Johns Hopkins University School of Medicine
Division of Neuroimmunology and Neurological Infections, Department of Neurology

Author Of 1 Presentation

Neuro-Ophthalmology Oral Presentation

PS15.04 - The presence of epiretinal membranes in multiple sclerosis may be associated with increased disability

Speakers
Presentation Number
PS15.04
Presentation Topic
Neuro-Ophthalmology
Lecture Time
13:27 - 13:39

Abstract

Background

Neuroglial cells are implicated in the pathobiology of Multiple sclerosis (MS). Müller glia, specialized radial glial cells of the retina responsible for helping maintain retinal neuronal integrity, are postulated to be activated in MS. Müller glia activation is also implicated in epiretinal membrane (ERM) formation, an aberrant healing response to retinal damage.

Objectives

To examine ERM prevalence in MS, and differences in expanded disability status scale (EDSS) and optical coherence tomography (OCT) measured retinal layer thicknesses, between MS patients with (ERM-MS) and without ERMs (non-ERM-MS).

Methods

In this cross-sectional study, 1463 MS patients (2926 eyes) underwent Cirrus spectral-domain OCT (with automated macular layer segmentation). All scans underwent qualitative and quantitative quality control (QC), and ERM presence was recorded. Excluding patients with optic neuritis history, ERM-MS (n=48) were matched 1:1 to non-ERM-MS based on age, body mass index (BMI) and sex. Fellow eye layer thicknesses of ERM-MS were compared to the average binocular layer thicknesses of non-ERM-MS patients, to investigate the possibility of a phenotype effect. Mixed effects linear regression models were used in analyses.

Results

ERM prevalence in this MS cohort was 4.9%. Post-matching mean age and BMI were respectively 60.7 years (SD 6.3) and 28.2 kg/m2 (SD 9.6) in ERM-MS, and 60.4 years (SD 5.7) and 27.5 kg/m2 (SD 8.9) in non-ERM-MS (p=0.7 for both). Both groups had 77.1% females. Median EDSS was 4 (IQR 2.5-6.5) in ERM-MS and 3 (IQR 1.5-6) in non-ERM-MS (difference: 1.1, CI: 0.2 – 1.9, p=0.021). Mean ganglion cell-inner plexiform layer (GCIPL) thickness was 67.1 um (SD 6.5) in ERM-MS and 70.2 um (SD 6.2) in non-ERM-MS (difference: -3.1, CI: -6.3 – -0.1, p=0.049). Moreover, mean retinal pigment epithelium (RPE) thickness was 31.6 um (SD 1.3) in ERM-MS and 32.4 um (SD 0.9) in non-ERM-MS (difference: -0.7 um, CI: -1.3 - -0.1, p=0.017).

Conclusions

Our findings suggest ERM-MS patients phenotypically have higher EDSS scores, and lower GCIPL and RPE thicknesses, as compared to non-ERM-MS patients. Blood-retinal barrier disruption due to retinal inflammation, among other reasons, may activate Müller glia in MS. This may help explain our finding that ERM presence in MS may be associated with disability. Moreover, RPE cells may be recruited in the ERM formation process, similarly explaining our finding of reduced RPE thickness among ERM-MS patients.

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Author Of 3 Presentations

Neuro-Ophthalmology Late Breaking Abstracts

LB1217 - Macular pigment concentration and distribution in multiple sclerosis (ID 2084)

Speakers
Presentation Number
LB1217
Presentation Topic
Neuro-Ophthalmology

Abstract

Background

Oxidative stress is implicated in inflammation and neurodegeneration in multiple sclerosis (MS). Similar to the brain, the retina is susceptible to reactive oxygen species (ROS). Macular pigment (MP), consisting primarily of the carotenoids lutein (L) and zeaxanthin (Z) blocks deleterious blue light, and provides anti-oxidant protection. To date, there has been a paucity of study of MP in MS.

Objectives

To examine MP concentration and distribution in MS eyes relative to healthy control (HC) eyes using macular pigment optical density (MPOD) imaging.

