WHAT IS THE PUPIL
The pupil of the eye is the dark aperture defined by the medial border of the iris. The size of this opening is determined by the balance of tone of the two smooth muscles of the iris, the sphincter iridis and dilator pupillae, the actions of which cause pupillary constriction and dilation, respectively. Similar to an adjustable iris of an automatic camera, the size of the pupil varies in response to the amount of ambient light that stimulates the retina, a physiologic property mediated by the direct light reflex. Accordingly, the size and reactivity of the pupil provide information regarding the integrity of the autonomic nervous system and afferent visual pathway. In clinical practice, abnormalities of these functions are usually identified by observing anisocoria or impairment of the direct light reaction. For the most part, evaluation of the pupil is objective, and often quantifiable, two properties that are ideally suited to the neurologic examination. Although various other aspects of normal pupil physiology and abnormal pupil signs are discussed in this section, those features that are relatively common or clinically relevant to the practicing neurologist will be emphasized. Loewenfeld's (1) text is the current authoritative source for the reader interested in more detail than is presented here.
ANATOMY OF THE PUPILLARY PATHWAYS
Iris: Anatomy, Vascular Supply, Color
The iris is formed by differentiation of the embryonal optic cup. The two smooth muscles and the epithelium are derived from the neuroectodermal layer whereas the stroma is derived from the mesodermal layer. As reviewed by Hogan and coworkers (2), the fully developed iris consists of several layers (Fig. 1). The iris sphincter is oriented meridionally. Its fibers are intimately interwoven within the stroma so that the muscle still works to constrict the pupil even when a segment of it is injured as a result of, for example, intraocular surgery. Myoepithelial cells of the dilator are oriented radially from the iris root to the pupil border, so that when the muscle contracts, it draws the iris peripherally and causes the pupil to dilate.
Fig. 1 Structures of the iris. The a indicates the anterior border layer that terminates at the pigmentary ruff of the pupillary border (b). The c indicates the iris sphincter muscle, which is oriented circumferentially within the stroma and located deep to the anterior border layer; d indicates vessels that traverse the stroma and sphincter muscle; f indicates the iris dilator muscle, which is oriented radially and located deep to the stroma. The dilator terminates at the mid-sphincter position (arrow), at which point cuboidal epithelial cells (g) continue to the pupillary margin to form the anterior epithelial layer; j indicates the tall columnar cells that make up the posterior epithelial layer. (Hogan MJ, Alvarado JA, Weddell JE [eds.]: Histology of the Human Eye. An Atlas and Textbook, p 231. Philadelphia: WB Saunders, 1971, with permission.)
The color of the iris is determined, at least in part, by the degree of pigmentation of the epithelium and by the amount of stromal melanocytic proliferation that occurs following birth (3). The stroma has little pigment at birth so that shorter wavelengths of light (i.e., blue) pass through this layer and are reflected back by the pigmented posterior epithelium. If pigmentation does not develop during the next several months, then the iris color remains blue. If the iris is heavily pigmented at birth or becomes heavily pigmented during infancy, then the color appears dark and brown. The degree of iris pigmentation is an important factor to consider when using ophthalmic drops. Topical agents applied to eyes that are more darkly pigmented tend to have a slower onset and longer duration of action, probably because the drug binds to melanin and is released slowly.
The iris vessels are oriented radially within the stroma and arise from two vascular systems derived from the ophthalmic artery, the long posterior ciliary arteries and the anterior ciliary arteries (4). The two long posterior ciliary arteries enter the posterior globe and travel forward between the sclera and choroid to anastomose near the anterior portion of the ciliary body to form the greater arterial circle. This anastomosis sends radial twigs anteriorly into the iris. The anterior ciliary arteries are branches of the muscular arteries that reach the globe by traveling within the rectus muscles. They send superficial radial branches forward into the iris. An occlusion of the central retinal artery does not directly affect the iris because its blood supply involves the ciliary branches of the ophthalmic artery. However, an occlusion of the ophthalmic or the internal carotid arteries, when associated with poor collateral ocular circulation, can cause signs of anterior ocular segment ischemia, including rubeosis iridis and a dilated, poorly reactive pupil (5).
