Pupillary disorders usually fall into one of three major categories: (1) abnormally shaped pupils, (2) abnormal pupillary reaction to light, or (3) unequally sized pupils (anisocoria). Occasionally pupillary abnormalities are isolated findings, but in many cases they are manifestations of more serious intracranial pathology.
The pupillary examination is discussed in detail in Chapter 2 . Pupillary neuroanatomy and physiology are reviewed here, and then the various pupillary disorders, grouped roughly into one of the three listed categories, are discussed.
Neuroanatomy and Physiology
The major functions of the pupil are to vary the quantity of light reaching the retina, to minimize the spherical aberrations of the peripheral cornea and lens, and to increase the depth of field (the depth within which objects will appear sharp). In most individuals the two pupils are equal in size, and each is situated slightly nasal and inferior to the center of the cornea and iris ( Fig. 13.1 ).
The iris contains the two muscles that control the size of the pupil. Contraction of the dilator muscle leads to pupillary enlargement (mydriasis), while sphincter muscle contraction causes pupillary constriction (miosis). The sphincter muscle wraps 360 degrees around the pupillary margin, and the dilator muscle similarly encircles the pupil but is more peripherally located.
Normally, light directed at either eye leads to bilateral pupillary constriction, and this pupillary light reflex is mediated by a parasympathetic pathway (see Fig. 13.2 for details). Light entering the eye causes retinal photoreceptors to hyperpolarize, in turn causing activation of retinal interneurons and ultimately the retinal ganglion cells. Additionally, intrinsically photosensitive retinal ganglion cells (ipRGCs) containing melanopsin, a photopigment, can be activated by light without photoreceptor input. The ipRGCs are most sensitive to blue light, and the preservation of circadian rhythms and the pupillary light reflexes in patients with severe photoreceptor diseases and Leber’s hereditary optic neuropathy can be explained by intact ipRGC function.
Retinal ganglion cell axons activated by photoreceptors and ipRGCs together mediate the pupillary light reflex and travel through the optic nerve, chiasm, and optic tract to reach the pretectal nuclei (afferent arc). Interneurons then connect the pretectal nuclei to the Edinger–Westphal nuclei. Although these connections are bilateral, the input into the Edinger–Westphal nuclei is predominantly from the contralateral pretectal nucleus. Since the afferent pupillary fibers leave the optic tract before the lateral geniculate nucleus, isolated lesions of the geniculate, optic radiations, and visual cortex generally do not affect pupillary size or reactivity. Efferent parasympathetic fibers, arising from the Edinger–Westphal nucleus, exit the midbrain within the third nerve (efferent arc). Within the subarachnoid portion of the third nerve, pupillary fibers tend to run on the external surface, making them more vulnerable to compression or infiltration and less susceptible to vascular insult. Within the anterior cavernous sinus, the third nerve divides into two portions. The pupillary fibers follow the inferior division into the orbit, where they then synapse at the ciliary ganglion, which lies in the posterior part of the orbit between the optic nerve and lateral rectus muscle ( Fig. 13.3 ). The ciliary ganglion issues postganglionic cholinergic short ciliary nerves, which initially travel to the globe with the nerve to the inferior oblique muscle, then between the sclera and choroid, to innervate the ciliary body and iris sphincter muscle. Fibers to the ciliary body outnumber those to the iris sphincter muscle by 30 : 1.
The near response consists of pupillary constriction, accommodation (change in the shape of the lens), and convergence of the eyes (see Chapter 2 ). Although the pathways are uncertain, the supranuclear control for the near response likely arises from diffuse cortical locations. Stimulation of the peristriate cortex (areas 19 and 22) in primates can evoke a near response, but more recent evidence suggests the lateral suprasylvian area is also related to the control of lens accommodation. The signals converge in the rostral superior colliculus, near which a group of midbrain near-response neurons coordinates the pretectum for accommodation and miosis, the mesencephalic reticular formation for accommodation and vergence, and the raphe interpositus for visual fixation. The final signal for pupillary miosis during near viewing is still mediated by the Edinger–Westphal nuclei.
Pupillary dilation is the function of the oculosympathetic system (the ocular part of the sympathetic nervous system), which consists of three neurons beginning in the posterolateral hypothalamus and ending at the iris and eyelids (see Fig. 13.4 for details). The first-order neuron projects from the hypothalamus through ill-defined brainstem pathways to synapse on the intermediolateral cell column in the spinal cord at C8–T2 (ciliospinal center of Budge). The second-order neuron (preganglionic) leaves the spinal cord and travels over the apex of the lung before ascending with the internal carotid artery to synapse at the superior cervical ganglion. In the region of the lung apex, the sympathetic pathway lies in close proximity to the lower brachial plexus. The third-order neuron (postganglionic) travels along the internal carotid into the cavernous sinus, after which the sympathetic pathways follow the sixth nerve, then the nasociliary nerve (a branch of the first division of the trigeminal nerve), then the long ciliary nerve into the orbit. This neuron releases the neurotransmitter norepinephrine at the iris dilator muscle.
