Tonic pupil

INTRODUCTION AND DEFINITION — The tonic pupil, sometimes called Adie tonic pupil or simply the Adie pupil, is the term used to denote a pupil with parasympathetic denervation that constricts poorly to light but reacts better to accommodation (near response), such that the initially larger Adie pupil becomes smaller than its normal fellow and remains tonically constricted, redilating very slowly when exposed to dark.

Although the eponym credits Adie with its discovery [1], the tonic pupil was originally described nearly synchronously by Adie, Morgan, Symonds, and Holmes in 1931 [2-5].

EPIDEMIOLOGY — The tonic pupil is a common cause of anisocoria, or unequal pupils. The prevalence of the Adie pupil is approximately two cases per 1000 population. Although patients of all ages are affected, the mean age is 32 years, and there is a female predominance (2.6:1) for the idiopathic variety (Adie tonic pupil).

PATHOGENESIS — The tonic pupil is the result of damage to the parasympathetic ciliary ganglion. The parasympathetic innervation to the iris and ciliary body travels with the third cranial nerve and synapses in the ciliary ganglion. After damage to the ciliary ganglion, reinnervation and upregulation of the postsynaptic receptors occurs, a process known as denervation supersensitivity. The number of axons destined for the ciliary body, however, is approximately 30 times the number that supply the pupil. After denervation occurs, the reinnervation may be aberrant, and fibers formerly destined for the ciliary body now travel to the pupil (aberrant regeneration).

Activation of the near response in this situation produces a better near reaction than light reaction (light-near dissociation of the pupils), and the reaction is tonic.

CAUSES — Most cases of the tonic pupil are idiopathic and referred to as the Adie tonic pupil. However, the tonic pupil can be caused by local disorders within the orbit affecting the ciliary ganglion including tumor, inflammation, trauma, surgery, or infection (table 1) [6-45].

Systemic autonomic neuropathies can also affect the ciliary ganglion and produce the tonic pupil. As examples:

●Ross syndrome – This syndrome is characterized by a triad of tonic pupil, hyporeflexia, and segmental anhidrosis [16,38,43,45].

●Harlequin syndrome – This syndrome is characterized by absence of flushing and sweating on one side of the body, particularly the face, arm, and chest. Some patients (13 percent in one series) also have a tonic pupil, although a Horner syndrome is more common and may coexist with a tonic pupil [46,47].

The infectious and inflammatory causes of the tonic pupil are further expanded in the table (table 2) as are the autonomic or peripheral neuropathic etiologies (table 3).

CLINICAL FEATURES — The clinical features of the Adie tonic pupil are as follows (table 4):

●Poor or absent pupillary light reaction

●Segmental palsy of the sphincter

●Tonic pupillary near response with light-near dissociation

●Cholinergic supersensitivity of the denervated muscles

●Accommodation paresis (that tends to recover)

●Induced astigmatism at near and tonicity of accommodation

●Occasional "ciliary cramp" (accommodative spasm) with near work

●Occasional regional corneal anesthesia (trigeminal fibers in ciliary ganglion damaged)

The tonic pupil constricts poorly or not at all to light but reacts better to accommodation (near response), such that the initially larger tonic pupil becomes smaller than its normal fellow and remains tonically constricted, redilating very slowly when exposed to dark.

Patients may have decreased deep tendon reflexes in the complete Holmes-Adie syndrome (table 5), but most patients are otherwise asymptomatic.

DIAGNOSTIC EVALUATION — The diagnosis of a tonic pupil is made clinically as follows. Typical patients present with incidental anisocoria. The main clinical question in the patient with anisocoria is deciding whether the larger pupil or the smaller pupil is the problem. The key differentiating signs are:

●The pupillary reaction to light

●The pupillary near response

●The amount of anisocoria in the light and in the dark

Examination — Review of old photographs is useful for defining the duration of an anisocoria. Patients referred for pupil abnormalities should be told to bring as many old photographs of themselves as possible to the appointment. (See "Approach to the patient with anisocoria".)

