Issues of Concern
Anatomy and Physiology of Pupil Size
The pupil is a circular aperture in the center of the iris that modulates the amount of light entering the eye and reaching the retina. Pupil size is tightly regulated by a complex interconnection of nerves, muscles, and other anatomical structures that allow the eye to adjust the amount of light reaching the retina, optimizing the quality of visual information.[1]
The iris is a pigmented muscular structure between the cornea and lens that controls pupil size. The iris contains the sphincter pupillae and the dilator pupillae muscles. The sphincter pupillae is a circular muscle that contracts to decrease pupil size in a process known as miosis. The dilator pupillae is a radial muscle that contracts and enlarges the pupil, a phenomenon called mydriasis.[5]
The autonomic nervous system regulates the iridic muscles. Miosis is induced by parasympathetic stimulation via the primary nerve pathway comprising the Edinger-Westphal nucleus, oculomotor nerve (CN III), ciliary ganglion, and short ciliary nerves. Mydriasis is the result of sympathetic stimulation of the dilator pupillae. The primary nerve pathway for sympathetic control of the pupil originates in the hypothalamus, descends to the ciliospinal center of Budge, extends through the lateral horn of the spinal cord at the C8 to T2 levels, ascends through the sympathetic chain to the superior cervical ganglion, and proceeds along the long ciliary nerves to the eye.[6] Both the sympathetic and parasympathetic systems work in tandem to dynamically adjust pupil size according to light levels, emotional state, cognitive processing, and distance of focus.[4]
Pupillary constriction reduces the amount of light entering the eye, increases the depth of focus due to the pinhole effect, and enhances visual acuity. Pupillary dilation allows more light to reach the retina and provides better illumination at the expense of image sharpness.[4][7] This dynamic modulation of light entry by the pupil plays a critical role in vision, particularly in determining visual resolution.
Clinical Examination and Testing
Pupil size can be evaluated clinically using various methods. The handheld light examination provides a gross estimate of pupil size and reactivity to light. Quantifying pupil size in light and dark conditions is integral to the comprehensive pupillary examination. Pupil diameter is measured in millimeters using a pupil gauge typically printed on a near vision reading card or dedicated tool.[8] This technique provides a consistent and reproducible method for measuring pupil size, enabling monitoring of changes in pupillary response over time.
Assessment of dynamic pupillary responses can provide valuable insights into visual function and the integrity of the afferent and efferent pathways of the pupillary light reflex. Pupillography, a technique that quantifies pupillary responses to visual stimuli, can reveal abnormalities undetectable by standard clinical examination.[9] Pupillometers provide precise measurements and are useful when documenting small, clinically significant changes or performing a more detailed assessment of the pupillary light reflex.[10] Modern dynamic infrared pupillography promotes assessing the complex aspects of pupillary behavior, improving the understanding of diseases affecting the afferent visual and pupillomotor pathways.[11]
Visual Implications of Pupil Size
Pupil size significantly affects visual resolution due to diffraction and aberration. Decreased pupil size increases light diffraction and reduces image sharpness. Increased pupil size increases light aberration and leads to a distorted image. Intermediate optimal pupil size is approximately 2 mm to 4 mm, where the combined effects of diffraction and aberration are minimal and visual resolution is the sharpest.[12]
Depth of Focus
The depth of focus describes the range within which an object can move towards or away from the eye while maintaining a clear image of the retina. Pupil size plays a significant role in determining the depth of focus. Decreasing pupil size increases the depth of focus; objects are seen clearly over a greater range of distances. This principle is the "pinhole effect," where a small aperture can increase focus depth and improve visual acuity. This effect occurs because the pinhole blocks unfocused peripheral light rays and permits only parallel rays to enter the eye; parallel rays do not require refraction to focus on the retina.[13]
The relationship between depth of focus and pupil size can be quantitatively expressed by the following:
s/p = d/(f+d), where
s is the diameter of the blur circle on the retina
p is the diameter of the pupil
d is the depth of focus
f is the focal length
Thus, when p is smaller, d increases, s is smaller, and the image is clearer.[14]
The pinhole effect is often utilized in vision tests in a clinical setting. For instance, if vision improves when looking through a pinhole, this suggests that the vision loss is due to a refractive error, such as myopia, hyperopia, or astigmatism, rather than a pathology of the eye.[15]
Light Aberration
Pupil size plays a significant role in forming optical aberrations, which are deviations from the ideal path of light as it passes through the optical system. These optical aberrations can degrade the quality of the image projected onto the retina, affecting visual function. Optical aberrations influenced by pupil size include spherical aberration and astigmatism of oblique incidence.[16]
Spherical aberration occurs when light rays passing through different parts of a lens focus at distinct points. More precisely, bundles of light rays close to the lens' axis focus at 1 point, while peripheral rays, which bend more dramatically, intersect the optical axis nearer to the lens and focus at a separate point. This discrepancy results in multiple focal points and a blurred image.[17]
Astigmatism of oblique incidence emerges when light rays penetrate the eye at an angle other than perpendicular to the cornea. The oblique angle can lead to uneven refraction of light, causing the light to focus at numerous points on the retina rather than a single focal point. This aberration can cause a blurred or distorted image, with various parts of the image focusing at different depths.[18]
Pupil size significantly influences these aberrations. A dilated pupil allows more peripheral light rays to enter the eye, shifting the average focal point and inducing slight myopia. A dilated pupil also permits increased oblique light rays to enter the eye, exacerbating astigmatism of oblique incidence. A constricted pupil blocks these peripheral and oblique light rays, reducing the aberrations and potentially enhancing visual clarity.[16] The relationship between pupil size and spherical aberration is particularly relevant in refractive surgeries, where patients with naturally larger pupils may experience more significant postoperative spherical aberrations, leading to symptoms like glare or halos, especially in low-light conditions when the pupil is dilated.[19]
