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ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 7  |  Page : 1069-1075

Inner and outer retina findings determined by optical coherence tomography in different subtypes of multiple sclerosis


1 Neurology Clinic, Gaziler Physical Teraphy Rehabilitation Training and Research Hospital, Department of Neurology, Ankara, Turkey
2 Ophthalmology Clinic, Ministry of Health Ankara City Hospital, Ankara, Turkey

Date of Submission02-Jun-2021
Date of Acceptance24-May-2022
Date of Web Publication20-Jul-2022

Correspondence Address:
Dr. S Yurtogullari
Baglica mah. Hilal.cd. Yasemin evleri Sitesi D3/36 Etimesgut/Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_1568_21

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   Abstract 


Background: Integrity of outer retinal bands among multiple sclerosis (MS) subtypes remains unclear, however alterations of thickness in retinal layers is well described. Aim: The objective of the study was to determine the alterations in the thickness of the inner and outer layers of the retina and the findings in both layers detected by optical coherence tomography (OCT) among patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). Patients and Methods: A total of 132 eyes from 66 patients with multiple sclerosis (MS) (70 eyes from 35 patients with RRMS and 62 eyes from 31 patients with SPMS) and 72 eyes from 36 healthy controls were included in the study. The external structures of the retina, including the outer limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ), were examined using OCT in RRMS, SPMS, and healthy control groups. The correlation of neurological disability expressed by the Expanded Disability Study Scale (EDSS) score, best-corrected visual acuity, and duration of disease among OCT parameters was also analyzed. Results: In eyes, with no history of previous optic neuritis (ON), the macular nerve fiber layer, the internal plexiform layer of ganglion cells (GCIPL), and the total thickness of the retinal layer were thinner in the SPMS group than in the RRMS group (P < 0.05, in each comparison). EZ was more vulnerable among the three hyperreflective external retinal zones in the retina of patients with SPMS than in patients with RRMS (P = 0.016). Conclusions: Alterations in retinal thickness in MS are not limited to the inner layers of the retina and also occur in the outer structures of the retina.

Keywords: Inner retinal layers, multiple sclerosis subtypes, optical coherence tomography, outer retinal hyperreflective bands


How to cite this article:
Yurtogullari S, Erbahceci I E. Inner and outer retina findings determined by optical coherence tomography in different subtypes of multiple sclerosis. Niger J Clin Pract 2022;25:1069-75

How to cite this URL:
Yurtogullari S, Erbahceci I E. Inner and outer retina findings determined by optical coherence tomography in different subtypes of multiple sclerosis. Niger J Clin Pract [serial online] 2022 [cited 2022 Aug 19];25:1069-75. Available from: https://www.njcponline.com/text.asp?2022/25/7/1069/351449




   Introductıon Top


Multiple sclerosis (MS) is an autoimmune and chronic inflammatory central nervous system (CNS) disorder characterized by axonal loss and neurodegeneration.[1] Involvement of visual pathways is frequent in MS patients apart from optic neuritis (ON).[2],[3]

Imaging retina by SD-OCT is noninvasive, reproducible, and expetidious technique unlike routine imaging technique of CNS by MRI that renders retina unsurpassed. The external limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ) are the first three hyperreflective bands of the outer retina detected in SD-OCT images.[4] Integrity of these hyperreflective bands displays foveal photoreceptor health and integrity.[5]

Recent studies have focused on functional impairment of outer retinal layers in MS,[6],[7],[8] though structural abnormalities of the ELM, EZ, and IZ have not been determined yet. We aimed to determine whether intergrity of outer retinal bands alters and is related to neurologic disability expressed by expanded disability study scale (EDSS) score among MS subtypes. Each single retinal layer thickness was also detected among study groups.


   Materıals and Methods Top


Patients undergoing treatment for MS were recruited from Neurology Department of Ataturk Education and Research Hospital, Turkey for this prospective observational clinical trial. The study group comprised 66 patients diagnosed according to McDonald diagnostic criteria for MS. MS subtypes were identified by neurologists and MS patients enrolled in the study were diagnosed as relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). Age and gender matched patients without any systemic or ocular disease constituted healthy control group.

Confirmed diagnosis of RRMS or SPMS and being 18 to 65 years were inclusion criteria of the study. Refractive errors (spherical equivalent ≥ - 5.0 D, ≥ + 2.5 D and ≥ ± 2.5 Dcyl), medium opacities, coexisting ocular diseases, and additional neurological disease other than MS and systemic disease were the exclusion criteria of the study.

