Retinal Oxygen Metabolism and Haemodynamics in Patients With Multiple Sclerosis and History of Optic Neuritis

Martin Kallab, Nikolaus Hommer, Andreas Schlatter, Gabriel Bsteh, Patrick Altmann, Alina Popa-Cherecheanu, Martin Pfister, René M Werkmeister, Doreen Schmidl, Leopold Schmetterer, Gerhard Garhöfer, Martin Kallab, Nikolaus Hommer, Andreas Schlatter, Gabriel Bsteh, Patrick Altmann, Alina Popa-Cherecheanu, Martin Pfister, René M Werkmeister, Doreen Schmidl, Leopold Schmetterer, Gerhard Garhöfer

Abstract

Vascular changes and alterations of oxygen metabolism are suggested to be implicated in multiple sclerosis (MS) pathogenesis and progression. Recently developed in vivo retinal fundus imaging technologies provide now an opportunity to non-invasively assess metabolic changes in the neural retina. This study was performed to assess retinal oxygen metabolism, peripapillary capillary density (CD), large vessel density (LVD), retinal nerve fiber layer thickness (RNFLT) and ganglion cell inner plexiform layer thickness (GCIPLT) in patients with diagnosed relapsing multiple sclerosis (RMS) and history of unilateral optic neuritis (ON). 16 RMS patients and 18 healthy controls (HC) were included in this study. Retinal oxygen extraction was modeled using O2 saturations and Doppler optical coherence tomography (DOCT) derived retinal blood flow (RBF) data. CD and LVD were assessed using optical coherence tomography (OCT) angiography. RNFLT and GCIPLT were measured using structural OCT. Measurements were performed in eyes with (MS+ON) and without (MS-ON) history for ON in RMS patients and in one eye in HC. Total oxygen extraction was lowest in MS+ON (1.8 ± 0.2 μl O2/min), higher in MS-ON (2.1 ± 0.5 μl O2/min, p = 0.019 vs. MS+ON) and highest in HC eyes (2.3 ± 0.6 μl O2/min, p = 0.002 vs. MS, ANOVA p = 0.031). RBF was lower in MS+ON (33.2 ± 6.0 μl/min) compared to MS-ON (38.3 ± 4.6 μl/min, p = 0.005 vs. MS+ON) and HC eyes (37.2 ± 4.7 μl/min, p = 0.014 vs. MS+ON, ANOVA p = 0.010). CD, LVD, RNFLT and GCIPL were significantly lower in MS+ON eyes. The present data suggest that structural alterations in the retina of RMS patients are accompanied by changes in oxygen metabolism, which are more pronounced in MS+ON than in MS-ON eyes. Whether these alterations promote MS onset and progression or occur as consequence of disease warrants further investigation. Clinical Trial Registration: ClinicalTrials.gov registry, NCT03401879.

Keywords: microcirculation; multiple sclerosis; optical coherence tomography angiography; retinal blood flow; retinal oxygen saturation.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Kallab, Hommer, Schlatter, Bsteh, Altmann, Popa-Cherecheanu, Pfister, Werkmeister, Schmidl, Schmetterer and Garhöfer.

Figures

FIGURE 1
FIGURE 1
Total retinal blood flow (A) and retinal oxygen extraction (B) in eyes with history of acute optic neuritis (MS+ON), in contralateral eyes with no history of ON (MS-ON) and healthy control eyes are significantly different between the study groups upon ANOVA analysis. MS+ON eyes showed significantly reduced total retinal blood flow and oxygen extraction as compared to MS-ON and healthy eyes. Data are presented as means ± standard deviation. ∗p < 0.05, ∗∗p < 0.01, ns, not significant.
FIGURE 2
FIGURE 2
Capillary density (A) and large vessel density (B) in eyes with history of acute optic neuritis (MS+ON), in contralateral eyes with no history of ON (MS-ON) and healthy control eyes are significantly different between the study groups upon ANOVA analysis. MS+ON eyes showed a significantly reduced capillary density as compared to MS-ON and healthy eyes while large vessel density was significantly different between healthy and MS+ON eyes, only. Data are presented as means ± standard deviation. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ns, not significant.

