If the light reaction is poor in both eyes but the near reaction is intact, the patient has bilateral light-near dissociation of the pupils. Table 20–1 lists the causes of light-near dissociation.

Argyll Robertson pupils are small and irregular and are characterized by light-near dissociation, variable iris atrophy, and normal afferent visual function. They are classically described with neurosyphilis, and the lesion is within the rostral midbrain and pretectal oculomotor light reflex fibers on the dorsal side of the Edinger-Westphal nucleus. There is sparing of the near fibers that approach this nucleus more ventrally. The pupils are small because supranuclear adrenergic inhibitory fibers to the Edinger-Westphal nucleus are blocked. Patients with diabetes may also have small, poorly reactive pupils with light-near dissociation that may appear similar to the Argyll Robertson pupil.

Is There Other Evidence for a Third Nerve Palsy?

Patients with anisocoria and a poorly reactive pupil should be evaluated for ipsilateral third nerve palsy. Sunderland and Hughes suggested that an extraaxial lesion compressing the third nerve (e.g., unruptured intracranial aneurysm) may cause a dilated pupil in isolation or with minimal ocular motor nerve paresis. Anisocoria or a dilated pupil in the absence of an extraocular motility deficit and/or ptosis, however, is rarely due to a third nerve paresis (Sunderland, 1952). Intracranial aneurysms (e.g., posterior communicating artery-internal carotid artery junction) often produce a fixed and dilated pupil (pupil-involved third nerve palsy), but this is almost always associated with other signs of a third nerve palsy (Miller, 1985). Walsh and Hoyt reported a patient with headache and a unilateral dilated pupil who was found to have an aneurysm at the junction of the superior cerebellar artery and basilar artery (Walsh, 1969). One week later, however, the patient developed other signs of a third nerve palsy. Payne and Adamkiewicz reported a case of unilateral internal ophthalmoplegia with a posterior communicating aneurysm, but this patient also had an intermittent exotropia and variable ptosis (Payne, 1969). Crompton and Moore reported two cases of isolated pupil dilation due to aneurysm, but these patients developed severe headache and eventual signs of a third nerve palsy (Crompton, 1981). Fujiwara et al reviewed 26 patients with an oculomotor palsy due to cerebral aneurysm and reported three with only ptosis and anisocoria (Fujiwara, 1989).

A careful history is usually all that is required for patients with inadvertent or intentional (e.g., glaucoma medication, treatment with topical cycloplegics for uveitis) exposure to agents that may affect pupil size (e.g., mydriatics or miotics). Table 20–2 lists some medications and environmental agents that may result in mydriasis or miosis. Pharmacologically induced pupil abnormalities may produce a large pupil due to increased sympathetic tone with dilator stimulation (e.g., ocular decongestants, adrenergic inhalants in the intensive care unit, etc.) or decreased parasympathetic tone with sphincter block (e.g., belladonna alkaloids, scopolamine patch, anticholinergic inhalents, topical gentamicin, lidocaine injection in orbit, etc.). Small pupils might indicate decreased sympathetic tone or increased parasympathetic stimulation (e.g., pilocarpine glaucoma drops, anticholinesterases such as flea collar or insecticides, etc.).

Nurses, physicians, and other health care workers are particularly prone to inadvertent or intentional exposure to pharmacologic mydriatics. The pupil size of patients with pharmacologic sphincter blockade is often quite large (8 to 12 mm in diameter). This large, dilated pupil is much greater than the mydriasis usually seen in typical third nerve palsy or tonic pupil syndromes. The pupils are evenly affected for 360 degrees, unlike the irregular pupil seen in the tonic pupil or iris trauma. Topical pilocarpine 1% can be used as a simple test for pharmacologic blockade. A pupil dilated from a third nerve palsy will constrict to pilocarpine 1%, but a pupil with a parasympathetic pharmacologic blockade will constrict poorly or not at all to topical miotics. An acute tonic pupil may be unreactive to either light or near stimuli and may be difficult to distinguish from a pharmacologically dilated pupil or acute traumatic iridoplegia.

Adrenergic pharmacologic mydriasis (e.g., phenylephrine) typically produces blanched conjunctival vessels, retains residual light reaction, and produces a retracted upper lid due to sympathetic stimulation of the upper lid retractor muscle. Most “eye-whitening” over-the-counter eyedrops (e.g., oxymetazoline, phenylephrine) contain sympathomimetics too weak to dilate the pupil unless the corneal epithelium is breached (e.g., contact lens wear). Exposure to anticholinesterases can result in a miotic pupil (Apt, 1995; Ellenberg, 1992). For cases of presumed isolated dilated or constricted pupils due to pharmacologic exposure, we recommend close follow-up to ensure that the pupil returns to normal size. Confirmatory pharmacologic testing could be considered in atypical or persistent cases (class IV, level C).

Are Intermittent or Transient Pupillary Phenomena Present?

Transient mydriasis or miosis has been reported in the following conditions: cluster or migraine headaches (Drummond, 1991); migraine aura without headache (Soriani, 1996); astrocytoma (Berreen, 1990); Horner’s syndrome after carotid puncture; during or after seizure activity (Masjuan, 1997); after reduction of bilateral orbital floor fractures (Stromberg, 1988); and in normal individuals. Episodic miosis with ptosis accompanied by ipsilateral nasal stuffiness may occur without headache (cluster sine headache) (Salveson, 2000). Tadpole-shaped pupils due to segmental spasm of the pupil sphincter may also be related to a partial postganglionic Horner’s syndrome or migraine phenomenon (occurs between rather than with headache attacks). Some of these phenomena represent true sympathetic irritation or excess, but the mechanism remains controversial. If the transient or intermittent nature of the mydriasis can be firmly established, then these patients should not undergo arteriography or other testing and should simply be followed for 24 to 48 hours, at which point improvement would indicate the benign nature of the mydriasis.

