suggest pontine hemorrhage, narcotic intoxication, or pilocarpine use. Extremely large pupils suggest parasympathetic pharmacologic blockade from either topical or systemic drugs, use of stimulants, or a state of high anxiety.

Pupil Irregularity

Congenital iris malformations such as coloboma or aniridia result in abnormal pupil shape and reactivity. Acquired conditions that damage the mechanical compliance of the iris stroma or iris musculature can result in an irregular pupil. Blunt trauma to the eye can cause focal tears in the sphincter muscle. An iridodialysis occurs when the outer edge of the iris is torn away from its ciliary attachment. Intraocular inflammation can damage the iris or cause it to adhere to the lens or cornea (synechiae). Neovascularization can also distort the iris and impair pupillary reactivity. A surgical procedure in the anterior segment may affect the shape or function of the pupil, and cataract surgery is probably the leading cause of a misshapen pupil in an adult.

Two rare conditions of focal abnormality in iris innervation may cause pupillary irregularity:

1.Tadpole pupil. This disorder is due to a focal spasm of the iris dilator muscle, causing a peaking of the pupil that lasts a few minutes. This phenomenon may occur numerous times over several days or a week and then disappear. It is a mild condition in most patients, but a small percentage harbor an underlying sympathetic lesion; thus, pharmacologic testing for Horner syndrome is recommended.

2.Midbrain corectopia. In rare cases, eccentric or oval pupils are present in patients with rostral midbrain disease. This abnormality is presumably caused by incomplete damage of the pupillary fibers, leading to selective inhibition of iris sphincter tone.

Balaggan KE, Hugkulstone CE, Bremmer FD. Episodic segmental iris dilator muscle spasm. The tadpole-shaped pupil. Arch Ophthalmol. 2003;121(5):744–745.

Anisocoria

Asymmetry of efferent signals to the iris muscles produces inequality in the diameters of the 2 pupils called anisocoria, which may be physiologic or pathologic. A proposed algorithm for evaluating a patient with isolated anisocoria characterized by unilateral pupillary dysfunction is shown in Figure 10-1. A discussion of specific disorders follows.

Assuming that only 1 pupil is faulty, anisocoria becomes more apparent in dim light under the following conditions.

Mechanical anisocoria

Occasionally, previous trauma (including surgery) or inflammation can lead to adhesions between the iris and the lens or intraocular lens. Such adhesions may prevent pupillary dilation in conditions of dim illumination. Posterior synechiae should be visible with a magnifying lens or slit lamp.

Pharmacologic miosis

The use of pilocarpine may result in a small, poorly reactive pupil. Anisocoria will not be present if both eyes have been treated, but the use of pilocarpine in 1 eye may lead to diagnostic confusion. Pharmacologic anisocoria is observed less often than it was in the past because of the wider range of choices in glaucoma medications.

Physiologic anisocoria

See the section Anisocoria Equal in Dim and Bright Light included earlier in this chapter.

Horner syndrome

A lesion at any point along the oculosympathetic pathway results in Horner syndrome, which is characterized clinically by ipsilateral miosis, facial anhidrosis, and ptosis. The combination of upper lid ptosis and lower lid ptosis (rising of the lower lid) due to denervation of both tarsal muscles results in a noticeably narrower palpebral fissure and the false impression of enophthalmos. In the acute phase, conjunctival hyperemia and ocular hypotony can also be present. The distribution of anhidrosis depends on the location of the lesion. Interruption of the central (first-order) or preganglionic (second-order) neuron causes anhidrosis of the ipsilateral face. Lesions at or distal to the superior cervical ganglion—that is, the postganglionic (third-order) neuron—result in anhidrosis limited to the ipsilateral forehead. When the lesion is congenital, iris heterochromia develops (the affected iris appears lighter in color).

The pupillary light reflex is normal in patients with Horner syndrome. The affected pupil, however, is slower to redilate than the normal pupil is when the lights are turned off. The oculosympathetic dysfunction of the pupil can also be confirmed pharmacologically with topical eyedrops: either cocaine or apraclonidine. Cocaine blocks the re-uptake of norepinephrine released at sympathetic nerve terminals in the eye, causing pupillary dilation, eyelid retraction, and conjunctival blanching in the unaffected eye. In Horner syndrome, little or no norepinephrine is released into the synaptic cleft. Therefore, cocaine has no effect, and the miotic pupil remains unchanged. The test is performed by instilling 2 drops of cocaine, 4% or 10%, in each eye and measuring the amount of anisocoria after 45 minutes. A postcocaine anisocoria of 1 mm or more is diagnostic of Horner syndrome on the side of the smaller pupil (see Fig 10-1). Eyes with iris synechiae and a mechanically immobile pupil can cause false-positive cocaine test results, but such findings can be readily distinguished through slit-lamp examination. In addition, after instillation of topical phenylephrine, 10% (a strong, direct-acting sympathomimetic drug), a mechanically restricted pupil will remain small but a Horner pupil will readily dilate.

Topical apraclonidine (either 0.5% or 1%) is gaining popularity for use in a pharmacologic diagnostic test for Horner syndrome. This drug has a weak α1-adrenergic agonist action, which in

most normal eyes has little effect on pupil size. In sympathetically denervated eyes, however, the iris dilator is supersensitive to adrenergic substances, and the pupil with Horner syndrome will dilate in response to topical apraclonidine. In addition, Horner syndrome ptosis improves or resolves in response to apraclonidine (Fig 10-2). Denervation supersensitivity typically occurs several days after injury to the sympathetic pathway, though in rare cases, it may occur as early as several hours after symptom onset. Apraclonidine use is generally avoided for children younger than 1 year, in whom it may cause central nervous system depression and even acute respiratory arrest. Cocaine remains a better choice for this age group given its lower risk of adverse events. Brimonidine cannot be used as a substitute for apraclonidine for Horner syndrome testing.

