Immunophenotyping in routine clinical practice for predicting treatment response and adverse events in patients with MS.

Background: Recent studies proposed cellular immunoprofiling as a surrogate for predicting treatment response and/or stratifying the occurrence of adverse events (AEs) in persons with multiple sclerosis (pwMS). However, applicability in real-world circumstances is not sufficiently addressed. Objective: We aimed to explore whether standard routine clinical leukocyte phenotyping before treatment initiation could help stratify patients according to treatment response or AEs in a real-world MS cohort. Methods: In this retrospective study, 150 pwMS were included, who had been newly initiated on a disease-modifying drug (DMD) and had been assessed for standard immunophenotyping before DMD initiation (baseline) and at least once during the following year. Multivariate models were used to assess an association of immune subsets and the association between immune cell profiles regarding treatment response and AEs. Results: We found that the composition of T cell subsets was associated with relapse activity, as an increased proportion of CD8+ lymphocytes at baseline indicated a higher likelihood of subsequent relapse (about 9% per 1% increase in CD8+ proportion of all CD3+ cells). This was particularly driven by patients receiving anti-CD20 therapy, where also EDSS worsening was associated with a higher number of CD8+ cells at baseline (3% increase per 10 cells). In the overall cohort, an increase in the proportion of NK cells was associated with a higher risk of EDSS worsening (5% per 1% increase). Occurrence of AEs was associated with a higher percentage of T cells and a lower number of percentual NKT cells at baseline. Conclusion: Immune cell profiles are associated with treatment response and the occurrence of AEs in pwMS. Hence, immunophenotyping may serve as a valuable biomarker to enable individually tailored treatment strategies in pwMS.

Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses.

BACKGROUND: Neuromuscular disorders (NMDs) are heterogeneous conditions with a considerable fraction attributed to monogenic defects. Despite the advancements in genomic medicine, many patients remain without a diagnosis. Here, we investigate whether a comprehensive reassessment strategy improves the diagnostic outcomes. METHODS: We analyzed 263 patients with NMD phenotypes that underwent diagnostic exome or genome sequencing at our tertiary referral center between 2015 and 2023. We applied a comprehensive reassessment encompassing variant reclassification, re-phenotyping and NGS data reanalysis. Multivariable logistic regression was performed to identify predictive factors associated with a molecular diagnosis. RESULTS: Initially, a molecular diagnosis was identified in 53 cases (20%), while an additional 23 (9%) had findings of uncertain significance. Following comprehensive reassessment, the diagnostic yield increased to 23%, revealing 44 distinct monogenic etiologies. Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4). Male sex reduced the odds of receiving a molecular diagnosis (OR 0.42; 95%CI 0.21-0.82), while a positive family history (OR 5.46; 95%CI 2.60-11.76) and a myopathy phenotype (OR 2.72; 95%CI 1.11-7.14) increased the likelihood. 7% were resolved through targeted genetic testing or classified as acquired etiologies. CONCLUSION: Our findings reinforce the use of NGS in NMDs of suspected monogenic origin. We show that a comprehensive reassessment enhances diagnostic accuracy. However, one needs to be aware that genetic diagnoses are often made with uncertainty and can even be downgraded based on new evidence.

Lower serum cholesterol levels as a risk factor for critical illness polyneuropathy: a matched case-control study.

Critical illness polyneuropathy (CIP) is a frequent and underdiagnosed phenomenon among intensive care unit patients. The lipophilic nature of neuronal synapses may result in the association of low serum cholesterol levels with a higher rate of CIP development. We aimed to investigate this issue in critically ill patients. All cases diagnosed with CIP in our tertiary care hospital between 2013 and 2017 were 1:1 matched with controls without the condition by age, sex, and ICD diagnoses. The main risk factors examined were the differences in change between initial and minimum serum total cholesterol levels, and minimum serum total cholesterol levels between matched pairs. Other predictors were serum markers of acute inflammation. We included 67 cases and 67 controls (134 critically ill patients, 49% female, 46% medical). Serum total cholesterol levels decreased more profoundly in cases than controls (median: -74 (IQR -115 to -24) vs. -39 (IQR -82 to -4), median difference: -28, 95% CI [-51, -5]), mg/dl). Minimum serum total cholesterol levels were lower in the cases (median difference: -24, 95% CI [-39, -9], mg/dl). We found significant median differences across matched pairs in maximum serum C-reactive protein (8.9, 95% CI [4.6, 13.2], mg/dl), minimum albumin (-4.2, 95% CI [-6.7, -1.7], g/l), decrease in albumin (-3.9, 95% CI [-7.6, -0.2], g/l), and lowest cholinesterase levels (-0.72, 95% CI [-1.05, -0.39], U/l). Subsequently, more pronounced decreases in serum total cholesterol levels and lower minimum total cholesterol levels during critical care unit hospitalizations may be a risk factor for CIP.

