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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.

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.

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.

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 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: 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.

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.

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.

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 has shown that patients with COMPASS-31 > 7.32 have statistically significant lower probability that they will be relapse free (p = 0.013). It has also shown that the relative risk reduction for occurrence of new relapse in participants with COMPASS 7.32 and total number of T2 lesions >3 increase the likelihood and the increasing supine level of epinephrine reduces the likelihood of 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 Conclusion This study provides evidence that ANS is an important contributor to development of disease activity in pwCIS.

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

U dijagnostici akutnoga vestibularnog sindroma (AVS) nužno je brzo i pouzdano razlikovanje između perifernih i centralnih uzroka. Novost u dijagnostici AVS-a jest metoda video head impulse testa (vHIT), koja se temelji na testiranju rotacijskog vestibulo-okularnog refleksa. vHIT je pokazao visoku specifičnost za periferno vestibularno oštećenje, ali i nešto nižu osjetljivost u usporedbi s kalorijskim testiranjem, što mu je glavna mana. Dosadašnja istraživanja pokazala su višestruku primjenjivost ove metode s naglaskom na potencijalnoj primjeni u hitnoj službi. Zbog svoje brzine i jednostavnosti primjene ova metoda naziva se i „očni EKG“. Ipak, metoda vHIT nije zamjena za dosadašnje metode testiranja vestibularnog sustava, već njihova nadopuna. U sklopu protokola HINTS (engl. Head impulse, Nystagmus, Test of Skew) pokazala je višu osjetljivost i specifičnost od difuzijskih sekvencija MR-a mozga pri detekciji moždanog udara s izoliranom vrtoglavicom. Primjena vHIT-a u hitnoj ambulanti i dalje je premalena u odnosu prema potencijalnoj dobiti koju ona donosi., In the diagnosis of acute vestibular syndrome (AVS) the key part is a quick and reliable differentiation between peripheral and central etiologies. Video head impulse test (vHIT) is a new method that is based on the examination of rotational vestibulo-ocular reflex. vHIT has demonstrated high specificity for peripheral vestibular damage. Several studies have shown a broad applicability for vHIT, with an emphasis on potential use in the emergency department. It has been called “eye ECG” due to the speed and simplicity of this method use in AVS. However, vHIT is not a replacement for other methods in vestibular testing battery, rather their supplement. As a part of the HINTS (Head impulse, Nystagmus, Test of Skew) protocol it has shown higher sensitivity and specificity than diffusion weighted brain MRI in the detection of stroke with isolated vertigo. It is still under-utilized in the emergency department compared to the potential benefits it carries

Objectives The aim of this study was to investigate the role of the video head impulse test (vHIT) in the detection of brainstem lesions in patients with multiple sclerosis (MS). Methods One hundred thirty participants were enrolled: 66 healthy subjects (HC) (132 ears, 38 females, mean age 45.8 ± 13.7) and 64 MS patients (128 ears, 45 females, mean age 36.8 ± 9.1). The impulses of the head were delivered in 3 planes: lateral, right anterior-left posterior (RALP) and left anterior-right posterior (LARP) with a minimum of 5 head impulses in each plane and direction. vHIT pathology was defined if lateral gain or posterior/anterior slope was lower than 0.7. Results In HC there was no pathology on lateral and posterior canals, while 16 (12.5%) and 6 (4.7%) out of 128 ears had pathological results on lateral and posterior canals, respectively, in the MS group ( p p = 0.008, respectively). Posterior canal pathology was associated with higher EDSS ( p = 0.007). Mean gain of the lateral (0.900 ± 0.206 vs. 0.964 ± 0.167, p = 0.007, respectively) and slope of anterior canals (1.223 ± 0.248 vs. 1.338 ± 0.348, p = 0.005, respectively) was significantly reduced in MS group compared to HC. MS patients with clinically evident brainstem dysfunction had significantly higher percentage of pathologies of posterior canals p = 0.017. MS patients with brainstem lesions (specifically midbrain and pontine lesions) had significantly higher percentage of pathologies of posterior canals p = 0.039 ( p = 0,028 and p = 0.007, respectively). Discussion Current research has already shown the capability of vHIT to differentiate peripheral causes of vertigo from their central counterparts. However, several publications have shown that central causes of vertigo, especially brainstem stroke can influence vHIT results. Conclusion Our results indicate that vHIT can detect brainstem dysfunction in patients with MS. Significance vHIT can be impaired when central part of the vestibular system is damaged.