Дискриминативная ассимиляция магического и ретинального нерва, толщина слоя в множестве склероза и оптического нерита.

I NTRODUCTION

Multiple sclerosis (MS) is a common chronic progressive inflammatory autoimmune disease of the central nervous system (CNS) in young adults, which results in inflammation, demyelination of nerves, axonal loss, and ultimately destruction of oligodendrocytes. 1 2 3 According to the Global Burden of Disease data, in 2019, approximately 60,000 new cases of MS and over 22,000 MS-related deaths were reported worldwide; moreover, the global number of incident cases, deaths, and disability-adjusted life years showed a significant upward trend between 1990 and 2019. 4

The common manifestations of MS include sensory disorders, muscle weakness, gait ataxia, incontinence, and cognitive and visual problems. 5 Clinical observations and studies have shown that vision disorders are among the common problems of MS patients, with optic neuritis (ON) as the presenting sign in about 20% of cases. 6 Visual problems in MS patients are often due to the involvement of the anterior visual pathway, especially the optic nerve and retina, occurring during the course of the disease in more than 50% of patients. 7 Structurally, the retina is a nonmyelinated part of the CNS, and optical coherence tomography (OCT) is able to specifically evaluate axons in the retina. Therefore, OCT-derived retinal parameters can be a good measure to evaluate the state of neuronal damage in MS patients. 8 9 10

The changes in OCT indices, especially the retinal nerve fiber layer (RNFL) thickness around the optic nerve head, the ganglion cell/inner plexiform layer (GCIPL) thickness, and macular volume can be used as markers to check the level of involvement and progression in MS. 7 11 12 Although the MS diagnosis and progression follow-ups today are fundamentally based on brain and spinal cord magnetic resonance imaging (MRI) and cerebrospinal fluid examination, 13 these methods are time-consuming, expensive, and sometimes invasive. 14 Hence, the use of noninvasive technologies such as OCT can provide useful complementary information in this area. The significance of this issue is evident, as studies have shown that the extent of RNFL thinning can serve as an indicator for predicting cognitive status and physical disability in patients with MS. 15

Various studies have examined OCT imaging characteristics in patients with MS. 7 11 12 16 17 18 Some of these studies investigated the pattern of changes in retinal parameters during the course of the disease, 7 some compared the OCT parameters between healthy group and MS patients with and without ON, 17 and others compared the values between the fellow eyes of MS patients. 18 While several studies have investigated the diagnostic performance of OCT parameters in MS, findings remain heterogeneous due to differences in OCT devices, patient populations, disease stages, and definitions of ON. 14 Since the retinal thickness is significantly influenced by race 19 and MS has a high and growing prevalence in Iran, 20 the present study aimed to present a comprehensive descriptive evaluation of macular and RNFL thicknesses among different quadrants in Iranian MS patients with and without ON, compared to healthy controls, as well as to determine the diagnostic cutoffs, sensitivity, and specificity of the above parameters.

M ETHODS

The present cross-sectional study was conducted in 2019. The study included MS patients and healthy controls; MS patients were further divided into MS patients with and without ON. All MS patients had been diagnosed at least 5 years before enrollment, with a confirmed diagnosis of definite MS based primarily on Poser’s criteria in some cases, as was standard practice in our clinical setting at the time of initial diagnosis. However, all diagnoses were further corroborated by brain MRI findings (McDonald criteria). 21 A single experienced neurologist reviewed all clinical and imaging data to confirm diagnostic consistency across the study. The control group were those who did not have MS based on clinical workup and MRI. The ON was diagnosed by an ophthalmologist based on clinical signs and symptoms at the time of examination, including optic disk edema, periorbital pain during eye movement, color vision deficiency, and relative afferent pupillary defect. 22

The inclusion criteria for the present study comprised individuals aged between 30 and 45 years, with no history of taking medications that affect contrast sensitivity and visual acuity (e.g., amiodarone, isotretinoin, and chlorpromazine), no history of Parkinson’s disease, and no other ocular pathologies impacting corrected visual acuity (e.g., diabetic retinopathy, glaucoma, keratoconus, cataract, and corneal opacity). Participants were restricted to ages 30–45 years to reduce the impact of age-related structural changes in the retina and to align with the typical age range of MS onset in our population. 23 Following participant selection, the objectives and procedures of the study were explained, and written informed consent was obtained. Ocular examinations and imaging were then conducted as the next step.

