A window into the brain: an in vivo study of the retina in schizophrenia using optical coherence tomography.

Retinal nerve fibre layer (RNFL) thickness and macular volume (MV) can be measured in vivo using optical coherence tomography (OCT) providing a "window into the brain". RNFL and MV are promising biomarkers in neurological diseases. This study explores the potential of RNFL and MV to detect axonal abnormalities in vivo in schizophrenia and their correlations with clinical features. OCT was performed in 49 patients (38 schizophrenia, 11 schizoaffective disorder) and 40 healthy controls matched for age and gender. Group comparisons were made between whole retina and quadrant RNFL thickness and MV using multi-level analyses. In patients, associations were sought between RNFL and MV with symptom severity (positive/negative). Patients and controls had similar whole retina RNFL thickness (p=0.86) and MV (p=0.64), but RNFL in the right nasal quadrant of the schizoaffective group was thinner than in the schizophrenia group (p=0.02). In patients, positive symptom severity was associated with smaller MV (right ß=-0.54, p=0.02; left ß=-0.49, p=0.04). Normal MV and RNFL thickness suggests unmyelinated axons in patients with schizophrenia/schizoaffective disorder remain unaffected. Longitudinal studies using higher resolution OCT will clarify whether progressive RNFL and MV changes occur and whether they can be used as state or trait markers in schizophrenia.

Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study.

BACKGROUND: More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis. METHODS: Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200. FINDINGS: We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio. INTERPRETATION: Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection. FUNDING: Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

BACKGROUND: No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". METHODS/DESIGN: MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. RESULTS: Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. CONCLUSIONS: In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00395200).

A method for measuring the cross sectional area of the anterior portion of the optic nerve in vivo using a fast 3D MRI sequence.

PURPOSE: To investigate the three-dimensional (3D) fast-recovery fast spin-echo accelerated (FRFSE-XL) sequence as a new application for measuring the intraorbital optic nerve (ION) mean cross-sectional area in vivo and to determine its value within a commonly used high resolution imaging protocol. MATERIALS AND METHODS: The entire ION was scanned in nine healthy volunteers (mean age 32 +/- 4 years) using the 3D FRFSE-XL sequence and a commonly used high resolution short-echo fast fluid-attenuated inversion-recovery (sTE fFLAIR) sequence with identical slice locations at 1.5T. The mean cross-sectional area from both sequences was measured on a slice-by-slice basis from 3 mm behind the globe to the orbital apex. The reproducibility of both techniques was assessed from repeated scans (scan-rescan) and repeated image analysis (intraobserver). RESULTS: Measurement of the mean cross-sectional area of the anterior 9 mm segment of the ION was only possible using the 3D FRFSE-XL sequence with a mean area of 11.6 +/- 2.2 mm(2) (scan rescan COV = 3.3 +/- 1.5, intraobserver COV = 2.4 +/- 0.02) whereas the remainder segment of the ION (i.e., 9 mm behind the globe to the orbital apex) could only be measured with the use of the sTE fFLAIR with a mean area of 8.5 +/- 1.7 mm(2) (scan rescan COV = 4.9 +/- 2.5 and intraobserver COV = 3.70 +/- 0.03). CONCLUSION: The 3D FRFSE-XL allows fast and reproducible measurement of the cross-sectional area of the anterior 9 mm segment of the ION, which is not possible using commonly used imaging sequences due to image degradation from motion, and is of complementary value to the existing imaging protocol for ION atrophy quantification.

Assessing structure and function of the afferent visual pathway in multiple sclerosis and associated optic neuritis.

The afferent visual pathway is commonly affected in MS. Assessment of the afferent visual pathway using clinical, imaging and electrophysiological methods not only provides insights into the pathophysiology of MS, but also provides a method of investigating potential therapeutic measures in MS. This review summarises the various assessment methods, in particular imaging techniques of the visual pathway. Retinal nerve fibre layer (RNFL) thickness is usually reduced following an episode of optic neuritis. Techniques such as optical coherence tomography, scanning laser polarimetry, and confocal scanning laser ophthalmoscopy are used to quantify RNFL thickness. MRI of the optic nerve is not routinely used in the diagnosis of MS or optic neuritis, but is valuable in atypical cases and in research. T2- weighted images of the optic nerve usually show the hyperintense lesion in optic neuritis and gadolinium enhancement is seen in the acute attack. Quantifying atrophy of the optic nerve using MRI gives an indication of the degree of axonal loss. Magnetization transfer ratio (MTR) of the optic nerve provides an indication of myelination. Diffusion tensor imaging (DTI) of the optic nerve and optic radiation provide information about the integrity of the visual white matter tracts. Functional MRI following visual stimulation is used to assess the contribution of cortical reorganisation to functional recovery following optic neuritis. Investigations including logMAR visual acuity, Sloan contrast acuity, Farnsworth- Munsell 100-hue colour vision tests and Humphrey perimetry provide detailed quantitative information on different aspects of visual function. Visual evoked potentials identify conduction block or delay reflecting demyelination. These collective investigative methods have advanced knowledge of pathophysiological mechanisms in MS and optic neuritis. Relevant ongoing studies and future directions are discussed.