constriction in both eyes when the light is presented to either eye. An abnormal response is characterized by larger pupils when the light is directed into the affected eye than when the light is directed into the normal eye (Figure 14-11).

As the intensity of the light increases, stronger constrictions occur when light is presented to a normal eye. There is a threshold, however, beyond which no increase occurs. A very bright light can be used for detecting subtle defects; however, the luminance level should be recorded because a future change in the measured RAPD might reflect only a different light condition.41,42

Clinical Comment: Afferent

Pupillary­ Defect in Cataract

It would appear likely that a dense cataract would cause an RAPD because less light penetrates a cataract to stimulate the retina. In a clinical situation, however, a dense cataract has been found to cause an RAPD in the contralateral eye.43,44 Light scattered back to the retina from the lens opacity probably produces an enhanced pupillary response, which is manifested as an RAPD of the contralateral eye.

Clinical Comment: Optic Neuritis

The most common site of damage in an RAPD is the optic nerve. Ninety percent of patients with optic neuritis exhibit an RAPD during some stage of the disease.39

DISRUPTION WITHIN THE CENTRAL NERVOUS SYSTEM

A lesion in the midbrain can involve the pretectal nucleus, the fibers leaving the nucleus, or the parasympathetic Edinger-Westphal nucleus. Damage to the pretectal nucleus might not cause a pupillary defect as fibers from the other pretectal nucleus still supply both parasympathetic nuclei.

Injury to the dorsal tegmentum of the midbrain, that interrupts the fibers from the pretectal nucleus to the parasympathetic third-nerve nucleus, if limited to one side and affecting all fibers into the Edinger-Westphal nucleus, results in a pupil that shows a poor direct and consensual response but does constrict with the near response. This pupillary response is commonly called the Argyll Robertson pupil and is said to show a “lightnear dissociation.45” Since the fibers carrying the message for the near reaction approach the Edinger-Westphal nucleus from a more ventral location, they do not pass through the affected area of the midbrain. Since the pathway from the frontal eye fields is intact and the efferent path is viable, the sphincter and ciliary muscle still will constrict to a near object.46 In the Argyll Robertson pupil, the retained near response exceeds the best directlight response (Figure 14-12), and when the patient looks from near to distant, the pupils redilate briskly.

A

B

C

FIGURE 14-11

Swinging-flashlight test.  A, Response is equal and symmetric, indicating no relative pupillary defect. B, Response is unequal, with both pupils growing larger as light is directed into the right eye, indicating a grade 1+ (relative afferent pupillary defect, right eye (RAPD OD). C, Unequal pupillary response in which both pupils enlarge as light is directed into the left eye, indicating a grade 3+ relative afferent pupillary defect, left eye (RAPD OS).

Because the fibers that carry inhibitory feedback to the parasympathetic nucleus also pass through the dorsal midbrain, miosis is a component of the Argyll Robertson syndrome and is evident in darkness, with the affected pupil smaller than would be seen in the normal individual.24 The Argyll Robertson syndrome is bilateral in approximately 80% to 90% of cases, but the two sides may be affected unequally.24 Diabetic neuropathy, alcoholic neuropathy, or neurosyphilis is suspected in a complete Argyll Robertson pupil that involves both sides. A near response that exceeds the light response is always a sign of a pathologic pupil.24

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B

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FIGURE 14-12

Argyll Robertson pupil, right eye (OD).  A, Poor direct response OD and normal consensual response left eye (OS). B, Normal direct response OS and poor consensual response OD. C, Normal near response in both eyes.

DISRUPTION IN THE EFFERENT PATHWAY

A lesion in the efferent pathway will cause the eye to show poor direct and consensual pupillary responses and a poor near response. The pupil appears large on clinical presentation, and other ocular structures are involved. Damage in the oculomotor nucleus or nerve could involve the superior rectus, medial rectus, inferior rectus, inferior oblique, or levator muscle, and the patient should be examined for related ocular motility impairment. The parasympathetic fibers in the oculomotor nerve are often spared in ischemic lesions, as from diabetes, but are especially vulnerable to compression because the fibers are superficial as the nerve emerges from the midbrain.24 Third nerve involvement that includes a dilated pupil is highly suspicious of a compressive intracranial lesion.

