Wegener’s Granulomatosis, PHACE Syndrome: Rarities With Anesthetic Implications

Anesthesiology News

Wegener’s Granulomatosis

What Is It?

Wegener’s granulomatosis, first described by Peter McBride in 1897 and later by Friedrich Wegener (1936 and 1939), is a chronic, immunologic, systemic disorder characterized mainly by necrotizing granulomatosis and polyangiitis throughout the respiratory tract combined with glomerulonephritis. It is a form of vasculitis that affects small, medium and occasionally large arterioles. Venules also may be affected. The cause is unknown, although genetics may be involved. The risk for inheritance of Wegener’s granulomatosis appears to be low. Anti–neutrophilcytoplasmic antibodies (ANCAs) may be elevated.¹ ANCAs activate neutrophils, increase their adherence to endothelium and induce degranulation, thus damaging endothelial cells. Damage to vessel walls, especially of arterioles, may result. Because of recent research that incriminated Wegener in Nazi war crimes, a suggestion has been made to abandon the eponym and change to ANCA-associated granulomatous vasculitis or granulomatosis with polyangiitis (GPA).²

Incidence

The prevalence of GPA is estimated at three in 100,000 individuals. It occurs more commonly in whites than in blacks, and is exceedingly rare in Japan. There is no sex difference. The mean age of onset is approximately 40 years, but GPA can occur at any age.

Diagnosis

Establishing the diagnosis of GPA requires findings of granulomatous inflammation involving the respiratory tract and vasculitis of small- to medium-sized vessels.³ Biopsy shows leukocytoclastic vasculitis with necrotic changes and granulomatous inflammation. Rhinitis is the first sign in most people. In addition, finding two or more of the following criteria has a sensitivity of 88.2% and a specificity of 92%: nasal or oral inflammation, abnormal chest x-ray with infiltrates or cavities, microhematuria or red cell casts, and biopsy finding of granulomatous inflammation in arterial or perivascular areas. In addition, saddle nose deformity and sclerokeratitis may be found. Abnormal hematologic values include markedly elevated erythrocyte sedimentation rate, normocytic normochromic anemia, leukocytosis, thrombocytosis and mild hypergammaglobulinemia (particularly of the immunoglobulin A class).

Treatment

Treatment of GPA consists of a combination of corticosteroids and cytotoxic agents to induce and then maintain remission.⁴ Remission can be brought on using methotrexate and steroids for non–organ-threatening disease, followed by methotrexate for maintenance. For organ-threatening disease, pulsed IV cyclophosphamide or rituximab (Rituxan, Genentech) with steroids is recommended, followed by azathioprine and steroids. Severe kidney vasculitis uses the same regimen but with the addition of plasma exchange. Kidney transplant is a last resort. High doses of cyclophosphamide with pulsed methylprednisolone are indicated for pulmonary hemorrhage. Five-year survival is more than 80%, but long-term complications are common (86%), including chronic kidney failure and deafness.

Anesthetic Precautions

Long-term steroid therapy is associated with an immunocompromised state, increased risk for infection, easy bruisability, gastrointestinal bleeding and ulceration, decreased bone density and hyperglycemia. A supplemental dose of corticosteroids may be indicated. Hearing loss may hamper obtaining informed consent. Reflux disease should be addressed. Difficult intubation should be anticipated secondary to septal deviation and perforation, gingivitis, mandibular bone destruction with loose teeth, mucosal ulceration and tracheal stenosis. Ventilation is made difficult by pulmonary infiltrates and nodules, cavities, hemorrhage, and rarely bronchial stenosis. Arthritis makes patient positioning difficult. Progressive kidney failure (in 75% of patients) alters the excretion of drugs, fluids and electrolytes. Drugs with active or toxic metabolites dependent on renal excretion include opioids (morphine and meperidine), benzodiazepines (diazepam and midazolam), muscle relaxants (vecuronium and pancuronium) and sodium nitroprusside. Succinylcholine should be used sparingly because cyclophosphamide inhibits pseudocholinesterase.

If coronary involvement is present, anesthetic management should aim to avoid increased preload or afterload, or tachycardia. In cases of valvular heart defects or cardiomyopathy, extensive monitoring and the use of adjuncts such as pacemakers and vasodilator drugs may be indicated. Digital arteritis and infarcts at the tips of the digits may impair the ability to accurately measure oxygen saturation. Indwelling arterial lines must be used cautiously to limit arterial punctures. Sensory neuropathy (10% of patients) should be documented.

Prior to administering a regional technique, adequate coagulation status should be determined.

References

1. Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117(1):39-50.
2. Lubitz MG. Granulomatosis with polyangiitis: A moral impetus for change. JAMA Otolaryngol Head Neck Surg. 2018;144(2):101.
3. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: Proposal of an international consensus conference. Arthritis Rheum. 1994:37(2):187-192.
4. Singer O, McCune WJ. Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. Curr Opin Rheumatol. 2017:29(3):248-253.

PHACE Syndrome

What Is It?

