Summary Optical coherence tomography (OCT) is a new method that could aid analysis of neurodegeneration in multiple sclerosis (MS) by capturing thinning of the retinal nerve fibre layer (RNFL). ...Meta-analyses of data for time domain OCT show RNFL thinning of 20·38 μm (95% CI 17·91–22·86, n=2063, p<0·0001) after optic neuritis in MS, and of 7·08 μm (5·52–8·65, n=3154, p<0·0001) in MS without optic neuritis. The estimated RNFL thinning in patients with MS is greater than the extent expected in normal ageing, probably because of retrograde trans-synaptic degeneration and progressive loss of retinal ganglion cells, in addition to the more pronounced thinning caused by optic neuritis if present. RNFL thickness correlates with visual and neurological functioning as well as with paraclinical data. Developments that could improve understanding of the relation between structure and function in MS pathophysiology include spectral or Fourier domain OCT technology, polarisation-sensitive OCT, fluorescence labelling, structural assessment of action-potential propagation, and segmentation algorithms allowing quantitative assessment of retinal layers.
Neuromyelitis optica (NMO, Devic’s syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and ...treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.
Retinal optical coherence tomography (OCT) is an imaging biomarker for neurodegeneration in multiple sclerosis (MS). In order to become validated as an outcome measure in multicenter studies, ...reliable quality control (QC) criteria with high inter-rater agreement are required.
A prospective multicentre study on developing consensus QC criteria for retinal OCT in MS: (1) a literature review on OCT QC criteria; (2) application of these QC criteria to a training set of 101 retinal OCT scans from patients with MS; (3) kappa statistics for inter-rater agreement; (4) identification reasons for inter-rater disagreement; (5) development of new consensus QC criteria; (6) testing of the new QC criteria on the training set and (7) prospective validation on a new set of 159 OCT scans from patients with MS. The inter-rater agreement for acceptable scans among OCT readers (n = 3) was moderate (kappa 0·45) based on the non-validated QC criteria which were entirely based on the ophthalmological literature. A new set of QC criteria was developed based on recognition of: (O) obvious problems, (S) poor signal strength, (C) centration of scan, (A) algorithm failure, (R) retinal pathology other than MS related, (I) illumination and (B) beam placement. Adhering to these OSCAR-IB QC criteria increased the inter-rater agreement to kappa from moderate to substantial (0.61 training set and 0.61 prospective validation).
This study presents the first validated consensus QC criteria for retinal OCT reading in MS. The high inter-rater agreement suggests the OSCAR-IB QC criteria to be considered in the context of multicentre studies and trials in MS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. ...The aim of this first-in-man trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1-20, MOG35-55, MBP13-32, MBP83-99, MBP111-129, MBP146-170, and PLP139-154). An open-label, single-center, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen-coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (>1 × 10(9)) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach.
Optic neuritis is an inflammatory optic neuropathy that affects many patients with multiple sclerosis (MS) at some point during their disease course. Differentiation of acute episodes of ...MS-associated optic neuritis from other autoimmune and inflammatory optic neuropathies is vital for treatment choice and further patient management, but is not always straightforward. Over the past decade, a number of new imaging, laboratory and electrophysiological techniques have entered the clinical arena. To date, however, no consensus guidelines have been devised to specify how and when these techniques can be most rationally applied for the diagnostic work-up of patients with acute optic neuritis. In this article, we review the literature and attempt to formulate a consensus for the investigation of patients with acute optic neuritis, both in standard care and in research with relevance to clinical treatment trials.
Background:
REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing–remitting multiple sclerosis (RRMS) patients.
Objective:
To examine the ...efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients.
Methods:
Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60.
Results:
In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable.
Conclusion:
Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.
Objective
Automated quantification of infratentorial multiple sclerosis lesions on magnetic resonance imaging is clinically relevant but challenging. To overcome some of these problems, we propose a ...fully automated lesion segmentation algorithm using 3D convolutional neural networks (CNNs).
