Introduction

The surface of the human retina contains about 6 million cones and 100 million rods. Cones transmit color information; rods focus on greater sensitivity to low-light conditions. The fovea is the center of the retina and predominately concentrated with cones to accommodate high visual acuity in high light conditions. Photon-powered isomerization of rhodopsin, a complex consisting of vitamin-A derived retinal, and the protein opsin is the molecular mechanism of action for retina cells (photoreceptors).[1][2][3]

Issues of Concern

Within rhodopsin, light absorption leads to a chemical reaction that forces part of the rhodopsin molecule to translocate, by changing protein conformation and exposing active sites. This activated form of rhodopsin is known as metarhodopsin. MetarhodopsinII activates many copies of the G protein transducin (by replacing transducin's GDP with GTP). Activated transducin complexes and activates cyclic nucleotide phosphodiesterase (PDE), which can itself hydrolyze 1000 molecules of cGMP to 5'-GMP per second. cGMP-gated channels in the plasma membrane of these rods (or cones) allow sodium ion influx at high cGMP concentrations; this is balanced by cation exchanger-mediated glutamate efflux, maintaining cell depolarization (dark conditions). At low cGMP concentrations, these channels close, stopping sodium ion influx and reducing glutamate efflux, all leading to cell hyperpolarization (light conditions). Thus light-induced rod/cone state changes lead to hyperpolarization of the photoreceptor cells; which cease to transmit the neurotransmitter glutamate. Conversely, photoreceptor cells without the presence of light exist in the depolarized state and continuously release glutamate.

Light response is a one-to-one effect. The enzyme rhodopsin kinase quickly binds metarhodopsin II, phosphorylating and halting its activity. The protein arrestin binds phosphorylated metarhodopsin II. Innate GTPase activity in transducin eventually degrades bound GTP to GDP, leading to PDE dissociation and inactivation. MetarhodopsinII is unstable and will split within minutes, leading to opsin and free trans-retinal. Trans-retinal is transported to pigment epithelial cells that convert trans-retinal back to 11-cis-retinal, which eventually is recombined with opsin within cones/rods to reform rhodopsin. Guanylate cyclase restores cGMP concentration, and the cone/receptor is ready to respond to another light exposure event.

Additionally, phototransduction is subject to regulation by a calcium-mediated pathway to quickly diffuse a large gradient response, in such circumstances as sudden flashes of light in the dark. In dark conditions, intracellular calcium level is high due to calcium diffusion through cGMP-gated channels. Lack of frequent light response allows more calcium to enter the cell per second, due to high intracellular cGMP concentrations. Calcium ion binding to rhodopsin kinase increases the rate of rhodopsin phosphorylation, reducing transducin activation. Calcium ion binding to guanylate cyclase accelerates the restoration of cGMP concentration. And calcium ion binding to calmodulin increases cGMP affinity to its gated channel. 

Color vision results from the combination of signals from three visual pigment types within cones: that of red, green, and blue, which correspond to cone types L, M, and S (RGB-LMS). Those colors correspond to the wavelengths of peak light absorption intensities of the modified chromophores. L cones have peak absorptions at 555 nm to 565 nm, M cones at 530 nm to 537 nm, and S cones at 415 nm to 430 nm. Thus color vision arises from the shifted cones' peak absorption levels and ultimately the brain's interpretation of the composition of these points of wavelength absorption. The entire pathway is sometimes referred to as the retinoid cycle.[4][5][6][3]

Clinical Significance

Improper Color Vision Recognition/Color Blindness

Many forms of color vision recognition abnormalities are present in the population, with most having a genetic origin (congenital). Very few individuals are truly color blind, but instead, see a disrupted range of colors. The most common forms are protanopia and deuteranopia, conditions arising from loss of function of one of the cones, leading to dichromic vision. Protanopia is the loss of L cones (red) resulting in green-blue vision only. Deuteranopia is the loss of M cones (green) resulting in red-blue vision only. Both are X-linked alleles, therefore almost exclusively occurring in males, occurring with a prevalence of 1%. Loss of S cones does rarely occur in 0.01% of males and females. In these cases, one of the cones is not expressed, and physically in its place, one of the others is expressed.

Similar to above, but not as severe in its symptoms, is the condition anomalous trichromatic vision (tritanomaly), where all three cones are present but the color vision is aberrant. The two common forms, protanomaly, and deuteranomaly result in L or M cones, respectively, being replaced with a cone of intermediate spectral tuning. Both are X-linked and occur in 7% of males.[7]

Non-Color Vision Associated Diseases Affecting the Cones

In addition to disorders of proper color recognition, many diseases in vision display phototransduction defects affecting many portions of the signal pathway and its regulation. Here, not only is color vision function lessened but scotopic (low-light, rod-associated) vision as well.

