Autonomic nervous system education in Europe: EAN/EFAS/INUS survey on curricula and skills in autonomic medicine of European neurology residents and consultants.

BACKGROUND AND PURPOSE: Centers for training in autonomic nervous system (ANS) disorders are not widely available and the recent coronavirus 2019 pandemic temporarily reduced training opportunities in autonomic medicine across European countries. Here we evaluated the current state of education, clinical skills and postgraduate educational preferences on ANS disorders of European neurology residents and consultants. METHODS: A 23-item questionnaire was developed and distributed online amongst European neurology residents and consultants via mailing lists of the European Academy of Neurology. The questions assessed demographics, current training opportunities and learning preferences in ANS disorders. Six multiple-choice questions were used to self-evaluate knowledge of ANS disorders. RESULTS: In all, 285 individuals answered the survey (60% female, mostly 25-34 years of age). All respondents considered clinical autonomic skills necessary for good clinical neurological practice, and 92% would like to increase their ANS knowledge. Female respondents and those who trained in Southern/Eastern/Greater Europe more frequently judged ANS skills important for clinical practice than male respondents (p = 0.012) and respondents from Northern/Western Europe (p = 0.011). Female and younger respondents felt less confident in managing ANS disorders (p = 0.001 and p < 0.001, respectively). Respondents below 45 years of age (p < 0.001) and those with lower confidence in managing ANS disorders (p = 0.004) were more likely to recommend that ANS education is embedded in the residency curriculum. CONCLUSIONS: Most European neurology residents and consultants reported a need for more autonomic education, with additional gender, age and regional differences. These findings underscore the importance of increasing the educational content on autonomic medicine in European medical and postgraduate curricula.

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

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

Alopecia associated with dimethyl fumarate treatment for multiple sclerosis.

After 2 weeks of treatment, a woman with multiple sclerosis treated with dimethyl fumarate developed alopecia. Considering the adverse events, the therapy was discontinued, leading to alopecia regression during the next 3 months. Although the precise mechanism has not been completely elucidated, glutathione depletion or downregulation of aerobic glycolysis are considered to be potential reasons for hair loss induction. The incidence and mechanism of this uncommon adverse reaction to dimethyl fumarate should be further investigated.

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

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

Sudomotor dysfunction in people with neuromyelitis optica spectrum disorders.

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

Miller Fisher syndrome following Pfizer COVID-19 vaccine.

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.

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

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

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

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

Peripheral nervous system in multiple sclerosis-understanding the involvement via autonomic nervous system.

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.

Effectiveness and safety of alemtuzumab in the treatment of active relapsing-remitting multiple sclerosis: a multicenter, observational study.

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.

The incidence of postural orthostatic tachycardia syndrome in the population of Zagreb, Croatia.

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.

Autonomic symptom burden is an independent contributor to multiple sclerosis related fatigue.

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.

Performance of the COMPASS-31 questionnaire with regard to autonomic nervous system testing results and medication use: a prospective study in a real-life setting.

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.

Association of Autonomic Nervous System Abnormalities on Head-Up Tilt Table Test with Joint Hypermobility.

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.

Postural Orthostatic Tachycardia Predicts Early Conversion to Multiple Sclerosis after Clinically Isolated Syndrome.

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.

Clinical Neurophysiology of Multiple Sclerosis.

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.

Validation and cross-cultural adaptation of the COMPASS-31 in Croatian and Serbian patients 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 (P<0.001). Furthermore, significant differences between MS phenotypes were detected for bladder and gastrointestinal domains and for the COMPASS-31 total score (PP<0.001, P=0.005, and P=0.027, respectively). Finally, significant differences between MS phenotypes in patients with score >0, 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<0.001, respectively). CONCLUSION: COMPASS-31 represents a valid and acceptable self-assessment instrument for the detection of dysautonomia in MS patients.

Sympathetic cardiovascular and sudomotor functions are frequently affected in early multiple sclerosis.

OBJECTIVE: The aim of this study was to determine the prevalence of autonomic dysfunction using the composite autonomic scoring scale (CASS) and heart rate variability (HRV) in patients with clinically isolated syndrome (CIS) and to correlate autonomic dysfunction with other measures of MS disease activity. METHODS: CASS, HRV and plasma catecholamines during supine and tilted phase were performed in 104 CIS patients. MRI findings were analyzed for total number of lesions and the presence of brainstem and cervical spinal cord lesions. RESULTS: Autonomic dysfunction (CASS >1) was present in 59.8 % of patients, parasympathetic dysfunction in 5 %, sympathetic in 42.6 % and sudomotor in 32.7 % of patients. Patients with autonomic dysfunction on CASS had lower level of norepinephrine in the supine position compared to patients without autonomic dysfunction (1.06 ± 0.53 vs. 1.37 ± 0.86, p = 0.048). The CASS score showed positive correlation with s-HF (r = 0.226, p = 0.031), s-SDNN (r = 0.221, p = 0.035), t-HF (r = 0.225, p = 0.032), and t-HFnu (r = 0.216, p = 0.04), and a negative correlation with t-LF/HF (r = -0.218, p = 0.038). More patients with MRI brainstem lesions had a positive adrenergic index (p = 0.038). Patients with MRI brainstem lesions also had a lower t-SDNN (26.2 ± 14.2 vs. 32 ± 13.3, p = 0.036) and a lower t-LF (median 415.0 vs. 575.5, p = 0.018) compared to patients without these lesions. Patients with adrenergic index ≥1 had a significantly higher standing heart rate compared to patients with an adrenergic index of 0 (96 ± 13.5 vs. 90 ± 12, p = 0.032). CONCLUSION: Autonomic (primarily sympathetic) dysfunction is present in a large proportion of early MS patients and it seems to be related to brainstem involvement.