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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.

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.

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.

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.

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.

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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.

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.

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.

BACKGROUND AND PURPOSE: As a high proportion of people with clinically isolated syndrome (pwCIS) exhibit sympathetic adrenergic and sudomotor dysfunction, the aim of this study was to investigate the evolution of autonomic nervous system (ANS) abnormalities in pwCIS over a 2-year follow-up. METHODS: This was a prospective cohort study in which 121 pwCIS were enrolled and followed for 2 years. After 2-year follow-up, data were available for 84 pwCIS. ANS symptoms were evaluated with the Composite Autonomic System Score-31 (COMPASS-31) and results of the ANS tests were expressed using the Composite Autonomic Scoring Scale (CASS) at baseline and visit at month 24. Symptomatic dysautonomia was defined if the patient had a COMPASS-31 value above the median of the whole cohort at baseline evaluation (COMPASS- 31 > 6.79) and CASS score >0. RESULTS: Complete CASS data at baseline and month 24 were available for 62 patients ; in 24 (38.7%) patients there was worsening, in 16 (25.8%) there was improvement and in 22 (35.5%) there was no change in CASS score. In 90% of pwCIS (72 of 80) there was no change in parasympathetic nervous system tests, whereas 47.3% (35 of 74) had either worsening or improvement in sympathetic adrenergic and 28.6% (20 of 70) had either worsening or improvement in sudomotor function. A multivariable regression model identified the total number of T2 lesions as an independent predictor for worsening of symptomatic dysautonomia. No predictors for worsening or improving of CASS score were identified. CONCLUSION: A substantial proportion of pwCIS experienced worsening of ANS abnormalities during the 2- year follow-up and magnetic resonance imaging parameters seemed to predict these abnormalities.

Objectives To investigate differences in hemodynamic profile between hyperadrenergic and non-hyperadrenergic postural orthostatic tachycardia syndrome (POTS) in response to head-up tilt test (HUTT). Methods Ten patients with hyperadrenergic and 33 patients with non-hyperadrenergic POTS underwent HUTT consisting of a 10-min supine phase and 30-min 70° tilted phase. Heart rate (HR), systolic and diastolic blood pressure (dBP), and heart rate variability (HRV) parameters of the two groups were compared. Results Hyperadrenergic patients had higher supine HR (82.6 ± 16.3 bpm vs. 73.8 ± 10.4 bpm, p=0.048). Supine HRV analysis showed significantly lower cardiac vagal activity and possible predominance of cardiac sympathetic activity in the hyperadrenergic group. Non-hyperadrenergic patients had lower dBP during the first four minutes of tilt. Furthermore, 60% of non-hyperadrenergic patients had lower average dBP in the 1st minute of tilted phase when compared to supine values, whereas only 2 of 10 hyperadrenergic patients exhibited the same response. Syncope or intolerable symptoms, causing early ending of HUTT, developed earlier in the non-hyperadrenergic group (8.9 ± 6.8 min vs. 21.2 ± 3.5 min, p=0.001). Conclusion Hyperadrenergic and non-hyperadrenergic type of POTS seem to have distinctly different response to HUTT. Significance This study has shown significant differences in hemodynamic response to HUTT between hyperadrenergic and non-hyperadrenergic type of POTS indicating possible differences in their pathophysiology.

OBJECTIVES: The aim of this study was to determine the extent of autonomic dysfunction in patients with clinically isolated syndrome (CIS) by using a standardized battery of autonomic tests in the form of the Composite Autonomic Scoring Scale (CASS). ----- METHODS: This was a prospective, cross sectional study which included 24 consecutive patients who were diagnosed with CIS and 17 healthy controls. In all participants, heart rate and blood pressure responses to the Valsalva maneuver, heart rate response to deep breathing and blood pressure response to passive tilt were performed. In 16 patients, Quantitative Sudomotor Axon Reflex Test (QSART) and catecholamine measurement was performed. ----- RESULTS: The proportion of CIS patients with pathological adrenergic index was statistically significantly higher compared to healthy controls (12 vs 2, p=0.018), while there was no difference in cardiovagal index between groups. Five patients had a sudomotor index of 1 (in 4 there was hypohydrosis

