Diplopia

Diplopia is the perception of two images of one object. It is monocular (persists with one eye covered) or binocular (disappears when either eye is covered). Monocular diplopia is almost always ocular (refractive, corneal, lens). Binocular diplopia indicates misalignment of the eyes from disease of the extraocular muscles, the neuromuscular junction, the cranial nerves (III, IV, VI), the brainstem, or the orbit.

Anatomy. The oculomotor nerve (III) supplies the medial, superior and inferior recti, inferior oblique and levator palpebrae, and the pupil constrictor. The trochlear nerve (IV) supplies the superior oblique. The abducens nerve (VI) supplies the lateral rectus. The cavernous sinus contains III, IV, V1, V2 and VI and the internal carotid artery.

Classification. Monocular (refractive error, astigmatism, keratoconus, dry eye, cataract, retinal disease, polyopia), and binocular: neurogenic (III, IV, VI palsy, brainstem, internuclear ophthalmoplegia), neuromuscular junction (myasthenia gravis), muscle (thyroid eye disease, myositis, orbital fracture, restrictive), decompensated phoria, and central (skew deviation, convergence insufficiency).

Key distinctions. Painful third nerve palsy with a dilated pupil indicates aneurysm until proven otherwise. Fluctuating diplopia worse in the evening with ptosis indicates myasthenia. Horizontal diplopia worse at distance indicates sixth nerve palsy. Vertical diplopia with head tilt indicates fourth nerve palsy. Diplopia with proptosis indicates orbital disease.

History:

• onset (sudden, gradual)
• constancy or intermittency
• orientation (horizontal, vertical, oblique, torsional)
• worse at distance or near
• direction of gaze that worsens
• head tilt or turn
• disappearance with one eye closed
• painful or painless
• ptosis
• fatigue (diurnal variation)
• headache
• facial pain or numbness
• hearing loss
• vertigo
• limb weakness
• dysarthria
• dysphagia
• recent trauma
• diabetes, hypertension, cardiovascular disease
• giant cell arteritis symptoms
• thyroid symptoms
• cancer history
• infection
• previous squint or glasses
• drugs

Drug history. Anticonvulsants (phenytoin, carbamazepine), sedatives, alcohol, botulinum toxin, aminoglycosides and other drugs aggravating myasthenia, and statins.

Examination.

• Cover each eye to distinguish monocular and binocular diplopia. Pinhole test.
• Visual acuity, colour vision, pupils (size, reaction, relative afferent defect), lid position (ptosis, lid retraction), and proptosis (exophthalmometry).
• Eye movements in nine positions of gaze (duction and version), saccades, cover test and alternate cover test, and red glass test.
• Head posture, Parks three step test (fourth nerve), forced duction (restriction), and Hess chart or Lees screen.
• Fatigability on sustained upgaze for 60 seconds (myasthenia), ice pack test for ptosis.
• Fundus (papilloedema, optic atrophy), corneal sensation, facial sensation and power, hearing, and a full neurological examination including gait, cerebellar and long tract signs.
• Temporal artery examination, thyroid examination, and blood pressure.

Red flags

• Painful third nerve palsy, especially with pupil dilation or sudden severe headache (aneurysm)
• Diplopia with other cranial nerve deficits, hemiparesis, ataxia or reduced consciousness (brainstem stroke)
• Diplopia with facial pain or numbness, or with proptosis and chemosis (cavernous sinus, orbital disease)
• Age over 50 with headache, jaw claudication or scalp tenderness (giant cell arteritis)
• Papilloedema, headache and vomiting (raised intracranial pressure)
• Fatigable ptosis with bulbar weakness or respiratory weakness (myasthenic crisis)
• Diplopia after head or orbital trauma (blow out fracture, brainstem injury)
• Unilateral loss of vision, or pain with eye movement
• Diplopia with fever, ear disease or sinusitis (Gradenigo syndrome, orbital and intracranial infection)
• Cancer history

Special groups. Children: congenital squint, fourth nerve palsy, sixth nerve palsy with raised pressure, leukaemia, and brainstem glioma. Pregnancy: venous sinus thrombosis, pre-eclampsia, Wernicke encephalopathy with hyperemesis, and idiopathic intracranial hypertension. Older adults: microvascular cranial nerve palsy, giant cell arteritis, stroke.

