Severe Isolated Cognitive Relapse in Multiple Sclerosis - Indication for High Efficacy Therapy?

Isolated cognitive relapses (ICRs) are transient deficits in cognitive performance that are not accompanied with other symptoms typical for multiple sclerosis (MS). They are often missed and can lead to long-term cognitive decline. Considering possible devastating consequences of cognitive impairment, especially in working adults, and high economic burden of MS, it is of great importance to establish whether ICRs are sufficient to start with high efficacy therapy. 42-year- old women with a recent diagnosis of relapsing-remitting multiple sclerosis developed significant impairment in almost all cognitive domains, with dominant difficulties in naming and low performance in phonemic fluency tasks, consistent with ICR. Her brain MRI showed new lesions affecting the anterior part of the thalamus and her condition partially improved on intravenous corticosteroid therapy. While waiting the disease-modifying therapy to begin, for what was now highly active MS, she developed subarachnoid haemorrhage which further narrowed the treatment options. This case illustrates the complexity of managing patients with MS and ICRs in at least three aspects. Firstly, the lack of uniform definition resulting in diagnostic delay of highly active MS and ICRs. Secondly, optimal treatment choices are often limited due to safety issues and reimbursement reasons. And thirdly, there is still an open question about the right treatment option for ICRs, so more research is needed

Influence of resistance exercise on autonomic nervous system and sleep

Physical activity changes our body in many aspects, including autonomic regulation of cardiovascular system and thermoregulation, changes in metabolism, secretion of hormones and, as a consequence, mental changes. Acute effect of physical effort is increased sympathetic activity leading to condition known as ''fight or flight'' which includes tachycardia, tachypnea, blood pressure increase, pupil dilatation and increased attention. Parasympathetic activity is increased between series of trainings, during the resting state, and its effect is often referred to as ''rest and digest'' state. It includes increased salivation, drop in heart rate, bronchoconstriction, myorelaxation and pupil constriction. There are other factors responsible for the influence of exercise on our body. Good feelings and better memory after exercise are caused by secretion of various compounds, such as BDNF, dopamine and endorphins, as well as blood flow, leading to the use of exercise as therapeutic method but also as an agent of addiction. Sleeping is also altered by physical activity directly through nervous system and indirectly through metabolism and hormones. There are various types, aerobic and resistance, and frequencies of physical activity that can be used as treatment of many disorders and states. In this article we will discuss multiple benefits of resistance training on autonomic nervous system function and sleep

Excessive daytime sleepiness as cardiovascular risk in Croatian obese patients

Introduction: Excessive daytime sleepiness (EDS) is a very common complaint, especially in obese patients and is a potentially alarming symptom related to many risk factors and comorbidities1. In obese patients obstructive sleep apnea (OSA) is quite common. Our goal was to assess the connection between EDS and hypertension in Croatian obese patients. Patients and Methods: This cross-sectional study was carried out in a tertiary healthcare centre in an outpatient clinic for treatment of obesity. 49 participants were included. Inclusion criterion was BMI>30 kg/m2. Epworth Sleepiness Scale (ESS), consisting of 8 questions, every question ranged from 0-3 (overall range 0-24) was used to assess EDS. Spearman correlation coefficient, Welch t-test, chi-squared test and regression analysis were used. They were divided into 4 and 3 categories. 4 categories: 0-7, 8-9, 10-15 and 16-24. Many researches take ESS score 10 or greater as excessive daytime sleepiness, so our results were also interpreted as 3 categories: 0-7, 8-9 and 10 or greater. Results: Mean age of our participants was 50.29 ± 11.91 years. Overall mean BMI was 44.64±8.12 kg/m2. Results on ESS divided into 4 categories (Figure 1) were statistically significant correlated to hypertension: χ2= 9.61; p = .02. Also, results on ESS in 3 categories (Figure 2) were statistically significant correlated to hypertension: χ2(2) = 9.43; p = .009. Results on ESS were not significantly connected to AHI index (ESS in 4 categories: χ2(9)=8.43, p=.49; ESS in 3 categories : χ2(6)=6.45, p=.37). Furthermore, results on ESS were not correlated to sex (ESS in 4 categories χ2(3)=0.85, p=.84 and ESS in 3 categories: χ2(2)=0.56, p=.76). Conclusion: Our results show that the presence of hypertension alters the result on the ESS and is most visible in the so-called “borderline” area for the ESS score 8-9 in both divisions (into 3 and 4 categories), which shows a possible underestimation of the risk of the population achieving the result on the ESS <10, which is consistent with the studies of Borsini et al.