Pharmacologic Testing of the Pupils
As will be discussed, pharmacologic testing helps confirm the clinical diagnosis of many pupillary abnormalities. Some general guidelines need to be followed in this regard. By disrupting the corneal epithelium, corneal reflex evaluation and applanation or pneumotonometry may alter corneal permeability of the drug and therefore should not be performed on the same day as pharmacologic testing. In general, the drops should be instilled in the inferior cul-de-sac, with care taken to use the same size drop in each eye. Drop administration should be repeated 1–5 minutes later. The pupil sizes then can be measured 30–45 minutes after instillation of the last set of drops. Baseline and test pupillary sizes are best measured in the same lighting conditions, and photographic documentation before and after testing can be helpful.
Pupillometry: an Additional Tool
Pupillometry, the computerized measurement of pupillary responses to light stimulation, can be used to characterize relative afferent pupillary defects (RAPDs) objectively in patients with or without vision loss. In addition, pupillometry has been used in the intensive care setting to document abnormalities in pupillary reactivity related to increases in intracranial pressure in patients with traumatic brain injury.
Abnormally Shaped Pupils
Irregularly shaped pupils may be congenital or acquired ( Box 13.1 ). Congenital conditions include the following:
Aniridia, in which the iris is hypoplastic, creating a large pupillary opening. Associated ocular findings often include cataracts, glaucoma, and impaired vision due to macular or optic nerve hypoplasia. Patients with aniridia, genitourinary anomalies, mental retardation, and a defect in the PAX6 gene on chromosome 11p13 are predisposed to Wilms’ tumor.
Ectopia lentis et pupillae, a rare heritable condition limited to the eyes in which lens dislocations may be associated with oval, ellipsoid, or slitlike displaced pupils.
An iris coloboma is an inferior or infranasal notch in the iris ( Fig. 13.5 ). This anomaly may be accompanied by chorioretinal or optic nerve colobomas, which like the iris abnormality are defects in closure of the embryonic fissure. Colobomas may occur in isolation in healthy individuals or in patients with chromosomal duplication or deletions. They may also be seen in complex congenital disorders such as CHARGE syndrome (C, coloboma; H, heart disease; A, atresia or stenosis of the choanae; R, retarded growth and development or central nervous system anomalies; G, genital hypoplasia; and E, ear anomalies or deafness).
Anterior chamber cleavage anomalies, such as Peters (central corneal defects) or Rieger syndrome (peripheral corneal defects), also may be associated with misshapen pupils accompanied by abnormal adhesions between the cornea and iris.
Ectopic pupils (misplaced—also called corectopia ) may be inherited as an isolated ocular finding. Patients with these anomalies may require further genetic evaluation. An idiopathic tractional corectopia, in which a fibrous structure tethers the pupillary margin to the peripheral cornea and causes a misplaced pupil, has also been described.
Persistent pupillary membranes may cause spokelike opacities across the pupil. These derive from persistence of the tunica vasculosa lentis, which supplies blood to the developing crystalline lens and normally disappears by the 34th week of gestation.
Ectopia lentis et pupillae
Anterior chamber cleavage anomalies
Persistent pupillary membranes
Iridocorneal endothelial syndrome
Trauma (accidental or surgical)
Iris atrophy (e.g., diabetes, herpetic disease)
Neurologic (e.g., tonic pupils, midbrain damage (corectopia), tadpole-shaped pupils)
Acquired causes of abnormally shaped pupils include the following:
Iritis, inflammation of the iris, may lead to adhesions between the iris and lens (posterior synechiae) and cause pupillary distortion ( Fig. 13.6A ).
Trauma may result in an iris tear or rupture of the iris sphincter. The ocular trauma may be accidental ( Fig. 13.6B ), or the iris may be damaged during anterior segment surgery.
Iridocorneal endothelial syndrome (ICE) usually affects young woman and may result in a pupil with segmental reaction mimicking a tonic pupil. The patient usually has characteristic focal corneal endothelial layer irregularity and glaucoma, but the iris changes may predominate the examination.
Neurologic conditions such as tonic pupils; neurosyphilis; severe damage to the midbrain, which can rarely cause pupillary corectopia ( Fig. 13.7 ); tadpole-shaped pupils; and other processes (e.g., herniation) associated with coma. These entities are all described in more detail later.
Defective Pupillary Light Reaction Associated With Vision Loss
In these cases the direct pupillary reaction to light is abnormal because of a disturbance within the afferent arc of the pupillary light reflex. In most such instances, there is associated visual loss.
Relative Afferent Pupillary Defect
The swinging flashlight test and the detection and grading of RAPDs are discussed in Chapter 2 . Abnormal visual acuity and color vision, a central scotoma, and an RAPD collectively are highly suggestive of an optic neuropathy, although a large macular or other retinal lesion could produce similar findings. In bilateral optic nerve disease, an RAPD may not be present unless the visual loss is asymmetric. An individual with severe unilateral visual loss, no RAPD, and a normal ocular examination may have nonorganic visual loss. An RAPD is not associated with visual loss due to corneal, lens, and vitreous opacities and refractive errors, but a densely amblyopic eye may have a mild RAPD. Nevertheless, an amblyopic eye with an RAPD generally requires further investigation to exclude an acquired optic neuropathy. When anisocoria is present, care should be taken to avoid overcalling an RAPD. In this setting, a false RAPD can be seen on the side of the smaller pupil as less light enters this eye than the fellow eye.
