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Background: Ocrelizumab is the only disease-modifying therapy (DMT) approved for the treatment of people with primary progressive multiple sclerosis (pwPPMS)., Objectives: To provide real-world evidence of ocrelizumab effectiveness and safety in pwPPMS in Croatian MS centers., Methods: A retrospective observational multi-center study of pwPPMS who were started on ocrelizumab in 7 MS centers in Croatia., Results: We identified 230 pwPPMS of whom 176 fulfilled the inclusion criteria. The median follow-up of the cohort was 2.73 (0.51-5.77) years. During the follow-up, 50 (28.4%) pwPPMS experienced confirmed disability worsening (CDW) and 19 (10.8%) stopped treatment with ocrelizumab. Baseline EDSS >5 was a statistically significant positive predictor for the development of CDW and/or stop of the treatment due to any cause (OR 2.482, 95% C.I. 1.192-5.166, p = 0.015). However, there was no significant difference in the development of CDW and/or stop of the treatment due to any cause if stratifying the patients based on active PPMS, age at treatment start (≤55 years vs >55 years), disease duration at treatment start (≤10 years vs >10 years), or EDSS at treatment start (≤5.0 vs >5.0). During the follow-up, 26 (14.8%) pwPPMS experienced infusion reactions, 64 (36.4%) had an infection and 4 (2.3%) developed a tumor. The percentage of pwPPMS with low levels of IgG was persistently above 10% and with low levels of IgM was persistently above 20% after cycle 4., Conclusion: Our real-world data support the use of ocrelizumab in a much broader pwPPMS population than in the original randomized controlled trial., Competing Interests: Declaration of competing interest MH, IA, BB, TG, MKS: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Novartis, Pliva/Teva, Roche, Zentiva, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals. VBK: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Pliva/Teva, Roche. NG: Nothing to disclose. IL: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Novartis, Roche, Merck, Biogen, Sanofi, Pliva. SP: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Novartis, Roche, Merck, Biogen, Zentiva, Pliva. TMZ: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Roche, Biogen, Teva/Pliva, Merck, Sanofi, Novartis. MK: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Novartis, Biogen, Merck, Sanofi. SKP: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Roche, Biogen, Boerhringer, Teva/Pliva, Merck, Novartis. AA: Nothing to disclose. There was no support from any organization for the submitted work; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest TS, MS, AK, AJ, LC: Nothing to disclose. IA, BB, TG, MH: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals. MKS: received consultation and/or speaker fees from: Sanofi Genzyme, Roche., (Copyright © 2024. Published by Elsevier B.V.)

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 (M0 s1-6 ). All ANS tests were repeated after at least 6 months of treatment with siponimod (M6)., Results: In all 6 intervals after siponimod ingestion (M0 s1-6 ), 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., (Copyright © 2022. Published by Elsevier B.V.)

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 6 th 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 5 th 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 3 rd 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., (Copyright © 2022. Published by Elsevier B.V.)

