Color vision is an important part of human visual perception. However, true trichromatism is relatively unique to primates among mammals, and arose by duplication and divergence of the photopigment genes for the M-cones and L-cones on the X-chromsome. Most eutherian (placental) mammals, including dogs, cats, and mice, are dichromats. Multiple hypotheses exist regarding the evolutionary pressures promoting the development of this enhanced color vision, suggesting it may be related to enhanced object recognition, improved foraging ability, and social communication.
The human retina has two basic photoreceptor cell types: rods and cones. Rods are larger than cones, cylindrically shaped, and absent from the central fovea. Cones are smaller, conical in shape, and present in the fovea. Cones have three subtypes, named according to the wavelength corresponding to their peak absorption. S-cones have a λmax of 426nm, M-cones have a λmax of 530nm, and L-cones have a λmax of about 555 nm. The gene encoding the S-cone opsin is located on chromosome 7, while the gene encoding the M-cone and L-cone opsins are located on the X chromosome. M-cones and L-cones are vastly more populous than the S-cones. S-cones account for only 7% of all cones, are absent from the central fovea, and reach their maximum concentration at about 1o eccentricity. L-cones outnumber M-cones in a ratio that varies among individuals from approximately 1:1 to nearly 4:1, although this appears to have only a minor impact on color perception. Light information is processed and transmitted through the first-order neurons of the visual pathway, the bipolar cells, to the three types of retinal ganglion cells: midget cells, parasol cells, and small bistratified cells. Some degree of color opponency is encoded at this level. From here, color information from the M-cones and L-cones is largely transmitted through the midget cells to the four dorsal parvocellular layers in the lateral geniculate nucleus (LGN). Information from the S-cones, reflecting blue-yellow contrast, is transmitted through the small bistratified cells to the koniocellular cells of the LGN. This pathway is targeted by blue-on-yellow, short wavelength automated perimetry (SWAP) for the detection of early glaucomatous visual field loss. Some information is also transmitted through the parasol cells to the two ventral layers, the magnocellular layers, of the LGN, which do not encode color information, but rather contrast in luminance. This magnocellular pathway is utilized in Frequency Doubling Perimetry (FDT) in evaluating glaucoma. Transmission from the retinal ganglion cells to the LGN constitutes the second-order neurons. The afferent transmission of color information beyond the LGN, through the third-order neurons, becomes less neatly defined. Put simply, it proceeds to the V1, V2 and V4 cortical areas of the occipital lobe for primary visual processing, after which point the information is transmitted to the inferior temporal lobes and prefrontal cortex for interpretation. The V1 area is the striate cortex, and has relatively few cells for color processing, whereas the V4 area has many. Damage to the ventral occipital cortex can produce complete cerebral achromatopsia, while damage to the occipotemporal lobe can cause partial cerebral achromatopsia, or hemiachromatopsia.
The visual phototransduction cycle among rods, S-cones, M-cones, and L-cones is similar, with differences in the opsin component responsible for variances in the absorption spectrum. Rods and cones are different in that cones are less sensitive to light and have a faster response time. The opsin is a G-protein coupled receptor (GPCR) which exists in the cell membrane of the outer segment discs of the photoreceptor cell, and prior to the visual phototransduction pathway, it is covalently bonded to 11-cis-retinal. Incident photons stimulate photoisomerization of the 11-cis-retinal to all-trans-retinal, releasing it from the opsin protein. This causes a conformational change in the opsin GPCR, stimulating an intracellular signal transduction cascade that lowers intracellular cGMP and closes GMP-gated calcium channels and hyperpolarizes the photoreceptor cell. The all-trans-retinal undergoes a number of chemical changes and translocation to the RPE where it is esterified by lecithin:retinol acyltransferase (LRAT), and converted to 11-cis-retinol by RPE65. Then in the RPE it is oxidized to 11-cis-retinal before translocation again to the photoreceptor outer segment for re-integration into the opsin protein. LRAT mutations are associated with Leber Congenital Amaurosis subtype 14 (LCA-14), and has been the target of gene therapies with early promising results. RPE65 is associated with LCA-2 and Retinitis pigmentosa (RP), and is the target of voretigene neparvovec-rzyl (Luxturna) the first FDA-approved gene therapy.