The anatomy of the eye naturally mitigates some spherical aberration. The cornea and lens are the primary refracting components of the eye. Each displays variations in curvature and refractive index, limiting spherical aberration. The peripheral cornea has a flatter curve than the central cornea, reducing the bending of peripheral rays. The refractive index of the natural lens is higher in the central region, creating a more substantial refractive effect on the paraxial rays and reducing spherical aberration.[20]
Interestingly, at approximately 19 years of age, the opposing spherical aberrations of the cornea and lens perfectly balance each other, minimizing overall spherical aberration. However, the aging lens gradually induces more spherical aberration than the cornea can offset, and spherical aberration increases with age. This physiological change is partially counteracted by a concurrent age-related reduction in pupil size, allowing fewer peripheral rays to enter the eye and reducing the impact of this age-related increase in spherical aberration.[21]
Wavefront Aberrations
Wavefront aberrations are deviations in the light path as they propagate through the eye, which can degrade the retinal image quality.[22] The relationship between pupil size and wavefront aberrations is rooted in the principles of optical physics, precisely Fermat's principle, which is integral to understanding how light travels through the eye.[23]
Fermat's principle, or the principle of least time, asserts that light follows the path that requires the least time when traveling from 1 point to another. This principle is fundamental to wavefront analysis, which uses the difference in light paths to construct a wavefront map. Wavefront mapping provides a comprehensive understanding of the eye's optical aberrations, going beyond traditional measurements of refractive errors.[24]
The number of light rays entering the eye increases with increasing pupil size. The light waves passing through the peripheral cornea and lens must travel a longer path, which increases transit time and affects the shape of the wavefront, leading to an increase in higher-order aberrations, such as coma, trefoil, and spherical aberration. These higher-order aberrations decrease visual performance, particularly under low-light conditions when the pupil is dilated.[16]
The center of the pupil is the reference point for wavefront analysis, and a relationship exists between pupil position and wavefront aberration. When the center of the pupil is displaced from the visual axis, as in corectopia, wavefront aberrations may be enhanced.[25] In clinical practice, understanding the effect of pupil size and position on wavefront aberrations can help customize refractive surgeries, improve the design of intraocular lenses, and provide better patient-specific optical corrections.
Light Diffraction
Diffraction refers to spreading light waves as they encounter a boundary or aperture.[26] Diffraction occurs when light passes through the pupil; the degree of diffraction is inversely proportional to pupil size. A larger pupil offers a broader path for traversing light waves, reducing diffraction and enabling more incoming light to reach the retina directly.[27] Larger pupils improve an image's perceived brightness and contrast and are advantageous in low-light conditions.
Conversely, a smaller pupil increases the degree of diffraction by deflecting more light waves from their original path as they pass through the narrowed aperture, spreading the light out over a larger area of the retina, resulting in a blurred image.[28] A small pupil does impart the benefit of the pinhole effect, enhancing the depth of field and visual acuity, especially in bright conditions where excessive light could lead to overstimulation of the photoreceptors.[29] However, a pupil that is too small may contribute to poor vision under low-light conditions due to insufficient light reaching the retina.[28]
Distortion
Distortion is the variation in magnification across the field of view, causing straight lines to appear curved or skewed in the visual image. Distortion is also affected by pupil size. Distortion occurs secondary to the varying angles of incidence and different degrees of refraction as light rays pass through optical components.[30] The 2 primary types of distortion are pincushion distortion, where lines bend outwards from the center, and barrel distortion, where lines bend inwards towards the center.[31]
Light rays traveling along the lens's optical axis encounter no refraction and do not deviate from their path. Straight lines in the visual field that pass through the optical axis remain straight in the retinal image.[32] However, distortion can occur for lines not passing through the optical axis; the degree of distortion increases proportionally to the distance from the optical axis. Light rays entering the eye that do not pass through the optical axis strike the cornea and lens at varying angles, leading to differential bending or refraction of light across the lens surface.[33] Increasing pupil size increases distortion, and smaller pupils reduce distortion.[34]
Astigmatism
Astigmatism is present when the eye's refractive power is not uniform in all directions. In astigmatism, the curvature of the cornea or lens varies between the vertical and horizontal meridians, causing light from a single point source to form 2 line foci at different distances, leading to a blurred image.[35]
Pupil size can impact the perceived effects of astigmatism. When the pupil is small, the amount of light passing through the peripheral parts of the cornea, where astigmatism is often most pronounced, is reduced. A smaller pupil partially mitigates the blurring effect of astigmatism and improves visual acuity. Conversely, when the pupil is large, peripheral light rays are allowed into the eye, potentially exacerbating the effects of astigmatism.[36]
Contrast Sensitivity
Contrast sensitivity is the ability to discern subtle variations in shades of gray or contrasts between an object and its background. An important aspect of this concept is the contrast threshold, the minimum contrast required to discern a certain size letter.[37] For example, the contrast threshold for a 20/400 letter is 2% to 3%, and the threshold for smaller letters is higher. In other words, our ability to discern the size of letters depends on their contrast.[38]
Contrast reserve refers to the ratio of the actual contrast of an object to the contrast threshold, which is the minimum contrast needed for an observer to discern the object. A larger contrast reserve implies that the object is easier to see, as its contrast significantly exceeds the minimum level required for visibility.[39] Specific charts, like the Pelli-Robson Contrast Sensitivity Chart, LEA Vision Screening Chart, and Vistech Contrast Test System, are used to measure contrast sensitivity.[38]
