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Acs0624 Raynaud Phenomenon
- 1. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 24 RAYNAUD PHENOMENON — 1
24 RAYNAUD PHENOMENON
Tina R. Desai, M.D., F.A.C.S., and Ryan Headley, M.D.
Raynaud phenomenon is an episodic, exaggerated vascular Pathophysiology of Raynaud Phenomenon], but an attack may
response to cold or emotional stimuli, typically involving the fin- also be elicited by generalized cooling of the entire body. In addi-
gers.The classic triphasic color change, first described by Maurice tion, attacks may be precipitated by any stimulation of the sympa-
Raynaud in 1862, consists of initial pallor (secondary to vaso- thetic nervous system, especially at times of emotional stress.
spasm), followed first by cyanosis (from deoxygenation of the sta- As a rule, Raynaud phenomenon is more likely to affect the
tic blood) and then by rubor (as blood flow to the digits is restored hands than the feet. It is characterized by the sudden occurrence
and reactive hyperemia ensues).1 This classic manifestation of of cold digits in association with sharply demarcated pale skin—
Raynaud phenomenon occurs in as many as two thirds of affect- the so-called ischemic phase. Eventually, the skin may become
ed patients; however, less common variants of the phenomenon cyanotic. Subsequently, rapid restoration of blood flow to the dig-
(e.g., pallor followed by cyanosis alone and pallor followed by its results in reactive hyperemia—the reperfusion phase. Attacks
rubor alone) also exist. typically start in a single digit and spread symmetrically to other
Raynaud phenomenon occurs throughout the world. Overall, it digits, eventually involving both hands. Other sites may be involved
tends to be more common in colder climates. In warmer areas of as well—notably, the ears, the nose, the nipples, the face, and the
the United States and Spain, the prevalence ranges from 3% to knees. Ischemic attacks may be accompanied by mottling of the
5%, whereas in cooler areas, the prevalence ranges from 15% to
20%.2-4 In a study of the African-American population, the preva-
lence was 3%.5 Table 1 Conditions Associated with
Raynaud Phenomenon20
Classification Systemic sclerosis syndrome (scleroderma)
Raynaud phenomenon is generally classified as either primary or Systemic lupus erythematosus
Dermatomyositis or polymyositis
secondary. Primary Raynaud phenomenon occurs as an isolated
Rheumatoid arthritis
finding in an otherwise healthy individual; secondary Raynaud Rheumatologic diseases Takayasu arteritis
phenomenon is caused by an associated disease (in most cases, an Giant cell arteritis
autoimmune disease) or by identifiable environmental or chemical Thromboangiitis obliterans
exposure [see Table 1].6 The two types are distinguished from each Primary biliary cirrhosis
other on the basis of clinical criteria, and the distinction has signif-
Vibration (hand/arm vibration syndrome)
icant prognostic implications. Mechanical injury
Frostbite
With primary Raynaud phenomenon, the typical age of onset is
15 to 30 years, symptoms are generally symmetrical and less severe, Recurrent trauma or injury Crutch pressure
to large vessels Thoracic outlet syndrome
patients are more likely to be female, and multiple family members
may be affected.7 With secondary Raynaud phenomenon, the typ- Arterial diseases Brachiocephalic atherosclerosis
ical age of onset is greater, symptoms are usually more severe, and
Migraine or vascular headache
a systemic inflammatory disorder is commonly involved. In fact, Vasospastic disorders
Prinzmetal angina
Raynaud phenomenon is a prominent component of many
autoimmune disorders, occurring in 90% of patients with sclero- Carcinoid syndrome
derma, 10% to 45% of patients with systemic lupus erythematosus Endocrine disorders Pheochromocytoma
(SLE), one third of patients with Sjögren syndrome, 20% of pa- Hypothyroidism
tients with dermatomyositis or polymyositis, and 10% to 20% of Ovarian cancer
Malignant diseases
patients with rheumatoid arthritis.8 In 0% to 13% of patients who Angiocentric lymphoma
present with primary Raynaud phenomenon, an identifiable con-
Cryoglobulins
nective tissue disorder develops within a few years after presenta- Cold agglutinins
tion.9,10 The best predictors of transition to such a disorder are (1) Abnormal blood elements
Paraproteinemia
serologic findings that are positive for autoantibody and (2) sugges- Polycythemia
tive physical findings (e.g., abnormal nailfold capillary patterns,
Parvovirus B19
cutaneous telangectasias, puffy fingers, and sclerodactyly).6,10 Infections
Helicobacter pylori
Bleomycin, vinblastine
Clinical Evaluation and Investigative Studies Polyvinyl chloride
Chemicals or drugs Beta blockers
CHARACTERISTIC FINDINGS Ergots (e.g., methysergide)
Interferon alfa, beta
Exacerbation of Raynaud phenomenon typically occurs after Tegafur
direct exposure of an extremity to cold temperatures [see Sidebar
- 2. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 24 RAYNAUD PHENOMENON — 2
skin on the arms and legs. During the ischemic phase, patients
may complain of paresthesias and clumsiness in the involved
extremities. In the most severe cases of secondary Raynaud phe- Pathophysiology of Raynaud Phenomenon
nomenon, critical ischemia may cause painful digital ulceration.
