Characteristics and predictors of sexual dysfunction in men with multiple sclerosis.

PURPOSE: To validate and culturally adapt the Sexual Health Inventory for Men (IIEF-5) and the Premature Ejaculation Diagnostic Tool (PEDT), to compare the frequency and severity of erectile dysfunction (ED) and premature ejaculation (PE) in male individuals with MS (mwMS) in comparison with healthy controls (HC) and to investigate predictors of the severity of ED and PE in mwMS. METHODS: 216 consecutive mwMS and 37 HC completed IIEF-5 and PEDT. Additionally, 114 mwMS completed the Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory (BDI-2), Composite Autonomic System Score-31 (COMPASS-31), and the 5-level EQ-5D questionnaire. RESULTS: The test-retest reliability was satisfactory for both questionnaires, with acceptable reliability for both questionnaires. mwMS scored less on IIEF-5 compared to HC (23, IQR 18.25-25 vs 24, IQR 20.25-25, p = 0.028). ED was present in 39.4 % of mwMS and 27.8 % of HC (p = 0.198). Definite PE was present in 12.1 %, and possible PE in 7.8 % of mwMS; and 5.6 % and 11.1 % of HC respectively (p = 0.496). An increase in EDSS was a positive predictor (Exp(B) 1.455, 95 %CI 1.135-1.886, p = 0.003) and the presence of cremasteric reflex was a negative predictor (Exp(B) 0.381, 95 %CI 0.183-0.790, p = 0.010) for the presence of ED. For the PE, disease duration was the only positive predictor in a univariable logistic regression (Exp(B) 1.084, 95 %CI 1.019-1.153, p = 0.070). CONCLUSION: SD is frequent in mwMS with EDSS being a positive and the presence of cremasteric reflex a negative predictor of ED and disease duration a positive predictor of PE symptoms.

The impact of the comorbid seizure/epilepsy on the health related quality of life in people with multiple sclerosis: an international multicentric study.

Introduction: The health-related quality of life (HRQoL) of people with (Pw) multiple sclerosis (MS) is usually deteriorated. It has been recently suggested that comorbidities may have the negative influence on the quality of life of the PwMS, but according to the best of our knowledge, only one study investigated, although in a very small cohort, the impact of individual comorbidity on the quality of life of PwMS. The aim of our investigation was to assess, in an international, multicentric study, the impact of comorbid seizure/epilepsy on the HRQoL in PwMS. Methods: We conducted cross-sectional study at numerous neurological centers in Serbia, Croatia, Bulgaria, Montenegro, Northern Macedonia, and Bosnia and Herzegovina (Federation of Bosnia and Herzegovina and Republic of Srpska). For each patient, demographic and clinical data were collected, including Expanded disability status scale (EDSS) score. Beck Depression Inventory (BDI) and the 36-Item Short Form Health Survey (SF-36) questionnaires were administered to all patients. Results: The study comprised 326 PwMS in total, 127 PwMS with seizure/epilepsy and 209 PwMS without. Both mean Physical health composite (PHC) and mental health composite (MHC) scores, were statistically significantly higher in PwMS without seizure/epilepsy, implicating worse quality of life in PwMS with comorbid seizure/epilepsy. Presence of seizure/epilepsy in pwMS was statistically significant independent predictor of both PHC and MHC, in multivariate linear regression model after adjustment for potential confounding variables. The hierarchical multivariate regression analysis was performed in order to establish the most important predictors of the PHC and MHC of the SF-36, in PwMS with seizure/epilepsy; older age, higher level of disability, as measured by EDSS, higher depression score, drug-resistant epilepsy and shorter time since last seizure were found to significantly predict worse MHC score in PwMS with seizure/epilepsy. Discussion: Our results point to the possible role of theinterventions related to the adequate control of epilepsy along with improvement of the mental health status to be important in order to reduce MS burden in the PwMS with comorbid seizure/epilepsy.

The Interconnection between Carotid Intima-Media Thickness and Obesity: Anthropometric, Clinical and Biochemical Correlations.

