Spectral Analysis of Heart Rate Variability: Time Window Matters

Spectral analysis of heart rate variability (HRV) is a valuable tool for the assessment of cardiovascular autonomic function. Fast Fourier transform and autoregressive based spectral analysis are two most commonly used approaches for HRV analysis, while new techniques such as trigonometric regressive spectral (TRS) and wavelet transform have been developed. Short-term (on ECG of several minutes) and long-term (typically on ECG of 1–24 h) HRV analyses have different advantages and disadvantages. This article reviews the characteristics of spectral HRV studies using different lengths of time windows. Short-term HRV analysis is a convenient method for the estimation of autonomic status, and can track dynamic changes of cardiac autonomic function within minutes. Long-term HRV analysis is a stable tool for assessing autonomic function, describe the autonomic function change over hours or even longer time spans, and can reliably predict prognosis. The choice of appropriate time window is essential for research of autonomic function using spectral HRV analysis

The Investigation of the Cardiovascular and Sudomotor Autonomic Nervous System—A Review

The autonomic nervous system as operating system of the human organism permeats all organ systems with its pathways permeating that it is involved with virtually all diseases. Anatomically a central part, an afferent part and sympathetic and parasympathetic efferent system can be distinguished. Among the different functional subsystems of the autonomic nervous system, the cardiovascular autonomic nervous system is most frequently examined with easily recordable cardiovascular biosignals as heart rate and blood pressure. Although less widely established, sudomotor tests pose a useful supplement to cardiovascular autonomic assessment as impaired neurogenic sweating belongs to the earliest clinical signs of various autonomic neuropathies as well as neurodegenerative disorders and significantly reduces quality of life. Clinically at first, the autonomic nervous system is assessed with a detailed history of clinical autonomic function and a general clinical examination. As a lof of confounding factors can influence autonomic testing, subjects should be adequately prepared in a standardized way. Autonomic testing is usually performed in that way that the response of the autonomic nervous system to a well-defined challenge is recorded. As no single cardiovascular autonomic test is sufficiently reliable, it is recommended to use a combination of different approaches, an autonomic test battery including test to measure parasympathetic and sympathetic cardiovascular function (deep breathing test, Valsalva maneuver, tilt, or pressor test). More specialized tests include carotid sinus massage, assessment of baroreceptor reflex function, pharmacological tests or cardiac, and regional hemodynamic measurements. Techniques to measure functional integrity of sudomotor nerves include the quantitative sudomotor axon reflex sweat test, analysis of the sympathetic skin response as well as the thermoregulatory sweat test. In addition to these rather established techniques more recent developments have been introduced to reduce technical demands and interindividual variability such as the quantitative direct and indirect axon reflex testing or sudoscan. However, diagnostic accuracy of these tests remains to be determined. We reviewed the current literature on currently available autonomic cardiovascular and sudomotor tests with a focus on their physiological and technical mechanisms as well as their diagnostic value in the scientific and clinical setting

Fingolimod in a patient with heart failure on the background of pulmonary arterial hypertension and coronary artery disease

Background: Fingolimod is the first oral immunomodulatory therapy approved for highly active relapsing remitting multiple sclerosis. Based on the distribution pattern of fingolimod interacting sphingosine-1-phosphat receptors in organism including immune system and cardiovascular system clinical monitoring of patients and evaluation of adverse events are recommended. Despite extensive data on cardiovascular safety, experience with fingolimod in patients with concomitant cardiological disease, especially within the pulmonary circulation, is rare. Case presentation: We report the case of a 46-year-old woman presented with relapsing remitting multiple sclerosis and severe idiopathic pulmonary arterial hypertension. Fingolimod was initiated because of disease activity of multiple sclerosis with two relapses and gadolinium-enhancing lesions in MRI. The patient demonstrated stable disease course of idiopathic pulmonary arterial hypertension when fingolimod was started. Fingolimod therapy did not alter or even worsen the pulmonary or cardiovascular conditions during first dose application as well as follow up of nine months. Conclusion: In this report, we present the first case of fingolimod treatment in a patient with highly active multiple sclerosis and severe idiopathic pulmonary arterial hypertension. We suggest an interdisciplinary approach with detailed cardiopulmonary monitoring for safety in such patients