PHACE syndrome is characterized by vascular, nerve and cutaneous lesions in multiple systems, resulting in structural and functional impairments. The syndrome’s name is an acronym for its manifestations: posterior fossa anomalies, hemangiomas, arterial lesions, coarctation of the aorta, and eye anomalies.¹ It is sometimes referred to as PHACES syndrome, with the “S” denoting the possibility of sternal clefting or supraumbilical raphe (midline lesions). The etiology is unknown. Possible causes include hypoxia, abnormality of mesodermal vascular endothelial cells, genetic abnormality and abnormality of interstitial mesenchymal stem cells. Migraine headaches, seizures, developmental delays, speech delays and ischemic strokes are not uncommon.

Incidence

PHACE is a relatively newly described entity.¹ More than 400 cases have been described in the literature, although this number may be underreported as most patients identified had severe disease. The syndrome also may appear in individuals with few symptoms.

Diagnosis

Diagnosis of PHACE requires the presence of characteristic segmental hemangiomata or hemangioma greater than 5 cm on the face or scalp plus one major criterion or two minor criteria as listed below.^2,3 Possible PHACE requires the presence of a hemangioma greater than 5 cm on the face or scalp plus one minor criterion. Females are nine times more likely than males to be afflicted, suggesting X-linked dominant inheritance, with lethality in male patients. However, no familial cases have been reported, and disease severity in male patients has not been systematically studied. Hemangiomas of the face, neck or scalp occur in more than 95% of patients. Posterior fossa anomalies include Dandy-Walker, subependymal or arachnoid cysts; hypoplasia of the cerebrum or vermis; absent foramen lacerum or pituitary gland; microcephaly; and multiple lesions of the cerebral arterial supply. Cardiac lesions include coarctation, patent foramen ovale, aortic arch aneurysms, dextrocardia and ventral and atrial septal defects, valvular atresias, tetralogy of Fallot and pulmonary stenosis, among others.⁴ Ocular changes include hypoplasia of the optic nerve, cataracts, persistent fetal vasculature and sclerocornea. Other midline abnormalities have been described as well as endocrine and dental changes, speech and language delays, and deafness.

Treatment

Medications for hemangioma in PHACE syndrome include beta blockers; glucocorticoids; and mTOR (mammalian target of rapamycin) gene inhibitors, such as dactolisib (BEZ235, NVP-BEZ235), rapamycin (sirolimus) and everolimus (Afinitor).⁵ Propranolol has been used to treat infantile capillary hemangiomas; it induces vasoconstriction, decreases expression of vascular endothelial growth factor and basic fibroblast growth factor through downregulation of the RAF-mitogen–activated protein kinase pathway and the triggering of apoptosis of capillary endothelial cells. Propranolol should not be used in patients who have bronchospasm, congestive heart failure, hypotension, bradycardia or heart block.

Anesthetic Precautions

Neurologic, cardiac, otolaryngologic and ophthalmologic consults are essential given the varying nature and presentation of PHACE syndrome.⁶ Hemangiomas near the eye cause vision problems and are likely to break open and bleed, a situation that is often very painful. Mask ventilation must be done carefully. Difficult intubation should be anticipated related to micrognathia. Airway hemangiomas occur much more commonly (63%) in children with cutaneous hemangiomas. Subglottic hemangiomata occurring in otherwise asymptomatic children may cause complete obstruction during studies such as MRI scans when the patient is sedated and spontaneously breathing.7 These lesions may also bleed with instrumentation or intubation of the airway. Children should be considered to have an airway hemangioma until proven otherwise. Awake flexible fiber-optic endoscopy or video laryngoscopy is preferred. Anomalous cerebral blood flow increases the risk for strokes and seizures. Hypotension should be treated immediately. Neuromonitoring with the bispectral index, near-infrared spectroscopy and transcranial Doppler is indicated to detect and prevent cerebral ischemia. Patients with seizures require anticonvulsant therapy throughout the perioperative period. Succinylcholine should be avoided if the patient is receiving beta blockers because profound bradycardia may occur with neostigmine. Propranolol may cause hypoglycemia.

References

1. Frieden IJ, Reese V, Cohen D. PHACE syndrome: The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol. 1996;132:307-311.
2. Metry D, Heyer G, Hess C, et al. Consensus statement on diagnostic criteria for PHACE syndrome research conference. Pediatrics. 2009;124(5):1447-1456.
3. Garzon MC, Epstein LG, Heyer GL, et al. PHACE syndrome: Consensus-derived diagnosis and care recommendations. J Pediatr. 2016;178:24-33.
4. Martinez AC, Gonzalez MR, Fernandez IB, et al. Hemangioma, aortic coarctation and intracranial dolichoectasia: PHACE syndrome. Pediatr Int. 2017;59(2):230-233.
5. Peng SH, Yang KY, Chen SY. Research progresses in the pathogenesis, diagnosis and treatment of infantile hemangioma with PHACE syndrome. Zhongguo Dang Dai Er Ke Za Zhi. 2017;19(12):1291-1296. [translated from Chinese]
6. Fernandes S, Kakade A, Jetpurwala AMJ. Dental management of PHACE syndrome under general anesthesia. J Indian Soc Pedod Prev Dent. 2011;29(6 suppl 2):S66-S69.
7. Shah MS, Verghese ST. When faced with anesthetizing an infant with PHACE syndrome: Watch out for an airway-occluding subglottic hemangioma! A A Case Reports. 2017;9(11):334-335.