Objective To investigate the correlation of the vestibular evoked myogenic potential (VEMP) score with Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Paced Auditory Serial Addition Test (PASAT) and EDSS in patients with multiple sclerosis (MS). Methods This prospective, cross sectional study included 52 patients with clinically isolated syndrome (CIS). Cervical VEMP (cVEMP) and ocular VEMP (oVEMP), analyzed in the form of the cVEMP, oVEMP and VEMP scores, T25FW, 9HPT, PASAT and Expanded Disability Status Scale (EDSS) were performed. Results The only predictor of walking impairment in this study was general disability as measured by the EDSS, after controlling for age, gender, PASAT and EDSS the effect of VEMP score was non-significant (p = 0.419). 9HPT of the dominant hand did not correlate with the oVEMP score (rs = 0.258, p = 0.065), however after controlling for age, gender, PASAT and EDSS, the effect of the oVEMP score on 9HPT of the dominant hand was statistically significant (p = 0.017). After controlling for age, gender and oVEMP score, the effect of the PASAT on 9HPT variable for the non-dominant hand was statistically significant (p = 0.001). Conclusion We found possible effects of brainstem dysfunction on walking impairment, however they were not seen after correction for EDSS and cognitive dysfunction. On the other hand, dominant hand function seems to be influenced by upper brainstem dysfunction measured with oVEMP, while cognitive dysfunction is related to non-dominant hand function.

Ocrelizumab is an anti-CD20 monoclonal antibody used in the treatment of relapsing remitting and primary progressive multiple sclerosis. The main side effects are infusion-related with long term administration raising the risk of infections. During randomized controlled trials five cases of pancreatitis have been reported. We present a case of a patient with no risk factors for pancreatitis who after administration developed acute pancreatitis albeit with a good recovery.

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.

