Search

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 ± 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.

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.

Background Tilt table test represents a valuable diagnostic method in assessing patients with transient loss of consciousness and confrming the diagnosis of vasovagal syncope. However, the test lacks standardization, and various protocols exist in diferent centers. The aim of this study was to compare the diference 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 frst 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

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.

Traditionally, the management of active relapsing remitting MS was based on the, so-called, maintenance therapy, which is characterized by continuous treatment with particular disease modifying therapy (DMT), and a return of disease activity when the drug is discontinued. Another approach is characterized by a short treatment course of a DMT, which is hypothesized to act as an immune reconstitution therapy (IRT), with the potential to protect against relapses for years after a short course of treatment. Introduction of monoclonal antibodies in the treatment of MS has revolutionized MS treatment in the last decade. However, given the increasingly complex landscape of DMTs approved for MS, people with MS and neurologists are constantly faced with the question which DMT is the most appropriate for the given patient, a question we still do not have an answer to. In this product review, we will discuss the first DMT that acts as IRT, an anti-CD52 monoclonal antibody alemtuzumab and an anti CD20 monoclonal antibody, ocrelizumab that has the potential to act as an IRT, but is administered continuously. Special emphasis will be given on safety in the context of COVID-19 pandemics and vaccination strategies.

Alemtuzumab is a humanized anti-CD52 antibody that is registered for treatment of highly active relapsing-remitting multiple sclerosis. Disease activity after alemtuzumab treatment is infrequent. It may be a result of lack of lymphocyte depletion due to development of neutralizing autoantibodies. On the other hand, severe disease activity has been described after alemtuzumab, which is suggested to be caused by B-cell hyperpopulation. We present a case of a person with multiple sclerosis with severe disease activation after alemtuzumab administration that may represent paradoxical B cell-mediated disease activity. The patient was successfully treated with ocrelizumab.

Objective: So far, a limited number of real-world evidence studies about the effectiveness and safety of alemtuzumab (ALM) have been published, some of them with a relatively small number of included patients. We aimed to study the efficacy and safety of ALM in real-world clinical practice in two MS centers in Slovenia and Croatia. Methods: This was a retrospective chart review of 71 consecutive patients with relapsing-remitting MS who were treated with ALM from 2015 till 2018. The following data were collected: gender, age at disease onset, disease duration at ALM initiation, previous disease modifying therapy, number of relapses, active MRI lesions, and EDSS in the year prior to ALM initiation and every year of follow- up. Results: All patients completed the standard dosing schedule and were followed for a mean time of 3.2±1.1 years after the initiation of treatment. Complete data for the 2 years after treatment (relapses, EDSS, and MRI) were available for 48 patients, of which 14 (29.2%) achieved NEDA. Clinical NEDA was achieved in 38 out of 63 participants (60.3%). In year 1, 24 out of 57 (42.1%) patients achieved NEDA. In year 2, 26 out of 41 (63.4%) patients achieved NEDA. Lower EDSS prior to starting ALM was the only independent predictor of NEDA in a multivariable model. Adverse events occurred in 58 participants (84.1%), with no new safety signals identified. Conclusion: According to the data from our cohort of early active RRMS patients we conclude ALM efficacy remains high in the real-world clinical practice.

Objectives To report clinical outcome, development of humoral and T-cell mediated immunity in convalescent COVID-19 people with multiple sclerosis (pwMS) treated with ofatumumab in the ALITHIOS study from a single center. Methods Testing for SARS-Cov2 IgG antibodies was performed on two occasions with at least three months apart between the two testing. During the second antibody testing, interferon-γ ELISpot was used to assess cellular immunity. Results All four subjects had mild COVID-19 infection without any sequelae. In all subjects except subject 2, COVID-19 was confirmed with PCR. Subjects 1, 2 and 4 had normal levels of IgM and IgG without measurable counts of CD19 cells prior to COVID-19. Subject 3 administered the last dose of ofatumumab 24 days prior to COVID-19 symptoms, but had a gap of 28 weeks of ofatumumab application beforehand due to low IgM levels. Subject 4 received COVID-19 vaccinations before second testing, so second testing and T-cell immunity testing were not performed. Subjects who were CD19 depleted did not had measurable levels of SARS-Cov2 IgG antibodies. Subject 3 had first and second SARS-COV2 titer of 118 U/ml and > 250 U/ml, respectively. All three pwMS showed T cell immunity against SARS-CoV-2. Quotient of basal spots divided by interferon-γ secreting spot forming units were 4, 8 and 14.7 SI in subjects 1, 2 and 3, respectively (>3 considered reactive). Conclusion While no antibody response was observed in pwMS who were CD19+ lymphocyte depleted, T cell immunity against SARS-CoV-2 was observed in all three pwMS treated with ofatumumab., Graphical abstract Unlabelled Image

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.

