What are the differential diagnoses for anisocoria in a patient with a normal brain CT and no motor weakness?

Differential Diagnoses for Anisocoria with Normal CT Brain and No Motor Weakness

In a patient with anisocoria, normal brain CT, and no motor weakness, the differential diagnosis should systematically evaluate for benign physiologic anisocoria, Horner syndrome, Adie tonic pupil, pharmacologic mydriasis, and third nerve palsy (particularly pupil-sparing microvascular causes), while urgently excluding pupil-involving third nerve palsy from posterior communicating artery aneurysm. 1

Immediate Assessment Framework

The critical first step is determining which pupil is abnormal by examining pupillary responses in both bright and dim illumination, then assessing for associated findings including ptosis, extraocular movement limitations, or other neurological signs. 1

Benign Causes

Physiologic Anisocoria

• Pupil size difference typically less than 1mm with normal light reactivity in both pupils 1
• No ptosis, no extraocular movement abnormalities, and no other associated findings 1
• Present in approximately 20% of the normal population 2
• This is the most common cause when neuroimaging is normal 3

Pharmacologic Mydriasis

• Can result from topical anticholinergics, antihistamines, tropane alkaloids, or inadvertent exposure to mydriatic agents 1
• The dilated pupil will not constrict with pilocarpine 1%, which distinguishes it from neurologic causes 1, 2
• Consider occupational or accidental exposure (scopolamine patches, nebulized bronchodilators, plants) 3
• Critical pitfall: Always obtain detailed medication history including eye drops, patches, and over-the-counter medications 3

Neurologic Causes Requiring Further Evaluation

Horner Syndrome

• Presents with miosis (smaller pupil on affected side), ptosis (typically mild, 1-2mm), and anhidrosis (depending on lesion location) 1, 2
• The anisocoria is more pronounced in dim lighting as the affected pupil dilates poorly 2
• Pharmacologic testing with cocaine 10% or apraclonidine can confirm the diagnosis 2
• Causes include carotid dissection, lung apex tumors, brainstem lesions, or idiopathic 2
• Even with normal CT, consider MRI/MRA of brain and neck if Horner syndrome is suspected, particularly to exclude carotid dissection 1

Adie Tonic Pupil

• Presents with a dilated pupil that reacts sluggishly or not at all to light but shows slow, tonic constriction to near stimuli 1, 2
• More common in young women 2
• The pupil shows denervation supersensitivity and will constrict to dilute pilocarpine 0.1% (whereas normal pupils require higher concentrations) 2, 4
• Usually benign and postganglionic parasympathetic denervation 2

Third Nerve Palsy (Pupil-Sparing)

• Classic presentation: complete ptosis, complete extraocular motility dysfunction, but normal pupillary function 5, 1
• Almost always secondary to microvascular disease associated with diabetes, hypertension, or hyperlipidemia 5, 1
• Critical caveat: If there is partial extraocular muscle involvement or incomplete ptosis, even with a normal pupil, you cannot assume microvascular etiology—proceed with MRI with gadolinium and MRA or CTA 5, 1
• Typically resolves within 3 months with observation 5

Third Nerve Palsy (Pupil-Involving)

• This is a medical emergency requiring urgent neuroimaging with MRI with gadolinium and MRA or CTA to rule out posterior communicating artery aneurysm 5, 1
• If high suspicion persists despite normal MRA/CTA, catheter angiography should be considered 5
• Other causes include tumors (meningioma, schwannoma, metastases), trauma, subarachnoid hemorrhage, demyelinating disease, and leptomeningeal disorders 5
• If neuroimaging is normal, proceed with serologic testing for infectious diseases (syphilis, Lyme) and consider lumbar puncture 5

Traumatic and Structural Causes

Traumatic Mydriasis

• Slit-lamp examination may reveal irregular pupil shape suggesting traumatic sphincter damage 1
• History of trauma may be remote or forgotten 6
• Intraocular foreign body (IOFB) can present with anisocoria and should be considered, especially before ordering MRI as metallic objects can move and cause serious complications 6
• Review orbital cuts on existing CT imaging if available 6

Iris Pathology

• Iritis, posterior synechiae, or congenital abnormalities can cause irregular pupils 1
• Requires slit-lamp biomicroscopy for diagnosis 1

Diagnostic Algorithm

1. Examine pupillary responses in bright and dim lighting to determine which pupil is abnormal 1
2. Assess for ptosis, extraocular movements, and other cranial nerve findings 5, 1
3. Perform slit-lamp examination to assess pupil shape, iris integrity, and anterior segment 1
4. Check for relative afferent pupillary defect (RAPD), which suggests optic nerve or retinal pathology 1

Pharmacologic Testing When Diagnosis Unclear

• Pilocarpine 1%: Pharmacologic mydriasis will not constrict; neurologic causes will constrict 1, 2
• Pilocarpine 0.1%: Adie pupil shows supersensitivity and constricts; normal pupils do not 2
• Cocaine 10% or apraclonidine: Confirms Horner syndrome 2

Red Flags Requiring Urgent Advanced Imaging

Despite normal CT, the following warrant MRI with gadolinium and MRA or CTA 5, 1:

• Any pupil-involving third nerve palsy 5, 1
• Partial third nerve palsy (incomplete ptosis or partial extraocular muscle involvement) even without pupil involvement 5, 1
• Anisocoria with headache, altered mental status, or progressive neurological deficits 1
• Suspected Horner syndrome (to exclude carotid dissection) 1
• Multiple cranial nerve palsies suggesting cavernous sinus pathology 1

Common Pitfalls to Avoid

• Do not assume microvascular third nerve palsy unless there is complete ptosis, complete motility dysfunction, and completely normal pupil 5, 1
• Do not order MRI before excluding IOFB with careful history and review of CT orbital cuts 6
• Do not miss pharmacologic causes—always obtain detailed medication and exposure history 1, 3
• Do not attribute large RAPD to amblyopia alone—always search for compressive optic neuropathy or retinal pathology 1
• Do not assume physiologic anisocoria if difference exceeds 1mm or if any associated findings are present 1