Methods

In this cross-sectional study, 27 MS patients (47 eyes) and 19 HCs (37 eyes) underwent MPOD imaging on a Spectralis (Heidelberg) device. MP absorbs blue light, but allows the free passage of green light. MPOD imaging involves the subtraction of blue from green wavelength auto-fluorescence macular scans, providing the optical density (OD) of MP. Radii of interest for MPOD were 0°, 0.23°, 0.51°, 0.98° and 1.99° degrees of eccentricity from the fovea, as well as peak, and half-peak MPOD locations. Study participants completed dietary L & Z screening questionnaires. Mixed effects linear regression models were used in analyses.

Results

Mean MPOD at 0° was 0.52 density units (d.u.) (SD 0.14) in MS and 0.63 d.u. (SD 0.18) in HC eyes (difference: -0.10 d.u., CI: -0.18 - -0.01, p=0.027). The median MPOD peak location eccentricity was 0.08° (IQR: 0 - 0.12) in MS and 0.04° (IQR: 0 - 0.08) in HC eyes (difference: 0.10°, CI: 0.01 - 0.20, p=0.031). Mean MPOD at the peak location was -0.09 d.u. lower in MS eyes relative to HC eyes (CI: -0.18 - -0.01, p=0.04). In addition, the half-peak MPOD location, similar to the MPOD peak location, was situated further from the fovea in MS eyes relative to HC eyes (difference: 0.28°, CI: 0.10 - 0.47, p=0.002). Analyses adjusted for age, body mass index, sex, and L & Z dietary scores, showed similar differences for MPOD at 0° eccentricity, and at the peak MPOD location, between MS and HC eyes.

Conclusions

Our findings suggest MP concentrations are reduced in MS eyes, with peak and half-peak MPOD locations shifted further from the fovea than in HC eyes. Increases in ROS consuming antioxidant MPs, and/or dysfunction in proteins transferring carotenoids to the fovea, among other reasons, may help explain reductions in MPOD in MS eyes. Our preliminary finding warrant further study, in larger, prospective MS cohorts, including determination of their clinical relevance.

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Biomarkers and Bioinformatics Poster Presentation

P0036 - Cerebral hypometabolism is a marker of disease severity in multiple sclerosis: a non-invasive imaging study using T2-Relaxation-Under-Spin-Tagging MRI (ID 1856)

Speakers
Presentation Number
P0036
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Metabolic dysfunction at a cellular level is a crucial element of progressive neuronal dysfunction, and ultimately neurodegeneration in multiple sclerosis (MS). Changes in retinal superficial vascular plexus (SVP) density, which is known to be reduced in MS, may in part reflect metabolic demand in the neuronal layers of the retina, and could accordingly provide insight regarding concurrent metabolic alterations in the brain.

Objectives

To compare cerebral metabolism in people with MS (PwMS) to healthy controls (HCs) using T2-Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI, and assess whether cerebral hypometabolism is related to reduced SVP density measured using optical coherence tomography angiography (OCTA).

Methods

In this cross-sectional study, PwMS and HC underwent TRUST and PC MRI to derive the oxygen extraction fraction (OEF; a measure of the efficiency of cerebral tissue in extracting oxygen from circulating blood) and cerebral metabolic rate of oxygen consumption (CMRO2; a volume-adjusted measure of cerebral tissue metabolism). A subset of PwMS underwent OCTA, with quantification of retinal SVP density using a deep neural network based-algorithm. Statistical analyses were adjusted for age and intra-subject inter-eye correlations, where relevant.

Results

We included 49 PwMS and 80 HCs. Overall, OEF was lower, and CMRO2 trended towards being lower, in PwMS as compared to HCs (OEF: 35.9% [SD 5.1] vs. 40.9%, [SD 5.1], p=0.04; CMRO2: 156.3 umol/mL/min [SD 23.9] vs. 158.7 umol/mL/min [SD 19.9], p=0.08). Lower CMRO2 was associated with longer MS disease duration (p=0.02), higher expanded disability status scale score (p=0.01) and lower subcortical gray matter volume fraction (p=0.04). Additionally, lower CMRO2 was associated with higher age in PwMS (p=0.02), but not in HCs (p=0.19), in whom effective neurovascular coupling is expected to maintain a fairly constant rate with aging. Lower OEF correlated with lower retinal SVP density in PwMS (r=0.32, p=0.02).

