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Содержание Raynaud's syndrome Clinical description Patient evaluation Ancillary evaluation Surgical therapy

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RAYNAUD'S SYNDROME

Raynaud's syndrome defines a condition characterized by episodic vasospasm resulting in closure of the small arteries and arterioles of the distal parts of the extremities in response to cold exposure or emotional stimuli. The fingers and hands are most frequently involved, although in many patients the toes and feet may be similarly affected. Classically, the episodes consist of intense pallor of the distal extremities followed by cyanosis and rubor on rewarming, with full recovery requiring 15 to 45 minutes. Many patients, however, develop only pallor or cyanosis during attacks, and it is now clear that the classic tricolor pattern occurs only in a small number of patients. A number of patients who complain of cold hands without digital color changes have abnormal arteriographic and blood flow findings identical to those of patients with classic digital color changes, thus leading to the suggestion that digital color change may not be essential for the diagnosis.

PATHOPHYSIOLOGY

The pallor in the early stage of Raynaud episodes is initiated by severe spasm of the arteries and arterioles, which causes cessation of capillary perfusion. Resultant hypoxia and the accumulation of the metabolic products of regional anaerobic metabolism cause the capillaries and probably the venules to dilate. This is followed by a slight relaxation of the arteriolar spasm with the entry of a small amount of blood into the dilated capillaries, which rapidly becomes desaturated, producing cyanosis. Rubor results from the entry of increasing amounts of blood into dilated capillaries. The episode terminates with the entry of a normal volume of blood through the relaxed arterioles and the return of the dilated capillaries to normal.

The mechanism of vasoconstriction that occurs during an episode of Raynaud's syndrome has interested investigators for more than a century. Raynaud's suggestion that the episodes represented sympathetic nervous system hyperactivity was largely disproved by Lewis in the 1920s and 1930s. He concluded that the digital arteries in this condition close completely on exposure to cold and that this closure is responsible for the clinical symptoms. Based on failure to prevent cold-induced vasospasm by digital nerve conduction anesthesia, Lewis proposed the theory of local vascular wall hyperresponsiveness to cold exclusive of sympathetic innervation, a condition he termed local vascular fault. In the succeeding years, the nature of the local fault has never been defined.

Patients with Raynaud's syndrome may be divided into two distinct pathophysiologic groups: obstructive and spastic. Patients with obstructive Raynaud's syndrome have a significant obstruction of the palmar and digital arteries caused by one of a variety of diseases, two of the more frequent being chronic arteritis associated with autoimmune disease and arteriosclerosis. To experience a Raynaud episode, the patient must have sufficiently severe arterial obstruction to cause significant reduction in resting digital artery pressure, a condition that requires obstruction of both arteries of a single digit. In such patients a normal vasoconstrictive response to cold is sufficient to overcome the diminished intraluminal distending pressure and cause arterial closure. This apparently correct theory predicts that all patients with arterial obstruction of the hand sufficient to cause resting digital hypotension experience episodes of cold-induced Raynaud's syndrome. Patients with spastic Raynaud's syndrome do not have significant palmar-digital artery obstruction and accordingly have normal digital artery pressure at room temperature. Arterial closure in these patients is caused by the markedly increased force of cold-induced arterial spasm.

A number of studies have suggested altered adrenoceptor activity as a mechanism of Raynaud's syndrome. Early studies with the sympathetic blocking drug reserpine demonstrated increased digital blood flow in patients with Raynaud's syndrome. Laboratory studies showed a marked reduction in cold-induced digital artery vasospasm after the intra-arterial administration of reserpine. This suggested that patients with Raynaud's syndrome may possess abnormal adrenergic receptors that become increasingly sensitive to stimulation after cold exposure.

In recent years, knowledge of human adrenergic receptor function has increased markedly with the characterization of the alpha 1- and alpha 2-adrenoceptors. The alpha 2-adrenoceptors, which were initially thought to be presynaptic and inhibitory, are now known to occur both presynaptically and postsynaptically and may be facilitative as well as inhibitory. Alpha 2-adrenoceptors are present in a pure population on human platelets. Although the precise relationship between platelet adrenoceptor activity and that of arteries has not been established, a clear precedent exists for a direct relationship between blood cell and tissue levels of adrenoceptors in biologic systems. Laboratory studies have demonstrated that platelets from patients with Raynaud's syndrome have elevated levels of alpha 2-adrenoceptors, a finding confirmed by others. Freedman demonstrated increased peripheral vasoconstriction in response to intra-arterial infusions of both alpha 1- and alpha 2-agonists. An elevation in the number of alpha 2-receptor sites, receptor hypersensitivity, and alterations in the number of receptors exposed at any one time have been forwarded as possible mechanisms of alpha-adrenergic–induced Raynaud's syndrome.