Serum neurofilament light chain as an early diagnostic biomarker for critical illness polyneuropathy.

BACKGROUND: Critical illness polyneuropathy (CIP) commonly occurs in critical care unit (CCU) patients, but timely diagnosis can be challenging. Therefore, new biomarkers, such as serum neurofilament light chain (sNfL), could help to improve early identification of patients with this condition. METHODS: CIP was diagnosed or excluded with neurological assessment and nerve conduction measurement in a prospective study of CCU patients. sNfL and secondary predictors for neuropathy (neuron-specific enolase (NSE), S100, folic acid, and vitamin B12) were measured at admission. Cases and controls were compared regarding the predictors. RESULTS: Nineteen patients met the inclusion criteria. CIP was considered definitely or most likely present in seven (37%, cases) and definitely or most likely absent in 12 individuals (63%, controls). At admission, sNfL levels were significantly higher in the cases than in the controls: 405 (IQR 77 to 835) vs. 27 (IQR 12 to 90) pg/mL; difference of medians 375, 95% confidence interval [14, 736], pg/mL; P=0.04. We found no significant differences regarding the secondary predictors at baseline. Cases had longer durations of CCU stay (median 19 (IQR 11 to 44) vs. 8 (IQR five to ten) and increased mortality (57% vs. 33% deceased) compared to controls. CONCLUSIONS: Levels of serum neurofilament light chain are higher in patients who develop CIP soon after CCU admission and might be helpful in identifying those individuals early.

Diagnostic Performance of Adding the Optic Nerve Region Assessed by Optical Coherence Tomography to the Diagnostic Criteria for Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The optic nerve has been recommended as an additional region for demonstrating dissemination in space (DIS) in diagnostic criteria for multiple sclerosis (MS). The aim of this study was to investigate whether adding the optic nerve region as determined by optical coherence tomography (OCT) as part of the DIS criteria improves the 2017 diagnostic criteria. METHODS: From a prospective observational study, we included patients with a first demyelinating event who had complete information to assess DIS and a spectral domain OCT scan obtained within 180 days. Modified DIS criteria (DIS + OCT) were constructed by adding the optic nerve to the current DIS regions based on validated thresholds for OCT intereye differences. Time to second clinical attack was the primary endpoint. RESULTS: We analyzed 267 patients with MS (mean age 31.3 years [SD 8.1], 69% female) during a median observation period of 59 months (range: 13-98). Adding the optic nerve as a fifth region improved the diagnostic performance by increasing accuracy (DIS + OCT 81.2% vs DIS 65.6%) and sensitivity (DIS + OCT 84.2% vs DIS 77.9%) without lowering specificity (DIS + OCT 52.2% vs DIS 52.2%). Fulfilling DIS + OCT criteria (≥2 of 5 DIS + OCT regions involved) indicated a similar risk of a second clinical attack (hazard ratio [HR] 3.6, CI 1.4-14.5) compared with a 2.5-fold increased risk when fulfilling DIS criteria (HR 2.5, CI 1.2-11.8). When the analysis was conducted according to topography of the first demyelinating event, DIS + OCT criteria performed similarly in both optic neuritis and nonoptic neuritis. DISCUSSION: Addition of the optic nerve, assessed by OCT, as a fifth region in the current DIS criteria improves diagnostic performance by increasing sensitivity without lowering specificity. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that adding the optic nerve as determined by OCT as a fifth DIS criterion to the 2017 McDonald criteria improves diagnostic accuracy.

Reported neurological symptoms after severe acute respiratory syndrome coronavirus type 2 infection: A systematic diagnostic approach.

