Aquaporin-4 Autoantibody Detection by ELISA: A Retrospective Characterization of a Commonly Used Assay

Objective. Aquaporin-4 (AQP4) serum autoantibodies are detected by a variety of methods. The highest sensitivity is achieved with cell-based assays, but the enzyme-linked immunosorbent assay (ELISA) is still commonly utilized by clinicians worldwide. Methods. We performed a retrospective review to identify all patients at the University of Utah who had AQP4 ELISA testing at ARUP Laboratories from 2010 to 2017. We then reviewed their diagnostic evaluation and final diagnosis based on the ELISA titer result. Results. A total of 750 tests for the AQP4 ELISA were analyzed, and 47 unique patients with positive titers were identified. Less than half of these patients (49%) met the clinical criteria for neuromyelitis optica spectrum disorder (NMOSD). In cases of low positive titers (3.0–7.9 U/mL, n = 19 ), the most common final diagnosis was multiple sclerosis (52.6%). In the moderate positive cohort (8.0–79.9 U/mL, n = 14 ), only a little more than half the cohort (64.3%) had NMOSD. In cases with high positives (80–160 U/mL, n = 14 ), 100% of patients met clinical criteria for NMOSD. Conclusions. Our data illustrates diagnostic uncertainty associated with the AQP4 ELISA, an assay that is still commonly ordered by clinicians despite the availability of more sensitive and specific tests to detect AQP4 autoantibodies in patients suspected of having NMOSD. In particular, low positive titer AQP4 ELISA results are particularly nonspecific for the diagnosis of NMOSD. The importance of accessibility to both sensitive and specific AQP4 testing cannot be overemphasized in clinical practice.

A Tripartite Knowledge Translation Program: Innovative Patient-Centered Approach to Clinical Research Participation for Individuals with Multiple Sclerosis

Background. Knowledge translation (KT) models that represent an individual’s perspective are a sign of effective KT. Some common challenges in KT include participant engagement, organization of the team, and time demands of the participants. We implemented a unique tripartite KT program to (1) share current research, (2) inform persons living with multiple sclerosis (pwMS) about the clinical research process, and (3) invite pwMS to immediately participate in clinical research. The primary aim was to determine participants’ perspectives on the value and acceptability of an experiential research program offered at a patient and family educational conference. Methods. A team of researchers identified factors that would impact the logistics of hosting an experiential research program at a conference and designed a unique tripartite KT program. The local multiple sclerosis (MS) society was engaged to select an appropriate location and invite stakeholders to the conference. A survey to determine participants’ perspectives on the value and acceptability of the experiential research program was developed and analyzed. Results. 65 pwMS attended the conference, and 44 (67.7%) participated in the on-site experiential research program. 72.7% of the participants completed the survey, of which 93.8% stated that they strongly agree or agree with the following statements: “Did you feel like participating in research today was a valuable experience to you?” and “Did you feel like you were contributing to MS research?” 100% of the participants agreed or strongly agreed when asked “would you like to see more research activities taking place at these kinds of events?” Conclusions. This paper describes the logistics and challenges of conducting an experiential KT program, which proved to be rewarding for pwMS. The majority of pwMS attending the conference agreed to participate in the on-site experiential research program and an overwhelming majority of participants felt the experience was valuable.

Quantitative Magnetic Resonance Imaging Analysis of Early Markers of Upper Cervical Cord Atrophy in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

Purpose. To quantitatively analyze the C2/C3 segments of the spinal cord on magnetic resonance imaging (MRI) scans of neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (RRMS) patients in their first five years of the disease and to investigate the intergroup differences regarding markers of spinal cord atrophy and their correlations with expanded disability status scale (EDSS). Materials and Methods. Twenty NMOSD patients and twenty RRMS patients, within their first five years of the disease, were enrolled in this cross-sectional study. All patients underwent spinal cord MR imaging using 1.5 Tesla systems, and C2/C3 portions of the spinal cord were segmented in the obtained scans. C2/C3 anteroposterior diameter (C2/C3 SC-APD), transversal diameter (C2/C3 SC-TD), and cross-sectional area (C2/C3 SC-CSA) were quantitatively measured using Spinal Cord Toolbox v.4.3. Results. Three NMOSD patients were seropositive for anti-AQP4 IgG. The mean C2/C3 SC-CSA in NMOSD patients was significantly lower than in RRMS patients. NMOSD patients had significantly lower C2/C3 SC-TDs than RRMS patients. With the three anti-AQP4+ patients excluded from the analysis, C2/C3 SC-TD was negatively correlated with EDSS. Conclusion. In the early stages of the disease, quantitative evaluation of C2/C3 spinal cord parameters, including cross-sectional area and transversal diameter in NMOSD patients, appears to be of potential diagnostic and prognostic value.

