Diagnostic Approach to Pupillary Abnormalities

Abstract

Purpose of Review:

This article presents an overview of the common and various kinds of pupillary disorders that can be encountered in an outpatient setting.

Recent Findings:

The dorsal midbrain is a site where lesions may produce either an afferent or an efferent pupillary defect. The classic pupillary syndrome secondary to a dorsal midbrain lesion is bilateral light-near dissociation. Another recognized deficit is bilateral mydriasis. Recent reports have documented unilateral mydriasis, unilateral light-near dissociation, and a relative afferent pupillary defect without visual loss in association with lesions of the dorsal midbrain. These are rare syndromes.

Summary:

Careful history and examination can often identify and localize the pupillary disorder, as well as guide appropriate evaluation.

RELATIVE AFFERENT PUPILLARY DEFECT

Assuming that motor nerves to pupil and iris muscles are intact, an asymmetry of light signaling between the two eyes will result in a difference in pupil responses between stimulation of the right versus the left eye. This is the relative afferent pupillary defect (RAPD), best seen with alternating light stimulation (Figure 12-1). An RAPD is a sensitive indicator of optic nerve dysfunction. Subtle RAPDs are often present before loss of visual acuity or even visual field loss in cases of optic nerve compression. In addition, a small RAPD can usually be detected in patients with previous optic neuritis in whom acuity and field have recovered. Less commonly, an RAPD may also result from severe retinal disorders, such as central retinal artery occlusion or large retinal detachments. These disorders typically require substantial retinal damage, and thus significant visual loss, to produce an RAPD.

Figure 12-1.

Example of the use of alternating light to detect a relative afferent pupillary defect. A, The patient is seated in a dim room and fixating at distance. B, A bright focal light illuminates the right eye for 2 to 3 seconds, and a strong pupillary constriction (direct and consensual) is noted. C, The light is quickly swung across the nose to illuminate the left eye for 2 to 3 seconds, and a less-vigorous pupillary constriction is seen. When the light is returned to the right eye, the stronger reaction will be evident (not shown). This patient has a left relative afferent pupillary defect.

In a patient with a homonymous hemianopia, the presence of an RAPD in the eye with temporal field loss localizes the lesion to the contralateral optic tract.1 The contralateral sidedness of the RAPD is attributed to the greater number of ganglion cells and greater light sensitivity of the nasal retina (temporal visual field) compared with the temporal retina. The fundus reveals optic atrophy with an optic tract lesion, typically in a characteristic band or bow-tie pattern.

This nasal:temporal asymmetry of retinal sensitivity is also the basis of a midbrain RAPD, also called a tectal RAPD.2 The afferent pupillomotor signal carried in the optic tract passes through the brachium of the superior colliculus to synapse in the pretectal olivary nucleus of the dorsal midbrain. A unilateral lesion of the dorsal midbrain may thus produce an RAPD without visual loss. Other situations that might result in an RAPD without visual loss are prior ocular trauma or an asymptomatic previous episode of optic neuritis. Sometimes a notably large anisocoria, especially in darkly pigmented eyes, may lead to sufficient inequality of retinal illumination to create an RAPD. As a general rule, it will take at least 3 mm of anisocoria to observe a subtle RAPD on the side of the smaller pupil. Patients with Leber hereditary optic neuropathy or autosomal dominant optic atrophy have bilateral central visual loss and profound optic atrophy, and yet the pupil light reflexes are remarkably preserved. This visual-pupillary dissociation is caused by a differential susceptibility among retinal ganglion cell types to neurodegeneration caused by mitochondrial dysfunction.3 Histologically, it appears that pupil-serving ganglion cells are relatively spared in these disorders, and in the rare instance of unilateral involvement, an RAPD may not accompany the visual loss. In such a circumstance, the absence of RAPD on the side of the optic neuropathy may lead to the diagnostic pitfall of assigning a refractive or even nonorganic cause to the visual loss.

ONE LARGE PUPIL THAT FAILS TO CONTRACT TO LIGHT

Three common mechanisms result in a poor light reflex: (1) damage to the iris sphincter muscle, (2) interruption in the oculoparasympathetic pathway, and (3) pharmacologic effect. These mechanisms of unilateral mydriasis are discussed in further detail in this section.