The study adhered to the tenets of the Declaration of Helsinki and was approved by the Ataturk Education and Research Hospital Ethics Committee of Ankara. All patients received eye examination including best-corrected visual acuity (BCVA) using Snellen chart, anterior segment and fundus examination by an ophthalmologist and SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) images. Physical disability level was determined by the treating MS specialist and graded according to the EDSS.

Optical coherence tomography

The SD-OCT was performed by the same operator. OCT images that were of acceptable quality as defined by the OSCAR-IB criteria[9] were incorporated into the study.

Total retinal thickness was measured by using Macula Map X-Y scan pattern that evaluates 6 × 6 mm area centered on the fovea. Thickness of macular ganglion cell-inner plexiform layer complex (GC-IPL), macular nerve fiber layer (NFL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), and photoreceptor (PR) layer were segmented automatically and measured manually by the caliper measurement tool embedded in SD-OCT system [Figure 1]a. These layers were studied in three concentric rings centered in the fovea: central (1 mm), inner ring (1–3 mm), and outer ring (3–6 mm), which was determined by the Early Treatment Diabetic Retinopathy Study (ETDRS).[10] Inner and outer rings were segmented into four quadrants (inner/outer superior, inner/outer inferior, inner/outer nasal, and inner/outer temporal) and means of four quadrants in inner and outer rings were calculated and analyzed [Figure 1]b.
Figure 1: (a) A cross-sectional view of macula SD-OCT scan demonstrating the macular layer segmentation included in the study. (b) ETDRS grid; the central circle is with a diameter of 1 mm. The inner ring consists of the four quadrants surrounding the central circle with a diameter of 1-3 mm. The outer ring consists of the four quadrants surrounding the inner ring, with a diameter of 3-6 mm. (c) Analysis of peripapillary RNFL thickness; thickness of all quadrants were included in the study. (d) Healthy OCT scan of three hyperreflective bands analyzed in the study. Early Treatment of Diabetic Retinopathy Study: ETDRS, ELM: external limiting membrane, EZ: ellipsoid zone, IZ: interdigitation zone

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Peripapiller retinal nerve fiber layer (pRNFL) thickness was obtained from a circular scan with a diameter of 3.4 mm positioning on middle of the optic disc center. pRNFL was automatically segmented as central, temporal, inferotemporal, superotemporal, nasal, superonasal, and inferonasal quadrants [Figure 1]c.

The three hyperreflective outer retinal bands (ELM, EZ and IZ) were identified according to the classification by International Nomenclature for Optical Coherence Tomography panel.[11] The disruption of ELM, IZ, and EZ was determined as the loss of the continuous back-reflection line that characterizes each layer. The disruption of these layers was interpreted in the central 1 mm of the three consecutive horizontal scans and the median scan was located in the fovea. The disruption of the foveal ELM, EZ, and IZ was graded as line not visible, disrupted in at least one scan (band defect) and continuous line (intact band) [Figure 1]d.

Statistical analysis

All analysis and calculations were performed via IBM SPSS Statistics 22.0 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.).

The BCVA was determined using Snellen chart and converted to the logarithm of the minimal angle of resolution (logMAR) for the statistical analysis. The means of OCT measurements were compared by one-way ANOVA test between groups. The OCT measurements were compared with type of MS and the presence of ON by Mann–Whitney U test. Spearman rank correlation was used to determine correlations between retinal layers and pRNFL thickness and integrity of outer retinal bands with mean EDSS score, disease duration, and BCVA among MS subgroups. A P value < 0.05 was considered as statistically significant.


   Results Top


A total of 66 MS (132 eyes) patients were compared with 36 healthy (72 eyes) controls. [Table 1] shows the demographics and clinical characteristics of the MS patients and healthy controls. Thirthy-one (47%) of the MS patients had secondary progressive MS (SPMS) (Mean ± SD; 39.74 ± 8.6; range 25–49 years), while 35 (53%) had relapsing-remitting MS (RRMS) (Mean ± SD; 33.63 ± 8.04, range 20–46 years). There was a significant age difference observed between SPMS and RRMS groups; RRMS patients were younger than SPMS patients (P = 0.004). Patients with SPMS had a longer mean disease duration compared to RRMS patients (6.48 ± 2.54 vs. 4.29 ± 2.96 years; P = 0.002). The EDSS score was significantly higher in SPMS patients 4.87 ± 1.79 compared to RRMS patients 1.65 ± 0.76 (P < 0.001). BCVA was significantly worse in RRMS group and SPMS group compared to healthy controls (P < 0.001 and P < 0.001) [Table 1].
Table 1: Demographics and clinical characteristics of study groups

