OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) causes disabling and persistent central neuropathic pain (NP). Because the pain syndrome in NMOSD is severe and often intractable to analgesic treatment, it interferes with quality of life in patients. No interventional trials have been published looking at response to interventions for pain in NMOSD. This is a synthesis of the literature surveying the impact on quality of life of interventions in all mechanisms of central spinal NP. This review has important implications for management of pain in NMOSD. METHODS AND DATA SOURCES: A systematic database search was conducted using PubMed, Embase, and CINAHL Plus with keywords including spinal cord, quality of life, and neuropathic pain in an attempt to identify original research that targeted spinal NP treatment and used quality of life as an outcome measure. Both pharmacologic and nonpharmacologic treatments were sought out. RESULTS: Twenty-one studies meeting our eligibility criteria were identified and evaluated, 13 using pharmacologic treatments and 8 using nonpharmacologic interventions. Overall, sample sizes were modest, and effects on decreasing pain and/or improving quality of life were suboptimal. CONCLUSIONS: This review provides researchers with a foundation from which to start a more thorough and thoughtful investigation into the management of NP in NMOSD and underscores the importance of including quality of life as a clinically meaningful outcome measure.

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

Introduction

Superficial siderosis is a rare, neurodegenerative disease caused by toxic accumulation of hemosiderin on the surface of the brain and the spinal cord, most commonly from chronic subarachnoid hemorrhage.

Aims

The aim of this study was to assess the clinical and radiological outcomes of superficial siderosis patients using deferiprone, a cell permeant iron chelator. Subjects obtained pre- and post-treatment brain MRIs and weekly laboratory tests. Osirix software was used to develop a method of quantifying hemosiderin deposition. Three-dimensional whole brain images of gradient echo images were rendered and compared by dividing the mean T2 hyperintensity to the maximal cerebrospinal fluid signal.

Results

A total of 38 subjects completed the study, of which clinical and radiological data were available for 30. The average age was 64 years (range 37-86), 53% were male, 94% were white. Nineteen subjects (63%) reported either no progression of disease or an improvement in at least one neurological domain, with 40% of patients reporting a stabilization in hearing function and 30% reporting stable or improved coordination and walking. By MRI, there was an overall mean increase in T2 hyperintensity of the whole brain of 1%-13% over the 2-year time period in half of patients, indicating a reduction hemosiderosis. There were no cases of agranulocytosis, and declines of white blood cells counts and neutrophils averaged <10%. Fatigue was the most common side effect.

Conclusion

This is the first long-term prospective study of superficial siderosis on the iron chelator, deferiprone. MRI quantification of hemosiderin appears to demonstrate a measurable reduction in half of patients and this correlated with a stabilized or improving disease course. A future placebo-controlled trial is necessary to determine whether deferiprone is an effective therapy for superficial siderosis.

Background

Debate exists about whether neuromyelitis optica spectrum disorder seronegative disease represents the same immune-mediated attack on astrocytic aquaporin-4 as in seropositive disease.

Objective

We investigated whether response to common treatments for neuromyelitis optica spectrum disorder differed by serostatus, as assessed by change in annualized relapse rate.

Methods

We performed a multicenter retrospective analysis of 245 patients with neuromyelitis optica spectrum disorder who were treated with either rituximab or mycophenolate mofetil as their first-line immunosuppressive treatment for disease prevention. Patients were followed for a minimum of 6 months following treatment initiation.

Results

In those started on rituximab, the pre-treatment annualized relapse rates for seropositive and seronegative patients were 1.81 and 1.93, respectively. On-treatment annualized relapse rates significantly declined to 0.32 (seropositive; p < 0.0001) and 0.12 (seronegative; p = 0.0001). In those started on mycophenolate mofetil, the pre-treatment annualized relapse rates for seropositive and seronegative patients were 1.79 and 1.45, respectively. On-treatment annualized relapse rates declined to 0.29 (seropositive; p < 0.0001) and 0.30 (seronegative; p < 0.005).

Conclusion

In this international collaboration involving a large number of neuromyelitis optica spectrum disorder patients, treatment was effective regardless of serostatus. This suggests that treatment should not differ when considering these treatments.

Objective

To identify genetic differences among siblings with a family history of idiopathic transverse myelitis (ITM).