Damage to the ciliary ganglion or the short ciliary nerves could be caused by local injury or disease and results in a tonic pupil, which is characterized by poor pupillary light response and loss of accommodation. Decreased corneal sensitivity often occurs because some afferent sensory fibers from the cornea pass through the short ciliary nerves and the ganglion.47 The affected muscle may exhibit cholinergic denervation supersensitivity, a physiologic phenomenon resulting from injury to the fibers directly innervating muscles.48 The near response is retained, but it is delayed and slow, and the pupil redilates sluggishly. One theory postulates that

because the density of the innervation to the ciliary muscle is much greater than the density of innervation to the sphincter, some ciliary muscle nerve fibers remain intact. With near stimulation, these fibers release acetylcholine, which diffuses into the aqueous humor and then causes the supersensitive sphincter to constrict.49 In late stages of this condition, the pupil becomes tonic and the miotic near reaction difficult to demonstrate, but the accommodative facility appears to recover, perhaps as a result of regeneration of the fibers.20,50

Clinical Comment: Adie’s Tonic Pupil

If the cause of the tonic pupil is not apparent, the syndrome is called Adie’s tonic pupil. The typical patient with Adie’s pupil is a woman 20 to 40 years of age; 90% of these patients also have diminished tendon reflexes. Because

of this systemic manifestation, it is believed that similar degenerative processes are occurring in the ciliary ganglion and in the dorsal column of the spinal cord,51 but the cause is unknown.52 If pupillary constriction in early Adie’s pupil is examined with the biomicroscope, segmental constriction affecting only a section of the iris may be evident.53 An Adie’s pupil that has been tonic for years eventually becomes smaller and does not dilate well in the dark; thus it is the larger pupil in light and the smaller one in darkness.50

In the differential diagnosis of Adie’s pupil, a very mild, ­direct-acting cholinergic agonist can be used because the sphincter muscle is supersensitive.20,54 A dilute ­concentration of pilocarpine (0.125%) has minimal effect on a normal sphincter but will cause significant clinical miosis in a supersensitive­ sphincter. Some investigators believe that a normal pupil can respond to the 0.125% pilocarpine and recommend­ using a 0.0625% pilocarpine solution.55 With one drop instilled in each eye, the Adie’s pupil should show a much greater constriction than the normal pupil (Figure 14-13).

There is indication that a tonic pupil might in some cases be associated with autoimmune disease.56

Clinical Comment: Fixed, Dilated

Pupil

Recent onset of a fixed, dilated pupil could be caused by accidental drug-induced mydriasis. Investigation of the individual’s profession might indicate the handling of drugs (pharmacists, nurses) or chemicals that could exert such an effect (farmers, crop dusters, exterminators). Such a pupil will not respond to 0.125% pilocarpine. Some over-the- counter drops that promise to “get the red out” may also cause a dilated pupil.

DISRUPTION IN THE SYMPATHETIC PATHWAY

An interruption in the sympathetic pathway causes miosis. The usual tone that the dilator muscle normally exerts is not present, and there is no counteracting pull against the sphincter muscle, making the pupil smaller

A

B

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D

E

FIGURE 14-13

Adie’s pupil OD.  A, Presenting anisocoria; right pupil is larger than left pupil. B, Poor direct response OD and normal consensual response OS. C, Normal direct response OS and poor consensual response OD. D, Slow and long-lasting near response. E, Pilocarpine 0.125% instilled in both eyes. Miosis OD, no response OS.

