Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis: a longitudinal OCT study

Inner nuclear layer; Multiple sclerosis; Optical coherence tomographyCapa nuclear interna; Esclerosis múltiple; Tomografía de coherencia ópticaCapa nuclear interior; Esclerosi múltiple; Tomografia de coherència òpticaBackground: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. Objective: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS. Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. Results: There was a significant increase in INL volume in eyes with new MSON during the study (N=61/1562, β=0.01mm3, p<.001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (β=0.005, p=.025). INL volume was independent of disease progression (β=0.002mm3, p=.474). Conclusion: Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials

Exploring Vitreous Haze as a Potential Biomarker for Accelerated Glymphatic Outflow and Neurodegeneration in Multiple Sclerosis: A Cross-Sectional Study

Background: The glymphatic system removes neurodegenerative debris. The ocular glymphatic outflow is from the eye to the proximal optic nerve. In multiple sclerosis (MS), atrophy of the optic nerve increases the glymphatic outflow space. Here, we tested whether vitreous haze (VH) can provide novel insights into the relationship between neurodegeneration and the ocular glymphatic system in MS. Methods: This cross-sectional study comprised 315 persons with MS and 87 healthy controls (HCs). VH was quantified from optical coherence tomography (OCT) volume scans. Neurodegeneration was determined on three-dimensional T1 (3DT1) MRI, lesion detection on fluid-attenuated inversion (FLAIR), and layer thickness on OCT. Generalized estimating equations, corrected for age, were used to analyze associations between VH and metrics for neurodegeneration, demographics, and clinical scales. Group differences were determined between mild, moderate, and severe disability. Results: On the group level, VH scores were comparable between MS and control (p = 0.629). In MS, VH scores declined with disease duration (β = −0.009, p = 0.004) and age (β = −0.007, p = 0.001). There was no relation between VH scores and higher age in HCs. In MS patients, VH was related to normalized gray (NGMV, β = 0.001, p = 0.011) and white matter volume (NWMV, β = 0.001, p = 0.003), macular ganglion cell–inner plexiform layer thickness (mGCIPL, β = 0.006, p < 0.001), and peripapillary retinal nerve fiber layer thickness (pRNFL, β = 0.004, p = 0.008). VH was significantly lower in severe compared to mild disability (mean difference −28.86%, p = 0.058). Conclusions: There is a correlation between VH on OCT and disease duration, more severe disability and lower brain volumes in MS. Biologically, these relationships suggest accelerated glymphatic clearance with disease-related atrophy

Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis;a longitudinal OCT study

Background: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. Objective: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS. Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. Results: There was a significant increase in INL volume in eyes with new MSON during the study (N = 61/1562, beta = 0.01mm(3), p<.001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (beta = 0.005, p =.025). INL volume was independent of disease progression (beta = 0.002mm(3), p =.474). Conclusion: Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials

Retinal atrophy in relation to visual functioning and vision-related quality of life in patients with multiple sclerosis

BACKGROUND: Inner retinal layer atrophy in patients with multiple sclerosis (MS) has been validated as a structural imaging biomarker for neurodegeneration. OBJECTIVE: To determine how retinal layer thickness relates to high-contrast visual acuity (HCVA), low-contrast visual acuity (LCVA) and vision-related quality of life (QoL) and to investigate the effect of previous episodes on MS-associated optic neuritis (MSON). METHODS: Spectral-domain optical coherence tomography (SD-OCT) was performed in 267 patients with MS. Images were segmented for the peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell inner plexiform layer (GCIPL). Ophthalmological evaluations included history of MSON, HCVA, LCVA, and vision-related QoL. RESULTS: Independent of MSON, HCVA and LCVA were significantly associated with pRNFL and GCIPL thicknesses. Vision-related QoL was positively associated with pRNFL (β = 0.92, p = 0.06) and GCIPL (β = 0.93, p = 0.02) thicknesses. These associations were independent of MSON. Not only binocular but also monocular atrophy of the inner retinal layers was associated with lower vision-related QoL. CONCLUSION: This study showed that retinal atrophy has a significant impact on visual functioning in patients with MS. OCT may therefore provide useful insight to patients with visual dysfunction, and our findings support including OCT and vision-related QoL measures into optic neuritis treatment trials

Cognitive impairment in patients with multiple sclerosis is associated with atrophy of the inner retinal layers

