Adherence to Subcutaneous Interferon Beta-1a in Multiple Sclerosis Patients Receiving Periodic Feedback on Drug Use by Discussion of Readouts of Their Rebismart® Injector: Results of the Prospective Cohort Study REBIFLECT.

INTRODUCTION: Consistent treatment adherence is an important determinant of durable response in multiple sclerosis (MS). Published data indicate that adherence to > 80% of prescribed doses may be considered optimal. Feedback of electronic application monitoring data to patients has been considered a promising means to support high adherence. METHODS: The 2-year prospective non-interventional study REBIFLECT conducted at outpatient neurological centers (731 patients at 134 study sites in Germany) investigated whether treatment adherence to subcutaneous (sc) interferon beta-1 injection during a 1-year period is enhanced by regular physician-patient talks reflecting dosing data recorded by the application device in the context of clinical data or disease parameters. Qualitative adherence was defined as number of weeks with properly distributed injections per total number of weeks with prescribed injections. Quantitative adherence was defined as number of administered injections per prescribed injections. RESULTS: Overall median qualitative adherence was 90.5%. Approximately 70% of patients with adherence data available in the respective periods had a qualitative treatment adherence of 80-100%. With a mean of 97.9% quantitative adherence was very high and remained stable in the 2-year observation period. The stability of this effect is demonstrated by the subgroup with just one reflection talk (≥ 100%) and only a slight decrease in the subgroup with more than five reflection talks (97.9%). CONCLUSION: Treatment adherence with the Rebismart® device was generally very high, consistent with other non-interventional studies. The first reflection talk supported by RebiSmart® induces excellent adherence, stabilized by repetition. Reflection to patients of subcutaneous interferon beta-1a treatment monitored by RebiSmart® is recommended to ensure prolonged strong treatment adherence.

MRI-Based Brain Volumetry at a Single Time Point Complements Clinical Evaluation of Patients With Multiple Sclerosis in an Outpatient Setting.

Purpose: Thalamic atrophy and whole brain atrophy in multiple sclerosis (MS) are associated with disease progression. The motivation of this study was to propose and evaluate a new grouping scheme which is based on MS patients' whole brain and thalamus volumes measured on MRI at a single time point. Methods: In total, 185 MS patients (128 relapsing-remitting (RRMS) and 57 secondary-progressive MS (SPMS) patients) were included from an outpatient facility. Whole brain parenchyma (BP) and regional brain volumes were derived from single time point MRI T1 images. Standard scores (z-scores) were computed by comparing individual brain volumes against corresponding volumes from healthy controls. A z-score cut-off of -1.96 was applied to separate pathologically atrophic from normal brain volumes for thalamus and whole BP (accepting a 2.5% error probability). Subgroup differences with respect to the Symbol Digit Modalities Test (SDMT) and the Expanded Disability Status Scale (EDSS) were assessed. Results: Except for two, all MS patients showed either no atrophy (group 0: 61 RRMS patients, 10 SPMS patients); thalamic but no BP atrophy (group 1: 37 RRMS patients; 18 SPMS patients) or thalamic and BP atrophy (group 2: 28 RRMS patients; 29 SPMS patients). RRMS patients without atrophy and RRMS patients with thalamic atrophy did not differ in EDSS, however, patients with thalamus and BP atrophy showed significantly higher EDSS scores than patients in the other groups. Conclusion: MRI-based brain volumetry at a single time point is able to reliably distinguish MS patients with isolated thalamus atrophy (group 1) from those without brain atrophy (group 0). MS patients with isolated thalamus atrophy might be at risk for the development of widespread atrophy and disease progression. Since RRMS patients in group 0 and 1 are clinically not distinguishable, the proposed grouping may aid identification of RRMS patients at risk of disease progression and thus complement clinical evaluation in the routine patient care.

Fully automatic detection of deep white matter T1 hypointense lesions in multiple sclerosis.

A novel method is presented for fully automatic detection of candidate white matter (WM) T1 hypointense lesions in three-dimensional high-resolution T1-weighted magnetic resonance (MR) images. By definition, T1 hypointense lesions have similar intensity as gray matter (GM) and thus appear darker than surrounding normal WM in T1-weighted images. The novel method uses a standard classification algorithm to partition T1-weighted images into GM, WM and cerebrospinal fluid (CSF). As a consequence, T1 hypointense lesions are assigned an increased GM probability by the standard classification algorithm. The GM component image of a patient is then tested voxel-by-voxel against GM component images of a normative database of healthy individuals. Clusters (≥0.1 ml) of significantly increased GM density within a predefined mask of deep WM are defined as lesions. The performance of the algorithm was assessed on voxel level by a simulation study. A maximum dice similarity coefficient of 60% was found for a typical T1 lesion pattern with contrasts ranging from WM to cortical GM, indicating substantial agreement between ground truth and automatic detection. Retrospective application to 10 patients with multiple sclerosis demonstrated that 93 out of 96 T1 hypointense lesions were detected. On average 3.6 false positive T1 hypointense lesions per patient were found. The novel method is promising to support the detection of hypointense lesions in T1-weighted images which warrants further evaluation in larger patient samples.

Hypothalamo-pituitary-adrenal axis activity predicts disease progression in multiple sclerosis.

Clinical studies have shown that groups of multiple sclerosis (MS) patients exhibit a chronically activated hypothalamo-pituitary-adrenal (HPA) axis. However, the association of HPA axis activity and disease progression in MS is unknown. In this longitudinal study over a 3-year follow-up period, we report that patients who exhibited stronger HPA reactivity at baseline were significantly more likely to experience progression as measured by the Expanded Disability Status Scale (EDSS) during the follow-up period. Furthermore, HPA axis activity correlated with progression ratings and cognitive impairment three years later. Tests of HPA axis activity may be useful biomarkers for disease progression in MS.

Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis.

Hypothalamo-pituitary-adrenal (HPA) dysregulation has recently been demonstrated in multiple sclerosis (MS) by means of combined dexamethasone corticotropin-releasing hormone (Dex-CRH) suppression tests. Authors found a correlation with course of disease and to a lesser extent with depressive symptoms. In this study, we aimed to further evaluate whether HPA disturbances in MS are correlated with cognitive impairment, disability status, and fatigue. Dex-CRH tests were performed in a total of 40 patients and 11 healthy controls. Concomitantly, cognitive impairment was evaluated using the symbol digit modalities test and fatigue was assessed by different fatigue severity scales. When comparing patient subpopulations to healthy subjects, Dex-CRH stimulation tests indicated an HPA hyperactivity in primary and secondary progressive MS, while relapsing-remitting patients had response patterns similar to controls. However, results were only significant for one of the six analysed parameters, i.e. area under the curve calculations of ACTH stimulation. Within the patient sample, clear-cut differences emerged between groups of different cognitive impairment, being significant for all ACTH response parameters. Our results suggest an HPA hyperactivation related to increased cognitive impairment. Indicators of HPA axis activation further correlated substantially with neurologic disability, but only moderately with duration of disease and even less with depressive symptoms and fatigue. We conclude that the observed dysregulation is more likely a secondary effect of the extent of brain damage rather than primarily involved in the pathogenesis of MS.