Stationary Night Blindness (CSNB)

One such disease is congenital stationary night blindness. It is a genetic defect resulting in functional cones but dysfunctional rods. In this disease, many potential culprits have been identified including abnormal rhodopsin, arrestin, rod transducin, rod phosphodiesterase, and rhodopsin kinase. Studies have demonstrated that in some populations of this disease rods are stuck permanently outputting light signal. There are currently no treatments for this disorder. In CSNB, b-waves are reduced (in CSNB type 2) or absent (in CSNB type 1) during an electroretinogram (ERG).

Retinitis Pigmentosa (RP)

Another disease affecting rod function is retinitis pigmentosa, which is a progressive degeneration of the retina leading to blindness, of genetic origins. Frequently, it begins in early phase as night blindness and eventually progresses to loss of vision of mid-periphery leading to the center, manifesting as tunnel vision. These clinical manifestations are associated with faulty rod functioning; if cones begin to be affected then, blindness eventually results. RP is characterized by reduced or absent A-waves and b-waves during an ERG. It has a prevalence of 1 in 3500 individuals.

Malnutrition-Associated

Deficiency in the essential nutrient vitamin A leads to night blindness, and can eventually lead to permanent blindness through the deterioration of the receptor outer segments.

Experimental Therapies

Currently, there are no FDA-approved treatments for CSNB or RP. However, there is the promise of gene-therapy interventions on the horizon. The recent completion of several phase I/II clinical trials of retinal gene therapies utilizing adeno-associated virus (AAV) have shown moderate success in preventing disease onset and progression for several years following treatment. At present, knowledge of specific abnormal phototransduction genes for a given disease is key to even minimal treatment.[3]

Common Reversible Causes

Alcoholism has been associated with worsened scores on color blindness aptitude tests, case reports of which improved during and after hospital stays.[8]

Ethambutol Toxicity (TB treatment) can result in severe red-green color blindness. Full color vision usually returns several months after stopping the drug.[9]

Phenytoin Toxicity has been reported to cause long-standing but reversible loss of color vision. Typically, normal acuity does return until about a year after discontinuing the drug.[10]

PDE5 Inhibitors such as sildenafil and tadalafil have been reported to rarely cause transient loss of color vision. This is thought to be due to cross-reactivity to the PDE6 present in retinal photoreceptors. In a case report, full-color acuity as demonstrated by Isahara plate tests returned 1-week post-administration.[11]

Obstructive jaundice can cause transient loss of color vision which returns once the underlying jaundice is corrected. It is thought that the elevated bilirubin is the mechanism involved.[12]

Poorly-controlled Systemic lupus erythematosus (SLE) can lead to chiasmal disease (optic neuritis) which manifests as temporal hemifield defects, decreased visual acuity as gaged by a Snellen test, and variable loss of color vision ability. Full return to baseline acuity is common with aggressive treatment of the SLE.[13]

Acute occupational exposure to toluene causes reversible loss of color vision in about 25 percent of people, specifically confusion in the blue-yellow spectrum. Return to baseline typically occurs 3 days after the last exposure.[14]

Enhancing Healthcare Team Outcomes

Color blindness is a group of eye disorders that affect the perception of color. The most common color vision deficiency is a red-green color vision. Affected individuals often have difficulty differentiating between shades of yellow, red and green. Blue-yellow color vision defects are rare. Color vision problems can also be due to medications, chemical exposure, and old age. Once diagnosed, there is no cure for inherited color deficiency but those related to medications, injury or illness can be improved. Thus, besides the ophthalmologist, the nurse and pharmacist must be aware of color vision defects and their causes. Any drug known to affect color vision should be discontinued. The patient should be referred to the ophthalmologist or optometrist for specially designed tinted eyeglasses or red-tinted contact lens.[15](level III)

Outcomes

Color vision deficiency may limit jobs in certain professions but the condition is not life-threatening. While the Occupational and Safety Health Administration (OSHA) neither precludes employers from requiring normal vision for essential job duties nor requires employers to maintain a color-blind aware environment, the organization has deferred to the society standards of specific professions. For example, the standard ASME (American Society of Mechanical Engineers) B30.2-2001, Overhead, and Gantry Cranes requires that operators of cab-operated and pulpit-operated cranes be able to distinguish between colors if such is needed for proper equipment operation. 

The recent availability of a tinted lens and glasses has allowed most people to adapt to various deficits. In the future, gene therapy may be available to restore vision in those with hereditary disorders of colored vision deficiency.[16][17] (Level III)[3]