For the pupil to constrict or dilate, it must overcome a variable degree of resistance offered by the iris tissue (6). In addition, the contractile forces of the smooth muscles of the iris are probably dependent on the same length-tension relationships that are inherent to other smooth muscles. For example, a large pupil in which the iris sphincter is stretched can probably generate a greater contraction force than a smaller pupil in which the sphincter is more lax (7). The mechanical properties of the pupil are important to consider when performing and interpreting pharmacologic testing for anisocoria. For example, a large pupil caused by conditions other than parasympathetic denervation constricts more than a smaller pupil in response to the same dose of a topically applied cholinergic agonist (8).
Parasympathetic Pathway of the Pupil and the Third Nerve
The tone of the iris sphincter (responsible for pupillary constriction) and the ciliary muscle (responsible for accommodation) is controlled by the parasympathetic nervous system through a two-neuron pathway, the efferent limb of the pupillary light reflex (Fig. 2). The preganglionic pupillomotor fibers originate from the visceral oculomotor nuclei of the dorsal midbrain--the Edinger-Westphal and anterior median nuclei and the nucleus of Perlia. Of these, the Edinger-Westphal nucleus, a collection of cell bodies located in the dorsomedial portion of the oculomotor nuclear complex, are the best characterized (9). The parasympathetic cellular component of the oculomotor nuclear complex, which gives rise to fibers that innervate the ciliary muscle, is intimately integrated within the same region as the Edinger-Westphal nucleus (10).
Fig. 2 Anatomy of the pupillary light reflex pathway. (Miller NR: Walsh And Hoyt's Clinical Neuro-Ophthalmology, p 421. Vol 2, 4th ed. Baltimore: Williams & Wilkins, 1985, with permission.)
The third cranial nerve passes through the midbrain and exits in the interpeduncular fossa where it then enters the subarachnoid space. Fibers destined to innervate the intraocular muscles are located peripherally along the axial length of the third cranial nerve, concentrated along the superior medial aspect of the nerve trunk near the brain stem (11) (Fig. 3). The peripheral location of the pupillomotor fibers makes them susceptible to injury if an aneurysm compresses the third cranial nerve in this location.
Fig. 3 Location of pupillomotor fibers are depicted as dark regions on cross-sections of the right (R) and left (L) oculomotor nerve at various locations along its course, including its emergence from the brain stem in the interpeduncular fossa (1), the midsubarachnoid segment (2), the level of the dorsum sella before it enters the cavernous sinus (3), and the point in the anterior cavernous sinus where it divides into the superior division (SD) and the inferior division (ID) (4). (Kerr FWL: Neuro-ophthalmology. In Smith JL [ed.]: Symposium of the University of Miami and the Bascom Palmer Eye Institute, p 54. Vol IV. St Louis: CV Mosby, 1968 with permission.)
The oculomotor nerve then courses within the cavernous sinus where it bifurcates into an inferior and superior division near the anterior superior orbital fissure. The preganglionic pupillomotor fibers travel with the inferior division through the superior orbital fissure along with fibers that innervate the ciliary, inferior rectus, inferior oblique, and medial rectus muscles. Within the orbit, the parasympathetic fibers synapse in the ciliary ganglion, a small structure residing in the orbital fat near the orbital apex.
Postganglionic parasympathetic fibers proceed anteriorly as short ciliary nerves to the posterior globe. They pierce the sclera and travel within the subchoroidal space toward the anterior ocular segment to innervate the iris sphincter and ciliary muscles. Roughly 97% of postganglionic fibers innervate the ciliary muscle, whereas only 3% of the short ciliary nerves innervate the iris sphincter (9). This proportion is important in the pathophysiology of Adie's tonic pupil and is discussed in a later section. Despite considerable controversy, no consistent evidence supports the existence of a direct parasympathetic pathway from the brain stem to the intraocular muscles that bypasses a synapse in the ciliary ganglion in humans (12).
Acetylcholine is the neurotransmitter released at both the preganglionic presynaptic terminal within the ciliary ganglion and the postganglionic neuromuscular junction in the iris. The postsynaptic cholinergic receptor of the iris sphincter is muscarinic. Acetylcholine is hydrolyzed by acetylcholinesterase. Various naturally occurring and commercially available agents influence pupil size following topical application by interfering with the cholinergic synapse (13) (Table 1).