References

    1. Alonso R., Gonzalez-Moron D., Garcea O. (2018). Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: a review. Mult. Scler. Relat. Disord. 22 77–82. 10.1016/j.msard.2018.03.007
    1. Balci S., Yildiz M. B., Ozcelik Kose A., Suer D., Turan Vural E., Emir C., et al. (2020). Optic Nerve Head Changes in Patients with Optic Neuritis Secondary to Multiple Sclerosis: a Comparison of the Affected and Fellow Healthy Eyes. Medeni. Med. J. 35 330–337.
    1. Balk L. J., Twisk J. W., Steenwijk M. D., Daams M., Tewarie P., Killestein J., et al. (2014). A dam for retrograde axonal degeneration in multiple sclerosis? J. Neurol. Neurosurg. Psychiatry 85 782–789. 10.1136/jnnp-2013-306902
    1. Barcelos I. P., Troxell R. M., Graves J. S. (2019). Mitochondrial Dysfunction and Multiple Sclerosis. Biology 8:37. 10.3390/biology8020037
    1. Bata A. M., Fondi K., Szegedi S., Aschinger G. C., Hommer A., Schmidl D., et al. (2019). Age-Related Decline of Retinal Oxygen Extraction in Healthy Subjects. Invest. Ophthalmol. Vis. Sci. 60 3162–3169. 10.1167/iovs.18-26234
    1. Britze J., Frederiksen J. L. (2018). Optical coherence tomography in multiple sclerosis. Eye 32 884–888.
    1. Britze J., Pihl-Jensen G., Frederiksen J. L. (2017). Retinal ganglion cell analysis in multiple sclerosis and optic neuritis: a systematic review and meta-analysis. J. Neurol. 264 1837–1853. 10.1007/s00415-017-8531-y
    1. Bsteh G., Berek K., Hegen H., Altmann P., Wurth S., Auer M., et al. (2021). Macular ganglion cell-inner plexiform layer thinning as a biomarker of disability progression in relapsing multiple sclerosis. Mult. Scler. 27 684–694. 10.1177/1352458520935724
    1. Bsteh G., Hegen H., Altmann P., Auer M., Berek K., Zinganell A., et al. (2020). Validation of inter-eye difference thresholds in optical coherence tomography for identification of optic neuritis in multiple sclerosis. Mult. Scler. Relat. Disord. 45:102403. 10.1016/j.msard.2020.102403
    1. Bsteh G., Hegen H., Teuchner B., Amprosi M., Berek K., Ladstatter F., et al. (2019a). Peripapillary retinal nerve fibre layer as measured by optical coherence tomography is a prognostic biomarker not only for physical but also for cognitive disability progression in multiple sclerosis. Mult. Scler. 25 196–203. 10.1177/1352458517740216
    1. Bsteh G., Hegen H., Teuchner B., Berek K., Wurth S., Auer M., et al. (2019b). Peripapillary retinal nerve fibre layer thinning rate as a biomarker discriminating stable and progressing relapsing-remitting multiple sclerosis. Eur. J. Neurol. 26 865–871. 10.1111/ene.13897
    1. Chua J., Hu Q., Ke M., Tan B., Hong J., Yao X., et al. (2020). Retinal microvasculature dysfunction is associated with Alzheimer’s disease and mild cognitive impairment. Alzheimers Res. Ther. 12:161.
    1. Confavreux C., Vukusic S., Moreau T., Adeleine P. (2000). Relapses and progression of disability in multiple sclerosis. N. Engl. J. Med. 343 1430–1438. 10.1056/nejm200011163432001
    1. Davies A. L., Desai R. A., Bloomfield P. S., Mcintosh P. R., Chapple K. J., Linington C., et al. (2013). Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann. Neurol. 74 815–825. 10.1002/ana.24006
    1. Doblhoff-Dier V., Schmetterer L., Vilser W., Garhofer G., Groschl M., Leitgeb R. A., et al. (2014). Measurement of the total retinal blood flow using dual beam Fourier-domain Doppler optical coherence tomography with orthogonal detection planes. Biomed. Opt. Express 5 630–642.
