Anisocoria and Pupillary Abnormalities


Anisocoria and Pupillary Abnormalities

Careful examination of pupillary reaction to light and near stimuli, the difference in anisocoria in light and dark, and attention to distinctive associated signs and symptoms facilitate differentiating the abnormalities in pupil size and response to stimuli. Old photographs may be helpful in defining the duration of anisocoria. Generally, the history and examination help distinguish the major entities causing an abnormal large pupil (e.g., third nerve palsy, tonic pupil, iris damage, pharmacologic dilation, or sympathetic irritation) or small pupil (e.g., Horner’s syndrome, simple anisocoria, pharmacologic miosis). Pharmacologic testing confirms the diagnosis and facilitates topographic localization in many cases. Our algorithm cannot account for patients with multiple causes for anisocoria. For example, Slavin reported a case of physiologic anisocoria with Horner’s syndrome and equal-sized pupils (Slavin, 2000).

Is the Anisocoria More Apparent in the Light or in the Dark?

If the anisocoria is greater in dim light (stimulates dilation of the pupils), then the defect is in the sympathetic innervation of the pupil. If the anisocoria is greater in bright light (stimulates constriction of the pupil), then the lesion is in the parasympathetic innervation of the pupil. If a large pupil is poorly reactive to light and the visual afferent system is normal, then a defect in the efferent parasympathetic innervation to this pupil is likely (Burde, 1992). If the light reaction is difficult to compare to the fellow eye, then a measurement of the anisocoria in light and dark may help determine the pupillary abnormality.

Is Light-Near Dissociation Present?

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).

Table 20–1. Etiologies of Light-Near Dissociation

Bilateral afferent disease

Bilateral anterior visual pathway (optic nerve, chiasm, tract)

Bilateral retinopathy

Midbrain lesions

Dorsal midbrain syndrome (Parinaud’s syndrome)


Wernicke’s encephalopathy and alcoholism


Pineal tumors

Vascular disease

Argyll Robertson pupil

Diabetes (autonomic neuropathy)

Tonic pupils (e.g., local orbital, neuropathic, Adie’s pupil)

Aberrant third nerve regeneration (not sparing of near but “restoring” of near)

Syringomyelia (rare)

Familial amyloidosis

Spinocerebellar ataxia type 1 (SCA-1) (Mabuchi, 1998)

Basilar aneurysms can produce isolated internal ophthalmoplegia, but this finding is rare and usually the patient rapidly develops signs of external ophthalmoplegia due to third nerve dysfunction. Gale and Crockard observed transient unilateral mydriasis in a patient with a basilar aneurysm (Gale, 1982). Miller reported an isolated internal ophthalmoplegia in a patient with a basilar aneurysm (Miller, 1985). Wilhelm et al described an oculomotor nerve paresis that began as an isolated internal ophthalmoplegia in 1979 and then developed into a more typical third nerve palsy in 1993 due to a neurinoma of the third nerve (Wilhelm, 1995). Kaye-Wilson et al. also described a patient who initially had only minimal pupil signs due to a neurinoma of the third nerve (Kaye-Wilson, 1994). A mydriatic pupil was the presenting sign of a common carotid artery dissection with the pupil dilation preceding other signs and symptoms of a third nerve palsy and cerebral ischemia (Koennecke, 1998). These cases are uncommon presentations, and in general an isolated dilated pupil is more likely to be due to local iris abnormalities, the tonic pupil syndrome, or pharmacologic dilation than third nerve palsy (class IV, level C).

Other rare cases of interpeduncular cyst, mesencephalic hemorrhage, presumed ocular motor nerve inflammation due to meningitis (e.g., bacterial, cryptococcal or tuberculous basal), and direct head trauma to the third nerve at the posterior petroclinoid ligament have been described that presented with an isolated, unilateral, fixed, and dilated pupil. Other neurologic signs of a third nerve palsy, however, were present or appeared over time in almost all these patients. Unilateral pupillary involvement from probable preganglionic oculomotor nerve dysfunction (normal ductions but pupil minimally reactive to light; however, reacted well to near stimuli) has also been described with superficial siderosis of the central nervous system (CNS) with selective involvement of the superficially located pupillary fibers (Pelak, 1999). In a patient with an isolated dilated pupil in the presence of normal extraocular motility, a third nerve palsy can be safely excluded in almost every circumstance simply with close follow-up (class IV, level C).

In indeterminate cases, topical pilocarpine 1% can be used as a simple test for third nerve palsy versus pharmacologic blockade (see below). A pupil dilated from a third nerve palsy will constrict to pilocarpine 1%, but one with a parasympathetic pharmacologic blockade will not.

