Angioedema can be classified into hereditary and acquired forms. Three types of autosomal dominant hereditary angioedema (HAE) exist (types I, II, and III), and two acquired types exist (hypersensitivity and non-hypersensitivity angioedema).⁵,¹⁰ However, from an etiopathogenic point of view, angioedema is better classified broadly into hypersensitivity (histaminergic angioedema) and non-hypersensitivity (nonhistaminergic angioedema) types, the former being mediated by histamine release while the latter is mediated by bradykinin release.¹,⁵,⁶ Other causes of angioedema that cannot strictly be classified into either category include idiopathic angioedema and pseudoallergic angioedema. The latter is associated with the use of nonsteroidal anti-inflammatory drugs and occurs due to the inhibition of cyclooxygenase 1 enzyme.⁵,⁶,⁷

The causes of hypersensitivity angioedema are numerous and include dietary or therapeutic ingestants, inhalant medications, parenterally administered drugs, and insect venoms.¹,¹⁰ The list of foods includes peanuts, shellfish, milk, and eggs, while the list of drugs includes penicillin and sulfa drugs.⁵ This mast cell disease, mediated by histamine release, causes an increase in endothelial permeability with extravasation of intravascular fluid into the interstitial tissues, resulting in edema.⁴ Sensitized individuals have circulating and cell-bound IgE to the particular sensitizing agent. On reexposure, patients undergo an immediate hypersensitivity (type I) reaction with the release of several vasoactive substances, including histamine and serotonin.¹

Patients with non-hypersensitivity angioedema may be suffering from a hereditary (HAE, 11q12) or an acquired form of angioedema (AAE). Both conditions are attributed to an abnormal complement response that develops due to a hereditary or acquired deficiency or malfunction of complement 1 esterase inhibitor (C1-INH). Both are mediated by bradykinin and not histamine release.⁵ The list of acquired causes of C1-INH deficiency includes lymphoproliferative disorders (lymphoma, monoclonal gammopathies) and some autoimmune tissue diseases.⁵,⁸ Bradykinin release causes a rapid increase in the vascular permeability of submucosal or subcutaneous capillaries and postcapillary venules resulting in localized plasma extravasation, a situation that is not dissimilar to the pathogenic events observed with hypersensitivity angioedema.⁵

Most patients with angioedema describe a tingling or burning sensation. However, itching is not a typical symptom, and some patients may even be entirely asymptomatic except for the edema.⁴ Patients who present to the ophthalmologist with an alarming upper and lower eyelid non-hypersensitivity angioedema may be suffering from HAE or AAE. Both conditions are attributed to an abnormal complement response that develops due to a hereditary or acquired deficiency or malfunction of C1-INH. A history of a known allergic reaction to food or medications may be elicited from the patient.⁵ The acute picture typically begins either immediately or 1 to
2 days after an allergenic event has taken place.¹,³ Alternatively, a history of recurrent, episodic, nonpitting, nonpruritic angioedema or a positive family history may be obtained from patients with HAE.² Patients should be asked explicitly about lip or tongue swelling, abdominal pain, and difficulty breathing or swallowing.⁵ The edema is usually moderate to severe and nonpitting, and can be erythematous or skin colored (Figure 48.1). Because the edema is nongravitational and posturally independent, it typically involves both the upper and lower eyelids.¹,⁵ Angioedema may or may not be associated with urticarial wheals, but desquamation of the skin is unusual unless rubbing occurs. The ophthalmic examination will usually reveal no ocular abnormality.³,⁵,⁶,¹⁰