Ophthalmology: Neurophthalmology

• Neuro-ophthalmology: Unequal Pupils | Horner Syndrome | Double Vision | Third Nerve Palsy | Fourth and Sixth Nerve Palsies | Internuclear Ophthalmoplegia and Myasthenia | Visual Field Defects
• The eye in systemic disease: Thyroid Eye Disease | Inflammatory and Rheumatic Disease | Infection and the Eye | Other Systemic Clues in the Eye | Drugs That Harm the Eye | Eye Tumours
• Children's eyes: Squint and Amblyopia | White Pupil and Retinoblastoma | Retinopathy of Prematurity | Other Childhood Eye Problems
• Revision: Drug Reference Table | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

👁️ The eye as a window — the pupils, eye movements and fundus give vital clues to neurological and systemic disease. A painful Horner syndrome may be a carotid dissection; a third nerve palsy with a dilated pupil may be an aneurysm about to burst; uveitis may be the first sign of sarcoidosis or ankylosing spondylitis. In children, early detection of squint, amblyopia and a white pupil saves sight and lives.
Your four questions for every patient: Which pupil is abnormal — the big one or the small one? Is the double vision binocular, and which nerve or muscle is weak? Is there a systemic disease or drug behind this? In a child — is the red reflex normal, and are the eyes straight?

Unequal Pupils

• Physiological anisocoria — up to 1 mm difference in about 20% of people; the same in light and dark; normal reactions.
• Key question: which pupil is abnormal?
  • Difference bigger in the dark — the small pupil can't dilate: Horner syndrome, Argyll Robertson pupil, pilocarpine drops, uveitis (with a red eye).
  • Difference bigger in bright light — the large pupil can't constrict: third nerve palsy, Adie pupil, dilating drugs, trauma, acute angle closure.

↑ Back to index

Horner Syndrome

• What it is: Damage to the sympathetic pathway to the eye.
• Features:
  • Miosis (small pupil) with dilation lag.
  • Mild ptosis (and slight raising of the lower lid).
  • Anhidrosis (reduced sweating) of the face — if the lesion is before the carotid bifurcation.
  • Apparent enophthalmos.
  • Heterochromia (lighter iris) if congenital.
• Causes — follow the pathway:
  • Central (brainstem, cord): lateral medullary stroke, MS, syringomyelia, tumours.
  • Pre-ganglionic (chest and neck): Pancoast tumour (apical lung cancer — shoulder pain, hand weakness), neck trauma or surgery (thyroid, carotid), cervical rib, central lines.
  • Post-ganglionic (carotid and skull base): carotid artery dissection, cluster headache, cavernous sinus lesions.
• Tests:
  • Apraclonidine drops — the Horner pupil dilates (reversal of anisocoria) — confirms the diagnosis.
  • Acute, painful Horner (neck, face or head pain) — same-day CT or MR angiography of head and neck for carotid dissection (stroke risk).
  • Otherwise imaging along the whole pathway (MRI head and neck, chest imaging for Pancoast tumour).

⚠️ Safety Pearl: A new Horner syndrome with neck pain or headache is a carotid dissection until proven otherwise — image urgently, even in young people after minor neck trauma.

↑ Back to index

Double Vision

• Step 1 — cover one eye:
  • Goes away = binocular diplopia: the eyes are misaligned (nerve, muscle, or neuromuscular junction problem).
  • Persists in one eye = monocular diplopia: an eye problem — cataract, astigmatism, dry eye, corneal disease. Not neurological.
• Step 2 — horizontal or vertical?
  • Horizontal — sixth nerve palsy, INO, medial rectus problems (thyroid, myasthenia).
  • Vertical — fourth nerve palsy, third nerve palsy, thyroid eye disease (inferior rectus), skew deviation (brainstem), orbital floor fracture.
• Step 3 — which direction is it worst? Images are furthest apart when looking in the direction of the weak muscle.
• Step 4 — other clues:
  • Pupil involvement; ptosis.
  • Fatigability (myasthenia).
  • Proptosis, lid retraction (thyroid eye disease).
  • Headache, papilloedema (raised ICP), GCA symptoms (over 50).
  • Other cranial nerves (cavernous sinus, brainstem), ataxia.
• Acute binocular diplopia — same-day assessment (stroke, aneurysm, GCA, raised ICP). No driving until resolved or adapted (DVLA).
• Symptom relief — patch one eye (alternate in children to avoid amblyopia), prisms on glasses, botulinum toxin, squint surgery once stable.

