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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 3  |  Page : 216-221

Retinal nerve fiber layer thickness in multiple sclerosis subtypes


1 Department of Neurology, Ain Shams University, Cairo, Egypt
2 Department of Ophthalmology, Ain Shams University, Cairo, Egypt

Date of Web Publication13-Aug-2015

Correspondence Address:
Dina A Zamzam
Department of Neurology, Ain Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1083.162052

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  Abstract 

Background
Optical coherence tomography (OCT) is a promising tool for detecting subclinical changes in retinal nerve fiber layer (RNFL) and macular volume in multiple sclerosis (MS).
Objectives
The aim of the study was to assess the relationship of retinal changes in different MS subtypes with and without optic neuritis (ON) with clinical disability, duration of illness, and MRI results.
Methods
Twenty-four patients with relapsing-remitting subtype and 12 patients with secondary progressive subtype, of age range 16-55 years, with and without ON, and 16 age-matched and sex-matched healthy controls were enrolled in this study; in total, there were 15 male and 37 female participants. Patients were subjected to history, clinical evaluation, Extended Disability Status Score for disease severity, MRI brain with contrast, and OCT to assess the RNFL and macular volume of the optic nerve. The control group underwent OCT.
Results
RNFL thinning was highly correlated in both subtypes with and without ON in all field quadrants compared with the healthy controls. In addition, retinal and macular thickness inversely correlated with Extended Disability Status Score and disease duration in the progressive group than in the relapsing-remitting type. MRI with contrast inversely correlated with both macular and RNFL thickness in the progressive type.
Conclusion
Retinal axonal loss is more prominent in advanced stages of disease with proportionally greater thinning in eyes previously affected by clinically evident ON. In the absence of clinically evident ON, OCT is a promising potential biomarker of retinal pathology in MS subtypes.

Keywords: multiple sclerosis subtypes, optical coherence tomography, retinal nerve fiber layer thickness, central macular thickness


How to cite this article:
Zamzam DA, Gaafar AA, Ismail AT, Elbassiouny A, Tork MA, Hamdy H. Retinal nerve fiber layer thickness in multiple sclerosis subtypes. Egypt J Neurol Psychiatry Neurosurg 2015;52:216-21

How to cite this URL:
Zamzam DA, Gaafar AA, Ismail AT, Elbassiouny A, Tork MA, Hamdy H. Retinal nerve fiber layer thickness in multiple sclerosis subtypes. Egypt J Neurol Psychiatry Neurosurg [serial online] 2015 [cited 2017 Jun 23];52:216-21. Available from: http://www.ejnpn.eg.net/text.asp?2015/52/3/216/162052


  Introduction Top


Multiple sclerosis (MS) is considered a chronic inflammatory disease of the central nervous system (CNS). It may cause demyelination and axonal degeneration. Most MS patients present with a relapsing-remitting disease course (RRMS) that may transform into secondary progressive multiple sclerosis (SPMS), whereas a smaller percentage of patients present with primary progressive course (PPMS) from the start [1]. The retina is the only place where a tissue layer made up of unmyelinated axons can be imaged directly [2],[3]. Axonal and neuronal degeneration is an important feature of MS. Many studies have demonstrated thinning of the retinal nerve fiber layer (RNFL) [4],[5]. Optical coherence tomography (OCT) is an increasingly recognized, noninvasive tool in MS imaging that allows investigation of the retina [6]. OCT studies in MS have primarily focused on evaluation of the RNFL. The etiology of retinal changes in MS is thought to be secondary to optic nerve demyelination. The application of nonconventional MRI techniques has led to only modest achievements in linking imaging data with clinical measures of disease severity for MS [7]. Data on differences in OCT findings between MS subtypes are scarce and conflicting. Yet, cross-sectional studies show more thinning of RNFL in progressive forms of MS compared with the RRMS form. However, it remains unsure whether these differences are due to the disease subtype per se, or are related to disease duration, lesions, or severity [8].