A pupil that reacts poorly to light is obviously the pathologic one, if one pupil is poorly reactive and the other pupil is normally reactive. In these circumstances, the anisocoria is generally less in the dark and more in the light (poor constriction of affected pupil). Patients with an impaired light reaction should be tested for a pupillary near response.

A normal near response in the setting of an impaired or absent light response is termed "light-near dissociation." This finding can be unilateral or bilateral. Bilateral light-near dissociation of the pupils is demonstrated, if the light reaction is poor and the near reaction is intact in both eyes. The table lists the causes of light-near dissociation (table 6).

The tonic pupil is distinguished from other causes of light-near dissociation by the tonicity of the near reaction. The tonic reaction is the result of iris sphincter supersensitivity to acetylcholine. The pupil is often irregular. When stimulated, the pupil response is strong and tonic, and relaxation is slow and sustained.

Initially, there may be an isolated internal ophthalmoplegia, and in the acute stage there may be no reaction to light or near at all. This presentation may mimic pharmacologic dilation of the pupil. In this setting, the diagnosis of a tonic pupil can usually be made by observation, as the light-near dissociation and denervation supersensitivity develop over time. Some segments of the pupil may react normally (vermiform movements), while other segments may not react to light well or at all (sector paresis).

Although the tonic pupil is usually larger than the uninvolved fellow eye, over time the pupil tends to become smaller (the "little old Adie" pupil). Approximately 20 percent of Adie pupils are bilateral with a 4 percent incidence of bilateral involvement per year (picture 1). The key finding in the miotic long-standing Adie pupil will be the poor light reaction and the tonic near response.

Pharmacologic testing — No further pharmacologic testing is typically necessary if the characteristic features of the Adie tonic pupil are present (figure 1 and table 5).

Otherwise, low-dose pilocarpine (one-eighth to one-tenth percent) may be useful to demonstrate the cholinergic supersensitivity in the tonic pupil. After the administration of the dilute pilocarpine, a more miotic response will be seen compared with the fellow eye (figure 1).

Unfortunately, cholinergic supersensitivity is not uniformly present in tonic pupils (approximately 80 percent) and is not specific for postganglionic parasympathetic denervation. Both eyes should be tested, as some patients may respond to low-dose pilocarpine, especially patients who have light-colored irises [7].

Supersensitivity has also been reported after preganglionic lesions of the third nerve. In addition, as stated previously, an acute Adie tonic pupil may not have had time to develop postganglionic supersensitivity, and absent supersensitivity does not exclude the diagnosis in this setting. Because this presentation may mimic pharmacologic dilation, the patient should be followed over time to allow the additional typical findings of tonic pupil to develop.

ETIOLOGIC EVALUATION — Patients with a defined etiology (eg, local orbital disorders or known systemic autonomic neuropathy) for the tonic pupil do not generally require additional evaluation (table 1 and table 2 and table 3). Likewise, no additional testing is necessary if the clinical or pharmacologic diagnosis of the typical Adie tonic pupil is made (table 5).

Symptoms or signs of gastrointestinal, cardiac, or segmental hypohidrosis and areflexia should prompt evaluation for systemic dysautonomia (eg, Ross syndrome) in patients with tonic pupils.

Patients with unexplained bilateral tonic pupils should probably have serologic testing for syphilis [8] (see "Syphilis: Screening and diagnostic testing"). In one series of 60 patients with tonic pupils, 5 of 29 had positive serologic tests for syphilis and in addition had bilateral tonic pupils [9].

While syphilis may infrequently produce the tonic pupil, late syphilis is associated with the Argyll Robertson pupil (see "Neurosyphilis"). In addition to light-near dissociation, the Argyll Robertson pupil is typically miotic and irregular. However, Argyll Robertson pupils are not tonic. They constrict quickly to near and redilate quickly when removed from the near stimulus.

