Kim Lea Young

Retinal Damage in Multiple Sclerosis Disease Subtypes Measured by High-Resolution Optical Coherence Tomography

Background. Optical coherence tomography (OCT) has facilitated characterisation of retinal alterations in MS patients. Only scarce and in part conflicting data exists on different MS subtypes. Objective. To analyse patterns of retinal changes in different subtypes of MS with latest spectral-domain technology. Methods. In a three-centre cross-sectional study 414 MS patients and 94 healthy controls underwent spectral-domain OCT examination. Results. Eyes of MS patients without a previous optic neuritis showed a significant reduction of both retinal nerve fibre layer (RNFL) thickness and total macular volume (TMV) compared to healthy controls independent of the MS subtype (P < 0.001 for all subtypes). RNFL thickness was lower in secondary progressive MS (SPMS) eyes compared to relapsing-remitting MS (RRMS) eyes (P = 0.007), and TMV was reduced in SPMS and primary progressive MS (PPMS) eyes compared to RRMS eyes (SPMS: P = 0.039, PPMS: P = 0.005). Independent of the subtype a more pronounced RNFL thinning and TMV reduction were found in eyes with a previous optic neuritis compared to unaffected eyes. Conclusion. Analysis of this large-scale cross-sectional dataset of MS patients studied with spectral-domain OCT confirmed and allows to generalize previous findings. Furthermore it carves out distinct patterns in different MS subtypes.

Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography

Sir, We read the recent Brain publication by Saidha et al. (2011) with great interest. In their manuscript, the authors suggested that primary retinal pathology detectable by optical coherence tomography (OCT) defines a subset of patients with multiple sclerosis (Saidha et al ., 2011). This subgroup of patients, which they termed ‘macular thinning predominant phenotype’, was reported to exist in ∼10% of the entire multiple sclerosis cohort examined by spectral domain OCT (Cirrus) at the authors’ centres. The macular thinning predominant OCT phenotype was defined by a combination of average macular thickness below the 5th percentile, with ipsilateral normal average retinal nerve fibre layer (RNFL) thicknesses (between the 5th and 95th percentiles of RNFL values from the manufacturers normative database), in one or both eyes, in the absence of a history of acute optic neuritis in affected eyes (Saidha et al ., 2011). Sixty-two per cent (31/50) of patients fulfilling the macular thinning predominant OCT criteria had a macular thickness below the 1st percentile. In addition, there was a remarkable male preponderance among patients with the macular thinning predominant phenotype (70% male versus 30% female), a difference that was even more pronounced (77.4% male versus 22.6% female) among those patients with very low macular thicknesses (<1st percentile). These in vivo findings are in line with a recent post-mortem analysis reporting retinal pathology in multiple sclerosis beyond damage to the RNFL and the ganglion cell layer (Green et al ., 2010). These data are intriguing in that they point to a novel concept of primary retinal damage in multiple sclerosis. They indicate that retinal pathology might not only develop as a consequence of inflammatory attacks to the anterior optic pathway causing …

Loss of retinal nerve fibre layer axons indicates white but not grey matter damage in early multiple sclerosis.

Optical coherence tomography (OCT) has shown thinning of the retinal nerve fibre layer (RNFL) and total macular volume (TMV) in multiple sclerosis (MS) patients. Measures of retinal atrophy are associated with the brain parenchymal fraction (BPF) assessed by magnetic resonance imaging (MRI). However, in MS, data on the relation of OCT measures and grey and white matter volumes are contradictory. We performed a prospective cross‐sectional study with a statistically pre‐defined endpoint to test our hypothesis that OCT measures of neuro‐axonal degeneration are related to global and partial brain atrophy in early forms of MS.

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response

Objective To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD). Design This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes. Results 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065). Conclusions Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.

Increased Perfusion in Normal Appearing White Matter in High Inflammatory Multiple Sclerosis Patients

Purpose Although cerebral perfusion alterations have long been acknowledged in multiple sclerosis (MS), the relationship between measurable perfusion changes and the status of highly active MS has not been examined. We hypothesized that alteration of perfusion can be detected in normal appearing white matter and is increased in high inflammatory patients. Materials and Methods Thirty-three patients with relapsing-remitting MS underwent four monthly 3T MRI scans including dynamic susceptibility contrast perfusion-weighted MRI. Cerebral blood flow (CBF) and cerebral blood volume (CBV) were measured in normal appearing white matter. Patients were stratified in a high- and low-inflammatory group according to the number of new contrast enhancing lesions. Results Thirteen patients were classified as high-inflammatory. Compared to low-inflammatory patients, the high-inflammatory group demonstrated significantly higher CBV (p = 0.001) and CBF (p = 0.014) values. A mixed model analysis to assess independent variables associated with CBV and CBF revealed that white matter lesion load and atrophy measurements had no significant influence on CBF and CBV. Conclusion This work provides evidence that high inflammatory lesion load is associated with increased CBV and CBF, underlining the role of global modified microcirculation prior to leakage of the blood-brain barrier in the pathophysiology of MS. Perfusion changes might therefore be sensitive to active inflammation apart from lesion development without local blood–brain barrier breakdown, and could be utilized to further assess the metabolic aspect of current inflammation.