    1. Dutta R., Mcdonough J., Yin X., Peterson J., Chang A., Torres T., et al. (2006). Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 59 478–489. 10.1002/ana.20736
    1. Farci R., Carta A., Cocco E., Frau J., Fossarello M., Diaz G. (2020). Optical coherence tomography angiography in multiple sclerosis: a cross-sectional study. PLoS One 15:e0236090. 10.1371/journal.pone.0236090
    1. Fernandes D. B., Raza A. S., Nogueira R. G., Wang D., Callegaro D., Hood D. C., et al. (2013). Evaluation of inner retinal layers in patients with multiple sclerosis or neuromyelitis optica using optical coherence tomography. Ophthalmology 120 387–394. 10.1016/j.ophtha.2012.07.066
    1. Feucht N., Maier M., Lepennetier G., Pettenkofer M., Wetzlmair C., Daltrozzo T., et al. (2019). Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis. Mult. Scler. 25 224–234. 10.1177/1352458517750009
    1. Fondi K., Wozniak P. A., Howorka K., Bata A. M., Aschinger G. C., Popa-Cherecheanu A., et al. (2017). Retinal oxygen extraction in individuals with type 1 diabetes with no or mild diabetic retinopathy. Diabetologia 60 1534–1540. 10.1007/s00125-017-4309-0
    1. Garcia-Martin E., Ara J. R., Martin J., Almarcegui C., Dolz I., Vilades E., et al. (2017). Retinal and Optic Nerve Degeneration in Patients with Multiple Sclerosis Followed up for 5 Years. Ophthalmology 124 688–696. 10.1016/j.ophtha.2017.01.005
    1. Garhofer G., Bek T., Boehm A. G., Gherghel D., Grunwald J., Jeppesen P., et al. (2010). Use of the retinal vessel analyzer in ocular blood flow research. Acta Ophthalmol. 88 717–722. 10.1111/j.1755-3768.2009.01587.x
    1. Halder S. K., Milner R. (2021). Hypoxia in multiple sclerosis; is it the chicken or the egg? Brain 144 402–410. 10.1093/brain/awaa427
    1. Hammer M., Vilser W., Riemer T., Mandecka A., Schweitzer D., Kuhn U., et al. (2009). Diabetic patients with retinopathy show increased retinal venous oxygen saturation. Graefes Arch. Clin. Exp. Ophthalmol. 247 1025–1030. 10.1007/s00417-009-1078-6
    1. Hammer M., Vilser W., Riemer T., Schweitzer D. (2008). Retinal vessel oximetry-calibration, compensation for vessel diameter and fundus pigmentation, and reproducibility. J. Biomed. Opt. 13:054015. 10.1117/1.2976032
    1. Haufschild T., Shaw S. G., Kesselring J., Flammer J. (2001). Increased endothelin-1 plasma levels in patients with multiple sclerosis. J. Neuroophthalmol. 21 37–38. 10.1097/00041327-200103000-00011
    1. Hokazono K., Raza A. S., Oyamada M. K., Hood D. C., Monteiro M. L. (2013). Pattern electroretinogram in neuromyelitis optica and multiple sclerosis with or without optic neuritis and its correlation with FD-OCT and perimetry. Doc. Ophthalmol. 127 201–215. 10.1007/s10633-013-9401-2
    1. Hommer N., Schmidl D., Kallab M., Bauer M., Werkmeister R. M., Schmetterer L., et al. (2021). The Effect of Orally Administered Low-Dose Dronabinol on Retinal Blood Flow and Oxygen Metabolism in Healthy Subjects. J. Ocul. Pharmacol. Ther. 37 360–366. 10.1089/jop.2020.0131
    1. Hubbard L. D., Brothers R. J., King W. N., Clegg L. X., Klein R., Cooper L. S., et al. (1999). Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 106 2269–2280. 10.1016/s0161-6420(99)90525-0
    1. Jiang H., Delgado S., Tan J., Liu C., Rammohan K. W., Debuc D. C., et al. (2016). Impaired retinal microcirculation in multiple sclerosis. Mult. Scler. 22 1812–1820. 10.1177/1352458516631035