Methods

We compared whole-exome sequencing (WES) on germline samples from the 2 affected sisters with ITM with 3 of their healthy siblings.

Results

The 2 sisters with ITM both had acute onset of sensory loss in the legs, weakness, and bowel/bladder dysfunction. The first developed ITM at age 15 years with a clinical nadir of complete paralysis, which slowly recovered over a few years. MRI demonstrated a persistent T2 lesion in the lower thoracic cord. The second developed ITM at age 50 years with a nadir of sensory loss from T6 down and paraparesis in the legs, associated with an MRI lesion at T6. She also made a partial recovery with treatment. Both sisters are homozygous for a missense variant in VPS37A (c.700C>A, p.Leu234Ile) identified by WES. We performed targeted sequencing of VPS37A in an additional 86 samples from patients with ITM and 175 with other diseases to investigate the p.Leu234Ile variant. We identified another patient with ITM homozygous for the same rare variant. No patients with multiple sclerosis, neuromyelitis optica, other neurologic conditions, or any healthy controls in public databases were homozygous for this variant.

Conclusions

A rare missense variant in VPS37A may predispose to development of ITM. Further studies are necessary to determine the frequency of this variant in the patient population and the mechanism through which it contributes to the risk of disease.

Objective

Blood tests to monitor disease activity, attack severity, or treatment impact in neuromyelitis optica spectrum disorder (NMOSD) have not been developed. This study investigated the relationship between serum glial fibrillary acidic protein (sGFAP) concentration and NMOSD activity and assessed the impact of inebilizumab treatment.

Methods

N-MOmentum was a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial in adults with NMOSD. sGFAP levels were measured by single-molecule arrays (SIMOA) in 1,260 serial and attack-related samples from 215 N-MOmentum participants (92% aquaporin 4-immunoglobulin G-seropositive) and in control samples (from healthy donors and patients with relapsing-remitting multiple sclerosis).

Results

At baseline, 62 participants (29%) exhibited high sGFAP concentrations (≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (hazard ratio [95% confidence interval], 3.09 [1.6-6.1], p = 0.001). Median (interquartile range [IQR]) concentrations increased within 1 week of an attack (baseline: 168.4, IQR = 128.9-449.7 pg/ml; attack: 2,160.1, IQR = 302.7-9,455.0 pg/ml, p = 0.0015) and correlated with attack severity (median fold change from baseline [FC], minor attacks: 1.06, IQR = 0.9-7.4; major attacks: 34.32, IQR = 8.7-107.5, p = 0.023). This attack-related increase in sGFAP occurred primarily in placebo-treated participants (FC: 20.2, IQR = 4.4-98.3, p = 0.001) and was not observed in inebilizumab-treated participants (FC: 1.1, IQR = 0.8-24.6, p > 0.05). Five participants (28%) with elevated baseline sGFAP reported neurological symptoms leading to nonadjudicated attack assessments.

Interpretation

Serum GFAP may serve as a biomarker of NMOSD activity, attack risk, and treatment effects. ANN NEUROL 2021;89:895-910.

OBJECTIVE:To study the effect of pregnancy on the frequency of neuromyelitis optica spectrum disorder (NMOSD) relapse and evaluate rates of pregnancy-related complications in an international multicenter setting. METHODS:We administered a standardized survey to 217 women with NMOSD from 7 medical centers and reviewed their medical records. We compared the annualized relapse rate (ARR) during a baseline period 2 years prior to a participant's first pregnancy to that during pregnancy and to the 9 months postpartum. We also assessed pregnancy-related complications. RESULTS:There were 46 informative pregnancies following symptom onset in 31 women with NMOSD. Compared to baseline (0.17), ARR was increased both during pregnancy (0.44; p = 0.035) and during the postpartum period (0.69; p = 0.009). The highest ARR occurred during the first 3 months postpartum (ARR 1.33). A total of 8 of 76 (10.5%) with onset of NMOSD prior to age 40 experienced their initial symptom during the 3 months postpartum, 2.9 times higher than expected. CONCLUSIONS:The postpartum period is a particularly high-risk time for initial presentation of NMOSD. In contrast to published observations in multiple sclerosis, in neuromyelitis optica, relapse rate during pregnancy was also increased, although to a lesser extent than after delivery.