Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: https://www.tandfonline.com/loi/ihop20
The Differential Diagnosis of Raynaud's Phenomenon Fredrick M. Wigley To cite this article: Fredrick M. Wigley (1991) The Differential Diagnosis of Raynaud's Phenomenon, Hospital Practice, 26:7, 63-84, DOI: 10.1080/21548331.1991.11704208 To link to this article: https://doi.org/10.1080/21548331.1991.11704208
Published online: 17 May 2016.
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Citing articles: 4 View citing articles
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The Differential Diagnosis of Raynaud 's Phenomenon FREDRICK M. WIGLEY Johns Hopkins University
T
he circulation supplying the skin has the dual role of preserving tissue nutrition and maintaining a normal body temperature. In correspondence to this unique combination of functions, the skin circulation is regulated not only by blood flow into true capillaries but also by arteriovenous shunts that can rapidly produce a 10- to 20-fold change in the rate of cutaneous blood flow. In normal persons, the skin of the fingers and palms, the knees, and the toes and soles is densely populated with capillaries and arteriovenous shunts. When the skin is exposed to cold, the shunts close and cutaneous blood flow decreases, slowing heat loss to the environment. As a result, the skin becomes cool to the touch. Patients with Raynaud's phenomenon appear to have an exaggeration of this normal response to cold. The exaggeration manifests itself by an increased sensitivity to cold, by a more profound decrease in peripheral blood flow, and by a slower recovery of normal blood flow. In the late nineteenth century, Maurice Raynaud observed abnormal vascular reactivity in the peripheral circulation of some individuals-an abnormality sometimes associated with tissue necrosis. Several investigators advanced the concept that the phenomenon represents a heterogeneous group of disorders. Today, the clinician divides patients with Raynaud's phenomenon into two major categories. In secondary Raynaud's phenomenon, an associated disorder can be presumed to be the cause of the patient's abnormal vessel reactivity. In primary Raynaud's phenomenon, the cause remains undefined. The following case presentations illustrate the features of the phenomenon and the need for careful clinical assessment in seeking an etiologic diagnosis. Dr. Wigley Is Associate Professor of Medicine, Johns Hopkins University School of Medicine, and Chief, Rheumatology Division, Francis Scott Key Medical Center, Baltimore. Hospital Practice July 15. 1991
63
Case 1 Presentation An 18-year-old woman moved from Florida to the Northeast .l"1 to begin her college education. At home, she had noticed that in air-conditioned rooms her hands were colder than those of her friends. Now, in her first experience of a northern winter, her fingers not only were cold but also were blue around the fingertips. On one occasion, while holding a cold drink, she saw that her entire index finger was pale white and the others were bluegray. Cold-induced attacks became frequent, particularly when she moved rapidly from a warm environment to a cold--or merely cool-one. Typically, all of the fingers of both hands would become discolored and feel numb, with a pins-and-needles sensation over the fingertips. During these episodes, her hands would feel clumsy but not painful. If she ran hot water over her fingers, they would look flushed in about 15 minutes but still would feel cold and damp to someone else's touch. Although she had never looked, she suspected that her feet were also affected. They were cold and numb when her hands were symptomatic. The patient felt frightened by these episodes. She admitted being under a great deal of stress. She also said that her fmgers became pale and cyanotic when she was emotionally upset, even when her skin was not exposed to cold. She described occasional fatigue and occasional "nervous stomach" manifested by lower abdominal cramps. She had not experienced muscular pains, cutaneous ulcers or rashes, swelling of the fmgers or joints, fever, weight loss, dryness of the mucous membranes, or decreased exercise tolerance. In fact, she felt well, aside from her attacks. She did not smoke and was not using any medications, including birth control pills and over-the-counter cold preparations. Physical findings were normal, except that at the beginning of the examination all of her fingers and toes were cyanotic, from the tips to the metacarpal and metatarsal phalangeal joints. Moreover, her fingers and toes felt cool, and cutaneous capillary filling was slowed. At the end of the examination, the fingers and toes looked flushed, and capillary filling had returned to normal. Her blood pressure was 110/70 in both arms, and pulses were strong and equal in the arms and legs. An Allen test, in which the patient makes a tight fist and the examiner temporarily compresses the ulnar or radial artery, showed normal filling of the palmar arches, with a dominant radial artery. The radial pulses did not change in response to alterations in the position of the arm. The Adson test for thoracic outlet syndrome was performed bilaterally. In this test, the patient extends the neck, turns the head, and takes a deep breath, and the examiner tests for diminution of the radial pulse. The results were negative. There were no vascular bruits over any major vessel, and cardiac examination was unremarkable. Nail-fold capillaries, examined under low-power microscopy, were not abnormal (Figure 1). 64
Hospital Practice July 15, 1991
Figure 1. Examination of nail-fold capillary loops by wide-field microscopy helps in differentiating primary, or idiopathic, Raynaud's phenomenon from cases likely to be secondary to a disease such as scleroderma. In primary Raynaud's phenomenon, loops tend to remain normal-that is, regular in both shape and spacing. In secondary cases, loops are often irregularly spaced and dilated, as shown.