Sphincter Muscle Damage

The term mechanical anisocoria is used when impaired pupil movement is caused by damage to the iris framework, in particular, damage to the iris sphincter muscle. In severe cases of sphincter damage, the pupil is fully dilated and fixed, resembling a pharmacologically dilated pupil. Clues that iris damage is the cause include distortion of the pupillary shape, sphincter tear, iris transillumination defects, synechiae (fibrosis), intraocular inflammation, and pigment dispersion. To identify these findings that indicate structural damage to the iris, a slit-lamp examination or ophthalmic consultation, or both, is required. Causes include ocular trauma, infection, ischemia, intraocular surgery, laser treatment, and acute-angle closure glaucoma (Case 12-1). When painful, these pupillary conditions may superficially resemble intracranial pathology, but careful history and examination often point to their ocular nature.

Case 12-1

A 68-year-old man with blurry vision underwent uncomplicated phacoemulsification with intraocular lens implantation (cataract surgery) in his right eye. No postoperative pain, corneal edema, or increased intraocular pressure was present. Postoperative care included a topical antibiotic and anti-inflammatory medication. On postoperative day 1, a right mydriasis was noted (right pupil 7 mm compared with left pupil 4.5 mm). Examination was otherwise unremarkable. On postoperative day 4, the patient reported glare. The dilated pupil failed to constrict to topical 2% pilocarpine. Weeks later, his status was unchanged and development of iris atrophy was noted.

Comment. This curious and unpredictable complication of cataract surgery (or other anterior segment surgery) is known as Urrets-Zavalia syndrome.4 The exact mechanism is unclear and likely multifactorial. Elevated intraocular pressure in the first 24 hours after surgery has been identified as an associated factor and, in such cases, is thought to provoke iris ischemia. In other cases, intraoperative trauma to the ciliary ganglion or an idiosyncratic toxic reaction to anesthesia have been suggested mechanisms. The degree of pupillary mydriasis is variable, and the pupil shape is neither irregular nor distorted. All patients with Urrets-Zavalia syndrome show impaired or no response to topical pilocarpine. About 70% of patients recover some pupillary reactivity within 1 to 2 months, which is important for reduction of symptomatic glare and photophobia. In the remaining 30%, the pupil remains permanently dilated and fixed. Pupilloplasty may be considered for disabling symptoms related to excessive light, and patients should be monitored for secondary glaucoma.

Oculoparasympathetic Palsy

The neurologic basis for a large, poorly reactive pupil is interruption within the oculoparasympathetic pathway, which mediates pupillary constriction and lens accommodation. This two-neuron pathway originates at the Edinger-Westphal subnucleus of the oculomotor nuclear complex in the rostral ventral midbrain and relays at the ciliary ganglion.

Postganglionic parasympathetic fibers carried in the short ciliary nerves pierce the back of the globe and travel anteriorly in the sclera to reach the iris sphincter and the ciliary muscle. The neurotransmitter at the postganglionic synapse is acetylcholine.

Injury to the oculomotor nerve with damage to the preganglionic parasympathetic fibers is a well-known cause of unilateral mydriasis. The presence of accompanying eyelid or ocular motor deficits localizes the lesion to the oculomotor nerve. An isolated unilateral mydriasis as the sole manifestation of an oculomotor nerve palsy is exceedingly rare. The pitfall occurs when ocular motor deficits are very subtle and clinically overlooked, leading to the mistaken impression of an isolated pupillary abnormality. Cross-cover or Maddox rod testing in all gaze positions is a simple and rapid means to identify the ocular deviation. Both tests can be performed in the clinic or even at bedside and are an excellent means to detect small ocular deviations and avoid a missed diagnosis of early or partial oculomotor nerve palsy. See the article “Diagnostic Approach to Diplopia” by Marc Dinkin, MD, in this issue of CONTINUUM for a review of techniques to detect a subtle eye misalignment.

Damage to the ciliary ganglion or the short ciliary nerves is a postganglionic parasympathetic injury causing denervation of the iris sphincter (iridoplegia) and ciliary muscle (cycloplegia). Associated symptoms are photophobia and difficulty with near vision. In unilateral cases, the lesion is typically in the orbit or eye; when bilateral, a generalized autonomic neuropathy should be considered.

A tonic pupil is so-named because of the subsequent aberrant regeneration that follows postganglionic parasympathetic denervation of the eye.5 The denervation is typically incomplete, resulting in sectoral palsy of the iris sphincter. At the slit lamp in the ophthalmology office, this sectoral palsy is visible as a focal flattening of the pupil margin (paralyzed segment) contrasted against focal segments that remain contractile (Figure 12-26).7 It is a powerful clinical finding because sectoral palsy of the iris sphincter is not seen with acute oculomotor nerve palsy or with pharmacologic mydriasis.

