Relationships Between Retinal Axonal and Neuronal Measures and Global Central Nervous System Pathology in Multiple Sclerosis

Saidha, Shiv; Sotirchos, Elias S.; Oh, Jiwon; Syc, Stephanie B.; Seigo, Michaela A.; Shiee, Navid; Eckstein, Chistopher; Durbin, Mary K; Oakley, Jonathan D.; Meyer, Scott A.; Frohman, Teresa C.; Newsome, Scott D.; Ratchford, John N.; Balcer, Laura J.; Pham, Dzung L.; Crainiceanu, Ciprian M.; Frohman, Elliot M.; Reich, Daniel S.; Calabresi, Peter A.

doi:10.1001/archneurol.2013.573

Cited by 13 publications

(11 citation statements)

References 36 publications

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“…23,24 Considering region-specific pathologic differences, prior studies have found limited correlations between measures of SC and brain atrophy (SC-CSA and BPF), suggesting that pathogenic mechanisms in MS evolve independently to an extent in the brain and SC, particularly in progressive phases of disease, supporting the idea that MS disease mechanisms may differentially affect specific regions of the CNS. 14,25,26 Our observations of moderate correlations between SC and retinal measures, but absent correlations between measures of SC and brain atrophy support the notion that MS disease pathology is nonuniform in distinct CNS compartments, 27,28 and suggest there are clinically relevant pathologic processes occurring in the SC and retina that are distinct from those in the brain. Moreover, our observations of stronger SC and retinal correlations in progressive patients support the view that immunopathologic and tissue injury mechanisms of MS differ by disease subtype, and may be indicative of more uniform pathologic changes occurring in PPMS and SPMS, although these progressive MS subtypes may not be equivalent pathologically.…”

Section: Resultssupporting

confidence: 67%

“…Our findings expand on prior studies that demonstrated that retinal layers (pRNFL and GCL 1 IPL) reflect global clinical and radiologic CNS processes in MS, and that specific retinal layers may reflect differential pathologic processes, including neurodegeneration and inflammation. 27,29 Our findings suggest that not only do retinal and SC-MRI measures reflect global pathologic processes in MS that are not adequately captured by brain atrophy alone, but that the regional and global pathologic processes that SC-MRI reflect are distinct from those that are captured by retinal measures, and that these processes independently contribute to mediating clinical disability in various functional systems. These findings highlight the importance of including an assessment of multiple compartments of the CNS affected by MS to better understand both global and regional disease processes, their interplay, and how they contribute to clinical disability in various functional systems.…”

Section: Resultsmentioning

confidence: 84%

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Relationships between quantitative spinal cord MRI and retinal layers in multiple sclerosis