Ocular examinations included measurement of uncorrected distance visual acuity (UCDVA) using a digital visual acuity chart (Chart SC 1600 Pola, Nidek Co., Ltd, Gamagori, Japan) at a distance of 6 m in logMAR criteria, objective refraction using an auto-refractometer (ARK-1, Nidek Co., LTD, Aichi, Japan) followed by subjective refraction, measurement of best-corrected visual acuity based on subjective refraction results in the mentioned distance and criteria for UCDVA, and anterior and posterior segment ocular health examination using a slit-lamp biomicroscope (BQ-900, Haag-Streit AG, Koeniz, Switzerland) and +90 diopter (D) lens. The OCT imaging was performed using Cirrus High-Definition Optical Coherence Tomography (HD-OCT) 4000 (Carl Zeiss Meditec, Dublin, CA) following pupillary dilation with two drops of tropicamide 1%. A single trained operator completed OCT imaging in all study participants. The Macular Cube 512 × 128 protocol (128 consecutive line scans in a 6 mm × 6 mm square grid) and the Optic Disc 200 × 200 protocol (200 consecutive line scans in a 6 mm × 6 mm square grid) were used. In case of any measurement error or low OCT image quality, imaging was repeated. Eyes with any abnormal findings in OCT images, images with signal strength <6, or decentered images were also excluded. Exclusion criteria were a history of any ocular surgery, a history of glaucoma or using glaucoma medications, and spherical equivalent refraction worse than −6.00 D. Besides, patients with ON who had a normal MRI were excluded from the study to ensure the homogeneity of diagnosis.

Statistical analysis

Due to the strong correlation between the left and right eyes in macular thickness ( r = 0.932) and RNFL thickness ( r = 0.873), only right eye data were used. The mean and standard deviation (SD) of macular and RNFL thicknesses were reported in total MS patients and normal control groups; the above information was also presented separately for individuals with MS, categorized according to the presence or absence of ON. Independent samples t -tests were conducted to compare the evaluated parameters between MS patients and normal participants, as well as between MS patients with and without ON. To investigate the diagnostic value of macular and RNFL indices in diagnosing MS from normal as well as ON in MS patients, the sensitivity and specificity of each index were reported based on the best cutoff point. The best cutoff point (highest sensitivity and specificity) was determined based on the Youden index. Finally, to show the diagnostic value of each of these indicators, the area under the receiver operating characteristic [ROC] curve (AUC) was reported, and its graph was drawn for some variables with the highest AUC. In addition to AUC and 95% confidence intervals, optimal cutoff points were established using Youden’s Index, and positive likelihood ratios and negative likelihood ratios were documented.

The study protocol received approval from the Ethics Committee of the Tehran University of Medical Sciences and was carried out in accordance with the principles outlined in the Helsinki Declaration. Written informed consent was obtained from all participants (Ethical code: IR.TUMS.MEDICINE.REC.1399.315).

R ESULTS

One hundred and thirty-three individuals were recruited in this study. Of these, 66 and 67 were in the MS and control groups, respectively. Among the MS group, 18 cases had ON. The mean age was 37.64 ± 5.27 years in the MS group and 38.45 ± 4.60 years in the control group ( P = 0.346). 53.5% of the MS group and 46.5% of the control group were male.

The mean spherical equivalent was −0.25 ± 1.11 D (range, −4.62 to + 3.13 D) in the normal group, −0.54 ± 0.93 D (range, −3.00 to + 1.75 D) in MS patients without ON, and −0.78 ± 1.74 D (range, −5.12 to + 1.00 D) in MS patients with ON ( P = 0.164).

Table 1 shows the mean ± SD of the central macular thickness, sectoral macular thickness, overall RNFL thickness, and sectoral RNFL thickness in MS and control groups, as well as in MS patients with and without ON. As shown in Table 1 , the MS group had significantly lower mean overall RNFL thickness and sectoral RNFL thicknesses in all quadrants compared to the control group. The MS with ON group had significantly lower mean overall RNFL thickness and sectoral RNFL thicknesses in the superior and inferior quadrants compared to the MS without ON group.