Figure 12-2.

Example of distortion of pupil shape caused by sectoral palsy of the iris sphincter. In this patient with a tonic pupil, the area of normally innervated sphincter lies between the 11 o’clock and 4 o’clock hours and demonstrates thickening of the pupillary ruff (the darkly pigmented and irregular margin of the pupil ) and puckering of the iris stroma, changes consistent with sphincter contraction. The paralyzed sector is between the 4 o’clock and 8 o’clock hours. Note the looseness of the adjacent iris stroma and the flattening of the radius of pupil curvature.

Reprinted with permission from Kawasaki A, Continuum (Minneap Minn).6 © 2009 American Academy of Neurology. journals.lww.com/continuum/Fulltext/2009/08000/ANISOCORIA.17.aspx.

Within the 1 or 2 weeks of its denervation, the iris sphincter will become supersensitive to cholinergic agents such as pilocarpine diluted to a concentration of 0.125% or less. Following 1 drop placed in each eye, a positive response to dilute pilocarpine is either (1) the larger pupil constricts 0.5 mm more than the normal pupil or (2) the larger pupil becomes the smaller pupil (Table 12-1). Cholinergic supersensitivity is nonspecific for tonic pupil; it is simply an indicator of parasympathetic denervation of the iris, and thus, it is also present with oculomotor nerve palsy.8 Absence of cholinergic supersensitivity does not rule out tonic pupil because only about 80% of patients demonstrate this finding.

Table 12-1.

Pharmacologic Testing for Cholinergic Denervation Supersensitivity

Within the first 1 or 2 months of injury, the short ciliary nerves regenerate. A relative abundance of accommodative fibers repairs innervation of the ciliary muscle. Along the way, some accommodative fibers aberrantly reinnervate the iris sphincter, restoring constriction of the pupil to near effort in a slow and tonic fashion. (Case 12-2). The pupil response to light, however, remains forever defective. The combination of a poor pupil light reflex with a better pupil near response is termed light-near dissociation.

Most cases of tonic pupil are idiopathic in origin; this is also known as Adie pupil. In some patients with idiopathic tonic pupil syndrome, muscle-stretch reflexes are noted to be diminished or absent. It is presumed that the same mechanism that results in a ciliary ganglionopathy also affects the dorsal root ganglia. The combination of tonic pupil and areflexia is known as Adie or Holmes-Adie syndrome and prognosis is benign.

Case 12-2

A 24-year-old man had a minor bicycle accident without head or orbital trauma. One month later, he noted blurry vision and mild frontal headache during reading. A friend pointed out that his left pupil was dilated, but he did not seek medical advice until several weeks later. Examination revealed a large left pupil (8 mm) that was barely reactive to light stimulation but did constrict slowly to near effort (Figure 12-3). At the slit lamp, sectoral palsy of the iris was observed. Eye movements were full, and his eyes were normally aligned in all gaze directions. Muscle-stretch reflexes in lower extremities were absent. A diagnosis of Adie syndrome was made. Serologic tests for syphilis and sarcoidosis were sent and later returned negative. His accommodation was improved at 6-month follow-up, but pupillary findings were otherwise unchanged.

Figure 12-3.

Unilateral tonic pupil and Holmes-Adie syndrome. A, Under bright illumination, the right pupil is contracted but the left pupil remains dilated. B, Both pupils contract well to near effort. The left pupil thus demonstrates pupillary light-near dissociation.

Comment. A unilateral tonic pupil may occur from a variety of local processes affecting the ciliary ganglion or short ciliary nerves, such as orbital trauma (accidental or iatrogenic), tumor, ischemia, or infection. While the temporal association to his accident might suggest trauma as a cause in this patient, he had no head or orbit trauma. In most patients, a unilateral tonic pupil is a spontaneous idiopathic condition. Migraine-related ciliary ganglionopathy has been proposed as one cause of tonic pupil,10 but this patient had not had migraine headaches. When diminished muscle-stretch reflexes are an associated finding, the condition is called Adie pupil or Holmes-Adie syndrome. Neuroimaging is not indicated for the patient with a typical tonic pupil, but it is wise to rule out syphilis as a possible cause.