A Descriptive Correlational Study to Evaluate Three Measures of Assessing Upper Extremity Function in Individuals with Multiple Sclerosis

Background. Activities of daily living and quality of life (QOL) are hindered by upper extremity (UE) impairments experienced by individuals with multiple sclerosis (iMS). The Nine-Hole Peg Test (9-HPT) is most frequently used to measure UE function. However, it does not measure peoples’ ability to perform routine tasks in daily life and may not be useful in iMS who cannot pick up the pegs utilized in the 9-HPT. Therefore, we evaluated three measures to explore a more comprehensive assessment of UE function: Upper Extremity Function Scale (UEFS), Action Research Arm Test (ARAT), and the 9-HPT. The objectives were to quantitatively assess the relationship between these measures of UE function, understand if the measures correlate with QOL as calculated by the MS Quality of Life-54 (MSQOL-54), and to determine differences in the measures based on employment status. Methods. 112 (79 female) iMS were prospectively recruited for this descriptive correlational study. Inclusion criteria were as follows: confirmed diagnosis of MS or clinically isolated syndrome, age ≥ 18 years, and ability to self-consent. All statistical analyses including Spearman’s correlation coefficient ( r s ) and Kruskal-Wallis tests were performed using SPSS. Results. A moderate correlation ( r s = − 0.51 ; p < 0.001 ) was found between the ARAT and 9-HPT scores for the more impaired hand. Likewise, a moderate correlation was found between UEFS and the physical health composite scores (PHCSs) of MSQOL-54 ( r s = − 0.59 ; p < 0.001 ). Finally, performances on ARAT, 9-HPT, and UEFS differed between the employed individuals and those on long-term disability ( p = 0.007 , p < 0.001 , and p = 0.001 ). Conclusion. The UEFS moderately correlated with the QOL measure, and considering the UESF is a patient-reported outcome, it could be used to complement routinely captured measures of assessing UE function. Further study is warranted to determine which measure, or combination of measures, is more sensitive to changes in UE function over time.

State-of-the-Art Review: Demyelinating Diseases in Indonesia

Demyelinating diseases are more common in Indonesia than previously believed. However, it is still a challenge for a country such as Indonesia to implement the scientific medical advances, especially in the diagnostic process of demyelinating diseases, to achieve the best possible outcome for these groups of patients, within the constraints of what is socially, technologically, economically, and logistically achievable. In this review, we address the 4 major classes of demyelinating disease: multiple sclerosis (MS), neuromyelitis optica (NMO), anti-MOG-associated encephalomyelitis (MOG-EM), and acute disseminated encephalomyelitis (ADEM), and discuss their prevalence, demographics, clinical diagnosis workup, and imaging features in the Indonesian population, as well as the challenges we face in their diagnosis and therapeutic approach. We hope that this overview will lead to a better awareness of the spectrum of demyelinating diseases of the central nervous system in Indonesia.

Pulmonary Function and Respiratory Muscle Strength in Patients with Multiple Sclerosis