Although classically described with neurosyphilis, other entities may produce pupillary light-near dissociation. These etiologies include diabetes, chronic alcoholism, encephalitis, multiple sclerosis, peripheral nerve disease (eg, Charcot-Marie-Tooth), rare midbrain tumors, herpes zoster, neurosarcoidosis, and lymphocytic meningoradiculitis.

Patients with light-near dissociation of the pupils in the setting of a third nerve palsy including aberrant regeneration of the third nerve or other dorsal midbrain signs should undergo neuroimaging, preferably magnetic resonance imaging of the brainstem with contrast. Patients with systemic autonomic neuropathies (eg, Ross syndrome) should undergo appropriate general neurologic and other testing as indicated.

TREATMENT — Most patients with a tonic pupil do not require any treatment. Patients with an underlying systemic cause for their tonic pupils should have treatment directed at their other autonomic neuropathies.

Although patients with Adie syndrome may complain of difficulty reading due to accommodative paresis, this usually improves spontaneously. Unequal power bifocal reading aids or a unilateral frosted bifocal segment may be necessary for patients with permanent accommodative paresis. Topical low-dose pilocarpine or physostigmine may help with symptomatic patients but can precipitate ciliary spasm, induce myopia, cause brow ache, or worsen the appearance of the anisocoria [6].

PROGNOSIS — The Adie tonic pupil is benign, and most patients only require reassurance once the diagnosis is confirmed. Angle-closure glaucoma has been rarely reported secondary to the tonic pupil, once in association with plateau iris [10,11].

The accommodative paresis tends to resolve spontaneously over several months. The pupil light reaction usually does not recover and may even become weaker over time with an increasing light-near dissociation. In some patients, the pupil becomes smaller with time ("little old Adie").

SUMMARY AND RECOMMENDATIONS

●Pathogenesis and causes – The tonic pupil results from parasympathetic denervation at the level of the ciliary ganglion and postganglionic nerves. (See 'Pathogenesis' above.)

Most cases of the tonic pupil are idiopathic and referred to as the Adie tonic pupil. However, the tonic pupil can be caused by local disorders within the orbit affecting the ciliary ganglion including tumor, inflammation, trauma, surgery, or infection. (See 'Causes' above.)

●Clinical features and evaluation – The tonic pupil is a common cause of anisocoria. The tonic pupil constricts poorly or not at all to light but reacts better to accommodation (near response), such that the initially larger tonic pupil becomes smaller than its normal fellow and remains tonically constricted, redilating very slowly when exposed to dark.

The main clinical question in the patient with anisocoria is deciding whether the larger pupil or the smaller pupil is abnormal. The key differentiating signs are the pupillary reaction to light, the near response, and the amount of anisocoria in the light and in the dark. (See 'Diagnostic evaluation' above.)

Tonic pupil is distinguished from other causes of light-near dissociation by the tonicity of the near reaction. (See 'Diagnostic evaluation' above.)

●Diagnosis – Pharmacologic testing is usually not necessary if the typical clinical features of the tonic pupil are present. Otherwise, low-dose pilocarpine may be useful to demonstrate the cholinergic supersensitivity in the tonic pupil. (See 'Diagnostic evaluation' above.)

●Evaluation for underlying cause – Patients with a defined etiology for the tonic pupil do not generally require additional evaluation. Likewise, no additional testing is necessary if the clinical or pharmacologic diagnosis of the typical unilateral Adie tonic pupil is made. (See 'Etiologic evaluation' above.)

Patients with unexplained bilateral tonic pupils should probably have serologic testing for syphilis, and patients with light-near dissociation of the pupils in the setting of a third nerve palsy or other dorsal midbrain signs should undergo neuroimaging. (See 'Etiologic evaluation' above.)

●Treatment – Most patients with a tonic pupil do not require any treatment. Those who have an identified cause of tonic pupil should receive appropriate treatment directed at the underlying cause. (See 'Treatment' above.)

●Prognosis – The Adie tonic pupil is benign, and most patients only require reassurance once the diagnosis is confirmed. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Claudia Prospero Ponce, MD, and Aroucha Vickers, MD, who contributed to an earlier version of this topic review.