Asymmetric chiasmal syndromes may be associated with an RAPD, especially if an eye has subnormal visual acuity. Isolated optic tract lesions may have a contralateral RAPD, despite normal visual acuities, because the defective temporal field in the contralateral eye is 61–71% larger than the nasal field of the ipsilateral eye, the nasal retina has a greater photoreceptor density, and the ratio of crossed to uncrossed fibers in the chiasm is 53 : 47. The magnitude of the RAPD in this setting may reflect the relative light sensitivity of the intact temporal versus nasal field. Less commonly, when an optic tract disturbance is associated with an incongruous homonymous hemianopia with greater involvement of the nasal field, the RAPD will be in the eye ipsilateral to the lesion. Behr’s pupil (a large contralateral pupil) and Wernicke’s hemianopic pupil, one which reacts more briskly to light projected from within the intact hemifield than to light within the abnormal field, have been associated with optic tract syndromes. However, in clinical practice they are rarely identified, and the reliability of both signs has been questioned. RAPDs in patients with hemianopias due to retrogeniculate lesions have been reported, but in those cases concomitant optic tract involvement was not convincingly excluded.
Exceptional cases of RAPDs without visual loss can be associated with lesions in the midbrain pretectum, which contains afferent pupillary fibers and the pretectal nuclei, but no visual fibers ( Fig. 13.8 ). Due to more contralateral nasal than ipsilateral temporal fiber involvement of the afferent pathway as in an optic tract lesion, the RAPD is usually contralateral to the lesion. Most of these patients have other signs of dorsal midbrain involvement, such as upgaze paresis, ataxia, or fourth nerve dysfunction.
Pupillometry studies have demonstrated that some individuals with normal visual function can have subtle RAPDs which may fluctuate (up to 0.3 log units) when tested over years. Whether the RAPDs were due to test artifact or were reflective of asymmetry in the visual pathways was unclear.
Amaurotic (Deafferented) Pupil
In the absence of any optic nerve or retinal function, or both, the eye is completely blind (i.e., has no light perception (NLP)), and the pupil will be unreactive to even the brightest direct light stimuli because it is deafferented. If the fellow eye is normal and light is directed at it, the pupillary reaction in the affected eye (consensual) should be intact. An amaurotic pupil confirms blindness if the patient claims not to see anything out of that eye. However, if the pupil reacts to direct light in an eye with purported blindness, the visual loss is either nonorganic or has a cortical basis or the patient is a poor observer. In certain conditions such as Leber’s hereditary optic neuropathy there may be a mismatch with relatively preserved pupillary reaction due to intact ipRGC function and very poor vision. Bilateral deafferentiation will result in an increase in the resting size of both pupils, as less total light is able to reach the midbrain pretectum.
Deafferented pupils can also react during attempted viewing of near targets and thus exhibit light-near dissociation ( Table 13.1 ). Even individuals who are bilaterally blind can attempt to look at their thumb placed a few inches in front of their face and stimulate the near reflex, as this task can be accomplished using proprioceptive clues.
|Deafferentation||Associated visual loss|
|Tonic pupil||Tonic redilation; denervation hypersensitivity (see Box 13.2 )|
|Tectal lesions (Parinaud syndrome)||Associated upgaze paresis|
|Argyll Robertson pupils||Small; no pupillary response to direct or consensual light stimulation|
|Aberrant regeneration of the third nerve||Miosis during adduction; other signs of third nerve paresis|
|Diabetes||Irregularly shaped pupil; history of retinal photocoagulation; other evidence of autonomic neuropathy|
Defective Pupillary Light Reaction Unassociated With Vision Loss
Defective pupillary light reactivity in most of these cases is related to dysfunction within the efferent arc of the pupillary light reflex. Lesions in the midbrain pretectum may also cause similar dysfunction. The major causes of this pupillary abnormality are highlighted in Table 13.2 . A dilated pupil accompanied by eye movement or eyelid abnormalities suggests a lesion proximal to the ciliary ganglion (preganglionic), while an isolated dilated pupil would be more likely associated with a postganglionic process.
|Dorsal midbrain||Tectal pupil (Parinaud syndrome)|
|Argyll Robertson pupil|
|Third nerve||Third nerve palsy|
|Ciliary ganglion||Tonic pupil (e.g., Adie syndrome)|
|Miller Fisher syndrome|
Lesions affecting the dorsal midbrain, causing the pretectal, or Parinaud, syndrome (see Chapter 16 ), may interfere with pupillary reactivity by disrupting ganglion cell axons entering the pretectal region. The pretectal nuclei may also be involved. Bilaterally the pupils may be midposition to large and exhibit light-near dissociation due to intact supranuclear influences upon midbrain accommodative centers ( Fig. 13.9 , ). Usually both pupils are involved, although size and light reactivity may be asymmetric. Occasionally the near response may also be defective, as accommodative and convergence insufficiency can be observed. The diagnosis is suggested when other features of Parinaud syndrome, such as upgaze paresis, convergence retraction saccades, and eyelid retraction, are evident. Common causes include pineal region tumors and hydrocephalus, so abnormal pupils suggestive of a tectal lesion mandate neuroimaging.