Background: Inner retinal layer (IRL) atrophy is a potential biomarker for neurodegeneration in multiple sclerosis (MS). Objective: To investigate the relationship between cognitive impairment and IRL atrophy in MS. Methods: Cross-sectional study design, including 217 patients and 59 healthy controls. Subjects were investigated clinically, underwent retinal optical coherence tomography (OCT) and comprehensive cognitive assessments. The association between these modalities was evaluated by regression analyses. Results: Of the patients, 44.2% were cognitively impaired. In the absence of multiple sclerosis–associated optic neuritis (MSON), cognitively impaired patients had a significantly lower mean peripapillary retinal nerve fiber layer (pRNFL, Δ: 8.13 µm, p < 0.001) and mean macular ganglion cell–inner plexiform layer (mGCIPL, Δ: 11.50 µm, p < 0.001) thickness compared to cognitively preserved patients. There was a significant association between the presence of cognitive impairment and pRNFL (odds ratio (OR): 1.11, 95% confidence interval (CI): 1.04–1.18, p = 0.001) and mGCIPL (OR = 1.11, 95% CI = 1.05–1.18, p < 0.001) atrophy. This association was masked by the severe IRL atrophy seen following MSON. Conclusion: The strong relationship between cognitive impairment across multiple cognitive domains and atrophy of the pRNFL and mGCIPL in patients who never suffered from MSON suggests that OCT is useful in assessing central nervous system neurodegeneration in MS

Longitudinal development of PHOMS suggest a novel pathological pathway in MS.

OBJECTIVE Peripapillary Hyperreflective Ovoid Mass-like Structures (PHOMS) are a new spectral domain Optical Coherence Tomography (OCT) finding. METHODS Prospective, longitudinal study. Patients (n=212) with MS (n=418 eyes), 59 healthy controls (HC, n=117 eyes) and 267 non-MS disease controls (534 eyes). OCT and Diffusion Tensor Imaging. RESULTS There were no PHOMS in HC eyes (0/117, 0%). The prevalence of PHOMS was significantly higher in patients with MS (34/212, p=0.001) and MS eyes (45/418, p=0.0002) if compared to HC (0/59, 0/117). The inter-rater agreement for PHOMS was 97.9%, kappa 0.951. PHOMS were present in 16% of patients with relapsing remitting, 16% of patients with progressive and 12% of patients with secondary progressive disease course (2% of eyes). There was no relationship of PHOMS with age, disease duration, disease course, disability or disease modifying treatments. The fractional anisotropy of the optic radiations was lower in patients without PHOMS (0.814) if compared to patients with PHOMS (0.845, p=0.03). The majority of PHOMS remained stable, but increase in size and de novo development of PHOMS were also observed. In non-MS disease controls, PHOMS were observed in intracranial hypertension (62%), ODD (47%), anomalous optic discs (44%), isolated optic neuritis (19%) and optic atrophy (12%). INTERPRETATION These data suggest that PHOMS are a novel finding in MS pathology. Future research is needed to determine if development of PHOMS in MS is due to intermittently raised intracranial pressure or an otherwise impaired "glymphatic" outflow from eye to brain. This article is protected by copyright. All rights reserved

Quantification of Visual Fixation in Multiple Sclerosis

Purpose: Eye movement abnormalities are common in multiple sclerosis (MS), and infrared oculography is a noninvasive method for quantification. This study aims to describe and classify abnormalities of visual fixation and their clinical relevance in MS. Methods: A validated standardized infrared oculography protocol, Demonstrate Eye Movement Networks with Saccades, was used for quantifying gaze stability during a fixation task in MS patients and healthy controls. Saccadic intrusions, gaze drift, and stability of fixation around the drift line were used to subclassify MS patients by performing receiver operating characteristic analyses of different parameters. The relationship between the presence of abnormalities of fixation and visual functioning was analyzed using logistic regression models, which was adjusted for possible confounders. Results: This cross-sectional study included 213 subjects with MS and 57 healthy controls. Square wave jerk abnormalities were present in 24% of MS patients. The prevalence was higher in more disabled subjects. The presence of larger square wave jerks (with a higher amplitude) in the MS patients was related to complaints of focusing on stationary objects (odds ratio, 2.2; P = 0.035) and a lower vision-related quality of life (odds ratio, 2.56; P = 0.012). Conclusions: This study provided a comprehensive overview of the characteristics of problems with visual fixation in subjects with MS. The most important and most common finding was the presence of larger square wave jerks during fixation, which was related to visual functioning in daily life