Monocular diplopia

• Refractive error and astigmatism, keratoconus, corneal scarring, dry eye, cataract, lens subluxation, iridectomy, macular disease, retinal detachment

Cranial nerve palsy

• Third nerve: microvascular (diabetes, hypertension), posterior communicating artery aneurysm, uncal herniation, tumour, trauma, cavernous sinus lesion, giant cell arteritis, basilar artery lesions, meningitis, migraine
• Fourth nerve: congenital decompensation, trauma, microvascular
• Sixth nerve: microvascular, raised intracranial pressure (false localising), tumour (skull base, nasopharyngeal carcinoma, clivus), Gradenigo syndrome, trauma, multiple sclerosis, Wernicke encephalopathy, meningitis, viral

Brainstem and central

• Brainstem stroke, internuclear ophthalmoplegia (multiple sclerosis, stroke), one and a half syndrome, skew deviation, brainstem tumour, Wernicke encephalopathy, Miller Fisher syndrome, Bickerstaff encephalitis, botulism

Neuromuscular junction and muscle

• Myasthenia gravis, Lambert Eaton syndrome (rarely)
• Thyroid eye disease, orbital myositis, orbital inflammatory syndrome, orbital tumour, orbital cellulitis, blow out fracture with muscle entrapment, chronic progressive external ophthalmoplegia, Brown syndrome

Cavernous sinus and orbital apex

• Cavernous sinus thrombosis, carotid cavernous fistula, internal carotid aneurysm, pituitary apoplexy, meningioma, nasopharyngeal carcinoma, Tolosa Hunt syndrome, mucormycosis and aspergillosis

Other

• Decompensated strabismus (phoria), convergence insufficiency, ocular motor apraxia, giant cell arteritis, sarcoidosis, diabetes related, Graves disease, drug effect (alcohol, anticonvulsants), functional and psychogenic

Reasoning. Decide monocular or binocular. For binocular diplopia, identify the pattern of weakness and associated signs, localise to nerve, junction, muscle or brainstem, and image according to risk.

First line. Cover tests, ocular motility examination, pupils, fundus, blood pressure and capillary glucose. A normal pupil does not exclude aneurysm in a partial third nerve palsy.

Blood tests.

• Glucose and HbA1c.
• ESR, C reactive protein and platelet count (giant cell arteritis).
• Full blood count, urea, creatinine, electrolytes and lipids.
• Thyroid function and thyroid antibodies.
• Acetylcholine receptor and muscle specific tyrosine kinase antibodies (myasthenia).
• Anti-GQ1b antibodies (Miller Fisher syndrome).
• Syphilis serology, HIV, and Lyme serology in endemic areas.
• Antinuclear antibody, ANCA and angiotensin converting enzyme.
• Thiamine status in at risk patients (treat without waiting).

Imaging. Emergency CT head and CT angiography for painful or pupil involving third nerve palsy, acute neurological signs or sudden severe headache; MRI brain and orbits with gadolinium for isolated palsies with other features, young patients, progressive palsy, or when no improvement after 3 months; MRI and MR angiography or catheter angiography for aneurysm; CT orbits for trauma and thyroid eye disease; CT or MRI venography for cavernous sinus thrombosis.

Other tests. Edrophonium or ice pack test and single fibre electromyography, repetitive nerve stimulation for myasthenia; chest CT for thymoma. Lumbar puncture with opening pressure after imaging (over 25 cmH2O in adults is abnormal) and cerebrospinal fluid analysis for meningitis, demyelination, and carcinomatous meningitis. Temporal artery ultrasound or biopsy. Orthoptic assessment with Hess chart and prism measurement.

Limitations. Microvascular palsies are a diagnosis of exclusion and need follow up. MRI may be normal in early brainstem stroke. Antibody tests are negative in about 50 percent of ocular myasthenia.

Emergencies.