Is There Evidence for Pharmacologic (or Toxic) Mydriasis or Miosis?

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.

Table 20–2. Medications and Environmental Agents Associated with Mydriasis or Miosis

Ocular mydriatics



Topical parasympatholytics (anticholinergics)


Cyclopentolate (Cyclogyl)





Tropicamide (Mydriacyl)


Topical sympathomimetics (adrenergic)

Apraclonidine (α-adrenergic agonist) (Morales, 2000)


Dipivalyl epinephrine (Propine)

Phenylephrine (NeoSynephrine)

Cocaine (e.g., topical placed in nose may back up into conjunctival sac)

Ocular decongestants (tetrahydrozoline hydrochloride, phenerimine maleate, chlorpheniramine maleate) (Gelmi, 1994)

Topical dexamethasone (vehicle in Decadron)

Topical apraclonidine

Aerosolized albuterol sulfate—ipratropium bromide (anticholinergic) given by loosely fitting mask (Goldstein, 1997)

Adrenergic drugs given in a mist for pulmonary therapy may escape around mask and condense in conjunctival sac

Anesthetic agents for the airway

Phenylephrine/lidocaine spray (Prielipp, 1994)

Nasal vasoconstrictor (phenylephrine)

Aerosolized atropine (Nakagawa, 1993)

Local and systemic mydriatics (Miller, 1985)

Atropine (IV) in general anesthesia


Barracuda meat


Cocaine (Stewart, 1999)


Epinephrine (Perlman, 1991)




Lidocaine local injection (e.g., orbital injection)

Lysergic acid diethylamide



Nutmeg (? may not have an effect on pupils)

Pimozide (? patient also treated with benztropine)

Propantheline bromide (Pro-Banthine)

Scopolamine methylbromide (Nussdorf, 2000)


Transdermal scopolamine patches

Tricyclic antidepressants


Alkaloids (belladonna alkaloids) (anticholinergic effect)

Jimson weed (Datura stramonium)

Blue nightshade or European bittersweet (Solanum dulcamara)

Deadly nightshade (Atropa belladona)

Henbane (Hyoscamus niger)

Moonflower (Datura wrightii or D. meteloides)

Other Datura species (D. suaveolans [angel’s trumpet], aurea, Candida, sanguinea, stramonium, wrightii) (Wilhelm, 1994)


Siderosis bulbi/iron mydriasis—occult intraocular iron foreign body (Monteiro, 1993; Scotcher,1995)

Hypromellose viscoelastic in cataract surgery (Tan, 1993)

Ocular miotics



Parasympathomimetics (cholinergic)



Methacholine (Mecholyl)

Organophosphate esters

Physostigmine (eserine)


Sympatholytics (antiadrenergic)

Adrenergic blockers

Thymoxamine hydrochloride

Dapiprazole (“RevEyes”)

Dibenzyline (hemoxybenzamine)

Phentolamine (Regitine)

Tolazoline (Priscoline)


Timolol with epinephrine

Systemic miotics

Adrenergic blockers



Lidocaine (extradural anesthesia)



Morphine and other narcotics



Flea collar (anticholinesterase)

Pyrithens and piperonyl butoxide (insecticide) (anticholinesterase)

Jacobson reported 24 patients with benign episodic unilateral mydriasis (Jacobson, 1995). The median age of the patients was 31 (range, 14 to 50) and the median duration of events was 12 hours (range, 10 minutes to 7 days). Associated symptoms included visual blur, headache, orbital pain, monocular photophobia, monocular red eye, monocular diplopia, and monocular positional transient obscurations. Some cases were thought due to parasympathetic insufficiency of the iris sphincter. These patients had associated impaired near vision, impaired accommodative function, and the anisocoria increased with added ambient light. Other patients had sympathetic hyperactivity of the iris dilator associated with normal near vision and normal reaction of the pupil during the attack. No associated neurologic disorders were found in these patients. We do not recommend any further evaluation for isolated transient unilateral mydriasis (class IV, level C).

Is a Structural Iris Abnormality Present?

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).

Table 20–3. Clinical Characteristics of Abnormalities of the Iris Structure

No associated ptosis or ocular motility disturbance (vs. third nerve palsy)

Pupil often irregular with disruption of pupillary margin due to tears in iris sphincter (vs. the smooth margin seen in drug-related pupillary abnormalities)

Irregular contraction of the pupil to light

Eventually iris atrophy may occur

Poor or no response to direct parasympathomimetic (e.g., 1% pilocarpine)

Table 20–4. Etiologies of Abnormalities of Iris Structure

Congenital aplasia of the iris sphincter and dilator muscles (Buys, 1993)

Increased intraocular pressure due to acute angle closure glaucoma (sphincter paresis due to iris ischemia)

Intraocular inflammation (e.g., iritis)

Ischemia (e.g., ocular ischemic syndrome, iris ischemia after anterior chamber air/gas injection after deep lamellar keratoplasty for keratoconus) (Maurino, 2002)

Mechanical (e.g., iris tumor, intraocular lens)

Surgical (e.g., iridectomy, iridotomy, iris damage)


Blunt trauma (traumatic iridoplegia)

Sphincter tears at the pupillary margin

Atonic pupil after cataract extraction (Behndig, 1998)

Is a Tonic Pupil Present?

