Preserved T cell responses to SARS-CoV-2 in anti-CD20 treated multiple sclerosis.

BACKGROUND: Optimal management of anti-CD20-treated patients with multiple sclerosis (pwMS) is an important clinical task during the current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. OBJECTIVES: To characterize humoral and cellular immune responses to SARS-CoV-2 vaccinations/infections in a longitudinal cohort of anti-CD20 treated (n = 175) and anti-CD20 therapy-naïve (n = 41) pwMS. METHODS: Anti-SARS-CoV-2 spike protein immunoglobulin G (IgG) and IgA, virus neutralizing capacity, IgG avidity and SARS-CoV-2-specific T cells were determined. RESULTS: Following two SARS-CoV-2 vaccinations, not only SARS-CoV-2 spike protein IgG and IgA, but also neutralizing capacity and avidity of SARS-CoV-2 IgG were lower in anti-CD20-treated (n = 51) than in anti-CD20 therapy-naïve pwMS (n = 14) and in healthy controls (HC, n = 19). However, in all anti-CD20-treated pwMS vaccinated twice (n = 26) or infected with SARS-CoV-2 (n = 2), in whom SARS-CoV-2-specific T cells were measured, SARS-CoV-2-specific T cells were detectable, at levels similar to those of twice-vaccinated anti-CD20 therapy-naïve pwMS (n = 7) and HC (n = 19). SARS-CoV-2-S1 IgG levels (r = 0.42, p = 0.002), antibody avidity (r = 0.7, p < 0.001), and neutralizing capacity (r = 0.44, p = 0.03) increased with time between anti-CD20 infusion and second vaccination. Based on detection of SARS-CoV-2 antibodies, SARS-CoV-2 infections occurred in 4 out of 175 (2.3%) anti-CD20-treated pwMS, all of whom recovered fully. CONCLUSIONS: These findings should inform treatment decisions and SARS-CoV-2 vaccination management in pwMS.

Differences in Advanced Magnetic Resonance Imaging in MOG-IgG and AQP4-IgG Seropositive Neuromyelitis Optica Spectrum Disorders: A Comparative Study.

Aims: To explore differences in advanced brain magnetic resonance imaging (MRI) characteristics between myelin oligodendrocyte (MOG) immunoglobulin (IgG) and aquaporin-4 (AQP4) IgG seropositive (+) neuromyelitis optica spectrum disorders (NMOSD). Methods: 33 AQP4-IgG and 18 MOG-IgG seropositive NMOSD patients and 61 healthy control (HC) subjects were included. All 112 participants were scanned with the same standardized MRI-protocol on a 3-Tesla MRI-scanner. Brain volume and diffusion tensor imaging (DTI) parameters were assessed. Results: MOG-IgG+ patients showed reduced parallel diffusivity within white matter tracts compared to HC whereas AQP4-IgG+ showed no significant brain parenchymal damage in DTI analysis. AQP4-IgG+ patients showed reduced whole brain volumes and reduced volumes of several deep gray matter structures compared to HC whereas MOG-IgG+ patients did not show reduced brain or deep gray matter volumes compared to HC. Conclusions: Microstructural brain parenchymal damage in MOG-IgG+ patients was more pronounced than in AQP4-IgG+ patients, compared with HC, whereas normalized brain volume reduction was more severe in AQP4-IgG+ patients. Longitudinal imaging studies are warranted to further investigate this trend in NMOSD. Our results suggest that MOG-IgG+ and AQP4-IgG+ NMOSD patients differ in cerebral MRI characteristics. Advanced MRI analysis did not help to differentiate between MOG-IgG+ and AQP4-IgG+ patients in our study.

Olfactory and Gustatory Dysfunction in Patients With Autoimmune Encephalitis.

Objective: To test the hypothesis that olfactory (OF) and gustatory function (GF) is disturbed in patients with autoimmune encephalitides (AE). Methods: The orthonasal OF was tested in 32 patients with AE and 32 age- and sex-matched healthy controls (HC) with the standardized Threshold Discrimination Identification (TDI) score. This validated olfactory testing method yields individual scores for olfactory threshold (T), odor discrimination (D), and identification (I), along with a composite TDI score. The GF was determined by the Taste Strip Test (TST). Results: Overall, 24/32 (75%) of patients with AE, but none of 32 HC (p < 0.001) had olfactory dysfunction in TDI testing. The results of the threshold, discrimination and identification subtests were significantly reduced in patients with AE compared to HC (all p < 0.001). Assessed by TST, 5/19 (26.3%) of patients with AE, but none of 19 HC presented a significant limitation in GF (p < 0.001). The TDI score was correlated with the subjective estimation of the olfactory capacity on a visual analog scale (VAS; rs = 0.475, p = 0.008). Neither age, sex, modified Rankin Scale nor disease duration were associated with the composite TDI score. Conclusions: This is the first study investigating OF and GF in AE patients. According to unblinded assessment, patients with AE have a reduced olfactory and gustatory capacity compared to HC, suggesting that olfactory and gustatory dysfunction are hitherto unrecognized symptoms in AE. Further studies with larger number of AE patients would be of interest to verify our results.

Assessment and comparison of the max-ICH score and ICH score by external validation.