Signal processing in color interpretation is complex and highlighted by a few points. First, there is considerable overlap among the absorption spectra of the cone photoreceptor pigments, especially between the M-cones and L-cones, which have a 96% mutual similarity, compared to only a 43% similarity with S-cones. Thus, while a single photon will have a tendency to interact with the photopigment with the strongest absorption spectrum in its wavelength, one cannot determine the wavelength of a photon by examining a single photopigment and therefore requires the comparative interaction of multiple photons to different photoreceptors to distinguish colors. This is called the “principle of univariance”. Second, in any given spot of the retina, only one photoreceptor cell is present. Therefore, the perception of color vision must be determined by the encoding of signals from multiple local photoreceptors. It is believed that the local ratio of photoreceptor activity plays a significant role in color determination. This is also implicated in the phenomenon of “color constancy”, whereby humans can perceive two objects to be of similar color, despite variations in lighting conditions that may change the precise wavelength of light emitted by the object. Third, there are about 5 million cones and 100 million rods in the human retina, which vastly outnumber the 1-1.2 million retinal ganglion cells which travel through the optic nerve, suggesting that first-order neurons perform some visual processing of color information.
Kollner’s rule, proposed in 1912, refers to apparent effect that retinal and macular pathology tend to cause blue-yellow color deficiencies (similar to tritanomaly), where as optic nerve pathology tends to cause red-green color deficiency (similar to protanomaly or deuteranomaly). Work by Dr. Nork published in 2000 evaluated this rule and discussed evidence supporting the selective S-cone loss in diabetic retinopathy and retinal detachment, as well as M-cone and L-cone loss in glaucoma. It was proposed that the equal loss of M-cone and L-cone in glaucoma manifested in difficulty with interpretation of the color yellow, and thus manifested on testing as a blue-yellow opponency deficit.
Classification of Color Vision Deficiency (Dyschromatopsia)
Color deficiencies can be categorized based on many features. In general, congenital color deficiencies are typically bilateral and static (non-progressive). Acquired dyschromatopsia is more likely to be unilateral and progressive. The inherited color vision deficiencies can be organized as below:
Inherited Color Vision Deficiencies
- Anomalous Trichromatism
- Protanomaly (1% of males)
- Deuteranomaly (5% of males)
- Tritanomaly (0.0001% of males)
- Protanopia (1% of males)
- Deuteranopia (1% of males)
- Tritanopia (0.001% of males)
- Monochromatism / Achromatopsia
- Typical (rod monochromatism)
- Atypical (blue-cone monochromatism)
The prefixes “protan”, “deutan”, and “tritan” refer to the L-cones, M-cones, and S-cones, respectively.
The suffix “anomaly” references an absorption spectrum that is shifted compared to the typical, and the suffix “anopia” references the complete absence of that cone type.
A group of genetic, congenital disorders of the cone cell photopigment which results in abnormalities of the absorption spectrum, resulting in altered perception of color. Multiple deficiencies exist, with nomenclature reflecting the affected cone type (protan, deutan, or tritan), as well as the pattern of dysfunction (anomaly vs anopia).
Individuals with anomalous trichromatism have three separate photopigments, but one of the photopigments is altered to have an abnormal absorption spectrum of light, decreasing the ability for color differentiation among certain color hues. The degree of dysfunction varies among individuals, and mildly affected individuals may pass some of the less sensitive color deficiency testing, such as the Farnsworth Panel D-15 hue test.
Individuals with hereditary dichromatic color vision deficiency have completely lost the function of one cone photopigment. They only require 2 primary colors to make a color match on the color match testing. Those with protanopia and deuteranopia are considered to fall in the category of “red-green colorblindness”, but exhibit more severe deficiencies than those with anomalous trichromatism.
In monochromatism (also known as achromatopsia), an individual is unable to differentiate between different wavelengths of light. That is, any color may be matched with any other on color-match testing by modulating the source’s intensity. There are two main causes of achromatopsia: Rod monochromatism, which is the total absence of cones, and S-cone monochromatism, which is the absence of both M-cones and L-cones.