Pharmacologic Mydriasis

Topical mydriatic agents can be divided into two categories: parasympathetic inhibitors (anticholinergic substances) and sympathomimetics. Products containing atropinelike, anticholinergic substances include scopolamine patch, certain insecticides, plant-based belladonna alkaloids such as Jimson weed, and anticholinergic inhalants used to treat respiratory disease.10 A pupil dilated by an anticholinergic substance, eg, an atropinized pupil, is enormously large, on the order of 8 mm to 9 mm, and nonreactive to light and near stimulation. It is distinguished from a denervated pupil by the absence of sectoral palsy and unresponsiveness to topical cholinergic agonists such as 2% pilocarpine.

Sympathomimetics are adrenergiclike substances that cause pupillary dilation by excessively stimulating the dilator muscle, but no paralysis of the sphincter muscle occurs. Thus, a sympathetically dilated pupil retains some degree of a light reaction and will constrict well to full-strength pilocarpine. Additional clues to sympathomimetic mydriasis are preserved near vision, conjunctival blanching, and eyelid retraction. Examples of topical sympathomimetic agents include epinephrine, phenylephrine, ephedrine, hydroxyamphetamine, cocaine, ocular decongestants, and adrenergic inhalants. Even in patients using eye drops in both eyes, asymmetric absorption can lead to anisocoria.

SMALL PUPIL(S) WITH POOR LIGHT REFLEX

Diagnostic considerations of a small pupil (unilateral or bilateral) that contracts poorly to light are chronic-tonic pupil; neuropathic pupils caused by diabetes mellitus or chronic alcoholism; neurosyphilitic pupils; aberrant regeneration of the oculomotor nerve; systemic medications such as opioids; fibrous adhesions caused by previous intraocular inflammation, eg, iritis or uveitis; dispersion and aggregation of intraocular pigment pseudoexfoliation syndrome; and pharmacologic miosis.

In the patient with tonic pupil, the baseline size of the pupil decreases over time because of tonic firing in the aberrant accommodative fibers innervating the sphincter (Figure 12-4). After several months or years, it is common for a chronic-tonic pupil to be the larger pupil in room light and the smaller pupil in dim light because tonicity prevents it from full constriction and full dilation. This has been termed “a little old Adie.”11 Similarly, in the patient with a chronic oculomotor nerve palsy, regenerating motor fibers can mistakenly innervate the iris sphincter. Over time, as the number of aberrant motor fibers increases, the resting size of the pupil becomes smaller, as occurs with a chronic-tonic pupil.12

Figure 12-4.

A 62-year-old woman referred for small pupils with absent light reflexes. The pupils were said to dilate normally to standard dilating eye drops. A, Pupils fail to dilate well in darkness. The right pupil is 3 mm and the left pupil is 2.5 mm. B, Bright light fails to reduce pupil size. C, Both pupils show a slow but visible contraction to near effort, thus demonstrating tonicity and bilateral light-near dissociation, consistent with a diagnosis of bilateral chronic-tonic pupils. Syphilis serologies were negative.

The Argyll Robertson pupil is one manifestation of neurosyphilis. Both pupils are very small (less than 2 mm) and irregular. The pupils do not react to light, but the near response is normal and brisk (light-near dissociation).13 The briskness of pupillary movement to near effort distinguishes Argyll Robertson pupils from bilateral chronic-tonic pupils, which have a slow and sustained near response.

Experts suggest that diabetic pupils are small due to iris structural changes related to chronic hyperglycemia, so-called sticky pupils. These pupils are poorly reactive to light, demonstrate no light-near dissociation, and tend to dilate poorly in darkness.

ANISOCORIA WITH NORMAL PUPIL LIGHT REFLEX

If the pupillary light reflex is normal in both eyes, it can be assumed that the oculoparasympathetic system and iris sphincter are intact. Anisocoria with normal pupil light reflex will be more apparent in dim light compared to bright light and is most commonly a physiologic anisocoria or an oculosympathetic palsy, ie, Horner syndrome.

Physiologic Anisocoria

The prevalence of physiologic anisocoria is nearly 20% of the general population. Also known as simple, essential, or benign anisocoria, physiologic anisocoria typically measures 1.0 mm or less, although the magnitude of anisocoria in an individual can vary from day to day. Rarely, physiologic anisocoria can change sides. In other words, the larger pupil appears sometimes on the right side and sometimes on the left side. The anisocoria is slightly more marked under dim lighting conditions. The most important features of physiologic anisocoria are normal pupillary constriction to light, normal pupillary redilation in darkness, and normal responses to pharmacologic agents such as topical cocaine, apraclonidine, or dilute pilocarpine.

Horner Syndrome

Horner syndrome is a combination of upper eyelid ptosis and ipsilateral miosis that is caused by interruption of sympathetic innervation to that side of the head and eye.14 Conjunctival vasodilation and hyperemia may be present the first few weeks following acute denervation injury. If the patient has inverse (lower eyelid) ptosis, the combined upper and lower eyelid ptosis decreases the palpebral fissure notably to give a false impression of a smaller eye (called enophthalmos) (Figure 12-5). Ptosis can, however, be absent in 12% to 13% of patients with Horner syndrome. Anhidrosis of varying degree occurs on the side of the sympathetic defect. The clinical feature that best differentiates Horner syndrome from physiologic anisocoria is slow redilation of the smaller pupil in darkness, so-called dilation lag. This finding is diagnostic for Horner syndrome but is demonstrable in only about 50% of patients. Therefore, definitive diagnosis of Horner syndrome often requires a pharmacologic test. Currently, the two topical agents used for this purpose are cocaine and apraclonidine.

Figure 12-5.

Example of oculosympathetic defect on left side. This patient was referred for possible left enophthalmos (A). Formal measure of the forward displacement of the globes using a Hertel exophthalmometer failed to confirm a true enophthalmic position of the left eye. Examination of the orbit and eyes (B) revealed upper and lower eyelid ptosis and narrowed palpebral fissure on the left, and anisocoria, later confirmed to be Horner syndrome.

Cocaine blocks the reuptake of norepinephrine released at the neuromuscular junction of the iris dilator muscle and normally results in pupillary dilation, conjunctival blanching, and eyelid retraction. A sympathetically denervated eye fails to respond to cocaine, and the anisocoria is typically enhanced by cocaine. A postcocaine anisocoria of 1.0 mm or more is considered diagnostic of a Horner syndrome.15 Iris adhesions can mechanically restrict the pupil so that it dilates poorly in darkness or to topical cocaine, creating confusion with Horner syndrome. However, a Horner pupil dilates well to direct topical sympathomimetics, such as 10% phenylephrine, whereas a mechanically restricted pupil remains miotic. Apraclonidine is a glaucoma medication that has weak α₁-agonist activity, which can be used to look for adrenergic denervation supersensitivity.16 Table 12-26 summarizes the method and interpretation of these two eye drops tests.

Table 12-2.

Pharmacologic Testing for the Diagnosis of Horner Syndrome^a

The sympathetic pathway to the eye is an ipsilateral, three-neuron pathway with two relay centers (ciliospinal center of Budge-Waller and the superior cervical ganglion) (Figure 12-617). The first-order neuron originates in the hypothalamus and synapses in lower cervical-upper thoracic spinal cord (C8-T2). The second-order neuron exits the spinal cord and passes across the apex of the lung and under the subclavian artery to synapse in the superior cervical ganglion. The third-order neuron is intimately associated with the carotid artery; at the carotid bifurcation, the vasomotor and sweating fibers travel primarily with the external carotid artery, whereas the oculosympathetic fibers travel with the internal carotid artery and reenter the intracranial space via the carotid canal. At the orbital apex, the oculosympathetic fibers follow the nasociliary nerve to the eye. Thus, Horner syndrome can be classified by the location of the lesion: central (first-order neuron), preganglionic (second-order neuron), and postganglionic (third-order neuron).

Figure 12-6.

Schematic illustration of the three-neuron oculosympathetic pathway.

Reprinted with permission from Liu GT, et al, WB Saunders.17 © 2001 Elsevier, Inc.

Localization of the lesion can be inferred from associated symptoms and signs.14 If available, 1% hydroxyamphetamine is also used for localization but must be done at least 24 hours after other diagnostic eye drops testing. Signs and symptoms such as complete hemianhidrosis, vertigo, nystagmus, diplopia, altered facial sensation, contralateral fourth nerve palsy, crossed sensory/motor signs, spastic paraparesis, and cervical radiculopathy suggest central Horner syndrome. Face and neck anhidrosis, neck scar from prior trauma or intervention, arm pain, and hoarse voice suggest a preganglionic lesion. Ipsilateral face or head pain, ipsilateral monocular visual loss, dysphagia, and dysgeusia suggest a postganglionic lesion, particularly carotid dissection. Table 12-3 lists some of the more common causes of Horner syndrome.

Table 12-3.

Common Causes of Horner Syndrome

Imaging of Horner syndrome is directed, when possible, by associated localizing symptoms and signs. The following is a suggestion for investigation of patients with Horner syndrome: brain and neck MRI for central and postganglionic Horner syndrome, neck and chest MRI for preganglionic Horner syndrome, and additional arteriographic images of the aortic arch branches for preganglionic and of the extracranial internal carotid artery for postganglionic Horner syndrome (Case 12-3).18 If MRI is unavailable, a contrasted neck and chest CT can be used to explore the upper thorax for mass lesions. A simple chest x-ray is considered insufficiently sensitive to discern a small mediastinal mass. When looking for a carotid dissection, angiographic images are included in the MRI evaluation, but these may be negative. In such cases, a careful review of the axial fat-saturated T1 images through the skull base may reveal the dissection. An isolated Horner syndrome that is longstanding or associated with known trauma does not necessarily require imaging.

Case 12-3

A 50-year-old man had noted sudden onset of right ptosis and anisocoria 3 weeks earlier. Around the same time, he had intense paresthesias on the right side of his scalp and mild right frontal headache. These symptoms spontaneously resolved during 1 week. Occasionally, he still noted a burning sensation across his scalp, and, after urging from his wife, he finally came to medical attention. Close examination revealed an asymmetry of upper eyelid crease and almost 1 mm right upper eyelid ptosis but no anisocoria. The remainder of his neurologic and ophthalmic examinations was normal. Following instillation of 4% cocaine in each eye, failure of the right pupil to dilate was definitively demonstrated (Figure 12-7). Instillation of 10% phenylephrine dilated both pupils equally. A diagnosis of Horner syndrome was made and, despite extensive investigations, including MRI of head and neck with angiographic images of the internal carotid artery, no specific cause was found. He was given low-dose aspirin and was doing well at 1-year follow-up.

Figure 12-7.

Patient with right Horner syndrome with minimal clinical signs. A, Observable ptosis or miosis is absent. B, Pupillary examination in darkness confirms absence of anisocoria. Closer inspection of eyelids reveals a minimal right upper eyelid ptosis and asymmetry of eyelid creases. C, Forty-five minutes after instillation of topical cocaine in both eyes, expected pupillary dilation and eyelid retraction on the left side occur. The right pupil has remained the same size.

Comment. In the acute setting, the diagnosis of Horner syndrome should be clinically based and, if accompanied by headache or pain, be treated as a clinical emergency to rule out acute carotid dissection. Appropriate investigations should be undertaken based on the clinical diagnosis and not await pharmacologic confirmation. In this case, the patient did not seek medical attention at the moment of onset of ptosis and anisocoria. As it happened, these clinical manifestations as well as the headache resolved rapidly. In such cases of a seemingly transient Horner syndrome, pharmacologic testing, even at a later date, is important because it may be the only objective evidence of a persistent and underlying sympathetic deficit. In this patient, a thorough evaluation revealed no underlying pathology, and management was individualized as the patient was concerned about the risk of stroke from an undetected carotid dissection.

PUPILLARY LIGHT-NEAR DISSOCIATION

Light-near dissociation occurs when a near response exceeds the best pupillary constriction that bright light can produce. The most common cause of light-near dissociation is optic neuropathy, unilateral or bilateral, in which reduced light impulses to the pretectal olivary nucleus initiate a weak light reflex. This form of light-near dissociation is often unappreciated because the visual loss and relative afferent pupillary defect indicate the site of neurologic damage. In other words, the near response is not commonly examined in blind persons, but were it done, a normal brisk pupillary constriction would be observed.

The second kind of light-near dissociation arises from a lesion of the dorsal midbrain that interrupts fibers of the light reflex pathway but spares the more ventrally located fibers of the near reflex pathway. Classically, the pupils are midsized and show light-near dissociation bilaterally. Associated findings include bilateral eyelid retraction (Collier sign), vertical gaze palsy, accommodative paresis, and convergence-retraction nystagmus; this constellation of findings is known as Parinaud syndrome. A recent report has described unilateral mydriasis with light-near dissociation due to dorsal midbrain lesions.19

The third mechanism leading to light-near dissociation is injury and regeneration of oculoparasympathetic fibers, as previously discussed with tonic pupil. Aberrant regeneration of fibers of the oculomotor nerve occurs in the setting of a compressive lesion or following trauma.12,20 When motor fibers are misdirected to the iris sphincter, a synkinesis occurs; in other words, a pupillary constriction is evoked by an eye movement. If the synkinetic pupil movement occurs with adduction, it can resemble light-near dissociation (Figure 12-8).