Regression to the Mean and Predictors of MRI Disease Activity in RRMS Placebo Cohorts - Is There a Place for Baseline-to-Treatment Studies in MS?

Background Gadolinium-enhancing (GD+) lesions and T2 lesions are MRI outcomes for phase-2 treatment trials in relapsing-remitting Multiple Sclerosis (RRMS). Little is known about predictors of lesion development and regression-to-the-mean, which is an important aspect in early baseline-to-treatment trials. Objectives To quantify regression-to-the-mean and identify predictors of MRI lesion development in placebo cohorts. Methods 21 Phase-2 and Phase-3 trials were identified by a systematic literature research. Random-effects meta-analyses were performed to estimate development of T2 and GD+ after 6 months (phase-2) or 2 years (phase-3). Predictors of lesion development were evaluated with mixed-effect meta-regression. Results The mean number of GD+-lesions per scan was similar after 6 months (1.19, 95%CI: 0.87-1.51) and 2 years (1.19, 95%CI: 1.00-1.39). 39% of the patients were without new T2-lesion after 6 month and 19% after 2 years (95%CI: 12-25%). Mean number of baseline GD+-lesions was the best predictor for new lesions after 6 months. Conclusion Baseline GD-enhancing lesions predict evolution of Gd- and T2 lesions after 6 months and might be used to control for regression to the mean effects. Overall, proof-of-concept studies with a baseline to treatment design have to face a regression to 1.2 GD+lesions per scan within 6 months.

T1- Thresholds in Black Holes Increase Clinical-Radiological Correlation in Multiple Sclerosis Patients.

BACKGROUND Magnetic Resonance Imaging (MRI) is an established tool in diagnosing and evaluating disease activity in Multiple Sclerosis (MS). While clinical-radiological correlations are limited in general, hypointense T1 lesions (also known as Black Holes (BH)) have shown some promising results. The definition of BHs is very heterogeneous and depends on subjective visual evaluation. OBJECTIVE We aimed to improve clinical-radiological correlations by defining BHs using T1 relaxation time (T1-RT) thresholds to achieve best possible correlation between BH lesion volume and clinical disability. METHOD 40 patients with mainly relapsing-remitting MS underwent MRI including 3-dimensional fluid attenuated inversion recovery (FLAIR), magnetization-prepared rapid gradient echo (MPRAGE) before and after Gadolinium (GD) injection and double inversion-contrast magnetization-prepared rapid gradient echo (MP2RAGE) sequences. BHs (BHvis) were marked by two raters on native T1-weighted (T1w)-MPRAGE, contrast-enhancing lesions (CE lesions) on T1w-MPRAGE after GD and FLAIR lesions (total-FLAIR lesions) were detected separately. BHvis and total-FLAIR lesion maps were registered to MP2RAGE images, and the mean T1-RT were calculated for all lesion ROIs. Mean T1 values of the cortex (CTX) were calculated for each patient. Subsequently, Spearman rank correlations between clinical scores (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite) and lesion volume were determined for different T1-RT thresholds. RESULTS Significant differences in T1-RT were obtained between all different lesion types with highest T1 values in visually marked BHs (BHvis: 1453.3±213.4 ms, total-FLAIR lesions: 1394.33±187.38 ms, CTX: 1305.6±35.8 ms; p<0.05). Significant correlations between BHvis/total-FLAIR lesion volume and clinical disability were obtained for a wide range of T1-RT thresholds. The highest correlation for BHvis and total-FLAIR lesion masks were found at T1-RT>1500 ms (Expanded Disability Status Scale vs. lesion volume: rBHvis = 0.442 and rtotal-FLAIR = 0.497, p<0.05; Multiple Sclerosis Functional Composite vs. lesion volume: rBHvis = -0.53 and rtotal-FLAIR = -0.627, p<0.05). CONCLUSION Clinical-radiological correlations in MS patients are increased by application of T1-RT thresholds. With the short acquisition time of the MP2RAGE sequences, quantitative T1 maps could be easily established in clinical studies.