Background and Objectives: Carotid intima-media thickness (CIMT) and obesity are considered independent determinants of cardio- and cerebrovascular events. The aim of our study was to investigate the effect of obesity on CIMT and to define which traditional cardiovascular risk factors correlate the most with CIMT values in patients with obesity. Materials and Methods: Anthropometric measurements were collected for the whole study group, as well as body composition and blood pressure data, and biochemical blood analyses were also performed. Results: Although our study group was significantly older according to vascular compared with chronological age, the mean CIMT values were lower when compared with the reference values. We found a statistically significant correlation of CIMT with chronological and vascular age, systolic blood pressure, fasting glucose, total cholesterol and triglyceride levels, waist-to-hip ratio, waist circumference, body muscle mass and skeletal muscle mass index. Atherosclerotic Cardiovascular Disease (ASCVD) risk assessment and SCORE (Systematic COronary Risk Evaluation) showed significant positive correlations, but there was only a weak correlation of ASCVD with CIMT. Conclusions: To deduce, since no diagnostic tool currently includes body weight as an individual risk factor, further trials are highly needed to determine if SCORE, SCORE2, ASCVD risk assessment or CIMT would be the most accurate and relevant diagnostic tool for prediction of risk for future CV events in patients with obesity.

Cladribine tablets in people with relapsing multiple sclerosis: A real-world multicentric study from southeast European MS centers.

BACKGROUND: Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS). OBJECTIVES: To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS). METHODS: A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries. RESULTS: We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment. CONCLUSION: Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals.

COVID-19 vaccination uptake in people with multiple sclerosis compared to the general population.

OBJECTIVE: To determine the COVID-19 vaccine uptake among people with multiple sclerosis (pwMS) compared to the general population in Croatia. METHODS: Data from all pwMS entered in the MS Base register until March 24th, 2022 were extracted including age, sex, MS phenotype, disease-modifying therapy (DMT), and date of COVID-19 vaccination. Data on the general population of Croatia were obtained from the vaccination register of the Croatian Institute of Public Health. RESULTS: 64.4% pwMS were fully COVID-19 vaccinated which was comparable to 66.3% of the general population. More pwMS were fully vaccinated in the age group 20-24 (74.1% vs 51.7%), and fewer pwMS were fully vaccinated in the age group 65-69 (33.3% vs 80.4%) compared to the general population of the same age group, respectively. PwMS who received at least one dose of any COVID-19 vaccine were older (40.5 vs 37.6 years, p = 0.01), had higher EDSS (2.0 vs 1.0, p = 0.025), and had longer disease duration (6.39 vs 5.35 years, p = 0.02), were more likely to have progressive disease course (p = 0.049) and were on high efficacy DMTs (p = 0.045) compared to unvaccinated pwMS. Longer disease duration positively predicted vaccine uptake. CONCLUSION: Croatia has suboptimal COVID-19 vaccination uptake without a significant difference between the general population and pwMS.

A complex interplay between autonomic symptoms and symptoms of depression, anxiety, and stress.

BACKGROUND: We evaluated the influence of symptoms of depression, anxiety, and stress on the results of COMPASS-31 in a large population of people referred to the head-up tilt test (HUTT) and healthy controls (HC). METHODS: Nine hundred fifty-nine consecutive patients referred to HUTT and 518 HC were enrolled. All participants completed Composite Autonomic Symptom Score-31 (COMPASS-31). Stress symptoms were evaluated by Depression, Anxiety, and Stress-21 (DASS-21) questionnaire. We corrected the result of the COMPASS-31 with the independent predictors in order to improve the specificity of the test. RESULTS: In both patients and HC, COMPASS-31 was higher in participants with depression, anxiety, and stress symptoms (all p < 0.001). In a multivariable linear regression analysis, HC was negative, while female sex and symptoms of depression, anxiety, and stress were independent positive predictors of COMPASS-31. In HC, COMPASS-31 had a median of 7.913, and this value differentiated between HC and patients with a high sensitivity of 87% and low specificity of 50%. In order to adjust the value of COMPASS-31 with the parameters that were significant in the multivariable linear regression model, we calculated the new corrected COMAPSS-31 (cCOMPASS-31), which had comparable sensitivity of 77%, but an increased specificity of 73%. CONCLUSION: This study has shown that symptoms of depression, anxiety, and/or stress worsen the perceived severity of autonomic symptoms in people with symptoms of orthostatic intolerance and healthy population. cCOMPASS-31 is a valuable tool that can help clinicians in discerning the true autonomic background of patients' complaints.

How to explore and explain autonomic changes in multiple sclerosis.