Argyll Robertson Pupils
Argyll Robertson pupils also exhibit light-near dissociation with a brisk constriction during near viewing but typically are miotic, are slightly irregular, and dilate poorly in the dark ( Fig. 13.10 ). The pupil does not react to light regardless of which eye is stimulated. Technically, to have an Argyll Robertson pupil, the involved eye must have some vision, to ensure the light-near dissociation is not due to a deafferented pupil. This pupillary abnormality is highly suggestive of syphilis and should therefore prompt serologic and fluorescent treponemal antibody absorption (FTA-ABS) testing. However, it is nonspecific and may also be caused by diabetes. The lesion responsible for Argyll Robertson pupils is uncertain but may result either from a disturbance in the midbrain light-reflex pathway between the pretectal and Edinger–Westphal nuclei or from damage to the ciliary ganglia.
Third Nerve Palsy
Because the third nerve carries parasympathetic fibers originating from the Edinger–Westphal nuclei, injury to the third nerve often results in an ipsilateral poorly reactive or unreactive pupil.
Signs and symptoms. In a pupil-involving third nerve palsy, the pupil is large and does not constrict to light, either directly or consensually, or during near viewing (internal ophthalmoplegia) ( Fig. 13.11 ). Usually either ptosis or a deficit in adduction, depression, or elevation of the eye, or a combination of these findings (external ophthalmoplegia), will assist in the diagnosis of a third nerve palsy, but in very rare instances a dilated pupil is the only manifestation. In inferior division third nerve palsies, the pupil and inferior rectus muscles are involved. In a pupil-sparing third nerve palsy, the eye movements or lid are affected, but the pupil retains normal size and reactivity.
Because a dilated pupil exposes spherical aberrations of the lens and cornea, some patients with pupil-involving third nerve palsies complain of blurry vision in that eye. Because this is a refractive problem, a pinhole occluder resolves the visual symptom. Abnormal miosis during attempted ocular adduction or depression may be a sign of aberrant regeneration (synkinesis or misdirection) following a third nerve palsy ( Fig. 13.12 and ). The phenomenon results when fibers that had previously supplied the medial rectus or inferior rectus regenerate and accidentally reach the ciliary ganglion, then connect with postganglionic neurons, which innervate the pupil. In these situations the pupil does not react to direct or consensual light stimulation but contracts during ocular adduction or depression. Segmental contraction of the iris sphincter during eye movements (Czarnecki’s sign ) may also be observed in these instances. Furthermore, because postganglionic accommodative fibers far outnumber those dedicated to the pupillary light reflex (see Tonic Pupils ), pupillary miosis during near viewing is more likely to recover than constriction to direct light (light-near dissociation). These pupillary signs are sometimes accompanied by other manifestations of aberrant regeneration of the third nerve, such as elevation of the ptotic eyelid during adduction or depression of the eye.
Etiology . Pupil involvement is commonly seen in nuclear, fascicular, and especially subarachnoid third nerve palsies. As alluded to earlier, the external location of the pupillary fibers of the third nerve renders them particularly vulnerable to compression and infiltration in subarachnoid processes such as meningitis, aneurysmal compression (posterior communicating or internal carotid), and uncal herniation (Hutchinson’s pupil). Pupil-sparing third nerve palsies in middle-aged to elderly patients are usually related to diabetes or hypertension but occasionally can be seen even in fascicular or subarachnoid third nerve palsies from other causes. However, an aneurysm that presents initially with external ophthalmoparesis or ptosis alone typically will involve the pupil within several days.
Aberrant regeneration most commonly occurs in traumatic or compressive third nerve palsies, sometimes with congenital or tumor-related third nerve palsies, but almost never in diabetic or hypertensive third nerve palsies.
Pharmacologic testing . A chronically dilated pupil due to a third nerve palsy may be difficult to distinguish from a tonic pupil (see later discussion). Although the latter redilates slowly after constriction, both may exhibit light-near dissociation, segmental paresis of the iris sphincter, and denervation hypersensitivity. The last characteristic, demonstrated by pupillary constriction following instillation of dilute (0.125%) pilocarpine eye drops, does not seem to depend on whether the lesion is anatomically before or after the ciliary ganglion (i.e., preganglionic or postganglionic), or whether there is aberrant regeneration. Jacobson has offered the following explanations for denervation hypersensitivity in preganglionic third nerve lesions: (1) transsynaptic degeneration of postganglionic axons; (2) the greater sensitivity of larger pupils than smaller ones to dilute pilocarpine; and (3) upregulation of acetylcholine receptors because of decreased cholinergic stimulation following third nerve injury. Denervation hypersensitivity in acute pupil-involving third nerve palsies, due to unclear mechanisms, is less common but has been observed.
