Abstract
Introduction
We aimed to investigate the prevalence and pattern of color vision deficiency (CVD) in relapsing-remitting multiple sclerosis (RRMS) patients, with or without a history of optic neuritis (ON), and to assess its potential as a marker of subclinical optic pathway dysfunction.
Methods
Color vision was assessed in a large cohort of 345 RRMS patients using the Waggoner Computerized Color Vision Test, screening for protan, deutan, tritan, and composite color deficiencies, with severity grading based on score thresholds. Statistical differences between eyes with a history of ON, fellow eyes without ON, and eyes from MS patients with no history of ON were analyzed using multivariable logistic regression, controlled for age, gender, disease duration, Expanded Disability Status Scale, and treatment status.
Results
Out of the 676 eyes analyzed, CVD was observed in 76.0% of ON-affected eyes, 65.1% of fellow eyes without ON, and 62.3% of eyes from patients without ON. Multivariable logistic regression showed ON-affected eyes had significantly higher odds of severe CVD compared to fellow eyes (OR = 2.48, p = 0.020), which in turn had higher odds of moderate CVD compared to the no-ON group (OR = 2.27, p = 0.010). Conversely, the no-ON group had higher odds of mild CVD compared to fellow eyes without ON (OR = 2.01, p = 0.003). Composite CVD was the most frequent type (57.7%), with tritan deficiencies being the most common pure type (39.9%). Fellow eyes demonstrated higher odds of composite CVD compared to the no-ON group (OR = 1.97, p = 0.016).
Conclusions
CVD is highly prevalent in MS even without clinical ON, indicating diffuse, subclinical optic pathway damage.
Keywords: Color vision, Optic neuritis, Multiple sclerosis
Introduction
Multiple sclerosis (MS) is a chronic demyelinating and axonal degenerative disease of the central nervous system that frequently involves the visual pathways, with optic neuritis (ON) representing one of the most common early manifestations [1]. While visual acuity often recovers following ON, subtle visual dysfunction may persist, including impairments in contrast sensitivity and color perception [2–4]. Recent evidence suggests that even in the absence of clinical ON, patients with MS may experience visual pathway involvement due to both diffuse axonal damage and demyelination [5].
Three types of cone cells mediate color vision in the retina, each sensitive to different wavelengths of light: S-cones (short wavelengths, perceive blue = tritan), M-cones (medium wavelengths, perceive green = deutan), and L-cones (long wavelengths, perceive red = protan). Their absorption peaks correspond to 560 (red), 530 (green), and 425 (blue) nm, respectively [6]. The L- and M-cones predominate with an approximate ratio of 2:1, forming the dense photoreceptor mosaic of the fovea, whereas S-cones constitute only 5–10% of the total cone population and are absent from the central 100 μm of the foveal pit [7–9]. L- and M-cones are arranged in a quasi-random mosaic across the foveal and parafoveal regions, exhibiting substantial interindividual variation (1:1–16:1) that does not appreciably affect color perception [8, 10–12].
Toward the periphery, the relative proportions of L-, M-, and S-cones become progressively more balanced, reflecting a transition from foveal specialization to a more uniform photoreceptor distribution [10, 13, 14]. The retinal ganglion cells (RGCs) then process the signals, performing multilevel integration. Using unique coding strategies that include frequency, time-scale features, synchronous response, and individual neuron firing patterns, the RGCs transmit color information to the optic nerve [15, 16]. The optic nerve comprises over a million nerve fibers and carries the processed signals from the retina to the lateral geniculate nucleus, which then relays the signals to the visual cortex [17]. Within the visual cortex, particularly within V1, V2, and V4, the signals are interpreted as colors, shapes, and movement [18–20]. Finally, the visual information is integrated with other sensory and cognitive information in the brain’s perirhinal cortex, enabling complex visual perception and recognition, such as identifying objects and understanding the context within images [21].
In ON, inflammation and demyelination of the optic nerve disrupt the transmission of visual signals. This disruption can affect the transmission of signals from the cone cells, leading to a diminished or altered perception of colors. In accordance, color vision deficiency (CVD) is prevalent in ON and can persist even after visual acuity and spatial vision deficits are resolved [4, 22, 23]. Although CVD is frequently observed in ON, its specific characteristics in MS remain poorly defined.