↑ Back to index

Third Nerve Palsy

• The third (oculomotor) nerve supplies most eye muscles (medial, superior and inferior recti, inferior oblique), the lid elevator, and the pupil constrictor.
• Features:
  • Ptosis (often complete).
  • Eye "down and out" (lateral rectus and superior oblique unopposed).
  • Dilated, unreactive pupil in compressive lesions.
  • Double vision (if the lid is lifted).
• The pupil rule:
  • Pupil involved (dilated) — compression until proven otherwise: posterior communicating artery aneurysm (often with headache), uncal herniation, tumour. Needs emergency CT angiography (or MRA).
  • Pupil spared — usually microvascular ischaemia (diabetes, hypertension, older age); often painful; recovers within 3 months. Still needs imaging in younger people, incomplete palsies, or if other signs develop.
• Other causes: GCA, cavernous sinus disease (with IV, V1, V2 and VI involvement), midbrain stroke, trauma, pituitary apoplexy.
• Coma with a dilating pupil — tentorial (uncal) herniation: neurosurgical emergency.

⚠️ Safety Pearl: A painful third nerve palsy with a dilated pupil is a posterior communicating artery aneurysm until proven otherwise — CT angiography the same day. A rupture is often fatal.

↑ Back to index

Fourth and Sixth Nerve Palsies

• Fourth (trochlear) nerve palsy — weak superior oblique:
  • Vertical double vision, worse looking down and in — trouble going down stairs and reading.
  • Head tilted away from the affected side.
  • Causes: Head injury (the commonest), congenital (decompensates in adulthood — check old photos for head tilt), microvascular.
• Sixth (abducens) nerve palsy — weak lateral rectus:
  • Horizontal double vision, worse looking towards the affected side and at distance.
  • The eye can't abduct (turn out); turns in at rest.
  • Causes:
    • Microvascular (diabetes, hypertension).
    • Raised intracranial pressure — a "false localising sign" (long course of the nerve); check for papilloedema.
    • Tumours (skull base, nasopharyngeal carcinoma, clivus).
    • Trauma; MS; Wernicke's encephalopathy; GCA.
    • Gradenigo syndrome (middle ear infection spreading to the petrous apex) in children.
• Microvascular palsies recover within about 3 months; image if not recovering, in younger people, or with other signs.
• Over 50 — check ESR and CRP (GCA).

↑ Back to index

Internuclear Ophthalmoplegia and Myasthenia

• Internuclear ophthalmoplegia (INO) — a lesion of the medial longitudinal fasciculus (MLF) in the brainstem:
  • On looking to one side, the eye on the side of the lesion fails to adduct (turn in), and the other eye shows nystagmus as it abducts.
  • Convergence is usually preserved.
  • Causes: MS (young people, often bilateral), brainstem stroke (older people, one side).
• Ocular myasthenia gravis:
  • Fatigable ptosis and variable double vision — worse at the end of the day; can mimic any nerve palsy.
  • Pupils always normal.
  • Ice pack test — ptosis improves after 2 minutes of cold.
  • Acetylcholine receptor (and MuSK) antibodies; single-fibre EMG; CT chest (thymoma).
  • About half develop generalised myasthenia within 2 years.
  • Pyridostigmine; steroids; immunosuppression.
• Other causes of restricted eye movements:
  • Thyroid eye disease (restriction, especially looking up).
  • Orbital floor fracture.
  • Miller Fisher syndrome (ophthalmoplegia, ataxia, areflexia; anti-GQ1b).
  • Wernicke's encephalopathy (with confusion, ataxia, nystagmus) — IV thiamine now.
  • Mitochondrial disease (slow, symmetrical, no diplopia).
  • Progressive supranuclear palsy (can't look down).
• See the Neuromuscular Disease and Neurological Localisation chapters.

↑ Back to index

Visual Field Defects

• Homonymous hemianopia usually prevents driving (DVLA field standard).
• See the Neurological Localisation and Pituitary chapters.