  Aim of work Top


In this study, we aimed to evaluate the role of OCT in MS subtypes, with and without a history of optic neuritis (ON), and to correlate our findings with disease duration, clinical measures of disability, and brain MRI.


  Patients and methods Top


Twenty-four patients with clinically definite RRMS according to McDonald's criteria 2010 [9] and 12 patients with SPMS were recruited from the outpatient clinics and the Neurology department, Ain Shams University Hospitals. Sixteen age-matched and sex-matched healthy controls with a visual acuity (VA) of 20/30 or better, with no ophthalmic or neurologic diseases or a medical history of diabetes mellitus, hypertension, or renal or liver diseases were subjected for OCT. Patients aged 16-50 years of both sexes were included. We excluded (a) patients with a recent clinical diagnosis of ON (<6 months) before the study, (b) patients with a refractive error of ± ≥5.0 D, (c) patients with a history of eye disease that may impact significantly on OCT measures such as glaucoma, anterior ischemic optic neuropathy, or congenital abnormalities of the optic nerves, or history of ocular surgery or penetrating trauma, (d) patients with other medical diseases such as hypertension or diabetes mellitus, (e) patients with a VA 20/200 (Snellen scale) or less in both eyes (because this would preclude some of the examinations), and (f) patients with a contraindication to MRI.

The patients were subjected to (a) history taking and complete neurological examination, (b) evaluation of the level of disability from MS assessed with the Extended Disability Status Score (EDSS) [10], with duration calculated as time since diagnosis in years, (c) brain MRI with contrast, (d) VA using Snellen test, and fundus examination, and (e) spectral domain OCT examination using the Heidelberg Engineering Spectralis (Heidelberg Engineering, Heidelberg Germany). RNFL images were acquired by taking three circular 3.4-mm-diameter scans, centered on the optic disc, the mean of which was used to express RNFL thickness in four quadrants (temporal, superior, inferior, and nasal). The thicknesses of the quadrants were automatically calculated by the OCT device software. Macular thickness maps were acquired by making six radial linear scans, centered on the fovea, and by construction of a map from these scans.

Statistical analysis

Quantitative data are presented as mean and SD. Categorical results are presented as numbers of cases and percentages. Quantitative variables were compared using the Student t-test or the Mann-Whitney U-test, depending on the distribution of data. Categorical variables were compared using the χ2 -test or Fisher's exact test. Pearson's correlation coefficient was used to assess the correlation between quantitative variables. The receiver operating characteristic curve was used to evaluate the sensitivity and specificity for quantitative diagnostic measures that categorize cases into one of two groups. A significance level of P less than 0.05 was used in all tests. All statistical procedures were carried out using SPSS version 15 for Windows (SPSS Inc., Chicago, Illinois, USA).


  Results Top


Thirty-six hospital-based patients with clinically confirmed MS were divided into patients with the RRMS subtype and those with the SPMS subtype. Patients with the RRMS subtype were 24 in number (four male and 20 female patients; age 29.37 ± 8.61); 22 eyes had ON, and the remaining 26 eyes had no ON. Patients with the SPMS subtype were 12 in number (five male and seven female patients; age 34.5 ± 9); six eyes had ON, and 18 eyes had no ON. Sixteen matched healthy controls (six male and 10 female individuals; age 29.4 ± 21) were also included. EDSS showed significant correlation in the SPMS group compared with the RRMS group. The mean duration of illness was 5.4 and 7.4 years in RRMS and SPMS, respectively. The mean EDSS was 2.48 in RRMS versus 4.92 in SPMS patients [Table 1].
Table 1: Comparison of demographic data between rela psing-remitting multiple sclerosis and secondary progressive multiple sclerosis subtypes

