Anisocoria - Ophtnotes

Summary

Anisocoria is a condition involving unequal pupil sizes. The many causes of anisocoria range from benign to serious, life-threatening conditions.

Aetiology

Anisocoria is a condition in which the pupils are of different sizes. Anisocoria is derived from the Greek “aniso-” meaning unequal, and “kore” meaning pupil. It is caused by a defect in the efferent pathway of pupillary light response. As a reminder, the diagram below summarises the pupillary light reflex neural pathway. The pupillary response is controlled by the sympathetic and parasympathetic pathways, which innervate the pupillary dilator and pupillary sphincter muscles respectively. It is a balance between sympathetic and parasympathetic tone that determines pupil size.

Schematic of pupillary light reflex pathway

The sympathetic pathway causes mydriasis (dilation of the pupil). Sympathetic fibres arise in the hypothalamus, synapse with interneurons at the C8-T2 level of the spinal cord, and then travel via the sympathetic chain, synapsing with a third neuron in the superior cervical ganglion. These third-order neurons travel through the cavernous sinus and enter the orbit as the short and long ciliary nerves, which innervate the dilator pupillae muscle. See our notes on Horner’s syndrome for a more detailed explanation of this pathway.

The parasympathetic pathway controls miosis (constriction of the pupil) by activating the iris sphincter muscle. The parasympathetic pathway originates in the brainstem, then travels alongside the oculomotor nerve to innervate the iris sphincter. This pathway is activated by the pupillary light reflex and accommodation.

Image showing anisocoria, with a mydriatic right pupil. Image courtesy of Macchiailo et al.

Anisocoria can be subdivided into the following groups:

An inhibition of constriction of the pupil on one side. The pathological pupil is more dilated than the normal pupil, and this difference is more obvious in light conditions.

An inhibition of dilatation of the pupil on one side. The pathological pupil is more constricted than the normal pupil, and this difference is more obvious in dark conditions.

Different pupil sizes whereby the difference remains the same in light and dark conditions

Causes of anisocoria greater in bright light

Anisocoria that is more pronounced in bright light is caused by an impaired ability of the pupil to constrict. The pathological pupil is therefore relatively dilated compared to the non-pathological pupil.

Third nerve palsy

The parasympathetic neurons run along the periphery of the oculomotor nerve (CN3). Therefore, lesions that compress CN3 will also affect the parasympathetic fibres. This inhibits the signal to the sphincter pupillae, causing a fixed dilation of the pupil on the affected side.

Other findings in a CN3 palsy are:

Ptosis of the affected upper eyelid (due to inhibition of the levator palpebrae superioris)

The affected eye will be abducted and depressed – ”down and out” (due to unopposed action of the lateral rectus and superior oblique, the two extraocular muscles not innervated by the oculomotor nerve)

Photograph of a patient with a right oculomotor nerve palsy, demonstrating a fixed, dilated “down and out” right pupil. The right eyelid has to be held by the examiner due to ptosis resulting from the third nerve palsy. Image courtesy of Hakim et al.

Compression of the oculomotor nerve can be caused by:

Raised intracranial perssure

Trauma

Neoplasm

Cavernous sinus thrombosis

Posterior communicating artery aneurysm – a very worrying lesion which can be acutely fatal

Described here are the causes of a ‘surgical’ third nerve palsy, whereby the pupil is dilated due to external compression of the peripheral fibres (i.e. the parasympathetic neurons) of the oculomotor nerve. A ‘medical’ third nerve palsy, often caused by diabetes mellitus or hypertension microangiopathy, affects the vasa vasorum but spares the peripheral fibres of the oculomotor nerve. Therefore, a medical third nerve palsy usually spares the pupil.

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Migraine

Migraine headaches can cause anisocoria associated with pain. Usually, the pupil is dilated, and will resolve once the headache is over.

Cycloplegic medications

Cycloplegic medications cause paralysis of the sphincter pupillae, causing unopposed pupillary dilation. The pupil will usually be unreactive to light due to the paralysis. Examples include the anticholinergics atropine, cyclopentolate and tropicamide.

Sympathomimetics

Sympathomimetic eye drops activate the dilator pupillae, thereby causing mydriasis of the pupil. The pupil should still react to light to some extent. The dilation is not as great compared to cycloplegics.

Adie Tonic pupil

An Adie Tonic or Holmes-Adie pupil is caused by parasympathetic denervation to the post-ganglionic supply to the sphincter pupillae and ciliary body of the affected pupil. The affected pupil appears to be abnormally dilated at rest, and has a poor or sluggish pupillary constriction in bright light. The pupil constricts more notably when it accommodates, and it typically remains tonically constricted with slow re-dilation.

90% of cases occur in women aged 20-40 years, 80% are unilateral and 70% are associated with reduced deep tendon reflexes (known as Adie’s syndrome). An Adie tonic pupil is often idiopathic or follows a viral illness, but other causes include trauma, ocular surgery, vasospasm due a migraine, and tumours.