Contrast sensitivity and reserve are critical for recognizing facial expressions, reading, night driving, and many other real-world visual tasks that demand more than high contrast acuity, the ability to discern fine details.[40] Contrast sensitivity is affected by physiological and pathological eye conditions. Theoretically, larger pupils allow more light to reach the retina, potentially enhancing contrast sensitivity, especially in dim light. However, larger pupils also let in more aberrant, off-axis light rays, which could potentially decrease contrast sensitivity. On the other hand, smaller pupils limit these optical distortions and restrict the light influx, which can decrease contrast sensitivity, particularly in low-light conditions.[41]
Any ocular pathology causing irregularities or distortions in the optical pathway can degrade contrast sensitivity. This includes corneal conditions that cause irregular astigmatism or corneal edema, lens changes like cataracts or refractive errors, and retinal or optic nerve disorders. Keratoconus and corneal scarring can induce significant optical distortions, reducing contrast sensitivity.[42] Cataracts can scatter light as it passes through the eye, disrupting the formation of a clear, contrasted image on the retina.[43] Age-related macular degeneration and diabetic retinopathy can directly affect the photoreceptor cells responsible for detecting contrast and detail, diminishing contrast sensitivity.[44]
Retinal Luminance
Retinal luminance is the amount of light per unit area falling on the retina. Pupil size controls retinal luminance by regulating the amount of light entering the eye. Larger pupils increase retinal luminance, enhancing vision in low-light conditions, but can cause excessive brightness and decreased contrast sensitivity in brightly lit conditions; this is why patients with dilated pupils often experience light sensitivity or photophobia in bright environments.[45]
Pupil size influences the magnitude of electrical responses in full-field electroretinogram (ffERG) testing, which measures cone cell function in the retina. A study involving the Diopsys® NOVA fixed-luminance flicker ffERG device found that the measured electrical response increased with pupil size in terms of pupil diameter and pupil area. This suggests the need to consider pupil size when conducting and interpreting ffERG testing, with specific reference ranges potentially enhancing the clinical utility of such tests.[46]
Peripheral Field
Peripheral vision is outside the center of our gaze. Larger pupils may enhance peripheral field vision due to the increased area of light entry, and smaller pupils may restrict the peripheral field of vision. Activities requiring a broad visual field, such as motor vehicle operation, may be impacted by pupil size conditions.
Studies have indicated that pupil dilation and constriction can cause statistically significant changes in threshold sensitivities in automated perimetry tests. A study found that pupil dilation in normal subjects worsened the mean defect by an average of 0.83 dB, suggesting a decline in threshold sensitivities. Valid comparisons of results from serial visual field testing would require either controlling the effect of pupil dilation or adjusting for it.[47] Pupillary constriction can also affect perimetry results, worsening the mean defect by an average of 0.67 dB. These changes underscore the significance of maintaining consistent pupillary diameters during serial automated visual field examinations.[48] Changes in pupil size are not recommended before peripheral field testing.
Flicker Sensitivity
Flicker sensitivity is the ability of the visual system to detect fluctuations in light intensity over time and can be influenced by pupil size.[49] Flicker sensitivity is important in clinical and professional environments that require rapid light adjustments, like professional sports or aviation.
A study on the effects of pupil size on the fixed-luminance flicker full-field electroretinogram (ffERG), a test used to assess cone cell function, demonstrated an increase in ffERG magnitude with increased pupil size. The study found that the pupil's diameter and area were significantly associated with the magnitude of flicker ffERG, with the ERG magnitude tending to increase by 1.08 µV for every 1 mm increase in pupillary diameter.[46] This research suggests that the effect of pupil size on flicker sensitivity is not straightforward and may depend on the specific measurements and methods used.
Circle of Least Confusion
The circle of least confusion is the point along the optical axis where a bundle of light rays converges most narrowly. This point forms the sharpest image within the optical system. It is not a true focus point where all rays converge, but rather the point of optimal focus where the area outside of perfect focus, or blur circle, is at its smallest diameter. The circle of least confusion is critical to understanding astigmatism and presbyopia.[50]
In conditions such as astigmatism, the eye's cornea or lens (or both) have an irregular or asymmetrical curvature.[35] This irregularity refracts incoming light unevenly, leading to multiple focal points in front of and/or behind the retina. This divergence results in blurred or distorted vision, as a clear image cannot form on the retina. However, these multiple foci overlap at a certain point along the optical axis to create the circle of least confusion, where the image is comparatively less blurred.
The size of the pupil significantly impacts the circle of least confusion. When the pupil is smaller (as in miosis), fewer peripheral light rays enter the eye, reducing the lens's aberrations and moving the circle of least confusion closer to the retina, increasing the sharpness of the image. Conversely, when the pupil is larger (as in mydriasis), more peripheral rays are allowed in, which increases lens aberrations and moves the circle of least confusion farther from the retina, reducing the sharpness of the image.[50]
Pupil Size and Cataract Location
Pupil size can influence how certain types of cataracts affect vision. For example, a cortical cataract, which affects the lens's outer layer, significantly impacts vision when the pupil is dilated. This is because a larger pupil exposes more of the affected lens areas. Conversely, a posterior subcapsular cataract near the back of the lens is usually more bothersome when the pupil is small, such as in brightly lit conditions. This is because light tends to pass directly through the back of the lens on its way to the retina.[51]
Impact of Corectopia and Polycoria on Vision
The precise location of the pupil within the iris, known as the pupil center, is critical for optimal vision. When the pupil is decentered or displaced from its normal central position, it can profoundly affect visual function. A decentered pupil is termed corectopia.[52]
One condition that can lead to a decentered pupil is iridocorneal endothelial (ICE) syndrome. The decentered pupil in ICE syndrome can cause various visual symptoms, including blurred or distorted vision, glare, and monocular diplopia.[53]
The hallmark of ICE syndrome is the movement of the corneal endothelium (the inner layer of cells on the cornea) onto the iris, which can cause changes to the iris, like atrophy and hole formation, resulting in polycoria and corectopia.