BACKGROUND AND PURPOSE: Following increasing demands of patients with suspected neurological symptoms after infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the Department of Neurology at the Medical University of Vienna established a new outpatient clinic to systematically assess, diagnose, and document neurological complaints potentially associated with a prior SARS-CoV-2 infection. METHODS: The data presented here include prospectively collected 156 outpatients from May 2021 to April 2022. Patients underwent semistandardized interviewing about symptoms with reported onset after SARS-CoV-2 infection, neurological examination, and comprehensive diagnostic workup. RESULTS: Reported new onset symptoms after infection included fatigue (77.6%), subjective cognitive impairment (72.4%), headache (47.7%), loss of smell and/or taste (43.2%), and sleep disturbances (42.2%). Most patients had a mild coronavirus disease (COVID-19) disease course (84%) and reported comorbidities (71%), of which the most frequent were psychiatric disorders (34%). Frequency of symptoms was not associated with age, sex, or severity of COVID-19 course. A comprehensive diagnostic workup revealed no neurological abnormalities in the clinical examination, or electrophysiological or imaging assessments in the majority of patients (n = 143, 91.7%). Neuropsychological assessment of a subgroup of patients (n = 28, 17.9%) showed that cognitive impairments in executive functions and attention, anxiety, depression, and somatization symptoms were highly common. CONCLUSIONS: In this systematic registry, we identified fatigue, cognitive impairment, and headache as the most frequently reported persisting complaints after SARS-CoV-2 infection. Structural neurological findings were rare. We also suspect a link between the growing burden of the COVID-19 pandemic on personal lives and the increase in reported neurological and psychiatric complaints.

The diagnostic and prognostic utility of repetitive nerve stimulation in patients with myasthenia gravis.

Repetitive nerve stimulation (RNS) is a standard test for the diagnosis of myasthenia gravis (MG), where decrement of compound muscle action potentials (CMAP) corresponds to clinical muscle fatigability. Our aim was to ascertain the diagnostic and prognostic utility of RNS in MG patients. This study included MG patients treated between 01/2000 and 12/2016, with an observational period of at least one year and a minimum of two neurological examinations. Clinical and electrophysiological data were retrospectively gathered from patient records, and CMAP decrement was correlated with autoantibody titers and clinical disease severity at different time points. Ninety-four patients were included, with 88.3% of the cohort testing positive for acetylcholine receptor autoantibodies (AChR-Abs). RNS sensitivity was higher in patients with generalized disease (71.6%) than in purely ocular MG (38.5%). CMAP decrement did not significantly correlate with AChR-Ab titers, nor with clinical symptom severity at the time of testing or last follow up. However, there was a significant correlation between CMAP decrement and the worst recorded clinical status on a group level. RNS testing is more sensitive in generalized disease and AChR-Ab positive patients, but our data do not support RNS as a tool for long-term outcome prediction. Future studies with a prospective study design could help to overcome a number of limiting factors discussed in our study.

Retinal layer thickness predicts disability accumulation in early relapsing multiple sclerosis.

BACKGROUND AND PURPOSE: This study was undertaken to investigate baseline peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness for prediction of disability accumulation in early relapsing multiple sclerosis (RMS). METHODS: From a prospective observational study, we included patients with newly diagnosed RMS and obtained spectral-domain optical coherence tomography scan within 90 days after RMS diagnosis. Impact of pRNFL and GCIPL thickness for prediction of disability accumulation (confirmed Expanded Disability Status Scale [EDSS] score ≥ 3.0) was tested by multivariate (adjusted hazard ratio [HR] with 95% confidence interval [CI]) Cox regression models. RESULTS: We analyzed 231 MS patients (mean age = 30.3 years, SD = 8.1, 74% female) during a median observation period of 61 months (range = 12-93). Mean pRNFL thickness was 92.6 µm (SD = 12.1), and mean GCIPL thickness was 81.4 µm (SD = 11.8). EDSS ≥ 3 was reached by 28 patients (12.1%) after a median 49 months (range = 9-92). EDSS ≥ 3 was predicted with GCIPL < 77 µm (HR = 2.7, 95% CI = 1.6-4.2, p < 0.001) and pRNFL thickness ≤ 88 µm (HR = 2.0, 95% CI = 1.4-3.3, p < 0.001). Higher age (HR = 1.4 per 10 years, p < 0.001), incomplete remission of first clinical attack (HR = 2.2, p < 0.001), ≥10 magnetic resonance imaging (MRI) lesions (HR = 2.0, p < 0.001), and infratentorial MRI lesions (HR = 1.9, p < 0.001) were associated with increased risk of disability accumulation, whereas highly effective disease-modifying treatment was protective (HR = 0.6, p < 0.001). Type of first clinical attack and presence of oligoclonal bands were not significantly associated. CONCLUSIONS: Retinal layer thickness (GCIPL more than pRNFL) is a useful predictor of future disability accumulation in RMS, independently adding to established markers.