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We compared RNFL and central macular thickness (CMT) in both MS subtypes with and without ON with the control group (RRMS, 48 eyes; SPMS, 24 eyes). RNFL thinning showed strong correlation in MS subtypes when compared with the control group (32 eyes) (P = 0.0001), whereas CMT showed significant correlation only with the RRMS subtype with no significant intergroup difference [Table 2].
Table 2: Comparison between multiple sclerosis subtypes with and without optic neuritis compared with controls as regards relapsing-remitting multiple sclerosis and central macular thickness

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We also compared RNFL and CMT in MS subtypes with EDSS and disease duration. Results revealed that EDSS inversely correlated with CMT in the RRMS subtype (r = -363, P = 0.011), whereas in the SPMS subtype EDSS (r = -507, P = 0.012) and disease duration (r = -455, P = 0.025) inversely correlated with RNFL thickness (higher EDSS and longer disease duration were associated with thinning RNFL) [Figure 1].
Figure 1: Correlations between extended disease disability scale (EDSS) and disease duration in multiple sclerosis subtypes with respect to central macular thickness (CMT) and retinal nerve fiber layer (RNFL) thickness.

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Correlations between MRI findings, including T2 lesions and contrast-enhanced lesions, and CMT and RNFL in the MS subtypes showed that MRI lesion load with contrast inversely correlated with CMT in RRMS (P = 0.032) and with RNFL and CMT in SPMS. The number of lesions increased, whereas RNFL thickness decreased (P = 0.046 and 0.045, respectively) [Table 3].
Table 3: Correlations between magnetic resonance imaging findings and central macular thickness and retinal nerve fiber layer thickness in multiple sclerosis subtypes

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As regards RNFL thickness and CMT measurements in MS subtypes, results showed that thinning of RNFL in all field quadrants strongly correlated with both MS subtypes, whereas CMT thinning significantly correlated with all field quadrants, sparing the nasal one in the RRMS subtype, and only correlated with the inferior quadrant in the SPMS group [Table 4].
Table 4: Correlations between quadrant measurements, retinal nerve fiber layer, and central macular thickness in multiple sclerosis subtypes

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On correlating MRI lesion load (enhanced lesions) and RNFL measurements we found a positive correlation between RNFL thinning of the inferior quadrant in the SPMS subtype and number of lesions in brain MRI [Table 5].
Table 5: Comparison between multiple sclerosis subtypes (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis) as regards average retinal nerve fiber layer quadrant thickness measurements and magnetic resonance imaging findings

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  Discussion Top


MS is a neurodegenerative disease characterized by axonal injury in the CNS, leading to progressive neurologic deficits. The axonal damage occurs in the early stages of the disease, not related to inflammatory or autoimmune activity against myelin; yet, the axonal degeneration is directly related to permanent functional disability [11],[12]. Axonal damage in these patients can be detected and measured by the level of RNFL using ocular imaging technologies.

In the present study 36 hospital-based patients with clinically definite MS according to McDonald's criteria 2010 [9] were divided into RRMS subtype (24 patients) and SPMS subtype (12 patients) with or without ON; the study also included 16 matched healthy controls. EDSS and disease duration inversely correlated with RNFL thickness and CMT in the SPMS subtype, whereas CMT was inversely correlated with EDSS in the RRMS subtype. These results are in agreement with those of Khanifar et al. [11], who found RNFL thickness decreased in patients with a duration of MS greater than 5 years compared with those with a duration less than or equal to 1 year. In contrast to our result, Serbecicet et al. [12] did not show differences in RNFL thickness or CMT between MS subtypes. Here we showed that RNFL thickness is significantly reduced in MS patients with and without ON compared with healthy controls (P = 0.0001) and there is significantly reduced CMT in the RRMS group (P = 0.02) with no intergroup difference (P = 0.254).