Management . If the patient has isolated pupillary dilation along with other signs of a third nerve palsy, an aneurysm of the posterior communicating artery should be considered until proven otherwise. To minimize risk and to screen for other possible compressive lesions, noninvasive angiography as well as routine brain imaging should be performed first. Either an emergent computed tomography (CT) and CT angiography or magnetic resonance imaging (MRI) and MRI angiography can be obtained. The choice of CT or MRI depends on which is more rapidly available, whether the patient is allergic to CT contrast, and whether MRI is contraindicated because of a pacemaker or metal in the body. If the scans are negative, conventional angiography may still be necessary as small symptomatic aneurysms can still be missed by CT or MRI angiography. Although CT angiography is emerging as a noninvasive technique for identification of posterior communicating artery aneurysms, the importance of the training and experience of the radiologist interpreting these studies is a critical component. Whether a catheter angiogram should be obtained in the setting of a negative MRI or CT angiogram continues to be a matter of debate and relies heavily on the correct performance and interpretation of the noninvasive study. CT angiography and subsequent catheter angiography can also demonstrate changes in aneurysm morphology occurring between studies, including sudden expansion leading to the acute appearance of a pupil-involving third nerve palsy.
The reader is referred to a more detailed discussion regarding the differential diagnosis and management of third nerve palsies, in addition to issues regarding pupil-involving versus pupil-sparing third nerve palsies and aberrant regeneration, in Chapter 15 .
Clinical symptoms and signs (see Box 13.2 ). Patients with a tonic pupil often discover that they have a unilateral, partially dilated pupil while looking in the mirror, or a friend notices the pupillary inequality. Affected individuals are usually otherwise healthy and more commonly female. They may be symptomatic with photophobia or difficulty reading with that eye. In general, the disorder is painless, although occasionally patients will complain of a cramping sensation in the affected eye from ciliary body spasm.
Anisocoria noticed by the patient or others
Difficulty refocusing from near to far stimuli
More common in women
Initially large in size, but in chronic cases can become more miotic
Light-near dissociation (sometimes miosis during near viewing is also lost acutely)
Anisocoria worse in the dark (when unilateral)
Vermiform movements of the iris
Loss of pupillary ruff
Depressed corneal sensation
Bilateral in 10% of cases
Denervation sensitivity, demonstrated by pupillary constriction following instillation of dilute (0.125%) pilocarpine
Characteristically the pupil is initially large, exhibits light-near dissociation ( Fig. 13.13 ), and redilates slowly after constriction after near fixation (hence the term “tonic”). In some patients, especially in early cases, the near response may also be defective, or the individual may have difficulty refixing from near to far visual targets (“tonic” accommodation). Corneal sensation may be depressed. On a slit-lamp examination, the pupil may be irregular, with sectoral paralysis (immobility of parts of the pupil during light stimulation), vermiform movements, and loss of pupillary ruff (the normal border of the pupil). After 1 or 2 months, a tonic pupil may become miotic and smaller than the fellow pupil. In most patients the disorder is unilateral, but in about 10% of cases, the other pupil may become involved months or years later.
Pathophysiology . The pupillary abnormality results from damage to the ciliary ganglion or the postganglionic short ciliary nerves (see Fig. 13.3 ), which innervate the pupillary sphincter and ciliary muscles (the latter is important for accommodation). Partial preservation of the pupil’s parasympathetic innervation results in areas of segmental contraction adjacent to sector paralysis. When normal portions of the pupil contract, they pull and twist paralyzed segments towards them. Accommodation paresis accounts for the difficulty with near vision, and the photophobia results from the poor pupillary constriction to light. The light-near dissociation can be explained by the 30 : 1 ratio of accommodative fibers arising from the ciliary ganglion relative to those responsible for pupillary constriction. Hence damage to the ciliary ganglion or short ciliary nerves would have a greater chance of disabling pupillary constriction to light than disrupting miosis during near viewing. Furthermore, as neuronal cell bodies in the ciliary ganglion sprout new axons following injury, postganglionic accommodative fibers may mistakenly reinnervate the iris sphincter. This misdirection results in excess pupillary constriction during accommodation.
Etiology . The causes of tonic pupils fall into four major groups:
Adie (or Holmes Adie) syndrome, which is a symptom complex consisting of tonic pupil(s) and absent deep tendon reflexes. The cause has yet to be elucidated, but the disorder may be explained by concurrent involvement of the ciliary and dorsal root ganglia or root entry zone.
Local ocular processes that affect the ciliary ganglion or short ciliary nerves, such as eye or orbital trauma, sarcoidosis, or viral illnesses (e.g., varicella), or ischemia (e.g., giant cell arteritis, other vasculitides, or strabismus surgery). Orbital tumors have also been reported in association with tonic pupils ( Fig. 13.14 ). Panretinal photocoagulation (laser) in patients with proliferative diabetic retinopathy may damage the ciliary nerves underlying the retina. The resultant pupil is typically irregularly shaped and poorly reactive to light ( Fig. 13.15 ). Other factors contributing to a poorly reactive pupil in diabetics can include iris ischemia, iris neovascularization, and associated autonomic neuropathy.
Reflecting autonomic dysfunction, tonic pupils uncommonly may occur in association with neurosyphilis, advanced diabetes mellitus, dysautonomias (e.g., Shy–Drager and Riley–Day syndromes), amyloidosis, Guillain–Barré syndrome, Miller Fisher variant (see below), Charcot–Marie–Tooth and Dejerine–Sottas neuropathies, Lambert–Eaton myasthenic syndrome, and paraneoplastic syndromes. Patients with tonic pupils associated with congenital neuroblastoma, Hirschsprung disease, and central hypoventilation syndrome have also been described.