The clinical and molecular landscape of congenital myasthenic syndromes in Austria: a nationwide study.

BACKGROUND: Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted. METHODS: We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria. RESULTS: Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0-4.3) in Austria. The most frequent genetic etiology was CHRNE (n = 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in DOK7 (n = 4), RAPSN (n = 3), COLQ (n = 2), GMPPB (n = 2), CHAT (n = 1), COL13A1 (n = 1), MUSK (n = 1) and AGRN (n = 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients. CONCLUSIONS: Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype-phenotype correlations that may help to improve the diagnostic approach and patient management.

Feasibility of a smartphone app to monitor patient reported outcomes in multiple sclerosis: The haMSter interventional trial.

Background: Monitoring of patient outcomes in multiple sclerosis (MS) is fundamental for individualized treatment decisions. So far, these decisions have been motivated by conventional outcomes, i.e., relapses or clinical disability supported by radiological disease activity. Complementing this concept, patient reported outcomes (PROs) assess individual health-related quality of life, among other constructs. Their inclusion in clinical routine, however, has been challenging as assessing them requires resources of time and personnel. Objective: This interventional feasibility study investigated the haMSter app, a mobile health solution for remote and longitudinal monitoring of PROs in a sample of people with MS (pwMS). Methods: The core feature of haMSter is the provision of three PRO questionnaires relevant to MS (anxiety/depression, MS-related quality of life, and fatigue) that patients can fill out once a month. For this feasibility trial, we offered 50 volunteers to use the haMSter app over six months and to take part in a haMSter study visit. This consultation concluded the study and participants had the opportunity to discuss their graphically plotted PRO results with their treating physician. Results: The main outcome was overall patient adherence to monthly completion of the PRO questionnaires, which remained high up to 4 months (98%) and dropped over time (months 5: 83% and 6: 66%). Exploratory outcomes included patient satisfaction as estimated on the Telemedicine Perception Questionnaire (TMPQ, 17-85 points). The mean TMPQ score was 64 (95%CI: 62-66) points, indicating a high degree of approval. Ancillary tests included subgroup analyses of participants with particularly high or low satisfaction and upper extremity disability as a potential obstacle to utility or acceptance. We found no distinct characteristics separating participants with high or low satisfaction. Conclusions: In this first feasibility trial, the haMSter app for longitudinal PRO monitoring was well received in terms of adherence and satisfaction. ClinicalTrials.gov identifier: NCT04555863.