than normal. Anisocoria (a difference in pupil size) is present under normal room light conditions but is more pronounced in dim light, with the normal eye having the larger pupil. The pupil responds briskly to light, but with slow and incomplete dilation in the dark. If the anisocoria decreases in bright lights and the pupils react normally to a light stimulus, the disruption is likely a sympathetic interruption to the dilator muscle or benign anisocoria.50

Clinical Comment: Benign

Anisocoria

Approximately 20% of the population have benign anisocoria (also called simple or physiologic anisocoria), which is usually more apparent in dim light than in room light, with the

difference between pupils usually less than 1 mm.50 Sometimes the anisocoria may switch sides, but both pupils are round and react well to all stimuli and dilate equally with the lights off. It represents an asymmetric balance between the sympathetic and parasympathetic innervation to the iris. Benign anisocoria may be caused by asymmetric supranuclear inhibition of the Edinger-Westphal nucleus.50

Clinical Comment: Horner’s

Syndrome

CLINICAL FEATURES

Damage in the sympathetic pathway to the head can cause Horner’s syndrome, which consists of ptosis, miosis, and facial anhidrosis (absence of sweat secretion). Loss of innervation to the smooth muscle of the upper eyelid causes ptosis, whereas loss of innervation to the lower eyelid causes it to rise slightly such that the palpebral fissure appears narrow, simulating enophthalmos (Figure 14-14).

The damage can occur anywhere along the sympathetic pathway in the brain, spinal cord, preganglionic path, or postganglionic path. Involvement of the central neuron, which sends its fiber from the hypothalamus through the spinal cord to a synapse with the preganglionic neuron in the cervical dorsal column, can also cause other problems (e.g., vertigo).

The preganglionic fibers leave the dorsal column of the spinal cord, pass into the chest, course over the apex of the lung, and loop around the subclavian artery en route to the superior cervical ganglion (Figure 14-15). These fibers can be damaged in thoracic injury or surgery or in metastatic disease involving the chest.6

The postganglionic fibers that enter the skull through the carotid plexus can be damaged by a fracture of the skull base or an injury to the internal carotid artery. Painful­ Horner’s syndrome is a classical symptom of carotid artery dissection and should be treated as an emergent situation­ .56 Horner’s in combination with a sixth nerve

­paresis indicates cavernous sinus involvement and a mass in or near the sinus must be ruled out.56 Damage along the rest of the postganglionic neuron can involve the nasociliary or long ciliary nerves.

IRIS HETEROCHROMIA IN HORNER’S PUPIL

Normal sympathetic innervation is necessary for the development and maintenance of iris melanocyte pigmentation. In congenital Horner’s syndrome, normal iris pigmentation fails to develop, and heterochromia is present (Figure 14-16). Heterochromia is rarely seen in acquired Horner syndrome but may develop after long-standing conditions.24

DIFFERENTIAL DIAGNOSIS

In addition to the clinical presentation of ptosis and miosis, dilation lag occurs in dim illumination, and this will differentiate Horner’s pupil from simple anisocoria. The normal pupil dilates within 5 seconds of lights being off because of the normal sympathetic activity to the dilator and the parasympathetic inactivation of the sphincter. In the Horner’s pupil there is no sympathetic activity, and the pupil thus dilates only from inactivation of the sphincter muscle and dilates more slowly, taking

10 to 20 seconds.50,56 Dilation lag does not occur with physiologic anisocoria.56

The location of the disruption of the sympathetic pathway is useful in determining appropriate care. In the ­differential diagnosis of Horner’s syndrome, diagnostic drugs used

to determine the site of interruption include cocaine and hydroxyamphetamine, the effects of which are shown in Figures 14-17 and 14-18. If the sympathetic pathway is intact, instillation of one drop of a 5% or 10% ophthalmic cocaine solution, an indirect-acting adrenergic agonist, causes dilation in 30 to 60 minutes.50,57,58 In contrast, with a disruption anywhere in the pathway, norepinephrine is lacking in the neuromuscular junction, and therefore cocaine has little or no effect, and the pupil dilates poorly.

