Patient- versus physician-reported relapses in multiple sclerosis: insights from a large observational study.

BACKGROUND AND PURPOSE: The patient's perspective is becoming increasingly important for endpoints in studies on multiple sclerosis. However, relapse data generated from the patient's perspective in combination with independent documentation by the physician are scarce. Our objective was to compare self-reported relapses by the patient to physician-documented relapses within a routine clinical practice setting of quarterly visits. METHODS: Two-year data (n = 1921 patients) were extracted from two prospective, non-interventional, multicentre cohort studies in Germany. The number of relapses independently reported by patients and physicians was analysed. In addition, inter-rater reliability and measures of validity were evaluated. Patterns of associations were investigated in subgroup analysis of sociodemographic, clinical and patient-reported outcome measures. RESULTS: Patients and physicians showed good overall agreement [κ = 0.78, 95% confidence interval (CI) 0.76-0.80]. Nevertheless, patients reported, on average, more relapses than physicians during follow-up (0.55 vs. 0.44; P < 0.001). Corresponding annualized relapse rates were 0.38 (95% CI 0.36-0.39) and 0.30 (95% CI 0.29-0.31), respectively. Differences between physicians and patients were particularly pronounced in patient groups with greater disability levels, decreased health-related quality of life or treatment satisfaction. The positive predictive value was 74.01% (95% CI 71.85-76.07), and the negative predictive value was 98.86% (95% CI 98.67-99.03). CONCLUSION: Some disagreement on the occurrence of relapses appears in specific patient subgroups, where factors such as pseudo-relapses or confounding factors may have promoted over- or under-reporting.

[Enhancing monitoring of disease progression-remote sensoring in multiple sclerosis]. / Remote-Sensoring ­ neue Optionen des Progressionsmonitorings bei Multipler Sklerose.

BACKGROUND: As a result of innovations in the digitalization of healthcare new technologies, such as remote sensoring are gaining in importance for the collection of real-life data in addition to the regular medical examination. This enables a closer view into the daily lives of patients with multiple sclerosis and a more detailed monitoring of disease progression. OBJECTIVE: This article gives a summary of sensor-based measurement technologies in the field of multiple sclerosis RESULTS: A wide variety of sensor-based measurement technologies are already available, which largely focus on gait analysis and mobility. Furthermore, there are many innovative approaches for a sensor-based collation of the multifocal symptoms of multiple sclerosis, for example technologies focus on the area of stress surveillance, the autonomic nervous system, GPS tracking and sleep monitoring. DISCUSSION: Despite the existence of many already available technologies, the aim is now to find a practical way to integrate them into the daily routine of patient monitoring, which includes standardized data collection, evaluation and interpretation. Only at this point a perspective benefit for treating physicians and patients can be achieved.

Perceptions on the value of bodily functions in multiple sclerosis.

BACKGROUND: In neurological diseases presenting with a plethora of symptoms, the value of bodily functions for a given patient might be a guide for clinical management. Multiple sclerosis (MS) is paradigmatic in this respect, and little is known about the value of different bodily functions of patients and their physicians' perceptions. METHODS: In a multicenter study, 171 patients with relapsing-remitting multiple sclerosis (RRMS), 61% with a clinically active disease within the last 2 years were followed over up to 3 years and yearly patients and their study physician rated on the perceived value of 13 bodily functions via a priority list. Differences between patients and physicians as well as modulating disease demographic factors were analyzed. RESULTS: Patients with RRMS rated visual function followed by thinking and memory and walking highest while physicians stressed mobility, followed by thinking and memory and alertness most. Ratings were independent from disease duration or disability. Strongest value judgment differences were seen in swallowing regarded more relevant by patients and hand function regarded more relevant by physicians. In general, patients' and physicians' ratings through time were quite stable. Collapsing physical items into a physical functioning scale and mental items in a mental function scale, both dimensions were regarded equally important by patients while physicians underscored physical functioning (P = .016). CONCLUSION: There are differences between patients and physicians in value statements of bodily functions in MS. In particular, visual functioning is under-recognized by physicians.

[Real-world evidence : Benefits and limitations in multiple sclerosis research]. / Real-world-Evidenz : Vorteile und Limitationen am Beispiel der Multiplen Sklerose.