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There was a significant thinning in central macular RNFL thickness among all groups and thinnest in SPMS group (P < 0.05, in each comparison). The central thickness of retina and GCIPL were significantly reduced in RRMS and SPMS groups compared to healthy controls (P < 0.001 and P = 0.036; P = 0.001 and P = 0.007, respectively). There was a significant thinning in mean parafoveal and perifoveal total retinal thickness, GCIPL, and macular NFL thickness of both RRMS and SPMS groups compared to control group and among MS subtypes, thinner in SPMS than RRMS (P < 0.05, in each comparison). Mean pRNFL thickness of SPMS patients was decreased in all quadrants compared with control subjects and in all quadrants apart from nasal quadrant compared with RRMS patients (P < 0.05, in each comparison).

When considering MS subgroups with prior ON history, thickness of macular NFL in all quadrants was reduced in RRMS and SPMS groups than control group (P < 0.005, in each comparison). The mean central, inner, and outer ring of total retinal thickness and GCIPL were thinner in RRMS and SPMS groups than control group (P < 0.005, in each comparison). All quadrants of pRNFL were thinner in SPMS group compared to control group (P < 0.005, in all comparison). It was also observed that EDSS score was lower in patients with RRMS than in patients with SPMS (P < 0.001). BCVA was significantly worse in RRMS and SPMS groups compared to control group (P < 0.001 and P < 0.001) and there was no significant difference in BCVA among MS subgroups (P = 0.294) [Table 2].
Table 2: Comparison of clinical characteristics and mean thicknesses of retinal layers and peripapiller RNFL between study groups with prior ON history

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When considering MS subgroups without prior ON history, thickness of macular NFL in all quadrants was decreased in RRMS and SPMS groups than control group, most prominent in SPMS group (P < 0.005, in each comparison). The mean inner and outer ring of total retinal thickness and GCIPL were reduced in RRMS and SPMS groups than control group and in SPMS group compared to RRMS group (P < 0.005). All quadrants of pRNFL thinning in SPMS group were observed when compared to control group (P < 0.005, in all comparison). EDSS score was lower in patients with RRMS than in patients with SPMS (P < 0.001). BCVA was significantly worse in RRMS group compared to SPMS group (P < 0.004) and no significant difference was determined in BCVA between MS subgroups compared to control group (P = 0.072 and P = 0.207). There were no significant differences of VEP among MS subtypes with or without history of ON (P > 0.05, in each comparison).

There were no OCT scans that are completely invisible of ELM, IZ, and EZ; therefore, hyperreflective bands were evaluated as continuous line and disrupted line in at least one OCT scan. EZ integrity was protected more common in RRMS than in SPMS (P = 0.016). There were no statistically significant differences in ELM and IZ integrity among MS subtypes (P = 0.418 and P = 0.127) though IZ was disrupted in 29 of 132 eyes of MS patients and ELM was disrupted in 34 of 132 eyes of MS patients without considering MS subtype and ON [Table 3].
Table 3: Outer retinal alterations between RRMS and SPMS groups

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Correlation analysis was performed among RRMS and SPMS patients regardless of ON history. In RRMS patients, disruption of both ELM and IZ was positively correlated with EDSS score (r = 0.419 P < 0.001 and r = -0.373; P = 0.001). No correlation was found between BCVA and measured OCT parameters and integrity of outer hyperreflective bands in either RRMS patients or SPMS patients (P < 0.05, in each comparison). Disruption of ELM integrity was positively correlated with disease duration independent of MS subtypes (r = 610 and P = 0.016)


   Dıscussıon Top


In eyes without prior ON, macular NFL, GCIPL, and total retinal layer thicknesses were reduced in SPMS than RRMS, though only central macular NFL was thinner in SPMS than RRMS patients with ON history. Parafoveal and perifoveal thicknesses of these layers were also decreased in SPMS patients than RRMS patients regardless of prior ON history and most prominent in SPMS patients. The pathological mechanism behind the reduction in retinal layers thickness in MS patients both with and without prior ON is still not entirely clear.[12] An amount of evidence revealed thinning of macular NFL and macular thickness in MS patients, independently of prior ON as observed in our study.