Case 1 Discussion ur patient's history is consistent with primary Raynaud's phenomenon. She has been having attacks of vasospasm induced by exposure to cold and aggravated, or even induced, by emotional stress, in the absence of any associated disorder. (She may, however, have an irritable bowel syndrome.) Her fear of the attacks probably intensifies them, in that release of sympathetic mediators promotes vasoconstriction. Since ,8-blockers and sympathomimetic drugs have been reported as either causing or aggravating Raynaud's phenomenon, her negative history for use of such agents is important. Primary Raynaud's phenomenon generally occurs in young women who are otherwise healthy. It usually begins a few months after menarche but may suddenly become clinically evident at any time in the second decade or later. The episodes are symmetric and most often involve both hands and both feet. While one finger can dominate the episode, the attack usually spreads to all fingers, involving them from the tip to the metacarpophalangeal joint. Tissue injury and necrosis are not a feature of primary Ray-
O
Hospital Practice July 15, 1991
65
naud's phenomenon, and a history of painful, intense attacks usually indicates an associated disease. In most patients, digital blood flow returns to normal approximately 15 minutes after the end of exposure to cold. Raynaud's phenomenon is classically described as occurring in three phases: pallor, cyanosis, and erythema (Figure 2). The pallor represents digital arterial closure. Cyanosis follows because of the pooling of deoxygenated blood during persistent vasospasm. The final erythema is a consequence of exaggerated reflow associated with vasodilation. However, patients with primary Raynaud's phenomenon do not always experience the classic triphasic color changes. Most commonly, they report "cold hands" or episodes of pale fingers rather than cyanotic fingertips. However, patients reporting cold hands often do not realize that their skin has had an abnormal color until they are shown some reference, such as a standard color chart of a typical episode. Recent population surveys suggest that Raynaud's phenomenon is underrecognized. It may affect 5% to 10% of the general population and as many as 20% to 25% ofyoungwomen. There is evidence to suggest that the phenomenon is a manifestation of a generalized disorder of vessel reactivity. And indeed, patients who have migraine headaches, atypical angina, or primary pulmonary hypertension have a greater prevalence ofRaynaud's pheno~ enon than would be expected in the general population. An episode of Raynaud's phenomenon may be hard to induce
in the clinic or laboratory, even in patients with a definite history of intense attacks. Studies have shown that the most effective strategy is to combine a central-body chill or other sympathetic stimulus with local exposure of a finger to cold. However, such efforts are usually unwarranted, since the history is diagnostic and most cold challenges are unpleasant or even painful and may be falsely negative. Mottling of the skin secondary to changes in capillary blood flow is easily induced by exposure to cold and does not represent the digital arterial closure of a true Raynaud's attack. The best chance of witnessing an attack is during the physical examination, when the patient usually is anxious (and the examining room usually is cool). A simple study that should be performed in all patients with Raynaud's phenomenon is the examination of the patient's nailfold capillaries. To see them more easily, oil (of the type used in oil-immersion microscopy) should be placed on the skin at the base of the fingernail before the area is inspected with either a wide-field microscope or an ophthalmoscope. Patients with normal capillaries probably have primary Raynaud's phenomenon. Patients with dilated, enlarged capillary loops are likely to have Raynaud's phenomenon secondary to another disease, such as scleroderma. Capillary changes may in fact be the earliest manifestation of such a process. (oontlnues)
66
Hospital Practice July 15, 1991
Arteriole Pallor
COLD
Artery Capillary Bed Arteriovenous Shunts
Cyanosis
COLD
REWARMING Erythema
Figure 2. Triphasic color changes in a classic episode of Raynaud's phenomenon begin on exposure to cold (or during emotional stress). The first change (top) is pallor, caused by vasoconstriction In digital arteries, arterioles,
RAYNAUD'S
and arteriovenous shunts. The ensuing cyanosis (middle) represents pooling of deoxygenated blood while vasospasm persists. The episode ends with vasodilation and erythema (bottom) when exposure to cold has ceased.
(continued)
In our patient, laboratory tests to support the clinical diagnosis of primary Raynaud's phenomenon could probably be limited to a complete blood count, urinalysis, and an assay of antinuclear antibodies. The presence of ANAs would not establish the presence of an autoimmune disease but would suggest heightened likelihood of a future rheumatic disorder. Although few long-term studies to define the natural course of primary Raynaud's phenomenon have been conducted, the available information suggests that about 10% to 15% of patients with apparently primary Raynaud's phenomenon develop signs of a secondary form of the phenomenon. The most common diseases to become clinically Hospital Practice July 15. 1991
67
manifest are rheumatologtc. In such cases, the underlying disorder usually develops within the first two years after the onset of Raynaud's symptoms. Careful examination and history taking at the outset might well reveal symptoms suggesting an early rheumatic process (e.g.. musculoskeletal pain) or signs such as a positive ANA test or an abnormal nail-fold capillary pattern.
Case 2 Presentation 40-year-old woman complained that for three months her fingers had been painfully sensitive to cold: Exposure to this stimulus made them suddenly tum pale and then blue, with an associated dull ache in the fingers. The attacks were symmetric, involving all her fingers and also her toes. A sudden change in temperature from warm to cold would easily provoke an attack, particularly if all of her body was chilled. The patient added that she could no longer wear rings. because her fingers had swelled. In addition, she had been fatigued, and her muscles and joints ached and were stiff. One week before she presented, a painful ulcer had developed on the tip of the right ring finger. She could not recall any fever or trauma, but for the past year she had experienced episodes of heartburn without anorexia or weight loss. She is a cigarette smoker. No one in her family had ever had a rheumatic disease. Physical examination showed normal vital signs, with normal pulses in the arms and legs and normal blood pressure in both arms. Her fingers indeed were diffusely swollen, but her joints were not inflamed. The skin of her distal fingers was somewhat tight. The patient's ulcer, 3 mm in diameter and with erythema in the surrounding skin, was still present on the distal right ring finger. Several telangiectases were noted on the palms and fingers. The hands felt cold, and the fingers had a persistent cyanotic appearance. Nail-fold microscopy demonstrated dilated nailfold capillaries.
