Aquaporin-4 Antibody Dynamics and Relapse Risk in Seropositive Neuromyelitis Optica Spectrum Disorder Treated with Immunosuppressants.

OBJECTIVE: To investigate aquaporin-4 antibody (AQP4-IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants. METHODS: This observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4-IgG and treated with immunosuppressants. Serum AQP4-IgG was detected by fixed cell-based assay every 6 months. RESULTS: After treatment with immunosuppressants, 128 patients became AQP4-IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4-IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001-1.035, p < 0.05). Independent risk factors for AQP4-IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack. INTERPRETATION: Patients with younger age at onset, poly-system involvement in the first attack, and unchanged or increased titer of AQP4-IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4-IgG becoming seronegative and change of AQP4-IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023;93:1069-1081.

Factors correlated with neuropathic pain in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuropathic pain in neuromyelitis optica spectrum disorder (NMOSD) is common but has always been overlooked. This study was conducted to explore factors correlated with neuropathic pain in NMOSD and to evaluate associations between pain and quality of life. METHODS: In this cross-sectional study, NMOSD patients were interviewed face-to-face. The Brief Pain Inventory, Douleur Neuropathique 4, and Neuropathic Pain Symptom Inventory scales were used to evaluate pain. Patients completed the Beck Depression Inventory-II and Social Functioning-36 tests to evaluate depression and quality of life. RESULTS: A total of 122 NMOSD patients were enrolled. Eighty-one (66.4%; 95% CI, 39.9% to 92.9%) had current pain, of which 35 (28.7%; 95% CI, 20.7% to 36.7%) had neuropathic pain. Forty-nine (40.2%; 95% CI, 31.5% to 48.9%) patients experienced depression, which was moderate to severe in 22 patients. Multinomial logistic regression showed that significantly more patients with neuropathic pain had depression than those with other pain (OR, 4.15; 95% CI, 1.40 to 12.35; P=0.010) or no pain (OR, 5.65; 95% CI, 1.74 to 18.18; P=0.004). Significantly more patients with neuropathic pain had initial spinal cord involvement than those in the no-pain group (OR, 15.78; 95% CI, 1.37 to 182.15; P=0.027). Quality of life was severely affected in NMOSD patients with neuropathic pain. Only 29.6% were treated with analgesics, and none were prescribed antidepressants. CONCLUSION: Depression was correlated with neuropathic pain and was often overlooked. Initial spinal cord involvement might indicate a higher risk for neuropathic pain. Neuropathic pain in NMOSD patients requires scrutiny.

Real-world outcomes of teriflunomide in relapsing-remitting multiple sclerosis: a prospective cohort study.

OBJECTIVES: To explore efficacy, risk factors, safety, and persistence of teriflunomide in relapsing-remitting multiple sclerosis (RRMS) cohort. METHODS: This prospective, observational cohort study included 217 consecutive teriflunomide treated RRMS patients, 192 of which with at least 3-month persistence on teriflunomide were included in effectiveness and risk factor analyses. Multivariate Cox proportional regression analysis was performed to identify factors associated with failure of no evidence of disease activity (NEDA) 3. RESULTS: At baseline 82% patients were treatment naïve while 18.0% interferon-ß1b treated patients had stopped treatments for more than 1 year. After treatment, 79.0% patients achieved NEDA 3 at 12-month, mean annualized relapse rate (ARR) reduced significantly (0.79 ± 0.80 vs 0.16 ± 0.70; P < 0.001), and mean expanded disability status score (EDSS) remained stable (1.40 ± 1.67 vs 1.56 ± 1.88; P > 0.05). Male sex (hazard ratio [HR] 1.856; 95% confidence interval [CI] 1.118-3.082, P < 0.05), baseline EDSS score ≥ 4 (HR 2.682; 95% CI 1.375-5.231, P < 0.01), and frequent relapses before treatment (HR 3.056; 95% CI 1.737-5.377, P < 0.01) were independent factors significantly associated with failure of NEDA 3. The most frequent adverse events (AEs) were hair thinning, alanine aminotransferase (ALT) elevation, and leukopenia, the latter two most commonly lead to teriflunomide discontinuation during the first 3 months. Persistence rates at 6, 12, and 24 months after teriflunomide initiation were 86.9%, 72.4%, and 52.8%, respectively. CONCLUSIONS: Our results support efficacy and tolerability of teriflunomide for treatment-naïve RRMS patients in real-world practice. Female patients, patients with less relapses and less disability before treatment are most likely to benefit from teriflunomide treatment.

