Sensitivity of optical coherence tomography and visual evoked potential in demyelinating optic neuritis

Youssef A.H Helmy; Emad A Sawaby; Mohammed A Awadalla; Shaymaa H Salah

doi:10.4103/ejos.ejos_18_20

ORIGINAL ARTICLE

Year : 2020 | Volume : 113 | Issue : 3 | Page : 83-90

Sensitivity of optical coherence tomography and visual evoked potential in demyelinating optic neuritis

Youssef A.H Helmy, Emad A Sawaby, Mohammed A Awadalla, Shaymaa H Salah
Department of Ophthalmology, Kasr Al Aini Hospital, Cairo University, Cairo, Egypt

Date of Submission	02-Apr-2020
Date of Acceptance	21-Apr-2020
Date of Web Publication	07-Sep-2020

Correspondence Address:
MD Shaymaa H Salah
Department of Ophthalmology, Cairo University, Saray Al-Manial, Kasr Al Aini Hospital, Ophthalmology Department Secretary, Al-Manial, Cairo 11559
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ejos.ejos_18_20

Abstract

Aim The aim of this study is to analyze the structural and functional abnormalities of the optic nerve in multiple sclerosis (MS) patients utilizing optical coherence tomography (OCT) and visual evoked potential (VEP). We compare between eyes with and without a history of neuritis.
Patients and methods A cross-sectional study which compared 60 eyes of MS patients with 20 eyes of the healthy control group. MS patients were classified into MS with optic neuritis (MS-ON, n=44) and MS without optic neuritis (MS-NON, n=16). Both VEP and OCT were done.
Results Both groups showed thinning in the retinal nerve fiber layer (RNFL), ganglion cell complex, and prolongation in latency (P100). The decrement in RNFL was more in the MS-ON group in superior RNFL, temporal RNFL, and average RNFL (P=0.002, 0.002, 0.03), respectively. In the MS-ON group, the average, temporal, and nasal RNFL showed significant negative correlation with latency of P100 (P=0.0001, 0.0001, 0.001), respectively. Latency of P100 showed higher sensitivity (52.3%) over temporal RNFL (43.2%) in detecting ON.
Conclusion Both VEP and OCT have been proven to be sensitive tools in the detection of optic neuropathy in MS. Latency showed the highest sensitivity followed by the temporal RNFL. Temporal RNFL and average ganglion cell complex can be a biomarker for both axonal and neuronal loss in eyes with and without neuritis. This loss can precede the demyelination process.

Keywords: demyelination, optical coherence tomography, optic neuropathy, peripapillary retinal nerve fiber layer, visual evoked potential latency

How to cite this article:
Helmy YA, Sawaby EA, Awadalla MA, Salah SH. Sensitivity of optical coherence tomography and visual evoked potential in demyelinating optic neuritis. J Egypt Ophthalmol Soc 2020;113:83-90

How to cite this URL:
Helmy YA, Sawaby EA, Awadalla MA, Salah SH. Sensitivity of optical coherence tomography and visual evoked potential in demyelinating optic neuritis. J Egypt Ophthalmol Soc [serial online] 2020 [cited 2023 Apr 2];113:83-90. Available from: http://www.jeos.eg.net/text.asp?2020/113/3/83/294444

Introduction

Multiple sclerosis (MS) is a chronic demyelinating inflammatory disorder of the central nervous system in young adults [1]. The Middle Eastern and North African countries were previously classified as areas of low to moderate risk of MS; now studies suggest an increasing prevalence of MS in our region [2]. Demyelinating optic neuritis (ON) is a common manifestation of MS and arises frequently as the first presentation of the disease. Hence, the ophthalmologists play an important role in the diagnosis and/or follow-up of those patients [3].