Inflammation within the eye can also lead to a decentered pupil through synechiae formation. Synechiae are adhesions that can form between the iris and other structures within the eye during inflammation. If synechiae form between the iris and the lens (posterior synechiae) or the cornea (anterior synechiae), they can pull the pupil off-center. This can result in an irregularly shaped or decentered pupil, which can cause similar visual symptoms as those seen in ICE syndrome.[54]
Decentered pupils can significantly impact visual quality, whether caused by ICE syndrome, inflammation with synechiae formation, or other conditions. The misalignment can cause light to enter the eye at unusual angles, leading to aberrations and decreased visual acuity. Treatment is complex and may involve addressing the underlying condition, using corrective lenses to improve vision, or, in some cases, surgical intervention to recenter the pupil.[52]
Polycoria, a condition characterized by the presence of more than 1 pupil in a single eye, can manifest in various situations, such as with ICE syndrome, after trauma, or due to incorrect placement of a peripheral iridotomy. Normal visual function is predicated on a single, round pupil that adjusts its size to regulate the amount of light entering the eye. The presence of multiple pupils can disrupt this light regulation process, leading to issues with visual acuity, contrast sensitivity, and depth perception.[55] The multiple pupils in polycoria are often of varying sizes and shapes and do not dilate or constrict uniformly. This disparity can result in uncontrolled light entry and exit, causing visual disturbances. These disturbances can manifest as blurred vision or monocular diplopia, particularly if the upper eyelid does not cover the additional pupils.[56] Additional causes of polycoria include true polycoria, a rare congenital polycoria characterized by multiple fully formed pupils in 1 or both eyes with their own sets of surrounding sphincter muscles, allowing them to constrict and dilate independently.[57] Additionally, pseudopolycoria, a more common condition, is where polycoria exists without full sets of sphincter muscles for each pupil. This condition may be seen in Axenfeld-Rieger syndrome, for example.[58] These, as well as ICE syndrome, are discussed further in the congenital pupil abnormalities section below.
Trauma, either surgical or accidental, can also result in multiple pupils if the iris is damaged or torn, creating additional openings that can mimic the appearance of extra pupils.[59] One such surgical procedure, a peripheral iridotomy, is performed as a treatment for certain types of glaucoma. This procedure involves creating a small hole in the peripheral iris to improve fluid drainage and lower intraocular pressure. However, if incorrectly placed, the iridotomy can appear as an additional pupil, causing light to enter the eye from an abnormal direction, leading to visual disturbances like monocular diplopia.[60]
Visual Axis, Optical Axis, and Angle Kappa
The human eye has 2 significant optical axes – the optical and visual axes, often referred to in the literature as the pupillary axis and the line of sight, respectively. The optical axis comprises an imaginary line perpendicular to the cornea, intersecting the center of the entrance pupil.[32] On the other hand, the visual axis is an imaginary line that connects the object in space, the centers of the entrance and exit pupils, and the foveal center. The visual axis is also known as the foveal-fixation axis.[61]
Due to the placement of the fovea, which is slightly temporal to where the pupillary axis intersects the posterior pole, a positive angle is formed between these 2 axes. This angle is known as the angle kappa. The optical axis, the visual axis, and the angle kappa are represented on a physical exam by the distance between the pupillary center and the corneal light reflex.[62] Different corneal topography systems have measured the angle kappa, including Synoptophore and Orbscan.[63]
Interestingly, angle kappa tends to be larger in hyperopic eyes than myopic eyes and is also typically larger in left eyes than right eyes and in exotropes compared to esotropes. Some studies show that angle kappa decreases with age, but the decrease is usually not clinically significant.[63]
These variances in angle kappa can have implications for surgical procedures like refractive surgery and cataract surgery. For instance, in patients with significant hyperopia, centering on the corneal light reflex during refractive surgery often results in better corrected and uncorrected visual acuity, less decentration of the ablation zone, and fewer higher-order aberrations. Likewise, in myopic individuals, a large angle kappa may necessitate centering closer to the visual axis for optimal results in refractive surgery.[64]
When considering using a multifocal intraocular lens (MFIOL) in cataract surgery, it may be beneficial to consider the angle kappa, especially for hyperopic patients with a large angle kappa. Eyes with a larger angle kappa tend to exhibit more glare and halos after cataract surgery with the placement of MFIOLs.[65] Several methods are proposed to accommodate for a large angle kappa in cataract surgery with MFIOL, including decentering the MFIOL towards the visual axis and gluing 1 haptic in place, centering the capsulorhexis on the coaxially sighted corneal light reflex, and postoperative pupilloplasty with argon laser to center the pupil more closely to the visual axis.[66][67]
Lastly, visual and optical axis concepts are instrumental in pediatric eye examinations for conditions like strabismus. In these examinations, tests like the Hirschberg test use the corneal light reflex to assess for ocular alignment, where the optical axes of the eyes should ideally be parallel.[68]
Glare
Glare can significantly impact visual function, especially in individuals with certain eye conditions such as cataracts. This is a visual sensation caused by excessive and uncontrolled brightness that can occur from a direct or reflected light source. Glare can be uncomfortable or disabling, affecting the ability to perform tasks like driving at night or reading.[69] The connection between glare and pupil size is noteworthy, as larger pupil size increases the likelihood of experiencing glare due to a broader pathway for light scatter. Conversely, a smaller pupil can limit light scatter and thereby reduce glare.[70]
The Brightness Acuity Test (BAT) is commonly used to assess the impact of glare, particularly in patients with cataracts. The BAT mimics a glare situation by asking the patient to read a standard acuity chart under varying brightness levels. The test results indicate how much the glare impacts the individual's visual acuity and can inform decisions about the timing and necessity of interventions like cataract surgery.[71] Cataracts can significantly increase glare sensitivity due to light scattering as it passes through the clouded lens. This scattering can cause a reduction in contrast sensitivity and increase perceived glare, leading to difficulties in vision, particularly in brightly lit conditions or at night.[72]
Clinical Significance
Pupillary Abnormalities
Iatrogenic
Refractive surgery: Procedures like LASIK (laser-assisted in situ keratomileusis) and SMILE (small incision lenticule extraction) aim to correct refractive errors by reshaping the cornea.[73] Understanding the relationship between pupil size and visual resolution can guide surgical planning and predict postoperative outcomes. For instance, if a patient's scotopic (low-light) pupil size significantly exceeds the area of the cornea reshaped by the laser (optical zone), they may experience night vision problems, such as glare, halos, and starbursts, due to peripheral aberrations.[74] Therefore, a comprehensive preoperative pupil size assessment under different lighting conditions can help minimize such postoperative complications through careful planning and informed patient discussion.
