CREST Syndrome

An autoimmune connective tissue disorder associated with anticentromere antibodies. A form of scleroderma associated with esophageal dysmotility. CREST is an acronym for calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasis.

Limited Scleroderma; Thibièrge-Weissenbach Syndrome (some authors use Thibièrge Weissenbach Syndrome to describe the calcinosis of the hand in combination with ischemia in the context of scleroderma).

First described in 1910 by G. Thibièrge and R.J.E. Weissenbach, two French physicians.

The incidence of CREST syndrome is not known. The incidence of systemic sclerosis in the general population is in the range of approximately 2-7:1,000,000 (with geographical differences). All ethnicities can be affected. Females are affected two to four times more often than males.

Although a few cases with an inheritance pattern have been described, in most cases autoimmune processes appear to be involved in the pathogenesis of this disorder. A genetic predisposition may be present.

The three primary pathologic processes of scleroderma are initially perivascular infiltration with predominantly lymphocytes and macrophages, followed by collagen (including fibronectin and proteoglycans) deposition with tissue thickening and fibrosis secondary to chronic activation of skin fibroblasts, and vascular changes mainly affecting the small arteries and presenting with endothelial injury, intima proliferation, vasospasms, and significantly decreased neovascularization. It has been suggested that several cytokines are involved in the pathogenesis of this disorder, particularly transforming growth factor β and interleukin-4, which are both present in increased concentrations in this disorder, while the level of interferon-γ, which acts as an inhibitor of collagen synthesis, is decreased.

The minimal diagnostic criteria for scleroderma required by the American College of Rheumatology include either the major criterion of proximal cutaneous scleroderma (defined as symmetric thickening, tightening, and induration of the skin of the fingers and the skin proximal to the metacarpophalangeal or metatarsophalangeal joints. The changes may affect the entire limb or spread to head, neck, and trunk) or two of the three minor criteria (i.e., sclerodactyly [aforementioned findings, but strictly limited to the fingers], digital [finger pad] pitting scars, or bilateral pulmonary fibrosis with reticular or reticulonodular pattern on the chest radiograph). The presence of anticentromere antibodies in the serum may be helpful for the diagnosis (positive in approximately 50% of patients with CREST syndrome), while only approximately 20% test positive for scleroderma antibody (SCL-70/topoisomerase I). However, overall the sensitivity and specificity of these antibodies are limited.

Two different forms of scleroderma have been recognized. The localized form includes morphea and linear scleroderma (“sclérodermie en coup de sabre” if located in the facial area) and does not result in visceral organ involvement. The two types of systemic scleroderma are limited scleroderma (80% of patients) and diffuse scleroderma (20%). In limited scleroderma, the disease usually progresses slowly (over several years) and, by definition, the skin involvement remains distal to elbows and knees (however, involvement of the face and neck may occur). In more than two thirds of patients, Raynaud phenomenon is the first sign of the disease, with the characteristic triphasic color changes starting with pallor (white; vasoconstriction), changing to cyanosis (blue; low blood flow), and finally erythema (red; postischemic hyperperfusion). Over the following years, the skin of the fingers becomes thicker as the disease progresses. Calcinosis of the skin is often located periarticular in the extremities and may initially be subclinical, but later becomes painful and exulcerates with perifocal inflammation. The calcinosis is clearly visible as white, crumbly deposits on the bottom of the ulcers. Acroosteolysis may occur. Paraspinal calcifications are uncommon, but may cause pain and neurologic symptoms. The majority of patients have some degree of intestinal dysmotility, which is clinically most noticeable in the esophagus and characterized by a decrease or loss of peristalsis in the distal part of the esophagus. In many of these patients, erosive esophagitis and gastroesophageal reflux (often associated with silent aspiration) and strictures are present. Complications such as Barrett esophagus and adenocarcinoma of the esophagus have been described. Other gastrointestinal problems include autonomic dysfunction, ileal, jejunal, and colonic diverticula (also called sacculations, in the colon typically located along the antimesenteric border), malabsorption, and bacterial overgrowth. The patient may complain of dyspepsia and diarrhea alternating with constipation. Hyperpigmentation and hypopigmentation of the skin and pruritus are common. Telangiectases are typically located on the face, chest, and hands, but also may be seen on the mucosa in the oral cavity and throughout the entire gastrointestinal tract, where they may cause recurrent bleeding. Approximately one fourth of patients develop pulmonary hypertension with dyspnea and chronic cough. Cardiac involvement can present with arrhythmias and conduction abnormalities, patchy areas of myocardial fibrosis, pericardial effusions, and right heart failure secondary to pulmonary hypertension. The vast majority of patients have generalized, but unspecific arthralgias with morning stiffness. Clinically apparent synovitis and erosive arthritis are uncommon. Tendon friction rubs can commonly be felt and/or heard in the area of the big joints. Flexion contractures may lead to reduced joint mobility. Muscle weakness (particularly proximal) may be explained by myositis with muscle atrophy, resulting in increased serum creatine phosphokinase levels. One third of patients suffer from sicca syndrome with xerostomia and xerophthalmia. The 10-year survival rate of scleroderma depends on the extent of the disease. In isolated sclerodactyly, the rate is approximately 70%, in skin involvement also proximal to the metacarpophalangeal joints but absent trunk involvement the rate is almost 60%, while in patients with diffuse skin involvement the rate is only approximately 20%. Renal failure (secondary to vascular changes and/or glomerulonephritis) accounts for approximately 50% of all scleroderma-related deaths in patients with widespread skin involvement, whereas patients with limited skin involvement commonly die of cardiac, pulmonary, or gastrointestinal complications.