Retinal Layer Thinning After Optic Neuritis Is Associated With Future Relapse Remission in Relapsing Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Remission of relapses is an important contributor to both short- and long-term prognosis in relapsing multiple sclerosis (RMS). In MS-associated acute optic neuritis (MS-ON), retinal layer thinning measured by optical coherence tomography (OCT) is a reliable biomarker of both functional recovery and the degree of neuroaxonal damage. However, prediction of non-ON relapse remission is challenging. We aimed to investigate whether retinal thinning after ON is associated with relapse remission after subsequent non-ON relapses. METHODS: For this longitudinal observational study from the Vienna MS database, we included patients with MS with (1) an episode of acute ON, (2) available spectral domain OCT scans within 12 months before ON onset (OCTbaseline), within 1 week after ON onset (OCTacute), and 3-6 months after ON (OCTfollow-up), and (3) at least 1 non-ON relapse after the ON episode. Subsequent non-ON relapses were classified as displaying either complete or incomplete remission based on change in the Expanded Disability Status Scale score assessed 6 months after relapse. Association of retinal thinning in the peripapillary retinal nerve fiber layer (ΔpRNFL) and macular ganglion cell and inner plexiform layer (ΔGCIPL) with incomplete remission was tested by multivariate logistic regression models adjusting for age, sex, disease duration, relapse severity, time to steroid treatment, and disease-modifying treatment status. RESULTS: We analyzed 167 patients with MS (mean age 36.5 years [SD 12.3], 71.3% women, mean disease duration 3.1 years [SD 4.5]) during a mean observation period of 3.4 years (SD 2.8) after the ON episode. In 61 patients (36.5%), at least 1 relapse showed incomplete remission. In the multivariable analyses, incomplete remission of non-ON relapse was associated with ΔGCIPL thinning both from OCTbaseline to OCTfollow-up and from OCTacute to OCTfollow-up (OR 2.4 per 5 µm, p < 0.001, respectively), independently explaining 29% and 27% of variance, respectively. ΔpRNFL was also associated with incomplete relapse remission when measured from OCTbaseline to OCTfollow-up (OR 1.9 per 10 µm, p < 0.001), independently accounting for 22% of variance, but not when measured from OCTacute to OCTfollow-up. DISCUSSION: Retinal layer thinning after optic neuritis may be useful as a marker of future relapse remission in RMS.

Impact of vaccination on COVID-19 outcome in multiple sclerosis.

BACKGROUND: COVID-19 continues to challenge neurologists in counselling persons with multiple sclerosis (pwMS) regarding disease-modifying treatment (DMT) and vaccination. The objective here was to characterize predictors of COVID-19 outcome in pwMS. METHODS: We included pwMS with PCR-confirmed COVID-19 diagnosis from a nationwide population-based registry. COVID-19 outcome was classified as either mild or severe. Impact of DMT, specifically anti-CD20 monoclonal antibodies, and vaccination on COVID-19 outcome was determined by multivariable models adjusted for a-priori-risk (determined by a cumulative risk score comprising age, disability and comorbidities). RESULTS: Of 317 pwMS with COVID-19 (mean age 41.8 years [SD 12.4], 72.9% female, median EDSS 1.5 [range 0-8.5], 77% on DMT [16% on antiCD20]), 92.7% had a mild course and 7.3% a severe course with 2.2% dying from COVID-19. Ninety-seven pwMS (30.6%) were fully vaccinated. After a median 5 months from vaccination to SARS-CoV-2 infection (range 1-9), severe COVID-19 occurred in 2.1% of fully vaccinated pwMS compared to 9.5% in unvaccinated pwMS (p=0.018). A-priori-risk robustly predicted COVID-19 severity (R2 0.605; p<0.001). Adjusting for a-priori-risk, anti-CD20 treatment was associated with increased COVID-19 severity (odds ratio [OR] 3.3; R2 0.113; p=0.003), but exposure to any other DMT was not. Fully vaccinated pwMS showed a significantly decreased risk for severe COVID-19 (OR 0.21, R2 0.144, p<0.001). CONCLUSIONS: In a population-based MS cohort, COVID-19 course is primarily predicted by a-priori-risk (depending on age, disability and comorbidities) explaining about 60% of variance. Anti-CD20 treatment is associated with a moderately increased risk, while reassuringly vaccination provides protection from severe COVID-19.

Humoral immune response to SARS-CoV-2 third vaccination in patients with multiple sclerosis and healthy controls: A prospective multicenter study.