Cataract surgery: In cataract surgery, the opaque crystalline lens is replaced with an artificial intraocular lens (IOL). The IOL's design and the surgical pupil's size can affect visual quality.[75] For instance, multifocal IOLs, which provide multiple focus points, may cause photic phenomena, such as halos and glare, mainly if the pupil is wide.[76] A concern exists for small pupils, but surgical techniques can overcome the aperture.[77] Thus, careful preoperative evaluation and appropriate IOL selection can help optimize postoperative visual outcomes.
YAG iridotomy and iridectomy: YAG Iridotomy and iridectomy are procedures performed to create an opening in the iris, the colored part of the eye that controls the pupil size. They are typically used as treatment options for specific types of glaucoma, including angle-closure glaucoma and pigment dispersion syndrome.[78] In YAG iridotomy, a laser creates a small hole in the peripheral iris, allowing the aqueous humor to flow freely from the posterior chamber to the eye's anterior chamber, reducing intraocular pressure.[79] The created hole's size and location can affect the light entering the eye, potentially causing visual disturbances like glare or double vision in some individuals. It is also important to consider that a patent iridotomy may cause a minor pupil size or shape alteration due to changes in the iris' structural integrity.[60] An iridectomy, on the other hand, involves the surgical removal of a portion of the iris tissue. The procedure is performed peripherally (similar to an iridotomy) or sectorally, depending on the underlying disease process.[80] As with an iridotomy, the procedure's effect on the pupil can depend on the location and extent of the iris tissue removal.
Iris repair surgery and artificial iris surgery: Iris repair surgery and artificial iris implantation address iris defects resulting from trauma, congenital anomalies, or prior ocular surgery. These defects can cause various visual disturbances due to an abnormally shaped or sized pupil, such as photophobia, glare, and decreased contrast sensitivity. Iris repair surgery seeks to reconstruct the damaged iris and restore the pupil's normal shape and size. This can involve suturing techniques to repair iris tears or using specialized devices to create an artificial pupil in cases of pupil dilation (mydriasis) that cannot be reversed medically.[81] An artificial iris can be implanted in more severe cases if the iris is extensively damaged or missing. This procedure involves replacing the natural iris with a custom-made, flexible silicone device that mimics the color and structure of the patient's iris. Artificial iris surgery can significantly improve visual function and cosmetic appearance. Still, careful patient selection and surgical technique are critical to minimize potential complications, such as glaucoma, corneal edema, and retinal detachment.[82] In both procedures, understanding the interplay between pupil size and visual resolution is paramount to optimize visual outcomes and patient satisfaction postoperatively. These surgical interventions often involve delicate and precise adjustments to the pupil's size and shape, aiming to balance the need for light entrance and the minimization of optical aberrations.[81]
Acquired Disorders
Alterations in pupil size, shape, and position can affect visual resolution and be an important clinical sign in various visual and systemic disorders. For example, relative afferent pupillary defect (RAPD), a discrepancy in pupillary constriction between the eyes when stimulated by light, indicates a significant lesion along the afferent pathway, such as optic neuritis or severe retinal disease.[83] Specific disorders are listed as follows.