Patients present with several risk factors for anesthesia. A thorough examination is recommended. The skin changes may result in microstomia with limited mouth opening (although much more common in diffuse scleroderma than in CREST syndrome), making tracheal intubation difficult. Pulmonary hypertension is a well-known and reported problem in these patients, and investigations should include auscultation (accentuated pulmonic component of the second heart sound) and pulmonary function tests (abnormal in the majority of patients) including measurement of the carbon monoxide diffusion capacity. High-resolution computed tomography scanning has proved to be a highly sensitive diagnostic tool for pulmonary fibrosis. Pulmonary venoocclusive disease has been described. Cardiac examination should include an electrocardiogram (24-hour electrocardiography if arrhythmias are suspected), and an echocardiogram to assess the extent of myocardial fibrosis and overall heart function (cor pulmonale secondary to pulmonary hypertension) and to exclude pericardial effusions. Arterial hypertension may result from renal disease. Primary biliary cirrhosis has been reported in a number of mainly female patients with CREST syndrome. Autoimmune hepatitis is considered rare. Preoperative laboratory investigations should include a complete blood count (microangiopathic hemolytic anemia secondary to small vessel disease and intestinal bleeding from telangiectases), serum concentrations of electrolytes, creatinine, urea, total protein, bilirubin, transaminases, and alkaline phosphatase, coagulation tests, and an arterial blood gas analysis in case of pulmonary disease. Hypergammaglobulinemia and elevated erythrocyte sedimentation rate are common, and renal involvement may result in proteinuria.

As mentioned, CREST syndrome has a milder course than diffuse scleroderma, so clinical findings usually are less severe. Pulmonary hypertension is a frequent finding, so drugs that increase pulmonary vascular resistance (e.g., nitrous oxide) should be avoided. For the same reason, acidosis and hypercapnia must be avoided. Hypoxemia is not well tolerated by these patients; induction and emergence of anesthesia in particular pose the highest risk for pulmonary hypertensive crisis. If a spontaneous breathing induction technique is preferred secondary to expected airway management difficulties, ventilation may require assistance to prevent hypercapnia. However, esophageal dysmotility and gastroesophageal reflux may predispose to regurgitation/aspiration, and a rapid-sequence induction technique is recommended. The thickened skin can make peripheral vascular access difficult. The femoral artery probably is preferred over the radial artery for invasive pressure monitoring in the presence of significant Raynaud symptomatology and calcinosis of the fingers. Depending on the degree of muscle weakness and pulmonary disease, prolonged postoperative mechanical ventilation may be required. Careful intraoperative positioning and padding as a result of limited joint mobility are required.

Dysproteinemia may result in altered protein binding of drugs and thus affect the efficacy (particularly for highly protein-bound drugs). Avoid vasoconstrictive drugs in the presence of Raynaud phenomenon. Use reduced doses of predominantly renally excreted drugs in the presence of renal failure and for drugs with mainly hepatic elimination in case of liver failure. Steroids usually are not effective in CREST syndrome, so a perioperative stress dose should not to be indicated.

Parry-Romberg Syndrome: Progressive facial hemiatrophy characterized by unilateral atrophy of the skin including the subcutaneous tissue and underlying bone or cartilage. In contrast to “sclérodermie en coup de sabre,” this form more often affects the lower half of the face (but is not limited to it) with cutaneous sclerosis and possible involvement of the tongue, developing teeth, lips, and salivary glands.

Raynaud Syndrome: A disorder characterized by short-lasting vasospasms of the small arteries of the arms and legs, hands, and feet. Usually diagnosed before 40 years of age.