BACKGROUND: Third vaccination against SARS-CoV-2 is recommended for patients with multiple sclerosis (pwMS), usually six months after the last vaccination. METHODS: In this prospective multicenter study on 292 pwMS and 46 healthy controls (HC), who had all received two vaccinations prior to study enrollment, SARS-CoV-2 IgG response was measured in the month before and 2-4 months after third vaccination. PwMS were categorized as follows: untreated (N-DMT, n = 32), receiving disease-modifying therapy (DMT) with expected humoral response (er-DMT: interferon-beta preparations, glatiramer acetate, dimethyl fumarate, teriflunomide, natalizumab, cladribine, alemtuzumab; n = 120) or no expected humoral response (nr-DMT: S1PMs, CD20mAb; n = 140). RESULTS: PwMS on nr-DMT had significantly lower median antibody levels before (12.1 U/ml [0.4-2500]) and after third vaccination (305 U/ml [0.4-2500]) in comparison to other groups (p<0.001). We did not find differences in antibody levels after homologous (n = 281; 2500 [0.4-2500]) and heterologous (n = 57; 2500 [0.4-2500]) vaccination regime regardless of the DMT group. The DMT group (ß= -0.60; 95% CI -1195.73, -799.10; p<0.001) was associated with antibody levels after third vaccination, while time to revaccination (6 months [1-13]) was not. After third vaccination, seropositivity was reached in 75.8% and 82.2% of pwMS on anti-CD20 mAbs and S1PMs, respectively. Complete B-cell depletion significantly decreased the probability of seroconversion even after the third vaccination (OR 0.14; p = 0.021), whereas time interval to last DMT intake and time to revaccination did not. Twenty-two patients reported a SARS-CoV-2 infection (3 N-DMT, 9 er-DMT, 10 nr-DMT), one being asymptomatic and the rest having a mild course. CONCLUSION: Humoral response to SARS-CoV-2 third vaccination in pwMS is excellent. While reduced by S1PMs and CD20mAb, protective response is still expected in the majority of patients.

Long-term outcome after COVID-19 infection in multiple sclerosis: a nation-wide multicenter matched-control study.

BACKGROUND: Long-term outcome after COVID-19 in patients with multiple sclerosis (pwMS) is scarcely studied and controlled data are lacking. OBJECTIVE: To compare long-term outcome after COVID-19 in pwMS to a matched control group of pwMS without COVID-19. METHODS: We included pwMS with PCR-confirmed diagnosis of COVID-19 and ≥6 months of follow-up available and, as a control group, pwMS matched 1:1 for age, sex, disability level and disease-modifying treatment type. RESULTS: Of 211 pwMS with COVID-19 (mean age 42.6 years [SD 12.2], 69% female, median EDSS 1.5 [range: 0-7.5], 16% antiCD20), 90.5% initially had a mild COVID-19 course. At follow-up, 70% had recovered completely 3 months (M3) after COVID-19, 83% after 6 months (M6) and 94% after 12 months (M12). Mild initial COVID-19 course was the only significant predictor of complete recovery (odds ratio [OR]: 10.5; p<0.001). Most frequent residual symptoms were fatigue (M3: 18.5%, M6: 13.7%, M12: 7.3%), hyposmia (M3: 13.7%, M6: 5.2%, M12: 1.7%) and dyspnea (M3: 7.1%, M6: 6.6%, M12: 2.8%). Compared to matched controls, fatigue, hyposmia and dyspnea were significantly more frequent at M3 and still slightly at M6, while there was no difference at M12. PwMS with COVID-19 had neither a significantly increased risk for relapses (OR 1.1; p=0.70) nor disability worsening (OR 0.96; p=0.60). DISCUSSION: Long-term outcome of COVID-19 is favourable in a large majority of pwMS with only a small proportion of patients suffering from persistent symptoms usually resolving after 3-6 months. COVID-19 is not associated with increased risk of relapse or disability.

Has the pandemic changed treatment strategy in multiple sclerosis?

BACKGROUND: Social distancing measures during the Covid-19 pandemic reduced access to health care and concerns were raised over the safety of immunosuppressive disease modifying treatments (DMT) for multiple sclerosis (MS). OBJECTIVE: To investigate changes in DMT prescription before and during the pandemic in a large and well-characterized real-world cohort of MS patients. METHODS: From the Vienna MS database (VMSD) we extracted MS patients who were initiated on a new DMT (both treatment-naïve and switching) between January 1st 2017 and December 31st 2021. Two time periods were defined: 1) the preCovid-19 era (January 1st 2017 to March 15th 2020, i.e. the day of the first lockdown in Austria) and the Covid-19 era (March 16th 2020 to December 31st 2021). Average annualized DMT prescription rates were descriptively compared between the two periods. RESULTS: The average annualized number of prescriptions in the preCovid-19 era was 90.3/year and dropped to 74.8/year (-17.2%) in the Covid-19 era, driven by a marked reduction to 41.7/year (-54%) in the first nine months of the Covid-19 era, partly offset by a rise to 101 in 2021. Use of alemtuzumab (-64%), antiCD20 (-49%), cladribine (-46%), and S1PM (-38%) was reduced, while natalizumab increased by 24%. Lower efficacy treatments remained stable. CONCLUSIONS: The pandemic coincides with a drop in DMT prescription, most markedly for immunosuppressive high-efficacy treatments, strongly suggesting the pandemic as the causal factor. If and how much this affects long-term outcome is yet to be determined.