↑ Back to index

Thyroid Eye Disease

• What it is: Autoimmune inflammation of the orbital fat and eye muscles, usually with Graves' disease (can occur with normal thyroid function or Hashimoto's). Smoking is the biggest modifiable risk factor.
• Features:
  • Lid retraction (white sclera visible above the iris) and lid lag.
  • Proptosis (exophthalmos).
  • Gritty, watery, red eyes; swollen lids; exposure keratopathy.
  • Double vision — restricted movements (inferior and medial recti most often; worse on looking up).
  • Pain behind the eyes and on movement (active disease).
• Sight-threatening (emergency):
  • Dysthyroid optic neuropathy — enlarged muscles compress the optic nerve at the orbital apex: reduced vision, poor colour vision, RAPD.
  • Corneal breakdown from exposure.
  • Treatment — IV methylprednisolone; urgent orbital decompression if no response.
• Course: An active inflammatory phase (6–24 months) then an inactive burnt-out phase.
• Management:
  • Stop smoking.
  • Restore normal thyroid function (avoid hypothyroidism).
  • Radioiodine can worsen eye disease — give steroid cover or choose another treatment if eye disease is active.
  • Mild — lubricants, sunglasses, sleep with head raised; selenium for 6 months.
  • Moderate to severe active — IV methylprednisolone weekly (EUGOGO regimen); mycophenolate; tocilizumab; orbital radiotherapy.
  • Teprotumumab (anti-IGF-1 receptor antibody) — MHRA-approved for moderate to severe disease; NICE appraisal not yet complete. Side effects: hearing loss, high glucose.
  • Inactive phase surgery — in order: orbital decompression, then squint surgery, then lid surgery.
• See the Thyroid Disease chapter.

↑ Back to index

Inflammatory and Rheumatic Disease

• Rheumatoid arthritis — dry eye (secondary Sjögren's), episcleritis, scleritis, peripheral ulcerative keratitis (corneal melting — emergency); hydroxychloroquine toxicity.
• Sjögren's syndrome — severe dry eyes and mouth.
• Axial spondyloarthritis (ankylosing spondylitis), reactive and psoriatic arthritis — acute anterior uveitis (HLA-B27); conjunctivitis in reactive arthritis.
• IBD — episcleritis (tracks bowel activity), uveitis, scleritis.
• Sarcoidosis:
  • Uveitis (anterior, intermediate or posterior), often both eyes.
  • Conjunctival nodules; enlarged lacrimal glands; dry eye.
  • Optic neuropathy.
  • Heerfordt syndrome — uveitis, parotid swelling, fever, facial palsy.
• Behçet's disease — hypopyon uveitis, retinal vasculitis (can cause blindness), with oral and genital ulcers.
• SLE — dry eye, cotton wool spots (retinal vasculitis), antiphospholipid-related vessel occlusions.
• GPA (ANCA vasculitis) — scleritis, peripheral ulcerative keratitis, orbital mass (proptosis), blocked tear duct.
• Giant cell arteritis — see the Retina and Visual Loss chapter.
• Juvenile idiopathic arthritis — silent uveitis (no red eye), especially in young girls with oligoarthritis and positive ANA; needs regular slit lamp screening.

↑ Back to index

Infection and the Eye

• HIV:
  • CMV retinitis — when CD4 is under 50: floaters and field loss; "pizza pie" appearance (white necrotic retina with haemorrhages). Treat with valganciclovir or IV ganciclovir, plus antiretroviral therapy.
  • Herpes zoster ophthalmicus in young people (test for HIV).
  • HIV microvasculopathy (cotton wool spots); Kaposi sarcoma of the lids or conjunctiva.
  • Immune recovery uveitis after starting antiretrovirals.
• Toxoplasmosis — the commonest cause of posterior uveitis: a white focus of retinochoroiditis next to an old pigmented scar ("headlight in the fog"). Treatment if near the macula or optic disc (e.g. co-trimoxazole, or pyrimethamine-based regimens).
• Syphilis — "the great imitator": any type of uveitis, optic neuritis, Argyll Robertson pupils. Test everyone with uveitis of unclear cause.
• TB — uveitis, choroidal granulomas.
• Infective endocarditis — Roth spots (haemorrhages with white centres), conjunctival haemorrhages, endogenous endophthalmitis.
• Candida bloodstream infection — endogenous endophthalmitis (fluffy white lesions); eye examination recommended.
• Toxocara — children with puppies: a white retinal mass (mimics retinoblastoma).
• Herpes simplex and zoster — keratitis, uveitis, acute retinal necrosis (severe).
• Chlamydia — adult inclusion conjunctivitis; trachoma (the world's leading infectious cause of blindness).

