Anterior pituitary axis hormones and outcome in acute ischaemic stroke

Abstract. Neidert S, Katan M, Schuetz P, Fluri F, Ernst A, Bingisser R, Kappos L, Engelter ST, Steck A, Müller B, Christ‐Crain M (University Hospital Basel, Basel, Switzerland; SphingoTec GmbH, Borgsorf, Germany; Kantonsspital Aarau, Aarau, Switzerland) Anterior pituitary axis hormones and outcome in acute ischaemic stroke. J Intern Med 2011; 269 : 420–432. Background. Early and accurate prediction of outcome in acute stroke is important and influences risk‐optimized therapeutic strategies. Endocrine alterations of the hypothalamic–pituitary axis are amongst the first measurable alterations after cerebral ischaemia. We therefore evaluated the prognostic value of cortisol, triiodothyronine (T3), free thyroxine (fT4), thyroid‐stimulating hormone (TSH) and growth hormone (GH) in patients with an acute ischaemic stroke. Methods. In an observational study including 281 patients with ischaemic stroke, anterior pituitary axis hormones (i.e. cortisol, T3, fT4, TSH and GH) were simultaneously assessed to determine their value to predict functional outcome and mortality within 90 days and 1 year. Results. In receiver operating characteristic curve analysis, the prognostic accuracy of cortisol was higher compared to all measured hormones and was in the range of the National Institutes of Health Stroke Scale (NIHSS). Cortisol was an independent prognostic marker of functional outcome and death [odds ratio (OR) 1.0 (1.0–1.01) and 1.62 (1.37–1.92), respectively, P < 0.0002 for both, adjusted for age and the NIHSS] in patients with ischaemic stroke, but added no significant additional predictive value to the clinical NIHSS score. Conclusion. Cortisol is an independent prognostic marker for death and functional outcome within 90 days and 1 year in patients with ischaemic stroke. By contrast, other anterior pituitary axis hormones such as peripheral thyroid hormones and GH are only of minor value to predict outcome in stroke.     

Comparative analysis of dimethyl fumarate and fingolimod in relapsing–remitting multiple sclerosis

Journal of Neurology - Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing–remitting multiple...     

The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL

Journal of Neurology -     

Use of log-scaled crowded visual acuity charts in clinical studies regarding amblyopia

Graefe's Archive for Clinical and Experimental Ophthalmology - Log-scaled crowded charts using standardized testing protocol are essential for precise and reproducible visual acuity (VA)...     

T cell receptor γδ repertoire is skewed in cerebrospinal fluid of multiple sclerosis patients: molecular and functional analyses of antigen-reactive γδ clones

To study the relevance of γδ T cells in multiple sclerosis (MS) we analyzed the T cell receptor (TCR) γδ repertoire and the antigen reactivity of γδ clones isolated from cerebrospinal fluid (CSF). In T cell cultures derived from CSF we found an increased percentage of Vδ1⁺ cells as compared to peripheral blood of the same donors. Phenotypic analysis of cells from MS CSF with Vγ- and Vγ-specific monoclonal antibodies (mAb) showed that the Vγ1 chain is most frequently associated with γ chains belonging to the VγI family. Sequence analysis of TCR genes revealed heterogeneity of junctional regions in both δ and γ genes indicating polyclonal expansion. γδ clones were established and some recognized glioblastoma, astrocytoma or monocytic cell lines. Stimulation with these targets induced serine esterase release and lymphokine expression characteristic of the T_H0-like phenotype. Remarkably, these tumor-reactive γδ cells were not detected in the peripheral blood using PCR oligotyping, but were found in other CSF lines independently established from the same MS patient. Altogether, these results demonstrate that in the CSF there is a skewed TCR γδ repertoire and suggest that γδ cells reacting against brain-derived antigens might have been locally expanded.     

Accurate,rapid and reliable,fully automated MRI brainstem segmentation for application in multiple sclerosis and neurodegenerative diseases

Neurodegenerative disorders, such as Alzheimer's disease (AD) and progressive forms of multiple sclerosis (MS), can affect the brainstem and are associated with atrophy that can be visualized by MRI. Anatomically accurate, large‐scale assessments of brainstem atrophy are challenging due to lack of automated, accurate segmentation methods. We present a novel method for brainstem volumetry using a fully‐automated segmentation approach based on multi‐dimensional gated recurrent units (MD‐GRU), a deep learning based semantic segmentation approach employing a convolutional adaptation of gated recurrent units. The neural network was trained on 67 3D‐high resolution T1‐weighted MRI scans from MS patients and healthy controls (HC) and refined using segmentations of 20 independent MS patients' scans. Reproducibility was assessed in MR test–retest experiments in 33 HC. Accuracy and robustness were examined by Dice scores comparing MD‐GRU to FreeSurfer and manual brainstem segmentations in independent MS and AD datasets. The mean %‐change/SD between test–retest brainstem volumes were 0.45%/0.005 (MD‐GRU), 0.95%/0.009 (FreeSurfer), 0.86%/0.007 (manually edited segmentations). Comparing MD‐GRU to manually edited segmentations the mean Dice scores/SD were: 0.97/0.005 (brainstem), 0.95/0.013 (mesencephalon), 0.98/0.006 (pons), 0.95/0.015 (medulla oblongata). Compared to the manual gold standard, MD‐GRU brainstem segmentations were more accurate than FreeSurfer segmentations (p < .001). In the multi‐centric acquired AD data, the mean Dice score/SD for the MD‐GRU‐manual segmentation comparison was 0.97/0.006. The fully automated brainstem segmentation method MD‐GRU provides accurate, highly reproducible, and robust segmentations in HC and patients with MS and AD in 200 s/scan on an Nvidia GeForce GTX 1080 GPU and shows potential for application in large and longitudinal datasets.     

Altered functional adaptation to attention and working memory tasks with increasing complexity in relapsing-remitting multiple sclerosis patients

As attention, processing speed, and working memory seem to be fundamental for a broad range of cognitive performance, the present study on patients with mild forms of relapsing-remitting multiple sclerosis (RR-MS) focused on these domains. To explore subtle neuropsychological changes in either the clinical or fMRI domain, we applied a multistep experimental design with increasing task complexity to investigate global brain activity, functional adaptation, and behavioral responses to typical cognitive processes related to attention and working memory. Fifteen patients with RR-MS (mean age 38 years, 22-49 years, 9 females, mean disease duration 5.9 years (SD = 3.6 years), mean Expanded Disability Status Scale score, 2.3 (SD = 1.3) but without reported cognitive impairment), and 15 age-matched healthy controls (HC; mean age, 34 years, 23-50 years, 6 women) participated. After a comprehensive neuropsychological assessment, participants performed different fMRI experiments testing attention and working memory. In the neuropsychological assessment, patients showed only subtle reduction in learning and memory abilities. In the fMRI experiments, both groups activated the brain areas typically involved in attention and working memory. HC showed a linear in- or decrease in activation paralleling the changing task complexity. Patients showed stronger activation change at the level of the simple tasks and a subsequent saturation effect of (de-)activation at the highest task load. These group/task interaction differences were found in the right parahippocampal cortex and in the middle and medial frontal regions. Our results indicate that, in MS, functional adaptation patterns can be found which precede clinical evidence of apparent cognitive decline.     

MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials

Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI--and patient--resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials.