AUTHOR AND EDITOR INFORMATION

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• Follow-up
• Miscellaneous
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INTRODUCTION

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• Introduction
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• Follow-up
• Miscellaneous
• Multimedia
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Background

Anisocoria, or a difference in pupil size, is a common condition. A variety of potential causes for anisocoria exist, ranging from trivial or normal variation to life threatening.

This article serves as an introduction to anisocoria, while specific causes are discussed in greater detail in Anisocoria in eMedicine's Neurology journal.

Pathophysiology

Anisocoria may result from any of several pathophysiologies; however, it is useful to keep in mind the basic anatomy when evaluating such patients. The iris, parasympathetic pupillary constrictors, and sympathetic pupillary dilators comprise the basic pupil control system.

Frequency

United States

No general statistics on the prevalence of anisocoria exist, probably because of the diversity of causes; however, anisocoria is a frequently encountered situation in the clinic. Physiologic anisocoria is believed to occur in about 20% of the population.

Mortality/Morbidity

Mortality and morbidity in anisocoria is entirely dependent upon the underlying cause. Several causes of anisocoria are life threatening, while other causes are completely benign. The first step in understanding the implications of anisocoria in any individual patient is localization of the problem.

Race

Dependent upon etiology

Sex

Dependent upon etiology

Age

Dependent upon etiology

CLINICAL

Section 3 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
• Multimedia
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History

History related to anisocoria varies with the pathophysiology. Many patients are discovered incidentally or are asymptomatic, while other patients present with diplopia, pain, headache, or blurred vision.

A history of prior ocular trauma, intraocular surgery, uveitis, environmental exposures (eg, pet flea collar, jimson weed), eye drop use, medications (eg, scopolamine patch), and occupation (eg, health care worker with pharmacologic mydriasis) is important to note.

Physical

Key aspects of the physical examination include the size of pupils in light; the size of pupils in dark; and the pupil reactivity to light and, where applicable, accommodation.

Ptosis and dysmotility should be documented in any evaluation of anisocoria. The slit lamp examination may be invaluable in the detection of iris notches (post trauma), posterior synechiae, and iris masses. The vermiform movements of an Adie pupil are best seen with the slit lamp.

In some algorithms for the workup of anisocoria, tonometry is included. However, the fixed mid-dilated pupil of angle-closure glaucoma usually is accompanied by a misty cornea that is seen readily on slit lamp examination. Usually, the contralateral eye also shows a narrow angle.
 

• Pupil size
  
  
  • The pupil size is assessed best with an obliquely placed Finnoff transilluminator with the patient viewing a distant object (to relax accommodation), while the level of ambient light is varied. It is recorded best as size of the individual pupils under these conditions, while such abbreviations as PERRLA (pupils equal round reactive to light and accommodation; accommodation refers to lens thickening, the only aspect of the near triad that is not visible) are best avoided.
  • Old photographs frequently are helpful in dating the onset of anisocoria, especially if the patient is asymptomatic (family album tomography [FAT scan]). Photographs may be examined with the 20-diopter lens or slit lamp for magnification purposes, and anisocoria often is apparent with this method when unaided photograph examination is revealing.
• Pupil reactivity
  
  
  • The transilluminator is used to assess pupillary reaction to light, while a near card is used to assess reaction to near. Extremely bright sources of light, such as the indirect ophthalmoscope, may produce a tonic or spasticlike reaction that may confuse interpretation. Pupil reactivity is graded subjectively from 0 (no reaction) to 4 (hyperreaction) in each eye. Symmetry of reaction is more important than the absolute reactivity in most patients. The near response is effort dependent, and an accommodative target is mandatory; avoid use of nonaccommodative targets (eg, examiner's finger or pen).
  • Results of the examination are integrated with additional testing to arrive at a diagnosis, as outlined in Media file 1.

Causes

Causes of anisocoria are quite varied. Several causes are discussed briefly below.

• Physiologic anisocoria
  • This condition is quite common, occurring in approximately 20% of the population. The pupils are normally reactive, and anisocoria almost always is less than 1 mm in light or dark. No associated features (eg, diplopia, visual loss) are present.
  
  
  • Old photographs often are helpful in dating the onset of anisocoria. No further evaluation or therapy is required in this condition.


• Horner syndrome
  • Horner syndrome results from sympathetic dysfunction of the eye, producing the classic combination of miosis, anhydrosis (depending on lesion location), and ptosis. Causes vary from benign to life threatening, and pathophysiology often predicts the presentation. Patients typically are visually asymptomatic; however, associated features may prompt presentation depending on pathophysiology.
  