    1. Johnson T. W., Wu Y., Nathoo N., Rogers J. A., Wee Yong V., Dunn J. F. (2016). Gray Matter Hypoxia in the Brain of the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis. PLoS One 11:e0167196. 10.1371/journal.pone.0167196
    1. Kleerekooper I., Petzold A., Trip S. A. (2020). Anterior visual system imaging to investigate energy failure in multiple sclerosis. Brain 143 1999–2008. 10.1093/brain/awaa049
    1. Knier B., Berthele A., Buck D., Schmidt P., Zimmer C., Muhlau M., et al. (2016). Optical coherence tomography indicates disease activity prior to clinical onset of central nervous system demyelination. Mult. Scler. 22 893–900. 10.1177/1352458515604496
    1. Linsenmeier R. A., Zhang H. F. (2017). Retinal oxygen: from animals to humans. Prog. Retin. Eye Res. 58 115–151. 10.1016/j.preteyeres.2017.01.003
    1. Liu Y., Delgado S., Jiang H., Lin Y., Hernandez J., Deng Y., et al. (2019). Retinal Tissue Perfusion in Patients with Multiple Sclerosis. Curr. Eye Res. 44 1091–1097. 10.1080/02713683.2019.1612444
    1. Mahad D., Ziabreva I., Lassmann H., Turnbull D. (2008). Mitochondrial defects in acute multiple sclerosis lesions. Brain 131 1722–1735. 10.1093/brain/awn105
    1. Mao P., Reddy P. H. (2010). Is multiple sclerosis a mitochondrial disease? Biochim. Biophys. Acta 1802 66–79.
    1. Murphy O. C., Kwakyi O., Iftikhar M., Zafar S., Lambe J., Pellegrini N., et al. (2020). Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures. Mult. Scler. 26 815–828. 10.1177/1352458519845116
    1. Oberwahrenbrock T., Schippling S., Ringelstein M., Kaufhold F., Zimmermann H., Keser N., et al. (2012). Retinal Damage in Multiple Sclerosis Disease Subtypes Measured by High-Resolution Optical Coherence Tomography. Mult. Scler. Int. 2012:530305.
    1. Olafsdottir O. B., Saevarsdottir H. S., Hardarson S. H., Hannesdottir K. H., Traustadottir V. D., Karlsson R. A., et al. (2018). Retinal oxygen metabolism in patients with mild cognitive impairment. Alzheimers Dement. 10 340–345. 10.1016/j.dadm.2018.03.002
    1. Palkovits S., Told R., Boltz A., Schmidl D., Popa Cherecheanu A., Schmetterer L., et al. (2014). Effect of increased oxygen tension on flicker-induced vasodilatation in the human retina. J. Cereb. Blood Flow Metab. 34 1914–1918. 10.1038/jcbfm.2014.161
    1. Petzold A., Balcer L. J., Calabresi P. A., Costello F., Frohman T. C., Frohman E. M., et al. (2017). Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 16 797–812.
    1. Reich D. S., Lucchinetti C. F., Calabresi P. A. (2018). Multiple Sclerosis. N. Engl. J. Med. 378 169–180.
    1. Sato Y., Nakajima S., Shiraga N., Atsumi H., Yoshida S., Koller T., et al. (1998). Three-dimensional multi-scale line filter for segmentation and visualization of curvilinear structures in medical images. Med. Image Anal. 2 143–168. 10.1016/s1361-8415(98)80009-1
    1. Schindelin J., Arganda-Carreras I., Frise E., Kaynig V., Longair M., Pietzsch T., et al. (2012). Fiji: an open-source platform for biological-image analysis. Nat. Methods 9 676–682. 10.1038/nmeth.2019
    1. Speciale L., Sarasella M., Ruzzante S., Caputo D., Mancuso R., Calvo M. G., et al. (2000). Endothelin and nitric oxide levels in cerebrospinal fluid of patients with multiple sclerosis. J. Neurovirol. 6 S62–S66.