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., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To evaluate clinical and laboratory effects of delaying ocrelizumab infusions during the COVID-19 pandemics in people with multiple sclerosis (pwMS)., Methods: We have retrospectively searched our electronic database and identified 33 pwMS who had a delay in treatment due to COVID-19 pandemics. The following data were extracted: age, sex, multiple sclerosis (MS) phenotype: relapsing-remitting (RRMS) or primary progressive multiple sclerosis (PPMS), disease duration, Expanded Disability Status scale (EDSS), previous disease modifying therapy (DMT), number of ocrelizumab cycles prior to the lockdown, dates of first ocrelizumab infusion, last ocrelizumab infusion prior to the lockdown and delayed ocrelizumab infusion after the lockdown. Flow cytometry results, relapses and EDSS progression prior to the delayed ocrelizumab infusion after the lockdown were extracted., Results: The mean time between two ocrelizumab infusion during the lockdown was 7.72±0.64 (range 6.07 to 8.92) months. The mean time between last ocrelizumab infusion and the lymphocyte sampling prior to post COVID infusion was 6.59±0.95 (range 5.18 to 8.49) months. In this period, none of the studied patients had a relapse. In a multivariable linear regression analysis, time from last ocrelizumab infusion to lymphocyte sampling prior to the next infusion was the only significant predictor for CD19 + B cells count, when corrected for the number of previous ocrelizumab cycles and MS phenotype (RRMS or PPMS) (B=7.981, 95% C.I. 3.277-12.686, p=0.002)., Conclusions: We have not shown clinical consequences of delaying ocrelizumab due to COVID-19 pandemics. However, the delay in dosing of ocrelizumab was an independent predictor of repopulation of B cells., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: The aim of the present study was to investigate the long-term evolution of tongue somatosensory evoked potentials (tSSEP) in people with multiple sclerosis (pwMS)., Methods: Out of initial 121 participants, after two-year follow-up, the data were available for 74 and after four-year follow-up for 58 pwMS. In all pwMS complete neurological examination, brain MRI, cervical spinal cord MRI (if available) and tSSEP were performed at baseline visit (M0). Complete neurological examination and tSSEP were performed 2 and 4 years later (M24 and M48). tSSEP results were interpreted in the form of ordinal tSSEP score and quantitative tSSEP zscore calculated from the sum of z-transformed tSSEP latencies., Results: Differences in tSSEP scores and tSSEP zscores in three different timepoints showed significant worsening of both scores over time. For the tSSEP score the difference was significant for M0-M24 and M0-M48 visits, but not for M24-M48 visits. For the tSSEP zscore the difference was significant for M0-M48 and M24-M48 visits, but not for M0-M24 visits. The only significant negative predictor found for the tSSEP score improvement was presence of cervical spinal cord lesions on the MRI. A moderate to high correlation was observed between both forms of tSSEP score at all three timepoints., Conclusion: This study demonstrates a significant deterioration of trigeminal sensory pathway in MS over time, giving further insight into trigeminal system damage in pwMS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the effect of intravenous immunoglobulins (IVIG) on prevention of postpartum relapses in women with relapsing-remitting multiple sclerosis (RRMS)., Methods: This was a retrospective study performed in Ljubljana, Slovenia where the practice for all pregnant women with RRMS is to receive IVIG after the delivery (10 g monthly, during first 6 months after delivery) and in Zagreb, Croatia where no such practice exists. The following data were collected: date of delivery, maternal age at delivery, year of the RRMS diagnosis, EDSS, disease modifying therapy prior to pregnancy, relapses in the year prior, during and in the period of one year after pregnancy., Results: Data on 132 pregnancies from 112 women (mean age at delivery 31.70±4.10, average disease duration 6.34±4.33) were analyzed. There was no association between the IVIG treatment and annualized relapse rate one year after the delivery (0.27 vs 0.38, rate ratio 1.409, 95% CI 0.764-2.598, p = 0.272). No risk factors for the postpartum relapse were identified (age at delivery, duration of RRMS, EDSS prior pregnancy, disease modifying therapy prior pregnancy, relapses in the year prior pregnancy, IVIG)., Conclusion: This study provides no evidence of benefit for postpartum administration of IVIG in women with RRMS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alemtuzumab is one of immunomodulatory drugs used for treatment of multiple sclerosis (MS). Although it is very effective it carries significant risk for various side effects. This paper reports a case of young patient who developed pulmonary embolism during the third cycle of alemtuzumab. It is suggested that awareness about possible vascular toxicity of this drug should be raised., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Standard therapy for a relapse of multiple sclerosis is a high dose pulse corticosteroid therapy. Cardiovascular adverse events ranging from palpitations to serious arrhythmias like atrial fibrillation and ventricular tachycardia have been associated with this treatment. The underlying mechanism behind the development of atrial fibrillation and treatment of multiple sclerosis relapse with steroids is still unclear. In this case, a 27-year-old male with multiple sclerosis is presented who developed atrial fibrillation on two occasions following two consecutive treatments with high dose methylprednisolone for the treatment of multiple sclerosis relapse. Extensive work-up revealed mild sympathetic autonomic system dysfunction. Based on this case and previous studies, we propose that a disturbed function of the autonomic system increases the risk of atrial fibrillation and/or other arrhythmias in people with multiple sclerosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: We aimed to evaluate the role of autonomic nervous system (ANS) abnormalities on disease activity (relapses and new MRI lesions) and disease progression in people with clinically isolated syndrome (pwCIS)., Methods: Out of 121 consecutive pwCIS, data on disease activity and progression after 2.9 (1.4-4.1) years of follow-up, was available for 94 pwCIS. Baseline characteristics included MRI parameters, Composite Autonomic System Score-31 (COMPASS-31), Composite Autonomic Scoring Scale, and supine and standing levels of epinephrine and norepinephrine., Results: Univariable logistic regression analysis revealed three predictors for occurrence of new relapse, COMPASS-31 > 7.32, total number of T2 lesions > 3 and decreasing supine level of epinephrine. The Kaplan-Meier survival analysis showed that patients with COMPASS-31 > 7.32 have statistically significant lower probability that they will be relapse free (p = 0.013). It has also showed that the relative risk reduction for occurrence of new relapse in participants with COMPASS < 7.32 was 46%. The multivariable regression model confirmed that COMPASS-31 > 7.32 and total number of T2 lesions > 3 increase the likelihood and the increasing supine level of epinephrine reduces the likelihood for a relapse. Finally, results of the Cox regression analysis showed, that after controlling for age, sex, total number of T2 lesions > 3 and supine level of epinephrine, the hazard for occurrence of new relapse for participants with COMPASS-31 > 7.32 is 2.7 times that of participants with COMPASS-31 < 7.32., Conclusion: This study provides evidence that ANS is an important contributor to development of disease activity in pwCIS., (Copyright © 2019. Published by Elsevier B.V.)