BACKGROUND: Real-world evidence (RWE) expands the data obtained in randomized clinical trials (RCTs), which are based on both homogeneous selected patient groups and limited study durations, to long-term experiences in clinical routine. In particular, chronic diseases such as multiple sclerosis (MS) with both heterogeneous pathologies and a growing number of therapeutic options require a careful RWE-based assessment of long-term efficacy and safety parameters. OBJECTIVE: This review presents RWE data sources applied in MS research and discusses potential quality standards. MATERIAL AND METHODS: This article is based on the results of an expert meeting of the authors held in October 2015 and a selective literature search. RESULTS: The RWE data sources include the reporting system of drug safety monitoring, non-interventional studies, MS-specific registries, administrative health databases, and electronic medical records. These data sources have different objectives and are subject to specific limitations with respect to the disease and therapy-relevant analytical options. The combination of different sources into an integrative approach might improve the validity of RWE in MS research; however, this objective requires the standardization of data collection and processing as well as the definition of uniform and transnational quality standards. CONCLUSION: There is still a need for high-quality, comprehensive, and valid RWE data as these data cover additional aspects of patient care and expand the data available by complementary information. Further development of an integrative RWE approach requires cooperation at various levels with the aim of the best possible standardization and harmonization of clinical MS data.

Adrenal medullary dysfunction as a feature of obesity.

BACKGROUND AND OBJECTIVE: Although there is strong evidence linking obesity with increased sympathoneural activity, involvement of the adrenal medulla is less clear. We therefore investigated adrenal medullary function under fasting and feeding conditions in normal weight (NW, n=33), overweight (OW, n=28) and obese (OB, n=36) adults (59% women). SUBJECTS AND METHODS: Ninety-seven healthy adults participated in a cross-sectional study with recruitment stratified according to BMI. Plasma for catecholamines and metanephrines was sampled in the fasting state, at 30-min intervals during a 120-min glucose tolerance test and during an euglycaemic-hyperinsulinaemic clamp (40 mU m-2 min-1 insulin dose). Body composition was determined by leg-to-leg bioelectrical impedance analysis. RESULTS: Obese subjects had the lowest fasting plasma concentrations of epinephrine (NW: 0.17, 95% confidence interval (CI): 0.14-0.20 nmol l-1; OW: 0.16, 95% CI: 0.12-0.19 nmol l-1; OB: 0.11, 95% CI: 0.08-0.13 nmol l-1; P=0.018) and metanephrine (NW: 0.17, 95% CI: 0.15-0.19 nmol l-1; OW: 0.15, 95% CI: 0.13-0.16 nmol l-1; OB: 0.13, 95% CI: 0.12-0.15 nmol l-1; P=0.022), the latter reflecting adrenal medullary store size. Fasting plasma epinephrine (r=-0.437; P<0.001) and metanephrine (r=-0.477; P<0.001) concentrations were additionally inversely correlated with whole-body fat percentage. Suppression of epinephrine secretion in response to carbohydrate ingestion was significantly blunted in overweight and obese subjects compared with the normal weight subjects (Pinteraction=0.045). Most of the variance in basal epinephrine was related to whole-body fat percentage (ß=-0.389, 95% CI: -0.09 to -0.69; P=0.012) that explained the lower concentrations of epinephrine and metanephrine in women than men. CONCLUSIONS: We provide evidence that adrenomedullary dysfunction is a characteristic feature of obesity that involves both reduced adrenal secretion of epinephrine and size of adrenal medullary epinephrine stores.

Immunomodulatory treatments and cognition in MS.

Cognitive impairments occur frequently and early in multiple sclerosis (MS) and contribute significantly to a reduced quality of life of patients with MS. Executive functions (EFs) play a pivotal role for the behavioral adaption to the environment and are also crucial for compensatory processes of cognitive impairments. Disease-modifying drugs (DMDs) are effective in reducing the frequency of relapses and slow the disease progression in MS. The effects of DMDs on cognitive impairments were reviewed with a special focus on EFs. Most studies show some beneficial effects of DMDs on cognition in MS, but the evidence for effects on EFs is sparse. Additionally, most studies suffer from methodological issues, small sample sizes and learning effects. We discuss that EFs may constitute a viable cognitive endpoint for cognitive impairments in MS, which could foster the early detection of subtle cognitive changes in MS.

New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.

