This scientific commentary refers to ‘Socioeconomic disparity is associated with faster retinal neurodegeneration in multiple sclerosis’ by Vasileiou et al. (doi:10.1093/brain/awab342).
OBJECTIVE:To develop consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results.
METHODS:A panel of experienced OCT researchers (including 11 ...neurologists, 2 ophthalmologists, and 2 neuroscientists) discussed requirements for performing and reporting quantitative analyses of retinal morphology and developed a list of initial recommendations based on experience and previous studies. The list of recommendations was subsequently revised during several meetings of the coordinating group.
RESULTS:We provide a 9-point checklist encompassing aspects deemed relevant when reporting quantitative OCT studies. The areas covered are study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition data analysis, recommended nomenclature, and statistical analysis.
CONCLUSIONS:The Advised Protocol for OCT Study Terminology and Elements recommendations include core items to standardize and improve quality of reporting in quantitative OCT studies. The recommendations will make reporting of quantitative OCT studies more consistent and in line with existing standards for reporting research in other biomedical areas. The recommendations originated from expert consensus and thus represent Class IV evidence. They will need to be regularly adjusted according to new insights and practices.
Summary Background Microcystic macular oedema (MMO) of the retinal inner nuclear layer (INL) has been identified in patients with multiple sclerosis (MS) by use of optical coherence tomography (OCT). ...We aimed to determine whether MMO of the INL, and increased thickness of the INL are associated with disease activity or disability progression. Methods This retrospective study was done at the Johns Hopkins Hospital (Baltimore, MD, USA), between September, 2008, and March, 2012. Patients with MS and healthy controls underwent serial OCT scans and clinical assessments including visual function. OCT scanning, including automated intraretinal layer segmentation, yielded thicknesses of the retinal nerve fibre layer, the ganglion cell layer plus inner plexiform layer, the INL plus outer plexiform layer (the combined thickness of these layers was used as a surrogate measure of INL thickness), and the outer nuclear layer. Patients with MS also underwent annual brain MRI scans. Disability scores were compared with the Wilcoxon rank-sum test. Mixed-effects linear regression was used to compare OCT measures and letter-acuity scores. Logistic regression was used to examine the relations of baseline OCT thicknesses with clinical and radiological parameters. Findings 164 patients with MS and 60 healthy controls were assessed. Mean follow-up was 25·8 months (SD 9·1) for patients with MS and 22·4 months (11·4) for healthy controls. Ten (6%) patients with MS had MMO during at least one study visit; MMO was visible at baseline in four of these patients. Healthy controls did not have MMO. Patients with MS and MMO had higher baseline MS severity scores (median 5·93 range 2·44–8·91) than those who did not have MMO at any time during the study (151 patients; 3·81 0·13–9·47; p=0·032), although expanded disability status scale (EDSS) scores were not significantly different (5·2 1·0–6·5 for patients with MS and MMO vs 2·5 0·0–8·0 for those without MMO; p=0·097). The eyes of patients with MS and MMO (12 eyes) versus those without MMO (302 eyes) had lower letter-acuity scores (100% contrast, p=0·017; 2·5% contrast, p=0·031; 1·25% contrast, p=0·014), and increased INL thicknesses (p=0·003) at baseline. Increased baseline INL thickness in patients with MS was associated with the development of contrast-enhancing lesions (p=0·007), new T2 lesions (p=0·015), EDSS progression (p=0·034), and relapses in patients with relapsing-remitting MS (p=0·008) during the study. MMO was not associated with disease activity during follow-up. Interpretation Increased INL thickness on OCT is associated with disease activity in MS. If this finding is confirmed, INL thickness could be a useful predictor of disease progression in patients with MS. Funding National Multiple Sclerosis Society, National Eye Institute, Braxton Debbie Angela Dillon and Skip Donor Advisor Fund.
Objective
Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the ...pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up. Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long‐term disability accumulation.
Methods
Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0–5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA‐DRB1*15:01 as covariates.
Results
Relapses were associated with a transient increase in disability over 1‐year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).
Interpretation
Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–remitting MS. Ann Neurol 2019;85:653–666
We have witnessed major successes in the development of effective immunomodulatory therapies capable of reducing adaptive immune-mediated myelin damage in MS over the last 30 years. However, until it ...is possible to prevent MS or initiate treatment before it has already caused lesions there is a need to repair myelin damage to prevent further axonal loss. The past decade has brought remarkable advances in our understanding of oligodendrocyte biology and the related search for remyelinating therapies in humans. In this review, we first outline the basic biology of central nervous system myelin and remyelination, including a discussion of the major identified pathways and targets that might help yield CNS remyelinating drugs. In conjunction, we provide an overview of techniques that have helped identify compounds capable of promoting oligodendrocyte precursor cell differentiation and myelination. This includes the methods for both initial
in vitro
screening and subsequent
in vivo
confirmation of the target. We then review methods proposed to quantify human remyelination
in vivo
, including visual evoked potentials and putative imaging modalities. As the remyelination era approaches, with the announcement of the first positive trial in remyelination, we are now tasked with answering new questions regarding patient-specific factors (e.g., age) that may influence the extent and optimal therapeutic window for remyelination.
Blood-derived biomarkers for brain and spinal cord diseases are urgently needed. The introduction of highly sensitive immunoassays led to a rapid increase in the number of potential blood-derived ...biomarkers for diagnosis and monitoring of neurological disorders. In 2018, the FDA authorized a blood test for clinical use in the evaluation of mild traumatic brain injury (TBI). The test measures levels of the astrocytic intermediate filament glial fibrillary acidic protein (GFAP) and neuroaxonal marker ubiquitin carboxy-terminal hydrolase L1. In TBI, blood GFAP levels are correlated with clinical severity and extent of intracranial pathology. Evidence also indicates that blood GFAP levels hold the potential to reflect, and might enable prediction of, worsening of disability in individuals with progressive multiple sclerosis. A growing body of evidence suggests that blood GFAP levels can be used to detect even subtle injury to the CNS. Most importantly, the successful completion of the ongoing validation of point-of-care platforms for blood GFAP might ameliorate the decision algorithms for acute neurological diseases, such as TBI and stroke, with important economic implications. In this Review, we provide a systematic overview of the evidence regarding the utility of blood GFAP as a biomarker in neurological diseases. We propose a model for GFAP concentration dynamics in different conditions and discuss the limitations that hamper the widespread use of GFAP in the clinical setting. In our opinion, the clinical use of blood GFAP measurements has the potential to contribute to accelerated diagnosis and improved prognostication, and represents an important step forward in the era of precision medicine.
Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of ...pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood–brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein–Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.
PDF
