Retinas have no myelin. Therefore they are an important place to observe MS underlying pathology. This paper reports microvascular changes without optic neuritis.
Microvascular changes in the macular and parafoveal areas of multiple sclerosis patients without optic neuritis
https://www.nature.com/articles/s41598-022-17344-3
Abstract
Retinal imaging has been proposed as a biomarker for neurological diseases such as multiple sclerosis (MS). Recently, a technique for non-invasive assessment of the retinal microvasculature called optical coherence tomography angiography (OCTA) was introduced.
We investigated retinal microvasculature alterations in participants with relapsing–remitting MS (RRMS) without history of optic neuritis (ON) and compared them to a healthy control group.
The study was performed in a prospective, case–control design, including 58 participants (n = 100 eyes) with RRMS without ON and 78 age- and sex-matched control participants (n = 136 eyes). OCTA images of the superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris (CC) were obtained using a commercial OCTA system (Zeiss Cirrus HD-5000 Spectral-Domain OCT with AngioPlex OCTA, Carl Zeiss Meditec, Dublin, CA).
The outcome variables were perfusion density (PD) and foveal avascular zone (FAZ) features (area and circularity) in both the SCP and DCP, and flow deficit in the CC. MS group had on average higher intraocular pressure (IOP) than controls (P < 0.001). After adjusting for confounders, MS participants showed significantly increased PD in SCP (P = 0.003) and decreased PD in DCP (P < 0.001) as compared to controls.
A significant difference was still noted when large vessels (LV) in the SCP were removed from the PD calculation (P = 0.004). Deep FAZ was significantly larger (P = 0.005) and less circular (P < 0.001) in the eyes of MS participants compared to the control ones. Neither LV, PD or FAZ features in the SCP, nor flow deficits in the CC showed any statistically significant differences between the MS group and control group (P > 0.186).
Our study indicates that there are microvascular changes in the macular parafoveal retina of RRMS patients without ON, showing increased PD in SCP and decreased PD in DCP. Further studies with a larger cohort of MS patients and MRI correlations are necessary to validate retinal microvascular changes as imaging biomarkers for diagnosis and screening of MS.
Silent retinal damage description
Re: Silent retinal damage description
Discussion
The aim of the current study was to evaluate retinal microvascular changes, specifically at the capillary network level, in patients with MSNON.
Our study shows that after accounting for the potential measurement bias of FAZ, OCT magnification correction with axial length measurements and projection artifacts of DCP, RRMS participants showed significantly increased PD in SCP, and significantly decreased PD in DCP as compared to healthy controls. Our data support the concept that there are alterations in the retinal microvasculature in RRMS that can be detected by means of OCTA, which may potentially be used as imaging biomarkers to identify and screen for MS.
In the past, OCT has been used to investigate potential neurodegenerative changes in retina. There is compelling evidence that patients with MS show thinning of the retinal neural tissue, indicating that changes in neurodegenerative changes of patients with MS are reflected in the eye. In particular, a recent meta-analysis of more than 25,000 patient records shows pronounced retinal thinning mostly in the peripapillary retinal nerve fiber layer as well as in the macular ganglion cell layer and IPL.
Although there is a general agreement that retinal thinning is consistently observed in patients with MS, OCTA studies investigating the microcirculation in patients with MS have revealed contradictory results. As such, it has been reported that SCP vascularization is increased and combined RNFL + GCIPL is decreased, whereas other studies found decreased vascular density and decreased or the same RNFL in patients with MS.
This also holds true for other OCTA derived parameters such as DCP, where the increased and decreased values have been observed, with retinal thinning association. In our recent OCT paper on the same cohort of patients, we demonstrated thinning of the peripapillary RNFL and inner macular ganglion cell complex. Importantly, the paper highlighted that the capability of OCT in MS differentiation is made more robust by accounting OCT scans for individual anatomical differences and incorporating information from both optic disc and macular regions, representing markers of axonal damage and neuronal injury, respectively.
Our results are in accordance with one previous study, which reported increased VD of the SCP and decreased RNFL + GCIPL, but they are in contrast to other, more recent experimental data, where most of the other studies revealed a decreased VD or did not report any differences for MSNON, with RNFL decreased or uninvestigated.
Only a few OCTA studies have investigated DCP VD in MS individuals, but again there is a lack of agreement between studies. One study showed a significant increase in VD in MSNON, whereas some data indicate a significant reduction in VD, and others did not observe any differences.
The reason for the contradicting results in both SCP and DCP has not yet been elucidated but may be due to methodological and technical limitations of OCTA and selection of study population. Study populations were heterogeneous in the above mentioned studies: some included only patients with RRMS, whereas others included all clinical forms of MS. Further, some studies included only MSNON, whereas others studied MS patients with history of ON (MSON) as well as MSNON.