The Epidemiology of COVID-19 and MS-Related Characteristics in a National Sample of People With MS in China.

Few studies have focused on immune status and disease activity in MS patients during the coronavirus disease 2019 (COVID-19) pandemic. The aim of this study is to investigate immune status, COVID-19 infection, and attacks in MS patients during the pandemic. An online questionnaire about COVID-19 infection, MS attack, and MS treatment during the pandemic was administered to all 525 MS patients registered in our hospital database from January 1, 2011, to June 1, 2020. Only 384 responded, of which 361 patients could be included in the final analysis. During the pandemic, 42.1% of the 361 patients and 65.0% of the 234 patients on immunotherapies were exposed to teriflunomide. Compared to patients who didn't receive treatment, patients exposed to DMTs had significantly lower levels of neutrophils (P < 0.01) and immunoglobulin G (P < 0.01), and patients exposed to immunosuppressants had significantly lower levels of immunoglobulin G (P < 0.05). Over 80% of our patients followed effective protective measures and none of the 361 MS patients in our cohort contracted COVID-19. Patients whose treatment was disrupted had a significantly higher annualized relapse rate (ARR) during than before the pandemic (P < 0.01), while the ARR of patients with continuous treatment or without treatment remained unchanged. During the pandemic, the risk of MS attack due to treatment disruption possibly outweighs the risk of COVID-19 infection under preventive measures, and MS treatment maintenance might be necessary.

The Impact of COVID-19 on Patients With Neuromyelitis Optica Spectrum Disorder Beyond Infection Risk.

There is an increasing need for better understanding of the impact of coronavirus disease 2019 (COVID-19) on patients with neuromyelitis optica spectrum disorder (NMOSD). A few pilot studies have investigated COVID-19 infections in NMOSD, but few studies have addressed disease activity and immune status of these patients during the pandemic. We carried out a cross-sectional study to examine immune status, relapses, and COVID-19 infections in a cohort of NMOSD patients using an electronic patient registry (MSNMOBase) for multiple sclerosis and related disorders. An online questionnaire was administered to all NMOSD patients in the registry from January 1, 2011, to June 1, 2020. Clinical demographic characteristics, immune status, relapses, treatments, COVID-19 infections, and preventive measures were evaluated. Of the 752 registered patients, 535 (71.1%) with qualified data were included. A total of 486 used preventive therapies during the pandemic, including mycophenolate mofetil (71.2%), azathioprine (13.3%), and other immunosuppressants (6.4%). Neither median immune cell counts nor immunoglobulin levels (p > 0.05) were significantly different between patients with or without immunosuppression. During the pandemic, no patients were diagnosed with COVID-19, and the majority (>95%) took one or more effective protective measures (e.g., wearing a mask and social distancing). However, a significantly higher annualized relapse rate (ARR) was observed in the 33 patients with treatment interruptions due to the pandemic compared to before it (p < 0.05), whereas ARR changes were not found in patients with continuous treatments or those without treatments (p > 0.05). Interruption frequency was significantly higher in patients with relapses compared to those without (34.9 vs. 15.7%, p < 0.01). For stable NMOSD patients during the pandemic, the risk of relapse due to treatment interruption may be higher than the risk of COVID-19 infection when protective measures are used, and continuous relapse-prevention treatments may be necessary.

A Case Report of Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Diagnosed After Long Term Diagnosis of Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids.