POTS (Postural Orthostatic Tachycardia Syndrome) is a condition caused by cerebral hypoperfusion which results in general weakness, dizziness, lightheadedness, fatigue upon standing and visual blurring or fogging of the visual fields. Syncope occurs in 40% of patients. Other predominantly orthostatic symptoms include palpitations, tremulousness and anxiety. Gastrointestinal symptoms, such as nausea, cramps, bloating, constipation, diarrhea and acrocyanosis, as well as edema due to low venous pooling, can also appear in some cases. This syndrome was first described in 1871 by physician Jacob Mendes Da Costa. Hallmark of this disorder is an exaggerated heart rate increase in response to postural change. A 29-year-old female patient was admitted to our hospital in December 2011 due to pharmacoresistant epilepsy from the age of 9. Clinically, according to the 2017 ILAE (International League Against Epilepsy) operational classification of seizure types, her seizures initially clinically presented as focal motor onset seizures to bilateral tonic-clonic seizures (central lobe seizures, prior referred as Jacksonian seizures of the left side of the body). Several years later, seizures of different origin also appeared and presented as focal impaired awareness seizures of motor onset with gestural automatisms and motor dysphasia, followed by sense of fear and panic attacks, with short-term postictal confusion, corresponding to left temporal lobe seizures. Brain MRI (Magnetic resonance imaging) showed bilateral frontoparietal polymicrogyria and right subependymal nodular grey matter heterotopia. At the age of 27, she also noticed palpitations and dizziness in standing upright that were relieved by sitting or lying flat. Due to complex malformation of cortical development patient was not considered as a candidate for resective neurosurgery. We decided to perform minimal invasive neurosurgical treatment implantation of vagal nerve stimulator (VNS). During the preoperative work-up head-up tilt test (HUTT) was performed that revealed POTS refractory to lifestyle modification measures. Cardiovascular ultrasound and holter-ECG were normal. One week after implantation, VNS was initiated at 0.25 mA (duty cycle set to 30-Hz signal frequency, 500-ms pulse width, 30 s ON-time and 3 min OFF-time). HUTT done at one month and three months after implantation was normal. VNS was gradually increased to 1 mA, which led to significant reduction in seizure rate and disappear- ance of orthostatic intolerance symptoms. POTS is defined by a heart rate increment of 30 beats/min or more within 10 min of standing on HUTT, in the absence of orthostatic hypotension. As a form of orthostatic intolerance, it particularly occurs in younger adults and children in response to postural stressors, with a female to male ratio of 4–5:1. The reason for this is not known, however, observed gender differences in muscle sympathetic nerve discharge characteristics in healthy patients may explain why women are more likely to develop POTS. The orthostatic nature of the symptoms is the primary clue to diagnosis. Pathophysiologically, POTS may involve sympathetic denervation in the lower limbs, a hyperadrenergic state and/or abnormalities in the noradrenaline transporter. VNSis a safe and effective adjunctive treatment fordrug-resistant epilepsy when surgery is inadvisable. In VNS therapy, the left vagal nerve is stimulated at the level of the neck by an electrode connected to a subcutaneous device. The left nerve is chosen to minimize the effect on heart rhythm, because most of the cardiovagal fibers course through the right vagal nerve. Efferent fibers of the vagal nerve originate from two separate nuclei in the brainstem, the dorsal motor nucleus and the nucleus ambiguus. They supply parasympathetic fibers to all internal organs except the suprarenal glands. Afferent fibers originate in the end organs and project to the nucleus tractus solitarius, from where axons project throughout the brain. These afferent axons and synapses are thought to be responsible for the therapeutic effect of VNS, since it reduces sympathetic nervous system and increases parasympathetic nervous system activity [3]. Increasing parasympathetic input to the heart via VNS is thought to be cardioprotective. Limited data suggest that long-term VNS therapy improves cardiac autonomic control and significantly attenuates heart failure (HF) development in the canine high-rate ventricular pacing model. VNS is a novel and potentially useful therapy for treating HF. Therapeutic effects of POTS are further being explored, currently there is ongoing clinical trial addressing the effects of transdermal vagal nerve stimulation and POTS. Optimal therapy of POTS remains uncertain. No intervention has been systematically studied. To our knowledge, this is the first reported case of the positive effect of VNS in a patient with POTS and epilepsy. Further studies with a larger number of patients are needed.

Aim: The aim of this study was to investigate the association of autonomic nervous system abnormalities on head-up tilt table test (HUTT) with generalized joint hypermobility, expressed by Beighton score (BS). Methods: This was a prospective study that included 115 consecutive patients (91 females; mean age 34.35 ± 14.11) referred either for the HUTT or testing of the cardiovascular autonomic reflexes together with HUTT. Generalized joint hypermobility was evaluated according to the BS system after which HUTT was performed. Clinically significant BS was considered if ≥4. Results: Fifteen patients (15.1%) had BS ≥4. Results of the HUTT were normal in 58 (50.4%) patients and in 57 (49.6%) patient HUTT was abnormal. Fifteen (13.0%) patients fulfilled criteria for orthostatic hypotension, 30 (26.1%) for reflex syncope and 21 (18.3%) for postural orthostatic tachycardia syndrome. Patients with pathological findings on HUTT had significantly higher BS compared to patients with normal HUTT (median 1 vs. 0, p = 0.001). There was a significant association between participants with BS ≥4 and pathological HUTT (χ[1] = 6.392, p = 0.011). Results of the multivariate regression analysis revealed that increase in the BS is associated with the increased likelihood of HUTT pathology (Exp[B] 1.44, 95% CI 1.084–1.922, p = 0.012), while increase in age is associated with lower risk of HUTT pathology (Exp[B] 0.968, 95% CI 0.939–0.998, p = 0.036). Conclusion: There is an association between autonomic nervous system abnormalities on HUTT test and generalized joint hypermobility.

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.