ICE syndrome: Iridocorneal endothelial syndrome (ICE syndrome) is a group of 3 ocular disorders: iris nevus (or Cogan-Reese) syndrome, Chandler syndrome, and essential (or progressive) iris atrophy. These disorders are distinguished by abnormalities of the cornea, iris, and often the angle of the anterior chamber of the eye, which can lead to the development of polycoria and corectopia. The hallmark of ICE syndrome is the movement of the corneal endothelium (the inner layer of cells on the cornea) onto the iris (the colored part of the eye), which can cause changes to the iris like atrophy and hole formation, resulting in polycoria. ICE syndrome often leads to the development of glaucoma.[55]
End-stage glaucoma: Glaucoma is a group of eye conditions that damage the optic nerve, vital for good vision. This damage is often caused by abnormally high pressure in the eye. In the late stages of this condition, glaucoma can result in an afferent pupillary defect. This pupillary response, also known as the Marcus Gunn pupil, can cause the pupil to react poorly or not at all to direct light but will constrict when the other healthy pupil is stimulated due to a consensual reflex.[84] Patients with end-stage glaucoma can also experience significant visual field loss, sometimes perceived as a dark spot or "blind spot" in their vision.[85]
Ocular trauma: Trauma can result in damage to various parts of the eye, including the iris. Direct injury to the iris sphincter muscle can lead to a condition known as traumatic mydriasis. In this condition, the pupil is dilated and is either sluggish or nonreactive to light. The shape of the pupil may be irregular if parts of the iris sphincter are torn. Patients with traumatic mydriasis can experience photophobia (sensitivity to light), difficulty focusing, and decreased visual acuity.[86] Head trauma and related brain injuries may also induce pupillary abnormalities.[87]
Multiple sclerosis and other demyelinating diseases: Multiple sclerosis is an autoimmune disease that affects the central nervous system by damaging the myelin sheath, the protective covering of nerve cells. When the optic nerve is affected (a condition known as optic neuritis), it can cause an afferent pupillary defect. Patients may experience symptoms such as blurred vision, eye pain, color vision abnormalities, and, in severe cases, blindness.[88]
Adie (tonic) pupil: This condition is typically seen in young women and presents as 1 pupil that is larger than the other (anisocoria) reacting sluggishly to light but has a slow, sustained response to accommodation (the near reflex). This is likely due to a viral or bacterial infection that causes damage to the postganglionic fibers of the ciliary ganglion. Over time, the affected pupil may become smaller or "miotic" due to the progressive denervation of the iris sphincter muscle.[89]
Neurosyphilis: One of the classic signs of neurosyphilis is Argyll Robertson pupils, a condition where the pupils are small, irregular, and do not react to direct light but constrict to accommodation. This condition is thought to be due to damage to the pretectal nuclei in the midbrain.[90]
Diabetes: Diabetes can cause numerous complications in the body, including damage to the nerves, known as neuropathy. In the case of autonomic neuropathy, the nerves that control involuntary body functions, such as the heartbeat, blood pressure, and pupil dilation and constriction, are damaged. This can lead to pupillary abnormalities, such as the Argyll Robertson pupil.[91]
Stroke and other central nervous system lesions: Strokes can cause various types of damage, depending on the affected area of the brain. In the case of a brainstem stroke, damage to the midbrain, where the Edinger-Westphal nucleus is located, can disrupt the efferent limb of the pupillary reflex, leading to unequal pupil sizes, a condition known as anisocoria.[92]
One common type of stroke-related anisocoria is Horner syndrome, characterized by miosis (constricted pupil), ptosis (drooping eyelid), and anhidrosis (decreased sweating) on 1 side of the face.[93] The syndrome occurs due to disrupted sympathetic nerve pathways that supply the face and eyes. In the context of pupil size, the syndrome results in miosis because the disrupted sympathetic nerves typically induce pupil dilation. When these nerves are interrupted, the unopposed action of the parasympathetic system leads to a constricted or "small" pupil on the affected side. Additionally, the affected pupil in Horner Syndrome typically has a slower-than-normal dilation response in dim light, a phenomenon known as dilation lag.[83]
The causes of Horner syndrome can be grouped into 3 categories based on the location along the sympathetic pathway where the disruption occurs: central, preganglionic, and postganglionic. Central causes originate in the brain and include conditions like stroke, tumor, or spinal cord injury. Preganglionic causes include conditions that impact the nerve fibers as they travel down the neck and upper chest, such as neck trauma, cervical spine surgery, or lung cancer. A Pancoast tumor, which is a type of lung cancer that develops at the top (apex) of the lung, is a classic preganglionic cause of Horner syndrome. The tumor's location at the lung apex allows it to invade the sympathetic chain in the neck, disrupting the nerve signals that cause the syndrome. Postganglionic causes are due to damage to the nerve fibers that run along the carotid artery to the eye, as can occur with carotid artery dissection or cavernous sinus thrombosis. Infections and surgical damage can also lead to postganglionic Horner syndrome.[93]
Third nerve palsy: Also known as oculomotor nerve palsy, this condition is characterized by weakness or paralysis of the muscles innervated by the third cranial nerve. This nerve supplies 4 of the 6 muscles that control eye movement, the muscle that elevates the upper eyelid, and the muscles involved in pupil constriction. Regarding pupil size, third nerve palsy can lead to a dilated or "large" pupil. The dilated pupil is due to paralysis of the parasympathetically innervated iris sphincter muscle supplied by the oculomotor nerve.[94] When these fibers are damaged, the unopposed action of the sympathetic system causes the pupil to dilate. In some cases, the affected eye may be "down and out" due to unopposed action of the lateral rectus and superior oblique muscles. A dilated pupil in third nerve palsy is particularly concerning because it can be a sign of a life-threatening condition, such as an aneurysm compressing the nerve.[95] Two important causes of third nerve palsies are discussed as follows.
Diabetic third nerve palsy: Diabetic third nerve palsy is typically caused by ischemia or insufficient blood supply to the nerve due to microvascular disease, a common complication of poorly controlled diabetes. This type of palsy tends to spare the pupil because of the nerve's blood supply arrangement. The parasympathetic fibers that control the pupil are located on the periphery of the nerve and receive blood supply from multiple sources, making them less susceptible to ischemia than the centrally located fibers that control the eye muscles. Patients with diabetic third nerve palsy present with sudden onset of pain around the eye or headache, followed by double vision. Symptoms may progressively worsen over several days and gradually improve over weeks to months. Pupil involvement is usually absent, which can aid in distinguishing this type of palsy from others.
[96] Posterior communicating artery third nerve palsy: Posterior communicating artery (PCOM) third nerve palsy typically results from an aneurysm in the posterior communicating artery. This aneurysm can compress the third cranial nerve, leading to dysfunction.
[95] The key difference between PCOM and diabetic third nerve palsy is the pupil's involvement. In PCOM palsy, because of the nerve's anatomical structure, the aneurysm tends to compress the outer fibers of the nerve, affecting the parasympathetic fibers that control the pupil and causing mydriasis.