In terms of macular thickness, the MS group had significantly lower mean thickness in the inner superior, outer inferior, outer superior, outer nasal, and outer temporal quadrants than in the control group. Comparison between MS patients with and without ON showed that the macular thickness in the inner superior and outer superior quadrants was significantly lower in those with ON. Macular volume was also significantly lower in the MS group than in the control group and in the MS with ON group compared to the MS without ON group.

Table 2 shows the sensitivity, specificity, associated criterion, and AUC of RNFL and macular indices to differentiate MS patients from normal controls. As shown in Table 2 , the overall RNFL thickness had a sensitivity of 87.88%, a specificity of 70.15%, and an AUC of 0.836 in diagnosing MS patients from normal people. Based on the Youden index, the best diagnostic criterion for the overall RNFL thickness was ≤94 μ. Among macular parameters, the outer superior sector demonstrated the highest sensitivity (86.4%) and the highest Youden index (0.312) for distinguishing MS patients from healthy controls, though its specificity was low (44.8%) and its AUC was modest (0.670). The outer nasal sector showed the highest AUC (0.680) among macular regions. The diagnostic values of other RNFL and macular indices are listed in Table 2 , and Figure 1 illustrates the ROC curve for the discriminant ability of overall RNFL and macular thickness and sectoral (superior, inferior, nasal, and temporal) between MS patients and normal individuals.

Table 3 presents the sensitivity, specificity, associated criterion, and AUC of RNFL and macular indices for diagnosing ON in MS patients. As shown in Table 3 , the overall RNFL thickness had a sensitivity of 72.22%, a specificity of 81.25%, and an AUC of 0.836 in diagnosing ON. Based on the Youden index, the best diagnostic criteria for overall RNFL thickness were ≤83 μ. After that, the inferior RNFL thickness had a high AUC (0.822). For differentiating MS patients with versus without a history of ON, the outer superior macular sector again showed the highest Youden index (0.403) among macular regions, with an AUC of 0.736, 61.1% sensitivity, and 79.2% specificity. Figure 2 illustrates the ROC curve for the diagnostic value of average macular thickness and RNFL and sectoral (superior, inferior, nasal, and temporal) in diagnosing ON in MS patients.

D ISCUSSION

The present study is one of the few studies that evaluated the sensitivity and cutoff of retinal parameters in diagnosing MS and also ON in MS patients.

The mean RNFL thickness in MS patients in the present study was 87.59 ± 6.62 μ, which was lower than the values reported in the studies by Khanifar et al . 24 and Talebi et al . 25 and higher than that reported in the studies by Al-Mujaini et al . 26 and Amirifard et al . 27 The present study, along with two conducted by Talebi et al . 25 and Amirifard et al ., 27 took place in three different regions of Iran. Although these studies have reported varying average RNFL thickness values in MS patients, this discrepancy may be attributed to factors such as race, 19 age distribution, and the type of OCT device used; some studies in this regard are presented in Table 4 . Some of the variation in the observed results may be attributed to the nature of MS subtypes; for example, Remoli-Sargues et al . 33 observed no association between a history of Epstein–Barr virus infection in MS patients and changes in the optic nerve. Besides, the use of different OCT devices may lead to slight variations in results, even within the same individual. 34

Although human retinal nerves lack myelin, 35 the present study demonstrated that the mean RNFL thickness was significantly lower in MS patients than compared to healthy controls (87.59 vs. 99.48 μ). Petzold et al . 36 also suggested in a review article that MS causes a decrease of about 7.08 μ in the average RNFL thickness in eyes without ON. Previous studies stated that the anterior parts of the visual pathway, including the optic nerve, optic chiasm, and optic tract, are among the most common areas of nerve inflammation, axonal loss, axonotmesis, 37 and degeneration in MS. 38 Moreover, there is a good correlation between RNFL thickness and MRI findings in diseases involving the optic nerve. 39 Puthenparampil et al . 40 reported a significant inverse relationship between the RNFL thickness and the amount of lesion in the optic radiation’s white matter in patients with MS. In total, the available reports indicate the destructive effect of MS on the RNFL thickness.