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.

Aim To determine the influence of high-efficacy disease modifying therapy (DMT) on the development of IgG SARS-CoV-2 antibody response in COVID-19 convalescent people with multiple sclerosis (pwMS). Methods Seventy-four pwMS taking high-efficacy DMTs (specifically natalizumab, fingolimod, alemtuzumab, ocrelizumab, cladribine and ublituximab) and diagnosed with COVID-19 and 44 healthy persons (HC) were enrolled. SARS-CoV2 antibodies were tested with Elecsys® Anti-SARSCoV-2 S assay. Results pwMS taking high-efficacy DMTs had a significantly higher chance of having negative titer of SARS-CoV2 antibodies compared to healthy controls (33 negative pwMS [44.6%] compared to one negative HC [2.3%], p, Graphical abstract Unlabelled Image

Introduction Miller Fisher syndrome (MFS) is a rare variant of Guillain-Barre syndrome characterized by ataxia, areflexia, and ophthalmoplegia. We present a case of MFS following Pfizer COVID-19 vaccine. Case presentation A previously healthy 24-year-old female presented with binocular horizontal diplopia 18 days after receiving the first dose of Pfizer COVID-19 vaccine (Comirnaty®). Anti-ganglioside testing revealed positive anti-GQ1b antibodies. Intravenous immunoglobulins were administered, in a dose of 2 g per kg of body weight over 5 days. On a follow-up exam 3 weeks after the treatment, clinical improvement was noted with normal bulbomotor examination. Conclusion Patients with acute ophthalmoplegia occurring after COVID-19 vaccination should be screened for the presence of anti-GQ1b antibody. If the antibody is present, intravenous immunoglobulin should be administered as it may hasten clinical improvement. Supplementary Information The online version contains supplementary material available at 10.1007/s10072-021-05776-0.

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

BACKGROUND AND PURPOSE: The aim was to evaluate whether the addition of evoked potentials (EPs) which evaluate brainstem function to the EP score improves its ability to predict disease progression in people with clinically isolated syndrome (pwCIS). METHODS: For 94 pwCIS, data on disease activity and progression after 2.9 (1.4-4.1) years of follow-up were available. Baseline characteristics included magnetic resonance imaging (MRI) parameters, visual EPs, auditory EPs, somatosensory EPs of the median and tibial nerves, vestibular evoked myogenic potentials and tongue somatosensory EPs. RESULTS: A multivariable regression model including age, sex, total number of T2 lesions on baseline MRI and EP score >13 showed that the total number of T2 lesions on baseline MRI and EP score >13 increase the likelihood for sustained accumulation of disability (SAD). After controlling for age, sex and the total number of T2 lesions on baseline MRI, the hazard of SAD for participants with EP score >13 is 4.093 times that of participants with EP score ≤13. EP score >13 also increases the likelihood for progression measured with a composite measure of progression which uses the Expanded Disability Status Scale, the nine-hole peg test and the timed 25-ft walk (exp(B) = 5.577, 95% confidence interval 1.520-20.468, P = 0.01). CONCLUSION: The addition of EPs that evaluate brainstem function to the EP score enables prediction of the progression of disability in pwCIS.

Autonomic dysfunction (AD) is known to be frequent among multiple sclerosis (MS) patients, even in early stages of the disease. During the course of disease, AD becomes more pronounced, with patients in progressive stages of MS experiencing a higher autonomic burden than MS patients in relapsing-remitting stages. The same pattern of AD progression is true for sudomotor dysfunction, with 35% of MS patients with a relapsing-remitting phenotype experiencing sudomotor dysfunction compared to 73% of MS patients with a progressive phenotype. We present the case of a patient with primary progressive MS suffering from severe sudomotor dysfunction. The presented patient had avoided physical therapy as he could not tolerate the accompanying temperature rise. One way to deal with this obstacle is to cool the patient down prior to physical therapy or let the patient workout at a cooler room temperature. From a research point of view, sudomotor dysfunction detected in MS patients may actually be a sign of small fiber neuropathy and not just a reflection of central nervous system dysfunction, a possibility which requires further investigation.

