Milton Disease

Disorder of complement regulation in which C1 esterase inhibitor (C1INH), an inhibitor of spontaneous activation of C1, is lacking. This produces circumscribed, nonpitting subepithelial edema involving the lips, eyelids, tongue, larynx, pharynx, respiratory tract, gastrointestinal tract, renal system, and occasionally the central nervous system.

Angioedema; Hereditary Angioneurotic Edema; HANE Syndrome; C1 Esterase Inhibitor Deficiency.

Estimated incidence of the hereditary form is 1:50,000-150,000 live births in the United States.

In the hereditary form, transmission is via an autosomal dominant pattern, with males affected twice as often as females. Human C1 inhibitor gene is localized to chromosome 11q11-q13.1. In more than 20% of patients with hereditary angioedema, the mutations are de novo; thus there is no family history of the disease.

Hereditary angioneurotic edema (HANE) is caused by either the absence of C1INH (type I) or the presence of inactive C1INH (type II). Acquired forms result from either consumption of C1INH in association with benign or malignant B-cell lymphoproliferative disorders, connective tissue diseases, and monoclonal gammopathies (type I), or the presence of antibodies to C1INH (type II).

Positive family history and characteristic clinical presentation. Serum C1 esterase inhibitor deficiency in the hereditary form (5-30% of normal) and low C4.

Age at onset of HANE syndrome (Milton disease) is before 7 years in 50% of cases. Both inherited or acquired forms are characterized by recurrent attacks of nonpruritic and nonerythematous, often asymmetrical, edema affecting the extremities, abdomen, and face. Edema of the larynx and other portions of the airways is the most fearsome feature of this disorder and is the major cause of mortality, an outcome that could occur in up to 50% of these patients. Precipitating factors are minor trauma or emotional upset. Visceral involvement with crampy abdominal pain without peritoneal signs can lead to unnecessary laparotomy. Severe attacks of watery diarrhea are another manifestation of HANE. Edema of the airway is slowly progressive over hours, but local trauma, as in attempted tracheal intubation, can precipitate or aggravate the edema. During an attack, levels of C1 inhibitor and C4 and C2 are depressed. There are increased levels of thyroglobulin antibodies and thyroid microsomal antibodies in patients with hereditary angioedema. Androgen derivatives are useful for long-term prophylaxis because they increase hepatic synthesis of C1INH. Concentrates of C1 inhibitor are effective and without side effects in the treatment of severe acute attack.

Skin testing for anesthetic drugs is useless. Suitable premedication to allay anxiety. Investigations include coagulation status, C1NH and C4 levels in HANE, and electrolytes when there is diarrhea associated with gastrointestinal attacks. Because androgen derivatives used for prophylaxis may affect hepatic function, liver function tests should be performed. In HANE, attempts should be made to increase C1NH levels preoperatively by using androgens, antifibrinolytics, fresh-frozen plasma (FFP), or purified C1NH concentrate. If the patient is not receiving long-term therapy with androgens (e.g., danazol 200 mg TID for 5 days can be used in adults but is contraindicated in children; stanazol 2 mg/kg/day to a maximum of 6 mg/kg/day), these agents should be administered for several days prior to surgery; they often require 1 to 2 weeks to reach maximum effect. Alternatively, in case of emergency, 2 units of FFP or purified C1INH concentrate (25 U/kg) will restore the C1NH to a safe level (>40% of normal) for a duration between 1 and 4 days.

There is no influence of anesthetic drug choice. Local and spinal/extradural anesthesia has always been preferred in these patients. Avoid airway manipulation and tracheal intubation to limit mucosal damage and severe edema, where possible. Use of a laryngeal mask airway probably is unsafe because of the large contact surface and the potential postoperative complications of airway obstruction. If tracheal intubation is necessary, prophylaxis is mandatory but may not be completely effective. Facilities and equipment to treat anaphylaxis or airway obstruction (e.g., drugs, intubation equipment, and tracheostomy) should be available. Treat attacks of angioedema caused by C1NH deficiency with FFP or purified C1NH concentrate (25 U/kg) because patients will not respond to adrenaline, steroids, or antihistamines. Remember that C1NH levels will fall with hemodilution; this is especially important if the patient receives excessive fluids or undergoes cardiopulmonary bypass (level >50% of normal is necessary before bypass). Postoperative intensive care unit monitoring is recommended, depending on the type and extent of surgery.

Avoid drugs that may aggravate disease, such as salicylates and nonsteroidal antiinflammatory drugs (NSAIDs). Use the most “immunologically benign” agents and avoid histamine-releasing drugs where possible.