Autonomic dysfunction (AD) in people with MS (pwMS) is a frequent finding. This narrative review will present an overview of central neural mechanisms involved in the control of cardiovascular and thermoregulatory systems, and methods of autonomic nervous system testing will be discussed thereafter. Since the need for standardization of autonomic nervous system (ANS) testing, we will focus on the standard battery of tests (blood pressure and heart rate response to Valsalva maneuver and head-up tilt, and heart rate response to deep breathing test plus one of the tests for sudomotor function), which can detect ANS pathology in the majority of pwMS. The review will briefly discuss the other types of AD in pwMS and the use of appropriate tests. While performing ANS testing in pwMS one has to consider the multiple sclerosis phenotypes, disease duration, and its activity, the degree of clinical disability of patients included in the study, and the disease-modifying therapies taken, as these factors may have a great influence on the results of ANS testing. In other words, detailed patient characteristics presentation and patient stratification are beneficial when reporting results of ANS testing in pwMS.

Impact of the COVID-19 pandemic on clinical autonomic practice in Europe A survey of the European Academy of Neurology (EAN) and the European Federation of Autonomic Societies (EFAS).

OBJECTIVE: To investigate the impact of the coronavirus-disease-2019 (COVID-19) pandemic on European clinical autonomic practice. METHODS: Eighty-four neurology-driven or interdisciplinary autonomic centers in 22 European countries were invited to fill in a web-based survey between September and November 2021. RESULTS: Forty-six centers completed the survey (55%). During the first pandemic year, the number of performed tilt-table tests, autonomic outpatient and inpatient visits decreased respectively by 50%, 45% and 53%, and every-third center reported major adverse events due to postponed examinations or visits. The most frequent newly-diagnosed or worsened cardiovascular autonomic disorders after COVID-19 infection included postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension, and recurrent vasovagal syncope, deemed likely related to the infection by ≥50% of the responders. Forty-seven percent of the responders also reported about people with new-onset of orthostatic intolerance, but negative tilt-table findings, and 16% about people with psychogenic pseudosyncope after COVID-19. Most patients were treated non-pharmacologically and symptomatic recovery at follow-up was observed in ≥45% of cases. By contrast, low frequencies of newly-diagnosed cardiovascular autonomic disorders following COVID-19 vaccination were reported, most frequently POTS and recurrent vasovagal syncope, and most of the responders judged a causal association unlikely. Non-pharmacological measures were the preferred treatment choice, with 50-100% recovery rates at follow-up. CONCLUSIONS: Cardiovascular autonomic disorders may develop or worsen following a COVID-19 infection, while the association with COVID-19 vaccines remains controversial. Despite the severe pandemic impact on European clinical autonomic practice, a specialized diagnostic work-up was pivotal to identify non-autonomic disorders in people with post-COVID-19 orthostatic complaints.

Transverse myelitis following COVID-19: Insights from a multi-center study and systematic literature review.

INTRODUCTION: We aimed to provide insights into transverse myelitis (TM) following COVID-19 by analyzing cases treated at tertiary care neurology centers and a systemic review of the literature. METHODS: The retrospective observational multi-center study was conducted at the four university neurology departments in Croatia, Slovenia, Serbia, and Austria. We searched for acute myelitis cases that occurred during or after COVID-19. A systemic review of the literature on COVID-19 and transverse myelitis was performed. RESULTS: We identified 76 persons with TM associated with COVID-19, 13 from the multi-center study and 63 from the literature review. Most of the participants (55.6%) had an intermediate latency, 25.4% had short and 19% long latency from COVID-19 symptoms to TM. The clinical presentation consisted of the typical TM signs. More than half of the participants had inflammatory changes in the CSF, with rare patients having intrathecal OCB synthesis and positive serology for anti-MOG or anti-AQP4 antibodies. Persons with autonomic symptoms and CSF pleocytosis were significantly more common to have an intermediate latency of 8 to 21 days from COVID-19 to TM (p = 0.005 and p = 0.003; respectively). According to logistic regression analysis, only participants with lesions evident on spinal cord MRI compared to normal spinal cord MRI had reduced risks for poor recovery. >80% of participants were treated with a combination of corticosteroids and intravenous immunoglobulins or plasma exchange with 73% having incomplete recovery. CONCLUSION: Our study further characterizes clinical, laboratory, and MRI features, as well as treatment of TM associated with COVID-19.

Clinical autonomic nervous system laboratories in Europe: A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies: A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies.

BACKGROUND AND PURPOSE: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. METHODS: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. RESULTS: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). CONCLUSIONS: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.

Treatment of relapsing multiple sclerosis - recommendations of the Croatian Neurological Society.