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

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

Hypertension, obesity and STOP-Bang questionnaire in detecting obstructive sleep apnea

Introduction: Breathing-related sleep disorders (out of them, especially obstructive sleep apnea (OSA)) are often present in obese patients. Significant correlation between conditions such as OSA or metabolic syndrome and some anthropometric measures, most notably neck circumference (NC) has been found1. Our goal was to examine the difference in STOP-Bang questionnaire score in obese patients depending on presence of hypertension and to see whether the use of it can be useful as a screening test for OSA. Patients and Methods: This cross-sectional study was carried out in a tertiary healthcare centre in an outpatient clinic for treatment of obesity. 49 participants (BMI >30kg/m2) were included. Welch t-tests were used to compare STOP-Bang questionnaire scores to our researched subjects. Results: Mean age was 50.29±11.91 years. Overall mean BMI was 44.64±8.12 kg/m2. There was not significant correlation between STOP-Bang questionnaire score and sex: t(9.486)=-2.17; p=.06, diabetes mellitus: t(7.821)=-2.07; p=.07 nor prediabetes: t(19.696)=-0.92; p=.37. However, patients with hypertension (Figure 1) had significantly higher score on STOP questionnaire than patients without hypertension: t(24)=-3.32; p=.003. Conclusion: Our results showed that obese patients with hypertension have higher score on the STOPBang questionnaire and consequently higher chance of OSA. Bakhai et al. have also shown that hypertension is an independent risk factor for OSA2. Thus, the STOP-Bang questionnaire could be an effective tool in obese hypertensive patients as a screening test to increase the percentage of newly diagnosed OSA and initiate timely treatment

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

Management of infusion related reactions associated with alemtuzumab in patients with multiple sclerosis

OBJECTIVE: Infusion-associated reactions (IARs) occur in >90% patients with multiple sclerosis (MS) treated with alemtuzumab. We aimed to study the frequency of IARs at 2 sites using 5 days of steroids (1g/day of IV methylprednisolone), but otherwise distinct protocols. ----- METHODS: This was retrospective chart review of 38 consecutive MS patients who were treated with alemtuzumab from June 2015 till February 2017 at Department of Neurology, University Hospital Center Zagreb, Croatia and Department of Neurology, University Medical Center Ljubljana, Slovenia. ----- RESULTS: Seventeen patients (44.7%) did not experience IARs. Skin reactions and fever were the most common IARs attributed to alemtuzumab infusions and they were most frequent on Day 5 and Day 1, respectively. We have observed significant differences in the occurrence of fever (p = 0.005) depending on the site of alemtuzumab administration which could be explained by different antipyretics used; fever was absent in the Slovenian cohort because high dose intravenous metamizole was administered. Two out of 9 treatment naïve, and 19 out of 29 patients who previously received immunomodulatory treatment had IARs (χ2 = 5.208, p = 0.022). ----- CONCLUSION: Modified premedication scheme consisting of 1g/day of IV methylprednisolone throughout all 5 days of alemtuzumab treatment may reduce overall IARs. Intravenous administration of antipyretics may work better than oral administration

Establishing the diagnosis of multiple sclerosis in Croatian patients with clinically isolated syndrome: 2010 versus 2017 McDonald criteria

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

Cladribine tablets in people with relapsing multiple sclerosis : A real-world multicentric study from southeast European MS centers

Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS).To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS).A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries.We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment.Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals