Associations of Optical Coherence Tomography Parameters and Pathological Process in Multiple Sclerosis: Evidence from a Systematic Review and Meta-Analysis
Eleni Mitona1, Sygkliti-Henrietta Pelidou2,4*, Evangelia Ntzani3, Christos Bakirtzis4, Marina Boziki4, Ioannis Nikolaidis4, Christos Kalogeropoulos1 and Ioannis Asproudis1
1Department of Ophthalmology, University of Ioannina, Greece
2Department of Neurology, Division of Health Sciences, University of Ioannina, Greece
3Department of Epidemiology, Division of Health Sciences, University of Ioannina, Greece
4Department of Neurology, Aristotle University of Thessaloniki, Greece
Submission: July 15, 2019; Published: August 23, 2019
*Corresponding author: Sygkliti-Henrietta Pelidou, Department of Neurology, University of Ioannina, University Campus, Division of Health Sciences, Medical School, Ioannina, Greece
How to cite this article: Eleni Mitona, Sygkliti-Henrietta Pelidou, Evangelia Ntzani, Christos Bakirtzis, et al. Associations of Optical Coherence Tomography Parameters and Pathological Process in Multiple Sclerosis: Evidence from a Systematic Review and Meta-Analysis. Open Access J Neurol Neurosurg. 2019; 11(3): 555813. DOI: 10.19080/OAJNN.2019.11.555813.
Abstract
Introduction: The usefulness of Optical Coherence Tomography (OCT) in accessing axonal loss and visual pathway involvement in the pathological process of Multiple Sclerosis (MS) is increasingly accepted the last ten years. The present meta-analysis aimed to explore the current evidence regarding potential associations between OCT parameters and pathological process of MS.
Materials and Methods: A thorough systematic search and critical appraisal of existing medical literature was done using OCT to screen patients with MS. Pubmed/Medline databases were searched from 2006 to the end of February 2019 using the terms Optic Neuritis (ON), OCT, Retinal Nerve Fiber Layer (RNFL), and MS. The obtained data were analyzed by Cochrane Collaborations Review Manager 5.3.
Results: The identified 65 studies examined OCT parameters in patients with MS and healthy subjects. The estimated RNFL loss in MS patients with non-ON compared to controls was lower than the one following MSON. Greater retinal thinning was observed in patients’ eyes with prior history of ON than in those of controls. Moreover, visual acuity measurements were found to be strongly in consistent with the RNFL thickness values.
Conclusion: RNFL and Macular Volume (MV) measurements might be able to reveal information concerning the visual pathway axonal loss and neuronal cell thinning, regardless history of ON. RNFL thinning could be used as a possible MS outcome measure and as surrogate endpoint for MS disability. Furthermore, RNFL can provide complementary information in relation to MS patients’ vision.
Keywords: Ocular coherence tomography; Optic neuritis; Retinal nerve fiber layer; Multiple Sclerosis
Abbreviations: OCT: Optical Coherence Tomography; MS: Multiple Sclerosis; ON: Optic Neuritis; MRI: Magnetic Resonance Imaging; MSON: Multiple Sclerosis Optic Neuritis; MSNON: Multiple Sclerosis-Non Optic Neuritis; RNFL: Retinal Nerve Fiber Layer; MV: Macular Volume; BCVA: Best-corrected Visual Acuity; LCVA: Low-contrast Visual Acuity; VA: Visual Acuity; CS: Contrast Sensitivity; CI: Confidence Interval; OR: Odds Ratio
Introduction
Multiple Sclerosis (MS) is an autoimmune disease of the Central Nervous System (CNS) characterized by chronic inflammation and neurodegeneration. Axonal degeneration, although more profound in the later stages of the disease, may be present even in the early stages of the disease course. In addition, Optic Neuritis (ON) is an early feature of MS and almost 70-80% of patients develop ON during the course of their disease. Optical Coherence Tomography (OCT) is a relatively new imaging technique which serves as a promising and sensitive tool for measuring the thickness of the Retinal Nerve Fiber Layer (RNFL) and with a cost of approximately 10 to 15% less than that of Magnetic Regional Imaging (MRI) [1]. Several recent studies have denoted that OCT can detect RNFL thinning, regardless of ON clinical history, probably due to axon damage in the patients’ retinas, suggesting that this may be an effective biomarker.
In addition, OCT is a non-invasive technique which provides a reliable way for an in vivo optical biopsy of accessible tissues like the retina [2,3]. OCT has evolved into an interesting and highly accurate method for the imaging of neurodegeneration and axonal loss in MS within the last ten years. The RNFL consists mainly of retinal ganglion cell axons, which are unmyelinated and thus measures axonal loss [4]. A number of studies have also reported RNFL thinning in clinically unaffected eyes with MS when compared to healthy ones. The degree of reduction of the RNFL thickness following ON is consistent with the outcome of the quantitative analyses of visual dysfunction [5-8] as well as with the global measures of disability in MS as suggested in other studies [1,9]. A study performed by OCT supported that the detection of RNFL thickness loss is not confounded by any concurrent myelin loss in patients with a history of unilateral ON compared to the fellow eye [6]. Additional studies show that MS patients display RNFL thinning both with and without a history of ON [10,11]. In the present study we conducted a search of medical literature on all studies using OCT to screen patients with MS. Finally, RNFL thinning is discussed as a possible MS outcome measure, especially as a biomarker for MS disability [12,13].
Materials and Methods
Search strategy and selection criteria
We searched Pub Med/Medline database, from 2006 to the end of March 2019, using the generic terms Optic Neuritis, Ocular Coherence Tomography, Retinal Nerve Fiber, and Multiple Sclerosis. All the studies identified in this systematic review were using OCT technology based on the stratus OCT to screen patients with MS. The included publications were written in English language and RNFL, BCVA and MV measurements could be obtained from the eligible studies. Publications in languages other than English were excluded. In addition, experimental research in animal models was also excluded as well as review articles and case reports. Abstracts and full-texts included in the analysis were screened by titled and abstract by two of the authors independently (E.M. and S-H.P.) using the abovementioned inclusion and exclusion criteria. From each article we recorded the following data: name of the first author, title of the study, year and PMID of publication, number, sex, mean age of cases and controls in each study. Cochrane Collaborations Review Manager 5.3 was used for the analysis of the obtained data of each study.
Since the present study was based on data retrieved from the literature did not require ethical approval from our authorities.
Results
A total of 3265 studies matched the inclusion criteria (Figure 1) and considered for the study. A total of 1497 articles were excluded according to selection criteria. From the remaining 1768 articles, we excluded 47 articles of experimental research and 1608 articles as reviews or case reports. Finally, of the 113 articles included in the meta-analysis, 48 were further excluded as their data presentation lacked the necessary details for inclusion in the study. At the end, 65 articles were eligible for systematic review of OCT parameters in MS patients. Flow of information through the different phases of the literature search is shown in figure 1. The mean difference, which enables the comparison of the RNFL thickness among groups of interest, was chosen as an effect measure.
A total of 4 groups of studies were included in the systematic review: 1) Multiple Sclerosis Optic Neuritis (MSON) affected eyes compared to healthy controls (Figure 2), multiple sclerosisnon optic neuritis (MSNON) affected eyes compared to healthy controls (Figure 3), Macular Volume (MV) of patients with MS compared to healthy controls (Figure 4), and 4) Best-Corrected Visual Acuity (BCVA) of patients with MS compared to healthy controls (Figure 5).
RNFL in MSON and MSNON, MV and BCVA from the 65 eligible studies analyzed by Cochrane Collaborations Review Manager 5.3 program were as follows
RNFL MSON
The meta-analysis results of the 65 eligible studies which compared eyes of MS patients affected by ON (n=4118) with eyes of healthy controls (n=2742) gave an estimated average RNFL thinning following MSON of -11.47 μm [95% CI -11.74 to -11.21, n=6860, p<0.00001] (Figure 2).
RNFL MSNON
We singled out of 65 eligible studies for the meta-analysis 20 studies which compared the RNFL thickness of MSNON eyes with healthy controls eyes. The estimated RNFL loss in MSNON eyes (n=903) compared with controls ones (n=987) was lower (-2.60) than the one following MSON (-11.47), but the 95% CI was narrower -2.60 [-2.80 to -2.39, n=1890, p<0.00001] (Figure 3).
MV
We examined out of 65 studies eligible for the meta-analysis 16 studies comparing MV in eyes of MS patients with that of healthy controls. The summary data of 2282 investigated eyes (1619 with MS vs. 663 controls) are shown in Figure 4. The MV thickness among MS eyes and controls was within an estimated average of -0.23 μm [95% CI -0.26 to -0.20, n=2282, p<0.00001] (Figure 4).