TABLE 1. Topical Cholinergic Agents That Influence Pupil Size
==== Sympathetic Pathway of the Pupil ====
The tone of the iris dilator muscle is controlled by the sympathetic nervous system through the action of circulating catecholamines and, more directly, by a three-neuron pathway that extends from the hypothalamus to the iris (Fig. 4). The first order, or central, neurons of the oculosympathetic pathway originate mainly in the posterolateral region of the hypothalamus, descend ipsilaterally through the lateral brain stem and near the anterolateral columns of the cervical spinal cord, and synapse within the intermediolateral gray matter column of the lower cervical and upper thoracic spinal cord in a region referred to as the ciliospinal center of Budge and Waller (14). The first order neurons are susceptible to injury by a variety of acquired and congenital disorders that affect the brain stem or upper spinal cord (15).
Fig. 4 Anatomy of the oculosympathetic pathway. (Maloney WF, Younge BR, Moyer NJ: Evaluation of the causes and accuracy of pharmacologic localization in Horner's syndrome. Am J Ophthalmol 1980;90:394--402, Ophthalmic Publishing Company with permission.)
The second order, or preganglionic, neurons arise from the ciliospinal center and exit the spinal cord through the ventral roots of C8 through T2. These preganglionic fibers then proceed over the apex of the lung to the paravertebral sympathetic chain and extend rostrally to synapse in the superior cervical ganglion deep within the angle of the jaw. The second order neurons are particularly susceptible to injury by traumatic and mass lesions.
The third order, or postganglionic, oculosympathetic neurons originate from the superior cervical ganglion and travel as a plexus along the internal carotid artery through the base of the skull into the cavernous sinus. Sympathetic fibers that control facial sweating and vasoconstriction follow the external carotid artery to their effector organs, with one exception that occasionally has localizing value. Sudomotor fibers that innervate the medial aspect of the forehead and side of the nose, in some patients, travel with the oculosympathetic fibers along the internal carotid artery, and reach that portion of the face by way of the supraorbital artery or nerve (16, 17). Accordingly, injury to the third order sympathetic axons distal to the bifurcation of the common carotid artery leaves facial sweating intact except for small patches of anhidrosis on the forehead and nose.
Within the cavernous sinus, the carotid artery-associated sympathetic fibers join the abducens nerve for a short distance before jumping onto the ophthalmic division of the trigeminal nerve (18) (Fig. 5). The oculosympathetic fibers then travel through the superior orbital fissure with the nasociliary branch of the trigeminal nerve to enter the orbit. Those fibers destined to innervate the dilator muscle pass directly through the ciliary ganglion and travel to the iris between the sclera and the retina, radially and segmentally, as the long ciliary nerves. Other postganglionic sympathetic fibers innervate the upper and lower smooth eyelid retractor muscles of M�ller. The axons of the third order neurons are susceptible to injury by disorders that affect the carotid artery or the cavernous sinus.
Fig. 5 The course of the postganglionic segment of the oculosympathetic fibers from the internal carotid artery (ICA) to the orbit is depicted as a dotted line. Note that they briefly join the abducens nerve (cranial nerve VI) before joining the nasociliary branch of the of the ophthalmic division of the trigeminal nerve (V1) into the orbit. ON, optic nerve; V, trigeminal nerve. (Adapted from Miller NR: Walsh and Hoyt's Clinical Neuro-ophthalmology, p 428. Vol 2, 4th ed. Baltimore: Williams & Wilkins, 1985 with permission.)
Norepinephrine is tonically released from the presynaptic terminal of the postganglionic sympathetic neurons and interacts with an alpha-adrenergic receptor on the iris dilator. Most released norepinephrine undergoes presynaptic reuptake. If the three-neuron oculosympathetic pathway is intact, the tone of the iris dilator at any given moment is determined by the balance between the amount of norepinephrine released and the amount undergoing reuptake. A lesion anywhere along this pathway interrupts the tonic release of norepinephrine and results in a pupil smaller than its normally innervated fellow pupil. Clinically important adrenergic agents that influence the size of the pupil when applied topically are outlined in (Table 2)(13).