A
Case 2 Discussion the attacks ofRaynaud's phenomenon are painI nfulthisandpatient, relatively intense, and physical examination confirms soft-tissue swelling and tissue necrosis. Hence, it is appropriate to entertain strong suspicion of a secondary form of Raynaud's phenomenon. Several clues support this suspicion. The first is the patient's 68
Hospital Practice July 15, 1991
age. Patients with secondary Raynaud's phenomenon have a later age of onset (mean, 35 years) than do those with the primary phenomenon (mean, 15 to 20 years). Then, too, our patient shows signs and symptoms of a rheumatic disease, including fatigue, painfuljoints, and telangiectases. Her symptoms of reflux suggest that she may have esophageal dysmotility, often found in scleroderma. However, esophageal abnormalities are nonspecific and are also found in patients with primary Raynaud's phenomenon. A positive family history for a rheumatic disease would have been additional evidence of an autoimmune disorder, since many rheumatic diseases follow a pattern of genetic predisposition. Although Raynaud's phenomenon is present in more than 90% of patients with scleroderma, other rheumatic diseases have also been associated with Raynaud's attacks. Approximately 10% to 40% of patients with systemic lupus erythematosus, 30% of patients with dermatomyositis, and 20% of patients with Sjogren's syndrome have been found to experience the attacks. In contrast, Raynaud's phenomenon may be no more common in patients with rheumatoid arthritis than it is in the general population. Recent reports have suggested an increased prevalence of Raynaud's phenomenon among patients with primary fibromyalgta (fibrositis). Laboratory workup for this patient should be comprehensive, as an aid in defining the underlying disease process. The possibility of a rheumatic disease such as early scleroderma should prompt studies of antinuclear antibodies, cryoglobulins, and serum complement. In particular, systemic sclerosis (scleroderma) has been associated with the presence of anticentromere antibody or antitopoisomerase. Pulmonary function tests are a sensitive means of detecting early lung involvement and instituting therapeutic intervention. The overall diagnostic approach to the patient with Raynaud's phenomenon is based on the clinical clues in the case and on consideration of the potential causes of abnormalities in peripheral blood flow. Young women with mild, symmetric Raynaud's attacks who are healthy in other respects probably have primary Raynaud's phenomenon. Indeed, if the episodes are typical ofthe phenomenon and there are no clinical clues to an underlying associated disease, subsequent development of a defined cause of secondary Raynaud's phenomenon is very unlikely. Conversely, secondary Raynaud's phenomenon should be considered probable (and careful workup and follow-up are warranted) if the patient meets any of the following criteria: late age of onset of Raynaud's attacks; Raynaud's phenomenon in a male; asymmetric attacks; intense, painful attacks; signs of tissue necrosis; or signs or symptoms of a coexistent disease process. In a child of either sex, careful workup is indicated because of the obvious importance of detecting underlying disease. Hospital Practice July 15, 1991
69
Pathophysiology he mechanism of primary Raynaud's phenomenon is not completely understood. One theory suggests that an excess of circulating neurotransmitters causes exaggerated vasoconstriction in the peripheral circulation. The theory is supported by the clinical observation that emotional stress and other sympathetic stimuli can trigger or exaggerate a Raynaud's attack. Yet careful clinical observations (reported by Sir Thomas Lewis in 1930, and by others more recently) have shown that after sympathetic blockade, Raynaud's episodes do not abate. Circulating catecholamines are not consistently elevated in patients with primary Raynaud's phenomenon, and an increased abundance of adrenergic receptors is not consistently found. Moreover, the central nervous system's control of the sympathetic system appears to be normal. Investigations using animal blood vessels have shown that cold temperature may increase the expression of ll:z· adrenergic receptors and decrease the function of a 1-adrenergic receptors. Cold temperature, therefore, may facilitate cutaneous vasoconstriction via enhanced a 2 -adrenergic responses while inhibiting constriction mediated in deeper vessels by a preponderance of a 1-adrenergic receptors. In a recent study of normal women and men in identical environmental conditions, blood flow through the hand, a finger, or the skin of a finger in women was half that measured in men. In addition, when women were asked to perform a stressful task (mental arithmetic calculations), vasodilation occurred, rather than the expected vasoconstriction. Paradoxical vasodilation in response to mental stress is thought to unmask high levels of sympathetic tone. Thus, this study suggests that the gender difference in the incidence of Raynaud's phenomenon may be a reflection of enhanced sympathetic tone in women.