Since the retinal nerve fiber layer (RNFL) is composed of only unmyelinated axons, measuring RNFL thickness is considered an easy tool for quantifying any axonal loss in patients with MS [4]. Optical coherence tomography (OCT) is a noncontact, easy, and cheap technique that is used to measure peripapillary RNFL loss with high resolution and excellent reproducibility [5]. Moreover, OCT is used to assess the macular ganglion cell layer complex (GCC). Many previous studies have found statistically significant reductions in RNFL and GCC thickness among MS patients in both eyes with and without a history of ON [6],[7],[8].

Visual evoked potential (VEP) studies the functional aspect of the visual pathway, and has the ability to detect any blockage of impulses or conduction delay in the visual pathway, which can occur as a result of the demyelination that is the hallmark of MS, and hence the importance of studying the VEP in patients with MS [9].

Most studies in the literature have aimed to find a correlation between structural and functional changes, and to highlight which of them is better in terms of sensitivity and specificity [2],[3],[4],[5],[6],[7],[8],[9],[10],[11].

Patients and methods

Study design

This is a prospective study that was conducted in Kasr Al Ainy Medical Hospital, Cairo University. Sixty eyes of MS patients and 20 eyes of healthy controls were enrolled in this study. The research adhered to the tenets of the Declaration of Helsinki. The research was approved by Kasr Al Ainy Research Ethics Committee Board and written informed consent had been taken from all participants.

Participants

Thirty patients were diagnosed with MS according to the revised McDonald criteria [12]. Twenty eyes of healthy controls were recruited from healthy volunteers from among relatives of patients. They had neither ocular nor systemic diseases. Participants (patients and controls) with pathologic hyperopia or myopia (spherical refractive error >+/−3.00 D) were excluded.

All patients had neurological examination and radiological investigations. Ophthalmological examination including best-corrected visual acuity (BCVA) using decimal points were converted to logMAR scale for statistical analysis. Color vision was evaluated by 12 red-green pseudoisochromatic plates. The results of color vision were expressed in numbers from 0 to 12 denoting the number of plates identified by patients. Pupillary reflexes, ocular motility, and fundus examination with special emphasis on disk appearance were also recorded. All patients were asked for history of onset of ON. A history of ON was documented when there was an acute loss of vision lasting more than 24 h, associated with pain with eye movement, color desaturation, with or without optic nerve swelling. Number of attacks of diminution of vision was also documented.

The 60 eyes were further divided after clinical examination and according to history of ON into two groups: MS-ON (n=44 eyes) with ON and MS-NON (n=16 eyes) without ON. The eyes with glaucomatous optic neuropathy, macular disease, or ocular media opacities were excluded.

Optical coherence tomography

SD-OCT was done using the RTVue FD-OCT system (software version #6, 11, 0, 12; Optovue Inc., Fremont, California, USA). The RTVue-OCT uses a near-infrared light source at 840 nm. Pupils of all participants were dilated with 1% tropicamide. Scans for all participants were performed by two well-trained technicians. An internal fixation target was used to improve reproducibility, and a patch was placed over the untested eye. Protocols for macular and optic nerve head imaging were chosen (macular radial, MM5, 3D ONH, GCC) [13]. The optical principles and applications of the OCT have been described in detail elsewhere [14]. The 3D ONH consists of a 3D optic disk scan for the disk margin that automatically determines the retinal pigment epithelium margins, then an ONH scan to measure the optic disk parameters, and RNFL thickness over a circle of diameter of 3.45 mm, and centered on the predefined disk [15]. The parameters calculated are the average RNFL thickness in the temporal, superior, nasal, and inferior quadrant as well as the overall average along the entire measurement circle measured in micrometers. The GCC thickness is measured from the internal limiting membrane to the inner plexiform layer (IPL) boundary. The parameters obtained include the superior (above horizontal meridian), inferior (below horizontal meridian), and average thickness measured in micrometers.

Visual evoked potential

All participants underwent VEP using The Nihon Kohden (Nihon Kohden MEB-2300, Haryana, India). The participant was seated in a semidark room 40 cm away from a television screen; four electrodes were placed on the patient’s head (one on occiput, two laterals, and a ground electrode on the vertex). The participant was asked to fix on a central target taped to the screen 5 cm×5 cm. A strobe flashlight is suddenly illuminated to elicit flash response. The screen is turned on to reveal a checkerboard with a check size of 16 inches that reverses in pattern between black and white squares at a rate of 2 Hz. The latency of the first major positive peak in the VEP (P100 wave) was measured. The amplitude of the P100 component was also measured.