Idiopathic tonic pupils. Either unilateral or bilateral, these tonic pupils are unassociated with absent deep tendon reflexes, midbrain or orbital lesions, or systemic disorders.
Ross and harlequin syndromes are two rare focal dysautonomias frequently associated with pupillary abnormalities. Ross syndrome is characterized by the triad of tonic pupil, hyporeflexia, and segmental anhidrosis. It is probably related to injury to sympathetic and parasympathetic ganglion cells or their postganglionic projections and rarely can be associated with Horner syndrome. In contrast, harlequin syndrome, in which only half the face flushes or sweats, is more frequently characterized either by normal pupils or oculosympathetic paresis. However, in some instances tonic pupils and areflexia can occur.
Pharmacologic testing . Because of iris sphincter denervation cholinergic hypersensitivity, chronically tonic pupils will constrict following administration of dilute (0.125%) pilocarpine ( Fig. 13.13 ). Pilocarpine is a cholinergic substance that can act directly on the iris sphincter muscle at higher concentrations. However, normal pupils typically have little or no response to dilute pilocarpine. The test should be considered positive when the pupil in question constricts more than the fellow pupil (assuming the fellow pupil is normal). The solution can be premixed or made readily by combining 0.1 ml of 1% pilocarpine with 0.7 ml of sterile saline in a 1-ml tuberculin syringe. With the needle removed, the syringe can be used as a dropper, with care taken to administer the same size drops into each eye. More dilute concentrations of pilocarpine, such as 0.0625%, can be used to reduce the chance of a false-positive result.
Some caution is also necessary in interpreting the dilute pilocarpine test since some patients with preganglionic parasympathetic dysfunction (see previous discussion) will also respond to dilute pilocarpine.
Management . The presence or absence of deep tendon reflexes should be noted. The ocular motility and orbital examination should be done carefully to exclude any evidence of a third nerve palsy or orbital tumor.
Since tonic pupils may be a manifestation of neurosyphilis, FTA-ABS or microhemagglutination assay– Treponema pallidum (MHA-TP) testing should be obtained in those patients without a defined cause for their dilated pupil. In an elderly patient with a new-onset tonic pupil we would suggest obtaining an erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to screen for giant cell arteritis. No further laboratory workup is indicated, as tonic pupils otherwise usually have a benign cause.
Symptomatic treatment is sometimes helpful. Refractive correction may be prescribed for reading in those with accommodative insufficiency, for instance. Rarely, some patients find the anisocoria bothersome cosmetically, and these individuals might find pupil-forming contact lenses or dilute pilocarpine helpful. Dilute pilocarpine may also aid accommodation, and in addition may relieve photophobia. However, some patients find the induced pupillary miosis intolerably painful. Darkened lenses may aid photophobia.
Pharmacologically Dilated Pupils
Pupils dilated surreptitiously or as part of an ophthalmic evaluation with anticholinergic agents such as atropine, tropicamide, or cyclopentolate or sympathomimetic agents such as phenylephrine are generally large (>7–8 mm) and do not constrict to light stimulation or during near viewing. Pharmacologically dilated pupils can also occur accidentally in an individual who has contact with atropine-like drugs; a scopolamine patch; ipratropium ; or plants such as jimson weed (“corn picker’s pupil”), blue nightshade, or Angel’s Trumpet who then touches his or her eye or if a nasal vasoconstrictor sprays get into the eye. Other patients may consciously place mydriatic solutions in their eye as part of a functional illness (Munchausen syndrome, for example). In many cases the actual cause of the pharmacologic dilation cannot be identified despite careful review of the patient’s history. Pupils that are overly generous and unreactive but appear normal on slit-lamp examination should suggest pharmacologic dilation, because third nerve–related and tonic pupils tend to be smaller. In addition, unlike tonic pupils, pharmacologically dilated pupils do not constrict during near viewing. The lack of ptosis or ophthalmoplegia would exclude a third nerve palsy.
Pharmacologic testing . One percent pilocarpine drops will fail to constrict pharmacologically dilated pupils (examined after 30 minutes), because the postsynaptic receptors have been blocked. However, 1% pilocarpine would be effective in normal pupils, third nerve–related mydriasis, tonic pupils, and other preganglionic and postganglionic parasympathetic disorders, because in these cases the receptors at the iris constrictor muscle are either normal or hypersensitive. This test should be applied with caution, as pupils that are dilated due to traumatic iridoplegia and acute narrow-angle glaucoma would also fail to constrict with 1% pilocarpine (see later discussion). The 1% pilocarpine test should also be interpreted carefully if it is performed near the termination of pharmacologic blockade, since the affected pupil may constrict.
Neuromuscular Junction Blockade
Patients with botulism, who have defective release of acetylcholine, can develop bilaterally dilated pupils and accommodative paresis with varying degrees of ptosis and ophthalmoparesis. The eye findings are often accompanied by bulbar or generalized weakness. In general, the pupils are unaffected in myasthenia gravis, which affects nicotinic and not muscarinic cholinergic synapses. Both botulism and myasthenia gravis are discussed in more detail in Chapter 14 .