Figure 10-2 Apraclonidine test for Horner syndrome. A, A patient with suspected oculosympathetic defect (ptosis and miosis) on the right side. B, Following instillation of topical apraclonidine in both eyes, the right pupil has dilated and the anisocoria is now reversed, confirming Horner syndrome on the right side. Note also the resolution of lid ptosis, even to the point of retraction on the right side. (Courtesy of Aki Kawasaki, MD.)

Once Horner syndrome is diagnosed, topical hydroxyamphetamine (1%) can be used to localize the lesion. This drug enhances the release of presynaptic norepinephrine from an intact third-order (postganglionic) neuron. After instillation of hydroxyamphetamine, the normal pupil should dilate. If the pupil with Horner syndrome does not dilate, then a lesion of the postganglionic neuron is suspected. If both pupils dilate well, then the lesion is more proximal, either in the firstor secondorder neuron of the oculosympathetic pathway (see Chapter 1, Fig 1-39).

Because commercial preparations of topical hydroxyamphetamine have been difficult to obtain and their use has produced a high rate of false-negative results, hydroxyamphetamine for localization of Horner syndrome has fallen out of favor. In most instances, the clinical presentation is sufficient to suggest the site of injury and the necessary evaluation. The presence of ataxia, nystagmus, and hemisensory deficit points to a medullary lesion (eg, vascular insult, tumor, or demyelination), and magnetic resonance imaging (MRI) of the brain and upper cervical cord is recommended. Symptoms such as arm pain, cough, hemoptysis, and swelling in the neck suggest a second-order (preganglionic) lesion in the superior sulcus (Pancoast syndrome) or in the mediastinum, and cervicothoracic MRI is recommended. Other preganglionic lesions include thyroid mass, chest surgery, thoracic aortic aneurysms, or trauma to the brachial plexus (Fig 10-3).

Figure 10-3 Second-order neuron Horner syndrome. A, This patient demonstrates right-sided ptosis and miosis in bright light. B, The anisocoria increases in the dark. C, Following instillation of hydroxyamphetamine eyedrops (1%), both pupils dilate, indicating that the third order neuron is intact. D, The patient’s chest tomography demonstrates a right apical mass

(arrow) that proved to be a schwannoma. (Courtesy of Lanning B. Kline, MD.)

Symptoms associated with third-order (postganglionic) neuron injury include numbness over the first as well as the second or third divisions of cranial nerve (CN) V and double vision from sixth nerve palsy owing to a shared location of the sixth nerve and oculosympathetic fibers in the cavernous sinus. Isolated postganglionic Horner syndrome is often benign. If examination of old photographs verifies that the Horner syndrome has been present for several years, further investigation will probably be unrewarding. However, Horner syndrome associated with pain deserves extra attention.

Painful postganglionic Horner syndrome is a distinct clinical entity associated with several causes, most importantly carotid artery dissection (Fig 10-4). Pain from dissection is usually located around the temple and orbit, and may extend to the throat. Patients with painful postganglionic Horner syndrome may also have amaurosis fugax and altered taste (dysgeusia). This condition must be recognized because, in the acute stage, stroke is a possible complication. MRI typically shows an intramural hemorrhage, but in rare cases magnetic resonance angiography (MRA) or cerebral arteriography is needed to provide definitive evidence of dissection.

Figure 10-4 A, Internal carotid artery dissection. Axial MRI showing blood (arrow) in the wall of the right internal carotid artery (“crescent moon” sign). B, Catheter angiogram demonstrates “string” sign (arrows), confirming internal carotid

artery dissection. A = anterior; L = left; P = posterior; R = right. (Part A courtesy of Karl C. Golnik, MD; part B courtesy of Lanning B. Kline, MD.)

Cluster headache may also cause a painful Horner syndrome during an acute attack. The Horner syndrome often resolves but may become permanent after repeated attacks. Some patients, usually middle-aged men, have Horner syndrome and daily unilateral headaches not characteristic of cluster headache; Raeder paratrigeminal syndrome has been used to describe this condition, for which no underlying pathology can be identified. This syndrome is a diagnosis of exclusion made after careful evaluation for underlying pathology in the parasellar and cavernous sinus regions.

Congenital Horner syndrome is usually caused by birth trauma to the brachial plexus. Nontraumatic Horner syndrome in infants and children raises the possibility of neuroblastoma arising in the sympathetic chain of the chest. Imaging of the head, neck, and chest is recommended. Analysis for increased catecholamines and their metabolites in the urine is generally less sensitive than imaging studies for detecting neuroblastoma.

Kardon RH, Denison CE, Brown CK, Thompson HS. Critical evaluation of the cocaine test in the diagnosis of Horner’s syndrome. Arch Ophthalmol. 1990;108(3):384–387.

Mahoney NR, Liu GT, Menacker SJ, Wilson MC, Hogarty MD, Maris JM. Pediatric Horner syndrome: etiologies and roles of imaging and urine studies to detect neuroblastoma and other responsible mass lesions. Am J Ophthalmol. 2006;142(4):651– 659.

Morales J, Brown SM, Abdul-Ralim AS, Crosson CE. Ocular effects of apraclonidine in Horner syndrome. Arch Ophthalmol. 2000;118(7):951–954.