Figure 12-8.

Example of oculomotor synkinesis. A, In primary position, mydriasis of the left pupil and ptosis are present. B, On attempted downgaze, the pupil constricts simultaneously and the eyelid is retracted. These movements are caused by aberrant innervation of the iris sphincter and levator palpebrae muscles from fibers from the inferior rectus subnucleus.

Reprinted with permission from Gold DR, et al, Pract Neurol.20 © 2012 BMJ Publishing Group Ltd. pn.bmj.com/content/12/6/390.long.

TRANSIENT PUPILLARY PHENOMENA

Transient unilateral mydriasis can represent a potential emergency, but, in most cases, it is a benign phenomenon. In a patient with an intracranial mass lesion or acute pathology, such as edema or hemorrhage, unilateral pupillary dilation may indicate impending transtentorial herniation. Unilateral mydriasis is an early sign of a symptomatic intracranial aneurysm, but the pupillary dysfunction is not a transient abnormality and is nearly always accompanied by eyelid or eye muscle weakness. Perhaps the chief emergency associated with transient unilateral mydriasis to recognize is intermittent angle-closure glaucoma. Seeing halos around lights, pain or headache, and a red eye are clinical symptoms and signs. The pupil is mildly dilated and poorly reactive to light and darkness. Patients can have repeated self-limited episodes of subacute angle closure before a full-blown attack. An ophthalmic examination is necessary for timely confirmation of diagnosis and treatment to prevent permanent visual loss.

Benign causes of transient unilateral mydriasis include physiologic anisocoria, migraine, springing pupil. and tadpole pupil. Physiologic anisocoria is presumed to occur from small and fluctuating differences in the supranuclear modulating input to the paired parasympathetic Edinger-Westphal nuclei. In some patients, the degree of pupillary inequality can fluctuate from day to day and at times is so minimal as to go undetected by direct observation. Further discussion of physiologic anisocoria is found in the section “Anisocoria With Normal Pupil Light Reflex.”

Anisocoria during a migraine attack is a well-described yet poorly understood association. The mechanism is likely multifactorial. In some patients, migrainous vasospasm appears to cause a local and reversible ischemia of the ciliary ganglion, leading to transient episodes of dilated pupil and accommodative palsy during a migraine crisis. In rare patients with migraine, a permanent tonic pupil develops following an acute migraine crisis.9 In other migraineurs, sympathetic dysregulation, occurring either as increased or decreased activity, which may be unilateral or bilateral and asymmetric, has been described.21 It has also been suggested that some cases of anisocoria during migraine simply represent an exaggeration of an underlying physiologic anisocoria.

Springing pupil, also called benign episodic mydriasis, is a descriptive term for recurrent episodes of isolated unilateral mydriasis occurring in young adults, usually women with migraine.22 The mydriasis typically appears in the same eye but can alternate sides. Mydriasis usually lasts for several hours but may persist for days. When examined during an episode, some patients have a normal pupil light reflex, whereas others show a poor reaction to light with impaired accommodation. Benign episodic mydriasis probably represents a heterogeneous group of disorders, including migraine-associated anisocoria and physiologic anisocoria, with different mechanisms that result in transient and episodic anisocoria. It is not associated with any systemic or neurologic condition.

Tadpole pupil is a related entity in which episodes of pupillary distortion with peaking on one side result from focal spasm of the iris dilator muscle (Figure 12-923).24 In a small percentage of patients, a Horner syndrome later develops.

Figure 12-9.

Example of a tadpole pupil in two patients (self-photographed images). Note the distortion and elongation of one sector of the right pupil, presumably due to focal sympathetic hyperactivity.

Reprinted with permission from Höh AE, Beisse F, Der Ophthalmologe.23 © 2013 Springer-Verlag Berlin Heidelberg. link.springer.com/article/10.1007/s00347-013-2944-5.

