Anisocoria and abnormal pupillary reaction

Anisocoria is unequal pupil size (difference of more than 0.4 mm at rest; up to 20 percent of healthy people have a difference of 0.4 mm or more, usually under 1 mm). Abnormal pupillary reactions include sluggish or absent response to light, poor near response, light near dissociation, and a relative afferent pupillary defect.

Anatomy and physiology. The sphincter pupillae (parasympathetic, via the oculomotor nerve and ciliary ganglion) constricts the pupil. The dilator pupillae (sympathetic, via a three neuron pathway from the hypothalamus through the brainstem and cervical cord, the superior cervical ganglion and the carotid plexus) dilates it. The afferent limb is the optic nerve and tract.

Classification.

• Larger pupil abnormal (parasympathetic failure): third nerve palsy, Adie tonic pupil, pharmacological mydriasis, traumatic iris damage, acute angle closure, iris sphincter injury.
• Smaller pupil abnormal (sympathetic failure): Horner syndrome, pharmacological miosis (opioids, pilocarpine), inflammation (uveitis with posterior synechiae).
• Physiological (simple) anisocoria: equal difference in light and dark.
• Light near dissociation (Argyll Robertson pupil, dorsal midbrain syndrome, Adie pupil, diabetic autonomic neuropathy).
• Relative afferent pupillary defect: optic nerve or severe retinal disease.

Key distinctions. Anisocoria that is greater in the dark indicates a failure of the smaller pupil to dilate (Horner syndrome or physiological). Anisocoria that is greater in bright light indicates a failure of the larger pupil to constrict (third nerve palsy, tonic pupil, drug, iris damage). Ptosis with a dilated pupil and eye down and out indicates third nerve palsy.

History.

• Onset and duration (review old photographs and driving licence photos), sudden or gradual.
• Pain (eye, face, head, neck), headache (thunderclap), double vision, ptosis, light sensitivity, blurred near vision, facial sweating changes.
• Trauma (head, eye, neck, chest), eye surgery, and topical drops (mydriatics, miotics).
• Plants and drugs exposure (jimson weed, belladonna), scopolamine patches, inhaler contamination (ipratropium), nebulisers, cocaine, opioids.
• Syphilis risk, diabetes, neurological symptoms, cancer or smoking, and recent viral illness.

Drug history.

• Anticholinergics, atropine, scopolamine, tropicamide, cyclopentolate, ipratropium nebuliser spray, sympathomimetics, antihistamines, tricyclic antidepressants, and botulinum toxin.
• Opioids, pilocarpine, brimonidine, clonidine, organophosphates and cholinesterase inhibitors (miosis).
• Cocaine and amphetamines (mydriasis).

Examination.

• Pupil size in bright and dim light (in the dark with a dim light; measure), shape, position, and reaction to light (direct and consensual), near response, and speed of redilation.
• Swinging flashlight test for relative afferent pupillary defect.
• Lid position (ptosis or lid retraction, reverse ptosis), eye movements (limitations of adduction, elevation and depression), diplopia, corneal sensation, and facial sweating.
• Iris structure (sphincter tears, atrophy, synechiae, transillumination), cornea, anterior chamber (depth, cells), intraocular pressure, and fundus.
• Neck (bruit, tenderness), chest and neurological examination.

Red flags

• Painful or pupil involving third nerve palsy, thunderclap headache, or impaired consciousness (aneurysm, herniation, subarachnoid haemorrhage)
• Acute unilateral dilated unreactive pupil in a patient with head injury or reduced consciousness (uncal herniation)
• Painful Horner syndrome, neck pain, or recent neck or head trauma (carotid dissection)
• Horner syndrome with arm pain or lung disease (apical lung tumour), or in a child (neuroblastoma)
• Painful red eye with halos, fixed mid-dilated pupil (angle closure)
• Relative afferent pupillary defect with reduced vision (optic neuropathy, retinal detachment)
• Pupil abnormality with ophthalmoplegia, ataxia or confusion (Wernicke encephalopathy, Miller Fisher syndrome, botulism)
• Pupils reacting to near but not to light with syphilis risk (Argyll Robertson pupil)
• Pupil change after eye injury (open globe)

Special groups. Children: congenital Horner syndrome, neuroblastoma, third nerve palsy and iris defects (aniridia, coloboma). Pregnancy: Horner syndrome after delivery (epidural, neck strain), and pituitary disease. Older adults: microvascular third nerve palsy, giant cell arteritis. Region specific: neurosyphilis, snakebite (neurotoxic) and organophosphate poisoning.