Conclusions

Cerebral hypometabolism is evident in PwMS compared to HCs, and is associated with longer disease duration and greater disability. Furthermore, alterations in cerebral metabolism are mirrored by alterations in retinal SVP density, supporting the utility of these non-invasive imaging techniques to measure inter-linked pathobiological processes. The ability to detect metabolic dysfunction in-vivo in PwMS may help facilitate the identification of new therapeutic targets and outcome measures for clinical trials.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0251 - Early factors associated with later conversion to multiple sclerosis in patients presenting with isolated myelitis (ID 1848)

Speakers
Presentation Number
P0251
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

In patients presenting with ‘transverse myelitis’ without clinical or radiological evidence of inflammation/demyelination elsewhere in the central nervous system (i.e. isolated myelitis), it remains challenging to predict risk of later conversion to multiple sclerosis (MS).

Objectives

To identify early clinical and paraclinical factors that may help predict later conversion to MS in patients presenting with isolated myelitis.

Methods

In this retrospective cohort study, we examined a carefully defined population of patients who attended our specialized myelopathy clinic from 2010 to 2018. We included patients diagnosed with isolated myelitis who were followed clinically and radiologically for at least 1 year. We excluded patients with known MS (defined by the 2017 revised McDonald criteria), aquaporin-4 (AQP4)-IgG seropositivity, myelin oligodendrocyte glycoprotein (MOG)-IgG seropositivity, or other identified etiology of myelitis. Logistic regression was used to identify factors predictive of conversion to MS during follow-up.

Results

We included 100 patients (mean age 40.5 years [SD 12.6], 60% female). Over a median follow-up period of 4.3 years (range, 1.0-17.4 years), 25 patients (25%) converted to MS. Conversion to MS occurred in 25 of 77 patients (32%) with short-segment myelitis (longest cord lesion spanning <3 vertebral segments on MRI) as compared to zero of 23 patients with longitudinally-extensive myelitis (0%, p=0.002). Amongst patients with short-segment myelitis, factors identified as highly predictive of conversion to MS using multivariable logistic regression included positive cerebrospinal fluid (CSF)-restricted oligoclonal bands (adjusted odds ratio [OR] 9.18, 95% CI 2.06 to 41.02, p=0.004), younger age (adjusted OR 1.06 for each year younger, 95% CI 1.00 to 1.12, p=0.04) and longer follow-up period (adjusted OR 1.25 for each year longer, 95% CI 1.01 to 1.55, p=0.04). Conversion to MS occurred at a median of 2.77 years (range 0.20-4.39) after onset of myelitis.

Conclusions

Short-segment MRI cord lesion(s), positive CSF-restricted oligoclonal bands, younger age, and longer follow-up are all factors predictive of conversion to MS in patients presenting with isolated myelitis. Conversion to MS typically occurs within a few years after a bout of isolated myelitis, emphasizing the importance of close clinical and radiological follow-up after such an attack.

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Presenter Of 2 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0036 - Cerebral hypometabolism is a marker of disease severity in multiple sclerosis: a non-invasive imaging study using T2-Relaxation-Under-Spin-Tagging MRI (ID 1856)

Speakers
Presentation Number
P0036
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Metabolic dysfunction at a cellular level is a crucial element of progressive neuronal dysfunction, and ultimately neurodegeneration in multiple sclerosis (MS). Changes in retinal superficial vascular plexus (SVP) density, which is known to be reduced in MS, may in part reflect metabolic demand in the neuronal layers of the retina, and could accordingly provide insight regarding concurrent metabolic alterations in the brain.

Objectives

To compare cerebral metabolism in people with MS (PwMS) to healthy controls (HCs) using T2-Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI, and assess whether cerebral hypometabolism is related to reduced SVP density measured using optical coherence tomography angiography (OCTA).