Prognostic value of serum neurofilament light chain for disease activity and worsening in patients with relapsing multiple sclerosis: Results from the phase 3 ASCLEPIOS I and II trials

OBJECTIVE: This study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS). BACKGROUND: Previous DESIGN/METHODS: In this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (\u3emedian) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup. RESULTS: High versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p\u3c0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, -0.32% vs. -0.24%, p=0.044, and teriflunomide, -0.43% vs. -0.29%, p=0.002), thalamic volume (-0.56% vs. -0.31%, p=0.047 and -0.94% vs. -0.49%, p\u3c0.001), and WM volume (-0.30% vs. -0.19%, p=0.083 and -0.38% vs. -0.18%, p=0.003) but not of cGM volume (-0.39% vs. -0.32%, p=0.337 and -0.49% vs. -0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients. CONCLUSION: This study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients

Are Embodied Conversational Agents effective Tools for collecting Patient-reported Outcome Measures? – Towards a novel Approach in Multiple Sclerosis Care

Treating chronic diseases often involves repeated assessments from the patient’s perspective to guide therapy decisions and promote quality of care. Therefore, patient- reported outcome measures (PROMs) have been established in the form of questionnaires. One promising approach for collecting PROMs are embodied conversational agents (ECAs), which have the potential to make the questionnaire completion more engaging, interactive and lower the response burden for the patient. Building on Satisficing Theory, this research-in-progress paper reports on the design and preliminary evaluation of an ECA for multiple sclerosis patients. The results indicate that such a system meets the needs of the patients and motivates a comparative study to contribute further evidence on the use and advantage of ECAs for this purpose. Based on a literature review, an evaluation approach including a research model is derived, and implications for future research are discussed

Anti-Vascular endothelial growth factor therapy impairs endothelial function of retinal microcirculation in colon cancer patients – an observational study

Background: To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. Design and subjects: 20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres. Results: Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti-angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment. Conclusions: Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab

Predictors of Adherence Among Patients With Multiple Sclerosis Using the BETACONNECT® Autoinjector: A Prospective Observational Cohort Study

Background: In patients with multiple sclerosis (MS), non-adherence to disease-modifying drug therapy is associated with an increased rate of MS relapses. Early identification of patients at risk of non-adherence would allow provision of timely and individualized support. The aim of the BETAPREDICT study was to investigate potential predictors of adherence in patients with MS in Germany treated with interferon β-1b (IFNβ-1b) using the BETACONNECT® autoinjector. Methods: BETAPREDICT was a national, multi-center, prospective, non-interventional, single-arm, 24-month cohort study of patients with relapsing–remitting MS or clinically isolated syndrome receiving IFNβ-1b via the BETACONNECT® autoinjector (ClinicalTrials.gov: NCT02486640). Injection data were captured by the autoinjector. The primary objective was to determine baseline predictors of compliance, persistence, and adherence to IFNβ-1b treatment after 12- and 24 months using multivariable-adjusted regression. Secondary objectives included evaluation of satisfaction with the autoinjector, injection site pain, vitamin and nutrient supplementation, clinical course, and patient-related outcome measures. Results: Of 165 patients enrolled, 153 were available for analysis (120 with autoinjector data). Seventy-two patients left the study prematurely. Compliance (N = 120), persistence (N = 153), and adherence (N = 120) at 24 months were 89.1, 53.6, and 41.7%, respectively. Compliance at 12- and 24 months was predicted by intake of vitamin D supplements and absence of specific injection site reactions. Positive predictors of persistence included age (at 12- and 24 months) and previous duration of treatment (at 12 months), while intake of vitamins/nutrients other than vitamin D was a negative predictor (at 12 months). Positive predictors of adherence at 24 months were age and being experienced with IFNβ-1b. Higher scores in specific SF-36 subscales were positive predictors of medication-taking behavior at 24 months. Satisfaction with the autoinjector was high at baseline and 24 months (median score: 9 out of 10). Conclusions: Compliance with IFNβ-1b treatment among participants still under observation remained high over a 24-month period, while persistence and adherence continuously declined. Multiple factors affected medication-taking behavior, including patient characteristics, treatment history, injection site reactions, patients’ perception of their health and support programs. The importance of these factors may differ among patients according to their individual situation