    1. Stefánsson E., Olafsdottir O. B., Eliasdottir T. S., Vehmeijer W., Einarsdottir A. B., Bek T., et al. (2019). Retinal oximetry: metabolic imaging for diseases of the retina and brain. Prog. Retin. Eye Res. 70 1–22. 10.1016/j.preteyeres.2019.04.001
    1. Szegedi S., Hommer N., Kallab M., Puchner S., Schmidl D., Werkmeister R. M., et al. (2020b). Repeatability and Reproducibility of Total Retinal Blood Flow Measurements Using Bi-Directional Doppler OCT. Transl. Vis. Sci. Technol. 9:34.
    1. Szegedi S., Dal-Bianco P., Stögmann E., Traub-Weidinger T., Rainer M., Masching A., et al. (2020a). Anatomical and functional changes in the retina in patients with Alzheimer’s disease and mild cognitive impairment. Acta Ophthalmol. 98 e914–e921.
    1. Tan B., Sim R., Chua J., Wong D. W. K., Yao X., Garhofer G., et al. (2020). Approaches to quantify optical coherence tomography angiography metrics. Ann. Transl. Med. 8:1205. 10.21037/atm-20-3246
    1. Toosy A. T., Mason D. F., Miller D. H. (2014). Optic neuritis. Lancet Neurol. 13 83–99.
    1. Toussaint D., Perier O., Verstappen A., Bervoets S. (1983). Clinicopathological study of the visual pathways, eyes, and cerebral hemispheres in 32 cases of disseminated sclerosis. J. Clin. Neuroophthalmol. 3 211–220.
    1. Walter S. D., Ishikawa H., Galetta K. M., Sakai R. E., Feller D. J., Henderson S. B., et al. (2012). Ganglion cell loss in relation to visual disability in multiple sclerosis. Ophthalmology 119 1250–1257. 10.1016/j.ophtha.2011.11.032
    1. Wang L., Kwakyi O., Nguyen J., Ogbuokiri E., Murphy O., Caldito N. G., et al. (2018). Microvascular blood flow velocities measured with a retinal function imager: inter-eye correlations in healthy controls and an exploration in multiple sclerosis. Eye Vis. 5:29.
    1. Werkmeister R. M., Dragostinoff N., Palkovits S., Told R., Boltz A., Leitgeb R. A., et al. (2012a). Measurement of absolute blood flow velocity and blood flow in the human retina by dual-beam bidirectional Doppler fourier-domain optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 53 6062–6071. 10.1167/iovs.12-9514
    1. Werkmeister R. M., Palkovits S., Told R., Groschl M., Leitgeb R. A., Garhofer G., et al. (2012b). Response of retinal blood flow to systemic hyperoxia as measured with dual-beam bidirectional Doppler Fourier-domain optical coherence tomography. PLoS One 7:e45876. 10.1371/journal.pone.0045876
    1. Werkmeister R. M., Dragostinoff N., Pircher M., Gotzinger E., Hitzenberger C. K., Leitgeb R. A., et al. (2008). Bidirectional Doppler Fourier-domain optical coherence tomography for measurement of absolute flow velocities in human retinal vessels. Opt. Lett. 33 2967–2969. 10.1364/ol.33.002967
    1. Werkmeister R. M., Schmidl D., Aschinger G., Doblhoff-Dier V., Palkovits S., Wirth M., et al. (2015). Retinal oxygen extraction in humans. Sci. Rep. 5:15763.
    1. Yang R., Dunn J. F. (2015). Reduced cortical microvascular oxygenation in multiple sclerosis: a blinded, case-controlled study using a novel quantitative near-infrared spectroscopy method. Sci. Rep. 5:16477.
    1. Yang R., Dunn J. F. (2019). Multiple sclerosis disease progression: contributions from a hypoxia-inflammation cycle. Mult. Scler. 25 1715–1718. 10.1177/1352458518791683
    1. Yilmaz H., Ersoy A., Icel E. (2020). Assessments of vessel density and foveal avascular zone metrics in multiple sclerosis: an optical coherence tomography angiography study. Eye 34 771–778. 10.1038/s41433-019-0746-y

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