Introduction
Nyctalopia refers to night blindness or difficulty of the eye in visualizing under dim light or at night. Daytime vision, however, is unimpaired. Nyctalopia is due to the eye's inability to adapt quickly from lightness to darkness. The principle cell-type associated with Nyctalopia is rod cells. Rods are a type of photoreceptor cell present in the retina that transmits low-light vision and is most responsible for the neural transmission of nighttime sight. Rods have a singular photopigment, rhodopsin, which utilizes the protein scotopsin and the Vitamin A-derived cofactor, retinol.[1] This cascade is essential for the body's ability to regulate the pupillary light reflex. The pupillary light reflex allows unilateral afferent detection of changes in light energy entering the eye, and efferent adjustments in the pupillary sphincter and dilator pupillae muscles to initiate consensual constriction and dilation of the eyes. Pupil dilation is an adaptive response to changes in lightness and darkness.[2] Night blindness is the physical manifestation of impaired functioning of these processes.
Issues of Concern
Defective transmission of light through the lens, impairment of pupillary dilatation, nearsightedness, congenital or inherited development of the retina, and maladaptation of rod function due to Vitamin A deficiency are several etiologies of nyctalopia. These etiologies reflect the physiological balance necessary to transmit dim light to the retina and visual processing centers of the brain.
Cellular
The retina is located in the posterior portion of the eye and is the sensory component of the organ. The retina consists of specialized nerve cells that receive and process light energy and relay generated action potentials via the optic nerve to the brain. The retina consists of two photoreceptor types: rods and cones. Rods are more abundant, contain greater photopigment, have high sensitivity with lower visual acuity, and are achromatic, referring to the use of a singular photopigment, rhodopsin. The human retina consists of approximately 90 million rod cells, located in the highest density 15 to 20 degrees from the fovea. The fovea's location is in the center of the macula, which resides in line with the pupil and lateral to the optic nerve. Cones are more densely present in the fovea, exhibit higher visual acuity, confer color vision using trichromatic photopigments, and are present in numbers of approximately 6 million in the retina.[1] Cones are most active at higher light levels, referred to as photopic vision. Rods are conversely most active at lower light levels, or scotopic vision, and thus defective rod cell function may progress to symptoms of nyctalopia.[3]
Development
During the third month of embryological development, the precursors of rods and cones differentiate. In the 5th month of embryologic development, photoreceptors develop inner segments and in the seventh month, the outer segments differentiate.[4]
Mechanism
Light travels through the cornea, anterior chamber of the eye, the pupil (a hole in the center of the iris), lens, and posterior chamber before striking the retina. Within the retina, light travels past the ganglion and bipolar layers to strike the photoreceptors. The rod and cone photoreceptors convert light energy into neural impulses in the form of action potentials, which travel back through bipolar and ganglion cell layers and progress through the optic nerve. The optic nerve is a continuation of the optic disc, an area of the retina without photoreceptors, referred to as the “blind spot.” Neural activation progresses primarily to the lateral geniculate nucleus of the thalamus as well as the visual association and processing areas of the brain.[1] In the pupillary light reflex' afferent limb, a minority of fibers send a neural transmission to the pretectal area or pretectum. The pretectum is a group of seven nuclei in the midbrain responsible for initiating the efferent limb of the pupillary light reflex, in addition to playing a role in the optokinetic reflex, accommodation, antinociception, and rapid eye movement (REM) sleep.[5] In the efferent pupillary reflex, the pretectal nuclei project to bilateral Edinger-Westphal nuclei. The Edinger-Westphal nuclei then send impulses to the ciliary ganglion and activate the pupillary sphincter muscles to constrict the pupils.