BCVA
We examined out of 65 eligible studies for the meta-analysis 13 studies comparing BCVA of MS patients’ eyes with that of healthy controls. The summary data of 2652 investigated eyes (1447 with MS vs. 1205 controls) are shown in Figure 5. The BCVA among MS patients’ eyes and controls was within an estimated average of -0.17 [95% CI -0.19 to -0.15, n=2652, p<0.00001] (Figure 5).
Discussion
In the present study retinal measures for healthy controls were greater than those of MS patients with or without ON across all measured parameters. OCT is used to detect axonal loss in MS patients, even in those featuring subclinical defects. The visual acuity measurements were strongly in consistent with the RNFL thickness values, denoting that RNFL can provide complementary, not overlapping, information in relation to MS patients’ vision, thus highlighting the significance of examining vision in MS patients [7]. It is possible to detect any occurring deterioration of the optic nerve function even in MS patients exhibiting no prior symptoms of visual damage [14-16]. The RNFL reduction was also correlated with the visual field in MSON and MSNON patients, while in another study such correlation was observed only in MSON eyes [15]. A significant reduction in RNFL thickness was observed in MSON eyes which is consistent in all studies performed using separate methods of retinal fiber assessment [17]. The values of RNFL thickness and visual function were even more reduced in recurrent ON eyes, thus OCT was proposed as a biomarker for evaluation of the vision of MS patients [18,19]. After evaluating their findings, the authors concluded that repetitive inflammatory incidents could consequently lead to visual impairment. Retinal thinning was observed to be greater in patients’ eyes with prior history of ON than in those of controls [20].
Saxena et al. [21] evaluated that RNFL thinning in ON cases was linked to severe visual field deficiencies, while in MS cases was more associated with contrast sensitivity and stereo acuity. Additionally, eyes with an ON history had a significantly reduced RNFL thickness compared with that group of non-ON history [22]. RNFL reduction may manifest in both relapsing-remitting and secondary progressive MS patients [23]. Moreover, a steady reduction in average RNFL thickness in MSON eyes is advancing over time [24]. The RNFL reduction could be explained by secondary axonal degeneration linked to focal lesions affecting the visual pathways or by diffuse advancing axonal degeneration attributed to a compartmentalized progressive inflammation in the brain [24]. A subclinical RNFL thinning is likely to manifest even in MS patients without clinical ON history [25-28]. In many studies, the difference in RNFL thickness between MSON eyes and MSNON fellow eyes was reported statistically insignificant [29-40]. These findings highlight the significance of thoroughly investigating all evidence in MSNON in order to limit the risk of overlooking a more subtle RNFL loss due to an inferred retrograde trans-synaptic degeneration caused by the damaged anterior visual pathways in MSNON [41-59].
In addition, MV values of MS patients’ eyes evaluated within a 12-month period shown a decreasing trend in all patients. In these studies, MV reduction, both in MS patients and healthy controls, was similarly proportionate [59-61]. A Fast-Macular Thickness scanning was used in order to estimate MV. The authors suggested that MV assessment was more sensitive means of detecting age-related retinal alterations because the macula contains a proportionally higher number of ganglion cells in comparison to RNFL. Furthermore, MV reduction was observed on eyes of MS patients both with and without history of ON.
Moreover, a number of studies [62-65] reported correlation of the temporal sector with the visual acuity, in comparison to the correlations of the superior, inferior and nasal quadrant which detected no significant differences. In addition, MS patients displayed impaired Low-Contrast Visual Acuity (LCVA) in comparison to healthy controls [65]. According to that study, from the early stages of the disease up to the advanced ones, MS patients demonstrated impairment in LCVA as well as in color vision with gradually deterioration with progression of time.
Conclusion
OCT is an extensively recognized tool which is used to measure RNFL and MV thicknesses in MS patients. These measurements could provide valuable information regarding axonal loss and neuronal cell layer thinning regardless ON. Moreover, VA measurements were found to be strongly in consistence with the RNFL thickness values, denoting that RNFL can provide complementary but not overlapping information in relation to MS patients’ vision. Following axonal loss and axonal injury by means of OCT might be a useful and reliable measure in clinical studies evaluating neuroprotective therapies for MS.
Acknowledgment
The financial support of HELANI (Hellenic Academy of Neuroimmunology) to Sygkliti-Henrietta Pelidou is gratefully acknowledged. #authors contributed equally.
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