↑ Back to index

Other Systemic Clues in the Eye

↑ Back to index

Drugs That Harm the Eye

↑ Back to index

Eye Tumours

• Choroidal melanoma (uveal melanoma):
  • The commonest primary intraocular tumour in adults; often found on routine examination (pigmented mass), or blurred vision, flashes, field loss.
  • Spreads to the liver (check LFTs, liver imaging).
  • Treated at specialist centres — plaque brachytherapy, proton beam radiotherapy, or removal of the eye.
  • Metastatic disease — tebentafusp (for people with a specific HLA type).
  • Choroidal naevi are common and benign; monitored for change.
• Metastases to the eye — overall the commonest intraocular tumour (breast and lung cancer).
• Vitreoretinal lymphoma — older people with "uveitis" that doesn't respond to steroids; linked to CNS lymphoma.
• Eyelid tumours — basal cell carcinoma (most), squamous cell carcinoma, sebaceous carcinoma, melanoma, Merkel cell carcinoma.
• Conjunctival tumours — squamous cell carcinoma (HIV, sun exposure), melanoma, lymphoma (salmon-pink patch).
• Orbital tumours — lymphoma, cavernous haemangioma, meningioma, optic nerve glioma (NF1), lacrimal gland tumours, metastases. Present with proptosis, double vision or visual loss.
• Retinoblastoma — children (see below).

↑ Back to index

Squint and Amblyopia

• Squint (strabismus) — the eyes point in different directions:
  • Esotropia (turns in), exotropia (turns out), hyper- or hypotropia (up or down).
  • Concomitant (non-paralytic) — the angle is the same in all directions; common in children; often from long sight.
  • Incomitant (paralytic) — varies with gaze; nerve palsy or restriction; needs investigation.
• Tests:
  • Corneal light reflex (Hirschberg) — reflections should be in the same place in each pupil.
  • Cover test — cover the straight eye; the squinting eye moves to take up fixation.
  • Red reflex; acuity.
• Pseudosquint — wide nasal bridge and epicanthic folds make the eyes look turned in; light reflexes are symmetrical.
• Normal — intermittent squint can be normal in the first 3 months of life.
• Amblyopia ("lazy eye"):
  • Reduced vision in an eye that is otherwise healthy, because the brain didn't get a clear image during development.
  • Causes — squint, unequal glasses prescription (anisometropia), blocked vision (cataract, ptosis).
  • Treat early — best results before age 7–8, when the visual system is still developing.
  • Treatment — glasses first; then patching the good eye or atropine drops to blur it.
• Refer any child with a persistent squint; urgently if sudden onset, with a poor red reflex, headache, or other neurological signs (tumour, raised ICP).
• Squint surgery — to straighten the eyes (cosmetic and to help binocular vision).

↑ Back to index

White Pupil and Retinoblastoma

• Leukocoria — a white pupil (often first seen in a flash photograph) or an absent red reflex.
• Causes:
  • Retinoblastoma — must be excluded.
  • Congenital cataract.
  • Retinopathy of prematurity; Coats disease; toxocara; persistent fetal vasculature; retinal detachment.
• Retinoblastoma:
  • The commonest eye cancer of childhood — usually under 5.
  • RB1 gene (chromosome 13). Bilateral or family history = heritable (germline) form — also a lifelong risk of other cancers (osteosarcoma, soft tissue sarcomas), especially after radiotherapy.
  • Features: White pupil, new squint, red painful eye, poor vision, family history.
  • Referral (NICE NG12) — absent red reflex: refer urgently (within 2 weeks) for assessment for retinoblastoma. A new squint or change in vision: urgent if there is a family history of retinoblastoma.
  • Treatment at the national centres (London and Birmingham) — chemotherapy (IV or intra-arterial), laser, cryotherapy, plaque radiotherapy, or eye removal. Survival in the UK is over 95%.
  • Genetic testing and screening of siblings and offspring.
• Congenital cataract — found at the newborn and 6–8 week red reflex checks. Needs surgery within weeks to prevent dense amblyopia. Causes: genetic, infection (rubella, CMV, toxoplasmosis), galactosaemia, Down syndrome.

⚠️ Safety Pearl: Take a parent's concern about a "white eye in photos" seriously — examine the red reflex and refer urgently if it is absent or abnormal.

↑ Back to index

Retinopathy of Prematurity

• What it is: Abnormal blood vessel growth in the immature retina of premature babies; can cause retinal detachment and blindness.
• Risk factors: Low gestational age and birth weight; high or fluctuating oxygen levels; sepsis.
• Screening (UK guideline): Babies born before 31 weeks or weighing under 1,501 g — dilated eye examinations on the neonatal unit from a few weeks after birth.
• Treatment: Laser to the peripheral retina, or anti-VEGF injection.
• Prevention: Careful oxygen targeting in neonatal care.
• Long-term — higher risk of short sight, squint, amblyopia; follow-up.