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.

The autonomic nervous system (ANS) is the part of the central and peripheral nervous system, hierarchically organized into central autonomic network and the peripheral autonomic branches, that regulates functions which are mostly independent of human will. These include vital functions such as breathing, blood pressure maintenance, heart rate regulation, sweating, digestion, urination, sexual functions. Organ systems responsible for these functions are regulated by two inseparable parts of ANS, the sympathetic and parasympathetic systems, that exert the antagonistic effects. Although both the sympathetic and parasympathetic systems exhibit constant tonic activity the predominance of one or the other is determined by the specific external or internal stimuli the person is exposed to. A flight-or-fight reaction is typical for the prevailing sympathetic activity characterized by an increase in heart rate and blood pressure and centralization of the circulation. In contrast, the parasympathetic system is more active in the rest-and-digest circumstances and causes energy conservation and stimulation of the digestive system. The principal neurotransmitter of the sympathetic system is norepinephrine whereas the parasympathetic fibers are cholinergic. A detailed knowledge of ANS physiology is a prerequisite for the diagnosis and treatment of various causes of ANS dysfunction.

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.

Introduction: Multiple sclerosis (MS) is a chronic demyelinating immune mediated disease of the central nervous system. Autonomic dysfunction (AD) is frequently present in persons with MS (pwMS) and increases with disease duration and progression. Areas covered: Cardiovascular, genitourinary, and sudomotor autonomic dysfunction in pwMS are reviewed and managing of these disorders is addressed. Expert opinion: AD in pwMS can manifest with a myriad of symptoms including cardiovascular, urogenital, and sweating disorders. These symptoms can significantly impact the quality of life of pwMS with poor tolerance of upright position, difficulties in sexual function, and low endurance of physical activity especially in warm environments. Health professionals involved in care of pwMS should possess basic knowledge of the function of the autonomic nervous system and be informed of the way disorders of the autonomic function may manifest in pwMS in order to provide the proper care.

No abstract available

Aim: The aim of this review is to summarize the clinical and paraclinical findings that demonstrate that multiple sclerosis (MS) affects the peripheral nervous system (PNS) as well as the central nervous system (CNS). Methods: Narrative review. Results: MS is traditionally defined as a chronic demyelinating immune-mediated disease of the CNS. However, there is emerging evidence that MS is a disease that does not solely affect the CNS but can manifest with PNS involvement as well. Several pathology studies have reported on signs of demyelination in the PNS, as well as on structural and functional involvement of the PNS in persons with MS (pwMS). From the functional aspect, several studies have shown autonomic nervous system (ANS) involvement in the form of sudomotor dysfunction measured with quantitative sudomotor axon reflex test (QSART) in different stages of MS, adding to the growing body of evidence that indicate PNS involvement in MS. In this review the clinical, pathological, neurophysiological, and imaging findings that demonstrate that MS affects the PNS as well as the CNS are summarized, with the emphasis on the ANS abnormalities. Conclusion: Further large-scale research is needed in order to fully understand the frequency and importance of PNS affection in MS.

Autonomic nervous system (ANS) regulates many important systems in the human body, such as blood pressure, heart rate, digestion, respiratory system and many others. Dysfunction of the ANS is related to disorders in different systems in the human body, and it can be recognizable in the ANS biosignals. Digital signal processing (DSP) of the ANS biosignals provides information about the functioning of the autonomic nervous system, which is very useful in everyday clinical practice. There is a large variety of different methods for ANS signals analysis, with different features extracted. Due to the increase in the collectible amount of data, there is a growing demand for the automatization of the signal analysis process, which could reduce human error, save time and improve the quality and the accuracy of the calculated results.