[97] This distinction is of significant clinical importance, as a third nerve palsy with pupil involvement is considered a neurological emergency. The palsy requires immediate evaluation to rule out an aneurysm, which, if ruptured, can have severe consequences. Patients with a rupture of a posterior communicating artery aneurysm may present with a sudden onset of severe headache, often described as "the worst headache of my life."
[98]
In conclusion, a myriad of disorders and conditions can influence the size of the pupil. The pupil's size and reactivity provide essential information about the integrity of the visual and autonomic pathways and, therefore, are an integral part of the ophthalmic and neurological examination. Understanding these conditions and the impact on pupil size facilitates early diagnosis and appropriate management, preserving visual function and improving patient outcomes.
Congenital Disorders
Aniridia: A rare congenital disorder characterized by the complete or partial absence of the iris, leading to an enlarged pupil. The absence of the iris affects the visual appearance and impairs the eye's ability to adjust the amount of light entering, leading to light sensitivity. Aniridia may be accompanied by other eye problems such as nystagmus, glaucoma, and impaired visual acuity. Mutations in the PAX6 gene often cause it. Additionally, aniridia may not occur in isolation. It is part of Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome, seen in approximately 5% of aniridia cases.[99]
Congenital mydriasis: A condition where the individual is born with dilated pupils (mydriasis). This rare disorder usually affects both eyes. These pupils do not respond to light or accommodation. The mydriasis is often associated with connective tissue disorders, particularly Marfan syndrome.[89]
Horner syndrome: This condition is characterized by a combination of symptoms, including miosis (constriction of the pupil), ptosis (drooping of the upper eyelid), and anhidrosis (lack of sweating). In Horner syndrome, the affected pupil may react slowly to light and may not dilate as much as the unaffected eye in the dark. The pupillary defect is caused by damage to the sympathetic nerves controlling the eyes and face. The syndrome may be present at birth or acquired later in life.[93]
Coloboma: This is a condition where normal tissue in or around the eye is missing from birth. When it affects the iris, this can result in a keyhole or cat-eye-shaped pupil. Coloboma also occurs when a choroidal fissure gap fails to close during early prenatal eye development.[100]
True polycoria: A rare eye condition where multiple functioning pupils exist within a single iris in 1 or both eyes. The condition is distinguished by the fact that each of these pupils has its own sphincter and dilator muscles. This unique characteristic allows each pupil to constrict and dilate independently of the others, affecting how light enters the eye and, subsequently, the quality of the formed image on the retina. This condition is typically present from birth and is often associated with other ocular or systemic disorders, including Axenfeld-Rieger syndrome and iridocorneal endothelial (ICE) syndrome. Diagnosis is confirmed through slit lamp examination, where the presence of individual sphincter muscles around each pupil is detected.[57] The primary distinguishing feature between true polycoria and the more common pseudopolycoria is the presence of these individual muscle groups in the former. Pseudopolycoria lacks independent sphincter muscles for each opening, and thus, the additional 'pupils' cannot constrict or dilate independently. Management of true polycoria focuses on addressing the associated ocular or systemic conditions and improving visual acuity, which may involve corrective lenses or surgical intervention in some cases.[58] The impact on vision can range from minimal to severe, depending on factors such as the size, shape, and position of the additional pupils and the extent of associated ocular disorders.
Peters anomaly: This congenital disorder involves the clouded cornea and the iris adhering to the lens, affecting the pupil's shape and size. The disorder is often associated with other systemic anomalies.[101]
Axenfeld-Rieger syndrome: Axenfeld-Rieger syndrome is a group of rare genetic disorders involving eye, dental, facial, and systemic abnormalities. In terms of eye involvement, patients typically present with abnormalities in the anterior chamber, such as iris hypoplasia (underdeveloped iris), corectopia (displacement of the pupil), and polycoria (presence of more than 1 pupil). These can cause glaucoma and impaired vision. This condition is primarily caused by mutations in the PITX2 or FOXC1 genes, with an autosomal dominant inheritance pattern.[102]
Pharmacologic A
gents with Effects on Pupil Size
Mydriatics
Antimuscarinic (from weakest to strongest)
Tropicamide: A muscarinic antagonist that is used to dilate the pupil and paralyze the accommodation reflex, commonly used for ophthalmic examinations.
[103] Cyclopentolate: A muscarinic antagonist used for mydriasis and cycloplegia during eye examination and surgery. The antagonist has a longer duration of action compared to tropicamide.
[104] Homatropine: This drug, similar to atropine, is an antimuscarinic agent used to dilate the pupil and inhibit accommodation. Homatropine is typically used in ophthalmic examinations or the treatment of anterior uveitis, and its effects are shorter in duration than atropine.
[105] Atropine: An antimuscarinic agent that causes pupil dilation (mydriasis). Atropine paralyzes the accommodation reflex in diagnostic procedures or treating inflammatory conditions such as anterior uveitis.
[106] Scopolamine: An anticholinergic drug used for cycloplegia for diagnostic procedures and certain eye conditions. Scopolamine causes pupil dilation and inhibits accommodation.
[107]
Sympathomimetic
Phenylephrine: A sympathomimetic agent that causes pupil dilation. The drug is used for diagnostic purposes to promote visualization of the retina and other internal structures of the eye.
[108]
Miotics
Pilocarpine: A parasympathomimetic alkaloid that constricts the pupil (miosis). Pilocarpine is used in conditions like glaucoma to increase the outflow of aqueous humor and reduce intraocular pressure.
[109] Carbachol: A cholinergic drug that constricts the pupil. Carbachol is often used in the treatment of glaucoma to decrease intraocular pressure.
[110] Alpha-2 agonists: Drugs like clonidine, used for high blood pressure, can cause pupil constriction.
