Pupil size results from the activity of sympathetic and parasympathetic stimulation to the muscles of the iris. Under normal circumstances, bright light causes pupil constriction (miosis) due to increased parasympathetic activity, which stimulates the pupillary sphincter muscles.  Dimly lit conditions cause pupil dilation (mydriasis), which results from sympathetic stimulation of the pupillary dilator muscles. Pupil constriction also results from the accommodation reflex, the process responsible for focusing vision on a near object. It is important to note that pupil examination should always be performed under bright light (e.g. 240v wired direct ophthalmoscope).

Unequal pupils (anisocoria)

Anisocoria, which refers to asymmetry of pupil size, is commonly physiological, and may occur in up to 20% of the population. However, it may be a sign of serious underlying pathology, the most important examples of which are outlined below. In addition, other causes of anisocoria to be aware of include:

• Pharmacological e.g. pharmacological dilation following a recent visit to the ophthalmology clinic, or use of a hyoscine patch for motion sickness – this can occur if a patient rubs their eyes with their hand after it has been in contact with the patch.
• Iatrogenic e.g. recent cataract surgery
• Trauma: this can usually be elicited by the patient’s history. Note that a pear or tear drop-shaped pupil after trauma is a red flag for an open globe.

Unilateral mydriasis

Third nerve palsy

Third nerve palsy results from damage to the third cranial nerve, also known as the oculomotor nerve. This nerve innervates 4 extraocular muscles (superior rectus, medial rectus, inferior rectus, and inferior oblique), the pupillary sphincter muscles (responsible for pupil constriction) and the levator palpebrae superioris muscle (elevates the upper eyelid). The commonest causes of a third nerve palsy include:

• Ischaemic – patients with diabetes mellitus and hypertension at increased risk
• Compressive – resulting from intracranial aneurysm, haemorrhage, or tumour
• Raised intracranial pressure causing uncal herniation
• Traumatic
• Infiltrative e.g. leukaemia (rare)

On examination, a third nerve palsy can be identified by the following signs:

• Unilateral mydriasis with slow reactivity to light
• Eyelid ptosis
• ‘Down and out’ positioning of the eye with limited or loss of adduction, depression, and elevation

Detection of a third nerve palsy with pupillary involvement requires urgent investigation to assess for a compressive lesion, such as a posterior communicating artery aneurysm.

Holmes-Adie pupil

Holmes-Adie pupil refers to unilateral mydriasis with sluggish constriction to light but preserved accommodation reflex (i.e. pupil constriction when shifting from distance to near vision). When pupil constriction occurs, there is a delayed return to normal pupil size. It may also be described as a tonic pupil. It is a benign condition, and most commonly affects women between 20 and 40 years. Most cases are unilateral. When a Holmes-Adie pupil is associated with diminished tendon reflexes, the condition is termed ‘Holmes-Adie syndrome’.

Unilateral miosis

Horner’s syndrome

Horner’s syndrome results from damage to sympathetic pathway supplying the eye. The classical features are:

• Unilateral miosis
• Ipsilateral ptosis
• Anhidrosis – reduced sweating of the ipsilateral face or, depending on the site of damage to the sympathetic innervation, the entire ipsilateral body
• Enophthalmos (sunken appearance of the eye)

There are 3 types of lesions which can cause Horner’s syndrome, which is based upon the site of sympathetic pathway damage. These are categorised as:

• Central lesion – affects pathway between hypothalamus and cervical spinal cord, there the first order neuron synapses
• Preganglionic lesion – affects the second order neuron, which travels from the cervical spine to the superior cervical ganglion in the neck
• Postganglionic lesion – caused by damage to the third order neuron which runs from the superior cervical ganglion to innervate the structures of the eye

The causes of Horner’s syndrome can be divided based on the classification above. Examples of causes of each are listed below.

• Central:
  • Stroke
  • Intracranial tumour
  • Cervical cord pathology
  • Demyelinating disease
• Preganglionic:
  • Carotid and aortic dissection or aneurysm
  • Pancoast tumour
  • Thyroid tumour
  • Enlarged lymph nodes in the neck
• Postganglionic:
  • Internal carotid artery dissection
  • Cavernous sinus lesion
  • Otitis media
  • Nasopharyngeal neoplasm

Diagnosis of Horner’s syndrome can be made using apraclonidine eye drops. Historically, topical cocaine was also used to identify Horner’s syndrome. An MRI head & neck will be required once Horner’s syndrome is identified to determine the underlying cause, and therefore whether the lesion is central, preganglionic or postganglionic. 