  
  • Examination reveals anisocoria greater in dark, 1-2 mm ptosis, and dilation lag (slowed dilation of the affected pupil in dark). The anisocoria typically is less than 2 mm, and it is often indiscernible in room light. Inverse ptosis of the lower lid (which also has sympathetic innervation) is a helpful sign in Horner syndrome. Anhidrosis may be present if the lesion is proximal to the internal carotid artery origin.
  
  
  • Iris heterochromia (which usually is not manifest at birth) may suggest a diagnosis of congenital Horner syndrome.
  
  
  • Pharmacologic testing is helpful in the diagnosis and categorization of Horner syndrome. Cocaine, which prevents norepinephrine reuptake, will fail to dilate the affected side. The typical dose is 1-2 gtt of 4-10% solution, and corneal defects may result from repeated or higher dose application. Cocaine tests are interpreted based on postdrop anisocoria; postdrop anisocoria of greater than 0.8 mm correlates with greater than 1000:1 odds of Horner syndrome. False-positive results may result from pupillary inability to dilate (eg, mechanical restriction).
  
  
  • Hydroxyamphetamine (Paredrine) stimulates norepinephrine release from the postganglionic or third order sympathetic neuron. If the postganglionic neuron is diseased, dilation will not occur in response to hydroxyamphetamine, while a lesion proximal to the third order neuron results in normal dilation to hydroxyamphetamine. Paredrine can be obtained from specialty pharmacies, such as Leiter's Pharmacy (San Jose, CA; phone 800-292-6773) or Thayer's Pharmacy (Orlando, FL; phone 800-848-4809).
  
  
  • Lesions anywhere along the sympathetic course, from the ipsilateral hypothalamus, through the brainstem and cervical cord, to the level of C8-T1 root, over the lung apex, up the carotid artery into the cavernous sinus, out the superior orbital fissure, and through the orbit, may produce Horner syndrome. Common causes include Wallenberg lateral medullary syndrome (eg, infarction), cervical cord disease (eg, syrinx, trauma), apical lung disease (eg, neoplasm, carotid artery dissection), or cavernous sinus disease (eg, inflammatory, neoplastic). Associated signs and symptoms, as well as pharmacologic localization, dictate the appropriate evaluation in these patients.
  
  


• Oculomotor nerve palsy
  • Oculomotor nerve palsy (third nerve, CN III) may affect the pupil and ocular motility. The pupil in CN III palsy appears larger and poorly reactive compared to its fellow pupil, and anisocoria is most apparent in light. It is extremely rare for the pupil to be affected in isolation, and, accordingly, it is important to examine patients with anisocoria for dysmotility.
  
  
  • Causes of oculomotor palsy include life-threatening entities, such as uncal herniation and aneurysmal compression. Pupil-involved oculomotor palsies are more likely to be related to compressive lesions and should be evaluated emergently. The dilated pupil of uncal (transtentorial) herniation observed with mass lesions and increased intracranial pressure is known as Hutchinson pupil. See also Oculomotor Nerve Palsy.
  
  


• Tonic pupil
  • An Adie pupil is the prototype tonic pupil. Classically, the affected pupil is larger than the fellow eye, and it is poorly reactive to light. The pupil reacts vigorously to near stimuli, constituting one of the near-light dissociation syndromes. Near response in an Adie pupil is tonic, meaning the miosis persists longer in the affected eye with slow redilation after removal of the near stimulus.
  
  
  • Slit lamp examination reveals sector palsy of the pupil, and vermiform movements of the iris often are visible. The pupil typically reacts to weak pilocarpine solution (1/8-1/16%), while the normal eye does not react to this solution. An acute onset Adie pupil may not constrict with dilute pilocarpine.
  
  


• Pharmacologic: The pharmacologically dilated pupil is dilated maximally and nonreactive to both near stimuli and light stimuli. In contrast to CN III palsy, the examination findings are normal, including motility and the lids, and the pupil is greater in size than the typical CN III pupil. Pharmacologic proof is the pupil's failure to constrict to pilocarpine 1% solution.


• Iris damage/mechanical: Mechanical damage to the iris may produce anisocoria. This damage includes not only trauma but also surgery and previous inflammation or uveitis. Iris damage often is visible at the slit lamp (eg, iris notch) and may produce poor reactivity to both light stimuli and dark stimuli with variable size.

DIFFERENTIALS

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Other Problems to be Considered

Tonic pupil
Adie pupil
Pharmacologic pupil
Physiologic anisocoria
Raeder syndrome
Argyll Robertson pupils/syphilis
Parinaud dorsal midbrain syndrome

WORKUP

Section 5 of 11  

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Lab Studies

• Laboratory evaluation generally is not relevant in the workup of anisocoria, but it depends entirely upon the specific pathophysiology.
• Patients with bilateral tonic pupils might show some anisocoria. In patients with bilateral tonic pupils, syphilis serology has been advocated.