Previous studies on color vision in MS included small patient cohorts, a lack of standardization, and the use of non-digital color vision tests such as the Farnsworth-Munsell 100 Hue test [24], the Hardy-Rand-Rittler (HRR) pseudoisochromatic plates [25], and Ishihara plates [26] that rely on the observer’s experience leading to variability in diagnostic conclusions, all are less sensitive to mild or subclinical CVD especially those involving tritan defects, and depend on the lighting conditions during test administration that significantly affect results [27].
In the current study, we aimed to (1) determine the prevalence and severity of CVD in a large relapsing-remitting MS (RRMS) cohort specifically related to the occurrence of ON, (2) characterize the patterns of CVD relative to eyes with a history of ON, fellow eyes without ON, and eyes from MS patients with no history of ON, and (3) assess whether these impairments can serve as markers of subclinical visual pathway dysfunction. Our study holds significant importance for clinicians as objective CVD measurements not only reveal the impact of demyelination on visual pathways but also reflect broader disease activity.
Methods
Study Design
A retrospective, observational study analyzing three groups: RRMS patients who had experienced ON – the ON eye, RRMS patients who had experienced ON – the non-ON fellow eye, and RRMS patients who had never experienced ON, as shown in online supplementary Figure 1 (for all online suppl. material, see https://doi.org/10.1159/000549814). Inclusion criteria: RRMS diagnosis, complete Waggoner Computerized Color Vision Test (WCCVT) for the tested eye, and available age, gender, disease duration, Expanded Disability Status Scale (EDSS), and treatment status. Exclusion criteria: self-reported congenital color blindness and ocular comorbidities affecting color vision (e.g., advanced cataract, macular disease, glaucoma).
Color Vision Assessment
Color vision was evaluated using the digital WCCVT (https://waggonerdiagnostics.com/pages/wccvt) for each eye separately, starting with the right eye, in either daylight or under artificial light simulating daylight. The WCCVT protocol included the following sections: (1) General section: 25-plate screening test featuring plates like used in the Ishihara test that identifies protan and deutan deficiencies. A passing score was a score of 21 or higher. (2) Tritan section: 12 plates dedicated to identifying tritan (blue) deficiencies. A passing score was a score of 10 or higher. If a test fails, i.e., when an individual scores below the specified passing threshold in any of these sections, additional diagnostic tests were applied as follows: (3) Protan section: 32 desaturated plates quantifying protan (red) deficiencies. (4) Deutan section: 32 desaturated plates quantifying deutan (green) deficiencies. Figure 1 presents several examples of color vision test plates.
Fig. 1.
Examples of color vision test plates.
The severity grading for CVD was defined as mild deficiency for tritan: 6-9/12, protan/deutan: 15-32/32; moderate deficiency was defined as tritan: 3-5/12, protan/deutan: 4-14/32, and severe deficiency was defined as tritan: 0-2/12, protan/deutan: 0-3/32. The CVD scoring is specified in Table 1. Composite CVD was assigned when more than 2 cone-axis sections met failure/severity thresholds. When multiple deficiencies coexisted, severity was defined by the worst severity grade across failed axes.
Table 1.
Scoring and severity grading of CVD
| Category | Score range | Grading |
|---|---|---|
| General section (25 plates + 1 demo) | ||
| Pass | 21–25 Correct | Pass |
| Fail | 0–20 Correct | Fail |
| Tritan (12 plates) | ||
| Normal color vision | 10–12 Correct | Normal |
| Mild | 6–9 Correct | Mild |
| Moderate | 3–5 Correct | Moderate |
| Severe | 0–2 Correct | Severe |
| Protan (32 plates) | ||
| Mild | 15–32 Correct | Mild |
| Moderate | 4–14 Correct | Moderate |
| Severe | 0–3 Correct | Severe |
| Deutan (32 plates) | ||
| Mild | 15–32 Correct | Mild |
| Moderate | 4–14 Correct | Moderate |
| Severe | 0–3 Correct | Severe |
Statistical Analysis
Descriptive statistics was used to summarize demographic and clinical variables, including mean with standard deviation (SD) and medians with 25%–75% IQR. For summary statistics, we used the tableone package (V0.9.1) [28]. The chi-square test was applied to assess statistical differences between colors within a group, with p values calculated using the SciPy Python package (V1.15.2) [29]. Multivariable logistic regression was used to comprehensively control for the following covariates: age, gender, disease duration, EDSS, and treatment status using the statsmodels Python package (V0.14.5) [30]. All plots were made using the Matplotlib package (V3.10.0) [31]. All statistical analyses and the creation of the plots were done using Python software version 3.11.11, available at https://www.python.org.
Results
A total of 676 eyes were analyzed, divided into three groups – group 1: 146 eyes from 126 RRMS patients who experienced ON tested for the ON eye. For patients who experienced an episode of ON in each eye, both eyes were included (n = 20); group 2: 106 RRMS patients who experienced ON tested for the fellow eyes without ON; and group 3: 424 eyes from 212 RRMS patients that never experienced ON. Female patients constituted the majority in all groups. Demographics of the groups are presented in Table 2.
Table 2.
Comparison between groups
| | ON eye | Fellow eyes | No ON |
|---|---|---|---|
| Patients, n | 126 | 106 | 212 |
| Eyes, n | 146 | 106 | 424 |
| Age, years, mean (SD) | 45.0 (13.5) | 45.0 (13.6) | 39.3 (14.1) |
| Age at MS onset, years, mean (SD) | 28.8 (9.6) | 29.4 (10.2) | 30.5 (10.8) |
| Age at ON, years, mean (SD) | 33.8 (11.2) | 34.0 (11.8) | |
| Gender, female, n (%) | 92 (73.0) | 79 (74.5) | 130 (61.3) |
| Disease duration | |||
| Mean (SD) | 16.2 (9.8) | 15.6 (9.3) | 8.8 (9.9) |
| Median [Q1, Q3] | 15.0 [8.1, 23.2] | 14.9 [7.6, 21.6] | 4.8 [1.3, 13.2] |
| Disease duration at ON | |||
| Mean (SD) | 5.1 (6.8) | 4.6 (6.6) | |
| Median [Q1, Q3] | 1.3 [0.1, 8.4] | 0.9 [0.1, 6.5] | |
| EDSS | |||
| Mean (SD) | 2.6 (2.0) | 2.5 (1.9) | 1.7 (1.8) |
| Median [Q1, Q3] | 2.0 [1.0, 4.0] | 2.0 [1.0, 4.0] | 1.0 [1.0, 2.0] |
| ON at MS onset, n (%) | 34 (27.0) | 32 (30.2) | |
| Treated, n (%) | 79 (62.7) | 64 (60.4) | 103 (48.6) |
| Eyes with CVD, n (%) | 111 (76.0) | 69 (65.1) | 264 (62.3) |
| CVD severity, n (%) | |||
| Mild | 46 (41.4) | 36 (52.2) | 212 (80.3) |
| Moderate | 30 (27.0) | 21 (30.4) | 31 (11.7) |
| Severe | 35 (31.5) | 12 (17.4) | 21 (8.0) |
| CVD type, n (%) | |||
| Composite | 80 (72.1) | 50 (72.5) | 126 (47.7) |
| Deutan + protan | 6 (7.5) | 6 (12.0) | 24 (19.0) |
| Tritan + deutan | 36 (45.0) | 24 (48.0) | 61 (48.4) |
| Tritan + protan | 17 (21.2) | 14 (28.0) | 23 (18.3) |
| All affected | 21 (26.2) | 6 (12.0) | 18 (14.3) |
| p value | <0.001 | <0.001 | <0.001 |
| Pure | 31 (27.9) | 19 (27.5) | 138 (52.3) |
| Protan | 7 (22.6) | 7 (36.8) | 27 (19.6) |
| Deutan | 14 (45.2) | 7 (36.8) | 51 (37.0) |
| Tritan | 10 (32.3) | 5 (26.3) | 60 (43.5) |
| p value | 0.303 | 0.810 | 0.002 |
Group 1: CVD following Optic Neuritis – ON-Affected Eye
A total of 126 RRMS patients who had experienced ON were evaluated for color vision, including 92 (73.0%) females and 34 (27.0%) males, with 27% (34/126) experiencing ON at disease onset. The mean age at MS onset was 28.8 ± 9.6 years, disease duration at ON was 5.1 ± 6.8 years, and the time from the ON episode to the color vision testing was 11.2 ± 6.8 years.
Out of 146 eyes that experienced ON, CVD was observed in 76% (111/146) (Fig. 2a), of which 31.5% (35/111) were defined as severe CVD, 27% (30/111) as moderate, and 41.4% (46/111) as mild (Fig. 2b). The most prevalent form of CVD was a composite of various color deficiencies, found in 72.1% of the affected eyes (80/111) (Fig. 2c). The incidences of pure CVD were 22.6% for protan (7/31), 45.2% for deutan (14/31), and 32.3% for tritan (10/31), p = 0.303 (Fig. 2d).
Fig. 2.
CVD incidence (a), severity (b), types (c), and pure type incidence (d) in ON-affected eyes of MS patients.
Group 2: Fellow Eyes without ON
A total of 106 RRMS patients who had experienced ON underwent the WCCVT for the fellow eye, including 79 females (74.5%) and 27 males (25.5%). The mean age at MS onset was 29.4 ± 10.2 years, disease duration at ON was 4.6 ± 6.6 years, and the time from the ON episode to the color vision testing was 11.0 ± 6.7 years.
Out of the 106 fellow eyes without ON, CVD was observed in 65.1% (69/106) (Fig. 3a), of which 17.4% (12/69) were defined as severe CVD, 30.4% (21/69) as moderate, and 52.2% (36/69) as mild (Fig. 3b). The most prevalent form of CVD was a composite of various color deficiencies found in 72.5% of the affected eyes (50/69) (Fig. 3c). The incidences of pure CVD were: 36.8% for protan (7/19), 36.8% for deutan (7/19), and 26.3% for tritan (5/19), p = 0.810 (Fig. 3d).
Fig. 3.
CVD incidence (a), severity (b), types (c), and pure type incidence (d) in fellow eyes without ON.
Group 3: CVD in MS Patients without ON
A total of 212 RRMS patients, 130 females (61.3%) and 82 males (38.7%) who had never experienced ON were included. The mean age at MS onset was 30.5 ± 10.8 years, and disease duration at color vision testing was 8.8 ± 9.9 years.
Out of 424 eyes, CVD was observed in 62.3% (264/424) (Fig. 4a), of which 8% (21/264) were defined as severe CVD, 11.7% (31/264) as moderate, and 80.3% (212/264) as mild (Fig. 4b). The most prevalent form of CVD was a composite of various color deficiencies found in 47.7% (126/264) of the eyes (Fig. 4c). The incidences of pure CVD were: 19.6% for protan (27/138), 37.0% for deutan (51/138), and 43.5% for tritan (60/138), p = 0.002, suggesting a higher incidence in the pure tritan involvement (Fig. 4d).
Fig. 4.
CVD incidence (a), severity (b), types (c), and pure type incidence (d) in MS patients without ON.
CVD Pattern and Severity across Groups
The percentage of eyes with any level of CVD across groups was as follows: ON eyes – 76.0%, fellow eyes without ON – 65.1%, and MS without ON – 62.3%. Multivariable logistic regression adjusted for age, gender, disease duration, EDSS, and treatment status (online suppl. Table 1) disclosed no significant differences between groups in overall CVD prevalence. However, longer disease duration (OR = 1.04 per year, p = 0.012) and higher EDSS (OR = 1.36 per point, p < 0.001) were significant predictors of CVD presence.