Statistical analysis

Statistical analysis was performed using the Statistical Package for Social Sciences (version 15.0 for Windows; SPSS Inc., Chicago, Illinois, USA). The two-tailed unpaired t test was used to evaluate differences between controls and MS and between MS eyes with and without ON. All results were described in terms of mean±SD, minimum and maximum, and frequencies (number of cases) and percentages when appropriate. Correlation between various variables was done using the Spearman rank equation or Pearson’s equation according to the type of variables and P values were calculated. Comparison between results of VEP and OCT were done using χ² tests; significant differences were observed by calculating respective P values. P values less than 0.05 were considered statistically significant.

Results

Thirty MS patients, 18 women and 12 men, mean age 32.6±1.6 years (15–48 years). Mean duration of MS was 6.9±0.7 years (1–16 years). Ten healthy individuals (20 eyes) included six women and four men with a mean age of 32±5.5 years.

The MS patients were divided into two groups: MS-ON consists of 44 eyes (22 MS patients) with a history of ON and MS-NON consists of 16 eyes (eight MS patients). The mean number of attacks was 1.3±2 attacks (0–10 attacks), the median number of attacks was one attack per eye. The mean duration since the first attack of diminution of visual acuity was 5.7±0.7 years (1–16 years) ([Table 1]).

Table 1 Distribution of eyes according to the number of attacks of neuritis

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Visual function

In MS-ON, the mean BCVA was 0.5 (0.005–1.0), and the mean number of plates seen were seven plates per eye (0–12). Of the 44 eyes examined, 38 eyes showed a round, regular, and reactive pupillary reaction and the remaining six (13.63%) eyes showed relative afferent pupillary defect. In group B, the mean BCVA was 0.9 (0.32–1.0) and the mean number of plates seen were seven plates per eye (0–12). Of the 16 eyes examined all showed normal round, regular, and reactive pupillary reaction ([Table 2]).

Table 2 Best-corrected visual acuity and color vision in multiple sclerosis with optic neuritis, multiple sclerosis without optic neuritis

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Optical coherence tomography outcome

In MS-ON, RNFL (average, temporal, and nasal) showed significant reduction compared with the control group (P=0.00001, 0.00001, 0.001, respectively). Macular GCC (average, superior, and inferior halves) was significantly reduced compared with the control. Central foveal thickness (CFT) also showed significant decrease (226.5±29.4 vs. 269.9±s8.21, P=0.00001) ([Table 3]).

Table 3 Findings of best-corrected visual acuity, optical coherence tomography values (retinal nerve fiber layer, ganglion cell complex, and central foveal thickness), and visual evoked potential values (P100 absolute latency and amplitude) in both groups compared with the control group

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In MS-NON, only the temporal followed by average RNFL showed statistically significant decrease compared with the control (P=0.004 and 0.03, respectively). Moreover, the inferior half of macular GCC and average GCC showed significant reduction compared with control (P=0.01 and 0.04, respectively). CFT also showed significant decrease (219±29.5 vs. 269.9±8.21, P=0.00001) ([Table 3]).

Best-corrected visual acuity and visual evoked potential

As functional evaluation of both groups, BCVA was significantly reduced in MS-ON compared with the control group (0.24±0.25 vs. 0.0±0, P=0.004). Significant prolongation in P100 latency was found in both MS-ON, MS-NON (123.6±25.4 vs. 88.98±2.14, P=0.00001; 121±25.4 vs. 88.98±2.14, P=0.00001, respectively) but insignificant amplitude changes in both groups.