Untreated multiple sclerosis (MS) irretrievably leads to severe neurological impairment. In European health care systems, patient access to disease modifying therapies (DMT) is often confined to more advanced stages of the disease because of restrictions in reimbursement. A discrepancy in access to DMTs is evident between West and East European countries. In order to improve access to DMTs for people with MS (pwMS) living in Croatia, the Croatian Neurological Society issued new recommendations for the treatment of relapsing MS. The aim of this article is to present these recommendations. The recommendations for platform therapies are to start DMT as soon as the diagnosis is made. If poor prognostic criteria are present (≥9 T2 or FLAIR lesions on the initial brain and spinal cord magnetic resonance imaging [MRI] or ≥3 T1 lesions with postcontrast enhancement on the initial brain and spinal cord MRI or Expanded Disability Status Scale after treatment of the initial relapse ≥3), high-efficacy DMT should be initiated. If pwMS experience ≥1 relapse or ≥3 new T2 lesions while on platform therapies, they should be switched to high-efficacy DMT. Further efforts should be made to enable early and unrestricted access to high-efficacy DMT with a freedom of choice of an appropriate therapy for expert physicians and pwMS. The improvement of access to DMT achieved by the implementation of national treatment guidelines in Croatia can serve as an example to national neurological societies from other Eastern European countries to persuade payers to enable early and unrestricted treatment of pwMS.

Reorganization of the Brain Extracellular Matrix in Hippocampal Sclerosis.

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less intense diffuse WFA staining in Cornu Ammonis (CA) fields. Our findings suggest that PNN reduction, changed ECM protein, and glycosylation expression pattern in HS1 might be involved in the pathogenesis and persistence of drug-resistant MTLE by contributing to the increase of CA pyramidal neurons' excitability. This research corroborates the validity of ECM molecules and their modulators as a potential target for the development of new therapeutic approaches to drug-resistant epilepsy.

Blood pressure variability is altered in secondary progressive multiple sclerosis but not in patients with a clinically isolated syndrome.

OBJECTIVES: To investigate differences in beat-to-beat systolic blood pressure variability (SBPV) in people with secondary progressive MS (pwSPMS), clinically isolated syndrome (pwCIS) and healthy controls (HC). METHODS: This retrospective case-control study included 46 pwSPMS, 46 pwCIS and 44 HC. A semi-automated software made with MATLAB R2019b (The MathWorks, Inc.) was used for the evaluation of SBPV. The frequency domain characteristics observed were the power spectrum in the LF and HF bands and the LF/HF ratio. Data is expressed in absolute power (mmHg2) of LF and HF and ratio (LF/HF) during both supine and tilt-up phases of testing. RESULTS: There were no significant differences in mean systolic (sBP) or diastolic blood pressure (dBP) values during supine and tilt-up phases of testing between groups. During the supine phase of testing LF and LF/HF were significantly lower in the SPMS group (4.17±5.38 and 3.52±2.34, respectively) compared to the CIS (5.42±3.59, p = 0.015 and 5.92±4.63, p = 0.029, respectively) and HC group (6.03±4.55, p = 0.011 and 6.52 ±â€¯5.09, p = 0.010, respectively), while during the tilt-up phase, LF was significantly lower compared to both the CIS and HC group, and HF was significantly lower only compared to the CIS group. CONCLUSION: SBPV is altered in pwSPMS compared to pwCIS and normal controls. Further research in the field of MS related dysautonomia is warranted not only because of its relevance to comorbidities and MS symptoms, but also because of its likely involvement in the pathophysiology of MS.

Short- and long-term effects of siponimod on autonomic nervous system in secondary progressive multiple sclerosis.

OBJECTIVES: The aim of this study was to investigate the short- and long-term effects of siponimod on autonomic nervous system (ANS) function, in people with secondary progressive multiple sclerosis (pwSPMS) METHODS: The following ANS tests were performed in 26 pwSPMS: a 10 min supine resting position, Valsalva maneuver, deep breathing test and a 10 min tilt-up table test. Heart rate variability (HRV) was performed for the 10 min in supine resting position (M0) and for a 3 h period after siponimod treatment initiation (M0s1-6). All ANS tests were repeated after at least 6 months of treatment with siponimod (M6). RESULTS: In all 6 intervals after siponimod ingestion (M0s1-6), standard deviation of NN intervals (SDNN) was higher compared to M0. After 6 months of continuous treatment with siponimod, SDNN was significantly lower compared to M0. At M6, Valsalva ratio and respiratory sinus arrhythmia were lower compared to M0 values (1.510±0.338 vs 1.864±0.456, p=0.003 and 7.969±2.865 vs 13.091±4.687, p<0.001, respectively). Cardiovagal index was significantly higher at M6 compared to M0 (1 (range 0-2) vs 0 (range 0-1), p=0.008, respectively). Active Magnetic Resonance Imaging (MRI) one year prior to starting siponimod was a positive predictor of M6 SDNN and Adrenergic Index (AI) at M0 was a negative predictor of M6 SDNN. CONCLUSION: This study has shown an inverse relationship in short- versus long-term effects of siponimod on ANS function. A shift towards parasympathetic predominance was observed during the first three hours after ingestion, while after 6 or more months of continuous treatment with siponimod, a shift towards sympathetic predominance was observed.

