What is the differential diagnosis and management of miosis (pupillary constriction)?

Differential Diagnosis of Miosis

The differential diagnosis of miosis (pupillary constriction) includes opioid intoxication, Horner's syndrome, nerve agent exposure, myasthenia gravis (rare), and physiologic causes such as bright light exposure or accommodation. The most critical immediate considerations are opioid overdose and nerve agent exposure due to their life-threatening implications, while Horner's syndrome requires urgent neuroimaging to exclude serious underlying pathology 1, 2.

Life-Threatening Causes Requiring Immediate Action

Opioid Intoxication

• Miosis is strongly correlated with opioid exposure and response to naloxone administration, making it a key diagnostic finding in suspected overdose 1.
• The classic triad includes miosis, respiratory depression, and decreased level of consciousness 1.
• Peak opioid-induced miosis is best detected under moderately dim interior lighting (4-16 foot-lamberts) approximately 90 minutes after opioid administration 3.
• Miosis is a sign of opioid usage but NOT a sign of overdosage—the critical distinction is the presence of respiratory depression and altered consciousness 1.
• In suspected opioid overdose with unresponsiveness and absent or abnormal breathing, immediately activate emergency response, provide high-quality CPR with ventilations, and administer naloxone 1.
• Naloxone has an excellent safety profile and is unlikely to cause harm if given to someone without opioid overdose 1.

Nerve Agent Exposure

• Miosis ≤3 mm is a simple and sensitive index for nerve agent exposure in non-atropinized patients 1.
• Associated findings include severe rhinorrhea, dim vision, bronchospasm, bradycardia, excessive salivation, and sweating 1.
• Aggressive atropine administration is essential for survival, with treatment aimed at maintaining normal respiration, controlling seizures, and stabilizing cardiovascular conditions 1.
• Healthcare providers must wear full protective gear (gas mask and butyl rubber gloves) as ordinary surgical masks and latex gloves provide inadequate protection 1.

Neurologic Causes Requiring Urgent Evaluation

Horner's Syndrome

• The classic triad consists of ipsilateral ptosis, pupillary miosis, and facial anhidrosis 2, 4.
• Additional findings may include heterochromia iridis (in congenital cases), asymmetrical facial flushing, and loss of ciliospinal reflex 4, 2.
• Pharmacologic testing with apraclonidine eye drops can confirm the diagnosis—miosis reverses with apraclonidine instillation, causing relative mydriasis of the affected pupil 4.
• Urgent neuroimaging of the entire sympathetic pathway (head, neck, and thorax) is mandatory to exclude serious underlying disease including carotid dissection, apical lung tumor (Pancoast), or brainstem stroke 4, 2.
• The location of the lesion determines associated symptoms: first-order lesions (central) cause anhidrosis of entire body half; second-order lesions (preganglionic) cause anhidrosis of face and neck; third-order lesions (postganglionic) typically spare anhidrosis 2.

Third Nerve Palsy (Rare Pupillary Involvement)

• Pupil-involving third nerve palsy presents with miosis less commonly than mydriasis, but mild pupillary involvement can occur with vasculopathic lesions 1.
• Associated findings include ptosis, ophthalmoplegia affecting superior rectus, inferior rectus, medial rectus, and inferior oblique muscles 1.
• Pupil-involving third nerve palsy requires urgent neuroimaging (MRI with gadolinium and MRA or CTA) to exclude posterior communicating artery aneurysm 1.

Myasthenia Gravis (Uncommon Pupillary Finding)

• Pupils are typically NOT affected in myasthenia gravis, but rare cases show impaired or slow pupillary responses 1, 5.
• The characteristic presentation includes fatigable weakness, variable ptosis with Cogan lid-twitch sign, variable incomitant strabismus, and slow saccades 1, 5.
• The ice pack test is highly specific—application over closed eyes for 2-5 minutes demonstrates reduction of ptosis and improvement in ocular alignment 1, 5.
• Acetylcholine receptor antibody testing has 80-88% sensitivity for generalized myasthenia and 98-100% specificity 5.
• Single-fiber EMG has >90% sensitivity even in seronegative cases and is considered the gold standard electrophysiological test 1, 5.

Physiologic and Benign Causes

Normal Physiologic Miosis

• Pupil diameter decreases 1.0 mm with each log unit increase in lighting intensity 3.
• Accommodation for near vision causes physiologic miosis bilaterally 1.
• Pupil diameters are systematically larger (average 0.35 mm) with monocular viewing compared to binocular viewing 3.

Age-Related Changes

• Senile miosis occurs with advancing age due to iris stromal atrophy and decreased dilator muscle function 1.

Pharmacologic Causes

Topical Medications

• Pilocarpine and other cholinergic agonists used for glaucoma treatment cause miosis 1.
• Prostaglandin analogs may cause mild miosis 1.

Systemic Medications

• Cholinesterase inhibitors (pyridostigmine for myasthenia gravis) can cause miosis 1.
• Antipsychotic medications may cause miosis through central mechanisms 1.

Diagnostic Approach Algorithm

Step 1: Assess for life-threatening causes

• Check respiratory status, level of consciousness, and vital signs 1.
• If unresponsive with respiratory depression and circumstantial evidence of opioid exposure, administer naloxone immediately 1.
• If miosis with excessive secretions, bronchospasm, and bradycardia, suspect nerve agent and initiate atropine 1.

Step 2: Determine unilateral vs. bilateral involvement

• Unilateral miosis with ptosis and anhidrosis indicates Horner's syndrome—perform apraclonidine test and obtain urgent neuroimaging 4, 2.
• Bilateral miosis suggests opioid use, physiologic causes, or bilateral pharmacologic effect 1, 3.

Step 3: Evaluate associated ocular findings

• Variable ptosis with fatigable weakness suggests myasthenia gravis—perform ice pack test and check acetylcholine receptor antibodies 1, 5.
• Ophthalmoplegia with pupillary involvement requires urgent imaging for third nerve palsy 1.

Step 4: Consider medication history and environmental exposures

• Review all topical and systemic medications 1.
• Assess for occupational or intentional chemical exposures 1.

Critical Pitfalls to Avoid

• Do not assume miosis alone indicates opioid overdose—respiratory depression and altered consciousness must be present 1.
• Do not delay neuroimaging in Horner's syndrome even if a benign cause seems likely—life-threatening pathology must be excluded 4, 2.
• Do not dismiss mild or unilateral pupillary involvement in third nerve palsy—aneurysm can present with initially subtle pupillary signs 1.
• Do not rely solely on pupil size in dim lighting—opioid miosis is best detected under moderately dim conditions (4-16 foot-lamberts) 3.
• Do not forget that miosis from nerve agents requires full protective equipment for healthcare providers to prevent secondary contamination 1.