Further, technical limitations may account for the differences. Accurate assessment of OCTA metrics is challenging and may be affected by the physiologic variability of FAZ and projection artifacts. This holds particularly true for the FAZ in the DCP.
However, in the past only a few OCTA studies accounted for the FAZ in the deep plexus. This is a major limitation because the deep FAZ is considerably larger than superficial FAZ. In addition, while some studies have removed the projection artifacts in the DCP, others did not. In the current study, we quantified the PD of the DCP without the influence of FAZ and projection artifacts, which reduced measurement bias.
In the current study, superficial FAZ was significantly less circular in the eyes of MS participants than controls in univariate analysis, an effect that was not observed anymore in the multivariate analysis. We did not find any differences in superficial FAZ area between groups, neither in the univariate, nor in multivariate analysis. Interestingly, deep FAZ was significantly larger and less circular in MS participants than controls in both, univariate and multivariate analysis, which is compatible with the decreased PD of the DCP.
Overall, the FAZ features are limited by the physiological variability and may not be such a robust biomarker for the diagnosis and screening of MS.
The reason for the observed increase of VD in the SCP is unclear. One can speculate that it is related to diffuse chronic inflammation and consequently to increased angiogenesis. Inflammation may be regarded as causative to vascular changes in MS15. Widespread and subtle inflammation in MS has been observed in histopathologic studies, in both the retina and the brain. The increased VD in SCP could also reflect a compensatory response to retinal tissue hypoperfusion linked to angiogenesis. Tissue hypoperfusion can affect tissue oxygenation and induce hypoxia-like changes including vasodilatation in the retina. Such hypoxia can be the trigger for Vascular Endothelial Growth Factor (VEGF) release and several other pro-angiogenic molecules, which can lead to increased VD. Further studies are needed to elucidate this issue.
The current study has some strength and limitations that warrant further discussion.
- First we included a well phenotype cohort of RRMS individuals who were diagnosed according to the 2017 McDonald criteria16, a standardized study methodology which has been used in a variety of cohorts.
- Second, we have a high signal strength among our participants, which confirms the validity of our results.
- Third, we adjusted the possible confounding effects of age and gender during multivariate analysis and excluded possible confounding factors, such as PPMS, SPMS and any clinically relevant eye disease. Also, we excluded patients with any history of ON, in order to avoid a bias related to optic nerve direct damage, because ON can cause a decrease in VD in the posterior pole of the eye52, independently of the presence of MS.
However, our present study also has a few limitations.
- First, a quarter of eyes examinations were excluded because of poor quality OCTA scans. Such high exclusion is comparable to other studies using OCTA12 since the quality of the OCTA scans is dependent on good patient compliance and excellent target fixation. In the future, higher scan speeds with eye motion correction in challenging situations will eliminate this limitation.
- Second, cerebral perfusion was not measured in the same study cohort, and the link between the eye and the brain in tissue perfusion could not be established.
- Third, it remains unclear whether the changes of retinal capillaries are related to the prediction of disability progression, whole brain atrophy or the differential neuroprotective effects of disease-modifying therapies.
Finally, an increase in OCTA metric has been reported in patients with cataracts in the 3-month follow-up period after cataract surgery. Although our inclusion criterion was to allow individuals with more than 3 months of ocular surgery to participate, none of the included participant have undergone prior ocular surgery. As such, the OCTA metric was not confounded by ocular surgery.
The aim of the current study was to evaluate retinal microvascular changes, specifically at the capillary network level, in patients with MSNON.
Our study shows that after accounting for the potential measurement bias of FAZ, OCT magnification correction with axial length measurements and projection artifacts of DCP, RRMS participants showed significantly increased PD in SCP, and significantly decreased PD in DCP as compared to healthy controls. Our data support the concept that there are alterations in the retinal microvasculature in RRMS that can be detected by means of OCTA, which may potentially be used as imaging biomarkers to identify and screen for MS.
In the past, OCT has been used to investigate potential neurodegenerative changes in retina. There is compelling evidence that patients with MS show thinning of the retinal neural tissue, indicating that changes in neurodegenerative changes of patients with MS are reflected in the eye. In particular, a recent meta-analysis of more than 25,000 patient records shows pronounced retinal thinning mostly in the peripapillary retinal nerve fiber layer as well as in the macular ganglion cell layer and IPL.
Although there is a general agreement that retinal thinning is consistently observed in patients with MS, OCTA studies investigating the microcirculation in patients with MS have revealed contradictory results. As such, it has been reported that SCP vascularization is increased and combined RNFL + GCIPL is decreased, whereas other studies found decreased vascular density and decreased or the same RNFL in patients with MS.