Sudomotor dysfunction in people with neuromyelitis optica spectrum disorders.

BACKGROUND AND PURPOSE: The aim was to determine the extent of sudomotor dysfunction in people with neuromyelitis optica spectrum disorder (pwNMOSD) and to compare findings with a historical cohort of people with relapsing-remitting multiple sclerosis (pwRRMS). METHODS: Forty-eight pwNMOSD were enrolled from four clinical centers. All participants completed the Composite Autonomic Symptom Score 31 to screen for symptoms of sudomotor dysfunction. Sudomotor function was assessed using the quantitative sudomotor axon reflex test. The results were compared with a historical cohort of 35 pwRRMS matched for age, sex and disease duration. RESULTS: Symptoms of sudomotor dysfunction, defined by a score in the Composite Autonomic Symptom Score 31 secretomotor domain >0, were present in 26 (54%) of pwNMOSD. The quantitative sudomotor axon reflex test confirmed a sudomotor dysfunction in 25 (52.1%) of pwNMOSD; in 14 of them (29.2%) sudomotor dysfunction was moderate or severe. No difference was observed between pwNMOSD and pwRRMS in any of the studied parameters. However, symptomatic sudomotor dysfunction was more frequent in pwNMOSD (n = 8, 22.9%) compared to pwRRMS (n = 1, 3%; p = 0.028). In a multivariable logistic regression analysis, statistically significant predictors for symptomatic sudomotor failure were age and diagnosis of neuromyelitis optica spectrum disorder. CONCLUSIONS: Sudomotor dysfunction is common in pwNMOSD and more often symptomatic compared to pwRRMS.

Hypogammaglobulinemia, infections and COVID-19 in people with multiple sclerosis treated with ocrelizumab.

OBJECTIVE: To determine the influence of immunoglobulins (Ig) level on the rate of infections in people with multiple sclerosis (pwMS) treated with ocrelizumab. METHODS: We enrolled 109 consecutive pwMS treated with ocrelizumab with a mean follow-up of 2.69±0.56 (1.36-4.27) years. We have retrospectively searched our electronic database and the following information was collected: age, sex, MS characteristics, number of ocrelizumab cycles, infections, duration of the infection, hospitalization due to infection, treatment of the infection, and COVID-19 characteristics. Ig levels were measured within 14 days before each ocrelizumab infusion. RESULTS: Number of pwMS with values of IgM and IgG below lower level of normal at baseline was 3 (2.8%) and 2 (2.8%), respectively; and before 6th cycle of ocrelizumab 5 (13.5%) and 5 (13.5%), respectively. Levels of IgM were steadily decreasing over time, while levels of IgG started to show statistically significant drop only after 5th cycle of ocrelizumab. 58.7% pwMS experienced infection during treatment, with a median number of infections per pwMS being 1, range 0-4. Female sex increased the risk of any infection (HR 2.561, 95%CI 1.382-4.774, p=0.003). Higher age and smaller drop in IgM before 3rd ocrelizumab cycle increased the risk for infection requiring hospitalization (HR 1.086, 95%CI 1.018-1.159, p=0.013 and HR 9.216, 95%CI 1.124-75.558, p=0.039, respectively). Longer disease duration increased the risk for COVID-19 (HR 1.075, 95%CI 1.002-1.154, p=0.045). CONCLUSION: The present findings broaden limited real-world data on infection and COVID-19 risk in pwMS treated with ocrelizumab.

Comparison of pain-provoked versus standard 40-min tilt table test for the conformation of vasovagal syncope.