BACKGROUND: The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS: We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS: In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS: Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

[Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action]. / Monitoring von Blutparametern unter verlaufsmodifizierender MS-Therapie : Substanzspezifische Relevanz und aktuelle Handlungsempfehlungen.

With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.

Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review.

BACKGROUND: So far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population. OBJECTIVE: The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator. METHODS: A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year's duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared. RESULTS: Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately. CONCLUSION: Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

Attenuated brain-derived neurotrophic factor and hypertrophic remodelling: the SABPA study.

Brain-derived neurotrophic factor (BDNF) has been linked to neurological pathologies, but its role in cardiometabolic disturbances is limited. We aimed to assess the association between serum BDNF levels and structural endothelial dysfunction (ED) as determined by cross-sectional wall area (CSWA) and albumin/creatinine ratio (ACR) in black Africans. Ambulatory blood pressure (BP) and ultrasound CSWA values were obtained from 82 males and 90 females. Fasting blood and 8 h overnight urine samples were collected to determine serum BDNF and cardiometabolic risk markers, that is, glycated haemoglobin (HbA1c), lipids, inflammation and ACR. BDNF median split × gender interaction effects for structural ED justified stratification of BDNF into low and high (⩽/>1.37 ng ml(-1)) gender groups. BDNF values (0.86-1.98 ng ml(-1)) were substantially lower than reference ranges (6.97-42.6 ng ml(-1)) in the African gender cohort, independent of age and body mass index. No relationship was revealed between BDNF and renal function and was opposed by an inverse relationship between BDNF and CSWA (r=-0.17; P=0.03) in the African cohort. Linear regression analyses revealed a positive relationship between systolic BP and structural remodelling in the total cohort and low-BDNF gender groups. In the high-BDNF females, HbA1C was associated with structural remodelling. Attenuated or possible downregulated BDNF levels were associated with hypertrophic remodelling, and may be a compensatory mechanism for the higher BP in Africans. In addition, metabolic risk and hypertrophic remodelling in women with high BDNF underpin different underlying mechanisms for impaired neurotrophin homeostasis in men and women.

[Axon-reflex based nerve fiber function assessment in the detection of autonomic neuropathy]. / Axon-Reflex-basierte Nervenmessverfahren in der Diagnostik autonomer Neuropathie.

Axon-reflex-based tests of peripheral small nerve fiber function including techniques to quantify vasomotor and sudomotor responses following acetylcholine iontophoresis are used in the assessment of autonomic neuropathy. However, the established axon-reflex-based techniques, laser Doppler flowmetry (LDF) to assess vasomotor function and quantitative sudomotor axon-reflex test (QSART) to measure sudomotor function, are limited by technically demanding settings as well as interindividual variability and are therefore restricted to specialized clinical centers. New axon-reflex tests are characterized by quantification of axon responses with both temporal and spatial resolution and include "laser Doppler imaging (LDI) axon-reflex flare area test" to assess vasomotor function, the quantitative direct and indirect test of sudomotor function (QDIRT) to quantify sudomotor function, as well as the quantitative pilomotor axon-reflex test (QPART), a technique to measure pilomotor nerve fiber function using adrenergic cutaneous stimulation through phenylephrine iontophoresis. The effectiveness of new axon-reflex tests in the assessment of neuropathy is currently being investigated in clinical studies.

Attenuated NOx responses and myocardial ischemia, a possible risk for structural vascular disease in African men: the SABPA study.

Chronically elevated blood pressure has been associated with impaired NO-mediated vasodilation and structural vascular disease risk. This study aimed to determine whether significant associations exist regarding NO metabolite (NOx) responses, cardiovascular function and structural vascular disease in a cohort of African and Caucasian men. The study included 81 African and 94 Caucasian male teachers stratified via median splits into low and high NOx ethnic groups. Ambulatory blood pressure, electrocardiogram monitoring and ultrasound carotid intima-media thickness (CIMT) images were obtained. Cardiovascular measurements and fasting blood for NOx responses were measured during rest and on challenging the cardiovascular system with the Stroop colour-word conflict test. African men displayed significantly higher resting NOx as well as higher number of 24 h silent ischemic events than their Caucasian counterparts. Low NOx African men displayed enhanced α-adrenergic and ECG ST segment depression acute mental stress responses as well as 24 h silent ischemic events associated with CIMT (adjusted R(2) = 0.47; ß = 0.25; confidence interval (CI) = 0.13, 0.41). African men demonstrated a vulnerable cardiovascular profile. Novel findings revealed α-adrenergic-driven blood pressure responses and less NO bioavailability during acute stress. The association between myocardial ischemia and CIMT in this group emphasized their risk for future coronary artery disease and cerebrovascular events.