An Adie tonic pupil can be diagnosed with 0.1% pilocarpine (an M3 agonist), which causes significant constriction of the larger (Adie) pupil due to denervation hypersensitivity. Low-dose pilocarpine to both eyes is also used to treat Adie pupils. It causes constriction of the Adie pupil (due to denervation hypersensitivity) and has no effect on the normal pupil.

Traumatic mydriasis

Trauma or intraocular surgery can damage the iris or its supporting structures. Damage to the pupillary sphincter leaves the pupil dilated, possibly with an irregular shape, and unable to constrict. Traumatic mydriasis can improve with time or be permanent.

Causes of anisocoria greater in dim light

Anisocoria that is more pronounced in dim light is caused by an impaired ability of the pupil to dilate. The pathological pupil is therefore relatively constricted compared to the non-pathological pupil.

Horner’s syndrome

Horner’s syndrome results from a lesion along the three-neuron sympathetic pathway supplying the head and neck. It is characterised by a classic triad of clinical signs: ipsilateral ptosis (droopy eyelid), miosis (pupillary constriction) and anhidrosis (decreased sweating). Causes range from benign to serious, with acute onset Horner’s considered a neuro-ophthalmic emergency. See our notes on Horner’s syndrome for more detail.

The most important cause of a painful Horner’s syndrome is an internal carotid artery dissection. This should be investigated with MRI or MR/CT angiography.

Cholinergic medications

Cholinergic drugs cause miosis of the pupil by causing contraction of the sphincter pupillae. An example is pilocarpine, a muscarinic (M3) receptor agonist used to treat glaucoma.

Posterior synechiae

Development of posterior synechiae (abnormal adhesions between the iris and lens) can impair the ability of the pupil to fully dilate. Posterior synechiae are typically caused by inflammatory conditions such as uveitis.

Causes of anisocoria that is equal in bright and dim light

Physiological anisocoria

Physiological anisocoria is typically defined as a difference in pupil size of ≥0.4mm, with no secondary cause. It is in fact the most common cause of anisocoria, affecting up to 1 in 5 people. In physiological anisocoria, the difference in pupil sizes should remain the same in dim and bright light. The condition may be intermittent, permanent or even self-resolving.

Other pupillary defects

Whilst the following pupillary defects are not causes of anisocoria, they are important to learn about for the Duke-Elder exam, so we have provided a summary.

Relative Afferent Pupillary Defect (RAPD)

An RAPD, also known as a Marcus-Gunn pupil, is caused by a lesion of the optic nerve between the retina and pretectal nucleus, which mean there is a failure to transmit the light stimulus from the retina to the midbrain. The causes of an RAPD are consequently an incomplete optic nerve lesion or severe, asymmetrical retinal disease. There are many causes of an RAPD, summarised in the table below.

An RAPD is diagnosed clinically by the ‘swinging light test’. When the light is shone into the unaffected pupil, both pupils constrict, as the efferent pathway of the affected pupil is still intact, so a consensual pupillary constriction is produced. When the light is shone in the affected pupil, neither pupil constricts, as the afferent pathway in the affected pupil is disrupted. When the light is swung from the unaffected to the affected pupil, both eyes will therefore appear to dilate.

Argyll-Robertson pupil

Argyll-Robertson pupils are bilateral small, irregular pupils that do not react to light but still accommodate. In other words, the pupils will not constrict to light, but will constrict to near objects. Argyll-Robertson pupils are caused by a lesion of the dorsal midbrain that affects the pupillary reflex pathway. The accommodation reflex involves the ventral midbrain, hence is spared. The diagnosis is made on clinical examination.

The features of an Argyll-Robertson pupil (ARP) can be remembered using the mnemonic: Accommodation Reflex Present; Pupillary Reflex Absent (ARP; PRA).

References

Salmon, John F., and Jack J. Kanski. Kanski’s Clinical Ophthalmology: A Systematic Approach. Ninth Edition, Elsevier, 2020.

‘Pupillary Light Reflex’. Wikipedia, 7 Jan. 2023. Wikipedia, https://en.wikipedia.org/w/index.php?title=Pupillary_light_reflex&oldid=1132093314.

Payne, William N., et al. ‘Anisocoria’. StatPearls, StatPearls Publishing, 2022. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK470384/.

Modi, Pranav, and Tasneem Arsiwalla. ‘Cranial Nerve III Palsy’. StatPearls, StatPearls Publishing, 2022. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK526112/.

Macchiaiolo, Marina, et al. ‘An Unusual Case of Anisocoria by Vegetal Intoxication: A Case Report’. Italian Journal of Pediatrics, vol. 36, no. 1, July 2010, p. 50. BioMed Central, https://doi.org/10.1186/1824-7288-36-50.

Hakim, Wasim, et al. ‘An Acute Case of Herpes Zoster Ophthalmicus with Ophthalmoplegia’. Case Reports in Ophthalmological Medicine, vol. 2012, 2012, p. 953910. PubMed, https://doi.org/10.1155/2012/953910.