BACKGROUND: Tilt table test represents a valuable diagnostic method in assessing patients with transient loss of consciousness and confirming the diagnosis of vasovagal syncope. However, the test lacks standardization, and various protocols exist in different centers. The aim of this study was to compare the difference in sensitivity and time-to-syncope of tilt table test with a painful stimulus provocation compared to standard test with no provocation. METHODS: This was a prospective study that included consecutive patients diagnosed with vasovagal syncope who were referred for tilt table testing. Patients were randomly assigned to two groups: group 1 with pain provocation after the first 10 min of upright position and group 2 with no provocation with further 30 min of tilt in both groups. RESULTS: In group 1, 66 (78.6%) patients developed syncope while in group 2, 35 (44.3%) patients had syncope (p < 0.001). This represents an increase of 34.3% in TTT sensitivity with the application of painful provocation. According to results of the Cox regression, the hazard for developing syncope after the 10th min of the tilt for group 2 was 0.275 of the hazard of group 1 (95% C.I. 0.170-0.444, p < 0.001). CONCLUSION: Pain provocation is a useful method for increasing sensitivity and shortening the duration of tilt table testing.

Humoral and cellular immunity in convalescent and vaccinated COVID-19 people with multiple sclerosis: Effects of disease modifying therapies.

OBJECTIVES: To determine anti-SARS-Cov2 antibodies and T-cell immunity in convalescent people with multiple sclerosis (pwMS) and/or pwMS vaccinated against Covid-19, depending on the disease modifying therapy, and in comparison to healthy controls (HC). METHODS: 75 participants were enrolled: Group 1-29 (38.7%) COVID-19 convalescent participants; Group 2-34 (45.3%) COVID-19 vaccinated; Group 3-12 (16.0%) COVID-19 convalescent participants who were later vaccinated against COVID-19. Cellular immunity was evaluated by determination of number of CD4+ and CD8+ cells secreting TNFα, IFNγ, and IL2 after stimulation with SARS-CoV-2 peptides. RESULTS: pwMS treated with ocrelizumab were less likely to develop humoral immunity after COVID-19 recovery or vaccination. No difference was observed in the cellular immunity in all studied parameters between pwMS treated with ocrelizumab compared to HC or pwMS who were treatment naïve or on first line therapies. These findings were consistent in convalescent, vaccinated, and convalescent+vaccinated participants. COVID-19 vaccinated convalescent pwMS on ocrelizumab compared to COVID-19 convalescent HC who were vaccinated did not show statistically difference in the rate of seroconversion nor titers of SARS-CoV-2 antibodies. CONCLUSION: Presence of cellular immunity in pwMS on B-cell depleting therapies is reassuring, as at least partial protection from more severe COVID-19 outcomes can be expected.

Double immune reconstitution therapy: Cladribine after alemtuzumab in the treatment of multiple sclerosis.

BACKGROUND AND PURPOSE: Alemtuzumab, a monoclonal anti-CD52 antibody, and cladribine, a purine nucleoside analogue, are used for the treatment of highly active relapsing-remitting multiple sclerosis (MS). Both are administered as two short yearly courses but possess the ability to induce long-term remission, labeling them as immune reconstitution therapies. Although disease activity after alemtuzumab administration is rare, there are a small number of people with MS who will experience disease activity despite repeated alemtuzumab treatment. METHODS: We report on six patients with MS who experienced disease activity after alemtuzumab and were subsequently treated with cladribine and followed up for up to 2 years. RESULTS: None of the patients experienced relapses during the follow-up period and in all patients Expanded Disability Status Scale values remained unchanged. All patients had lymphopenia at one time point. In patients 1 and 2, at the nadir, the lymphopenia was grade 1, in patient 3 it was grade 2 and in patients 5 and 6 it was grade 3. No infections or malignancies were recorded during the follow-up. CONCLUSION: This report provides a framework for treating people with MS with sequential immune reconstitution therapies.

Humoral immune response to COVID-19 vaccines in people with secondary progressive multiple sclerosis treated with siponimod.

OBJECTIVE: The aim of this study is to determine a development of humoral response after COVID-19 vaccination in persons with secondary progressive multiple sclerosis (pwSPMS) on siponimod, compared to healthy controls (HC). METHODS: In 13 pwSPMS taking siponimod and 11 HC, testing for SARS-CoV2 antibodies was performed after vaccination against COVID-19. RESULTS: pwSPMS taking siponimod had a significantly lower titer of SARS-CoV2 antibodies compared to healthy controls (19.4 (0-250) vs. 250 (250), p>0.001). Two (15.4%) pwSPMS on siponimod had unmeasurable titers of SARS-CoV2-2 antibodies, while all HC had positive titers. CONCLUSION: Although the results of this study are limited by a small sample size, results have consistently shown low titers of SARS-CoV-2 IgG after COVID-19 vaccinations in pwSPMS on siponimod.