TABLE 2. Topical Adrenergic Agents That Influence Pupil Size
Physiological Responses and Properties of the Normal Pupil
Light Reflex and Factors that Influence parasympathetic Tone
Quanta of light absorbed by photoreceptors, both rods and cones, are transformed into electrical impulses that are transmitted through retinal bipolar cells to ganglion cells. The same population of photoreceptors that initiate the process of visual perception are used for the pupillary light reflex, as well. Rods are more sensitive for both functions in the dark adapted state, whereas cones are more sensitive in the light adapted state. Stimulation of the central retina elicits a larger pupil reaction than does stimulation of the peripheral retina for several reasons. The density of cones is greater than rods in this location. There is more of a one-to-one connection of photoreceptors with ganglion cells. The density of ganglion cells is greater in the central retina. As a clinical correlate, damage to the optic nerve that produces central visual field loss impairs the pupillary light reaction more than injury that produces a similar amount of peripheral visual field loss.
The unmyelinated axonal projections of the retinal ganglion cells form the nerve fiber layer of the retina. After proceeding toward the optic disc, the nerve fiber bundles pass though the lamina cribrosa. At that point, they become myelinated and form the optic nerves. Optic nerve fibers projected from the nasal retina of both eyes cross in the chiasm, whereas fibers from the temporal retina do not. In this way, light stimulation of one retina is projected bilaterally beyond the chiasm into the optic tract. The ratio of crossed to uncrossed fibers in each optic tract is roughly 53% to 47% (19), a proportion that is important to understanding the origin of an afferent pupillary defect in lesions affecting this segment of the anterior visual pathway.
Pupillomotor afferent fibers leave the posterior portion of the optic tracts before they synapse within the lateral geniculate nuclei and enter the dorsal midbrain by way of the brachium of the superior colliculus (see Fig. 2). From there, they synapse in the ipsilateral pretectal olivary nuclei (20, 21).
Although it remains pathologically unproved whether the same population of retinal ganglion cells that serves vision also conveys pupillomotor afferent information in humans, clinical observations suggest that such is the case. For example, the degree of impairment of the direct light reaction that occurs following injury to the afferent visual system is generally proportional to the amount of visual field loss associated with such injury (22-24). Conversely, some forms of optic neuropathy, such as recovered optic neuritis, show dissociated abnormalities between standard visual perimetry and pupil perimetry evoked by focal retinal stimulation (25) and have less correlation between the degree of visual field loss and impairment of the direct pupillary light reaction (24). This suggests that there may indeed be different populations of retinal ganglion cells subserving visual and pupillary functions.
The pretectal nuclei from each side send intercalated neurons forward to innervate the ipsilateral Edinger-Westphal nuclei and also send projections across the posterior commissure to the opposite pretectal nuclei (26). Accordingly, afferent pupillomotor input to the midbrain from one optic tract stimulates both Edinger-Westphal nuclear complexes, resulting in contraction of the ipsilateral pupil, the direct response, as well as contraction of the opposite pupil, the consensual response. In this way, bilateral pupil constriction can occur even with complete unilateral optic tract injury. Stimulation by light of the ipsilateral retina produces impulses that arrive in the contralateral midbrain from crossing fibers projecting from the nasal retina. Bilateral pupil constriction then occurs because both Edinger-Westphal nuclei receive pupillomotor input through direct and crossing intercalated pretectal neurons. A lesion of the afferent visual pathway does not produce anisocoria inasmuch as each pupil receives bilateral parasympathetic input.
Although the direct and consensual pupillary responses generally appear equal, some difference can be demonstrated when pupil reactions are measured using high resolution pupillographic techniques. In such experimental settings, the direct response of many healthy individuals is slightly greater than their consensual response, producing a difference in pupil size during unilateral light stimulation referred to as a contraction anisocoria or a consensual deficit. Contraction anisocoria likely results from asymmetric distribution of pupillomotor output from the pretectal olivary nuclei to the Edinger-Westphal nuclei. Under experimental conditions, contraction anisocoria occurs when the nasal retina is stimulated, providing pupillomotor input to the contralateral pretectal olivary nucleus (27). Because the direct pupillary reaction is greater than the consensual reaction, there must be greater outflow from the olivary nuclei to the contralateral Edinger-Westphal nuclei. The size of a contraction anisocoria is so small (on the order of 0.1 to 0.15 mm) that it is not likely to be identified in most clinical settings. However, you should be aware of this phenomenon to avoid the occasional confusion that may arise when carefully inspecting the direct and consensual reactions of patients with both afferent and efferent pupillary defects (28).
