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Author: Eric R Eggenberger, DO, MS, FAAN; Chief Editor: Hampton Roy Sr, MD more...
Background
Anisocoria, or unequal pupil sizes, is a common condition. The varied causes have implications ranging from life threatening to completely benign.
Pathophysiology
Various pathophysiological processes can cause anisocoria. However, pupil size depends upon the effects of the autonomic nervous system and the iris muscle. The parasympathetic system constricts the iris, while sympathetic channels dilate the iris. The sympathetic system begins in the hypothalamus, descends through the brain stem (including the lateral medulla) and into the cervical cord to synapse in the ciliospinal center of Budge-Waller at the C8-T1 level. The second-order neuron then exits the C8-T1 nerve root, travels over the lung apex, and ascends to the superior cervical ganglia with the carotid artery. The third-order neuron leaves the superior cervical ganglia to ascend with the internal carotid artery through the cavernous sinus, where fibers destined for the pupil dilator and the Mueller muscle of the eyelid
travel with the trigeminal nerve. Fibers destined to modulate sweating of the face travel with the external carotid artery. The parasympathetic fibers begin in the Edinger-Westphal subnucleus of cranial nerve III in the midbrain. Parasympathetic fibers destined for the iris sphincter travel with the oculomotor (cranial III) nerve.
Epidemiology
Frequency
United States Anisocoria is common, although no overall prevalence statistics are available. The incidence and prevalence data for anisocoria depend on the specific pathophysiology. The presence of physiologic anisocoria has been estimated at 20% of the normal population, so some degree of pupil difference may be expected in at least 1 in 5 clinic patients.
Mortality/Morbidity
Mortality and morbidity rates associated with anisocoria depend entirely upon the specific pathophysiology. Several causes of anisocoria are life threatening, including Horner syndrome due to carotid dissection or third nerve palsy due to aneurysmal expansion or rupture. Other causes of anisocoria are completely benign (eg, simple or physiologic anisocoria), although the evaluation of these disorders may produce morbidity inadvertently.
History
The history of anisocoria is dependent on the specific pathophysiology. The pupil size difference itself seldom produces specific symptoms. Associated features (with an underlying condition) may produce symptoms that lead to evaluation (eg, diplopia, photophobia, pain). Anisocoria may also be discovered incidentally by an observer. Onset of anisocoria: Old patient photographs often help to date anisocoria that is unaccompanied by other symptoms.
Physical
Key aspects of the physical examination (eg, pupil size in light, pupil size in the dark, pupil reactivity to light and dark) help to localize the problem. Additional historical features such as pain, diplopia, or ptosis help generate a differential diagnosis.
Pupil size (in mm) should be assessed in both light and dark. Illumination by shining a light obliquely from below the patient's face and a handheld pupil gauge (found on most near-vision cards) assist in accurate assessment. The abbreviation PERRLA (pupils equal, round, reactive to light and accommodation) is best avoided. "A" for accommodation actually refers to the lens thickening in response to a near target and cannot be observed by the unaided eye.[1] The use of a magnifying lens (eg, 20-diopter indirect ophthalmoscopy lens) or a slit lamp greatly assists this endeavor. Pupil reactivity o Pupil reactivity is graded subjectively on a scale of 0 (no reaction) to 4 (very brisk reaction), primarily to allow quantification of right and left asymmetry. o Similar to muscle stretch reflexes, symmetry is often more important than the absolute number grade. o Be careful to shine the light along the visual axis (this can be problematic if significant ocular misalignment exists). Contraction anisocoria is a phenomenon in which the pupil of a directly illuminated eye constricts more than the pupil of the contralateral eye. A study that used infrared binocular pupillography in 44 healthy girls and boys aged 6-16 years found that illuminating the right eye led to larger contraction anisocoria than stimulating the left eye, and that right-side lateralization of contraction anisocoria was much greater in the boys than in the girls.[2] Associated features o The presence of associated features should be checked carefully, as these are often key to the diagnosis. As in the evaluation of diplopia, several of the "Ps" are relevant: pupils, ptosis, proptosis, pain, poor movement/paresis, paresthesia. o Diplopia and ptosis may indicate the presence of a third nerve palsy. Pain often is associated with an expanding or ruptured intracranial aneurysm causing a compressive third nerve palsy or carotid dissections but is also typical of microvascular ocular motor neuropathies. Proptosis often indicates a spaceoccupying lesion within the orbit.
Causes
The causes of anisocoria are diverse and varied; refer to the following flowchart to deduce the specific cause.[3] See the diagram below.
Flowchart to assist in the diagnosis of anisocoria (modified with permission from Thompson and Pilley) For specific discussions of several of these topics, see the articles Oculomotor Nerve Palsy and Horner Syndrome.