Defensive coping facilitates higher blood pressure and early sub-clinical structural vascular disease via alterations in heart rate variability: the SABPA study.

OBJECTIVES: Defensive coping (AC) responses in urban African males have been associated with vascular responsiveness, partly explaining autonomic nervous system dysfunction. We therefore aimed to assess whether AC responses facilitate higher blood pressure and early sub-clinical structural vascular disease via alterations in frequency- and time-domain heart rate variability (HRV) responses. METHODS: We included 355 African and Caucasian men and women without pre-existing atrial fibrillation, aged 45 ± 9 years. Significant interaction on main effects (coping × ethnicity × gender) for left carotid intima media thickness far wall (L-CIMTf) and cross sectional wall area values necessitated selection of AC responders above mean via the Coping Strategy Indicator. We collected B-mode ultrasound L-CIMTf, ambulatory BP and-HRV data. Overnight fasting blood was obtained. RESULTS: Overall, Africans and AC Africans, mostly men, revealed a poorer lifestyle profile, higher prevalence of hypertensive status, disturbed sympathovagal balance and depressed HRV temporal and geometric patterns compared to the Caucasians (P ≤ 0.05). Moderately depressed non-linear and time-domain HRV (SDNN <100 ms) was prevalent in 28% of Africans compared to 11% of Caucasians. A similar trend was shown for the AC African participants (32%) compared to Caucasians (16%). Only depressed HRV time-domain (SDNN: adj. R(2) = 0.34; ß = -0.24; p = 0.08) and vagal-impaired heart rate responses (RMSSD: adj. R(2) = 0.28; ß = -0.28; p < 0.05) were associated with higher blood pressure and early structural vascular changes in AC African men. CONCLUSION: Defensive coping facilitated autonomic nervous system dysfunction, which was associated with higher blood pressure and sub-clinical structural vascular disease in an African male cohort.

[Chronically ill and unemployed? A review on vocational status in multiple sclerosis]. / Chronisch krank und ohne arbeit? Eine aktuelle analyse zur erwerbstätigkeit bei multipler sklerose.

BACKGROUND: Multiple sclerosis (MS) is one of the most common neurological disorders in young adults. It is characterised by a chronic progressive course with far reaching implications on the patient's private and professional life. Based on the current literature, employment status is analysed in relation to disease-specific, therapeutic, psychosocial, and socioeconomic factors. A special emphasis is placed on the vocational status of MS patients in Germany. RESULTS: According national and international studies, around 40 % of all MS patients are currently unemployed. Main reasons for early retirement are disease-specific factors such as impaired mobility, disability in the upper extremities, fatigue, and cognitive impairment. According to the German Multiple Sclerosis Registry (GMSR), these symptoms are still insufficiently treated. In patients with minor motoric impairment (EDSS ≤ 3.0), depressive symptoms seem to have a major impact on employment status. Disease progression, older age at diagnosis, and hard physical work are negative predictors in terms of employment situation. The lack of flexible working hours, the inability to have flexible resting times at work, a lack of understanding from colleagues and employers as well as the personal attitude were main non-disease-specific reasons for early retirement. CONCLUSIONS: The current knowledge on the vocational status in MS is mainly based on international studies (e. g., Scandinavia, England, USA, Australia, MSIF Survey). For Germany, only the GMSR supports significant information on the employment status of MS patients. According to the GMSR, ataxia, fatigue and cognitive dysfunction are still insufficiently treated - a situation that is at least partly due to insufficient treatment options. Comprehensive studies that focus on a broad range of possible influencing factors on vocational status of German MS patients are currently lacking.

Regular lipoprotein apheresis maintains residual cardiovascular and microvascular function in patients with advanced atherosclerotic disease.