The subgroup comparisons revealed a significant reduction in RNFL thickness in SPMS patients with ON when compared with RRMS patients, with no significant difference as regards CMT. Both RRMS and SPMS subtypes demonstrated average RNFL thinning, most conspicuously and severely in the temporal quadrant, which contains fibers of the papillomacular bundle. In agreement with our findings, studies have shown that OCT-measured RNFL thickness values are reduced in patients with MS with and without a history of ON, being more prominent in the temporal quadrant [13-16]. The reduction in RNFL thickness was suggested to be associated with diffuse axonal damage in the whole CNS of MS patients; however, in many RRMS patients the RNFL thickness was found to be within normal range [16].

Previous studies in MS have demonstrated thinning of the RNFL and a reduction in CMT most prominent in eyes previously affected by ON. Among MS subtypes, RRMS patients showed less RNFL thinning when compared with the SPMS subtype [17],[18]. In addition, the comparisons revealed reduction in RNFL thickness in SPMS-ON patients versus RRMS-ON, and no difference in CMT between the two groups. This is in contrast to other studies, which found a significant reduction of CMT in SPMS patients versus RRMS patients [15], and in accordance with previous studies that included only small sample sizes, especially for the progressive subtype, which may partly explain the inconsistent findings [19],[20].

Regarding the comparison of RNFL thickness in RRMS and SPMS patients, differences between SPMS-nonoptic neuritis (NON) and RRMS-NON eyes were less than the differences between SPMS-ON and RRMS-ON eyes (∼2.37 vs. ∼12.73 μm, respectively), which is in contrast to the study by Castello et al. [19], who found the differences between SPMS-NON and RRMS-NON eyes to be about twice that between SPMS-ON and RRMS-ON eyes and suggested that the impact of prior ON may overshadow the effects of disease subtype. This difference could be due to the small number of patients in our study.

There were significant differences in RNFL thickness within quadrants of the peripapillary retina when comparing patients with RRMS with those with the SPMS subtype, as there is more thinning in RNFL in SPMS compared with RRMS. CMT was significantly reduced in the RRMS subtype compared with controls (P = 0.02) with no difference in the SPMS subtype (P = 0.598). This is in contrast to the study by Pulicken et al [20], who found correlations of macular volumes and CMT with RNFL thickness in controls and all MS subtypes. This difference could be explained by the longest duration of disease in their study (mean average duration 11.7 years), whereas in our study it was 7.42 years for SPMS and 5.4 years for RRMS subtypes.

Our study showed inverse correlation between MRI lesion load with contrast and RNFL thickness and CMT in the SPMS subtype (P = 0.045 and 0.046, respectively) and with RNFL thickness in the RRMS subtype (P = 0.032). This is in agreement with the study by Siger et al. [18], who found in MS-NON a lower average RNFL thickness that was associated with an increased T1 lesion volume (P = 0.03) and T2-lesion volume (P = 0.001). In MS-ON there was a much weaker, nonsignificant correlation between RNFL thickness and T1 and T2 volumes.

In this study, we confirmed that the RNFL thickness in the ON-affected and ON-unaffected eyes of patients with MS subtypes is significantly reduced as compared with healthy controls. We identified patterns of RNFL thinning and CMT reduction in different MS subtypes both with and without a history of ON. Both RRMS and SPMS subtypes demonstrated average RNFL thinning, most conspicuously and severely in the temporal quadrant, which contains fibers of the papillomacular bundle. RNFL thickness and CMT correlated more strongly with MRI lesion load in the SPMS subtype than in the RRMS subtype with more thinning of average RRMS in the inferior quadrant. During the progressive phases of MS, axonal loss also occurs at the optic nerve; this axonal loss is detected by OCT as RNFL loss and is greater in the SPMS type.


  Conclusion Top


Retinal axonal loss is more prominent in advanced stages of disease with proportionally greater thinning in eyes previously affected by clinically evident ON. In the absence of clinically evident ON, OCT is a promising potential biomarker of retinal pathology in MS subtypes.

Acknowledgements

Nil.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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