T
Table 1. Mechanisms of Vasospasm Presenting as Raynaud's Phenomenon Decreased Blood Flow Mechanical impingement on vasculature (e.g., thoracic outlet syndrome) Arterial occlusive disease (e.g., atherosclerosis, polyarteritis nodosa)
Abnormal Blood Rheology Hyperviscosity (e.g., macroglobulinemia, cryoglobulinemia, polycythemia)
Intrinsic Vessel Disorder Diabetes Small-vessel vasculitis Scleroderma Chronic small-vessel trauma (e.g., occupational use of a pneumatic hammer)
Abnormal Vascular Reactivity Drugs (e.g., ,8-adrenergic blockers, sympathomimetics, ergot preparations, narcotics) ?Abnormal mediators (e.g., deficiency in endothelium-derived relaxing factor, elevation in endothelin-1)
70
Hospital Practice July 15. 1991
Patients with secondary forms of Raynaud's phenomenon (Table 1) provide insight into the pathophysiology of vasospasm in the peripheral circulation. For example, patients with carpal tunnel syndrome have been reported to experience Raynaud's episodes preceding or in conjunction with symptoms of mediannerve entrapment. The implication is that sensory and motor nerves are important in the normal control of regional blood flow. Reflex sympathetic dystrophy (RSD) involving the upper extremity may also present with changes in blood flow to the hand, and some studies have suggested that RSD syndrome is associated with an increase in sympathetic outflow. Although classic Raynaud's attacks are generally not seen in patients with RSD or nerve injury. rapid changes in skin temperature are common. Patients with thoracic outlet syndrome may present with unilateral vasospasm triggered by compression of proximal blood (continues)
RAYNAUD's
(continued)
vessels during changes in arm or body position. The compression leads to a critical decrease in blood flow and blood pressure in the peripheral vessel. Vasoconstriction ensues in the fingers because the pressure in the lumen of digital vessels is not sufficient to keep them open. Vascular occlusive disease can have a similar effect. Thus, diseases that may present with cold sensitivity and Raynaud's phenomenon include atherosclerosis, thromboangiitis obliterans, Takayasu's arteritis, and polyarteritis nodosa. Major-vessel occlusive disease should be considered if a patient has unilateral or asymmetric vasospasm or if the vasoconstriction extends from the fingers into the hand or arm. Patients with small-vessel disease may also present with Raynaud's phenomenon. In these cases, narrowing of the lumen of small vessels by disorders such as diabetes, small-vessel vasculitis, or a rheumatic disease (e.g., scleroderma) has meant not only that local blood flow is reduced but also that the vessels' capacity to remain patent is reduced. Vessel closure in the fingers may follow even a normal vasoconstrictive response to cold or other stimuli. Trauma affecting blood vessels may lead to Raynaud's phenomenon. Trauma to the palm of the hand has been reported to cause ulnar artery occlusion. Patients are usually men who use their hand as a hammer in their work. They present with cold sensitivity and Raynaud's episodes in the third, fourth, and fifth fingers of the dominant hand-the fingers supplied by the traumatized vessel. Repeated stress to small-vessel walls may be induced by use of vibratory tools such as pneumatic hammers or power saws. Patients with a hyperviscosity state secondary to paraproteinemia (macroglobulinemia) may present with Raynaud's phenomenon. In these cases, the vasculature may be normal, but the capacity of the blood to flow through the vessels is impaired. The consequent reduction in luminal pressure promotes vasoconstriction. Polycythemia (i.e., essential thrombocythemia and polycythemia vera) can likewise lead to peripheral vasospasm through changes in the rheologic properties of the blood. Cryoproteins, like those found in essential and secondary cryoglobulinemia and cold agglutinin disease, have also been associated with Raynaud's phenomenon. Cold-induced precipitation of the proteins may increase the viscosity of the blood and induce inflammation of the vessel wall. Studies have been inconsistent in determining whether hyperviscosity or other abnormal rheoiogic properties of the blood are important in the pathogenesis of vasospasm in patients with primary Raynaud's phenomenon. Estrogens have been implicated as hormones capable of increasing vessel reactivity and changing blood viscosity. For example, in vitro investigations using rat mesenteric arteries have shown that estrogens increase vascular sensitivity to catecholHospital Practice July 15, 1991
73
AXID®
amines. In this regard, it is of interest that some studies have demonstrated the development of abnormal cold sensitivity in warm-handed women at the time of menstruation. It is also remarkable that primary Raynaud's phenomenon is seen most commonly in women in their child-bearing years and that symptoms typically date from soon after menarche and show improvement after menopause. The various observations suggest that Raynaud's phenomenon may be more common in women than in men at least in part because of the influence of sex hormones on the regulation oflocal blood flow. Other circulating factors, including histamine and serotonin, have also been implicated as mediators of vascular reactivity and regional blood flow. In normal persons, intra-arterial serotonin produces a dose-related decrease in total and capillary blood flow through the fingertips. Moreover, ketanserin, an antagonist to the 5-HT2 variety of serotonin receptor, has been shown to produce vasodilation in the fingers of patients with Raynaud's phenomenon during cold challenge. In clinical trials, ketanserin improved the symptoms of patients with both primary and secondary Raynaud's phenomenon. Various drugs and toxins have been shown to cause or aggravate Raynaud's phenomenon. For example, ,8-adrenergic receptor blockers have been reported to produce the phenomenon in 4% to 40% of patients using these agents. It is not understood whether the peripheral vasoconstriction in these patients results from direct blockage of the receptors (which are known to be present on the digital arteriovenous shunts) or whether it represents a reflex response to a drug-induced decrease in cardiac output. Amphetamines and other sympathomimetic drugs may also cause or aggravate Raynaud's phenomenon. Ergot preparations have been associated with intense vasospasm triggered by stimulation of a-adrenergic receptors on blood vessels. Narcotics are vasoconstrictors and may therefore promote Raynaud's episodes. Use of vinblastine and bleomycin as cancer chemotherapy is commonly complicated by Raynaud's phenomenon. Oral contraceptives have been implicated in Raynaud's phenomenon but are probably not an important causative factor. Exposure to polyvinyl chloride has been associated with a systemic sclerodermalike illness incorporating Raynaud's phenomenon.