So far, a limited number of real-world evidence studies about the effectiveness and safety of alemtuzumab (ALM) have been published, some of them with a relatively small number of included patients. We aimed to study the efficacy and safety of ALM in real-world clinical practice in two MS centers in Slovenia and Croatia.This was a retrospective chart review of 71 consecutive patients with relapsing-remitting MS who were treated with ALM from 2015 till 2018. The following data were collected: gender, age at disease onset, disease duration at ALM initiation, previous disease modifying therapy, number of relapses, active MRI lesions, and EDSS in the year prior to ALM initiation and every year of follow-up.All patients completed the standard dosing schedule and were followed for a mean time of 3.2±1.1 years after the initiation of treatment. Complete data for the 2 years after treatment (relapses, EDSS, and MRI) were available for 48 patients, of which 14 (29.2%) achieved NEDA. Clinical NEDA was achieved in 38 out of 63 participants (60.3%). In year 1, 24 out of 57 (42.1%) patients achieved NEDA. In year 2, 26 out of 41 (63.4%) patients achieved NEDA. Lower EDSS prior to starting ALM was the only independent predictor of NEDA in a multivariable model. Adverse events occurred in 58 participants (84.1%), with no new safety signals identified.According to the data from our cohort of early active RRMS patients we conclude ALM efficacy remains high in the real-world clinical practice.

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

Highlights • A significant deterioration of the trigeminal sensory pathway function occurs in pwMS. • Cervical spinal cord lesions were negative predictor of tSSEP improvement. • There is a moderate to high correlation between ordinal and quantitative tSSEP scores calculations., 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.

Objective: The aim of this study was to identify whether autonomic nervous system (ANS) dysfunction identified prior to treatment initiation can predict siponimod related decrease in heart rate (HR) after treatment initiation. Methods: In 26 people with secondary progressive multiple sclerosis (SPMS) the following ANS testing protocol was applied: 10-min supine resting position, Valsalva maneuver, deep breathing test, 10 min tilt-up table test, 5-min supine resting period, ingestion of siponimod, followed by 180- min supine resting period recordings. Heart rate variability (HRV) parameters were investigated as possible predictors of decrease in HR (ΔHR) after treatment initiation. Results: After treatment initiation, there was a statistically significant drop in HR (71.1 ± 9.2 to 66.3 ± 8.1, p < 0.001) and elevation of systolic blood pressure (sBP) (113.2 ± 12.4 to 117.1 ± 10.8, p = 0.04). Values of the diastolic BP (dBP) followed similar trend as did sBP, however not reaching statistical significance (72.8 ± 9.6 to 74.9 ± 8.3, p = 0.13). In a multivariable regression model, disease duration and standard deviation of NN intervals (SDNN) were identified as independent predictors for ΔHR, where increase in SDNN and longer disease duration predict smaller ΔHR. Conclusion: ANS abnormalities may predict cardiovascular abnormalities associated with treatment initiation with siponimod. Significance: Results of this study may help mitigate risks associated with siponimod treatment.

Background: We investigated whether the results of autonomic function tests correlate with body composition and shape in healthy young people. Methods: We conducted cardiovascular reflex tests (heart rate [HR] and blood pressure [BP] responses to the Valsalva maneuver and HR response to deep breathing) and the tilt table test with 32 subjects (19 males ; mean age, 22.1±1.9 years). Participants also completed an anthropometric measurement sequence (weight ; height ; upper arm, hips, and waist circumference ; triceps and subscapular skinfold), bioelectric impedance testing, and hand grip strength measurements. Results: Markers of obesity, other anthropometric measures, functional measures, and the basal metabolic rate (BMR) were significantly positively correlated with systolic BP (SBP) and diastolic BP (DBP) in both the supine and tilted positions. There was a positive correlation between the difference in HR (ΔHR) between the tilt and supine body positions and markers of obesity, the functional marker of dominant handgrip strength, and BMR. Participants with a body mass index (BMI)

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.

Alemtuzumab is a humanized monoclonal antibody targeting CD52 protein that has shown great efficacy in the treatment of relapsing remitting multiple sclerosis and is associated with prolonged remission of the disease. Although it is highly effective, alemtuzumab can lead to serious adverse advents among which the most common are secondary autoimmune diseases. We present a patient who was treated with alemtuzumab for relapsing remitting multiple sclerosis. Her disease remained stable in a follow-up period of over ten years. However, during the follow-up period she developed thyroiditis one year, as well as systemic erythematous lupus seven years after the last alemtuzumab infusion, a disease not previously associated with alemtuzumab administration.