While pRNFL is the most studied OCT measure in MS, changes in GCIPL have advantages. GCIPL denotes retinal GC integrity as a neuronal marker in the afferent visual system. GCIPL is the thickest layer in the macula with a large dynamic range, which also renders GCIPL less vulnerable from the detriment of prior ON or swelling of acute ON[13] and axoplasmic flow stasis in optic nerve does not affect GCIPL unlike RNFL thickness.[14] Thus, GCIPL states disease progression more accurately. We observed GCIPL thinning in MS subgroups independent of prior ON history. GCIPL thinning was more prominent in SPMS compared to RRMS in patients with unaffected prior ON. Retrograde degeneration after a mild, subclinical ON: primary degeneration of the GCIPL neurons due to MS and lesions in the optic radiation via trans-synaptic degeneration could result in loss of retinal ganglion cells and their axons are possible leading cause of GCIPL loss.

We observed no changes in thickness of INL, ONL, OPL or PR layers when considering either ON history or MS subtypes. The reductions in the mean retinal thickness may reflect the thinning of the RNFL and GCIPL. We conclude an appreciable degeneration of the GCIPL and reduction of macular NFL and macular thickness in all MS subgroups independently ON history.

All quadrants of pRNFL thickness were reduced in SPMS patients with or without prior ON compared to control group. Thus, this study demonstrated that retinal axonal thinning begins in the course of MS and all quadrants of more extensive RNFL atrophy were observed in SPMS relative to RRMS independently of the occurrence of prior ON. Our results were consistent with previous studies that had shown greater pRNFL atrophy in patients with progressive forms of MS as compared to less advanced MS subtypes.[15],[16],[17] Therefore, these studies supported that RNFL thinning may be a structural marker, to distinguish MS subtypes, because the extent of axonal loss in the afferent visual pathway is appropriate with disease severity and progression.[14] Subclinical disease progression may elucidate the increased risk for axonal damage in SPMS patients independently of prior ON in our study. In addition, chronic axon damage can occur in MS patients apart from ON attacks or subclinical ON can also damage axons in purely progressive forms of MS.

There were reductions in inner retinal layers and alterations of outer hyperreflective bands integrity in this study. Retrograde degeneration may be limited to the inner retinal layers[18] and changes observed in the outer retinal layers may represent primary axonal degeneration in the course of MS.[19],[20],[21] With highly reproducible and relatively quick OCT image acquisition, determining the integrity of the EZ, IZ, and ELM has the capability of assessing the health of the outer retina in clinical and research settings. In addition, EZ has been shown to be associated with the visual function and is an important marker of visual outcomes in many retinal conditions.[22],[23]

We found that the EZ was more vulnerable hyperreflective band among the three retinal hyperreflective bands in the outer retina of SPMS patients compared to RRMS patients. Though there were no statistically significant differences in the continuity of IZ and ELM integrity among MS subtypes, IZ integrity was disrupted much more in RRMS patients and EZ was disrupted much more in SPMS patients. Disruption of ELM integrity was also correlated with disease duration independent of MS subtypes. These findings indicated that the EZ and IZ integrity may be used to detect and follow the alterations of the outer retina in MS patients and EZ integrity may be used to evaluate MS subtypes and ELM integrity may be used to determine disease progression and severity. Disruption of IZ and ELM integrity may be seen in early stages of disease process and restoration of IZ may be followed by ELM disruption. It is believed that axonal loss is not reversible in MS and may result in disability; in contrast, demyelination is reversible.[24] Demyelination of anterior visual pathway could eventuate with disruptions of outer retinal bands.

As best we know, there have been no studies published on determining structural properties of outer retinal hyperreflective bands in MS patients and differences in MS subtypes. This study has some limitations that evaluating retinal vasculature parameters with an accurate imaging method such as OCT-angiography and evaluating function of outer retinal layer with electrophysiological tests were not done. Further studies including all MS subtypes analyzing with simultaneously OCT, OCT-angiography, and electrophysiological tests are required.


   Conclusıon Top


Evaluation of inner and outer retina findings determined by SD-OCT may be a relatively low-cost method for quantifying the damage caused by MS and differing MS subtypes. Our findings provide evidence that alterations of retina in MS are not limited to the inner retina and structural changes of hyperreflective bands in outer retina could occur as well.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3]



 

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