The features of both Rod monochromatism and S-cone monochromatism are congenital sensory nystagmus, photophobia, and decreased visual acuity. Rod monochromatism exhibits variable expressivity, and visual acuity may range from 20/80 to 20/200. Achromatopsia is one of the classic 7 A’s which causes congenital sensory nystagmus, and can be differentiated from congenital motor nystagmus (CMN), as well as from aniridia, which may present similarly, by electroretinogram (ERG) testing. Achromatopsia will have an abnormal cone ERG, whereas CMN and aniridia will have normal cone ERG waveforms. Rod monochromatism may clinically be difficult to distinguish from S-cone monochromatism. S-cone monochromatism tends to have better visual acuity, in the 20/80 range, likely owing to the fact that there are a few S-cones in the fovea, but are generally not present in the center fovea. Specialized S-cone ERG testing may be helpful in distinguishing the two entities.
Genetics of Inherited Color Vision Deficiency
L-cones and M-cones share a common ancestry, likely having duplicated and diverged from a single gene on the X-chromosome. The M-cone and L-cone photopigments are both inherited through an X-linked recessive pattern, and are relatively common among males. Red-green color blindness is most common in men of Northern European descent and less common in those of African descent. The gene for the S-cone photopigment is located on chromosome 7 and so tritanomaly and tritanopia do not have a sex predilection. They are rare.
Since green and red genetic color deficiency is X-linked recessive, thus it is more common in males. Affected fathers may only pass the gene to a daughter. Females with only one copy will not have color vision deficits. Men with red/green color blindness have inherited it from their mother. Women with red/green color blindness have inherited it from each of their parents.
Acquired Color Vision Deficiencies
The differential diagnosis for acquired color vision abnormalities (dyschromatopsia) is broad.
The following entities may be associated with dyschromatopsia to varying degrees:
- Optic neuritis
- Optic neuropathy (e.g. compressive, ischemic)
- Central Serous Retinopathy
- Glaucoma (late finding, subtle)
- Diabetes (diabetic dyschromatopsia, rare)
- Dominant optic atrophy with blue dyschromatopsia
- Stargardt’s disease
Medication side effects which cause changes in color vision include sildenafil, digoxin, and medications which are toxic to the optic nerve. Sildenafil, a phosphodiesterase-5 inhibitor, is mainly used to treat erectile dysfunction; however, it also mildly inhibits phosphodiesterase-6 which is found in the retina and facilitates color vision. Inhibition of phosphodiesterase-6 stops the conversion of cGMP to GMP; accumulation of cGMP causes nucleotide-gated ion channels to remain open and prevents cone cell hyperpolarization. Use of Sildenafil at toxic levels can cause transient changes in color vision resulting in blue-tinted color vision (cyanopsia). Visual side effects resolved within hours to days after cessation of Sildenafil with no indications of chronic retinal injury.
Digoxin, a sodium-potassium ATPase inhibitor, is mainly used in the treatment of congestive heart failure. Visual side effects of digoxin include reduced visual acuity, blurred vision, yellow-tinted color vision (xanthopsia). While the exact mechanism is still unknown, it is theorized that digoxin inhibits sodium-potassium ATPase located in the retinal photoreceptors which are important for maintaining membrane potential. In conditions without light stimulation, dark current is the phenomenon when an influx of positive ions causes membrane depolarization. Therefore, digitalis toxicity lessens the membrane depolarization in retinal photoreceptors to explain digoxin’s visual side effects. Given the discovery of safer and more effective medications and Digoxin’s numerous side effects, one of which includes visual disturbances, current use of digoxin is uncommon.
Evaluation of Color Vision Deficiencies
Circular plates filled with colored dots in a background of other differently colored dots such that their arrangement produces either shapes or numerical values. This is the most common test for color deficiency and the test itself has had some changes over time. One of the more common forms is the Ishihara plates to evaluate primarily for protan and deutan defects. Patients with color vision deficiencies are unable to discriminate between colors on the plate and will see a different images than those seen by individuals with normal colored vision.