Comparing MS-ON and MS-NON there was a significant reduction in superior (111.3±20.6 vs. 130.5±18, P=0.002), nasal (75.5±21.3 vs. 87±18.1, P=0.048), and average (92.19±18.9 vs. 103.20±13.41, P=0.031) RNFL thickness, respectively. Also superior GCC showed significant reduction in MS-ON (82.7±12.17 vs. 90.4±11.3, P=0.045) ([Table 4]).

Table 4 Findings of best-corrected visual acuity, optical coherence tomography parameters (retinal nerve fiber layer, ganglion cell complex, and central foveal thickness), and visual evoked potential parameters (P100 absolute latency, and amplitude) in group multiple sclerosis with optic neuritis compared with group multiple sclerosis without optic neuritis patients

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Correlations in the multiple sclerosis-optic neuritis group

The average (r=−0.34, P=0.0001), temporal (r=−0.4, P=0.0001), nasal (r=−0.36, P=0.001), and superior RNFL (r=−0.21, P=0.051) showed significant inverse correlation with P100 latency in VEP, while no significant correlation with amplitude was found ([Figure 1]).

Figure 1 Scatter plot showing the significant correlation between temporal RNFL (a), and average RNFL (b) in group A with P100 latency in the same group. RNFL, retinal nerve fiber layer.

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Also, statistically significant inverse correlation was found between numbers of attacks and average RNFL (r=−0.35, P=0.02), temporal RNFL (r=−0.336, P=0.02), and nasal RNFL (r=−0.312, P=0.04), respectively.

Receiver-operating characteristic (ROC) curve analysis showed that P100 and RNFL T were not significant discriminators for ON (P>0.05). However, RNFL average, RNFL N, and RNFL S were significant discriminators for ON (P<0.05) ([Figure 2], [Table 5]).

Figure 2 ROC curves of temporal RNFL and P100 (a), and average, nasal, and superior RNFL and P100 (b) showing sensitivity and specificity. RNFL, retinal nerve fiber layer; ROC, receiver-operating characteristic.

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Table 5 Comparison between sensitivity of visual evoked potential and optical coherence tomography parameters in detecting demyelinating optic neuritis

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In MS-ON, the P100 latency showed the highest significance (52.3%), temporal RNFL (43.2%%), average, and superior RNFL with same sensitivity (40.9%), then the least sensitivity was for the nasal RNFL (37.5%).

Discussion

In MS patients, with and without a history of ON, the thinning of the peripapillary RNFL and macular GCC was reported in many previous studies [4],[8],[11]. About three-thirds of MS patients suffer from 10 to 40 µm of RNFL loss within a period of 3–6 months following the first inflammatory attack of the optic nerve [16]. At least 2 months are required for the degeneration to take place after pseudoedema of the optic nerve head during the attack [10]. In this prospective study, we analyzed the results obtained from average peripapillary RNFL and from the four main quadrants; also, macular GCC and the CFT were assessed both in MS patients with and without a history of ON.

In the MS-ON group (n=44), all peripapillary RNFL showed statistically significant thinning in the average RNFL (92.19±18.9 vs. 111.9±7.8 µm, P=0.0001). In addition, the highest decrement of RNFL thickness was observed in temporal (P=0.00001), followed by nasal (P=0.001) quadrants. The first attack in all eyes was dated at least 1 year before the study, which explains the overall thinning. In a previous prospective study using same protocols on the same OCT machine (Optovue), Cennamo et al. [11] compared 56 eyes in MS patients with the control group and the results were comparable to ours as regarding the average RNFL thinning in the neuritis subgroup (87.84±10.95 vs. 109.77±19.54 µm, P=0.001). In another study conducted on 50 eyes with ON using the same OCT machine, Vladimirova et al. [17] found a reduction in the average RNFL (83.38±11.317 µm). This thinning was not statistically compared with the control group but revealed thinning comparable to our results. The temporal RNFL in our study showed the most significant thinning (66.1±19.9 vs. 86.33±4.85 µm, P=0.0001). Henderson et al. [18] proved that the mean and temporal RNFL showed the most significant thinning in MS patients. Garcia-Martin et al. [19] proved, in 200 eyes with MS, significant thinning in average and all sectors of RNFL, with the most significant reduction in the temporal quadrant over the 5-year follow-up (53.65±13.13 vs. 65.87±9.56 µm) compared with normal control. The use of different machines and different age groups justifies the variations in values obtained from our study and theirs. It is obvious that MS does not only involve optic nerve sheaths, but also axons in the form of RNFL, and this involvement could be an early presentation. In our study, the average, temporal, and nasal RNFL also showed statistically significant inverse correlation with the numbers of attacks. This was also proved before in Naismith et al. [20].