Hydroxyamphetamine 1% can be administered to ­determine whether the damage is in the preganglionic or ­postganglionic pathway.59-61 A topical ­administration of this indirect-acting adrenergic agonist acts on the ­postganglionic fiber, causing release of norepinephrine. If the lesion is

in the preganglionic pathway, the postganglionic fiber still is viable and will contain stores of norepinephrine.

­Instillation of hydroxyamphetamine will cause release of the ­neurotransmitter, and dilation will occur. If the damage is in the ganglion or the postganglionic fiber, norepinephrine will not be stored in the nerve endings, and therefore no dilation will occur with instillation of hydroxyamphetamine.

The instillation should occur 24 to 48 hours after the cocaine test, and dilation may take up to an hour.50,62

In the presence of preganglionic and central lesions, the pupil on the affected side usually dilates more than the normal eye with hydroxyamphetamine instillation, either because of enhanced receptor sensitivity or because

the adrenergic nerve endings have accumulated more norepinephrine­ .62,63 In adults, central Horner’s syndrome is often related to stroke, preganglionic Horner’s often is associated­ with neoplasm, and postganglionic Horner’s syndrome­ may have a vascular cause.50

An alternative drug might be used in diagnosing ­postganglionic involvement because the dilator muscle could be supersensitive to a sympathomimetic and a ­solution of 1% phenylephrine could cause contraction. In the normal pupil, 1% phenylephrine will generally cause

continued on page 271

FIGURE 14-14

Postganglionic

Preganglionic

Central

FIGURE 14-15

Sympathetic innervation of the eye.  Preganglionic pathway courses from the superior cervical ganglion into the thoracic cavity before entering the skull. (From Maloney WF, Younge BR, Moyer NJ: Evaluation of the causes and accuracy of pharmacologic localization in Horner’s syndrome, Am J Ophthalmol 90:394, 1980. With permission from the Mayo Foundation.)

FIGURE 14-16

Ptosis and miosis in Horner’s syndrome. (From Kanski JJ, Nischal KK: Ophthalmology: clinical signs and differential diagnosis,

St Louis, 1999, Mosby.)

Iris heterochromia in congenital Horner’s syndrome. (From Kanski JJ, Nischal KK: Ophthalmology: clinical signs and differential diagnosis, St Louis, 1999, Mosby.)

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D

E

FIGURE 14-17

Horner’s syndrome.  A, Presenting anisocoria; left pupil is larger than right pupil. Ptosis OD. B, Anisocoria greater in dim illumination. C, Cocaine 5% instilled in each eye (OU). No response OD, mydriasis OS, interruption in sympathetic pathway OD. D, Hydroxyamphetamine 1% instilled OU. Mydriasis OU, interruption in preganglionic pathway OD. E, Hydroxyamphetamine 1% instilled OU. No response OD,

mydriasis OS, interruption in postganglionic pathway OD. Note also ptosis OD due to involvement of Müller’s muscle.

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B

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D

E

FIGURE 14-18

Dilation lag in 72-year-old man with Horner’s syndrome in left eye. A, Obvious anisocoria in bright illumination. B, Greater anisocoria at 4 to 5 seconds in darkness compared with (C) anisocoria at 10 to 12 seconds in darkness. D, Cocaine test for Horner’s syndrome. After instillation of 10% cocaine OU, there is dilation of normal right pupil but absence of dilation in left Horner’s pupil. E, Hydroxyamphetamine test in Horner’s syndrome. After instillation of 1% hydroxyamphetamine OU, there is dilation of normal right pupil but absence of dilation of left Horner’s pupil, indicating a postganglionic lesion. (From Bartlett JD, Jaanus SD: Clinical ocular pharmacology, ed 2, Boston, 1989, Butterworth-Heinemann.)