Horner syndrome
Two conditions produce normally reactive pupils with anisocoria greater in darkness: Horner syndrome and physiologic anisocoria. In the English-language literature, Horner syndrome refers to sympathetic paresis that affects the eye. Features include ptosis, miosis, and anhidrosis; however, the exact presentation varies with the site of the lesion. The causes vary from lifethreatening to benign conditions. The sympathetic pathway begins in the hypothalamus, travels down the brain stem (where it is most often disrupted in the lateral medulla), through the cervical spinal cord to the level of the ciliospinal center of Budge-Waller at C8-T1, then over the lung apex, ultimately ascending with the carotid artery into the cavernous sinus to the pupil dilators and the Muller muscle of the lid. The sudomotor sweat fibers supplying the face exit onto the external carotid and its branches. The sympathetic nerve pathway has 3 divisions: first order (hypothalamus to C8-T1), second order (C8-T1 to superior cervical ganglia), and third order (superior cervical ganglia to the pupil dilators and lid). Ptosis typically measures 1-2 mm; miosis often measures less than 2 mm and is greatest in the dark. The sympathetic fibers serve to dilate the pupil under conditions of dark or in response to psychosensory stimulation (ie, startle or pain). Dilation lag refers to the slowed dilation of the affected pupil in response to dark. It can be assessed by viewing the pupils through several cycles of light and dark stimulation. The anisocoria itself is asymptomatic, and the minimal ptosis often goes unnoticed. The associated features often prompt medical attention, or the condition may be discovered incidentally by an observer. Pharmacologic testing of Horner syndrome is helpful. Application of a 4-10% cocaine ophthalmic solution can determine whether Horner syndrome is present. However, it will not specify the site or cause. Cocaine prevents reuptake of norepinephrine and dilates a normal pupil
but not a sympathectomized pupil. After instilling 1-2 drops of 4-10% solution (painful for several minutes), postdrop anisocoria of greater than 0.8 mm correlates with greater than 1000:1 odds that the patient has Horner syndrome. The drops require approximately 30-45 min for greatest effect, and more than 2 drops may be toxic to the cornea. The test also results in positive urine drug screens for cocaine for several days. The cocaine drop test helps answer the question "Is this a Horner syndrome?", but it does not help further localization. Testing with cocaine can give equivocal results, and it can be difficult to obtain and safely store as a controlled substance. Apraclonidine 1% or 0.5% has been proposed as a substitute.[4, 5] In patients with Horner syndrome, reversal of anisocoria usually occurs after bilateral instillation of apraclonidine. However, false-negative results have been reported in this setting.[6] Hydroxyamphetamine (Paredrine) stimulates norepinephrine release from an intact third-order sympathetic neuron.
If the third-order neuron is intact and functional, hydroxyamphetamine will dilate the pupil. Conversely, if the third-order neuron is dysfunctional, the medication will not produce this effect. Because hydroxyamphetamine dilates the pupil if the first- or second-order ocular sympathetic neurons are dysfunctional, it is not a useful screening drug to detect Horner syndrome (see cocaine test already discussed). Accordingly, hydroxyamphetamine helps answer the question "Is the 3rd order sympathetic neuron intact?" The test is interpreted by calculating the difference between the degree of anisocoria before and after medication. If, after hydroxyamphetamine instillation, the anisocoria increases by 1.2 mm or more compared to before medication, the lesion is postganglionic with greater than 90% probability. Hydroxyamphetamine may be obtained from several pharmacies including Leiter's (San Jose, CA; phone 800-292-6773) and Thayer's (Orlando, FL; phone 800-848-4809).
Although the causes of Horner syndrome are variable, several conditions are relatively common.
First-order Horner syndrome often is caused by stroke, most commonly Wallenberg lateral medullary syndrome. Cervical spine disease may cause either a first- or second-order Horner syndrome depending on the pathophysiology (eg, disk disease or intrinsic cord disease such as syrinx, tumor, or inflammation). Lung apex lesions (eg, tumor) may produce a second-order Horner syndrome.
Carotid artery dissection often produces pain and is accompanied by Horner syndrome in
many patients. See the images below. Horner syndrome secondary to carotid dissection. Note that degree of anisocoria is relatively mild in room
light. Also, see the image below of the same patient. Horner syndrome due to carotid dissection. Note the increase in degree of anisocoria under dark conditions. Cavernous sinus disease may produce a third-order Horner syndrome, often accompanied by other symptoms such as diplopia.
Typical pupil in third nerve palsy, with mydriasis. Note the inability to adduct the right eye. This patient has a skull-based meningioma that is compressing the right third nerve. At rest, complete ptosis is present in the right eye; however, lid elevation with attempted adduction of the right eye is noted, which is consistent with aberrant regeneration.
An isolated dilated pupil without ocular dysmotility or ptosis rarely represents a third nerve palsy. It is more likely related to a tonic or a pharmacologically affected pupil.
Pharmacologic pupil
The pharmacologically dilated pupil is larger than in most other causes of anisocoria (often measuring 8-9 mm). The pupil fails to respond to light stimuli, near stimuli, or 1% pilocarpine solution; mechanical iris disruption can also account for such findings and can be distinguished with slit lamp examination. The remainder of the examination findings (ie, motility, eyelids, fundus) should be normal, except near acuity (which is normalized with the use of plus lens reading glasses). Instillation of atropine-like drugs may be either accidental or intentional, and potential sources of such exposure should be sought (eg, old eye drops in the house, exposure to medications such as inhalers[7] , exposure to toxic plants such as Datura [Angel's Trumpet][8] ).