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Briel Summary. Consun the pociage lltelllllre tor complete information. llldlcationund Uuge: 1. AcuWl duodenal ulcer- for up to 8weeks oflreatment. Most patients heal wnhm 4weeks. 2. Majntenance l!rerapy- for heale
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: https://www.tandfonline.com/loi/ihop20
The Differential Diagnosis of Raynaud's Phenomenon Fredrick M. Wigley To cite this article: Fredrick M. Wigley (1991) The Differential Diagnosis of Raynaud's Phenomenon, Hospital Practice, 26:7, 63-84, DOI: 10.1080/21548331.1991.11704208 To link to this article: https://doi.org/10.1080/21548331.1991.11704208
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ihop20
The Differential Diagnosis of Raynaud 's Phenomenon FREDRICK M. WIGLEY Johns Hopkins University
T
he circulation supplying the skin has the dual role of preserving tissue nutrition and maintaining a normal body temperature. In correspondence to this unique combination of functions, the skin circulation is regulated not only by blood flow into true capillaries but also by arteriovenous shunts that can rapidly produce a 10- to 20-fold change in the rate of cutaneous blood flow. In normal persons, the skin of the fingers and palms, the knees, and the toes and soles is densely populated with capillaries and arteriovenous shunts. When the skin is exposed to cold, the shunts close and cutaneous blood flow decreases, slowing heat loss to the environment. As a result, the skin becomes cool to the touch. Patients with Raynaud's phenomenon appear to have an exaggeration of this normal response to cold. The exaggeration manifests itself by an increased sensitivity to cold, by a more profound decrease in peripheral blood flow, and by a slower recovery of normal blood flow. In the late nineteenth century, Maurice Raynaud observed abnormal vascular reactivity in the peripheral circulation of some individuals-an abnormality sometimes associated with tissue necrosis. Several investigators advanced the concept that the phenomenon represents a heterogeneous group of disorders. Today, the clinician divides patients with Raynaud's phenomenon into two major categories. In secondary Raynaud's phenomenon, an associated disorder can be presumed to be the cause of the patient's abnormal vessel reactivity. In primary Raynaud's phenomenon, the cause remains undefined. The following case presentations illustrate the features of the phenomenon and the need for careful clinical assessment in seeking an etiologic diagnosis. Dr. Wigley Is Associate Professor of Medicine, Johns Hopkins University School of Medicine, and Chief, Rheumatology Division, Francis Scott Key Medical Center, Baltimore. Hospital Practice July 15. 1991
63
Case 1 Presentation An 18-year-old woman moved from Florida to the Northeast .l"1 to begin her college education. At home, she had noticed that in air-conditioned rooms her hands were colder than those of her friends. Now, in her first experience of a northern winter, her fingers not only were cold but also were blue around the fingertips. On one occasion, while holding a cold drink, she saw that her entire index finger was pale white and the others were bluegray. Cold-induced attacks became frequent, particularly when she moved rapidly from a warm environment to a cold--or merely cool-one. Typically, all of the fingers of both hands would become discolored and feel numb, with a pins-and-needles sensation over the fingertips. During these episodes, her hands would feel clumsy but not painful. If she ran hot water over her fingers, they would look flushed in about 15 minutes but still would feel cold and damp to someone else's touch. Although she had never looked, she suspected that her feet were also affected. They were cold and numb when her hands were symptomatic. The patient felt frightened by these episodes. She admitted being under a great deal of stress. She also said that her fmgers became pale and cyanotic when she was emotionally upset, even when her skin was not exposed to cold. She described occasional fatigue and occasional "nervous stomach" manifested by lower abdominal cramps. She had not experienced muscular pains, cutaneous ulcers or rashes, swelling of the fmgers or joints, fever, weight loss, dryness of the mucous membranes, or decreased exercise tolerance. In fact, she felt well, aside from her attacks. She did not smoke and was not using any medications, including birth control pills and over-the-counter cold preparations. Physical findings were normal, except that at the beginning of the examination all of her fingers and toes were cyanotic, from the tips to the metacarpal and metatarsal phalangeal joints. Moreover, her fingers and toes felt cool, and cutaneous capillary filling was slowed. At the end of the examination, the fingers and toes looked flushed, and capillary filling had returned to normal. Her blood pressure was 110/70 in both arms, and pulses were strong and equal in the arms and legs. An Allen test, in which the patient makes a tight fist and the examiner temporarily compresses the ulnar or radial artery, showed normal filling of the palmar arches, with a dominant radial artery. The radial pulses did not change in response to alterations in the position of the arm. The Adson test for thoracic outlet syndrome was performed bilaterally. In this test, the patient extends the neck, turns the head, and takes a deep breath, and the examiner tests for diminution of the radial pulse. The results were negative. There were no vascular bruits over any major vessel, and cardiac examination was unremarkable. Nail-fold capillaries, examined under low-power microscopy, were not abnormal (Figure 1). 64
Hospital Practice July 15, 1991
Figure 1. Examination of nail-fold capillary loops by wide-field microscopy helps in differentiating primary, or idiopathic, Raynaud's phenomenon from cases likely to be secondary to a disease such as scleroderma. In primary Raynaud's phenomenon, loops tend to remain normal-that is, regular in both shape and spacing. In secondary cases, loops are often irregularly spaced and dilated, as shown.