Sotirchos

Saidha

et al. 2015

Neurology

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Objective: To assess relationships between spinal cord MRI (SC-MRI) and retinal measures, and to evaluate whether these measures independently relate to clinical disability in multiple sclerosis (MS). Methods:One hundred two patients with MS and 11 healthy controls underwent 3-tesla brain and cervical SC-MRI, which included standard T1-and T2-based sequences and diffusion-tensor and magnetization-transfer imaging, and optical coherence tomography with automated segmentation. Clinical assessments included visual acuity (VA), Expanded Disability Status Scale, MS functional composite, vibration sensation threshold, and hip-flexion strength. Regions of interest circumscribing SC cross-sections at C3-4 were used to obtain cross-sectional area (CSA), fractional anisotropy (FA), perpendicular diffusivity (l t ), and magnetization transfer ratio. Multivariable regression assessed group differences and SC, retinal, and clinical relationships.Results: In MS, there were correlations between SC-CSA, SC-FA, SC-l t , and peripapillary retinal nerve fiber layer (pRNFL) (p 5 0.01, p 5 0.002, p 5 0.001, respectively) after adjusting for age, sex, prior optic neuritis, and brain atrophy. In multivariable clinical models, when SC-CSA, pRNFL, and brain atrophy were included simultaneously, SC-CSA and pRNFL retained independent relationships with low-contrast VA (p 5 0.04, p 5 0.002, respectively), high-contrast VA (p 5 0.06, p 5 0.008), and vibration sensation threshold (p 5 0.01, p 5 0.05). SC-CSA alone retained independent relationships with Expanded Disability Status Scale (p 5 0.001), hip-flexion strength (p 5 0.001), and MS functional composite (p 5 0.004). Conclusions:In this cross-sectional study of patients with MS, correlations exist between SC-MRI and retinal layers, and both exhibit independent relationships with clinical dysfunction. These findings suggest that the SC and optic nerve reflect ongoing global pathologic processes that supplement measures of whole-brain atrophy, highlighting the importance of combining measures from unique compartments to facilitate a thorough examination of regional and global disease processes that contribute to clinical disability in MS. Neurology ® 2015;84:720-728 GLOSSARY BPF 5 brain parenchymal fraction; CSA 5 cross-sectional area; DTI 5 diffusion tensor imaging; DW 5 diffusion weighted; EDSS 5 Expanded Disability Status Scale; FA 5 fractional anisotropy; FOV 5 field of view; GCL 5 ganglion cell layer; HC 5 healthy control; IPL 5 inner plexiform layer; lt 5 perpendicular diffusivity; MLR 5 multivariable linear regression; mRNFL 5 macular retinal nerve fiber layer; MS 5 multiple sclerosis; MSFC 5 multiple sclerosis functional composite; MT 5 magnetization transfer; MTR 5 magnetization transfer ratio; OCT 5 optical coherence tomography; PPMS 5 primary progressive multiple sclerosis; pRNFL 5 peripapillary retinal nerve fiber layer; RNFL 5 retinal nerve fiber layer; ROI 5 region of interest; RSEE 5 robust standard error estimation; SC 5 spinal cord; SPMS 5 secondary progressive mu...

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 84%

Relationships between quantitative spinal cord MRI and retinal layers in multiple sclerosis

Sotirchos

Saidha

et al. 2015

Neurology

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“…It is suggested that INL and ONL thinning in MS may also reflect global CNS processes. 31 Given that retinal layer thinning reflects brain atrophy and that neurodegeneration is considered the primary basis for disability in MS, our study findings provide further support that NAT may be a highly effective therapy in RRMS.…”