Significant differences were observed in CVD severity and pattern. ON-affected eyes demonstrated higher odds of severe CVD compared to fellow eyes without ON (OR = 2.48, 95% CI: 1.15–5.36, p = 0.020), with male gender (OR = 3.63, p < 0.001) and higher EDSS (OR = 1.24 per point, p = 0.004) strongly associated with severe CVD. Fellow eyes without ON exhibited higher odds of moderate CVD compared to the no-ON group (OR = 2.27, 95% CI: 1.22–4.24, p = 0.010). Conversely, the no-ON group had higher odds of mild CVD compared to fellow eyes without ON (OR = 2.01, 95% CI: 1.27–3.20, p = 0.003). Additionally, fellow eyes without ON had significantly higher odds of composite CVD compared to the no-ON group (OR = 1.97, 95% CI: 1.13–3.43, p = 0.016). Table 2 compares the demographics, incidence, severity, and subtype distribution of color vision defects between the groups.
CVD Pattern in MS: All Groups Combined
As our results demonstrate significant CVD in RRMS patients, whether with or without clinical ON, we combined all eyes to assess the pattern of color vision defects typical of MS (Table 3). When combining all tested eyes, we found that 65.7% of the eyes had CVD. Among these, the majority (66.2%) exhibited mild severity. Additionally, 57.7% of the eyes with CVD demonstrated the composite type of impairment. Among the pure types of impairment, tritan deficiency was the most prevalent, occurring in 39.9% of the eyes with CVD, p = 0.004.
Table 3.
MS CVD pattern
| | Overall |
|---|---|
| Eyes, n | 676 |
| Eyes with CVD, n (%) | 444 (65.7) |
| CVD severity, n (%) | |
| Mild | 294 (66.2) |
| Moderate | 82 (18.5) |
| Severe | 68 (15.3) |
| CVD type, n (%) | |
| Composite | 256 (57.7) |
| Deutan + protan | 36 (14.1) |
| Tritan + deutan | 121 (47.3) |
| Tritan + protan | 54 (21.1) |
| All affected | 45 (17.6) |
| p value | <0.001 |
| Pure | 188 (42.3) |
| Protan | 41 (21.8) |
| Deutan | 72 (38.3) |
| Tritan | 75 (39.9) |
| p value | 0.004 |
Discussion
In the current study, we observed a high prevalence of CVD in RRMS patients, including those without a clinical history of ON. Although cross-sectional, the inclusion of patients with long-term follow-up after ON enabled robust inference related to the persistent prevalence and pattern of CVD. CVD was comprehensively assessed by the WCCVT, a well-recognized color vision screening test, accepted by the US Army, including pilots’ color vision assessment [32]. It has 95% sensitivity and 100% specificity [33]. Studies have compared it favorably with traditional gold standard tests like the Farnsworth D-15, HRR, and Nagel anomaloscope [34].
The data reveal that CVD, particularly of the composite and tritan types, is a common and quantifiable visual deficit that reflects subclinical involvement of the optic pathways in RRMS. Similar to the Babinski sign, which suggests underlying corticospinal tract damage, these color vision disturbances may represent a “tip of the iceberg” phenomenon, where the optic nerve undergoes silent damage without a clinical event of ON. This highlights the importance of color vision testing in MS patients, as it can uncover early, subtle but significant optic nerve pathology that remains undetected in standard clinical evaluations.
This pattern reflects both anterograde and retrograde transsynaptic degeneration in MS. Acute optic neuritis drives anterograde atrophy of the lateral geniculate nucleus and visual cortex, while occipital lesions induce retrograde, subclinical injury to RGCs and the optic nerve, potentially explaining CVD even without clinical ON [35].
Additionally, our results support the notion that CVD in MS is not a localized sensory defect but may be indicative of more widespread neural involvement [36, 37]. Just as subtle motor or cognitive symptoms can arise from widespread, subclinical white matter lesions, composite and tritan color vision loss may represent a functional readout of MS-related sensory pathway damage [23, 25, 38]. In this way, color vision testing may serve as a model for detecting silent or diffuse neuroinflammatory and neurodegenerative activity.