Imaging Studies

• Evaluation depends on the specific type and cause of anisocoria. Imaging often is undertaken in Horner syndrome, and it may be aimed at the medulla, cervical cord, apex of the lung, carotid artery, or cavernous sinus, as indicated by the examination.

Other Tests

• Use of other tests depends upon the specific pathophysiology of the anisocoria.

Procedures

• Use of other procedures depends upon the specific pathophysiology of the anisocoria.

Histologic Findings

Histologic findings depend upon the specific pathophysiology of the anisocoria.

TREATMENT

Section 6 of 11  

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Medical Care

Medical care of patients with anisocoria is entirely dependent upon the etiology.

Surgical Care

Surgical care in anisocoria depends entirely upon the specific pathophysiology. Potential applications include neurosurgical care for aneurysm-related third nerve palsy mydriasis, ophthalmic surgical attention for traumatic iris defects, and vascular surgical consultation for Horner syndrome related to carotid dissection.

Consultations

Consultation may be useful depending upon the origin of the anisocoria.

Acute pupil-involved oculomotor palsy should be evaluated emergently by neuro-ophthalmology, neurology, or neurosurgery.

Neurology or neuro-ophthalmology consultation may assist in the evaluation of patients with Horner syndrome, especially if lateral medullary infarction or carotid dissection is in the differential diagnosis.

MEDICATION

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Medical therapy depends entirely upon etiology of the patient's anisocoria. Several drops are used in the diagnosis of anisocoria.

Drug Category: Anesthetics

Local anesthetics stabilize the neuronal membrane and prevent the initiation and transmission of nerve impulses, thereby producing the local anesthetic action.

Drug Category: Cholinergic agents

Dosage and frequency of administration must be individualized.

Drug Category: Sympathomimetics

Lower intraocular pressure mainly by increasing outflow and reducing production of aqueous humor.

FOLLOW-UP

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Further Inpatient Care

• Dependent upon etiology

Further Outpatient Care

• Dependent upon etiology
• In cases of persistent unequal accommodation (eg, Adie pupil, Horner syndrome), reading glasses or asymmetric bifocal adds can be prescribed.
• In patients with glare due to mydriasis, sunglasses may be helpful.

In/Out Patient Meds

• Dependent upon etiology

Transfer

• Dependent upon etiology

Deterrence/Prevention

• Dependent upon etiology

Complications

• Dependent upon etiology

Prognosis

• Dependent upon etiology

Patient Education

• Dependent upon etiology

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• The primary medicolegal pitfalls in evaluating anisocoria are misdiagnosis of a serious underlying cause. The patient presenting with a pupil-involved third nerve palsy, especially with pain, requires emergent evaluation. The primary concern in such patients is a compressive lesion, and a posterior communicating artery aneurysm is the most common life-threatening cause. Uncal herniation from increased intracranial pressure may produce an acute pupil-involved third nerve palsy; however, this condition is always accompanied by other signs of cerebral dysfunction (eg, coma).
• Horner syndrome may represent an emergency in the setting of carotid dissection. A painful Horner syndrome may herald carotid dissection, which may progress to cause ipsilateral cerebral ischemia and stroke.
• Horner syndrome is also part of the lateral medullary syndrome of Wallenberg (acute brainstem infarction in most patients). In this setting, Horner syndrome is invariably accompanied by other signs and symptoms (eg, ipsilateral facial numbness, contralateral body numbness, dysphagia, dysarthria, ipsilateral ataxia). Additionally, most patients demonstrate conjugate deviation of the eyes toward the side of the lesion following eye closure, which is a useful diagnostic sign.  

MULTIMEDIA

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Media file 1:  A flowchart to help in the diagnosis of anisocoria is shown.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
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• References

• Kardon RH, Denison CE, Brown CK, Thompson HS. Critical evaluation of the cocaine test in the diagnosis of Horner's syndrome. Arch Ophthalmol. Mar 1990;108(3):384-7. [Medline].
• Lowenfeld IE. "Simple central" anisocoria: a common condition, seldom recognized. Trans Am Acad Ophth & Oto. 1977;83:832.
• Lowenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Iowa State University; 1993.
• Miller NR, Newman NJ, eds. Walsh and Hoyt's Clinical Neuro-ophthalmology. Vol 1. 1998:827-1042.
• Thompson HS. Light-near dissociation of the pupil. Ophthalmologica. 1984;189(1-2):21-3. [Medline].
• Thompson S, Pilley SF. Unequal pupils. A flow chart for sorting out the anisocorias. Surv Ophthalmol. Jul-Aug 1976;21(1):45-8. [Medline].

Article Last Updated: Jun 29, 2007