Cases of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy who were initially diagnosed with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) were rarely reported. Herein, we reported a 31-year-old woman who presented with 7 years of recurrent headache. Her clinical history, symptoms, brain MRI enhancement features, and response to treatment during each attack were reviewed. Her brain MRI 7 years ago demonstrated characteristic pepper-like enhancement of pontine and cerebellum and her symptoms resolved completely after taking a high-dose of steroids. She was suspected with the diagnosis of CLIPPERS, and she experienced five relapses once the oral steroid was tapered below 20 mg/day. During her last relapse, she experienced fever and psychosis, and GFAPα-antibodies were detected in her serum and cerebrospinal fluid by antigen-transfected HEK293 cell-based assay (indirect immunofluorescence assay). She obtained relief again after steroid therapy, and her diagnosis converted to autoimmune GFAP astrocytopathy. Autoimmune GFAP astrocytopathy may mimic CLIPPERS, both clinically and radiologically. Long-term follow-up is essential for necessary diagnosis revision at each new attack in patients with a diagnosis of CLIPPERS.

Prediction of long-term disability in Chinese patients with multiple sclerosis: A prospective cohort study.

BACKGROUND: Much information about outcomes of multiple sclerosis (MS) has been studied in Caucasian cohorts. However, little is known about the predictors of long-term disability in Chinese patients with MS. The aim of this prospective, observational study is to identify the prognostic factors associated with long-term disability progression (expanded disability status scale, EDSS=6.0) in Chinese patients with relapsing-onset MS. METHODS: Based on data from the MSNMOBase registry within the neurology department of Peking Union Medical College Hospital (PUMCH) in China, this hospital-based cohort study was conducted to estimate the median time of attaining disability endpoint (EDSS = 6.0) by Kaplan-Meier curves, and identify factors that associated with disability progression by Cox proportional regression analysis. RESULTS: A total of 415 consecutive, eligible patients with MS were registered in the MSNMOBase of PUMCH and prospectively followed from 2011 to 2019. Of these patients, 365 patients with relapsing-onset MS were analyzed. The median time to reach an EDSS of 6.0 was 22.0 (95% CI 16.5-27.5) years. Age at disease onset greater than 50 years (HR 3.846, 95% CI 1.240-11.932, P=0.020), incomplete recovery from first attack (HR 2.107, 95% CI 1.168-3.800, P=0.013), and ≥2 relapses during the first 2 years after onset (HR 2.217, 95% CI 1.148-4.281, P=0.018) significantly associated with a higher hazard ratio to reach an EDSS of 6.0. CONCLUSIONS: Our results confirm the importance of age at onset, recovery from the first attack, and number of relapses during the first 2 years after disease onset as predictors of disability progression in Chinese patients with relapsing-onset MS.

Long-term efficacy of mycophenolate mofetil in myelin oligodendrocyte glycoprotein antibody-associated disorders: A prospective study.

OBJECTIVE: To investigate whether the use of mycophenolate mofetil (MMF) could reduce the relapse risk in patients with myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG)-associated disorders (MOGADs). METHODS: This prospective observational cohort study included patients with MOGAD at Peking Union Medical College Hospital between January 1, 2017, and April 30, 2019. The patients were divided into 2 groups: those with (MMF+) or without (MMF-) MMF therapy. The primary outcome was relapse at follow-up. We used Cox proportional hazards models to calculate hazard ratios (HRs) for relapse. RESULTS: Seventy-nine patients were included in our MOG cohort. Fifty (63.3%) were adults at index date, and 47 (59.5%) were women. Fifty-four (68.4%) were in the MMF+ group, and 25 (31.6%) were in the MMF- group. Clinical and demographic factors, MOG-IgG titer, and follow-up time (median, 472.5 days for MMF+, 261.0 days for MMF-) were comparable between the groups. Relapse rates were 7.4% (4/54) in the MMF+ group and 44.0% (11/25) in the MMF- group. Of all potential confounders, only the use of MMF was associated with reduced risk of relapse. The HR for relapse among patients in the MMF+ group was 0.14 (95% CI, 0.05-0.45) and was 0.08 (95% CI, 0.02-0.28) in a model adjusted for age, sex, disease course, and MOG-IgG titer. MMF therapy also remained associated with a reduced relapse risk in sensitivity analyses. Only one patient (1.9%) discontinued MMF therapy because of adverse effect. CONCLUSIONS: These findings provide a clinical evidence that MMF immunosuppression therapy may prevent relapse in patients with MOGAD. CLASSIFICATION OF EVIDENCE: This study provides class IV evidence that for patients with MOGAD, MMF reduces relapse risk.