Short-term and sustained clinical response following thymectomy in patients with myasthenia gravis.

BACKGROUND AND PURPOSE: This study was undertaken to investigate short- and long-term outcome following thymectomy in patients with acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis (MG). METHODS: Rates of clinical response (defined as minimal manifestation, pharmacological remission, or complete stable remission) lasting for at least 1 year were retrospectively analyzed using Cox proportional hazard models. The occurrence of relapses was recorded during follow-up. Clinical factors associated with achieving an initial or a sustained response were analyzed. RESULTS: Ninety-four patients with a median age of 33 years (interquartile range [IQR] = 22-51), 68% with nonthymomatous MG and 32% with thymoma-associated MG, were included. An initial clinical response was reached in 72% (68/94). Neither sex, age at onset, thymus histology, delay to surgery after disease onset, surgical approach, corticosteroid treatment, nor clinical severity before thymectomy was significantly associated with achieving this endpoint. During long-term follow-up (median = 89.5 months, IQR = 46-189.5), only half of the patients with an initial response (34/68) had a sustained response without relapses. No clinical factors predicted whether the response would become sustained. In patients without immunosuppressive treatment before thymectomy (n = 24), a high AChR-Ab reduction rate after thymectomy was associated with a higher likelihood of achieving an initial response (p = 0.03). CONCLUSIONS: Sustained long-term clinical response of MG patients after thymectomy is significantly lower than the initial response rates would suggest. The observation that none of the evaluated clinical factors was associated with a worse outcome supports the current clinical practice of patient selection for thymectomy. The relative decline of AChR-Abs after surgery appears to be a promising prognostic marker.

Clinico-genetic spectrum of limb-girdle muscular weakness in Austria: A multicentre cohort study.

BACKGROUND AND PURPOSE: Hereditary myopathies with limb-girdle muscular weakness (LGW) are a genetically heterogeneous group of disorders, in which molecular diagnosis remains challenging. Our aim was to present a detailed clinical and genetic characterization of a large cohort of patients with LGW. METHODS: This nationwide cohort study included patients with LGW suspected to be associated with hereditary myopathies. Parameters associated with specific genetic aetiologies were evaluated, and we further assessed how they predicted the detection of causative variants by conducting genetic analyses. RESULTS: Molecular diagnoses were identified in 62.0% (75/121) of the cohort, with a higher proportion of patients diagnosed by next-generation sequencing (NGS) than by single-gene testing (77.3% vs. 22.7% of solved cases). The median (interquartile range) time from onset to genetic diagnosis was 8.9 (3.7-19.9) and 17.8 (7.9-27.8) years for single-gene testing and NGS, respectively. The most common diagnoses were myopathies associated with variants in CAPN3 (n = 9), FKRP (n = 9), ANO5 (n = 8), DYSF (n = 8) and SGCA (n = 5), which together accounted for 32.2% of the cohort. Younger age at disease onset (p = 0.043), >10× elevated creatine kinase activity levels (p = 0.024) and myopathic electromyography findings (p = 0.007) were significantly associated with the detection of causative variants. CONCLUSIONS: Our findings suggest that an earlier use of NGS in patients with LGW is needed to avoid long diagnostic delays. We further present parameters predictive of a molecular diagnosis that may help to select patients for genetic analyses, especially in centres with limited access to sequencing.

Comparing humoral immune response to SARS-CoV2 vaccines in people with multiple sclerosis and healthy controls: An Austrian prospective multicenter cohort study.