Rhodopsin is the photopigment in rods. It is a G-protein-coupled receptor (GPCR) consisting of protein scotopsin and the Vitamin A-derived cofactor, retinol. Exposure to light allows for the isomerization of retinol from its 11-cis-retinal configuration into the active all-trans-retinal conformation. Isomerization of retinol into its active all-trans-retinal conformation then sets off a cascade of changes resulting in transformation into metarhodopsin II (Meta II). Meta II activates the transducin protein, followed by the transducin alpha subunit activating cyclic guanosine monophosphate phosphodiesterase (cGMP phosphodiesterase). In the resting or “dark” state, cGMP directly activates cation channels that cause net depolarization of rod photoreceptors (approximately -40mV), which continuously release glutamate neurotransmitter that hyperpolarizes some surrounding cells and depolarizes others. In the activation or “light” pathway, transducin alpha subunit activation of cGMP phosphodiesterase breaks down cGMP into GMP, thereby lowering cellular levels of cGMP and thus decreasing cation channel activity. The decrease cation channel activity causes the hyperpolarization of the rod photoreceptor and reduces the release of excitatory glutamate neurotransmitters by the rod cell. This overall increase in photon absorption and decreased glutamate release is recognized as a light sensation. Notably, rod cells exhibit significant signal amplification, as each rhodopsin GPCR may activate as many as 800 transducin proteins. Reversal of rods to the resting state is mediated by arrestin, rhodopsin kinase (RK), and the closure of cGMP channels. RK phosphorylates the cytosolic tail of rhodopsin, decreasing transducin activity. Arrestin increases GTP to GDP hydrolysis, thereby inactivating transducin, a G protein. The decreased intracellular calcium, caused by the closure of cGMP-sensitive cation channels in the activating pathways, triggers intracellular proteins to activate guanylate cyclase, which restores levels of cGMP. These pathways allow for plasma membrane depolarization in the restored resting state of rod cells.[1]
Related Testing
Refraction testing is used to detect changes in the various components of the eye that can contribute to an impaired focusing of light on the retina. It is helpful in the evaluation of nyctalopia as nearsightedness, or myopia is a common cause. Refraction testing involves a visual acuity test that most commonly consists of determining the smallest letters read by a patient on a standardized Snellen chart held twenty feet away. This process is done on each eye, individually and together. Refraction test using a phoropter allows for manual refraction determination utilizing a series of lens powers and patient’s experience of comparative clarity. Autorefractors and aberrometers are other commonly used equipment to test for refractive error.[6][7]
The slit-lamp is another piece of equipment widely used to evaluate the eye. A slit lamp is a binocular microscope used to examine structures of the eye under high magnification, often used to detect cataracts, a cause of nyctalopia.[8] Additionally, an electroretinogram (ERG) utilizes electrodes placed on the surface of the eye to distinguish its response to flashes of light. Visual field assessment with kinetic perimetry, using a Humphrey field analyzer or Goldmann perimeter, may be used to determine peripheral vision deficits. Visual field testing with ERG and clinical history are commonly central to a diagnosis of retinitis pigmentosa (RP), another cause of nyctalopia. The classic triad found under fundoscopic exam for retinitis pigmentosa include bony spicule pigmentation, optic disc pallor, and vascular narrowing; macular edema and subscapular cataracts are other notable findings. Newer modalities such as adaptive optics scanning laser ophthalmoscopy (AOSLO) have been increasingly utilized for high-resolution retinal examination for earlier detection, treatment, and evaluation.[9]
Blood testing of vitamin A (retinol) and glucose levels are other initial evaluations of rod function and retinal vasculature function, respectively.[10]
Pathophysiology
Retinitis pigmentosa is a genetic condition, most commonly exhibiting autosomal recessive inheritance, that often presents with nyctalopia as the primary presenting symptom. At a cellular level, it characteristically demonstrates a degeneration of the rod and cone photoreceptors with a preference for rods. Biochemical defects may contribute to multiple pathways, including ciliary transport dysfunction, intracellular endoplasmic reticular stress, and apoptosis, resulting in photoreceptor death. Degeneration and death of rods in early stages leads to loss of peripheral and nighttime vision, referred to as “tunnel vision.” Retinal pigment epithelium (RPE) and cone death occurs in later stages and is responsible for the loss of acuity, daytime vision, and eventually blindness. RPE cells detach and migrate to perivascular retinal areas, forming melanin pigment deposits in a characteristic bone spicule “star shape.”[11][12]
An obstruction to light in the anterior segment of the eye may lead to impaired travel of light energy to the retinal photoreceptors, such as the lens commonly in the form of cataracts, which can present as nyctalopia. Decreased activation of rod photoreceptors may present with disproportionately decreased processing of low-light environments.