This also holds true for other OCTA derived parameters such as DCP, where the increased and decreased values have been observed, with retinal thinning association. In our recent OCT paper on the same cohort of patients, we demonstrated thinning of the peripapillary RNFL and inner macular ganglion cell complex. Importantly, the paper highlighted that the capability of OCT in MS differentiation is made more robust by accounting OCT scans for individual anatomical differences and incorporating information from both optic disc and macular regions, representing markers of axonal damage and neuronal injury, respectively.
Our results are in accordance with one previous study, which reported increased VD of the SCP and decreased RNFL + GCIPL, but they are in contrast to other, more recent experimental data, where most of the other studies revealed a decreased VD or did not report any differences for MSNON, with RNFL decreased or uninvestigated.
Only a few OCTA studies have investigated DCP VD in MS individuals, but again there is a lack of agreement between studies. One study showed a significant increase in VD in MSNON, whereas some data indicate a significant reduction in VD, and others did not observe any differences.
The reason for the contradicting results in both SCP and DCP has not yet been elucidated but may be due to methodological and technical limitations of OCTA and selection of study population. Study populations were heterogeneous in the above mentioned studies: some included only patients with RRMS, whereas others included all clinical forms of MS. Further, some studies included only MSNON, whereas others studied MS patients with history of ON (MSON) as well as MSNON.
Further, technical limitations may account for the differences. Accurate assessment of OCTA metrics is challenging and may be affected by the physiologic variability of FAZ and projection artifacts. This holds particularly true for the FAZ in the DCP.
However, in the past only a few OCTA studies accounted for the FAZ in the deep plexus. This is a major limitation because the deep FAZ is considerably larger than superficial FAZ. In addition, while some studies have removed the projection artifacts in the DCP, others did not. In the current study, we quantified the PD of the DCP without the influence of FAZ and projection artifacts, which reduced measurement bias.
In the current study, superficial FAZ was significantly less circular in the eyes of MS participants than controls in univariate analysis, an effect that was not observed anymore in the multivariate analysis. We did not find any differences in superficial FAZ area between groups, neither in the univariate, nor in multivariate analysis. Interestingly, deep FAZ was significantly larger and less circular in MS participants than controls in both, univariate and multivariate analysis, which is compatible with the decreased PD of the DCP.
Overall, the FAZ features are limited by the physiological variability and may not be such a robust biomarker for the diagnosis and screening of MS.
The reason for the observed increase of VD in the SCP is unclear. One can speculate that it is related to diffuse chronic inflammation and consequently to increased angiogenesis. Inflammation may be regarded as causative to vascular changes in MS15. Widespread and subtle inflammation in MS has been observed in histopathologic studies, in both the retina and the brain. The increased VD in SCP could also reflect a compensatory response to retinal tissue hypoperfusion linked to angiogenesis. Tissue hypoperfusion can affect tissue oxygenation and induce hypoxia-like changes including vasodilatation in the retina. Such hypoxia can be the trigger for Vascular Endothelial Growth Factor (VEGF) release and several other pro-angiogenic molecules, which can lead to increased VD. Further studies are needed to elucidate this issue.
The current study has some strength and limitations that warrant further discussion.
- First we included a well phenotype cohort of RRMS individuals who were diagnosed according to the 2017 McDonald criteria16, a standardized study methodology which has been used in a variety of cohorts.
- Second, we have a high signal strength among our participants, which confirms the validity of our results.
- Third, we adjusted the possible confounding effects of age and gender during multivariate analysis and excluded possible confounding factors, such as PPMS, SPMS and any clinically relevant eye disease. Also, we excluded patients with any history of ON, in order to avoid a bias related to optic nerve direct damage, because ON can cause a decrease in VD in the posterior pole of the eye52, independently of the presence of MS.
However, our present study also has a few limitations.
- First, a quarter of eyes examinations were excluded because of poor quality OCTA scans. Such high exclusion is comparable to other studies using OCTA12 since the quality of the OCTA scans is dependent on good patient compliance and excellent target fixation. In the future, higher scan speeds with eye motion correction in challenging situations will eliminate this limitation.
- Second, cerebral perfusion was not measured in the same study cohort, and the link between the eye and the brain in tissue perfusion could not be established.
- Third, it remains unclear whether the changes of retinal capillaries are related to the prediction of disability progression, whole brain atrophy or the differential neuroprotective effects of disease-modifying therapies.
Finally, an increase in OCTA metric has been reported in patients with cataracts in the 3-month follow-up period after cataract surgery. Although our inclusion criterion was to allow individuals with more than 3 months of ocular surgery to participate, none of the included participant have undergone prior ocular surgery. As such, the OCTA metric was not confounded by ocular surgery.
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