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).

Table 20–5. Clinical Features of a Tonic Pupil

Poor pupillary light reaction

Segmental palsy of the sphincter

Tonic pupillary near response with light-near dissociation (near response not “spared” but “restored” due to aberrant regeneration)

Cholinergic supersensitivity of the denervated muscles

Accommodation paresis (that tends to recover)

Induced astigmatism at near

Tonicity of accommodation

Occasional ciliary cramp with near work

Occasionally regional corneal anesthesia (trigeminal ophthalmic division fibers in ciliary ganglion damaged)

Is the Tonic Pupil Isolated?

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).

Table 20–6. Etiologies of a Tonic Pupil

Local (ocular or orbital) lesion affecting ciliary ganglion or nerve

Infection (Capputo, 1992)

Campylobacter jejuni enteritis (Roberts, 1995)





Herpes simplex virus

Herpes zoster virus

HTLV-II (Hjelle, 1992)



Parvovirus B19 (Corridan, 1991)


Scarlet fever



Varicella virus (Hodgkins, 1993)

Viral hepatitis


Iritis/uveitis damage to ciliary ganglion

Rheumatoid arthritis


Vogt-Koyanagi-Harada syndrome (Kim, 2001 a)


Orbital vasculitis

Lymphomatoid granulomatosis (Haider, 1993)

Migraine (Purvin, 1995)

Giant cell arteritis

Orbital or choroidal tumor (Haider, 1993)

Polyarteritis nodosa (Bennett, 1999)

Local anesthesia (Perlman, 1991)

Inferior dental block

Injection of retrobulbar alcohol

Surgery (Bodker, 1993; Golnik, 1995; Halpern, 1995; Saiz, 1991)

Cataract surgery (Monson, 1992; Saiz, 1991)



Penetrating keratoplasty

Retinal surgery

Strabismus surgery

Orbital surgery (Bodker, 1993)

Laser therapy




Trauma (nonsurgical)

Blunt trauma to ciliary plexus

Orbital floor fracture

Retrobulbar hemorrhage

Damage to short ciliary nerves


Peripheral or autonomic neuropathy

Amyloidosis (Davies, 1999)



Familial dysautonomia

Hereditary neuropathy (e.g., Charcot-Marie-Tooth disease)

Guillain-Barré syndrome

Fisher syndrome (including isolated bilateral internal ophthalmoplegia with IgG anti-GQ1bantibodies) (Berlit, 1992; Caccavale, 2000; Cher, 1993; Igarishi, 1992; Ishikawa, 1990; Mori, 2001; Radziwill, 1998; Sawada, 1990)

Chronic inflammatory demyelinating polyradiculoneuropathy (Midroni, 1996)

Acute sensorimotor polyneuropathy with tonic pupils and abduction deficit with polyarteritis nodosa (Bennett, 1999)


Progressive autonomic failure

Shy-Drager syndrome

Ross’ syndrome (tonic pupil, hyporeflexia segmental anhidrosis) (Shin, 2000; Weller, 1992; Wolfe, 1995)

Sjögren’s syndrome (Bachmeyer, 1997; Vetrugno, 1997)

Systemic infectious (e.g., syphilis)


Eaton-Lambert syndrome (Wirtz, 2001)

Carcinomatous neuropathy

Congenital neuroblastoma with Hirschsprung disease and central hypoventilation syndrome (Lambert, 2000)

Unilateral Adie pupil in patient with small cell lung cancer and anti-Hu antibodies (Kimura Bruno, 2000)

Congenital neuroblastoma, Hirschsprung disease, central hypoventilation syndrome (Lambert, 2000)

Following oculomotor nerve palsy (Cox, 1991)

Adie’s tonic pupil syndrome



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.

Is the Pupillary Light Reaction Normal?

If the pupillary light reaction is normal in both eyes, then physiologic (simple) anisocoria (Lam, 1996), a Horner’s syndrome, sympathetic irritation, or pharmacologic mydriasis should be considered.

Is the Anisocoria Isolated?

Jun 4, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Anisocoria and Pupillary Abnormalities
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