Ocular Causes of Unreactive Pupils
The clinical history or slit-lamp examination may suggest the following conditions. Depending on disease severity, the pupillary constriction with 1% pilocarpine may be defective.
Ocular trauma. Following trauma to the eye, the pupil may be fixed and unreactive (traumatic iridoplegia). Responsible mechanisms include tears or trauma to the iris sphincter muscle, tearing of short ciliary nerves, dislocation of the lens into the pupillary plane, or compression of the ciliary nerves or ganglion by blunt trauma or a retrobulbar hemorrhage.
Angle-closure glaucoma. This disorder, an ophthalmic emergency, should be considered when the pupil is middilated and fixed and the patient acutely complains of visual loss, nausea, vomiting, eye pain, and a rainbow-colored halo seen around lights. Ocular pressures can be very high (>60 mmHg), and visual acuity may be markedly impaired. Slit-lamp examination will identify the characteristic shallow anterior chamber, cornea edema, and ciliary or conjunctival injection. Pupillary nonreactivity is the result of sphincter muscle ischemia. If left untreated, the pupil may remain fixed, and the iris can become atrophic.
Iritis. When affected by iritis, the pupil can be small, irregular, or poorly reactive (see Fig. 13.6A ) or demonstrate impaired dilation in the dark. Cells and flare in the anterior chamber, iris synechiae, and keratic precipitates seen on slit-lamp examination help establish the diagnosis. Photophobia is the major complaint, and there is less pain and the onset is more gradual than in angle-closure glaucoma. Because of the synechiae, the pupil dilates poorly and irregularly, even with mydriatics.
Congenital mydriasis. Albeit rare, in this condition children are born with fixed and dilated pupils that are unreactive to dilute or 1% pilocarpine. Accommodation is also affected. The cause is unknown. Congenital mydriasis in association with patent ductus arteriosus and megacystic microcolon have been documented.
The most common cause of asymmetric pupils (anisocoria) is nonpathologic simple (essential, physiologic) anisocoria ( Fig. 13.16 ). The latter occurs in 15–30% of the normal population and is characterized by normal pupillary constriction and dilation as well as little change in the net amount of anisocoria under light and dark conditions ( ). The pupillary inequality in some cases may be larger in the dark (see later discussion). Also, the difference is rarely more than 1 mm. Often the simple anisocoria will be evident on old photographs or a driver’s license, which can be viewed critically with a slit-lamp or 20-diopter lens. No further testing is necessary in these instances. Rarely, the pupil asymmetry can reverse from day to day in this condition (also see Idiopathic Alternating Anisocoria ). The cause of simple anisocoria is thought to be asymmetric supranuclear inhibition of the Edinger–Westphal nuclei.
If the anisocoria is not physiologic, the next issue to resolve is which pupil is the abnormal one, assuming the problem is unilateral. The process combines examination of the pupillary light reactions and measurements of the anisocoria in light and dark. If the pupillary inequality is greater in the light, and if one pupil is sluggish to light stimulation, then this pupil is the abnormal one. Likely the lesion lies in the efferent arc of the pupillary light reflex, or there may be pharmacologic blockade or iris damage. These pupillary abnormalities were discussed previously in the sections on pupils with defective reactions to light, and the differential diagnosis includes those entities listed in Table 13.2 .
A greater difference in darkness, with normal pupillary reactivity to light, implies either oculosympathetic paresis on the side with the smaller pupil or, less commonly, simple anisocoria, which may be less evident in light due to mechanical limitations of the iris.
Disorders of Pupillary Dilation: Oculosympathetic Disruption (Horner Syndrome)
Horner syndrome, characterized primarily by unilateral miosis, facial anhidrosis, and mild upper and lower eyelid ptosis ( Fig. 13.17 ), is the most important neuro-ophthalmic cause of a small pupil that dilates poorly in the dark. Box 13.3 lists the differential diagnosis of other entities which should be considered, and most of them have been discussed previously in other sections of this chapter.
Oculosympathetic paresis (Horner syndrome)
Tonic pupil (chronic)
Argyll Robertson pupil
Horner syndrome is a unique clinical sign, indicative of a remote process interrupting one of a series of three oculosympathetic neurons (see Fig. 13.4 ) that starts in the brain, descends to the upper chest, then ascends back to the eye. The benign nature of the ocular findings in Horner syndrome, affecting appearance but not visual function, sometimes belies the seriousness of the underlying etiology. The causes and management are discussed according to which neuron has been affected, and the management of Horner syndrome in childhood also is reviewed.
Clinical Signs and Symptoms in Horner Syndrome
Because of the lack of sympathetic input to the iris dilator muscle, Horner syndrome is strongly suggested when the anisocoria increases in the dark or if dilation lag of the miotic pupil is observed ( Box 13.4 , ). Dilation lag may be demonstrated at the bedside by turning the lights off and observing the pupils with a dim light directed from below the nose. The normal pupil dilates briskly, but it takes time for the sympathetically denervated pupil to reach its final resting state in the dark. Typically, measurements of pupil size are made at 5 and 15 seconds to document this dilation disparity in darkness, and there is usually more anisocoria at the earlier measurement. However, the absence of dilation lag does not exclude Horner syndrome. The pupil in Horner syndrome constricts normally during light stimulation and near viewing.