OBJECTIVE: To determine whether previously demonstrated beneficial short-term effects on cardiovascular function in regular users of lipoprotein apheresis would be sustainable over time. METHODS: Regular users of lipoprotein apheresis (n = 17) were studied between February 2009 and July 2010. All patients were examined for endothelial and autonomic function at baseline and at one year of regular treatment. Microvascular function was determined by flicker-induced vasodilation of retinal vessels using the Dynamic Vessel Analyzer. Autonomic regulation of blood pressure and heart rate upon cardiovascular perturbation by deep breathing at 0.1 Hz and orthostatic challenge was evaluated by trigonometric regressive spectral analysis. RESULTS: The acute improvement of cardiovagal function and venular endothelial function seen after a single lipoprotein apheresis was not evident at one year of regular treatment. However, baroreflex sensitivity showed an improved recovery after orthostatic challenge as compared to baseline measurements. Initially compromised autonomic and microvascular function had not further deteriorated at one year of regular lipoprotein apheresis treatment. CONCLUSION: In patients with advanced atherosclerotic disease regular lipoprotein apheresis treatment maintains residual cardiovascular functioning over time.

Metabolomic distinction of microvascular effects of lipoprotein apheresis--a pilot study.

OBJECTIVE: The study of small-molecule metabolites may assist in cardiovascular risk monitoring during therapy. We assessed whether acute changes in the metabolome by lipoprotein apheresis are able to predict changes in microvascular function. METHODS: We performed mass-spectrometry-based profiling of 186 metabolites in peripheral plasma of 21 hyperlipidemic patients before and after a single session of lipoprotein apheresis. To evaluate the capability of metabolites to predict microvascular outcome after apheresis, patients were stratified according to improvement and deterioration of retinal endothelial function. Endothelial function was assessed as the relative change in retinal vessel diameter in response to flicker light stimulation. RESULTS: We observed pronounced but not uniform changes in the metabolome after a single session of lipoprotein apheresis. Improvements in microvascular function were associated with a decline in lysophosphatidylcholines C14:0, C16:0, C16:1, C18:0, C18:1, C18:2, C20:4, C28:0, C28:1; in the amino acid serine and the dicarboxyacylcarnitine C12-DC. A positive relationship was found for methionine and ornithine. Applying decision tree and receiver-operator characteristic curve analysis, a change in serine of smaller than 11% by lipoprotein apheresis predicted an improvement of microvascular function with high sensitivity. CONCLUSION: Lipoprotein apheresis elicits changes in the metabolome favoring an anti-atherosclerotic environment. Monitoring the serine profile may assist in risk management of patients undergoing regular lipoprotein apheresis.

Defensive active coping facilitates chronic hyperglycaemia and endothelial dysfunction in African men: the SABPA study.

BACKGROUND: Dissociation between behavioural defensive active coping (AC) control albeit physiological "loss of control" responses was associated with silent ischaemia and structural wall abnormalities in African men. Whether it applies to structural alterations and endothelial dysfunction is uncertain. We therefore aimed to determine AC ethnic-gender specific receiver operating characteristic (ROC) carotid intima media far wall (CIMTf) cut points best associated with 24-h BP, -silent ischaemia and glycated haemoglobin (HbA1c). METHODS: Participants included African and Caucasians (N=317) without pre-existing stroke or atrial fibrillation, aged 45 ± 9 years. The Coping Strategy Indicator was used to measure AC. Ultrasound CIMTf, ambulatory BP, silent ischaemia and fasting blood samples were obtained. RESULTS: Between 69 and 77% of AC African men showed above normal diastolic BP and HbA1c levels compared to 44-48% of AC Caucasian men. In AC African women, 41-60% showed above normal BP, silent ischaemia and HbA1c levels compared to 17-44% of their Caucasian counterparts. ROC curve analyses, detecting optimal CIMTf cut points, ranged between 0.57 and 0.65 mm (BP) and 0.71 and 0.74 mm (silent ischaemia) in AC ethnic-gender groups. Only HbA1C (>5.7%), with a sensitivity/specificity 47%/74%, after controlling for confounders, predicted structural alterations at an optimal cut point of 0.69 mm in AC African men (OR 4.5; 95% CI 2.93-18.73). CONCLUSION: Novel findings of behavioural resilience were apparent in the AC African female despite a high prevalence of risk markers. In AC males, chronic hyperglycaemia facilitated endothelial dysfunction, i.e. a physiological "loss of control" and susceptibility to stroke risk.