[111]
Psychoactive agents
Psychoactive substances: Certain drugs, such as LSD, MDMA (ecstasy), and cocaine, can cause dilation of the pupils as part of the stimulant effect.
[112] Opioids: These medications, including morphine and heroin, tend to constrict the pupils. This effect is commonly referred to as "pinpoint pupils" or miosis.
[113]
Antidepressants and antipsychotics
Certain medications in these classes can cause changes in pupil size, often dilation. These include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and certain atypical antipsychotics.
[114]
Anticholinergic agents
Anticholinergic drugs: Medications with anticholinergic properties, such as some antihistamines, tricyclic antidepressants, and certain antiparkinsonian drugs, can cause dilation of the pupils.
[115]
These lists are not exhaustive; other pharmacologic agents also influence pupil size.
Perceptual Influence of Pupil Size
The relationship between pupil size and visual perception is an area of continued investigation. The pupils adapt to diverse light conditions, contracting in bright light and dilating in darkness to modulate the amount of light entering the eye. Yet, intriguingly, studies suggest that cognitive processes, including perceptual phenomena, can also trigger changes in pupil size, granting insight into the cognitive processes underpinning visual experiences.[116]
Psychologist Bruno Laeng spearheaded a series of studies exploring the interface between perception and pupil size, using static images designed to create an illusion of fluctuating brightness or darkness.[117][118] Two central images employed in these experiments are the Asahi illusion and an image depicting an expanding black hole.
The Asahi illusion is an image that, at first glance, resembles a glowing sun, consisting of a series of petal-like shapes surrounding a center. The petals follow a gradient from a yellow hue at the center to black at the edges, with the optical illusion design creating the impression that the center is significantly brighter than the surrounding areas. Despite the static nature of the image, the combination of the color gradient and the petal shape provides the impression that the white center is brighter than it is in reality. Remarkably, Laeng and his colleagues found that upon viewing the Asahi illusion, participants' pupils would constrict as though reacting to an actual increase in light intensity. This finding suggests that the mere perception of brightness, even without an actual increase in light, can lead to a physiological response in pupil size.[118]
In a later experiment, participants viewed an image of an expanding black hole, which imparts the impression of a progressively deepening darkness, even though the image is static. Similarly, the participants' pupils dilated in response to the perceived darkness rather than the actual luminance of the image, which remained constant.[117] Additional studies have expanded on observations into perception and pupil size. For example, pupil constriction is seen when viewing a picture of the sun.[119] Generating mental images of light and dark scenarios affects pupil size.[120]
Building upon this, another layer of complexity is relevant when considering the regulation of light perception by the retina. A study involving the application of tropicamide, a mydriatic agent, to 1 eye of participants showed an increase in perceived brightness when viewing geometric patterns with the treated eye, confirming that slight pupil dilations can significantly influence the perceptual experience of brightness. However, this change in perceived brightness did not correspond proportionally to the extent of pupil dilation, underlining the role of the retina's adaptive mechanisms, such as retinal bleaching and neural adaptation, in driving the perception of light.[121]
These studies indicate that perceptual systems can induce physiological changes in pupil size based on perceived rather than actual light levels. The findings underscore the extent to which the brain, in interpreting visual stimuli, produces changes in pupil size, reflecting subjective perception rather than the objective properties of the stimulus. This research offers valuable insights into the complex relationship between cognition, perception, and pupil size. By understanding how perceptual processes can induce changes in pupil size, we can deepen our knowledge of the interplay between visual perception and the physiological mechanisms that support it.[122]
Management Strategies
Pharmacological management: Drugs are commonly used to manage pupil abnormalities. For instance, pilocarpine is a parasympathomimetic agent that constricts the pupil and is useful in conditions like anisocoria or mydriasis.[123] Atropine, a parasympatholytic agent, is used to dilate the pupil in conditions like iritis to alleviate pain and prevent the formation of posterior synechiae (adhesions).[124]
Surgical management: Certain conditions, such as traumatic mydriasis or iris defects due to congenital conditions like aniridia, may necessitate surgical intervention. Procedures include iris reconstruction, the use of artificial iris implants, or suturing techniques to reduce the size of the pupil. Glaucoma associated with conditions like Axenfeld-Rieger syndrome may require surgical treatments such as trabeculectomy or tube shunt surgery to reduce intraocular pressure.[102]
Adaptive devices: In cases of significant light sensitivity due to large or irregular pupils, adaptive devices such as sunglasses or photochromic lenses can help manage symptoms. Pinhole glasses, which restrict the amount of light entering the eye and reduce the effect of refractive errors, may be beneficial.[125]
Low vision rehabilitation: Low vision rehabilitation services can help maximize remaining vision and improve the quality of life for individuals with significant visual impairment due to pupil abnormalities. Services might include occupational therapy to develop new skills, devices to enhance vision (like magnifiers or digital aids), and strategies to modify the environment for increased safety and function.[126]
Psychological support: Given the potential impact on visual function and appearance, individuals with pupil abnormalities may also benefit from psychological support and counseling to help cope with any emotional or psychological challenges associated with their condition.
As always, the most appropriate management strategy depends on the individual patient's circumstances, including the specific pupil abnormality, its severity, the presence of any associated conditions, and the patient's personal needs and preferences.
Conclusion
Pupil size is crucial in modulating visual resolution and is affected by physiological and pathological factors. A comprehensive understanding of the dynamic relationship between pupil size and visual resolution is essential in ophthalmology and optometry, allowing for accurate diagnosis and effective management of various ocular conditions.
In clinical practice, optimal patient care involves the appropriate management of diseases affecting the pupil and associated structures and the integration of knowledge about the influence of pupil size on visual resolution. This ensures the delivery of personalized care, considering individual differences in pupil size and potential effects on visual outcomes.