There are four different types of plates: transforming, vanishing, hidden digit, and classification with the following based on a 17-plate edition Ishihara test (plate #1 is a control plate universally read correctly. Individuals with congenital color vision abnormalities will identify a different number from the expected when reading the “transforming” plates #2-7 (Table 1). On the “vanishing” plates #8-13, they will not identify any number. The opposite is true for “hidden digit” plates (#14 and #15) in which patients with red-green color deficiencies will report seeing a number that cannot be seen those without color vision deficiencies. Lastly, the “classification” plates #16, 17 and 18 are used to determine the type of vision deficiency and severity. Individuals with protanopia will visualize a different number from those with deuteranopia.
In table 1, X indicates that an individual will be unable to read the plate. In the normal column is the expected result for individuals with good vision without any congenital deficiency of color vision.
|18||Both Lines||Both Lines||Purple Line||Red Line|
|19||No line||1 line||1 line||1 line|
|20||1 green line||No line||No line||No line|
|21||1 orange line||No line||No line||No line|
|22||Blue/green line||Blue-green & red line||No line||No line|
|23||Red & Orange line||Red & blue/green line||No line||No line|
|24||1 line||1 line||1 line||1 line|
Table 1: Interpretation of the standard Ishihara plates. Adapted from: Ishihara Test for Color Blindness (colour-blindness.com)
Individuals with optic neuritis or optic neuropathy will endorse red desaturation on bedside examination. This is performed by having the patient view a sharp red color while alternating between covering the two eyes. An individual with disease of the optic nerve may be able to quantify the degree of “red desaturation” in the affected eye. Red desaturation is a relative test, and thus reflects asymmetry between the eyes. Since it is commonly positive in optic neuropathies, its presence can correlate with a relative afferent pupillary defect (rAPD). However, the presence of an APD does not necessarily imply dyschromatopsia.
Nagel Anomaloscope color blindness test
The anomaloscope is an optical instrument that contains two light sources that have varying degrees of intensity and color. Patients are asked to adjust the settings of the light sources to combine relative amounts of red and green light until a baseline yellow is matched in color and intensity. The color vision classification system is based on the Rayleigh equation which is used to identify phenotypic variations in X-linked color-vision disorders. It is the most accurate instrument for assessing color vision, but is cumbersome and not widely used.
Color arrangement test involves one hundred tiles with slight differences in color and shade. Patients are asked to organize the tiles based on incremental changes in color.35 A patient’s score is determined based on 3 different factors: confusion angle, C-index and S-index. Confusion angle identifies the type of color deficiency with a positive angle considered a protan defect, between -12° and -65° a deutan defect and below that a tritan defect. C-index is determined by any error in the arrangement of tiles in comparison to a perfect Farnsworth panel-100 arrangement. Patients with excellent color vision will have scores closest to 1.00. S-index determines the selectivity or polarity in tile arrangement which describes any randomness or arrangement scatter. Scores closest to 1.00 are indicative of normal random scatter whereas polar scatter, dichromatic observers, will have higher S-index scores. These factors culminate into a whole numerical value with normal color vision with average scores between 20-60 while scores greater than 80 are concerning for color vision deficiencies.
Similar to the Farnsworth panel-100 with fewer colored plates, only 15, involved. The clinical utility of using the panel-15 instead of the panel-100 is due to the decreased test duration; the Farnsworth panel-15 can be completed in 3-5 minutes whereas it takes approximately 15-20 minutes to complete the Farnsworth panel-100. A study evaluating color vision deficiency in patients with glaucoma noted that while the Farnsworth panel-100 is a more accurate test, there is a strong enough correlation to suggest that the 15 tile test could be used to predict color vision deficiencies.
Gene therapy research with animal models for color vision deficiency has yielded positive results. Successful translation of this research on humans could possibly treat color vision deficiency.
There is no treatment for congenital color blindness. Typically, color blindness does not cause significant impairment; however, special contact lenses and glasses can be worn to minimize color differentiation deficits. For children, specialized learning aids can help overcome visual deficits.
