Luka Crnošija

Autonomic dysfunction in clinically isolated syndrome suggestive of multiple sclerosis

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 <50% and in 1 persistent foot hyperhidrosis). When combining adrenergic, cardiovagal and sudomotor index into CASS, 8 patients (50%) had evidence of autonomic dysfunction, 7 mild and one moderate. CONCLUSION Sympathetic nervous system is frequently affected in CIS patients. SIGNIFICANCE CASS is able to detect autonomic nervous system dysfunction in CIS patients.

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.

Progressive multiple sclerosis patients have a higher burden of autonomic dysfunction compared to relapsing remitting phenotype

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 < 0.001 and p < 0.001, respectively). Disease duration positively correlated with sudomotor index and total CASS (rs = 0.409, p < 0.001 and rs = 0.472, p < 0.001, respectively), while the Expanded Disability Status Scale (EDSS) positively correlated with sudomotor index and total CASS (rs = 0.411, p < 0.001 and rs = 0.402, p = 0.001, respectively) in all patients. Type of multiple sclerosis (pwRRMS or pwPMS) corrected for age, sex and disease duration, was a statistically significant predictor of CASS value (B = 1.215, p = 0.019). Compared to pwRRMS, pwPMS had a significantly lower standard deviation of NN intervals (SDNN), low frequency (LF), and high frequency (HF), during both the supine and tilt-up phases (all p-values <0.006). pwPMS had a significantly lower LF/HF (p = 0.008) during tilt-up. CONCLUSION There is a significant difference in autonomic function in pwRRMS and pwPMS; with pwPMS having a higher burden of AD, which is particularly evident for sweating dysfunction. SIGNIFICANCE Further research is needed to establish whether parasympathetic and sudomotor dysfunction may serve as markers of progressive MS.

Vestibular evoked myogenic potentials and MRI in early multiple sclerosis: Validation of the VEMP score

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.

Differences in neurohumoral and hemodynamic response to prolonged head-up tilt between patients with high and normal standing norepinephrine forms of postural orthostatic tachycardia syndrome

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 6min 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.

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.

Vestibular evoked myogenic potentials and video head impulse test in patients with vertigo, dizziness and imbalance

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<0.001), while no correlation was found in the groups 2 and 3. oVEMP and vHIT lateral canals asymmetries were significantly greater in patients with vestibular neuritis. Furthermore, positive correlations of oVEMP amplitudes with 60ms gain of the lateral semicircular canal and slope of the anterior semicircular canal on vHIT, and cVEMP with slope of the posterior semicircular canal on the vHIT were found. These changes were significantly more pronounced in patients with vestibular neuritis. In conclusion, VEMPs and vHIT data should be used complementarily; asymmetry on both tests strongly supports peripheral vestibular system involvement.

Tongue somatosensory evoked potentials reflect midbrain involvement in patients with clinically isolated syndrome

Aim To test the hypothesis that tSSEP findings reflect clinical and MRI MS lesions, the aim of this study was to investigate tSSEP changes in patients with clinically isolated syndrome (CIS) in relation to clinical and brainstem MRI findings. The second aim was to investigate whether the interpretation of the tSSEP results in the form of the tSSEP score enables better evaluation of the afferent trigeminal pathway involvement than analyzing each tSSEP parameter separately. Methods 115 consecutive CIS patients were enrolled from August 1, 2014 until March 1, 2016. Facial sensory symptoms and brainstem MRI (1.5 T) lesions were analyzed. tSSEP testing was performed for each patient from the raw tSSEP data. The tSSEP score was calculated separately for the left and right side (according to the cut-off values for absent response and prolonged latency of the main component, P1 (0 = normal response, 1 = prolonged latency, 3 = absent response) and the two values were summed. Results There was no difference in the absolute values of the tSSEP variables regarding the presence of clinical symptoms. No association was found between tSSEP abnormalities and clinical symptoms (P = 0.544). Brainstem lesions (midbrain and pons) were associated with the absent tSSEP responses (P = 0.002 and P = 0.005, respectively). tSSEP score was significantly higher in patients with brainstem lesions (P = 0.01), especially midbrain (P = 0.004) and pontine (P = 0.008) lesions. Binary logistic regression showed that tSSEP score had a significant effect on the likelihood that patients have midbrain MR lesions, χ2(1) = 6.804, P = 0.009; and the model correctly classified 87% of cases. Conclusions The consistent finding of this study was the association between tSSEP and midbrain lesions on MRI, indicating that tSSEP evaluates proprioception of the face. This study establishes the value of tSSEP in assessing brainstem function in early multiple sclerosis.

Hemodynamic profile and heart rate variability in hyperadrenergic versus non-hyperadrenergic postural orthostatic tachycardia syndrome

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.

Correlation of the VEMP score, ambulation and upper extremity function in clinically isolated syndrome.

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.