Aim: To estimate the incidence of postural orthostatic tachycardia syndrome (POTS) in the population of Zagreb, Croatia, and to determine the patients' demographic and clinical characteristics. ----- Methods: From 2012-2017, we identified patients with POTS by a retrospective analysis of medical records at University Hospital Center Zagreb. Crude incidence rates were directly standardized by age according to the European and World Standard Population. ----- Results: Out of 385 patients with suspected POTS, 23 had a definitive POTS diagnosis. The annual incidence ranged from 3.3 to 14.8 per 1000000 for both sexes combined. The highest incidence rates were in the age groups 18-29 and 30-39 years, with female predominance. The mean age at diagnosis was 30.7 years (standard deviation ±9.2, range 18-52). The median duration of symptoms at diagnosis was 7.5 months (range 3-180 months). Regarding associated comorbidities, two patients had chronic gastritis and one patient had each of the following: epilepsy, prior subarachnoid hemorrhage, anxiety, mitral insufficiency, obstructive sleep apnea, hypothyreosis, and irritable bowel syndrome. In patients not fulfilling the criteria for POTS, the most common alternative diagnoses were autonomic dysfunction due to multiple sclerosis in 22, anxiety disorder in 17, epilepsy in 16, and orthostatic tachycardia due to deconditioning in 13 patients. ----- Conclusion: The data obtained in this study can be used to optimize disease surveillance in population, comprehensive assessment of disease burden, and organization of health care services.

The aim of this study was to evaluate clinical and neurophysiological characteristics of Persistent postural-perceptual dizziness (PPPD) in a tertiary vertigo clinic. This was a cross-sectional study that included consecutive patients examined in the Vertigo clinic of the University Hospital Center Zagreb, Croatia. The following data were extracted from the electronic hospital records: age, sex, the duration of symptoms, initial trigger event, results of the caloric testing, video head impulse test (vHIT) for all six semicircular canals and ocular and cervical vestibular evoked myogenic potentials (oVEMP and cVEMP). During the study period 147 consecutive patients with dizziness were examined and 28 (19%) were diagnosed with PPPD, 68% of them were women and the mean age was 59.5 ± 15 years. The median duration of symptoms was 23 months. The most common initial event was vestibular neuritis in 39.3% of patients, followed by benign paroxysmal positional vertigo in 10.7% of patients. Caloric testing was performed in 25 patients. It revealed six cases of unilateral canal paresis. vHIT was performed in 24 patients. There were 13 pathological responses with three cases of lateral canal dysfunction, two cases of posterior, one case of anterior and seven cases of multiple canals affection. VEMP was performed in 23 patients. There were five isolated oVEMP pathologies, one isolated cVEMP pathology and 11 findings of a combined oVEMP and cVEMP pathology. This study provides clinical and neurophysiological data on PPPD and indicates the utility of complete neurophysiological assessment of vestibular function in this group of patients.

Objectives: To investigate a possible association between autonomic dysfunction and fatigue in people with multiple sclerosis. ----- Methods: In 70 people with multiple sclerosis early in the disease course (51 females, mean age 33.8 ± 9.1), quantitative sudomotor axon reflex tests, cardiovascular reflex tests (heart rate and blood pressure responses to the Valsalva maneuver and heart rate response to deep breathing), and the tilt table test were performed. Participants completed the Composite Autonomic Symptom Score 31, the Modified Fatigue Impact Scale, and the Epworth Sleepiness Scale, as well as the Beck Depression Inventory. Cutoff scores of ≥ 38 or ≥ 45 on the Modified Fatigue Impact Scale were used to stratify patients into a fatigued subgroup (N = 17 or N = 9, respectively). ----- Results: We found clear associations between fatigue and scores in subjective tests of the autonomic nervous system: fatigued patients scored significantly worse on Composite Autonomic Symptom Score 31, and there was a strong correlation between the Modified Fatigue Impact Scale and the Composite Autonomic Symptom Score 31 (rs = 0.607, p < 0.001). On the other hand, we found only modest associations between fatigue and scores in objective tests of the autonomic nervous system: there was a clear trend for lower sweating outputs at all measured sites, which reached statistical significance for the distal leg and foot. We found weak correlations between the Modified Fatigue Impact Scale and the Valsalva ratio (rs = - 0.306, p = 0.011), as well as between the Modified Fatigue Impact Scale and quantitative sudomotor axon reflex tests of the forearm, proximal, and distal lower leg (rs = - 0.379, p = 0.003; rs = - 0.356, p = 0.005; and rs = - 0.345, p = 0.006, respectively). A multiple regression model showed that the Composite Autonomic Symptom Score 31, Beck Depression Inventory, and Epworth Sleepiness Scale were independent predictors of fatigue (p = 0.005, p = 0.019, and p = 0.010, respectively). ----- Conclusion: These results suggest that-even early in the course of the disease-people with multiple sclerosis suffer from objective and subjective impairments of the autonomic nervous system. The results also point to an association between autonomic nervous system impairment and multiple sclerosis related fatigue.