In the MS-NON group, surprisingly the superior RNFL showed statistically significant increase compared with the normal control (130.5±18 vs. 112.9±5.8 µm, P=0.002). This is attributed to subclinical sectorial disk edema in some eyes without clinical evidence of ON. Only the temporal followed by average RNFL showed statistically significant decrease compared with the control (P=0.004 and 0.03, respectively). Vladimirova et al. [17] stated the same findings as average RNFL (99.13±14.482 vs. 110.28 μm). Cennamo et al. [11] compared eyes in MS patients with the control group and the results were comparable to ours as regarding the average RNFL thinning in the non-neuritis subgroup (94.86±11.64 vs. 109.77±19.54 µm, P=0.001). In a study by Fjeldstad et al. [21], eyes of individuals with MS with no previous neuritis had significantly decreased overall RNFL thickness (89.1 µm) compared with controls (98.0 µm) (P<0.05). MS mainly affected the temporal quadrant (56.6 vs. 67.8 µm, P<0.05).

Comparing both groups, we found an intergroup difference that was statistically significant; the MS-ON showed more reduction in RNFL in superior, average, and nasal quadrants (P=0.002, 0.031, 0.04, respectively). Analyzing these results shows that the average RNFL together with nasal and temporal quadrants are reduced in MS eyes with and without a history of neuritis. Previous studies stated the same findings [17],[22],[23]. The temporal quadrant seems to take the major part in this reduction and this was stated in Henderson et al. [18] and Garcia-Martin et al. [19] studies. As in eyes with previous attacks, RNFL can be tremendously affected by the recovery process from neuritis itself, decreased RNFL thickness in clinically unaffected eyes may be related to subclinical unnoticed attacks of neuritis, or from subtle ongoing demyelinating/degenerative process. From the previous results, we can deduce that in MS without clinical attacks of neuritis, the average RNFL suffer thinning, most severely in the temporal quadrant, which contains fibers of the papillomacular bundle; these represent axonal damage. Hence, MS-NON would be more suitable for monitoring subtle ongoing axonal damage independent of demyelination relapses [10]. Regarding the mean absolute latency of P100 in VEP, there was a statistically significant prolongation in both MS-ON and MS-NON groups (P=0.00001), with no intergroup difference. These were comparable with many previous studies [3],[7],[10],[17],[18],[20].

In our study, the ROC curve revealed the superior RNFL with a cutoff of 118.75 μm (ROC=0.24, P=0.003), the nasal RNFL with a cutoff of 81.25 μm (ROC=0.293, P=0.015), and the average RNFL with a cutoff of 98.69 μm (ROC=0.316, P=0.03). Fatehi et al. [3] found that the mean RNFL had the highest area under the curve (0.807 vs. 0.316 in our study). Again, the study did not apply the control group but depended on a single criterion for comparison which is abnormal VEP (P100 latency>115 ms). Oreja-Guevara et al. [22] documented that the presence of at least one quadrant of an optic nerve with an RNFL thickness at a P value less than 0.05 cutoff value had a sensitivity of 75% for predicting dissemination in the MRI, and hence OCT could identify axonal damage in initial stages of the disease.

In the MS-ON group, the average (r=−0.34, P=0.0001), temporal (r=−0.4, P=0.0001), nasal (r=−0.36, P=0.001), and superior RNFL (r=−0.21, P=0.051) showed significant inverse correlation with the P100 latency in VEP. These results were comparable with many previous results where the mean or average RNFL had the significant correlation with VEP [3],[10],[17].