↑ Back to index

Other Childhood Eye Problems

• Vision screening:
  • Newborn and 6–8 week checks — red reflex (cataract, retinoblastoma).
  • Orthoptist screening at age 4–5 — amblyopia and squint.
• Blocked tear duct (congenital nasolacrimal duct obstruction) — watery, sticky eye from birth; usually clears by 12 months; massage; probing if persistent.
• Congenital glaucoma — large eyes (buphthalmos), cloudy cornea, watering, photophobia. Urgent referral — surgery.
• Non-accidental injury — retinal haemorrhages (many, in several layers, extending to the periphery) in a baby with unexplained brain injury suggest abusive head trauma. Follow safeguarding procedures; ophthalmology examination with photographs.
• Periorbital and orbital cellulitis — see the Red Eye and Eye Emergencies chapter.
• Nystagmus in infancy — may be idiopathic or a sign of poor vision (albinism, congenital cataract, optic nerve problems) or brain disease; refer.
• Myopia in children — increasingly common; more time outdoors helps prevent it; low-dose atropine drops and special lenses can slow progression.
• Allergic eye disease and conjunctivitis — common; see the Red Eye chapter.

↑ Back to index

Drug Reference Table

↑ Back to index

Spot the Diagnosis

↑ Back to index

Exam-style Scenarios

1. A 42-year-old woman has a sudden severe headache and drooping of the right eyelid. The right eye is down and out and the right pupil is 7 mm and unreactive.
Answer: Third nerve palsy with pupil involvement — posterior communicating artery aneurysm.

• Emergency CT and CT angiography; neurosurgical referral.
• If subarachnoid haemorrhage: nimodipine, BP control, coiling or clipping.

2. A 38-year-old man has had left neck pain since a gym session 2 days ago. His left pupil is small and the left lid droops slightly.
Answer: Painful Horner syndrome — carotid artery dissection.

• Same-day CT or MR angiography of the head and neck.
• Antiplatelet (or anticoagulant) treatment per stroke team; look for TIA or stroke signs.

3. A 52-year-old smoker with Graves' disease has bulging eyes and now reduced vision and colour vision in the right eye with a right RAPD.
Answer: Dysthyroid optic neuropathy.

• Urgent ophthalmology; IV methylprednisolone.
• Orbital decompression if no rapid response.
• Stop smoking; keep thyroid function normal; avoid radioiodine without steroid cover.

4. A woman has taken hydroxychloroquine 400 mg daily for lupus for 6 years. She weighs 58 kg and has never had eye screening.
Answer: At risk of hydroxychloroquine retinopathy.

• Dose is about 6.9 mg/kg/day — above the 5 mg/kg limit; review dose with rheumatology.
• Refer for retinal screening now (OCT and fields), then yearly.

5. A mother says her 18-month-old's left eye "glows white" in photographs. The child has also developed an inward squint on that side.
Answer: Suspected retinoblastoma.

• Examine the red reflex; urgent ophthalmology referral (within 2 weeks; sooner per local pathway).
• Treatment at a national retinoblastoma centre; genetic testing (RB1) and sibling screening.

↑ Back to index

Key Points

• Anisocoria worse in the dark — small pupil abnormal (Horner); worse in light — large pupil abnormal (third nerve, Adie, drugs).
• Painful Horner syndrome = carotid dissection until proven otherwise; Horner with arm symptoms in a smoker = Pancoast tumour.
• Monocular diplopia is an eye problem (often cataract); binocular diplopia is a nerve, muscle or junction problem.
• Third nerve palsy with a dilated pupil = aneurysm until proven otherwise — CT angiography the same day.
• Fourth nerve: vertical diplopia going downstairs, head tilt; sixth nerve: can't abduct — consider raised ICP.
• INO: MS in the young, stroke in the old. Myasthenia: fatigable ptosis, normal pupils.
• Thyroid eye disease: stop smoking; radioiodine can worsen it; optic neuropathy needs IV steroids and decompression.
• Uveitis can be the first sign of HLA-B27 disease, sarcoid, Behçet's, syphilis, TB or lymphoma.
• Hydroxychloroquine: 5 mg/kg/day or less; yearly retinal screening after 5 years.
• Topiramate can cause bilateral angle closure; vigabatrin causes permanent field loss; tamsulosin affects cataract surgery.
• Amblyopia must be treated early (glasses, patching or atropine) — refer any persistent squint.
• Absent red reflex or white pupil in a child — urgent referral for retinoblastoma or cataract.
• Screen premature babies (under 31 weeks or under 1,501 g) for retinopathy of prematurity.