Background. In patients with multiple sclerosis (MS), there is a decline in muscle strength and physical capacity due to demyelination and axonal loss in the central nervous system. In patients with advanced MS or in a later stage of the disease, also respiratory impairment may occur. The degree of pulmonary dysfunction in the earlier stages of MS has not been thoroughly described. Therefore, the primary aims of this study are to describe pulmonary function and respiratory muscle strength in patients with a moderate disease course and to identify associations between respiratory muscle strength and functional capacity. Methods. A sample of 48 patients with a diagnosis of MS and mean age 56 ± 11 years was studied using a descriptive cross-sectional design. The patients had a disease duration of 24 ± 11 years and a median Expanded Disability Status Scale (EDSS) score of 4.5 (interquartile range 4.0-6.5). Pulmonary function assessed by spirometry, respiratory muscle strength, peak cough flow and peripheral oxygen saturation, subjective breathing and coughing ability, and physical capacity measured using the 6MWT were evaluated. Results. The patients had normal pulmonary function with no significant abnormalities in dynamic spirometry (vital capacity 103 ± 16 % predicted, forced expiratory volume in 1 second 95 ± 15 % predicted). Peak expiratory flow rate 89 ± 17 % predicted was in the lower limit of normal. Respiratory muscle strength, determined by maximal inspiratory (MIP) and expiratory (MEP) static pressures, was normal but with large differences between individuals. MIP ranged from 26 to 143 cmH2O ( 98 ± 31 % predicted); the MEP values ranged from 43 to 166 cmH2O ( 104 ± 29 % predicted), with two patients having values below the lower limit of normal. Significant positive associations between MIP as well as MEP were found in several pulmonary function variables. A significant negative association was found between EDSS score and MEP ( r = − 0.312 , p = 0.031 ). Mean peak cough flow was 389 ± 70 L/min, which is comparable with the values reported for healthy adults. The patients did not experience a severely decreased ability to take deep breaths or cough. There was a moderate correlation between MEP and physical capacity, as assessed by the 6MWT ( r = 0.399 , p = 0.010 ) and between peak expiratory flow (PEF) and the 6MWT ( r = 0.311 , p = 0.048 ). Conclusion. Respiratory muscle strength, pulmonary function assessed by spirometry, and peak cough flow were normal in patients with mild to moderate MS; however, there were large individual differences demonstrating low respiratory muscle strength in some patients. Significant associations between MEP and functional capacity and between MEP and disease severity were found, indicating that patients with impaired respiratory muscle strength have lower functional capacity and more severe disease.

Evaluation of Month of Birth in Neuromyelitis Optica Spectrum Disorders (NMSOD) and Multiple Sclerosis (MS)

Introduction. Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMO) are chronic immune-mediated diseases in the central nervous system (CNS). Environmental factors such as month of birth can be a trigger for these diseases. Therefore, we conducted this study to compare the months of birth in MS and NMOSD patients with the control group. Methods. In this cross-sectional study, 2345 patients with MS, 220 NMOSD patients, and 2174 healthy subjects were enrolled. Demographic information such as age, sex, month of birth, and education in three groups was extracted from the database. The associations between month of birth and MS were studied by binary logistic regression with adjusting for the year of birth. Results. There was a reduced birth rate in September-October in NMOSD ( OR = 0.309 , 95% CI: 0.150-0.636; p < 0.001 ) and MS patients ( OR = 0.470 , 95% CI: 0.374-0.591; p < 0.001 ) compared to the general population. The birth rate in March-April in MS was higher than the control group ( OR = 1.613 , 95% CI: 1.324-1.964; p < 0.001 ). There was no difference in the birth month distribution between the NMOSD and MS patients. No significant difference in MOB among different MS types was found. Conclusion. Our findings showed a decreasing risk of NMOSD and MS in individuals born in the autumn months and an increasing MS risk in spring. More studies are required to elucidate the association between the month of birth and risk of MS and NMOSD and the seasonality factors.