A rare cause of transient unilateral mydriasis is paroxysmal discharge of irritated cervical sympathetic nerves, which has been described in occasional patients with injury to the cervical spine, upper spinal cord, and brachial plexus. Typically, other signs of sympathetic hyperactivity, notably eyelid retraction, conjunctival blanching, and facial hyperhidrosis, are present. Some patients later develop a permanent Horner syndrome on the same side, presumably related to progressive damage to the nerves.

Figure 12-10.

Three patients with congenital Horner syndrome. All demonstrate straight hair ipsilateral to the side of the Horner syndrome. The first patient also demonstrates heterochromia irides (lighter colored iris on the side of the Horner syndrome).

Reprinted with permission from Wang FM, et al, J Neuro-Ophthalmol.25 © 2012 North American Neuro-ophthalmology Society. journals.lww.com/jneuro-ophthalmology/Fulltext/2012/06000/Unilateral_Straight_Hair_and_Congenital_Horner.8.aspx.

PEDIATRIC CONSIDERATIONS

A few comments that are pertinent to children are noted here. Leukocoria, or a white pupil, is a sign of potentially serious pathology, with retinoblastoma accounting for nearly 50% of cases. Children with acute tonic pupil are at risk to develop amblyopia in the eye with tonic pupil due to loss of accommodation. This unfortunate complication can be avoided with appropriate bifocal refractive correction until reading vision recovers. Diagnosis of Horner syndrome in the infant or child is based on clinical signs. If pharmacologic confirmation is desired, topical cocaine may be used. Apraclonidine is not used in infants younger than 12 months old as it may cause CNS and respiratory depression. Two interesting manifestations of congenital Horner syndrome are a lighter pigmented iris (blue eye) and straight hair on the side of the Horner syndrome (Figure 12-10).25 In the infant or child without a surgical history to the head or neck, the recommended evaluation for a Horner syndrome of unknown etiology is a thorough physical examination, spot urine testing for catecholamine metabolites to screen for neuroblastoma, and MRI of the brain, neck, and chest.26

KEY POINTS

• The presence of a relative afferent pupillary defect (RAPD) typically indicates neuroretinal damage in the ipsilateral eye. However, an RAPD with homonymous hemianopia signals an optic tract lesion, and RAPD without visual loss may arise from a dorsal midbrain lesion.

• Retinal light information for visual perception and for the pupil light reflex is carried on different fibers in the optic nerve. Mitochondrial optic neuropathy tends to spare the pupillary fibers.

• For practical purposes, a truly isolated unilateral mydriasis is not an oculomotor nerve palsy. It is an orbital or ocular lesion.

• In the patient with unilateral mydriasis, cross-cover or Maddox rod testing permits more precise distinction between preganglionic versus postganglionic oculoparasympathetic lesions.

• In the absence of structural iris damage, sectoral palsy of the iris sphincter is the earliest and most consistent sign of postganglionic oculoparasympathetic palsy, such as tonic pupil.

• In the acute phase of tonic pupil, the pupil is poorly responsive to light and near stimulation. Cholinergic sensitivity may not have developed yet (negative dilute pilocarpine test).

• The pupillary light-near dissociation associated with tonic pupil is not an acute finding. It is a sign of the reinnervation phase of tonic pupil.

• Exposure to parasympatholytic (anticholinergic) or sympathomimetic agents can lead to mydriasis.

• Preservation of the pupil light reflex and accommodation suggests a sympathetic mechanism of mydriasis.

• In patients without ptosis, Horner syndrome and physiologic anisocoria may be indistinguishable on clinical grounds.

• In cases of doubt or confusion, pharmacologic testing using either cocaine or apraclonidine reliably distinguishes Horner syndrome and physiologic anisocoria.

• Horner syndrome with hoarse voice (vocal cord palsy) suggests a lesion in the lower anterior neck. Horner syndrome with ipsilateral arm pain or arm weakness suggests an apical lung mass.

• Any acute painful Horner syndrome should be evaluated emergently for carotid dissection.

• Bilateral light-near dissociation in a patient with poor vision is likely bilateral optic neuropathy.

• Bilateral light-near dissociation in a patient with normal vision is a dorsal midbrain lesion until proven otherwise.

• Signs and symptoms of angle-closure glaucoma include acute headache and unilateral mydriasis that can resemble serious intracranial pathology.

• Benign episodic mydriasis is a diagnosis of exclusion based on a clinical description and a normal examination between episodes.

• Disorders of the cervical spine and spinal cord can cause transient mydriasis and other intermittent symptoms related to paroxysms of excessive sympathetic discharge.