• Painful or pupil involving third nerve palsy: emergency CT and CT angiography, neurosurgical referral for aneurysm (coiling or clipping), blood pressure control, and avoid delay.
• Acute stroke or brainstem syndrome: emergency stroke care. Give 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, or tenecteplase 0.25 mg/kg IV as a single bolus (maximum 25 mg).
• Keep blood pressure under 185/110 mmHg before and under 180/105 mmHg for 24 hours after thrombolysis.
• Aspirin 300 mg orally daily when thrombolysis is not given. Refer for thrombectomy in basilar occlusion.
• 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 if visual symptoms; same day specialist review.
• Wernicke encephalopathy (ophthalmoplegia, ataxia, confusion): 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.
• Myasthenic crisis: intensive care, intravenous immunoglobulin 0.4 g/kg daily for 5 days or plasma exchange; stop aggravating drugs (fluoroquinolones, aminoglycosides, macrolides, magnesium, beta blockers).
• Cavernous sinus thrombosis and orbital infection: admit. Give ceftriaxone 2 g IV every 12 hours plus metronidazole 500 mg IV every 8 hours.
• Add vancomycin 25 to 30 mg/kg IV loading dose (maximum 3 g), then 15 to 20 mg/kg every 8 to 12 hours adjusted to creatinine clearance and levels.
• Anticoagulation by specialist decision (enoxaparin 1 mg/kg subcutaneously every 12 hours, adjusted when creatinine clearance is under 30 mL/min).
• Mucormycosis: immediate ENT, ophthalmology and infectious disease referral; liposomal amphotericin B 5 mg/kg IV daily (up to 10 mg/kg with CNS disease), glycaemic control, and urgent surgical debridement.
• Raised intracranial pressure from tumour, hydrocephalus or idiopathic intracranial hypertension: neurosurgical referral; acetazolamide 500 mg orally twice daily increased by 500 mg weekly to a maximum of 4 g daily as tolerated (halve when creatinine clearance is 10 to 50 mL/min), weight loss, and visual field monitoring.
• Meningitis: ceftriaxone 2 g IV every 12 hours with dexamethasone 10 mg IV every 6 hours for 4 days (first dose before or with the antibiotic).

Interim symptomatic relief. Occlude one eye (patching alternating eyes, or a translucent occlusive lens on the glasses) to relieve diplopia, avoid driving and heights, and avoid prolonged patching in children (amblyopia).

Microvascular cranial 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, and observe: most recover within 3 to 4 months. Prisms (Fresnel) for residual diplopia, and re-image if no recovery by 3 months or new signs.

Ocular myasthenia. Pyridostigmine 30 to 60 mg orally three to four times daily (maximum 240 mg daily; reduce in renal impairment; muscarinic adverse effects), with prednisolone 10 to 20 mg daily increased slowly to 0.5 to 1 mg/kg on alternate days under neurology care (watch for transient worsening), and thymoma screening with chest CT; steroid sparing agents by specialists.

Thyroid eye disease. Smoking cessation, control of thyroid function, lubricants, selenium 100 micrograms orally twice daily for 6 months in mild disease, and prisms for diplopia.

For moderate to severe or sight threatening disease, give methylprednisolone 500 mg IV weekly for 6 weeks then 250 mg weekly for 6 weeks (cumulative dose under 8 g, with liver function monitoring). Orbital radiotherapy, decompression surgery or teprotumumab are used by specialists.

Strabismus surgery when disease is inactive for at least 6 months.

Orbital myositis and inflammatory disease. Prednisolone 1 mg/kg orally daily (maximum 60 to 80 mg) reduced by response under specialist care, after infection and tumour are excluded.

Blow out fracture. Ice and nasal precautions, oral antibiotic prophylaxis for 5 to 7 days (amoxicillin with clavulanic acid 625 mg three times daily), and early orbital surgery when muscle entrapment (urgent in children) or large defects with enophthalmos.

Multiple sclerosis (internuclear ophthalmoplegia). Methylprednisolone 1 g IV daily for 3 to 5 days for disabling relapse, and neurology care.

Convergence insufficiency and decompensated phoria. Orthoptic exercises (pencil push ups, computer based convergence therapy), prisms, and treatment of underlying fatigue or medication causes.

Strabismus in children. Early refraction, patching for amblyopia, and strabismus surgery by ophthalmology; paediatric neuroimaging for new sixth nerve palsy.

Botulinum toxin and surgery. Botulinum toxin injection or strabismus surgery for persistent stable deviation after 6 months, by ophthalmology.

Monitoring. Re-examine at 1 to 2 weeks and then every 4 to 6 weeks; measure deviation by Hess chart; watch for pupil involvement, new neurological signs and papilloedema; repeat imaging when no recovery by 3 months.

Referral and escalation. Immediate neurosurgical and stroke referral for aneurysm, stroke or brainstem syndromes. Same day ophthalmology and neurology for acute binocular diplopia with red flags. Orthoptics for all persistent diplopia. Endocrinology for thyroid eye disease. Neurology for myasthenia.

Admission criteria. Suspected aneurysm or stroke, cavernous sinus thrombosis, orbital or intracranial infection, giant cell arteritis with visual loss, Wernicke encephalopathy, myasthenic crisis, raised intracranial pressure, or neurological deterioration.

Discharge and safety netting. Return urgently for pain, new headache, drooping eyelid, pupil change, new weakness, speech or swallowing difficulty, loss of vision, or worsening double vision. Advise against driving until diplopia is controlled or compensated, and falls precautions.