The results of the present study showed that ON causes a further decrease in the RNFL thickness in patients with MS (82.28 vs. 89.58 μ). Petzfold et al . 36 reported that ON was associated with a reduction of about 20.38 μ in the RNFL thickness in MS patients. A similar finding has also been observed in other studies. 32 Various reasons have been proposed for this RNFL thinning, including axonal loss due to retrograde degeneration in patients with a history of ON; however, in patients without a clear history of ON, mild degrees of subclinical ON may have occurred. 6 It has been shown that ON causes a decrease in the RNFL thickness even in the absence of MS. Xu et al . 41 found that ON caused a decrease of 6 μ in the RNFL thickness in 84.1% of the eyes without MS. Maggio et al . 42 suggested that due to the degeneration of the posterior visual pathways in patients with a history of ON, changes in the RNFL thickness would have the best diagnostic value in eyes without a history of ON. It should be noted that axonal loss in MS is irreversible, and these changes can occur in different stages of this disease. 25 Gelfand et al . 43 found that in the absence of ON, changes in RNFL thickness are almost similar between MS subgroups.

The evaluation of RNFL thickness in different quadrants indicated that the RNFL in all four quadrants was significantly thinner in MS patients than in normal controls. It was also observed that ON was associated with a further decrease in the RNFL thickness in all four quadrants compared to other patients without ON; however, only the changes in the superior and inferior quadrants were statistically significant. Although the classification of retinal regions differs according to the type of OCT used in studies, the RNFL thickness followed the ISNT rule in all participants of the present study, including healthy subjects, and MS patients with and without ON. 44 According to the results, the highest and lowest RNFL thicknesses in both healthy people and MS patients were seen in the inferior and temporal quadrants, respectively. The thinning of the RNFL in the temporal quadrant associated with MS has been investigated and confirmed in multiple studies, including the performed studies by Noval et al ., 16 Abdul-Salam et al ., 45 Bock et al ., 31 , and Graham et al . 46 Nevertheless, Estiasari et al . 47 found that the major changes occurred in the nasal quadrant.

However, if we consider the percentage of RNFL thinning in each quadrant in the presence of MS compared to healthy controls, the most changes have occurred in the superior quadrant and the least changes in the temporal quadrant. Furthermore, the changes caused by the ON were more pronounced in the inferior quadrant. One of the possible reasons in this regard is that the fibers in the temporal quadrant are composed of axons of small cells, while the cells have larger dimensions in the superior and inferior quadrants. Therefore, damage to a cell theoretically causes more structural changes in the superior and inferior quadrants, while the lower thickness and smaller dimensions of these axons in the temporal quadrant would be accompanied by less structural but more functionally significant changes. 47 Furthermore, as described by Uctepe et al ., 48 the superior GCC thickness is significantly reduced in MS patients. Therefore, the specific retinal layer affected in MS may also contribute to variations in the observed results. While MS and ON lead to a decrease in RNFL thickness, it is necessary to consider the effect of other factors (such as interocular asymmetry, age, myopia, and glaucoma) on the RNFL thickness to minimize false positives. 49 In addition, reduced retinal thickness is a known side effect of MS medications. Consequently, variations in medication use may contribute to differing results across studies in this field. 50

One of the most important features of the present study is to evaluate the sensitivity and specificity of the RNFL thickness to discriminate the presence of MS and ON in these patients. Among the OCT parameters evaluated, average RNFL thickness demonstrated the highest diagnostic performance for distinguishing MS patients from healthy controls, with an AUC of 0.836, 87.9% sensitivity, and 70.2% specificity at a cutoff of ≤94 μm. Among the RNFL quadrants, the superior quadrant showed the best discriminatory ability, achieving an AUC of 0.807, 81.8% sensitivity, and 68.7% specificity at a cutoff of ≤114 μm. In contrast, the nasal quadrant provided the highest specificity (71.6%) for ruling in MS, albeit with lower sensitivity (65.2%), at a cutoff of ≤72 μm. For identifying ON within the MS patients, average RNFL thickness again performed best, with an AUC of 0.836, 72.2% sensitivity, and 81.3% specificity at a cutoff of ≤83 μm. The nasal RNFL quadrant, while highly sensitive (94.4%) for detecting prior ON at a cutoff of ≤73 μm, had poor specificity (37.5%), limiting its utility as a standalone diagnostic marker. An important point to consider is that the diagnostic values presented in this study can only be used for the Cirrus OCT.