The normal pupillary light reflex (Fig. 6). is initiated when light stimulates the neural elements of the retina. A brief latent interval from illumination of the retina to first contraction of the pupil, ranging from around 200 to 500 msec depending on the intensity of the light, reflects the conduction time of the pupillary light reflex (29). As higher intensities of light stimulation are used to elicit the pupillary light reaction, the latency decreases and the absolute amplitude and speed of pupillary contraction increase, up to a certain point, beyond which more robust pupillary contractions do not occur (30). If light stimulation is maintained beyond the initial pupillary contraction, a variable amount of redilation, called pupillary escape, is usually observed. The degree of pupillary escape observed for any one individual is highly variable and is inversely proportional to the intensity of light used to stimulate the retina (29).
Fig. 6 The normal pupillary light reflex is initiated following exposure to light. After a brief latency, both the right (solid line) and left (broken line) pupil constrict, then undergo a small amount of redilation (escape), followed by oscillations (hippus) if the light is sustained. Hippus is not a pathologic sign. (Corbett JJ, Thompson HS: Pupillary function and dysfunction. In Asbury AK, McKhann?
WI [eds.]: Diseases of the Nervous System. Clinical Neurobiology, p 607. Vol 1. Philadelphia: WB Saunders, 1986 with permission.)
In the dark-adapted state, the pupil has a much lower threshold to react in response to the same intensity of light used to stimulate the pupil in a light-adapted environment (31). This physiologic response parallels the sensory experience, as evidenced by the visual dazzle we perceive when a light is turned on in a dark room when we wake in the middle of the night. This phenomenon is important to consider when examining the pupils of a patient wearing a patch over one eye. The light adapted unpatched eye is relatively less sensitive to the effect of direct light than the occluded dark adapted eye when tested just after the patch is removed. The short-lived, relatively impaired direct-light reaction of the unpatched eye in this setting could be mistaken for the afferent pupillary defect associated with optic nerve disease.
The pupillary light reaction varies considerably from individual to individual, and even within the same individual, at different times. This variability is largely due to a combination of supranuclear inhibitory influences on the Edinger-Westphal nuclei associated with, among other factors, emotion and level of alertness, as well as excitatory influences on the iris dilator originating from the hypothalamic oculosympathetic outflow. When humans are awake and alert, the Edinger-Westphal nuclei receive a higher degree of supranuclear inhibitory input, whereas at the same time sympathetic tone is heightened, resulting in relatively large pupils. As people become fatigued and sleepy, inhibition of the Edinger-Westphal nuclei diminishes as does sympathetic tone, resulting in relatively smaller pupils.
Supranuclear factors can influence not only the size of the pupils but also the briskness and degree of the pupillary light reaction. For example, young people who are scared, excited, or anxious tend to have pupils that are larger and exhibit relatively reduced light reaction than the pupils of those who are calm or sedate. Bumke's sign is an archaic eponym referring to pupils that are large, have reduced pupillary unrest, and dilate poorly in response to psychosensory stimuli. This sign is nonspecific, often seen in young anxious individuals, and has no diagnostic importance.
When we shift our gaze from a distant object of interest to one which is closer, three coordinated neurologic events, referred to as near synkinesis, occur to maintain a sharply focused image on our retina: the pupils constrict to improve the depth of field; the ciliary muscle contracts to thicken the lens and allow accommodation; and, the eyes converge due to contraction of the medial rectus muscles to maintain foveation of the close image. The supranuclear pathway for near synkinesis remains largely undefined in humans. Unilateral stimulation of macaque monkey extrastriate cortex in the transition region between the temporal and occipital lobes produces bilateral accommodation and pupillary miosis, along with adduction of the ipsilateral eye, and occasional bilateral convergence movements (32). The centrifugal pathway from the posterior cortex follows a more ventrolateral course in the midbrain to the visceral oculomotor nuclei than does the midbrain pathway of the pupil light reflex. The clinical correlate of this anatomic separation is light-near dissociation, whereby a lesion that injures the dorsal midbrain sufficient to interfere with the pupil light reaction may not impair near-induced pupillary miosis.