Dilated pupil abnormal (poor constriction)

• Third nerve palsy: posterior communicating artery aneurysm, uncal herniation, tumour, trauma, cavernous sinus lesion, basilar artery lesion, giant cell arteritis, meningitis, microvascular (pupil sparing)
• Adie tonic pupil (post-viral, ciliary ganglion damage) and Holmes Adie syndrome (absent knee jerks)
• Pharmacological mydriasis (anticholinergic and sympathomimetic drugs, topical mydriatics, plant exposure)
• Iris sphincter damage (trauma, surgery, ischaemia, acute angle closure, uveitis), congenital (aniridia, coloboma)
• Post-ictal state, migraine (benign episodic mydriasis)

Small pupil abnormal (poor dilation)

• Horner syndrome, first order (brainstem, spinal cord, hypothalamus): lateral medullary stroke, syringomyelia
• Horner syndrome, second order (preganglionic): Pancoast tumour, thyroid and neck surgery, brachial plexus injury, chest trauma, aortic aneurysm
• Horner syndrome, third order (postganglionic): carotid dissection, cavernous sinus lesion, cluster headache, otitis media, skull base
• Pharmacological miosis (opioids, pilocarpine, organophosphates, clonidine)
• Posterior synechiae from uveitis, age related senile miosis, congenital miosis

Light near dissociation

• Argyll Robertson pupil (neurosyphilis, diabetes), dorsal midbrain syndrome (Parinaud: hydrocephalus, pinealoma, stroke), Adie pupil, severe afferent visual loss
• Aberrant regeneration of the third nerve, diabetic autonomic neuropathy, alcoholism, Lyme disease, sarcoidosis, multiple sclerosis, myotonic dystrophy

Afferent defect

• Optic neuritis, ischaemic optic neuropathy, compressive optic neuropathy, glaucoma, retinal detachment, central retinal artery or vein occlusion, macular disease, traumatic optic neuropathy

Physiological

• Simple anisocoria (equal in all lighting, varies from day to day)

Reasoning. Measure the pupils in light and dark to decide which pupil is abnormal. Then check for ptosis, eye movements and pain. Image urgently for pain, third nerve involvement or recent trauma.

First line. Pupil measurement (light and dark), swinging flashlight test, eyelid and eye movement examination, slit lamp (iris), intraocular pressure and neurological examination. Review of old photographs.

Targeted tests.

• Pilocarpine 0.1 percent (dilute) drops: a dilated pupil that constricts markedly (cholinergic supersensitivity) indicates Adie tonic pupil.
• Pilocarpine 1 percent: a pupil that fails to constrict indicates pharmacological blockade.
• Apraclonidine 0.5 or 1 percent drops (1 drop in each eye): reversal of anisocoria (the small pupil dilates by over 0.5 mm) after 30 to 45 minutes confirms Horner syndrome. It may be falsely negative in acute disease within 1 to 2 weeks.
• Hydroxyamphetamine 1 percent drops localise (pre versus postganglionic) where available.
• Emergency CT head, CT angiography or MR angiography for third nerve palsy with pupil involvement or pain, or for suspected aneurysm.
• MRI brain and orbits for isolated third nerve palsy in young patients.
• CT or MR angiography of head and neck from the aortic arch to the circle of Willis for painful Horner syndrome; MRI brain, cervical cord and neck for Horner syndrome; chest radiograph and CT chest for apical lesion.
• Blood tests: glucose and HbA1c, ESR, C reactive protein and platelets (giant cell arteritis), syphilis serology (and cerebrospinal fluid analysis when positive), HIV, Lyme serology in endemic areas, angiotensin converting enzyme, and thiamine status (treat without waiting).
• Optical coherence tomography and visual fields for optic neuropathy.
• Toxicology screen and poisoning history for pharmacological anisocoria.
• Urinary catecholamine metabolites and MRI for Horner syndrome in a child (neuroblastoma).
• Lumbar puncture after imaging for suspected meningitis, neurosyphilis, Miller Fisher syndrome (anti-GQ1b antibodies) or demyelination.

Limitations. The apraclonidine test can be falsely negative in acute and in mild disease. A normal angiogram does not exclude all aneurysms. Pharmacological tests need fresh drops without recent corneal manipulation.

Third nerve palsy with pupil involvement, pain or thunderclap headache (emergency).

Management includes:

• CT head and CT angiography
• neurosurgical referral for coiling or clipping of aneurysm
• blood pressure control
• subarachnoid haemorrhage care: paracetamol 1 g IV or orally every 6 hours for pain, nimodipine 60 mg orally or by nasogastric tube every 4 hours for 21 days started within 96 hours (30 mg every 2 hours if blood pressure falls; 30 mg every 4 hours in cirrhosis)
• reversal of anticoagulation (warfarin: vitamin K 5 to 10 mg IV with prothrombin complex concentrate 25 to 50 IU/kg adjusted to INR and product label; dabigatran: idarucizumab 5 g IV)

Uncal herniation (fixed dilated pupil with falling consciousness).