Color Vision correcting Glasses
Protanomaly and deuteranomaly are common. It can be difficult to distinguish red from green, and purple colors may appear blue. There exist commercially available glasses with proprietary lenses that selectively filter certain wavelengths to decrease overlap between the M-cone and L-cone spectra. A person with anomalous trichromatism wearing these lenses may notice an improvement in color discrimination. These lenses do not restore normal color vision to the wearer, and do not allow the wearer to see new colors. One study of a commercial brand of Color Vision Glasses found “it is possible that with a filter observers will be able to distinguish some colors, but to the detriment of others”. Multiple small studies have been performed with mixed results, some noting improvement of Ishihara testing and chromatic discrimination thresholds in deutan patients, without benefit in protan subjects. Another study found no improvement in the error score of the Farnesworth-Munsell D-100 for subjects using these lenses.
- Nathans, Jeremy, Darcy Thomas, and David S. Hogness. "Molecular genetics of human color vision: the genes encoding blue, green, and red pigments." Science 232.4747 (1986): 193-202.
- Surridge, Alison K., Daniel Osorio, and Nicholas I. Mundy. "Evolution and selection of trichromatic vision in primates." Trends in Ecology & Evolution 18.4 (2003): 198-205.
- Carroll, Joseph, and Bevil R. Conway. "Color vision." Handbook of Clinical Neurology. Vol. 178. Elsevier, 2021. 131-153.
- Baylor, DuA, B. J. Nunn, and J. L. Schnapf. "Spectral sensitivity of cones of the monkey Macaca fascicularis." The Journal of Physiology 390.1 (1987): 145-160.
- Hagstrom, Stephanie A., Jay Neitz, and Maureen Neitz. "Variations in cone populations for red–green color vision examined by analysis of mRNA." NeuroReport 9.9 (1998): 1963-1967.
- Brainard, David H., et al. "Functional consequences of the relative numbers of L and M cones." JOSA A 17.3 (2000): 607-614.
- Roorda, Austin, and David R. Williams. "The arrangement of the three cone classes in the living human eye." Nature 397.6719 (1999): 520-522.
- Field, Greg D., et al. "Functional connectivity in the retina at the resolution of photoreceptors." Nature 467.7316 (2010): 673-677.
- Conway, Bevil R., et al. "A tour of contemporary color vision research." Vision research 151 (2018): 2-6.
- Field, Greg D., et al. "High-sensitivity rod photoreceptor input to the blue-yellow color opponent pathway in macaque retina." Nature neuroscience 12.9 (2009): 1159-1164.
- Johnson, Chris A., et al. "Blue-on-yellow perimetry can predict the development of glaucomatous visual field loss." Archives of ophthalmology 111.5 (1993): 645-650.
- Cello, Kimberly E., Jacqueline M. Nelson-Quigg, and Chris A. Johnson. "Frequency doubling technology perimetry for detection of glaucomatous visual field loss." American journal of ophthalmology 129.3 (2000): 314-322.
- Hubel, David H., and Torsten N. Wiesel. "Receptive fields and functional architecture of monkey striate cortex." The Journal of physiology 195.1 (1968): 215-243.
- Desimone, Robert, et al. "Contour, color and shape analysis beyond the striate cortex." Vision research 25.3 (1985): 441-452.
- Beauchamp, Michael S., et al. "An fMRI version of the Farnsworth–Munsell 100-Hue test reveals multiple color-selective areas in human ventral occipitotemporal cortex." Cerebral cortex 9.3 (1999): 257-263.
- Paulson, Henry L., et al. "Hemiachromatopsia of unilateral occipitotemporal infarcts." American journal of ophthalmology 118.4 (1994): 518-523.
- Bouvier, Seth E., and Stephen A. Engel. "Behavioral deficits and cortical damage loci in cerebral achromatopsia." Cerebral cortex 16.2 (2006): 183-191.
- Ebrey, Thomas, and Yiannis Koutalos. "Vertebrate photoreceptors." Progress in retinal and eye research 20.1 (2001): 49-94.
- Arshavsky, Vadim Y., and Marie E. Burns. "Photoreceptor signaling: supporting vision across a wide range of light intensities." Journal of Biological Chemistry 287.3 (2012): 1620-1626.
- Batten, Matthew L., et al. "Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis." PLoS medicine 2.11 (2005): e333.
- Maguire, Albert M., et al. "Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial." The Lancet 374.9701 (2009): 1597-1605.
- Gardiner, Kristin L., et al. "Long-term structural outcomes of late-stage RPE65 gene therapy." Molecular Therapy 28.1 (2020): 266-278.