The aim of this study was to investigate the performance of the Composite Autonomic System Score-31 (COMPASS-31) questionnaire in a real- life setting in consecutive patients referred to the laboratory for objective testing of the autonomic nervous system (ANS), with the hypothesis that COMPASS-31 results differ depending on medications and findings of the tilt table test results. One hundred seventy- one consecutive patients (125 females, mean age 41.5 ± 19.3) referred for testing of the ANS were enrolled. Before testing, all patients completed the recently validated Croatian version of COMPASS-31. The following data were systematically collected for all patients: age, sex, diagnoses, and medications. Results of COMPASS-31 were significantly higher in patients taking medications with a known influence on the ANS (p < 0.001). Patients with postural orthostatic tachycardia had significantly higher orthostatic intolerance and vasomotor domains of COMPASS-31 (p = 0.048 and p = 0.022, respectively). Patients with a cardiovagal score ≥ 1 had a significantly higher vasomotor domain of COMPASS-31 compared to patients with normal results of ANS tests (p = 0.030). These findings suggest the COMPASS-31 might be a valuable screening tool for autonomic dysfunctions, as it is associated with impaired ANS tests, but usage of medications that modify the ANS should always be taken into account.

OBJECTIVE: To determine autonomic dysfunction (AD) differences in patients with relapsing remitting multiple sclerosis (pwRRMS) and progressive MS (pwPMS). ----- METHODS: Composite autonomic scoring scale (CASS) and heart rate variability (HRV) were performed in 40 pwRRMS and 30 pwPMS. ----- RESULTS: pwPMS had a significantly higher sudomotor index and total CASS score compared to pwRRMS (p

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.

AIM: To validate and cross-culturally adapt Croatian and Serbian versions of composite autonomic symptom score-31 (COMPASS-31) for the detection of dysautonomia in patients with multiple sclerosis (MS). ----- METHODS: A total of 179 patients, 67 with clinically isolated syndrome (CIS) and 112 with MS, completed the COMPASS-31 at two MS centers in Zagreb and Belgrade between April 1 and October 31, 2016. Demographic and clinical data including age, gender, MS phenotypes, and the Expanded Disability Status Scale (EDSS) score were collected. ----- RESULTS: The Cronbach's alpha coefficient of COMPASS-31 total score was 0.844 for the Croatian MS sample and 0.779 for the Serbian MS sample. A joint analysis yielded Cronbach's alpha coefficients ranging from 0.394 to 0.796, with values in four domains higher than 0.700. In Croatian and Serbian samples and the total study sample, the Cronbach's alpha coefficient of COMPASS-31 was 0.785. Reproducibility measured by intra-class correlation coefficient (ICC) was acceptable (ICC=0.795). With regard to the clinical validity, significant correlation was found between EDSS and the COMPASS-31 total score (P0, which implies the existence of at least one of the symptoms investigated in each domain, were detected for secretomotor and bladder domains (P=0.015 and PP

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.

BACKGROUND AND PURPOSE: The aim of this study was to determine the effect of food intake on the heart rate (HR) in postural orthostatic tachycardia syndrome (POTS). ----- METHODS: The following five-phase protocol was applied to 41 subjects who had a sustained HR increment of ≥30 beats/min within 10 min of standing in an initial tilt-table test: 1) 10-min supine phase, 2) 10-min 70°-tilted phase, 3) ingestion of 400 mL of Nutridrink Multi Fibre®, 4) 45-min supine phase, and 5) 10-min 70°-tilted phase. Subjects were divided into four groups: A) difference in HR for standing vs. supine (ΔHR) before the meal of ≥30 beats/min (n=13), B) ΔHR

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.