Careful slit-lamp biomicroscopy of the iris should be performed in all patients with anisocoria to exclude structural iris abnormalities or damage. In many cases, the pupil is irregular and the structural abnormality can easily be identified. Table 20–3 outlines the clinical features of structural iris abnormality and Table 20–4 lists some etiologies of structural damage to the iris. Abnormalities of the iris are a common cause of anisocoria. False-positive pharmacologic testing may result in patients with structural abnormalities of the iris that prevent dilation or constriction to pharmacologic agents. In these cases, it may be necessary to test the integrity of the pupil dilation or constriction capacity by applying a topical direct sympathomimetic or parasympathomimetic (class IV, level C).

The typical presentation of the tonic pupil is isolated anisocoria that is greater in light. Patients often present with acute awareness of the dilated pupil. The clinical features of a tonic pupil are listed in Table 20–5.

Pharmacologic testing with low-dose pilocarpine (1/8%) may demonstrate cholinergic supersensitivity in the tonic pupil (a more miotic response than the fellow eye). Leavitt et al suggested a solution of 0.0625% pilocarpine (Leavitt, 2002). Unfortunately, cholinergic supersensitivity is not uniformly present in tonic pupils (80% with topical pilocarpine testing) and is not specific for postganglionic parasympathetic denervation. Supersensitivity has been reported after oculomotor nerve palsy (Cox, 1991; Jacobson, 1990, 1994). In addition, larger-sized pupils normally constrict more than smaller pupils to the same dose of topical cholinergics. Jacobson recommends evaluating cholinergic supersensitivity responses in darkness to minimize the mechanical resistance factors of large and small pupil size (Jacobson, 1990, 1994). A larger pupil that becomes the smaller pupil in darkness after topical cholinergics is more likely a supersensitive response (Jacobson, 1990, 1994).

The history and examination should be able to differentiate the various associations of secondary pupils from idiopathic Adie’s tonic pupil syndrome. Table 20–6 lists the causes of a tonic pupil.

Is This Adie’s Tonic Pupil Syndrome?

The clinical features of Adie’s tonic pupil syndrome, based on Thompson’s extensive review (Thompson, 1977a,b) and the literature, is reported in Table 20–7. With the tonic pupil, the iris sphincter and ciliary muscles become supersensitive to acetylcholine, and thus when they are stimulated their response is strong and tonic and their relaxation is slow and sustained. Initially there is an isolated internal ophthalmoplegia, and in the acute stage there is no reaction to light or near stimuli at all. The diagnosis of a tonic pupil can usually be made on clinical grounds alone (class IV, level B).

What Causes the Adie’s Tonic Pupil Syndrome?

The pathophysiology of Adie’s tonic pupil is damage to the ciliary ganglion (Kardon, 1998; Phillips, 1996; Soylev, 1997). More than 90% of the ciliary ganglion cells normally serve the ciliary body and only 3% serve the iris sphincter. After damage to the ciliary ganglion, aberrant regeneration of fibers originally destined for the ciliary body now innervate the iris sphincter. The initially mydriatic pupil may become smaller over time (“little old Adie’s”) and indeed Adie’s tonic pupil may present as a miotic pupil (acute awareness rather than acute onset of anisocoria). Although most Adie’s tonic pupils present unilaterally, bilateral involvement may develop at a rate of 4% per year (Thompson, 1977a). Thompson reviewed 220 cases from the literature and reported that 20% were bilateral (Thompson, 1977a). Rarely, Adie’s syndrome may be associated with a chronic cough likely related to vagal involvement (Kimber, 1998).

Should Neuroimaging Studies Be Performed in Adie’s Syndrome?

Once the diagnosis of the Adie’s tonic pupil is confirmed clinically and/or pharmacologically, no neuroimaging studies are required (class III–IV, level C).

What Treatment Is Recommended for Adie’s Syndrome?

Patients with Adie’s syndrome often complain of difficulty reading due to accommodative paresis. The treatment of Adie’s tonic pupil is usually reassurance alone. Unequal bifocal reading aids or a unilateral frosted bifocal segment may be needed for patients with accommodative paresis. The use of topical low-dose pilocarpine or eserine has been suggested by some authors for Adie’s syndrome, but may precipitate ciliary spasm, induce myopia, cause browache, or worsen anisocoria due to miosis (Thompson, 1977a,b). We do not generally recommend treatment for Adie’s tonic pupil (class IV, level C).

When Does One Perform Syphilis Serology in Bilateral, Tonic or Miotic, Irregular Pupils with Light-Near Dissociation?

Thompson recommends that all patients with bilateral tonic pupils should have serologic testing for syphilis (Thompson, 1977a). Fletcher and Sharpe reported that five of 60 consecutive patients with tonic pupils had positive serology for syphilis (Fletcher, 1986). Of these patients, all were bilateral tonic pupils and none presented with acute mydriasis or cycloplegia. We recommend syphilis serology for unexplained bilateral tonic pupils (class IV, level C).

The Argyll Robertson pupil consists of bilateral, miotic, irregular pupils with light-near dissociation. Although classically described with neurosyphilis, other entities may produce a similar clinical syndrome. These etiologies include diabetes, chronic alcoholism, encephalitis, multiple sclerosis, degenerative diseases of the CNS (e.g., Charcot- Marie-Tooth), rare midbrain tumors, herpes zoster, neurosarcoidosis, and lymphocytic meningoradiculitis.

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