In the MS-ON subgroup in our study, the P100 latency showed the highest sensitivity to detect the nerve damage (52.3%), followed by temporal RNFL (43.2%), while the average RNFL showed 40.9% sensitivity. Naismith et al. [20] stated that in eyes with at least one attack, the sensitivity of average and temporal RNFL were the same (60%), while VEP was 81%. Di Maggio [10] found that VEP showed 85.7% sensitivity, while G (general) RNFL showed 67.9% sensitivity. This study did not use a control group for calculations but used the normative data of the machine only. This difference was not statistically significant. Vladimorov et al. [17] found VEP sensitive in 86.7%.

As macular GCC becomes one of the main prognostic values in demyelinating ON, we evaluated the average, superior, and inferior GCC and compared with the healthy control group. Average GCC showed a significant decrease (82.97±12.03, P=0.00001) in MS-ON and (87±12.80, P=0.04) in the MS-NON subgroup. We found that the intergroup difference was not significant except in superior GCC. In a study by Huang et al. [24], they found results comparable to ours in the MS-ON subgroup (n=22, P<0.05). Cennamo et al. [11] found that the average ganglion cell layer (GCL) was 79.9±9.68, P=0.001 in ON, and 86.73±10.25, P=0.001 in MS with and without neuritis respectively. Vladimirova et al. [17] found the mean GCC thickness was 79.18±7.457 μm in eyes with a history of neuritis, while in non-neuritis it was 92.25±13.609 μm compared with 99.82 μm (control). Gracia-Martin et al. [19] found significant thinning in average (IPL+GCL), P value less than 0.001. This shows that in chronic ON axonal (RNFL) and neuronal (RNFL+GCL+IPL) degeneration occurs with GCC loss occurring as early as 1 month even before the axonal loss alone [4],[8],[24].

The mean CFT in MS-ON in our study was 226.5±29.4 µm compared with healthy controls: 269.9±8.21 µm (P=0.00001). Gracia-Martin et al. [19] found significant thinning in CFT (248.9±8.9 vs. 253.3±8.2, P<0.001) after a 5-year follow-up. The effect of different machines and duration of disease (1–16 years in our study vs. 5 years in theirs) can explain the severe thinning in CFT in our results.

In MS-NON (n=16), the mean CFT was 219±29.5 µm compared with healthy controls: 269.9±8.21 µm (P=0.00001). This was comparable with the results obtained in a study by Fjeldstad et al. [21]. The patients with MS without neuritis (n=60 eyes) demonstrated significantly decreased average macular thickness (280 vs. 287 µm, P<0.05) compared with the control group. In a study conducted by Zamzama et al. [25], they found that there was significantly reduced central macular thickness in the MS group (n=48 eyes) with and without neuritis (95.33±11.34 vs. 113.78±15.18 µm, respectively, P=0.02). Furthermore, average GCC and CFT shows that damage occurs in the neuron, which may precede the axonal loss. This can serve as a tool in future trials for treatment with neuroprotective agents.

Our study had limitations such as the lack of large number of eyes, long-term follow-up, and classification of MS patients according to MS subtypes. Furthermore, the correlation of GCC with MRI could arouse new diagnostic and prognostic evidence.

Conclusion

Both VEP and OCT have been proven to be sensitive tools in the detection of optic neuropathy in MS. Latency showed the highest sensitivity (52.3%), followed by the temporal RNFL (43.2%). Temporal RNFL and average GCC can be a biomarker for both axonal and neuronal loss in eyes with neuritis and without neuritis. This loss can precede the demyelination process.

Acknowledgements

The study was implemented in the Laser Diagnostic and Therapeutic Unit, in Kasr Al Ainy Hospital in Cairo University.

Many thanks go to the Laser Diagnostic and Therapeutic Unit and Neurophysiological Unit in Kasr Al Ainy Hospital and Ophthalmology Department for their great efforts and help.

The manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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