Anisocoria noticed by the patient or others
Unassociated with visual loss
Anisocoria worse in the dark
Pupillary dilation lag
Minimal ptosis of the upper lid
“Inverse” or “upside-down” ptosis of the lower lid
Ocular hypotony, transient
Iris heterochromia (in congenital cases, typically)
Reversal of anisocoria following instillation of 0.5% or 1% apraclonidine eye drops into both eyes
Greater than 1 mm of relative anisocoria following instillation of 10% cocaine eye drops into both eyes
The upper lid ptosis is always mild and rarely ever covers the visual axis. The lower lid may be slightly elevated (lower eyelid, or upside-down, ptosis). The upper and lower eyelid ptosis (narrow palpebral fissure) may give the false impression that the eye is set back in the orbit (pseudoenophthalmos).
Horner syndrome by itself does not cause visual symptoms. However, disruption in sympathetic input to the eye may produce several other ocular signs. There may be conjunctival congestion or transient ocular hypotony. Because iris melanocytes require oculosympathetic input during development in early infancy, congenital Horner syndromes can be associated with an ipsilateral lighter-colored iris (iris heterochromia) ( Fig. 13.18 ). In rare instances, heterochromia may also result from acquired instances of Horner syndrome (see Fig. 13.17 ). Also, neurotrophic corneal endothelial failure has been reported in association with Horner syndrome.
Theoretically, lesions of the third-order neuron distal to the carotid bifurcation result in loss of sweating or flushing on just the medial aspect of the forehead and side of the nose, while more proximal lesions, including those of the first- and second-order neurons, decrease sweating or flushing in the whole half of the face ( Fig. 13.19 ). Hemibody sweating would also be anticipated from first-order neuron dysfunction. However, the expected patterns are present inconsistently, and the air conditioning in most hospitals and offices often masks any anhidrosis, making it a less important practical sign of Horner syndrome than the ptosis and miosis.
Etiology and Localization of Horner Syndrome
Table 13.3 outlines the causes of Horner syndrome according to localization and frequency. The various causes have been analyzed in large series, and the most common localization varies, most likely due to selection bias. In a study of inpatients with acquired oculosympathetic palsy, 63% had involvement of the first-order neuron, reflecting a large proportion of patients with strokes. The second-order neuron (preganglionic) was the most common lesion site in two other studies, while the third-order neuron (postganglionic) was most frequent in another, reflecting the authors’ interest in headaches. The ganglion referred to is the superior cervical ganglion; thus “preganglionic” refers to the second-order neuron, and “postganglionic” to the third-order neuron.
|First-order (central) neuron||Lateral medullary stroke||Hypothalamic, midbrain, or pontine injury|
|Spinal cord lesion|
|Second-order (preganglionic) neuron||Pancoast tumor||Cervical disc disease|
|Brachial plexus injury|
|Third-order (postganglionic) neuron||Carotid dissection||Intraoral trauma|
|Cavernous sinus lesion|
|“Small vessel” ischemia|
The presence of other clinical signs or symptoms may help localize the Horner syndrome. Sweat patterns have been mentioned already. Brainstem or spinal cord signs suggest involvement of the first-order neuron. Arm pain or a history of neck or shoulder trauma, surgery, or catheterization point to injury of the second-order neuron. Horner syndrome accompanied by ipsilateral facial pain or headache is characteristic of disorders that affect the third-order neuron.
The ciliospinal reflex may also help with localization in Horner syndrome. The reflex consists of bilateral pupillary dilation in response to a noxious stimulus, such as a pinch, on the face, neck, or upper trunk. Reeves and Posner showed that when there is a lesion of the first-order oculosympathetic neuron, the reflex is still intact. In contrast, in patients with injury to the second- or third-order neurons, which contain the efferent arm of the reflex, the pupil usually fails to dilate ipsilaterally.
Injury of the First-Order Neuron (Central Horner Syndrome)
Central Horner syndrome can be caused by lesions involving the descending oculosympathetic pathway in the hypothalamus, brainstem, or spinal cord.
Hypothalamic lesions . Injury to the neuronal cell bodies in the hypothalamus is a relatively infrequent etiology of Horner syndrome. The most common causes of dysfunction in this area are tumors or hemorrhages involving the thalamus or hypothalamus ( Fig. 13.20 ). Less commonly, a Horner syndrome is the result of hypothalamic infarction, occasionally combined with contralateral ataxic hemiparesis. Isolated infarction of the hypothalamus is an unusual event because of a rich blood supply to the hypothalamus, consisting of branches from the anterior cerebral artery and thalamoperforating arteries arising from the proximal portions of the posterior cerebral arteries near the basilar bifurcation, as well as short hypothalamic arteries that derive from the posterior segment of the posterior communicating artery. However, in some individuals with persistence of the fetal circulation, the hypothalamus is supplied directly by branches of the internal carotid artery. In such cases, large, deep cerebral infarcts may involve the hypothalamus when this artery is occluded, and these patients may have prominent sensory or motor signs or a hemianopia contralateral to the Horner syndrome.