Vitamin A, a fat-soluble vitamin primarily obtained from the diet in beta-carotene containing foods, deficiency can also cause nyctalopia. In the retinal rod photoreceptors, Vitamin A is a precursor substrate to 11-cis-retinal. The rhodopsin system is sensitive to dietary Vitamin A deficiency, and decreased Vitamin A intake may lead to low intracellular levels of 11-cis-retinal in the resting state, impairing dark adaption and manifesting as symptoms of night blindness.[13]
Clinical Significance
Nyctalopia may be the first presenting symptom of inherited conditions such as retinitis pigmentosa or acquired diseases such as vitamin A deficiency. Night blindness is sensitive and specific for serum retinol levels and is the earliest clinical manifestation of vitamin A deficiency. Night blindness may present with recurrent nighttime falls and difficulty with nighttime driving.[11]
Myopia, or nearsightedness, is refractive error pathology, which can cause nyctalopia. Refractive error refers to an abnormal change to an aspect of the eye that results in converging light prisms crossing at a focal point significantly in front of or behind the retinal plane. Myopia occurs due to an “elongated” eye in which the focal point converges in front of the retina, creating a progressively blurrier image of far distance objects. This blurriness may be accentuated in dim light, manifesting as a common etiology of nyctalopia. Corrective lenses and prescription eyeglasses based on calculated refractive error improve dim light vision.[6][7]
Hereditary retinal dystrophies are a rare, but significant, cause of nyctalopia. In congenital stationary night blindness (CSNB), there is impaired photoreceptor transmission leading to impaired dark adaptation. Complete type (CSNB1) and incomplete type (CSNB2) are rare heterogeneous conditions, most commonly X-linked. CSNB1 results from a diseased gene in the region between DXS556 and DXS8083 in Xp11.4-p11.3. CSNB1 characteristically results from mutations in genes involved in neurotransmitter detection by bipolar cells and reduced rod sensitivity up to 300x. A different locus is responsible for CSNB2, localized to the region between DXS722 and DXS8023 in Xp11.23; CSNB2 demonstrating membrane defects involved in neurotransmitter release by photoreceptor cells.[14][15]
Vitamin A deficiency is among the leading causes of blindness worldwide, particularly in developing countries. The World Health Organization estimates 254 million children have vitamin A deficiency, which is the most common cause of childhood blindness. An estimated 45% of these children are from South and Southeast Asia.[16][10] Xerophthalmia, Bitot spots, keratomalacia, conjunctival and corneal xerosis, retinopathy, developmental defects, and nyctalopia are among the associated clinical ocular findings. Vitamin A is necessary for normal visual function and maintenance of the corneal epithelium. Vitamin A is a visual pigment precursor, and subnormal levels of 11-cis-retinal may lead to a decline in the visual sensitivity of peripheral rod photoreceptors.[13] Nyctalopia associated with vitamin A deficiency is reversible and managed with retinal supplementation.[17]
Retinitis pigmentosa (RP), also known as hereditary retinal dystrophy, refers to a group of disorders with progressive loss of vision representing the most common inherited retinal disease. Nyctalopia is generally the first symptom of RP, followed by a gradual narrowing of the visual field or “tunnel vision” and eventually, total vision loss. Dyschromatopsia (loss of color discrimination), loss of acuity, photopsia (perceived flashes of light), and visual hallucinations are among other ocular signs and symptoms associated with RP. Isolated vision loss is termed nonsyndromic RP (70 to 80% of cases), with additional systemic symptoms termed syndromic RP.[12] Usher syndrome refers to partial or total hearing loss in conjunction with RP and is the most common form of syndromic RP.[18] Vitamin A supplementation may slow RP progression.[11]