Study on variation trend of repetitive nerve stimulation waveform in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons with no effective cure. Electrophysiological studies have found decremental responses during low-frequency repetitive nerve stimulation (RNS) except for diffused neurogenic activities. However, the difference between ALS and generalized myasthenia gravis (GMG) in terms of waveform features is unclear. In the current study, we explored the variation trend of the amplitudes curve between ALS and GMG with low-frequency, positive RNS, and the possible mechanism is discussed preliminarily. METHODS: A total of 85 ALS patients and 41 GMG patients were recruited. All patients were from Peking Union Medical College Hospital (PUMCH) between July 1, 2012 and February 28, 2015. RNS study included ulnar nerve, accessory nerve and facial nerve at 3 Hz and 5 Hz stimulation. The percentage reduction in the amplitude of the fourth or fifth wave from the first wave was calculated and compared with the normal values of our hospital. A 15% decrease in amplitude is defined as a decrease in amplitude. RESULTS: The decremental response at low-frequency RNS showed the abnormal rate of RNS decline was 54.1% (46/85) in the ALS group, and the results of different nerves were 54.1% (46/85) of the accessory nerve, 8.2% (7/85) of the ulnar nerve and 0% (0/85) of the facial nerve stimulation, respectively. In the GMG group, the abnormal rate of RNS decline was 100% (41/41) at low-frequency RNS of accessory nerves. However, there was a significant difference between the 2 groups in the amplitude after the sixth wave. CONCLUSIONS: Both groups of patients are able to show a decreasing amplitude of low-frequency stimulation RNS, but the recovery trend after the sixth wave has significant variation. It implies the different pathogenesis of NMJ dysfunction of these 2 diseases.

Systemic autoimmune diseases complicated with hydrocephalus: pathogenesis and management.

Systemic autoimmune diseases (SAIDs) represent a group of syndromes involving at least two organ systems. Classical SAIDs include connective tissue diseases, vasculitis, and granulomatous diseases, many of which involve the nervous system and result in different neurological manifestations. Hydrocephalus can be a rare but lethal complication of various SAIDs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), sarcoidosis, and primary vasculitis. However, the pathogenesis of SAIDs complicated with different types of hydrocephalus is varied and difficult to determine using the existing published data, and various manifestations and expressive forms of the conditions bring a substantial challenge to a timely clinical diagnosis and treatment. The commonly used medical management programs based on the etiology of hydrocephalus are anti-inflammatory or anti-infectious therapies, while surgical management such as ventriculoperitoneal shunts is effective most of the time. Further research should be directed toward improving our understanding of the pathogenesis of these conditions and determining the most effective method for treating this life-threatening condition.

Reference Values and Influencing Factors Analysis for Current Perception Threshold Testing Based on Study of 166 Healthy Chinese.

