What is the differential diagnosis for a patient presenting with anisocoria and a Glasgow Coma Scale (GCS) score of 15?

Differential Diagnosis for Anisocoria in a GCS 15 Patient

In a fully alert patient (GCS 15) with anisocoria, the differential diagnosis spans from benign physiological variants to life-threatening neurological emergencies, requiring systematic evaluation to distinguish between pharmacological, neurological, and ophthalmological etiologies. 1, 2

Primary Differential Categories

Benign/Physiological Causes

• Physiological anisocoria (20% of normal population): Pupil size difference ≤1mm that remains constant in light and dark, with normal reactivity in both pupils 1, 3
• Pharmacological anisocoria: Inadvertent exposure to mydriatic agents (scopolamine patches, nebulized bronchodilators, eye drops) causing unilateral fixed mydriasis in an otherwise neurologically intact patient 1, 4
• Prosthetic eye: Can be surprisingly difficult to detect in emergency settings and may mimic pathological anisocoria 5

Neurological Causes (Potentially Life-Threatening)

• Third nerve palsy: Typically presents with ptosis, ophthalmoplegia, and a dilated pupil; however, GCS 15 makes compressive lesions (aneurysm, uncal herniation) less likely but not impossible 1, 2
• Horner syndrome: Miosis with ptosis and anhidrosis; caused by disruption of sympathetic pathway (carotid dissection, apical lung tumor, brainstem stroke) 1, 3
• Traumatic mydriasis: Direct ocular trauma causing iris sphincter damage, even in patients with normal mental status 2

Ophthalmological Causes

• Adie tonic pupil: Dilated pupil with sluggish/absent light response but preserved near response; benign condition often affecting young women 1
• Acute angle-closure glaucoma: Mid-dilated fixed pupil with severe eye pain, corneal edema, and elevated intraocular pressure 2
• Inflammatory conditions: Uveitis, iris trauma, or prior ocular surgery 1, 2

Critical Clinical Approach

Immediate Assessment Priorities

• Rule out life-threatening causes first: Even with GCS 15, assess for signs of intracranial pathology (headache, vomiting, focal deficits, trauma history) that would mandate immediate CT imaging 6, 2
• Determine which pupil is abnormal: Test light reactivity in both eyes; the abnormal pupil is typically the one that doesn't react appropriately 1, 2
• Assess for associated symptoms: Ptosis (suggests Horner or third nerve), ophthalmoplegia (third nerve), eye pain (glaucoma), recent trauma (traumatic mydriasis or intracranial injury) 1, 2

Pharmacological Testing Algorithm

When clinical examination is equivocal, pharmacological testing differentiates causes 1:

• Cocaine 10% drops: Dilates normal pupils but fails to dilate Horner pupil (confirms sympathetic denervation) 1
• Apraclonidine 1%: Reverses anisocoria in Horner syndrome (miotic pupil dilates, normal pupil constricts); considered current gold standard with 95% sensitivity 1, 3
• Pilocarpine 0.1%: Constricts denervated Adie pupil due to supersensitivity but has no effect on normal pupils 1
• Pilocarpine 1%: Constricts normal pupils but fails to constrict pharmacologically dilated pupils 1

Pupillometry as Diagnostic Tool

• Automated pupillometry measuring dilation lag can discriminate Horner syndrome from physiological anisocoria with 95% sensitivity and 68% specificity, potentially obviating pharmacological testing 3
• Dilation lag measurement: Change in anisocoria at 3-4 seconds after light-off (Δ3-4) >0.35mm suggests Horner syndrome 3

Common Pitfalls to Avoid

• Do not assume benign etiology based solely on GCS 15: Patients with mild traumatic brain injury (GCS 15) can have intracranial lesions requiring intervention in 6-10% of cases, particularly with associated risk factors 6
• Do not miss pharmacological causes: Always inquire about medication patches, eye drops, or nebulizer use before pursuing extensive neuroimaging 4
• Do not overlook prosthetic eyes: Manually palpate the globe and check corneal reflex to identify artificial eyes that may be cosmetically indistinguishable 5
• Do not delay imaging in trauma patients: Any patient with head trauma and anisocoria requires CT imaging regardless of GCS, as pupillary inequality is a validated high-risk criterion 6
• Do not discharge without clear diagnosis: If anisocoria remains unexplained after initial evaluation, neurology or ophthalmology consultation is mandatory to prevent missing carotid dissection, aneurysm, or other progressive conditions 2

Specific Red Flags Requiring Immediate Imaging

• History of head trauma (even minor) with anisocoria 6
• New-onset severe headache suggesting subarachnoid hemorrhage or mass lesion 6
• Any focal neurological deficit accompanying anisocoria 6, 2
• Age >60 years with new anisocoria and trauma history 6
• Progressive symptoms or decreasing GCS from initial presentation 6