Review Questions
References
1.Ludwig PE, Jessu R, Czyz CN. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Oct 7, 2022. Physiology, Eye. [PubMed: 29262001]
2.Belliveau AP, Somani AN, Dossani RH. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 25, 2022. Pupillary Light Reflex. [PubMed: 30725865]
3.Grassmeyer JJ, Munakomi S. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Aug 29, 2022. Photopic Vision. [PubMed: 31194334]
4.Cowan CS, Renner M, De Gennaro M, Gross-Scherf B, Goldblum D, Hou Y, Munz M, Rodrigues TM, Krol J, Szikra T, Cuttat R, Waldt A, Papasaikas P, Diggelmann R, Patino-Alvarez CP, Galliker P, Spirig SE, Pavlinic D, Gerber-Hollbach N, Schuierer S, Srdanovic A, Balogh M, Panero R, Kusnyerik A, Szabo A, Stadler MB, Orgül S, Picelli S, Hasler PW, Hierlemann A, Scholl HPN, Roma G, Nigsch F, Roska B. Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution. Cell. 2020 Sep 17;182(6):1623-1640.e34. [PMC free article: PMC7505495] [PubMed: 32946783]
5.Büttner-Ennever JA, Horn AK. Anatomical substrates of oculomotor control. Curr Opin Neurobiol. 1997 Dec;7(6):872-9. [PubMed: 9464978]
6.Backhouse S, Fox S, Ibrahim B, Phillips JR. Peripheral refraction in myopia corrected with spectacles versus contact lenses. Ophthalmic Physiol Opt. 2012 Jul;32(4):294-303. [PubMed: 22577970]
7.Salmon TO, West RW, Gasser W, Kenmore T. Measurement of refractive errors in young myopes using the COAS Shack-Hartmann aberrometer. Optom Vis Sci. 2003 Jan;80(1):6-14. [PubMed: 12553539]
8.Bhati H, Manjusha R. Clinical study on evaluation of anti-cataract effect of Triphaladi Ghana Vati and Elaneer Kuzhambu Anjana in Timira (immature cataract). Ayu. 2015 Jul-Sep;36(3):283-9. [PMC free article: PMC4895755] [PubMed: 27313415]
9.van Huet RA, Siemiatkowska AM, Özgül RK, Yücel D, Hoyng CB, Banin E, Blumenfeld A, Rotenstreich Y, Riemslag FC, den Hollander AI, Theelen T, Collin RW, van den Born LI, Klevering BJ. Retinitis pigmentosa caused by mutations in the ciliary MAK gene is relatively mild and is not associated with apparent extra-ocular features. Acta Ophthalmol. 2015 Feb;93(1):83-94. [PubMed: 25385675]
10.West KP. Extent of vitamin A deficiency among preschool children and women of reproductive age. J Nutr. 2002 Sep;132(9 Suppl):2857S-2866S. [PubMed: 12221262]
11.O'Neal TB, Luther EE. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Aug 8, 2022. Retinitis Pigmentosa. [PubMed: 30137803]
12.Jaissle GB, May CA, van de Pavert SA, Wenzel A, Claes-May E, Giessl A, Szurman P, Wolfrum U, Wijnholds J, Fischer MD, Humphries P, Seeliger MW. Bone spicule pigment formation in retinitis pigmentosa: insights from a mouse model. Graefes Arch Clin Exp Ophthalmol. 2010 Aug;248(8):1063-70. [PubMed: 20012642]
13.Feroze KB, Kaufman EJ. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 21, 2022. Xerophthalmia. [PubMed: 28613746]
14.Boycott KM, Pearce WG, Musarella MA, Weleber RG, Maybaum TA, Birch DG, Miyake Y, Young RS, Bech-Hansen NT. Evidence for genetic heterogeneity in X-linked congenital stationary night blindness. Am J Hum Genet. 1998 Apr;62(4):865-75. [PMC free article: PMC1377021] [PubMed: 9529339]
15.Tsang SH, Sharma T. Congenital Stationary Night Blindness. Adv Exp Med Biol. 2018;1085:61-64. [PubMed: 30578486]
16.West KP. Vitamin A deficiency disorders in children and women. Food Nutr Bull. 2003 Dec;24(4 Suppl):S78-90. [PubMed: 17016949]
17.Imdad A, Mayo-Wilson E, Herzer K, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Cochrane Database Syst Rev. 2017 Mar 11;3(3):CD008524. [PMC free article: PMC6464706] [PubMed: 28282701]
18.Koenekoop R, Arriaga M, Trzupek KM, Lentz J. Usher Syndrome Type II. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. University of Washington, Seattle; Seattle (WA): Dec 10, 1999. [PubMed: 20301515]