What can cause periorbital edema besides Angiotensin-Converting Enzyme (ACE) inhibitors?

Causes of Periorbital Edema Beyond ACE Inhibitors

Periorbital edema has multiple etiologies including other medications (imatinib, NSAIDs, valproate, neprilysin inhibitors), endocrine disorders (hypothyroidism, hypopituitarism), hereditary angioedema, inflammatory conditions, infections, trauma, and renal/cardiac dysfunction. 1, 2, 3

Medication-Induced Causes

Tyrosine Kinase Inhibitors

• Imatinib causes periorbital edema in up to 70% of treated patients, making it the most common ocular side effect of this drug, likely through platelet-derived growth factor receptor inhibition 1
• Epiphora (excessive tearing) occurs in approximately 20% of patients due to conjunctival chemosis 1
• Diuretic therapy has limited benefit; changing to an alternative TKI is rarely appropriate but may be necessary in severe cases 1

Neprilysin Inhibitors (ARNIs)

• Neprilysin inhibitors combined with ACE inhibitors are contraindicated due to unacceptable angioedema risk through impaired bradykinin degradation 1
• ARNIs should not be administered within 36 hours of switching from or to an ACE inhibitor 1
• Patients with any history of angioedema should not receive ARNI therapy 1

NSAIDs

• Ibuprofen and naproxen can cause periorbital edema with associated itching, swelling, and erythema, typically developing after just 2 doses 4
• Symptoms resolve within 3 days of discontinuation 4
• NSAIDs cause edema through multiple mechanisms including increased vascular permeability and altered renal sodium handling 3

Other Medications

• Valproate can cause periorbital edema, typically appearing within 24 hours of administration and resolving within 5 days of discontinuation 5
• Amantadine produces reversible endothelial dysfunction with short-term use or permanent dysfunction with long-term use 1
• Bupropion has been associated with corneal edema 1
• Amiodarone, dietary calcium supplementation, and various chemotherapeutic agents can cause corneal opacification 1

Hereditary Angioedema

HAE with Normal C1 Inhibitor (HAE-nC1INH)

• Six genes are definitively linked to HAE-nC1INH: F12 (factor XII), PLG (plasminogen), ANGPT1 (angiopoietin-1), KNG1 (kininogen-1), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase-6) 1
• Two additional genes (CPN1 and DAB2IP) have been recently linked to HAE-nC1INH in families that also experienced hives 1
• HAE-FXII and HAE-PLG are clearly bradykinin-mediated 1
• Diagnosis requires recurrent angioedema without hives, strong family history, and normal C4 and C1INH levels 1

HAE with C1 Inhibitor Deficiency

• At least 95% of patients have reduced C4 levels even between attacks, increasing to virtually 100% during attacks 1
• A normal C4 level during an attack strongly suggests an alternative diagnosis 1

Endocrine Disorders

Hypothyroidism and Hypopituitarism

• Acute central hypothyroidism from pituitary tumor apoplexy can present with severe bilateral periorbital edema as the predominant manifestation 6
• Pituitary apoplexy may occur without classic symptoms of headache, visual disturbance, or altered mental status 6
• Replacement therapy with hydrocortisone and levothyroxine relieves periorbital edema associated with central adrenal insufficiency and hypothyroidism 6

Ophthalmologic Causes

Corneal Edema

• Fuchs dystrophy causes diurnal variation in symptoms, with worse vision upon waking that improves later in the day due to evaporation 1
• Elevated intraocular pressure from topical corticosteroids or chronic glaucoma can cause acute corneal edema 1
• Moderate to severe corneal or intraocular inflammation produces edema 1

Treatment Approach for Corneal Edema

• Topical sodium chloride 5% solution or ointment reduces edema through hyperosmotic effect 7
• Reduce intraocular pressure when elevated or in upper normal range 7
• Topical carbonic anhydrase inhibitors should not be first-line when endothelial dysfunction is present due to interference with the endothelial pump 7

Other Causes

Infectious and Inflammatory

• Infections, inflammation, and trauma are common causes requiring comprehensive evaluation 2
• Exposure to unusual infectious agents (Brucella, Borrelia burgdorferi) should be considered with relevant travel or animal exposure history 1

Trauma and Chemical Exposure

• Blunt or penetrating injury, forceps delivery, and chemical injury can cause periorbital edema 1
• Inadvertent corneal exposure to topical chlorhexidine during facial surgery preparation may cause endothelial toxicity 1

Renal and Cardiac Dysfunction

• Kidney or cardiac dysfunction remains a common systemic cause of periorbital edema 2, 6

Clinical Pitfalls

• Do not assume all periorbital edema is allergic or infectious—consider medication history extending back months to years, as some drugs (like imatinib) cause edema in the majority of patients 1
• Screen for C4 levels in recurrent angioedema without hives before assuming drug-related etiology, as this is cost-effective and identifies hereditary causes 1
• Consider endocrine causes when periorbital edema is bilateral and severe, particularly in elderly patients with fatigue and lethargy 6
• Remember that ACE inhibitor-induced angioedema can persist for at least 6 weeks after discontinuation 1