Abnormalities in presynaptic beta-receptors and alterations in levels of the vasoactive peptide endothelin, a potent vasoconstrictor, and calcitonin gene-related peptide, a potent vasodilator, have been advanced as causes of Raynaud's syndrome. These await further confirmation.

The role of the sympathetic nervous system remains unclear. In a series of papers by Lafferty and associates, abnormalities in the thermoregulatory response in patients with Raynaud's syndrome have been demonstrated by means of a test termed thermal entrainment. 24 In this test the blood flow patterns in one hand are measured while the contralateral hand is alternately dipped in baths of hot and cold water. There are clear differences in blood flow responses demonstrable between normals and controls. The obvious way to explain contralateral changes in blood flow is through the function of the sympathetic nervous system, although no research has been done to prove or disprove this hypothesis.

EPIDEMIOLOGY

The incidence of Raynaud's syndrome in the general population is not known with certainty. Several small studies indicate a remarkable incidence of 20% to 25% in cool, damp climates. It is unknown whether these environmental conditions increase the true incidence of Raynaud's syndrome or merely make the underlying abnormality clinically apparent.

Of considerable interest is the prevalence of Raynaud's syndrome in certain occupational groups, especially those who use vibrating tools or experience chronic cold exposure. This has received considerable attention in recent years, because of both the impaired lifestyle of the patients and the potential impact of this finding on industrial compensation claims. The incidence of digital ischemia among chainsaw operators and miners using vibrating equipment ranges from 40% to 90%, the wide variation in incidence being generally related to the length of exposure. A 50% incidence of Raynaud's syndrome has been reported among food workers who work in cold areas. The pathophysiologic mechanism underlying Raynaud's syndrome of occupational origin is unknown, because neither detailed sequential digital hypothermic tests nor angiography has been performed routinely. Available evidence suggests that the cases of short duration are probably vasospastic, whereas those of long standing may be primarily obstructive.

Women constitute 70% to 90% of most reported patients with Raynaud's syndrome. Typically, younger women present with spastic Raynaud's syndrome, and idiopathic Raynaud's syndrome without associated disease is most common in this age and sex group. Some patients initially found to have no associated disease eventually are shown to have an autoimmune disorder, although the frequency of this occurrence remains unknown. Older men who develop Raynaud's syndrome usually have the obstructive variety associated with digital artery occlusion, usually due to atherosclerosis.

CLINICAL DESCRIPTION

Most patients with spastic Raynaud's syndrome are women in whom the age at onset is typically younger than 30 years. Both hands are affected equally, and frequently the thumbs are spared. Although most patients have a mild associated vasospastic involvement of feet and toes, only about 10% of patients have a primary lower-extremity involvement. Obstructive Raynaud's syndrome appears to be about equally distributed between men and women, and the symptomatic onset occurs after age 40. The lower extremities are infrequently involved. A striking difference from the vasospastic variety is that the area of involvement is frequently limited to one or several fingers and often affects only one hand.

Most episodes of digital vasospasm are induced by environmental cold exposure, although emotional stimuli such as fear or anger may also produce episodes in about half the patients. The required stimulus may be as mild as a draft from an air conditioner or hand immersion in tap water. At the beginning of an episode, the patient usually experiences blanching or cyanosis of one or several fingers that may extend proximally to the metacarpophalangeal junction or even to the wrist. An episode is usually associated with an uncomfortable sensation of numbness. Severe pain is rare. The initial pallor or cyanosis persists for as long as the cold exposure continues and is followed by a gradual return to normal color 15 to 30 minutes after entering a warm area. Fingertip ulceration occurs only in the presence of widespread palmar or digital artery obstruction. Ischemic ulceration is never caused by vasospasm alone.

PATIENT EVALUATION

Historical information should be sought regarding symptoms of connective tissue disease, including arthralgia, dysphagia, skin tightening, xerophthalmia, or xerostomia. Symptoms of large-vessel occlusive disease, exposure to trauma or frostbite, drug history, and history of malignancy should also be sought. The skin of the hands and fingers should be inspected for ulceration or fingertip hyperkeratotic areas, suggesting healed ulcers. The hand and fingers should be examined for evidence of skin thinning, tightening, sclerodactyly, or telangiectasia, all of which may suggest associated autoimmune disease. The peripheral pulse status should be carefully noted, and special attention should be directed toward signs and symptoms of nerve compression syndrome. Carpal tunnel syndrome is seen with surprising frequency in Raynaud's syndrome patients, affecting about 15% of these individuals. 36 Patients who present with the sudden onset of digital ischemia should be questioned about coagulation abnormalities and a history of previous thrombotic episodes. It should be noted that the results of the physical examination are often completely normal in patients with Raynaud's syndrome. The diagnosis is made primarily from the history.