Background The aim of this study was to compare the results of the Composite Autonomic System Score 31 (COMPASS-31) questionnaire depending on the results of the head-up tilt-table test (HUTT). Methods We enrolled 575 consecutive patients referred for HUTT. Each participant completed the Croatian version of COMPASS-31 for a subjective evaluation of the autonomic symptoms and underwent HUTT. Patients with normal HUTT, but abnormal cardiovascular reflexes were excluded from the analysis (N = 210). Patients were then divided into 4 groups: normal HUTT (N = 197), vasovagal syncope (N = 84), postural orthostatic tachycardia syndrome (POTS) (N = 27) and orthostatic hypotension (OH) (N = 57). Results of COMPASS-31 were then compared between all four groups. Results Patients with normal HUTT had significantly higher results on COMPASS-31 compared to patients with syncope in vasomotor, secretomotor, gastrointestinal and bladder domains (0.512 vs 0.268, p = 0.025; 2.600 vs 1.633, p = 0.010; 4.573 vs 3.699, p = 0.024; and 1.105 vs 0.569, p = 0.001; respectively). In contrary, patients with normal HUTT had significantly lower results on COMPASS-31 compared to patients with POTS in orthostatic intolerance domain (14.010 vs 18.815, p = 0.028) and patients with OH in orthostatic intolerance, gastrointestinal, bladder and total COMPASS-31 score (14.010 vs 17.684, p = 0.016; 4.573 vs 5.780, p = 0.028; 1.105 vs 2.164, p Conclusion COMPASS-31 exhibits different results depending on the various types of ANS dysfunction and may serve as a screening tool for various disorders that affect ANS.

PURPOSE: The aim of this study was to investigate a relationship between sensory dysfunction examined with somatosensory-evoked potentials of the posterior tibial nerve (tSSEP) and walking speed in patients with clinically isolated syndrome. METHODS: In 120 patients (mean age 32.2 ± 8.7 years, 84 females), Expanded Disability Status Scale (EDSS), timed 25-foot walk test (T25FW), brain and spinal cord MRI, and tSSEP were performed. P40 latencies and N22a-P40 interlatencies were analyzed, and the z-score for each latency was calculated and combined into total tSSEP z-score. RESULTS: T25FW significantly correlated with total tSSEP z-score (rs = 0.211 ; P = 0.021). When looking at each component of the tSSEP separately, T25FW significantly correlated with z-scores of P40 wave latencies (rs = 0.223 ; P = 0.014) and N22a- P40 interlatencies (rs = 0.241 ; P = 0.008) of the left side. There were no significant correlations with N22a wave latencies. Patients who presented with transverse myelitis (N = 41) and patients who had spinal cord lesions on MRI (N = 53) had significantly higher total tSSEP z-score compared with other patients (0.07 vs. -0.28, P = 0.019 and -0.02 vs. -0.38 P = 0.023 ; respectively). Somatosensory-evoked potentials of the posterior tibial nerve z-score corrected for age, sex, cervical spinal cord MRI lesions, and total number of supratentorial T2 lesions was a statistically significant predictor for T25FW (B = 0.267, P = 0.023). CONCLUSIONS: Spinal somatosensory dysfunction is one of the factors associated with reduction in walking speed in early patients with multiple sclerosis. Somatosensory-evoked potentials of the posterior tibial nerve may potentially be useful in identifying patients at higher risk for the development of walking impairment in the future

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 in lateral (p

Background/Aims: There have been suggestions that interactions exist between the autonomic nervous system (ANS) and the immune system functions in multiple sclerosis (MS). We aimed to evaluate the ANS dysfunction, more specifically postural orthostatic tachycardia syndrome (POTS), as a possible predictor of conversion to MS in patients with clinically isolated syndrome (CIS). Methods: In this observational, prospective, longitudinal study, 84 patients were enrolled (56 females, mean age 32.9 ± 8.9 years). Disease activity during a 6-month period was monitored (relapses and/or MRI disease activity indicated by new T2 or T1 enhancing lesions), and the following predictors analyzed: age, Expanded Disability Status Scale, MRI midbrain, pontine or medulla oblongata lesions, and POTS on the head up tilt test. Results: POTS was identified in 8 (9.5%) patients. Of 84 patients, 62 (73.8%) completed the 6-month follow-up, and 28 (45.2%) patients converted to MS. Results of the multivariate regression analysis revealed age (10-year increase) and POTS as significant predictors of early conversion to MS (OR 2.34, 95% CI 1.15-4.78, p = 0.019 and OR 12.40, 95% CI 1.13-136.62, p = 0.040). The logistic model was statistically significant, χ2 (6) = 13.885, p = 0.031. Conclusion: POTS may be an indicator of a more active disease course in CIS patients and possibly be used as a prognostic factor.