Methods
The CNN was trained on a FLAIR image alone or on FLAIR and T1-weighted images from 1809 patients acquired on 156 different scanners. An additional training using an extra class for infratentorial lesions was implemented. Three experienced raters manually annotated three datasets from 123 MS patients from different scanners.
Results
The inter-rater sensitivity (SEN) was 80% for supratentorial lesions but only 62% for infratentorial lesions. There was no statistically significant difference between the inter-rater SEN and the SEN of the CNN with respect to the raters. For supratentorial lesions, the CNN featured an intra-rater intra-scanner SEN of 0.97 (R1 = 0.90, R2 = 0.84) and for infratentorial lesion a SEN of 0.93 (R1 = 0.61, R2 = 0.73).
Conclusion
The performance of the CNN improved significantly for infratentorial lesions when specifically trained on infratentorial lesions using a T1 image as an additional input and matches the detection performance of experienced raters. Furthermore, for infratentorial lesions the CNN was more robust against repeated scans than experienced raters.
Key Points
•
A 3D convolutional neural network was trained on MRI data from 1809 patients (156 different scanners) for the quantification of supratentorial and infratentorial multiple sclerosis lesions.
•
Inter-rater variability was higher for infratentorial lesions than for supratentorial lesions. The performance of the 3D convolutional neural network (CNN) improved significantly for infratentorial lesions when specifically trained on infratentorial lesions using a T1 image as an additional input.
•
The detection performance of the CNN matches the detection performance of experienced raters.
Natalizumab, an antibody against the α4 subunit of α4 integrins, has been approved for multiple sclerosis (MS) therapy based on its high efficacy and safety profile. However, natalizumab has been ...associated with the development of progressive multifocal leukoencephalopathy (PML), a disorder caused by JC virus (JCV) infection. In order to improve our understanding of the mechanism of action of natalizumab and to identify possible risk factors for PML development, we have characterized in detail the cell blood composition in MS patients treated with natalizumab for more than 30 months. Natalizumab induced the release of lymphoid‐ but not myeloid precursor cells, which resulted in a chronic increase ofT‐, NK‐ and particularly B cells. While the percentage of recent thymic emigrants (RTEs), naϊve, effector or memory T cells remained unchanged during treatment, a higher percentage of memory‐ and marginal zone (MZ)‐like, but not of naϊve B cells, was observed, which most likely is due to a decreased retention of these cells within the splenic MZ. The ability of natalizumab to influence B‐cell migration and homeostasis through the splenic MZ, where JCV has been detected, adds to the list of natalizumab effects and may contribute to PML development by disseminating JCV.
The objective is to estimate average global and regional percentage brain volume loss per year (BVL/year) of the physiologically ageing brain. Two independent, cross-sectional single scanner cohorts ...of healthy subjects were included. The first cohort (
n
= 248) was acquired at the Medical Prevention Center (MPCH) in Hamburg, Germany. The second cohort (
n
= 316) was taken from the Open Access Series of Imaging Studies (OASIS). Brain parenchyma (BP), grey matter (GM), white matter (WM), corpus callosum (CC), and thalamus volumes were calculated. A non-parametric technique was applied to fit the resulting age–volume data. For each age, the BVL/year was derived from the age–volume curves. The resulting BVL/year curves were compared between the two cohorts. For the MPCH cohort, the BVL/year curve of the BP was an increasing function starting from 0.20% at the age of 35 years increasing to 0.52% at 70 years (corresponding values for GM ranged from 0.32 to 0.55%, WM from 0.02 to 0.47%, CC from 0.07 to 0.48%, and thalamus from 0.25 to 0.54%). Mean absolute difference between BVL/year trajectories across the age range of 35–70 years was 0.02% for BP, 0.04% for GM, 0.04% for WM, 0.11% for CC, and 0.02% for the thalamus. Physiological BVL/year rates were remarkably consistent between the two cohorts and independent from the scanner applied. Average BVL/year was clearly age and compartment dependent. These results need to be taken into account when defining cut-off values for pathological annual brain volume loss in disease models, such as multiple sclerosis.
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