Short-term MRI measurements as predictors of EDSS progression in relapsing-remitting multiple sclerosis: grey matter atrophy but not lesions are predictive in a real-life setting

Background Magnetic resonance imaging (MRI) is the best biomarker of inflammatory disease activity in relapsing remitting Multiple Sclerosis (RRMS) so far but the association with disability is weak. Appearance of new MRI-lesions is used to evaluate response to immunotherapies in individual patients as well as being the most common primary outcome in phase-2 trials. Measurements of brain atrophy show promising outcomes in natural cohort studies and some phase-2 trials. From a theoretical perspective they might represent irreversible neurodegeneration and be more closely associated with disability. However, these atrophy measurements are not yet established as prognostic factors in real-life clinical routine. High field MRI has improved image quality and resolution and new methods to measure atrophy dynamics have become available. Objective To investigate the predictive value of MRI classification criteria in to high/low atrophy and inflammation groups, and to explore predictive capacity of two consecutive routine MRI scans for disability progression in RRMS in a real-life prospective cohort. Methods 82 RRMS-patients (40 untreated, 42 treated with immunotherapies, mean age 40 years, median Expanded Disability Status Scale (EDSS) of 2, underwent two clinically indicated MRI scans (3 Tesla) within 5–14 months, and EDSS assessment after a mean of 3.0 (1.5–4.2) years. We investigated the predictive value of predefined classifications in low/high inflammatory and atrophy groups for EDSS progression (≥1.5 if baseline EDSS = 0, ≥1.0 if baseline EDSS <5, ≥0.5 for other) by chi-square tests and by analysis of variance (ANOVA). The classifications were based on current scientific or clinical recommendation (e.g., treatment response criteria). Brain atrophy was assessed with three different methods (SIENA, SIENAX, and FreeSurfer). Post-hoc analyses aimed to explore clinical data and dynamics of MRI outcomes as predictors in multivariate linear and logit models. Results Progression was observed in 24% of patients and was independent from treatment status. None of the predefined classifications were predictive for progression. Explorative post-hoc analyses found lower baseline EDSS and higher grey matter atrophy (FreeSurfer) as best predictors (R2 = 0.29) for EDSS progression and the accuracy was overall good (Area under the curve = 0.81). Conclusion Beside EDSS at baseline, short-term grey matter atrophy is predictive for EDSS progression in treated and untreated RRMS. The development of atrophy measurements for individual risk counselling and evaluation of treatment response seems possible, but needs further validation in larger cohorts. MRI-atrophy estimates from the FreeSurfer toolbox seem to be more reliable than older methods.

Ruxolitinib treatment in a patient with neuromyelitis optica: A case report

Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing autoimmune demyelinating disease of the CNS that predominantly affects the optic nerves and the spinal cord.1 Because of the severity and poor recovery of attacks, aggressive immunosuppressive agents are used early in the clinical course to reduce relapse frequency. Apart from classical immunosuppressant agents, biologicals such as rituximab, eculizumab, or tocilizumab have been used for relapse prevention.2 Based on retrospective data, 17–53% of patients have break-through relapses under the most commonly used treatments azathioprine, mycophenolate mofetil, or rituximab.3

Chronic T2 Lesions in Multiple Sclerosis are Heterogeneous Regarding Phase MR Imaging.

PurposePhase imaging provides additional information on multiple sclerosis (MS) lesions and may in combination with mean diffusivity (MD) and magnetization transfer ratio (MTR) help differentiating heterogeneity of MS lesion pathology.MethodsMagnetic resonance imaging (MRI) was performed in 23 MS patients including diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and SWI. Mean values (MTR, MD, and homodyne filtered phase) from 138 chronic MS lesions and normal appearing white matter (NAWM) were obtained and correlations examined. For explorative analysis, a divisive hierarchical clustering algorithm was applied.ResultsPhase characteristics were an independent characteristic of chronic T2 lesions, as MTR and MD were not correlated with phase values (R = − 0.23, R = − 0.18). Dependent on MTR, MD, and phase, cluster analysis led to five lesion groups. Of the two groups with phase values close to NAWM, one presented with highest MD and most severe MTR decrease (p  =  0.01), the other with slight MD increase and MTR decrease. Two lesion groups with highest phase values (p  =  0.01) displayed slightly increased MD and moderate decrease in MTR. Clinical data including EDSS, disease duration, and age did not differ significantly between groups.ConclusionsIncreased phase is predominantly detectable in lesions with clear MTR decrease but only moderate MD increase. Phase images seem to represent an independent parameter for MS lesion characterization and may provide additional information on MS lesion heterogeneity.