OBJECTIVE: We tested the hypothesis that the maximally treated intracerebral hemorrhage (max-ICH) score is superior to the ICH score for characterizing mortality and functional outcome prognosis in patients with ICH, particularly those who receive maximal treatment. METHODS: Patients presenting with spontaneous ICH were enrolled in a prospective observational study that collected demographic and clinical data. Mortality and functional outcomes were measured by using the modified Rankin Scale at 3 months. The ICH score and max-ICH score incorporate measures of symptom severity, age, hematoma volume, hematoma location, and intraventricular hemorrhage, with the max-ICH score also including a term for oral anticoagulation and having 16 score categories vs 11 for the ICH score. We compared the area under the receiver operating characteristic curve (AUC) for the ICH score and max-ICH score for both mortality and poor functional outcome, defined as modified Rankin Scale scores 4-6. RESULTS: We analyzed outcomes for 372 patients, including 71 patients (19%) in whom care limitation/withdrawal of life support was instituted. Both the ICH score and max-ICH score showed good prognostic performance for 3-month mortality and poor functional outcomes in the full group as well as the subgroup with maximal treatment (i.e., no care limitations; AUC range 0.80-0.86), with no significant difference in AUC between the scores for either endpoint in either group. CONCLUSIONS: External validation with direct comparison of the ICH score and max-ICH score shows that their prognostic performance is not meaningfully different. Alternatives to simple scores are likely needed to improve prognostic estimates for patient care decisions.

Objective assessment of a relative afferent pupillary defect by B-mode ultrasound.

PURPOSE: To evaluate B-mode ultrasound as a novel method for objective and quantitative assessment of a relative afferent pupillary defect (RAPD) in a prospective case-control study. METHODS: Seventeen patients with unilateral optic neuropathy and a clinically detectable RAPD and 17 age and sex matched healthy controls were examined with B-mode ultrasound using an Esaote-Mylab25 system according to current guidelines for orbital insonation. The swinging flashlight test was performed during ultrasound assessment with a standardized light stimulus using a penlight. RESULTS: B-mode ultrasound RAPD examination was doable in approximately 5 minutes only and was well tolerated by all participants. Compared to the unaffected contralateral eyes, eyes with RAPD showed lower absolute constriction amplitude of the pupillary diameter (mean [SD] 0.8 [0.4] vs. 2.1 [0.4] mm; p = 0.009) and a longer pupillary constriction time after ipsilateral light stimulus (mean [SD] 1240 [180] vs. 710 [200] ms; p = 0.008). In eyes affected by RAPD, visual acuity correlated with the absolute constriction amplitude (r = 0.75, p = 0.001). CONCLUSIONS: B-mode ultrasound enables fast, easy and objective quantification of a RAPD and can thus be applied in clinical practice to document a RAPD.

B-mode ultrasound assessment of pupillary function: Feasibility, reliability and normal values.

PURPOSE: To evaluate B-mode ultrasound as a novel method for the examination of pupillary function and to provide normal values for the pupillary reflex as assessed by B-mode ultrasound. METHODS: 100 subjects (49 female, 51 male, mean [range] age 51 [18-80 years]) with no history of ophthalmologic disease, no clinically detectable pupillary defects, and corrected visual acuity ≥ 0.8 were included in this prospective observational study. B-mode ultrasound was performed with the subjects eyes closed using an Esaote-Mylab25 system according to current guidelines for orbital insonation. A standardized light stimulus was applied. RESULTS: The mean ± standard deviation left and right pupillary diameters (PD) at rest were 4.7 ± 0.8 and 4.5 ± 0.8 mm. Following an ipsilateral light stimulus (Lstim), left and right constricted PD were 2.8 ± 0.6 and 2.7 ± 0.6 mm. Following a contralateral Lstim, left and right constricted PD were 2.7 ± 0.6 and 2.6 ± 0.5 mm. Left and right pupillary constriction time (PCT) following ipsilateral Lstim were 970 ± 261.6 and 967 ± 220 ms. Left and right PCT following a contralateral Lstim were 993.8 ± 192.6 and 963 ± 189.4 ms. Patient age was inversely correlated with PD at rest and with PD after ipsilateral and contralateral Lstim (all p<0.001), but not with PCT. CONCLUSIONS: B-mode ultrasound is a simple, rapid and objective method for the quantitative assessment of pupillary function, which may prove useful in a variety of settings where eyelid retraction is impeded or an infrared pupillometry device is unavailable.

Olfactory dysfunction in patients with primary progressive MS.

OBJECTIVE: We tested the hypothesis that olfactory function is more impaired in patients with primary progressive MS (PPMS) than that in relapsing-remitting MS (RRMS). METHODS: Standardized olfactory testing was performed in 32 patients with PPMS, 32 patients with RRMS, and 32 healthy controls (HCs). Patients with olfactory dysfunction due to an alternative primary etiology were excluded. The validated olfactory testing method yielded individual scores for olfactory threshold, odor discrimination, and odor identification, along with a composite Threshold Discrimination Identification (TDI) score. RESULTS: Olfactory dysfunction was identified in 27 (84%) patients with PPMS, 10 (31%) patients with RRMS, and 1 (3%) HC. While age and sex were similar between PPMS and HCs, the TDI score and all olfactory subscores were significantly worse in patients with PPMS compared with HCs (all p < 0.001). After adjustment for differences in age, sex, Expanded Disability Status Scale (EDSS), and disease duration, odor discrimination, odor identification, and the composite TDI score were worse in patients with PPMS vs RRMS (p = 0.03, 0.04, and 0.02, respectively). Neither age, sex, EDSS, nor disease duration was significantly associated with the composite TDI score. CONCLUSIONS: Olfactory dysfunction was more frequent and severe in PPMS compared with RRMS, independent of disease duration and overall disability status. Further research on cellular level differences in olfactory neural pathways may lead to new insights about disease pathogenesis in MS.