Background To validate the VEMP score as a measure of brainstem dysfunction in patients with the first symptom of multiple sclerosis (MS) (clinically isolated syndrome (CIS)) and to investigate the correlation between VEMP and brainstem MRI results. Methods 121 consecutive CIS patients were enrolled and brainstem functional system score (BSFS) was determined. Ocular VEMP (oVEMP) and cervical VEMP (cVEMP) were analyzed for latencies, conduction block and amplitude asymmetry ratio and the VEMP score was calculated. MRI was analyzed for the presence of brainstem lesions as a whole and separately for the presence of pontine, midbrain and medulla oblongata lesions. Results Patients with signs of brainstem involvement during the neurological examination (with BSFS ≥ 1) had a higher oVEMP score compared to patients with no signs of brainstem involvement. A binary logistic regression model showed that patients with brainstem lesion on the MRI are 6.780 times more likely to have BSFS ≥ 1 (p = 0.001); and also, a higher VEMP score is associated with BSFS ≥ 1 (p = 0.042). Furthermore, significant correlations were found between clinical brainstem involvement and brainstem and pontine MRI lesions, and prolonged latencies and/or absent VEMP responses. Conclusions The VEMP score is a valuable tool in evaluation of brainstem involvement in patients with early MS.

The aim of this study was to compare vestibular evoked myogenic potentials (VEMP) and video head impulse test (vHIT) results in patients presenting with vertigo and dizziness. We retrospectively analyzed data of all patients with the chief complaint of vertigo, dizziness, or imbalance that underwent VEMP and vHIT from January 2015 to January 2016. A total of 117 patients (73 females, mean age 53.92±16.76) fulfilled inclusion criteria: group 1 included patients with the final diagnosis of vestibular neuritis (VN) (N=31 (16 right and 15 left VN)), group 2 included patients with the final diagnosis of vertigo of central origin (N=23) and group 3 included patients with the final diagnosis of unspecified dizziness (N=63). There was significant correlation between oVEMP asymmetry and asymmetry of the lateral canals 60ms gains on vHIT (r=0.225, p=0.026). Significant correlation between oVEMP and vHIT asymmetry was present in VN patients (r=0.749, p

Different neurophysiological methods such as evoked potentials (EP), testing of the autonomic nervous system (ANS) or polysomnography have the potential to detect clinically silent lesions or to confirm the existence of an association between a clinical symptom and multiple sclerosis (MS); previously undetected by MRI. Therefore, in the most recent MRI criteria for the diagnosis of MS (MAGNIMS consensus guidelines), neurophysiological confirmation of optic nerve dysfunction (slowed conduction on visual EP), support dissemination in space and, in patients without concurrent visual symptoms, dissemination in time. In this chapter we will review the existing evidence regarding the role of different neurophysiological tests (specifically the role of EPs, autonomic nervous system testing and sleep testing in MS) in the diagnosis and management of MS.

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab.