• Airway control, head of bed at 30 degrees, avoid hypotension and hypoxia.
• Mannitol 20 percent 0.5 to 1 g/kg IV over 15 to 20 minutes (stop if serum osmolality is over 320 mOsm/kg), or 3 percent sodium chloride 2 to 5 mL/kg IV over 10 to 20 minutes (stop at sodium over 155 to 160 mmol/L).
• Brief hyperventilation to a PaCO2 of 4.0 to 4.5 kPa as a bridge.
• Immediate neurosurgical care.

Painful Horner syndrome or carotid dissection (emergency). Give emergency stroke care: alteplase 0.9 mg/kg IV (maximum 90 mg, 10 percent as a bolus over 1 minute and the remainder over 60 minutes) within 4.5 hours when haemorrhage is excluded. Give aspirin 300 mg orally daily when thrombolysis is not given. Stroke specialists decide antithrombotic therapy (antiplatelet or anticoagulation for 3 to 6 months).

Acute angle closure glaucoma.

• Acetazolamide 500 mg IV or orally then 250 mg orally every 6 hours (avoid in sulphonamide allergy and severe renal impairment).
• Timolol 0.5 percent 1 drop (avoid in asthma, heart block, bradycardia).
• Apraclonidine 1 percent 1 drop.
• Pilocarpine 2 percent 1 drop once pressure is falling.
• Same day ophthalmology for laser iridotomy.

Apical lung tumour and other malignancy. Urgent oncology and cardiothoracic care with staging and biopsy.

Giant cell arteritis. Prednisolone 40 to 60 mg orally each morning started before biopsy, with aspirin 75 mg daily; methylprednisolone 500 mg to 1 g IV daily for 3 days with visual symptoms; same day specialist review.

Microvascular third nerve palsy (pupil sparing, painless, age over 50 with vascular risk factors). Control blood pressure, glucose and lipids, stop smoking, aspirin 75 mg daily, exclude giant cell arteritis, observe for recovery over 3 to 4 months, and re-image if there is no improvement or new signs.

Wernicke encephalopathy. Thiamine 500 mg IV infused over 30 minutes every 8 hours for 2 to 3 days, then 250 mg IV daily for 5 days (evidence on dosing is limited), then 100 mg orally three times daily; give before glucose; correct magnesium.

Neurosyphilis (Argyll Robertson pupil). Benzylpenicillin 3 to 4 million units IV every 4 hours (18 to 24 million units daily) for 10 to 14 days (Jarisch Herxheimer reaction possible). Arrange specialist infectious disease care and HIV testing, and treat contacts.

Adie tonic pupil. Reassurance, low vision glasses or pilocarpine 0.1 percent drops at bedtime for photophobia or blurred near vision (specialist), and assessment for autonomic features.

Pharmacological mydriasis. Identify and stop the agent, and reassure. Avoid pilocarpine challenge when angle closure is possible. Clean contaminated inhalers or nebuliser masks. Anticholinergic toxidrome needs supportive care (physostigmine 0.5 to 2 mg IV slowly under toxicology advice).

Opioid miosis. Naloxone 0.4 mg IV, repeated every 2 to 3 minutes and titrated to respiratory rate of 10 or more (0.04 to 0.1 mg doses in opioid dependent patients); observe for at least 4 to 6 hours after the last dose.

Organophosphate miosis. Decontamination, atropine 1 to 2 mg IV doubled every 5 minutes until secretions dry and the chest is clear, and pralidoxime 30 mg/kg IV over 30 minutes then 8 mg/kg/hour, with intensive care and poisons service advice.

Traumatic mydriasis and iris injury. Rule out open globe and intracranial injury, with same day ophthalmology. For traumatic iritis give cycloplegic drops (cyclopentolate 1 percent 1 drop three times daily) and prednisolone acetate 1 percent 4 times daily. Advise protective eyewear.

Uveitis with synechiae. Prednisolone acetate 1 percent 1 drop every 1 to 2 hours, tapered over 4 to 6 weeks, with cyclopentolate 1 percent 1 drop twice to three times daily or atropine 1 percent once daily. Specialists treat the underlying disease.

Simple anisocoria. Reassurance; no treatment.

Monitoring. Re-examine pupils and ptosis at 1 to 2 weeks; neurological observations and pupil checks every 15 minutes initially in head injury; repeat imaging when no recovery by 3 months; syphilis serology titres after treatment.

Referral and escalation. Immediate neurosurgery and stroke referral for third nerve palsy with pupil involvement, painful Horner syndrome, and herniation. Same day ophthalmology for angle closure, trauma and uveitis. Neurology for brainstem, midbrain and demyelinating causes. Oncology for tumours. Infectious disease for neurosyphilis.

Admission criteria. Suspected aneurysm or subarachnoid haemorrhage, herniation, dissection or stroke, angle closure not settling, open globe injury, Wernicke encephalopathy, poisoning, or neurological deterioration.

Discharge and safety netting. Return for new double vision, drooping eyelid, headache, neck pain, eye pain, reduced vision, weakness, speech or swallowing difficulty, or confusion. Advise on avoiding driving until diplopia and visual symptoms settle.