Case 1 Discussion ur patient's history is consistent with primary Raynaud's phenomenon. She has been having attacks of vasospasm induced by exposure to cold and aggravated, or even induced, by emotional stress, in the absence of any associated disorder. (She may, however, have an irritable bowel syndrome.) Her fear of the attacks probably intensifies them, in that release of sympathetic mediators promotes vasoconstriction. Since ,8-blockers and sympathomimetic drugs have been reported as either causing or aggravating Raynaud's phenomenon, her negative history for use of such agents is important. Primary Raynaud's phenomenon generally occurs in young women who are otherwise healthy. It usually begins a few months after menarche but may suddenly become clinically evident at any time in the second decade or later. The episodes are symmetric and most often involve both hands and both feet. While one finger can dominate the episode, the attack usually spreads to all fingers, involving them from the tip to the metacarpophalangeal joint. Tissue injury and necrosis are not a feature of primary Ray-
O
Hospital Practice July 15, 1991
65
naud's phenomenon, and a history of painful, intense attacks usually indicates an associated disease. In most patients, digital blood flow returns to normal approximately 15 minutes after the end of exposure to cold. Raynaud's phenomenon is classically described as occurring in three phases: pallor, cyanosis, and erythema (Figure 2). The pallor represents digital arterial closure. Cyanosis follows because of the pooling of deoxygenated blood during persistent vasospasm. The final erythema is a consequence of exaggerated reflow associated with vasodilation. However, patients with primary Raynaud's phenomenon do not always experience the classic triphasic color changes. Most commonly, they report "cold hands" or episodes of pale fingers rather than cyanotic fingertips. However, patients reporting cold hands often do not realize that their skin has had an abnormal color until they are shown some reference, such as a standard color chart of a typical episode. Recent population surveys suggest that Raynaud's phenomenon is underrecognized. It may affect 5% to 10% of the general population and as many as 20% to 25% ofyoungwomen. There is evidence to suggest that the phenomenon is a manifestation of a generalized disorder of vessel reactivity. And indeed, patients who have migraine headaches, atypical angina, or primary pulmonary hypertension have a greater prevalence ofRaynaud's pheno~ enon than would be expected in the general population. An episode of Raynaud's phenomenon may be hard to induce
in the clinic or laboratory, even in patients with a definite history of intense attacks. Studies have shown that the most effective strategy is to combine a central-body chill or other sympathetic stimulus with local exposure of a finger to cold. However, such efforts are usually unwarranted, since the history is diagnostic and most cold challenges are unpleasant or even painful and may be falsely negative. Mottling of the skin secondary to changes in capillary blood flow is easily induced by exposure to cold and does not represent the digital arterial closure of a true Raynaud's attack. The best chance of witnessing an attack is during the physical examination, when the patient usually is anxious (and the examining room usually is cool). A simple study that should be performed in all patients with Raynaud's phenomenon is the examination of the patient's nailfold capillaries. To see them more easily, oil (of the type used in oil-immersion microscopy) should be placed on the skin at the base of the fingernail before the area is inspected with either a wide-field microscope or an ophthalmoscope. Patients with normal capillaries probably have primary Raynaud's phenomenon. Patients with dilated, enlarged capillary loops are likely to have Raynaud's phenomenon secondary to another disease, such as scleroderma. Capillary changes may in fact be the earliest manifestation of such a process. (oontlnues)
66
Hospital Practice July 15, 1991
Arteriole Pallor
COLD
Artery Capillary Bed Arteriovenous Shunts
Cyanosis
COLD
REWARMING Erythema
Figure 2. Triphasic color changes in a classic episode of Raynaud's phenomenon begin on exposure to cold (or during emotional stress). The first change (top) is pallor, caused by vasoconstriction In digital arteries, arterioles,
RAYNAUD'S
and arteriovenous shunts. The ensuing cyanosis (middle) represents pooling of deoxygenated blood while vasospasm persists. The episode ends with vasodilation and erythema (bottom) when exposure to cold has ceased.
(continued)
In our patient, laboratory tests to support the clinical diagnosis of primary Raynaud's phenomenon could probably be limited to a complete blood count, urinalysis, and an assay of antinuclear antibodies. The presence of ANAs would not establish the presence of an autoimmune disease but would suggest heightened likelihood of a future rheumatic disorder. Although few long-term studies to define the natural course of primary Raynaud's phenomenon have been conducted, the available information suggests that about 10% to 15% of patients with apparently primary Raynaud's phenomenon develop signs of a secondary form of the phenomenon. The most common diseases to become clinically Hospital Practice July 15. 1991
67
manifest are rheumatologtc. In such cases, the underlying disorder usually develops within the first two years after the onset of Raynaud's symptoms. Careful examination and history taking at the outset might well reveal symptoms suggesting an early rheumatic process (e.g.. musculoskeletal pain) or signs such as a positive ANA test or an abnormal nail-fold capillary pattern.
Case 2 Presentation 40-year-old woman complained that for three months her fingers had been painfully sensitive to cold: Exposure to this stimulus made them suddenly tum pale and then blue, with an associated dull ache in the fingers. The attacks were symmetric, involving all her fingers and also her toes. A sudden change in temperature from warm to cold would easily provoke an attack, particularly if all of her body was chilled. The patient added that she could no longer wear rings. because her fingers had swelled. In addition, she had been fatigued, and her muscles and joints ached and were stiff. One week before she presented, a painful ulcer had developed on the tip of the right ring finger. She could not recall any fever or trauma, but for the past year she had experienced episodes of heartburn without anorexia or weight loss. She is a cigarette smoker. No one in her family had ever had a rheumatic disease. Physical examination showed normal vital signs, with normal pulses in the arms and legs and normal blood pressure in both arms. Her fingers indeed were diffusely swollen, but her joints were not inflamed. The skin of her distal fingers was somewhat tight. The patient's ulcer, 3 mm in diameter and with erythema in the surrounding skin, was still present on the distal right ring finger. Several telangiectases were noted on the palms and fingers. The hands felt cold, and the fingers had a persistent cyanotic appearance. Nail-fold microscopy demonstrated dilated nailfold capillaries.