- Pierce, Eric A., and Jean Bennett. "The status of RPE65 gene therapy trials: safety and efficacy." Cold Spring Harbor perspectives in medicine 5.9 (2015): a017285.
- Dhurandhar, Deven, et al. "Gene therapy in retinal diseases: A review." Indian Journal of Ophthalmology 69.9 (2021): 2257.
- Mitchell, D. E., and W. A. H. Rushton. "Visual pigments in dichromats." Vision research 11.10 (1971): 1033-1043.
- Foster, David H. "Color constancy." Vision research 51.7 (2011): 674-700.
- Kollner H. Die Störungen des Farbensinnes, ihre klinische Bedeutung ung ihre Diagnose. Berlin: Karger; 1912:234-258.
- Nork, T. Michael. "Acquired color vision loss and a possible mechanism of ganglion cell death in glaucoma." Transactions of the American Ophthalmological Society 98 (2000): 331.
- Neitz M, Patterson SS, Neitz J. Photopigment genes, cones, and color update: disrupting the splicing code causes a diverse array of vision disorders. Curr Opin Behav Sci. 2019;30:60-66.
- Shichi H. Color Blindness. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.
- Michael F. Marmor, Robert Kessler. “Sildenafil (Viagra) and Ophthalmology.” Survey of Ophthalmology. Volume 44, Issue 2. (1999): 153-162.
- Laties A, Zrenner E. Viagra (sildenafil citrate) and ophthalmology. Prog Retin Eye Res. 2002 Sep;21(5):485-506.
- Kinoshita J, Iwata N, Kimotsuki T, Yasuda M. Digoxin-induced reversible dysfunction of the cone photoreceptors in monkeys. Invest Ophthalmol Vis Sci. 2014 Feb 10;55(2):881-92.
- Birch J. Efficiency of the Ishihara test for identifying red-green colour deficiency. Ophthalmic Physiol Opt. 1997 Sep;17(5):403-8.
- National Research Council (US) Committee on Vision. Procedures for Testing Color Vision: Report of Working Group 41. Washington (DC): National Academies Press (US); 1981. Chapter 3. Color Vision Tests.
- Miyahara E. Errors reading the Ishihara pseudoisochromatic plates made by observers with normal colour vision. Clin Exp Optom. 2008;91(2):161-165. doi:10.1111/j.1444-0938.2007.00210.
- Garrett B, Dmytriw AA, Maxner C. Acute optic neuritis in multiple sclerosis. CMAJ. 2016;188(9):E199.
- Jägle H, Pirzer M, Sharpe LT. The Nagel anomaloscope: its calibration and recommendations for diagnosis and research. Graefes Arch Clin Exp Ophthalmol. 2005 Jan;243(1):26-32.
- Ghose S, Shrey D, Venkatesh P, Parmar T, Sharma S. A simple modification of the Farnsworth-Munsell 100-hue test for much faster assessment of color vision. Indian J Ophthalmol. 2014;62(6):721-723.
- Vingrys AJ, King-Smith PE. A quantitative scoring technique for panel tests of color vision. Invest Ophthalmol Vis Sci. 1988;29(1):50-63.
- Bassi CJ, Galanis JC, Hoffman J. Comparison of the Farnsworth-Munsell 100-Hue, the Farnsworth D-15, and the L'Anthony D-15 Desaturated Color Tests. Arch Ophthalmol. 1993;111(5):639–641. doi:10.1001/archopht.1993.01090050073032
- Gómez-Robledo, Luis, et al. "Do EnChroma glasses improve color vision for colorblind subjects?." Optics express 26.22 (2018): 28693-28703.
- Swarbrick, Helen A., et al. "The ChromaGen contact lens system: colour vision test results and subjective responses." Ophthalmic and Physiological Optics 21.3 (2001): 182-196.
- Mastey, Rebecca, et al. "Effect of “color-correcting glasses” on chromatic discrimination in subjects with congenital color vision deficiency." Investigative Ophthalmology & Visual Science 57.12 (2016): 192-192.
- Almutairi, Nawaf, et al. "Assessment of Enchroma Filter for Correcting Color Vision Deficiency." Pacific University (Oregon) (2017).