The higher rate of severe CVD in ON-affected eyes compared to fellow eyes or no-ON eyes further supports the idea that clinical ON causes greater and more persistent visual pathway damage, likely reflecting acute inflammatory demyelination with persistent sequelae [4]. However, the high prevalence of CVD in fellow eyes and no-ON eyes implies that subclinical damage is widespread in MS, consistent with the disease’s diffuse demyelinating nature, combined with axonal loss. Specifically, the presence of greater severity and composite CVD patterns in the fellow eyes without ON, compared to no-ON eyes, suggests subclinical optic nerve damage or transsynaptic involvement, supporting the concept of diffuse or bilateral pathway vulnerability [39].
Our study also highlights the value of composite CVD as an indicator for disease activity. These combined color impairments may represent overlapping dysfunction across multiple cone pathways or more generalized visual processing deficits due to broader neuroinflammatory involvement. Importantly, the WCCVT enabled standardized and rater-independent quantification of such complex deficiencies, overcoming limitations of traditional tests like Ishihara or Farnsworth-Munsell 100 Hue test [27].
The predominance of tritan defects is particularly noteworthy. This finding suggests that disruptions in the blue-sensitive cone pathway involving the koniocellular pathway are a predominant feature in MS, likely linked to generalized optic nerve dysfunction, while protan and deutan defects, involving the anatomically distinct parvocellular pathway, are the least frequent [40]. S-cones, which mediate blue color vision, are sparsely distributed and metabolically vulnerable, making them likely targets for early demyelinating or neurodegenerative processes [9, 41, 42]. This vulnerability may be amplified by their exclusion from the foveal center and reliance on a distinct pathway through the retina and optic nerve [43]. Moreover, S-cones may be more susceptible to mitochondrial dysfunction and inflammatory stress processes increasingly recognized in MS pathology [42, 44]. The well-documented red desaturation observed in ON, a known clinical hallmark of optic nerve dysfunction linked to the red-sensitive cone pathway and associated with protan defects, reflects a more pronounced and acute-phase injury [45]. In contrast, the more subtle impairments in the blue spectrum, as seen in our study and others [46], in no-ON eyes, suggest milder dysfunction affecting the tritan axis.
This study has several limitations. (1) The cross-sectional design limits causal inference regarding disease progression. (2) The absence of a healthy control group precludes estimation of excess risk relative to the general population. (3) The WCCVT, while practical and validated, has inherent constraints as its accuracy depends on screen calibration and ambient lighting conditions.
Conclusions
Our findings support the use of digital color vision testing as a practical, noninvasive, and scalable tool for routine assessment in MS. It enables early detection of subclinical visual pathway dysfunction and may assist in monitoring treatment response. Tritan and composite CVD, in particular, reflect underlying disease burden and may represent broader sensory involvement characteristic of MS.
Acknowledgment
We thank Terrace Waggoner for providing the WCCVT software.
Statement of Ethics
The Sheba Medical Center Institutional Review Board Committee approved the study (IRB approval No. SMC-5596-08). Informed consent was waived as the study was retrospective, observational, and non-interventional. Data were collected, coded, and analyzed in accordance with the ethical standards for human experimentation.
Conflict of Interest Statement
TW is the Chief Executive Officer of Waggoner Diagnostics, which developed the WCCVT software used in this study. The other authors have no conflicts of interest to declare.
Funding Sources
This study was supported by a research grant from the Claire and Amédée Maratier Institute for the Study of Blindness and Visual Disorders, Tel-Aviv University (Grant No. 0601258251).
Author Contributions
Guarantor of integrity of the entire study and study concepts and design: Yehuda Warszawer, Aviva Gal, and Anat Achiron. Data analysis: Yehuda Warszawer, Yael Nissan, and Anat Achiron. Statistical analysis and manuscript preparation: Yehuda Warszawer and Anat Achiron. Manuscript editing: Yehuda Warszawer, Aviva Gal, Terrace Waggoner, Yael Nissan, and Anat Achiron.
Funding Statement
This study was supported by a research grant from the Claire and Amédée Maratier Institute for the Study of Blindness and Visual Disorders, Tel-Aviv University (Grant No. 0601258251).
Data Availability Statement
The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request.