A
Case 2 Discussion the attacks ofRaynaud's phenomenon are painI nfulthisandpatient, relatively intense, and physical examination confirms soft-tissue swelling and tissue necrosis. Hence, it is appropriate to entertain strong suspicion of a secondary form of Raynaud's phenomenon. Several clues support this suspicion. The first is the patient's 68
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age. Patients with secondary Raynaud's phenomenon have a later age of onset (mean, 35 years) than do those with the primary phenomenon (mean, 15 to 20 years). Then, too, our patient shows signs and symptoms of a rheumatic disease, including fatigue, painfuljoints, and telangiectases. Her symptoms of reflux suggest that she may have esophageal dysmotility, often found in scleroderma. However, esophageal abnormalities are nonspecific and are also found in patients with primary Raynaud's phenomenon. A positive family history for a rheumatic disease would have been additional evidence of an autoimmune disorder, since many rheumatic diseases follow a pattern of genetic predisposition. Although Raynaud's phenomenon is present in more than 90% of patients with scleroderma, other rheumatic diseases have also been associated with Raynaud's attacks. Approximately 10% to 40% of patients with systemic lupus erythematosus, 30% of patients with dermatomyositis, and 20% of patients with Sjogren's syndrome have been found to experience the attacks. In contrast, Raynaud's phenomenon may be no more common in patients with rheumatoid arthritis than it is in the general population. Recent reports have suggested an increased prevalence of Raynaud's phenomenon among patients with primary fibromyalgta (fibrositis). Laboratory workup for this patient should be comprehensive, as an aid in defining the underlying disease process. The possibility of a rheumatic disease such as early scleroderma should prompt studies of antinuclear antibodies, cryoglobulins, and serum complement. In particular, systemic sclerosis (scleroderma) has been associated with the presence of anticentromere antibody or antitopoisomerase. Pulmonary function tests are a sensitive means of detecting early lung involvement and instituting therapeutic intervention. The overall diagnostic approach to the patient with Raynaud's phenomenon is based on the clinical clues in the case and on consideration of the potential causes of abnormalities in peripheral blood flow. Young women with mild, symmetric Raynaud's attacks who are healthy in other respects probably have primary Raynaud's phenomenon. Indeed, if the episodes are typical ofthe phenomenon and there are no clinical clues to an underlying associated disease, subsequent development of a defined cause of secondary Raynaud's phenomenon is very unlikely. Conversely, secondary Raynaud's phenomenon should be considered probable (and careful workup and follow-up are warranted) if the patient meets any of the following criteria: late age of onset of Raynaud's attacks; Raynaud's phenomenon in a male; asymmetric attacks; intense, painful attacks; signs of tissue necrosis; or signs or symptoms of a coexistent disease process. In a child of either sex, careful workup is indicated because of the obvious importance of detecting underlying disease. Hospital Practice July 15, 1991
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Pathophysiology he mechanism of primary Raynaud's phenomenon is not completely understood. One theory suggests that an excess of circulating neurotransmitters causes exaggerated vasoconstriction in the peripheral circulation. The theory is supported by the clinical observation that emotional stress and other sympathetic stimuli can trigger or exaggerate a Raynaud's attack. Yet careful clinical observations (reported by Sir Thomas Lewis in 1930, and by others more recently) have shown that after sympathetic blockade, Raynaud's episodes do not abate. Circulating catecholamines are not consistently elevated in patients with primary Raynaud's phenomenon, and an increased abundance of adrenergic receptors is not consistently found. Moreover, the central nervous system's control of the sympathetic system appears to be normal. Investigations using animal blood vessels have shown that cold temperature may increase the expression of ll:z· adrenergic receptors and decrease the function of a 1-adrenergic receptors. Cold temperature, therefore, may facilitate cutaneous vasoconstriction via enhanced a 2 -adrenergic responses while inhibiting constriction mediated in deeper vessels by a preponderance of a 1-adrenergic receptors. In a recent study of normal women and men in identical environmental conditions, blood flow through the hand, a finger, or the skin of a finger in women was half that measured in men. In addition, when women were asked to perform a stressful task (mental arithmetic calculations), vasodilation occurred, rather than the expected vasoconstriction. Paradoxical vasodilation in response to mental stress is thought to unmask high levels of sympathetic tone. Thus, this study suggests that the gender difference in the incidence of Raynaud's phenomenon may be a reflection of enhanced sympathetic tone in women.