Section: Comparison Of Rates Of Gcip Thinning Between Rrmssupporting

confidence: 65%

Disease-modifying therapies modulate retinal atrophy in multiple sclerosis

et al. 2017

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Objective: To retrospectively investigate whether disease-modifying therapies (DMTs) exert differential effects on rates of retinal atrophy in relapsing-remitting multiple sclerosis (RRMS), as assessed using optical coherence tomography (OCT).Methods: A total of 402 patients with RRMS followed at the Johns Hopkins MS Center who underwent Cirrus-HD OCT were assessed for eligibility. Inclusion criteria included at least 1 year of OCT follow-up and adherence to a single DMT during the period of follow-up. Combined thickness of the ganglion cell 1 inner plexiform (GCIP) and other retinal layers was computed utilizing automated macular segmentation. Retinal thickness changes were analyzed using mixed-effects linear regression.Results: The effects of glatiramer acetate (GA; n 5 48), natalizumab (NAT; n 5 46), and interferonb-1a subcutaneously (IFN SC ; n 5 35) and intramuscularly (IFN IM ; n 5 28) were assessed. Baseline analyses revealed no significant differences between groups in terms of age, sex, optic neuritis history, or follow-up duration. During follow-up, relative to NAT-treated patients, IFN SC -and GAtreated patients exhibited 0.37 mm/y (p , 0.001) and 0.14 mm/y (p 5 0.035) faster rates of GCIP thinning, respectively, adjusting for the interval between initiation of DMT and OCT monitoring (gap time), age, sex, relapses, and disease duration. In the IFN SC group, GCIP thinning was 1.53 mm/y faster during the first year of therapy vs during the time interval afterwards (p , 0.001).Conclusions: Rates of GCIP atrophy in patients with RRMS vary according to DMT utilization. Our findings support OCT for monitoring neurodegenerative treatment effects in the retina, an easily accessible tissue, and as a practical outcome measure in RRMS clinical trials. Neurology ® 2017;88:525-532 GLOSSARY AMT 5 average macular thickness; DMT 5 disease-modifying therapy; GA 5 glatiramer acetate; GCIP 5 ganglion cell 1 inner plexiform layer; HC 5 healthy control; IFN 5 interferon; IFN IM 5 intramuscular interferon-b-1a; IFN SC 5 subcutaneous interferon-b-1a; INL 5 inner nuclear layer; MME 5 microcystic macular edema; MS 5 multiple sclerosis; NAT 5 natalizumab; OCT 5 optical coherence tomography; ON 5 optic neuritis; ONL 5 outer nuclear layer; pRNFL 5 peripapillary retinal nerve fiber layer thickness; RRMS 5 relapsing-remitting multiple sclerosis.Although multiple sclerosis (MS) is conventionally regarded as an autoimmune, inflammatory, demyelinating disorder of the CNS, neurodegeneration resulting from these processes is recognized as the principal substrate of long-term disability.1,2 Currently available disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS) modulate or suppress the immune system, reducing the risk for future inflammation and associated neurodegeneration.3 Accordingly, the effect of DMTs on MRI-derived estimates of brain atrophy is a common outcome in MS trials. [4][5][6][7] Recent studies reveal that retinal atrophy mirrors brain atrophy over time in MS. 8 However, it remains unclear wh...

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“…These properties have allowed the ophthalmic community to better explore the retinal cell layers within the macula [1]. OCT has been particularly useful in the assessment and characterization of multiple sclerosis (MS) through the analysis of the thickness of various retinal layers [2][3][4]. It has also seen use for exploring numerous other diseases, including age-related macular degeneration [5], diabetes [6], Alzheimer's disease [7], Parkinson's disease [8], and glaucoma [9].…”

Section: Introductionmentioning

confidence: 99%

Analysis of macular OCT images using deformable registration

Chen¹,

Lang²,

Ying³

et al. 2014

Biomed. Opt. Express

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Optical coherence tomography (OCT) of the macula has become increasingly important in the investigation of retinal pathology. However, deformable image registration, which is used for aligning subjects for pairwise comparisons, population averaging, and atlas label transfer, has not been well-developed and demonstrated on OCT images. In this paper, we present a deformable image registration approach designed specifically for macular OCT images. The approach begins with an initial translation to align the fovea of each subject, followed by a linear rescaling to align the top and bottom retinal boundaries. Finally, the layers within the retina are aligned by a deformable registration using one-dimensional radial basis functions. The algorithm was validated using manual delineations of retinal layers in OCT images from a cohort consisting of healthy controls and patients diagnosed with multiple sclerosis (MS). We show that the algorithm overcomes the shortcomings of existing generic registration methods, which cannot be readily applied to OCT images. A successful deformable image registration algorithm for macular OCT opens up a variety of population based analysis techniques that are regularly used in other imaging modalities, such as spatial normalization, statistical atlas creation, and voxel based morphometry. Examples of these applications are provided to demonstrate the potential benefits such techniques can have on our understanding of retinal disease. In particular, included is a pilot study of localized volumetric changes between healthy controls and MS patients using the proposed registration algorithm.

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Relationships Between Retinal Axonal and Neuronal Measures and Global Central Nervous System Pathology in Multiple Sclerosis

Abstract: To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS).

Cited by 13 publications

References 36 publications

Relationships between quantitative spinal cord MRI and retinal layers in multiple sclerosis

Relationships between quantitative spinal cord MRI and retinal layers in multiple sclerosis

Disease-modifying therapies modulate retinal atrophy in multiple sclerosis

Analysis of macular OCT images using deformable registration

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