Pupil abnormalities

Pupillary reflex pathway:

image 18

Light reaches the retina, travels via ganglion cells to the optic nerve, which then forms the optic chiasm before diverging into the left and right optic tracts (nasal fibers decussate to the contralateral optic tract whilst temporal fibers continue ipsilaterally). The optic tracts travel to the pretectal nuclei, which then sends signals to bilateral Edinger-Westphal nuclei (preganglionic parasympathetic nuclei in the midbrain) giving rise to direct consensual reflex.

The efferent parasympathetic preganglionic fibers then travel via the oculomotor nerve to the ciliary ganglion, and from there postganglionic parasympathetic fibers supply the iris sphincter muscles to cause pupillary constriction (miosis).

Abnormalities can be grouped into:

  1. Small pupil
  2. Large pupil
  3. Abnormal reflexes
Small Pupil (miosis)

Bilateral (causes):

  • Opioids – always check the drug chart. Other signs of opioid overuse include respiratory depression
  • Pontine haemorrhage
  • Organophosphate / cholinergic poisoning
  • Argyll Robertson pupil:
    • This is due to a lesion in the Edinger-Westphal nuclei
    • Features = small pupils which accommodate but do not react to light
    • Commonly caused by neurosyphilis
    • Test: constricts further with physostigmine, does not dilate with atropine

Unilateral (causes):

  • Iatrogenic e.g miotic eye drops
  • Physiological – 1-2mm difference between pupils (anisocoria) can be normal as long as light reflexes are normal and there are no other symptoms
  • Horners Syndrome

Horners Syndrome
  • This is due to interruption to sympathetic pathway
  • Features = miosis + ptosis + depending on where the lesion is…
  • Central lesion (first order neuron):
    • First order neurons descend from the hypothalamus to the cervical spinal cord (C8-T2)
    • Additional symptoms: complete contralateral hemianhidrosis, contralateral hyperesthesia
    • Causes: hypothalamic tumour, brainstem infarction (Wallenberg syndrome), demyelinating disease, cervical cord trauma/tumour/syrinx
  • Preganglionic (second order neuron):
    • Second order neurons exit from the cervical spinal cord, travels in the cervical sympathetic chain via the brachial plexus, over the pulmonary apex, then synapses in the superior cervical ganglion, which is located near the angle of the mandible and bifurcation of the common carotid artery
    • Additional symptoms: face and neck anhidrosis, hoarse voice
    • Causes: cervicothoracic cord lesion, paravertebral/mediastinal/anterior neck tumour or trauma, epidural anaesthesia, sympathetic chain tumour (schwannoma), lower brachial plexus trauma, pulmonary apex lesion (Pancoast tumour), iatrogenic (chest drain / central line)
  • Postganglionic (third order neuron):
    • Third order neurons exit the superior cervical ganglion, enters the cranium by travelling within the adventitia of the internal carotid artery into the cavernous sinus, joins the first division of the trigeminal nerve and enters the orbit
    • Additional symptoms: ipsilateral face/head pain, ipsilateral visual loss
    • Causes: superior cervical ganglion tumour, jugular vein trauma, parapharyngeal surgery, internal carotid artery dissection, cluster headache, skull base pathology, cavernous sinus meningioma, carotid cavernous fistula
  • Characteristically there’s a dilation lag = slow redilation of small pupil in darkness due to damage to the sympathetic fibers supplying pupillary dilation
    • Testing
      • Cocaine does not dilate the small pupil. Cocaine prevents reuptake of neurotransmitter norepinephrine from the synaptic cleft, to result in pupillary dilation if sympathetic innervation was intact
      • Apraclonidine (weak alpha-1 agonist) and phenylephrine (sympathomimetic) dilates pupil. They downregulate norepinephrine release at the synaptic cleft, to cause denervation supersensitivity hence pupil dilation (there is upregulation of alpha-1-adrenergic receptors in Horner’s syndrome)
    • Imaging with brain/neck/chest MRI (or contrast CT if MRI unavailable) would be useful to delineate cause
Large Pupil (mydrasis)

Bilateral + impaired direct light reflex (causes):

  • Mydriatic eye drops (sympathomimetics = phenylephrine; cycloplegics = cyclopentolate, tropicamide, homatropine, atropine)
  • Brain herniation
  • Hypoxic / ischaemic encephalopathy

Unilateral + impaired direct light reflex (causes):

  • Tonic Adie pupil:
    • This is due to parasympathetic denervation at the ciliary ganglion
    • Impaired direct + consensual light reflex, and impaired accommodation
    • Causes: idiopathic, viral infection (e.g. varicella zoster), connective tissue diseases (e.g. Sjogren’s, rheumatoid arthritis), peripheral or autonomic neuropathies
    • Test: will constrict with cholinergic agents (2.5% methacholine or 0.1% pilocarpine)
    • Holmes-Adie syndrome = Tonic Adie pupil + poor/absent tendon reflexes
  • Compressive 3rd nerve palsy (oculomotor nerve palsy)
    • Pupil is dilated, eye is pointing down and out at rest
    • Pupil does not constrict to light shone in either eye, there is no accommodation
    • In ischaemic 3rd nerve palsy the pupil is spared
    • Investigations: MRI, CT angiography to exclude aneurysm
      Investigations for ischaemic causes: BP, FBC, ESR, HbA1c
Abnormal reflexes

RAPD = Marcus Gunn pupil

  • Pupil dilates on swinging light test
    In a normal swinging light test, both pupils constrict equally regardless of which eye is stimulated by light. In an abnormal swinging light test (positive RAPD), there is less pupil constriction in the affected eye (affected pupil appears to dilate when light re-shone onto it)
  • Caused by damage to the optic nerve: optic neuritis, ischaemic optic disease, severe glaucoma, trauma, radiation, tumour
  • Can also be caused by severe retinal detachment, severe macular degeneration and severe retinal infection
image 18 1

Light near dissociation

  • Near response (accommodation) exceeds best pupillary constriction to light
  • Causes:
    • Optic neuropathy causing reduced light impulse to pretectal nuclei)
    • Dorsal midbrain lesion
      Dorsal fibers carry signals for light pathway, whilst ventral fibers carry signals for accommodative pathway
    • Aberrant regeneration of oculomotor nerve fibers post compressive lesion or trauma such that motor fibers are misdirected to the iris sphincter


1. Kawasaki AK. Diagnostic approach to pupillary abnormalities. Continuum (Minneap Minn). 2014 Aug;20(4 Neuro-ophthalmology):1008-22. doi: 10.1212/01.CON.0000453306.42981.94. PMID: 25099106; PMCID: PMC10563972.

2. Belliveau AP, Somani AN, Dossani RH. Pupillary Light Reflex. 2023 Jul 25. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30725865.

3. Modi P, Arsiwalla T. Cranial Nerve III Palsy. 2023 Jul 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30252368.

4. Childs, Lucy and Curtis Edward Offiah. “The Oculo-Sympathetic Pathway: Radiological and Anatomical Correlates.” (2014).

Written by By Dr. Sandra Halim IMT2. Reviewed by Dr. Shruti Chandra ST3 Ophthalmology

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