The behavior of the pupil serves as an objective measure of the integrity of the near synkinesis. Because the oculomotor subnuclei subserving each component of the near synkinesis are different, the near response of the pupil (i.e., miosis) can occur independently of the integrity of either accommodation or convergence function. For example, a patient with an internuclear ophthalmoplegia whose ability to converge the eyes is markedly impaired should still be able to demonstrate miosis during a valid attempt at performing accommodation or convergence. When all three components of the near synkinesis are impaired, then the patient is either exhibiting poor effort, has some disorder affecting the central nervous system in a diffuse manner so that this cortically driven reflex is disturbed (e.g., toxic-metabolic encephalopathy), or has a disorder interrupting the final common pathway (e.g., botulism).
Spasm of the near reflex, conversely, is an example of a syndrome in which intermittent overaction of all three components of the near synkinesis occurs. Because near synkinesis is under conscious control, this disorder is usually considered functional in nature. More rarely, however, it has been described in patients with organic disorders, including head trauma, tumors, or inflammatory lesions of the posterior fossa (33, 34).
Dark Response and Factors that Influence Sympathetic Tone
When ambient light is reduced or abolished, both pupils dilate. In large part this results from active contraction of the iris dilator muscle mediated by the hypothalamic descending oculosympathetic pathway. A sympathetically mediated response cannot fully account for the dark reaction because a patient with a unilateral oculosympathetic defect will still demonstrate dark-induced mydriasis in that eye, although at a rate that is significantly slower than the rate that the opposite pupil dilates. This dilation lag is an important clinical sign associated with Horner's syndrome (35).
Active inhibition of the Edinger-Westphal nuclei during sudden darkness may also contribute to pupillary dilation in this setting (36). Supranuclear inhibition of the Edinger-Westphal nuclei also contributes to the reflex dilation of the pupil that occurs in association with arousal.
The tone of the iris dilator is actively influenced by factors related to the general sympathetic state of an individual. A state of arousal and heightened alertness enhance the activity of the hypothalamic sympathetic outflow. Any psychosensory stimulus, such as a sudden loud noise or pain, causes immediate reflex dilation of the pupil through the descending oculosympathetic pathway. The release of catecholamines from the adrenal gland also causes mydriasis, although these circulating hormones take several seconds to reach their effector organ and, hence, dilate the pupil more slowly than the more immediate response associated with stimulation of the direct oculosympathetic pathway.
Relationship Between Pupil Size and Age AND SIMPLE ANISOCORIA
The average pupil diameter of a term newborn infant is 3.6 mm, roughly 2 mm smaller than that of a young child. The smaller size of the newborn's pupil is due, in large part, to their sleepy existence throughout most of the day and the immaturity of their globe.
Their pupil reacts briskly in response to light stimulation (37).
The pupil progressively increases in size during the first two decades of life and thereafter gradually becomes smaller with increasing age (38, 39) (Fig. 7). The light reaction of some elderly patients with small, but otherwise normal, pupils may be reduced in amplitude compared with the light reaction of most younger individuals who generally have larger pupils. This observation results, in large part, from the physiologic principle that larger pupils constrict more than smaller pupils in response to the same degree of light stimulation as a result of mechanical limitations of the iris itself (7). In addition, however, the light reaction of elderly patients older than around 60 years of age may also appear slower than the reactions of younger patients. Loewenfeld (38) has convincingly argued that the changes of pupil size and reactivity that occur with age are best explained on the basis of progressive impairment of central inhibition of the Edinger-Westphal nuclei.
Fig. 7 Relationship between age and pupil size, determined using an infrared flash photograph technique with subjects placed in darkness for 3 minutes. The numbers above the abscissa indicate the number of subjects tested in each age range. (Reprinted with permission of Loewenfeld IE: "Simple, central" anisocoria: A common condition, seldom recognized. Trans Am Acad Ophthalmol, American Academy of Ophthalmology, San Francisco, 1977;82:832-839.)