Improving patient–physician dialog: commentary on the results of the MS Choices survey

Achieving good long- and short-term adherence to treatment for chronic diseases is important if patients are to gain the full benefits of treatment. Several barriers to adherence in multiple sclerosis (MS) have been identified and the healthcare team should work with patients to help them to overcome these obstacles. The MS Choices survey explored patient and physician perspectives on key aspects of MS diagnosis, treatment adherence, and disease management with the aim of improving understanding of the factors that influence patient behavior regarding treatment adherence. The survey found some important differences between patient and physician responses and here these findings are discussed in the context of personal clinical experience. Further, the possible implications of these findings for routine practice have been considered, and strategies that should be employed by MS physicians and nurses to help patients to adhere to their prescribed treatment are suggested

Case report: Variant-specific pre-exposure prophylaxis of SARS-CoV-2 infection in multiple sclerosis patients lacking vaccination responses

Sphingosine-1-phosphate receptor modulators and anti-CD20 treatment are widely used disease-modifying treatments for multiple sclerosis. Unfortunately, they may impair the patient’s ability to mount sufficient humoral and T-cellular responses to vaccination, which is of special relevance in the context of the SARS-CoV-2 pandemic. We present here a case series of six multiple sclerosis patients on treatment with sphingosine-1-phosphate receptor modulators who failed to develop SARS-CoV-2-specific antibodies and T-cells after three doses of vaccination. Due to their ongoing immunotherapy, lacking vaccination response, and additional risk factors, we offered them pre-exposure prophylactic treatment with monoclonal SARS-CoV-2-neutralizing antibodies. Initially, treatment was conducted with the antibody cocktail casirivimab/imdevimab. When the SARS-CoV-2 Omicron variant became predominant, we switched treatment to monoclonal antibody sotrovimab due to its sustained neutralizing ability also against the Omicron strain. Since sotrovimab was approved only for the treatment of COVID-19 infection and not for pre-exposure prophylaxis, we switched treatment to tixagevimab/cilgavimab as soon as it was granted marketing authorization in the European Union. This antibody cocktail has retained, albeit reduced, neutralizing activity against the Omicron variant and is approved for pre-exposure prophylaxis. No severe adverse events were recorded for our patients. One patient had a positive RT-PCR for SARS-CoV-2 under treatment with sotrovimab, but was asymptomatic. The other five patients did not develop symptoms of an upper respiratory tract infection or evidence of a SARS-CoV-2 infection during the time of treatment up until the finalization of this report. SARS-CoV-2-neutralizing antibody treatment should be considered individually for multiple sclerosis patients lacking adequate vaccination responses on account of their immunomodulatory treatment, especially in times of high incidences of SARS-CoV-2 infection

Approach to SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis

For more than a year now, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the coronavirus disease (COVID-19) pandemic with high mortality and detrimental effects on society, economy, and individual lives. Great hopes are being placed on vaccination as one of the most potent escape strategies from the pandemic and multiple vaccines are already in clinical use. However, there is still a lot of insecurity about the safety and efficacy of vaccines in patients with autoimmune diseases like multiple sclerosis (MS), especially under treatment with immunomodulatory or immunosuppressive drugs. We propose strategic approaches to SARS-CoV-2 vaccination management in MS patients and encourage fellow physicians to measure the immune response in their patients. Notably, both humoral and cellular responses should be considered since the immunological equivalent for protection from SARS-CoV-2 after infection or vaccination still remains undefined and will most likely involve antiviral cellular immunity. It is important to gain insights into the vaccine response of immunocompromised patients in order to be able to deduce sensible strategies for vaccination in the future