ANCILLARY EVALUATION

Hand arteriography was formerly used frequently in the evaluation of patients with Raynaud's syndrome. A detailed technique of cryodynamic arteriography provided important anatomic, pathophysiologic, and diagnostic information.

Increasingly sophisticated vascular laboratory techniques have largely replaced arteriography in the routine evaluation of patients with Raynaud's syndrome. Currently, arteriography is recommended only in patients presenting with unilateral ischemic digital ulceration to exclude embolization from a surgically correctable proximal arterial lesion.

The vascular laboratory has been of great help in objectively establishing the diagnosis of Raynaud's syndrome and allows a separation of spastic from obstructive Raynaud's syndrome.

Normal individuals show only a modest digital pressure drop with decreasing temperature. Patients with vasospastic Raynaud's syndrome show a similar curve until a critical temperature is reached, at which time abrupt arterial closure occurs. Patients with severe arterial obstruction parallel normal but with a much lower pressure, with closure occurring at about 20 to 30 mm. Hg.

The first vascular laboratory test used widely for objective diagnosis of Raynaud's syndrome was the measurement of fingertip temperature recovery after digital exposure to ice water.

Although normal individuals and patients with Raynaud's syndrome usually have similar resting digital temperatures and similar temperature drops after exposure to ice water, the time required for a return of digital temperature to normal averages 5 to 10 minutes in normal individuals and is prolonged to more than 20 minutes in most Raynaud's syndrome patients. Increasing experience has revealed that whereas this test is 100% specific, it is only about 50% sensitive and therefore is insufficiently accurate for clinical use.

The digital blood pressure response to 5 minutes of digital occlusive hypothermia as described by Lassen and associates has proved to be quite accurate in the vascular laboratory diagnosis of Raynaud's syndrome. In an evaluation of 100 patients at this institution, the test was found to be 87% specific and 90% sensitive, yielding an overall accuracy of 92%. This is the diagnostic test of choice in those occasional patients in whom a test is necessary. As noted previously, the diagnosis is usually established by the clinical history. However, the use of an objective test is most helpful in certain patient groups, including those in whom the diagnosis is in doubt, epidemiologic study groups, and those with pending litigation in whom historical accuracy is uncertain.

Digital photoplethysmography with digital blood pressure determination has become as accurate as arteriography in the detection of significant digital artery obstruction. A finding of an obstructive digital plethysmographic waveform with a digital pressure of more than 20 mm. Hg below brachial pressure establishes the diagnosis of significant digital artery obstruction. This, combined with the digital hypothermic blood pressure test described previously, allows accurate characterization of obstructive or spastic Raynaud's syndrome.

The extent of laboratory evaluation varies somewhat, depending on the findings of the history and physical examination. Minimal evaluation includes a hand roentgenogram for calcinosis or tuft resorption, complete blood cell count, sedimentation rate, and rheumatoid factor and antinuclear antibody tests to aid in the diagnosis of any associated autoimmune disease. Additional information such as protein electrophoresis and antibodies to a variety of nuclear antigens may subsequently be obtained. Upper-extremity nerve conduction testing should be considered if there is any clinical suspicion of carpal tunnel syndrome. Cases with a history of the sudden onset of digital occlusion should be evaluated for hypercoagulable states. Current screen consists of antithrombin III, protein S, and protein C levels as well as screening for the presence of lupus inhibitor and anticardiolipin antibodies.

TREATMENT

Satisfactory results have been reported with many different agents empirically selected on the basis of the presumed pathophysiology of Raynaud's syndrome. Unfortunately, objective evaluation of every form of treatment, including surgical sympathectomy, has been made impossible by largely anecdotal reports and lack of controlled studies. Nearly every type of treatment has been used successfully in at least one study population. Few, if any, agents currently used have been subjected to rigorous randomized, double-blind trials with parallel-group placebo control.

Most patients with Raynaud's syndrome have only mild symptoms, which respond well to simple conservative treatment, including the wearing of warm clothes and gloves and cold and tobacco avoidance. Patients who work in cold areas may not respond to any treatment until their occupational exposure is reduced. Because of the adverse digital circulatory effects of ergotamine tartrate and beta-adrenergic blocking drugs, equally effective alternative treatment should be sought in patients with Raynaud's syndrome.