Limited studies evaluated the sensitivity and specificity of RNFL thickness in discriminating MS. Among them, Costello et al . 51 suggested a peripheral RNFL thickness cutoff point of 75 μ for the appropriate visual recovery after ON. Coric et al . 52 suggested reducing the peripheral RNFL thickness to lower than 85 μ as a stage that increases the possibility of cognitive impairments related to MS. In a study by Garcia-Martin et al ., 53 an RNFL thickness cutoff point of 142 μ in the temporal quadrant with a sensitivity of 74% and a specificity of 73% was considered the most important index in diagnosing MS. Moreover, the highest AUC was calculated for the temporal quadrant RNFL thickness (0.732), followed by the overall RNFL thickness (0.698). It should be noted that the above-mentioned study used the Heidelberg Spectralis OCT. Khanifar et al . 24 observed that the highest odds ratios for detecting the presence of ON in patients with MS were related to the overall RNFL thickness and RNFL thickness in the temporal quadrant (1.33 for both). Overall, while some prior studies have highlighted the temporal RNFL quadrant as the most sensitive parameter for MS detection, particularly due to early involvement of the papillomacular bundle, 54 our findings indicate that the superior quadrant demonstrates superior diagnostic performance in our study. This discrepancy may stem from differences in OCT devices, population characteristics, or statistical approaches. Notably, our study used a cross-sectional design with strict age matching and excluded eyes with media opacities, which may have enhanced the detectability of diffuse axonal loss reflected in the superior sector.

Macular imaging using OCT, which is an indirect examination of the ganglion cell layer in this region, can provide valuable information about MS. 55 The results of the present study showed that except for an increase of one micron in the central subfield thickness (which was not statistically significant), MS caused a decrease in the macular thickness, and the presence of ON was associated with a further decrease in the macular thickness. Macular thinning due to damage to neuronal axons in MS is a finding that has been mentioned in limited studies. 56 57 Fjeldstad et al . 56 observed that the macular thickness was about 7 μ thinner in MS patients than in the control group. The present study is one of the few studies that evaluated the macular thickness in the inner and outer rings and four quadrants; the results showed that the macular thickness in the outer ring was thinner than the inner ring in all study participants. It was also found that the MS caused a decreased macular thickness in all four outer quadrants, while the macular thickness changes in the inner ring were not statistically significant. According to the results, the greatest macular thickness was related to the outer nasal quadrant, and the MS also resulted in the greatest thickness loss in this quadrant; these findings were also observed in a study by Satue et al . 58 It should be noted that the numerical values of the parameters in the present study were higher than that presented in the study by Satue et al ., 58 probably due to different population characteristics.

Most of the studies regarding the macular changes in MS have evaluated the macular volume, and their common finding is the reduction of the total macular volume (TMV) in this disease. 59 Dorr et al . 60 reported that TMV can be used as an indicator of brain atrophy in MS. In the present study, the mean TMV in patients with MS was equal to 9.95, which is higher than the values presented in the studies by Bock et al . 59 (6.83 measured by Stratus OCT), Burkholder et al . 61 (6.54 measured by Zeiss OCT-3), Eslami et al . 62 (6.95 measured by Heidelberg OCT), and Talebi et al . 25 (6.23 measured by stratus OCT). The most probable reason for this difference is the various OCT devices used in studies. The ganglion cells are mostly located in a ring of about 3.45 mm around the center of the fovea. 63 The default of the Cirrus OCT is to provide TMV in a wider circle; therefore, findings related to TMV must be analyzed and interpreted considering the type of OCT device. According to a study by Winges et al ., 64 the macular volume decreases by 5%–6% after an acute attack of ON in patients with MS, which is in line with the results of the present study. The reduction of TMV is directly correlated with the attenuation of visual functions. 59 It has also been suggested that the baseline TMV can be a very important factor to predict vision prognosis and the rate of blindness in 10 years after the onset of MS disease. 7