BACKGROUND AND PURPOSE: SARS-CoV2 vaccination is recommended for patients with multiple sclerosis (pwMS), but response may be limited by disease-modifying-treatments (DMTs). The aim of this study was to compare the rates of humoral immune response and safety of SARS-CoV-2 vaccines in pwMS and healthy controls (HCs). METHODS: In this multicenter prospective study on 456 pwMS and 116 HCs, SARS-CoV-2-IgG response was measured 3 months after the first vaccine dose. The primary endpoint was defined as proportion of patients developing antibodies (seroconversion). Secondary endpoints included antibody level, safety and efficacy. RESULTS: Compared to 97.4% in HCs, seroconversion occurred in 96.7% (88/91) untreated pwMS, 97.1% of patients (135/139) on immunomodulatory DMTs and 61.1% (138/226; p < 0.001) on immunosuppressive DMTs. Seroconversion was lowest in patients on antiCD20 monoclonal antibodies (CD20 mAbs; 52.6%) followed by sphingosine-1-phosphate-receptor-modulators (S1PMs; 63.6%). In the S1PM subgroup, seroconversion increased with lymphocyte count (odds ratio [OR] 1.31 per 0.1 G/L; p = 0.035). In pwMS on CD20 mAbs, B-cell depletion decreased seroconversion (OR 0.52; p = 0.038), whereas time since last DMT did not. Safety of SARS-CoV-2 vaccines in pwMS was excellent. CONCLUSIONS: Humoral response to SARS-CoV2 vaccines in pwMS is generally excellent. While reduced by immunosuppressive DMTs, most importantly by B-cell-depleting CD20 mAbs and S1PMs, seroconversion is still expected in the majority of patients. SARS-CoV2 vaccination should be offered to every MS patient.

B Cell Depletion and SARS-CoV-2 Vaccine Responses in Neuroimmunologic Patients.

OBJECTIVE: The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in patients with various neuroimmunologic disorders on anti-CD20 therapy. This included an analysis of the T cell vaccine response to the SARS-CoV-2 Delta variant. METHODS: We investigated prospectively humoral and cellular responses to SARS-CoV-2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti-CD20 therapy and 82 age- and sex-matched healthy controls. For quantification of antibodies, the Elecsys anti-SARS-CoV-2 viral spike (S) immunoassay against the receptor-binding domain (RBD) was used. IFN-gamma enzyme-linked immunosorbent spot assays were performed to assess T cell responses against the SARS-CoV-2 Wuhan strain and the Delta variant. RESULTS: SARS-CoV-2-specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti-CD20 treated patients. In contrast to the antibody response, the T-cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B-cell depleted compared to nondepleted patients. INTERPRETATION: Antibody responses to SARS-CoV-2 mRNA vaccinnation can be attained in patients on anti-CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID-19) in this high-risk population. ANN NEUROL 2022;91:342-352.

Humoral immune response after COVID-19 in multiple sclerosis: A nation-wide Austrian study.

BACKGROUND: Knowledge on immunity after SARS-CoV-2 infection in patients with multiple sclerosis (pwMS) and the impact of disease-modifying treatment (DMT) is limited. OBJECTIVE: To evaluate degree, duration and potential predictors of specific humoral immune response in pwMS with prior COVID-19. METHODS: Anti-SARS-CoV-2 antibody testing was performed in pwMS with PCR-confirmed diagnosis of symptomatic COVID-19 from a nation-wide registry. Predictors of seropositivity were identified by multivariate regression models. RESULTS: In 125 pwMS (mean age = 42.4 years (SD = 12.3 years), 70% female), anti-SARS-CoV-2 antibodies were detected in 76.0% after a median of 5.2 months from positive PCR. Seropositivity rate was significantly lower in patients on IS-DMT (61.4%, p = 0.001) than without DMT or immunomodulatory DMT (80.6%; 86.0%, respectively). In multivariate analysis, IS-DMT was associated with reduced probability of seropositivity (odds ratio (OR): 0.51; 95% confidence interval (95% CI): 0.17-0.82; p < 0.001). Predefined subgroup analyses showed marked reduction of seropositivity in pwMS on rituximab/ocrelizumab (OR 0.15; 95% CI: 0.05-0.56; p < 0.001). Rate of seropositivity did not change significantly over 6 months. CONCLUSIONS: Humoral immunity is stable after SARS-CoV-2 infection in MS, but is reduced by immunosuppressive DMT, particularly anti-CD20 monoclonal antibodies. This provides important evidence for advising pwMS as well as for planning and prioritizing vaccination.