Although a variety of vasodilator drugs have been used in the pharmacologic treatment of patients with Raynaud's syndrome, only about 10% of these patients require any treatment beyond avoidance of cold and of use of tobacco products. The primary difficulty with evaluation of the benefit of pharmacologic therapy in Raynaud's syndrome has been the lack of objective methods of assessing drug response. Currently no vascular laboratory test allows an objective assessment of drug benefit. It is unknown whether this reflects an actual absence of objective drug benefit or an insensitivity of the currently available vascular laboratory tests. Unfortunately, in the absence of adequate methodology, the assessment of efficacy of any drug devolves to the patient's subjective impression of benefit, an assessment that may be markedly affected by such variables as environmental temperature, the patient's emotional state, or concomitant medications.

Many patients require pharmacologic therapy only in winter months, with reserpine and guanethidine most commonly prescribed.

A number of other adrenergic blocking drugs, including alpha-methyldopa, tolazoline, phenoxybenzamine, and prazosin, have been used occasionally with anecdotal good results.

Other vasodilators have proved unsuccessful in the treatment of Raynaud's syndrome. The beta-stimulating drugs have been ineffective, the two most widely used being nylidrin and isoxsuprine. The topical vasodilators papaverine and niacin as well as the topical application of nitroglycerine have been generally ineffective. The antifungal drug griseofulvin was initially thought to be helpful, but recent experience has not confirmed the early reports.

The calcium channel–blocking agents represent compounds that have found wide clinical application. Nifedipine is the most potent peripheral vasodilator in this group and has been moderately effective in the treatment of Raynaud's syndrome, producing clinical improvement in 50% to 60% of patients studied. 42 Headache is a frequently encountered side effect and is of sufficient severity to cause discontinuation of the drug in 10% to 20% of patients. At present, extended-release nifedipine is the first-line drug for Raynaud's syndrome. Patients with spastic Raynaud's syndrome are more likely to respond to medication than those with obstructive Raynaud's syndrome.

A variety of new drugs and unconventional treatments have been proposed for Raynaud's syndrome. Beta-blockers, which have been implicated in the causation of drug-induced Raynaud's syndrome, have been suggested for the treatment of Raynaud's syndrome in combination with a calcium channel blocker. 2 Several patients who have failed to respond to a calcium channel blocker alone have had a beta-blocker (atenolol, 50 mg./day) added with good results. Prostaglandin E 1 appeared to be beneficial in a number of anecdotal reports, but a randomized, double-blind, placebo-controlled study failed to show benefit. Ketanserin is a selective serotonin-2 receptor blocker that has been reported useful in the treatment of obstructive Raynaud's syndrome, particularly that seen in association with scleroderma. 23 Plasmapheresis has been attempted on occasion, as have agents that reduce blood viscosity, fibrinogen concentration, and platelet activity, with questionable benefit. Treatment of associated autoimmune diseases does not appear to benefit patients with Raynaud's syndrome. Temperature biofeedback is an area of active research and has been successfully used in alleviating symptoms in patients with Raynaud's syndrome. 12

SURGICAL THERAPY

In a very small number of patients with Raynaud's syndrome, there is a proximal cause of upper extremity arterial insufficiency, sometimes associated with distal emboli to the palmar and digital arteries. The occasional patient with Raynaud's syndrome associated with subclavian, axillary, or brachial obstruction from arteriosclerosis; emboli; thoracic outlet syndrome; aneurysm; or trauma is an appropriate subject for vascular surgery and, in general, satisfactory results may be expected.

For the past half century, one of the frequent treatments for Raynaud's syndrome has been upper-extremity sympathectomy. Typically the patient experiences a few months of good results followed by a gradual recurrence of symptoms. It is unknown whether this represents an incomplete initial sympathectomy due to anatomic vagaries in the nerve distribution of the upper extremity or the development of receptor hypersensitivity to circulating catecholamines. Sympathectomy produces occasional anecdotal good long-term results, but in general these have been limited to patients with mild Raynaud's syndrome of the spastic variety. This is the same group of patients who respond best to pharmacologic treatment. Experiences with thoracoscopic sympathectomy have simplified the operative procedure, but equally disappointing long-term results in Raynaud's patients were obtained. There is general agreement that sympathectomy of the upper extremity is of little or no benefit in patients with Raynaud's syndrome who have associated connective tissue disease. At present, the modest surgical risk, expense, and mediocre long-term results of thoracic sympathectomy for Raynaud's syndrome constitute overwhelming arguments against its use; the procedure is not recommended. In contrast, lumbar sympathectomy for lower-extremity Raynaud's syndrome yields excellent long-term results. The reason for the difference between the results of upper and lower sympathectomy is unknown.