, EDSS increased slightly 6months postpartum with no statistical significance (p=0.102). In the group without immunosuppressive therapy, ARR increased during PP1 (p=0.014) and EDSS increased 6months postpartum as compared to BP (p=0.017). Moreover, the added EDSS value was higher in the group without immunosuppressive therapy than in the group with therapy (p=0.038). In 22 pregnancies from 16 patients, 16 pregnancies ended in live births and 6 pregnancies ended in abortions, including 2 spontaneous and 4 induced abortions. None of the children had congenital diseases or malformations. There were no records of abnormal growth among the children during 6months to 12years of follow-up. Untreated women showed a propensity for disease relapse in PP1 and increased degree of disability postpartum. Immunosuppressive therapy during pregnancy and postpartum period can reduce the risk of relapse and degree of disability. Immunosuppressive therapy with low-dose prednisone was relatively safe. However, the safety of azathioprine during pregnancy remains unclear and needs future reevaluation.

Female hormonal exposures and neuromyelitis optica symptom onset in a multicenter study.

Objective:To study the association between hormonal exposures and disease onset in a cohort of women with neuromyelitis optica spectrum disorder (NMOSD).Methods:Reproductive history and hormone use were assessed using a standardized reproductive survey administered to women with NMOSD (82% aquaporin-4 antibody positive) at 8 clinical centers. Using multivariable regression, we examined the association between reproductive exposures and age at first symptom onset (FS).Results:Among 217 respondents, the mean age at menarche was 12.8 years (SD 1.7). The mean number of pregnancies was 2.1 (SD 1.6), including 0.3 (SD 0.7) occurring after onset of NMOSD symptoms. In the 117 participants who were postmenopausal at the time of the questionnaire, 70% reported natural menopause (mean age: 48.9 years [SD 3.9]); fewer than 30% reported systemic hormone therapy (HT) use. Mean FS age was 40.1 years (SD 14.2). Ever-use of systemic hormonal contraceptives (HC) was marginally associated with earlier FS (39 vs 43 years, p = 0.05). Because HC use may decrease parity, when we included both variables in the model, the association between HC use and FS age became more significant (estimate = 2.7, p = 0.007). Among postmenopausal participants, 24% reported NMOSD onset within 2 years of (before or after) menopause. Among these participants, there was no association between age at menopause or HT use and age at NMOSD onset.Conclusions:Overall, age at NMOSD onset did not show a strong relationship with endogenous hormonal exposures. An earlier onset age did appear to be marginally associated with systemic HC exposure, an association that requires confirmation in future studies.

Pregnancy outcomes in aquaporin-4-positive neuromyelitis optica spectrum disorder.

To investigate the association between neuromyelitis optica spectrum disorder (NMOSD) and pregnancy outcome. An international cohort of women with aquaporin-4 antibody-positive NMOSD and ≥1 pregnancy was studied retrospectively. Multivariate logistic regression was used to investigate whether pregnancy after NMOSD onset was associated with an increased risk of miscarriage (cohort of 40 women) or preeclampsia (cohort of 57 women). Miscarriage rate was higher in pregnancies after NMOSD onset (42.9% [95% confidence interval 17.7%-71.1%] vs. 7.04% [2.33%-15.7%]). Pregnancies conceived after, or up to 3 years before, NMOSD onset had an increased odds ratio of miscarriage (7.28 [1.03-51.6] and 11.6 [1.05-128], respectively), independent of maternal age or history of miscarriage. Pregnancies after, or up to 1 year before, NMOSD onset ending in miscarriage were associated with increased disease activity from 9 months before conception to the end of pregnancy, compared to viable pregnancies (mean annualized relapse rate 0.707 vs. 0.100). The preeclampsia rate (11.5% [6.27%-18.9%]) was significantly higher than reported in population studies. The odds of preeclampsia were greater in women with multiple other autoimmune disorders or miscarriage in the most recent previous pregnancy, but NMOSD onset was not a risk factor. Pregnancy after NMOSD onset is an independent risk factor for miscarriage, and pregnancies conceived at times of high disease activity may be at increased risk of miscarriage. Women who develop NMOSD and have multiple other autoimmune disorders have greater odds of preeclampsia, independent of NMOSD onset timing.