Physiologic Anisocoria (Simple Anisocoria )
The ubiquitous phrase, "pupils equal, round, and reactive to light and accommodation (PERRLA)", rarely describes an accurate observation and is not consistent with the known high frequency of anisocoria in the population in general. Indeed, roughly 20% of patients at any given moment have a difference in pupil size of 0.4 mm or greater, an anisocoria readily identifiable with careful observation (40). Lam and colleagues (41) demonstrated that around twice that many healthy subjects have this degree of anisocoria at one time or another when serially examined twice daily for 5 consecutive days. Smaller degrees of anisocoria occur proportionately more frequently. If the light, near, and dark reactions of such pupils are otherwise normal, then that sign is referred to as simple, essential, or physiologic anisocoria.
Physiologic anisocoria often decreases with bright light and increases slightly in dim light or darkness, or during conditions that favor large pupils (e.g., pain or emotional excitement) (42). However, the difference in pupil size only rarely exceeds 0.8 mm in diameter (40, 43). The degree of anisocoria characteristically varies from examination to examination and may even alternate depending on which side the larger pupil is observed. Such variability has lead to a confusing and meaningless set of terms to describe such changes, including "springing" or "alternating anisocoria", and "see-saw mydriasis" (40). Although the physiologic substrate for simple anisocoria has not been fully defined, Lowenfeld (40) considers it a sign of asymmetric supranuclear inhibitory influence on the oculomotor visceral nuclei.
Physiologic anisocoria does not cause symptoms and is often identified when some other unrelated ocular symptom, most commonly blurred vision or pain, draws the patient's or physician's attention to examine the eyes with greater scrutiny than might otherwise occur. In that setting, a physician may be concerned that the larger pupil reflects an intracranial process affecting the oculomotor nerve, or that the smaller pupil is a sign of Horner's syndrome. When the diagnosis of physiologic anisocoria is confidently established by finding normal light, near, and dark reactions of the pupil, then no further evaluations are necessary. Inspection of all available photographs (e.g., driver's license) that might demonstrate pupil sizes can help establish how long the anisocoria has been present.
Physiologic anisocoria only rarely is as large as the anisocoria associated with Horner's syndrome. Unlike the affected pupil of Horner's syndrome, however, the smaller pupil of simple anisocoria does not have dilation lag nor does it fail to dilate in response to topical cocaine. When uncertainty exists concerning the presence of Horner's syndrome, which may be problematic in a patient with an exaggerated simple anisocoria or one with unrelated ipsilateral ptosis (e.g., levator disinsertion), I advocate using topical cocaine to resolve the issue.
Some normal subjects develop anisocoria only in lateral gaze, whereby the pupil in the abducted eye becomes larger and the pupil in the adducted eye becomes smaller. This uncommon physiologic sign is referred to as Tournay's phenomenon, to acknowledge the French neurologist who brought this to the attention of the medical community in 1917. Although the mechanism of Tournay's phenomenon is unknown, this sign is usually unrecognized clinically and has no certain diagnostic significance (44).
Pupillary Unrest and Hippus
The size of the pupils is in a constant state of flux determined mainly by the moment-to-moment balance of parasympathetic and sympathetic input to the iris muscles. Superimposed on this steady state of physiologic pupillary unrest are more rhythmic pupillary oscillations referred to as hippus, derived from the Greek word hippos, a horse (45). These oscillations vary in amplitude, but are typically around 0.5 mm in diameter and often visible to the examiner without the aid of magnification or recording devices, especially in young patients. Both pupils oscillate in synchrony regardless of whether one or both pupils are stimulated by light, implicating the central nervous system as the source generator of these physiologic pupillary movements.
Hippus is greatest in bright light and continues indefinitely when this condition is sustained (Fig. 8, see Fig. 6). With dim light, the amplitude and frequency of the oscillations gradually decrease. In darkness, the oscillations disappear (30). The amplitude and frequency of the oscillations are greater in a fatigued or drowsy subject and dampened when that subject is excited or alert (31, 46).
Fig. 8 Pupillogram of a healthy young subject showing continuous pupillary oscillations of both pupils when light is sustained, indicated by the dark arrow at the top of the recording. Note that the oscillations of the pupils are synchronous and demonstrate variable amplitude and frequency. This pattern of continuous irregular pupillary oscillations is normal. When light stimulation stops, hippus resolves. (Lowenstein O, Loewenfeld IE. Influence of retinal adaptation upon the pupillary reflex to light in normal man. Part I. Effect of adaptation to bright light on the pupillary threshold. Am J Ophthalmol 1959;48:536-549, Ophthalmic Publishing Company with permission).