Mechanical
Mechanical damage to the iris muscle itself resulting from trauma, surgical intervention (eg, cataract extraction), or inflammation (or the effects or prior inflammation) within the eye (uveitis) may produce anisocoria. Slit-lamp examination, often a helpful diagnostic tool, demonstrates iris thinning or defects, or evidence of previous or current inflammation.
Tonic pupil
Tonic pupils respond poorly to light but briskly to a near target. This condition constitutes one of the near-light dissociation syndromes. Other near-light dissociation syndromes include the following:
Autonomic neuropathies (eg, DM) Severe afferent system damage Aberrant regeneration CN3 Parinaud dorsal midbrain syndrome Argyll Robertson pupils
The classic tonic pupil is the Adie tonic pupil. Adie tonic pupil responds tonically to near stimulation (the pupil takes longer to redilate after near fixation). Slit-lamp examination is helpful, often demonstrating iris sector palsy (only a portion of the iris reacts to light), vermiform iris movements (radially oriented iris movements), and providing
excellent magnification to observe near-light dissociation. The pupil may be supersensitive to weak (1/8-1/16%) pilocarpine solution, which will not constrict a normal pupil. Transient anisocoria: This has been documented as an intermittent feature in several conditions. Most often, it reflects benign causes such as migraine headache, especially if no other associated features are present, but it can represent transient parasympathetic or sympathetic dysfunction from other causes.
Differentials
Basilar Artery Thrombosis Brainstem Gliomas Cardioembolic Stroke Cavernous Sinus Syndromes Cerebral Aneurysms Cervical Spondylosis: Diagnosis and Management Cluster Headache Dissection Syndromes Migraine Headache Migraine Headache: Neuro-Ophthalmic Perspective Migraine Headache: Pediatric Perspective Migraine Variants Multiple Sclerosis Neuro-Ophthalmic Examination Neuro-Ophthalmic History Neuro-ophthalmic Manifestations of Vascular Eye Diseases Raeder Paratrigeminal Syndrome
Laboratory Studies
Lab studies depend upon the specific etiology.
Imaging Studies
The use of imaging studies depends entirely upon the underlying cause of anisocoria. Horner syndrome due to lateral medullary syndrome usually can be confirmed by MRI of the head. Carotid dissection may be confirmed with magnetic resonance imaging (MRI) or angiography (MRA), contrast angiography, or Doppler ultrasound, depending on the segment involved, the level of suspicion, and the availability of imaging modalities.
Third nerve palsies with pupillary involvement should be presumed compressive in origin. An enlarging or leaking berry aneurysm, if suggested by the presentation, is the compressive lesion that requires most immediate diagnosis. The choice of imaging type is dependent on the suspected pathophysiology: a cerebral aneurysm would be best imaged with angiography, while skull-based neoplasms are best demonstrated by MRI.
Procedures
Procedures depend upon the specific etiology.
Histologic Findings
Depends upon the specific etiology
Medical Care
Medical care depends upon the underlying pathophysiology.
Surgical Care
Surgical care depends upon the specific etiology.
Consultations
Consultations depend upon the underlying cause. Compressive third nerve palsies may require neurosurgical intervention, while ophthalmologists may be helpful in other causes of anisocoria.
Medication Summary
Drugs commonly used in the diagnosis of anisocoria include cocaine, hydroxyamphetamine, and pilocarpine (0.1-1%).
Cocaine
Prevents norepinephrine reuptake and accordingly dilates eye with intact sympathetic nervous system supply. Decreases membrane permeability to sodium ions, which, in turn, inhibits depolarization and blocks conduction of nerve impulses.
Cholinergic agents
Class Summary
This agent is used for diagnostic testing related to tonic pupil (0.1% concentration) or pharmacologic dilation-induced anisocoria (1% concentration).
View full drug information
Does not normally constrict pupil; however, with tonic pupil, produces miosis due to cholinergic supersensitivity. Constricts normal pupil or mydriatic pupil due to oculomotor palsy; however, after pharmacologic dilation (eg, atropinelike agents), pilocarpine has no miotic effects.
Sympathomimetic agents
Class Summary
Hydroxyamphetamine is useful diagnostically to test integrity of the third-order sympathetic neuron.
Hydroxyamphetamine (Paredrine)
Dilates pupil if third-order sympathetic neuron intact, and fails to dilate pupil if third-order neuron impaired.
Apraclonidine (Iopidine)
Potent alpha-adrenergic agent selective for alpha2-receptors with minimal cross-reactivity to alpha1-receptors. Suppresses aqueous production. Reduces elevated, as well as normal, intraocular pressure (IOP) whether accompanied by glaucoma or not. Apraclonidine is relatively selective alpha-adrenergic agonist that does not have significant local anesthetic activity. Has minimal cardiovascular effects. Due to the weak, direct alpha-1 and alpha-2 receptor agonist effect, apraclonidine may reverse the Horner anisocoria (no effect on normal pupil, but Horner syndrome-related denervation supersensitivity produces pupil dilation).