T
Table 1. Mechanisms of Vasospasm Presenting as Raynaud's Phenomenon Decreased Blood Flow Mechanical impingement on vasculature (e.g., thoracic outlet syndrome) Arterial occlusive disease (e.g., atherosclerosis, polyarteritis nodosa)
Abnormal Blood Rheology Hyperviscosity (e.g., macroglobulinemia, cryoglobulinemia, polycythemia)
Intrinsic Vessel Disorder Diabetes Small-vessel vasculitis Scleroderma Chronic small-vessel trauma (e.g., occupational use of a pneumatic hammer)
Abnormal Vascular Reactivity Drugs (e.g., ,8-adrenergic blockers, sympathomimetics, ergot preparations, narcotics) ?Abnormal mediators (e.g., deficiency in endothelium-derived relaxing factor, elevation in endothelin-1)
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Patients with secondary forms of Raynaud's phenomenon (Table 1) provide insight into the pathophysiology of vasospasm in the peripheral circulation. For example, patients with carpal tunnel syndrome have been reported to experience Raynaud's episodes preceding or in conjunction with symptoms of mediannerve entrapment. The implication is that sensory and motor nerves are important in the normal control of regional blood flow. Reflex sympathetic dystrophy (RSD) involving the upper extremity may also present with changes in blood flow to the hand, and some studies have suggested that RSD syndrome is associated with an increase in sympathetic outflow. Although classic Raynaud's attacks are generally not seen in patients with RSD or nerve injury. rapid changes in skin temperature are common. Patients with thoracic outlet syndrome may present with unilateral vasospasm triggered by compression of proximal blood (continues)
RAYNAUD's
(continued)
vessels during changes in arm or body position. The compression leads to a critical decrease in blood flow and blood pressure in the peripheral vessel. Vasoconstriction ensues in the fingers because the pressure in the lumen of digital vessels is not sufficient to keep them open. Vascular occlusive disease can have a similar effect. Thus, diseases that may present with cold sensitivity and Raynaud's phenomenon include atherosclerosis, thromboangiitis obliterans, Takayasu's arteritis, and polyarteritis nodosa. Major-vessel occlusive disease should be considered if a patient has unilateral or asymmetric vasospasm or if the vasoconstriction extends from the fingers into the hand or arm. Patients with small-vessel disease may also present with Raynaud's phenomenon. In these cases, narrowing of the lumen of small vessels by disorders such as diabetes, small-vessel vasculitis, or a rheumatic disease (e.g., scleroderma) has meant not only that local blood flow is reduced but also that the vessels' capacity to remain patent is reduced. Vessel closure in the fingers may follow even a normal vasoconstrictive response to cold or other stimuli. Trauma affecting blood vessels may lead to Raynaud's phenomenon. Trauma to the palm of the hand has been reported to cause ulnar artery occlusion. Patients are usually men who use their hand as a hammer in their work. They present with cold sensitivity and Raynaud's episodes in the third, fourth, and fifth fingers of the dominant hand-the fingers supplied by the traumatized vessel. Repeated stress to small-vessel walls may be induced by use of vibratory tools such as pneumatic hammers or power saws. Patients with a hyperviscosity state secondary to paraproteinemia (macroglobulinemia) may present with Raynaud's phenomenon. In these cases, the vasculature may be normal, but the capacity of the blood to flow through the vessels is impaired. The consequent reduction in luminal pressure promotes vasoconstriction. Polycythemia (i.e., essential thrombocythemia and polycythemia vera) can likewise lead to peripheral vasospasm through changes in the rheologic properties of the blood. Cryoproteins, like those found in essential and secondary cryoglobulinemia and cold agglutinin disease, have also been associated with Raynaud's phenomenon. Cold-induced precipitation of the proteins may increase the viscosity of the blood and induce inflammation of the vessel wall. Studies have been inconsistent in determining whether hyperviscosity or other abnormal rheoiogic properties of the blood are important in the pathogenesis of vasospasm in patients with primary Raynaud's phenomenon. Estrogens have been implicated as hormones capable of increasing vessel reactivity and changing blood viscosity. For example, in vitro investigations using rat mesenteric arteries have shown that estrogens increase vascular sensitivity to catecholHospital Practice July 15, 1991
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AXID®
amines. In this regard, it is of interest that some studies have demonstrated the development of abnormal cold sensitivity in warm-handed women at the time of menstruation. It is also remarkable that primary Raynaud's phenomenon is seen most commonly in women in their child-bearing years and that symptoms typically date from soon after menarche and show improvement after menopause. The various observations suggest that Raynaud's phenomenon may be more common in women than in men at least in part because of the influence of sex hormones on the regulation oflocal blood flow. Other circulating factors, including histamine and serotonin, have also been implicated as mediators of vascular reactivity and regional blood flow. In normal persons, intra-arterial serotonin produces a dose-related decrease in total and capillary blood flow through the fingertips. Moreover, ketanserin, an antagonist to the 5-HT2 variety of serotonin receptor, has been shown to produce vasodilation in the fingers of patients with Raynaud's phenomenon during cold challenge. In clinical trials, ketanserin improved the symptoms of patients with both primary and secondary Raynaud's phenomenon. Various drugs and toxins have been shown to cause or aggravate Raynaud's phenomenon. For example, ,8-adrenergic receptor blockers have been reported to produce the phenomenon in 4% to 40% of patients using these agents. It is not understood whether the peripheral vasoconstriction in these patients results from direct blockage of the receptors (which are known to be present on the digital arteriovenous shunts) or whether it represents a reflex response to a drug-induced decrease in cardiac output. Amphetamines and other sympathomimetic drugs may also cause or aggravate Raynaud's phenomenon. Ergot preparations have been associated with intense vasospasm triggered by stimulation of a-adrenergic receptors on blood vessels. Narcotics are vasoconstrictors and may therefore promote Raynaud's episodes. Use of vinblastine and bleomycin as cancer chemotherapy is commonly complicated by Raynaud's phenomenon. Oral contraceptives have been implicated in Raynaud's phenomenon but are probably not an important causative factor. Exposure to polyvinyl chloride has been associated with a systemic sclerodermalike illness incorporating Raynaud's phenomenon.
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