Argyll-Robertson pupil

Argyll-Robertson pupil refers to a constricted pupil which has sluggish reaction to light, but a preserved accommodation reflex. It is most commonly due to neurosyphilis and develops in the context of prolonged untreated infection. Due to this, it is very rare in Western countries. Rarer causes include neurological damage secondary to diabetes, alcohol, and multiple sclerosis. It is most commonly bilateral. 

Anisocoria – summary

In practice, the most difficult distinction to make in a patient presenting with anisocoria is between Horner’s syndrome, Holmes-Adie pupil, and physiological anisocoria. This is because an Argyll-Robertson pupil is much more rarely seen, and a third nerve palsy is easier to distinguish given its other identifying clinical features. To help distinguish between Horner’s, Holmes-Adie and physiological anisocoria:

• Diluted topical pilocarpine 0.1% instilled in the larger pupil: In Holmes-Adie, the innervation to the iris and ciliary body is lost, resulting in ‘denervation sensitivity’, which refers to the upregulation of postsynaptic cholinergic receptors. Due to this process, a Holmes-Adie pupil will constrict with low dose pilocarpine, which is an abnormal response – low doses of pilocarpine will not constrict a normal pupil.
• Topical apraclonidine 0.5% instilled in the smaller pupil: This will reverse anisocoria due to Horner’s syndrome (i.e. dilate a constricted pupil). In a normal pupil, apraclonidine not produce this effect. This is again explained by denervation hypersensitivity.

In summary, after the above combination of tests, if the larger pupil constricts this suggests Holmes-Adie pupil; if the smaller pupil dilates this suggests Horner’s syndrome; and the absence of these responses suggests physiological anisocoria.

It should be noted that effect of ambient lighting conditions (how brightly lit the environment is) can also help to identify pathological anisocoria. Under low ambient light, if the anisocoria is exaggerated, the small pupil that fails to dilate is abnormal. However, if the anisocoria is greater in bright ambient light, the large pupil that fails to constrict is abnormal.

Bilateral mydriasis

There are numerous causes of bilateral mydriasis. These include:

• Medications – e.g. atropine, Parkinsonian drugs, cocaine
• Migraine
• Hyperthyroidism
• Severe traumatic brain injury
• Iatrogenic – e.g. recent bilateral ophthalmic surgery

Bilateral miosis

Bilateral miosis is most commonly a result of opioid use (‘pinpoint pupils’). Other causes include:

• Infancy – physiological
• Older adults – senile miosis
• Disease of the pons such as haemorrhage or neoplasm
• Argyll-Robertson pupil (see above).

Summary learning points

• Anisocoria is common but may indicate sinister underlying pathology
• Causes of unilateral mydriasis include third nerve palsy and Holmes-Adie pupil
• Causes of unilateral miosis include Horner’s syndrome and Argyll Robertson pupil
• Horner’s syndrome can be divided into central, preganglionic and postganglionic causes
• RAPD is caused by unilateral optic nerve or retinal damage and important causes include optic neuritis, glaucoma, and ischaemic optic neuropathy

References

Bengi Ece Kurtul, Pinar Altiaylik Ozer, Ayla Akca Caglar and Emrah Utku Kabatas (2016). Bilateral congenital mydriasis in a child case. Turk Pediatri Arsivi-turkish Archives of Pediatrics, [online] 51(3), pp.176–177. doi:https://doi.org/10.5152/turkpediatriars.2016.4194.

Dr Mary Lowth (2017). Pupillary Abnormalities. [online] Patient.info. Available at: https://patient.info/doctor/pupillary-abnormalities.

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Sweeney, A.R., Kedar, S., Prakalapakorn, S.G., Yen, M.T., Thyparampil, P., Marcet, M.M., Burkat, C.N. and Lee, S. (2023). Horner Syndrome – EyeWiki. [online] eyewiki.aao.org. Available at: https://eyewiki.aao.org/Horner_Syndrome.

The College of Optometrists (2022). Abnormalities of the Pupil. [online] www.college-optometrists.org. Available at: https://www.college-optometrists.org/clinical-guidance/clinical-management-guidelines/abnormalitiesofthepupil [Accessed 30 Jan. 2024].

Tidy, C. (2021). Cranial Nerve Lesions. [online] Patient.Info. Available at: https://patient.info/doctor/cranial-nerve-lesions#nav-3 [Accessed 30 Jan. 2024].

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Written by Dr Alice Ditchfield (FY3), Reviewed by Mr Andrew Coombes (consultant ophthalmologist).