Speed but Not Smoothness of Gait Reacts to Rehabilitation in Multiple Sclerosis

Introduction. Improved gait is one of the leading therapy goals in multiple sclerosis. A plethora of clinical timed trials and state-of-the-art technology-based approaches are available to assess gait performance. Objectives. To examine what aspects of gait react to inpatient rehabilitation in MS and which parameters should be best assessed. Design. In this longitudinal study, we examined the performance of 76 patients with MS to shed further light on factors influencing gait, associations between tests, and the reaction to inpatient rehabilitation during an average time span of 16 d. Setting. Private specialist clinic for inpatient neurorehabilitation. Main Outcome Measures. Clinical walk tests (timed 25-foot walk test at normal pace, maximum pace over 10 m or 6 min) and IMU-based measures of movement smoothness. Results. All gait parameters were strongly intercorrelated (all p < 0.05 ), and a model multiple linear regression for the 6MWT revealed short distance velocity (10 m) and movement smoothness as predictors in a strong model ( R 2 adjusted 0.75, p < 0.01 ). A second model with natural pace on short distance and movement smoothness was almost equally strong ( R 2 adjusted 0.71, p < 0.01 ). Patients improved their walking speed ( p < 0.01 ), but not smoothness ( p = 0.08 – 0.12 ), over the course of rehabilitation. Conclusions. Since we were not able to observe improvements in smoothness of gait, we conclude that rehabilitation programs should be adapted to the patient’s physiological capacities in order to allow for such improvements in smoothness of gait. Externally valid gait capacity (6MWT) could be predicted by a single walk for 10 s at natural pace.

Risk Factors Associated with Multiple Sclerosis: A Case-Control Study in Damascus, Syria

Objectives. To assess the probable risk factors associated with Multiple sclerosis among Syrian patients in the city of Damascus. Method. In a case-control study conducted from May to September 2020, 140 MS patients and 140 healthy controls were selected from two main hospitals in Damascus. Data regarding risk factors associated with MS was collected via a structured questionnaire and complementary laboratory tests. The statistical analysis was carried out by the SPSS Statistical Software Version 26. Results. Factors such as smoking, family history of MS, migraine, and vitamin D deficiency were associated with a higher risk of developing MS: Smoking ( OR = 2.275 95% CI (1.348-3.841) P = 0.002 ). Family history of MS ( OR = 3.970 95% CI (1.807-8.719) P ≤ 0.001 ). Migraine ( OR = 3.011 95% CI (1.345-6.741) P = 0.005 ). Vitamin D deficiency ( OR = 4.778 95% CI (2.863-7.972) P ≤ 0.001 ). However, factors such as diabetes, hypertension, a surgical history of appendectomy, tonsillectomy, and being the first-born in a family were statistically irrelevant: Diabetes ( OR = 0.652 95% CI (0.226-1.882) P = 0.426 ). Hypertension ( OR = 1.445 95% CI (0.724-2.885) P = 0.295 ) Appendectomy ( OR = 1.269 95% CI (0.486-3.317) P = 0.626 ) Tonsillectomy ( OR = 1.280 95% CI (0.576-2.843) P = 0.544 ). First-born Child ( OR = 0.933 95% CI (0.558-1.562) P = 0.793 ). Conclusion. Our study suggests that smoking, vitamin D deficiency, family history of MS, and migraine are probable risk factors for multiple sclerosis. Therefore, engaging in outdoor activities and maintaining a healthy diet—for females in particular—is highly recommended.

No Early Effect of Intrathecal Rituximab in Progressive Multiple Sclerosis (EFFRITE Clinical Trial)

Background. The progressive phase of multiple sclerosis (MS) is characterized by an intrathecal (IT) compartmentalization of inflammation, involving B-cells within meningeal follicles, and resisting all the available immunosuppressive treatments. A new therapeutic paradigm may be to target this inflammation by injecting immunosuppressive drugs inside the central nervous system compartment. Methods. We designed a single-center, open-label, randomized, controlled, phase II study designed to evaluate the safety and efficacy of IT rituximab in progressive MS (EFFRITE trial; ClinicalTrial Registration NCT02545959). Patients were randomized into three arms (1 : 1 : 1): control group, IT rituximab (20 mg, IT) group, and intravenous+IT (IV+IT) group. The main outcome was a change in levels of CSF biomarkers of inflammation (osteopontin). Secondary outcomes were changes in levels of CSF biomarkers of axonal loss (neurofilament light chain) and clinical and MRI changes. Results. Ten patients were included (2 : 4 : 4). No adverse event occurred. OPN level remained stable in CSF at each time point, whereas NFL had slightly decreased (-8.7%) at day 21 ( p = 0.02 ). Clinical parameters remained stable and leptomeningeal enhancements remained unchanged. Conclusion. Clinical outcome and biomarkers of inflammation were not dramatically modified after IT injection of rituximab, probably due to its limited efficiency in CSF. Drug issues for future studies are discussed.