Methods

In this cross-sectional study, PwMS and HC underwent TRUST and PC MRI to derive the oxygen extraction fraction (OEF; a measure of the efficiency of cerebral tissue in extracting oxygen from circulating blood) and cerebral metabolic rate of oxygen consumption (CMRO2; a volume-adjusted measure of cerebral tissue metabolism). A subset of PwMS underwent OCTA, with quantification of retinal SVP density using a deep neural network based-algorithm. Statistical analyses were adjusted for age and intra-subject inter-eye correlations, where relevant.

Results

We included 49 PwMS and 80 HCs. Overall, OEF was lower, and CMRO2 trended towards being lower, in PwMS as compared to HCs (OEF: 35.9% [SD 5.1] vs. 40.9%, [SD 5.1], p=0.04; CMRO2: 156.3 umol/mL/min [SD 23.9] vs. 158.7 umol/mL/min [SD 19.9], p=0.08). Lower CMRO2 was associated with longer MS disease duration (p=0.02), higher expanded disability status scale score (p=0.01) and lower subcortical gray matter volume fraction (p=0.04). Additionally, lower CMRO2 was associated with higher age in PwMS (p=0.02), but not in HCs (p=0.19), in whom effective neurovascular coupling is expected to maintain a fairly constant rate with aging. Lower OEF correlated with lower retinal SVP density in PwMS (r=0.32, p=0.02).

Conclusions

Cerebral hypometabolism is evident in PwMS compared to HCs, and is associated with longer disease duration and greater disability. Furthermore, alterations in cerebral metabolism are mirrored by alterations in retinal SVP density, supporting the utility of these non-invasive imaging techniques to measure inter-linked pathobiological processes. The ability to detect metabolic dysfunction in-vivo in PwMS may help facilitate the identification of new therapeutic targets and outcome measures for clinical trials.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0251 - Early factors associated with later conversion to multiple sclerosis in patients presenting with isolated myelitis (ID 1848)

Speakers
Presentation Number
P0251
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

In patients presenting with ‘transverse myelitis’ without clinical or radiological evidence of inflammation/demyelination elsewhere in the central nervous system (i.e. isolated myelitis), it remains challenging to predict risk of later conversion to multiple sclerosis (MS).

Objectives

To identify early clinical and paraclinical factors that may help predict later conversion to MS in patients presenting with isolated myelitis.

Methods

In this retrospective cohort study, we examined a carefully defined population of patients who attended our specialized myelopathy clinic from 2010 to 2018. We included patients diagnosed with isolated myelitis who were followed clinically and radiologically for at least 1 year. We excluded patients with known MS (defined by the 2017 revised McDonald criteria), aquaporin-4 (AQP4)-IgG seropositivity, myelin oligodendrocyte glycoprotein (MOG)-IgG seropositivity, or other identified etiology of myelitis. Logistic regression was used to identify factors predictive of conversion to MS during follow-up.

Results

We included 100 patients (mean age 40.5 years [SD 12.6], 60% female). Over a median follow-up period of 4.3 years (range, 1.0-17.4 years), 25 patients (25%) converted to MS. Conversion to MS occurred in 25 of 77 patients (32%) with short-segment myelitis (longest cord lesion spanning <3 vertebral segments on MRI) as compared to zero of 23 patients with longitudinally-extensive myelitis (0%, p=0.002). Amongst patients with short-segment myelitis, factors identified as highly predictive of conversion to MS using multivariable logistic regression included positive cerebrospinal fluid (CSF)-restricted oligoclonal bands (adjusted odds ratio [OR] 9.18, 95% CI 2.06 to 41.02, p=0.004), younger age (adjusted OR 1.06 for each year younger, 95% CI 1.00 to 1.12, p=0.04) and longer follow-up period (adjusted OR 1.25 for each year longer, 95% CI 1.01 to 1.55, p=0.04). Conversion to MS occurred at a median of 2.77 years (range 0.20-4.39) after onset of myelitis.

Conclusions

Short-segment MRI cord lesion(s), positive CSF-restricted oligoclonal bands, younger age, and longer follow-up are all factors predictive of conversion to MS in patients presenting with isolated myelitis. Conversion to MS typically occurs within a few years after a bout of isolated myelitis, emphasizing the importance of close clinical and radiological follow-up after such an attack.

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