The standard therapy of multiple sclerosis (MS) relapse is high-dose pulse corticosteroid therapy. Although commonly applied and usually well tolerated it may as well carry certain risks for people with MS, the more severe of them being hepatotoxicity. This report describes three cases of acute liver injury following pulse corticosteroid therapy with reference to other possible causative factors. Caution should be exercised when applying high-dose methylprednisolone given the potential liver related adverse events it may cause., (Copyright © 2018. Published by Elsevier B.V.)

Aim: To compare the sensitivity, specificity and accuracy of the 2010 and 2017 revisions of the McDonald criteria in a Croatian cohort of patients with a clinically isolated syndrome (CIS)., Methods: Prospectively collected data from 113 patients were retrospectively analyzed. Sensitivity, specificity and accuracy for both criteria were calculated regarding conversion to clinically definite multiple sclerosis (Poser CDMS) or multiple sclerosis (MS) (defined as fulfilment of clinical or MRI evidence for dissemination in space and the development of a second relapse and/or ≥1 new T2 lesions on the follow-up MRIs) during a two-year follow-up. Survival analysis was performed to estimate the cumulative risk of patients developing Poser CDMS. Binary logistic regression model was used to determine which variables are statistically significant predictors for the conversion to MS., Results: The 2017 revision had higher sensitivity (85 vs. 30% and 85 vs. 41%) and lower specificity (33 vs. 63% and 63 vs. 85%) compared to the 2010 revisions, for conversion to Poser CDMS and MS, respectively. Patients who did not meet the 2017 McDonald criteria had a higher chance of conversion-free survival for Poser CDMS than those who met the 2017 McDonald criteria (p = 0.037). Results of the multivariate regression analysis revealed that patients who at baseline fulfilled 2017 revisions of the McDonald criteria have the increased likelihood of conversion to MS (Exp(B) 9.68, 95%CI 3.62-25.90, p < 0.00001)., Conclusion: This study provides new information about the application of the 2017 revisions of the McDonald criteria in a Croatian cohort of patients with typical CIS., (Copyright © 2018. Published by Elsevier B.V.)

Background: The aim of this study was to investigate the potential role of video head impulse test (vHIT) in the detection of brainstem lesions in patients with multiple sclerosis (MS)., Methods: Sixty-eight participants were enrolled and divided into two groups: 39 healthy subjects (HC) (78 ears, 20 females, mean age 25,3±6,3) and 29 MS patients (58 ears, 14 females, mean age 33,7±7,7). Both groups underwent vHIT, and in MS group MRI was analyzed for the presence of brainstem lesions. vHIT pathology was defined as presence of overt saccades (<200ms) or lateral gain lower than 0.8 for lateral canal, and presence of overt saccades (<200ms) or posterior/anterior slope lower than 0.7., Results: In HC, decreased gain on horizontal canals was found in 8 out of 78 ears (11%), while 16 out of 58 ears (38%) had pathological results in the MS group. Mean gain of the lateral canals (60ms) was significantly reduced in MS group compared to HC (0.874±0143 vs. 0.954±0,170, p=0.004, respectively). Compared to HC overt saccades <200ms in the lateral canals (p=0.018) and in the posterior canals (p=0.011), overt saccades >200ms in lateral (p<0.001), anterior (p=0.019) and posterior canals (p=0.009), and covert saccades in the anterior (p=0.042) and posterior canals (p=0.046) were more frequent in the MS group. There was statistically significant association between the presence of BS MR lesions and bilateral pathology on vHIT for lateral semicircular canal (χ(1)=3.982, p=0.046)., Conclusion: These results indicate that vHIT can detect brainstem dysfunction in patients with MS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Erythromelalgia is a rare condition characterized by burning pain, erythema and increased temperature of the hands or the feet. Its etiology is not completely understood but it is believed that the underlying cause is a peripheral vascular dysfunction that leads to simultaneous tissue hypoxia and hyperemia. We present a rare co-occurrence of erythromelalgia and multiple sclerosis in a patient with autonomic nervous system dysfunction and propose a causative interconnection., (Copyright © 2016 Elsevier B.V. All rights reserved.)