Aims of the present study were: (1) to assess the incidence of vestibular neuritis (VN) in the adult population in two cities in Croatia, (2) to identify distribution of new VN cases in the different months and seasons by years, and (3) to identify comorbidities associated with VN. This is a prospective, population-based study conducted in the cities of Zagreb and Velika Gorica, Croatia in the 2011-2012 period. All diagnoses were confirmed either with caloric test or vestibular evoked myogenic potentials within 7 days of symptom onset. Following clinical parameters were collected from all patients: age, gender, side of the lesion, month and season of symptoms onset and comorbidities. We identified 79 new cases of VN (34 in 2011, 45 in 2012). The male to female ratio was 1.1:1. The mean age at the onset of the disease was 52.3 (range 20-86) years. The average annual incidence was 11.7 per 100, 000 (95 % CI 7.8-15.6) in the 2011 period and 15.5 per 100, 000 (95 % CI 11.0-20.0) in the 2012 period. For both years there was no statistically significant uneven distribution in the different months or seasons by years. The most frequent comorbidities present in VN patients were hypertension (30.4 %), diabetes mellitus (8.9 %), hyperlipidemia (7.5 %) and hypothyreosis (6.3 %). Our study has shown higher incidence of VN than previously reported. We have found no evidence of seasonality of VN and significant proportion of VN patients older than 50 years who had vascular risk factors present.

Background/Aims:The aim of the present study was to determine the optimum method to detect brainstem lesions in patients with Multiple Sclerosis (MS).Methods:72 patients with the diagnosis of relapsing-remitting MS were prospectively included. Brainstem functional system score (BSFS) (part of the expanded disability status scale (EDSS) evaluating brainstem symptomatology) was calculated. Magnetic resonance imaging (MRI) was performed on 1.5T and T1, T2, PD and fluid-attenuated inversion recovery (FLAIR) sequences were analyzed for presence of brainstem lesions. Auditory evoked potentials (AEP) and ocular and cervical vestibular evoked myogenic potentials (oVEMP and cVEMP) were performed according to the standardized protocol.Results:From 72 patients, 18 (25%) had clinical involvement of the brainstem. MRI showed brainstem involvement in 29 (40%) patients. Of the neurophysiological tests, AEP showed pathological result in 16 (22%) patients, oVEMP in 36 (50%) patients, cVEMP in 18 (25%) patients, and VEMP (combination of oVEMP and cVEMP) in 45 (63%) patients. VEMP detected brainstem lesions in higher percentage than clinical examination, MRI and AEP, which was statistically significant (< 0.0001, 0.012 and < 0.0001, respectively).Conclusions:Results of the present study have shown that VEMPs are the optimal method to detect brainstem lesions in multiple sclerosis and that they detect them significantly better than clinical examination, AEP or MRI.

Objective To investigate the optimal timing for blood sample collection of catecholamines and the possible correlations between neurohumoral and hemodynamic responses to prolonged head-up tilt (HUT) in postural orthostatic tachycardia syndrome (POTS). Methods Nineteen patients underwent a 30-minute, 70° HUT test. Blood samples (norepinephrine (NE), epinephrine and dopamine) were taken in the 10th minute of supine, and 10th, 20th and 30th minutes of HUT. Results There were no significant differences in the proportion of high and normal standing NE patients in the different time points. Mean NE (nmol/L) values in 10th, 20th and 30th minute of HUT were 4.37, 4.87, and 4.35 in the high standing NE, and 2.49, 2.59 and 2.88 in the normal standing NE group. High standing NE patients had higher blood pressure (BP) during the first 6 min of HUT (2nd minute after the HUT systolic BP (sBP): 118.29 ± 15.65 vs. 95.70 ± 13.43, p = 0.004; diastolic BP (dBP): 78.71 ± 6.68 vs. 65.10 ± 9.04, p = 0.003), while normal standing NE patients exhibited a drop in BP compared to resting values during the same time period. The normal standing NE group exhibited a progressive increase in norepinephrine values during the HUT. Conclusion One blood sample taken at the 10th minute of HUT correctly identifies high and normal standing NE POTS patients, but a small number of patients (1 out of 19, 5.2%) can be misidentified. High and normal standing NE POTS patients display distinctly different neurohumoral and hemodynamic responses to HUT.

A 33-year-old man, previously healthy, presented with a feeling of his right eyeball fluttering and oscillopsia lasting days. He had no headache, vertigo or gait problems. On neurological examination, there was a clockwise torsional nystagmus of the right eye with no nystagmus of the left eye (Figures 1,2; online supplementary videos 1 and 2). There was no other eye movement or other cranial nerve abnormalities, and remaining neurological examination was normal. …