The current perception threshold (CPT) is a device which can evaluate different sensory fibers quantitatively through different frequencies of the electrical stimulus and has been applied in clinical practice. Previous studies have implied that CPT values may be affected by age, gender, and other factors, yet not conclusively. The objective of our study is to clarify the influencing factors of CPT values and establish a reference value range. Twenty healthy volunteers recruited publicly and 146 subjects who took CPT tests in the census of the national project cardiovascular and cerebrovascular diseases in rural areas of China from 2013 to 2015 were analyzed. Past medical history and demographic characteristics such as age, gender, and occupation were collected. Each subject was tested on the left index finger (or back of the left hand) and the right hallux. CPT values of 2000, 250, and 5 Hz on both sites were recorded for statistical analysis. Gender differences were shown at 2000 Hz CPT on the back of the hand and hallux (p < 0.01), and male subjects had a higher CPT. Age had a positive correlation with 250 Hz CPT on the index finger (p < 0.05, r = 1.5), 2000 Hz CPT on the back of the hand (p < 0.001, r = 1.2) and index finger (p < 0.05, r = 2.5). Manual workers had a higher 250 Hz CPT on the hallux than mental workers (p < 0.01). After investigating the impact of different factors on CPT testing, we established the reference value for subjects with different characteristics.

Resection of melanocytic nevi as a potential treatment of anti-NMDAR encephalitis patients without tumor: report of three cases.

The most common underlying tumor associated with anti-N-methyl D-aspartate-receptor (NMDAR) encephalitis is ovarian teratoma. Resection of the underlying tumor may decrease exposure of autoantigen and make for faster response of immunotherapy and less relapse frequency. Similar to teratoma, expression of NMDAR in human epidermal melanocytes was suspected recently. The dense melanocytes in melanocytic nevus may serve as potential autoantigens and are prone to increase relapse frequency in the tumor-negative patients. Three patients with confirmed diagnosis of anti-NMDAR encephalitis were described here. They shared common features that the screening tests for an ovarian teratoma or other tumors were all negative, while they were found to have prominent melanocytic nevi on the skin and resection of the nevi likely played a positive effect on their persistent recovery. This is a report on treatment of anti-NMDAR encephalitis patients without underlying tumor through resection of melanocytic nevi. More clinical and experimental investigations are needed to prove its validity.

Management of hydrocephalus associated with autoimmune diseases: a series of 19 cases.

OBJECTIVES: To analyze the diagnosis and treatment of hydrocephalus associated with autoimmune diseases and to explore the possible mechanism of hydrocephalus in these patients. METHODS: A retrospective case series study was conducted at Peking Union Medical College Hospital, Beijing, China. Files were retrieved from the hospital archives by screening records from Jan 1990 to Jan 2016. Medical records were screened for data regarding (1) the number of patients diagnosed with hydrocephalus associated with autoimmune diseases, (2) the clinical manifestation of hydrocephalus associated with autoimmune disease, and (3) the outcomes of these patients treated with medication or ventriculoperitoneal shunt (VPS). RESULTS: A total of 19 of 19,643 hospitalized autoimmune diseases patients were found to have hydrocephalus. Seven of the 19 patients had systemic lupus erythematosus (SLE), 3 patients had Sjögren's syndrome, 2 patients had rheumatoid arthritis (RA), 1 patient had connective tissue disease, 1 patient had juvenile idiopathic arthritis (JIA), 1 patient had Guillain-Barre syndrome (GBS), 1 patient had systemic sclerosis, 1 patient had Crohn's disease, 1 patient had relapsing polychondritis (RPC), and 1 patient had autoinflammatory disease (AID). Of the 19 patients, 13 received medication treatment, and the most commonly used drugs were corticosteroids and mannitol. A total of 6 patients received both medication therapy and VPS treatment with a programable valve. After average follow-up lengths of 11 months for patients who received VPS and 8.2 for patients who received medical treatment, the clinical symptoms of patients treated by VPS or medication were improved (83% (5/6) vs. 15.4% (2/13), respectively), patients were in stable condition (17% (1/6) vs. 30.8% (4/13), respectively), and mortality decreased (0% vs. 53.8% (7/13), respectively). CONCLUSIONS: VPS along with corticosteroids and immunosuppressants represents an effective treatment approach for patients who suffer from hydrocephalus associated with autoimmune diseases.