An important point in interpreting macular thickness changes in MS is the effect of fingolimod, 65 which is used in the treatment of MS. Although MS causes a decrease in the macular thickness and volume, one of the side effects of the fingolimod is the formation of microcysts and macular edema, 66 which will increase the macular thickness. Therefore, knowledge of the drugs used by the patient, as well as visual observation of the macular structure, is important in interpreting the macular thickness and volume, and one should not solely rely on the numerical value of the parameters.

The results of the present study showed that a macular volume’s cutoff point of 10.2 had a sensitivity of 80.30% and a specificity of 47.76% in discriminating MS, and a cutoff point of 9.7 can distinguish the absence of ON with a specificity of 77.08% and a sensitivity of 55.56%. For macular volume, reduced values are indicative of neurodegeneration in MS and prior ON. Therefore, the reported cutoff points are upper thresholds for disease detection, and individuals with macular volume at or below these values are classified as positive. Limited studies have investigated the sensitivity and specificity of the macular parameters in diagnosing MS, and most of them were related to TMV. Among them, Pueyo et al . 67 reported the AUC of TMV in diagnosing MS equal to 0.792. The present study showed for the first time that the macular thickness in the outer superior quadrant with a cutoff point of 284 μ and a sensitivity of 86.36% and the nasal (cutoff point of 279 μ) and outer temporal (cutoff point of 249 μ) quadrants both with a specificity of 87.50% had the highest sensitivity in detecting MS and the highest specificity in detecting the absence of ON, respectively. These findings can serve as a starting point for determining the exact numerical value of the macular volume to diagnose the presence of MS.

Regarding the interpretation of the study findings, it is important to note that the time since MS diagnosis and the time since the most recent ON attack are key factors that can significantly influence retinal layer thickness. Studies have shown that RNFL thinning progresses dynamically over time; therefore, failure to consider this temporal variable can lead to misleading interpretations of cross-sectional data. 68 Given the cross-sectional nature of the present study, it is recommended that the findings be reviewed and confirmed in prospective cohort studies with accurate clinical timing to assess the generalizability of the cutoff points and the diagnostic value of OCT in MS.

This study has several limitations that should be considered when interpreting the findings. First, the small sample size in the ON group may have limited statistical power to detect subtle differences in retinal layer thicknesses. Second, clinical variables such as MS subtype, exact disease duration, and treatment profiles were not recorded in this study. Given that these factors may influence neuroaxonal loss and retinal layer thickness, their absence precludes adjustment for important confounders and should be considered when interpreting the results. Third, the ganglion cell was not assessed in this study. Although the use of Cirrus HD-OCT represents a strength, given the known device-dependency of certain thickness metrics, future studies should consider employing Spectralis OCT, which offers enhanced segmentation accuracy and layer-specific analysis, alongside a broader panel of structural parameters, including GCIPL and sectoral RNFL measurements. Finally, longitudinal validation of OCT findings, integrated with functional assessments (e.g., visual evoked potentials and disability metrics), would significantly strengthen the diagnostic and prognostic utility of OCT in clinical practice. In conclusion, the present study demonstrates that RNFL thinning is significantly associated with MS and further exacerbated by ON. Average RNFL thickness shows fair-to-good discriminative ability for distinguishing MS patients from healthy controls and for identifying ON within the MS cohort. In contrast, macular thickness parameters exhibit only modest and often nonsignificant diagnostic performance. While these OCT-derived structural metrics reflect neuroaxonal loss and may serve as useful complementary biomarkers in the clinical assessment of MS-related retinal damage, they should not be interpreted as stand-alone diagnostic tools. Given the cross-sectional design, chronic disease duration, and device-specific normative values, these findings require validation in prospective cohorts before any role in early diagnosis or routine clinical decision-making can be established.

Conflicts of interest

There are no conflicts of interest.

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