Raynaud phenomenon should be differentiated from simple Blood flow to the skin is regulated by a complex interaction between
the endothelium, vascular smooth muscle, circulating hormones, and
“cold hands” (a more common and benign condition). In patients
neural plexus. Patients with Raynaud phenomenon demonstrate an
with Raynaud phenomenon, cold hands occur in conjunction exaggerated vasomotor response to otherwise benign stimuli, no-
with clearly distinguished skin-color changes. Moreover, recovery tably cold exposure. Normally, on exposure to cold, blood flow to the
takes longer than it does in patients who merely have cold hands. skin is reduced in an effort to preserve core temperature. This natural
The guidelines for diagnosing Raynaud phenomenon are based response is mediated primarily by the sympathetic nervous system
on a history of color change on exposure to cold or other stimuli. via the neurotransmitter norepinephrine, which causes contraction of
vascular smooth muscle in the cutaneous arterial beds. This cold-
A history of repeated episodes of biphasic skin-color change on
induced vasoconstriction of cutaneous vascular smooth muscle
exposure to cold is indicative of Raynaud phenomenon. A histo- appears to be mediated specifically by the alpha2 receptor.40
ry of uniphasic skin-color change with paresthesias on exposure It has been suggested that the cold-induced vasoconstriction
to cold is suggestive. In the absence of any skin-color change, seen in primary Raynaud phenomenon is the result of exaggerated
Raynaud phenomenon is ruled out.11 Generally, additional diag- activity of the alpha2 receptors. This suggestion was supported by
nostic tests are unnecessary; however, both evaluation of digital the results of experiments that blocked the cold-induced vasocon-
pressure response to cooling and laser Doppler assessment of skin striction in primary Raynaud phenomenon by delivering alpha2 re-
ceptor antagonists locally.41 The mechanism of this Raynaud-specif-
perfusion pressure have been employed in this setting. There is ic hyperactive response has not been fully elucidated, though there is
evidence to suggest that laser Doppler assessment of skin perfu- evidence to indicate that the response may, in part, be attributable to
sion pressure is capable of distinguishing between normal control increased activity in the protein tyrosine kinase signal transduction
subjects, persons with primary Raynaud phenomenon, and per- pathway.42 Endothelial derangements may also contribute to the
sons with secondary Raynaud phenomenon.12-14 pathogenesis of primary Raynaud phenomenon through increased
Raynaud phenomenon should also be differentiated from carpal plasma concentrations of endothelin and decreased levels of nitric
oxide.43,44
tunnel syndrome and other neuropathies, which may cause cold
In secondary Raynaud phenomenon, it is generally accepted
sensitivity but do not induce the skin-color changes characteristic that vascular damage from the underlying disease (especially in the
of Raynaud phenomenon. Patients who have asymmetrical, per- case of scleroderma) is responsible for the disruption of normal va-
sistent, or positional symptoms should undergo a full evaluation somotor homeostasis. Activated or damaged endothelial cells exac-
for possible large vessel occlusive disease, embolism, or thoracic out- erbate vasospasm and further damage perfusion by mediating the
let compression, any of which might lead to hand-color changes. proliferation and contraction of smooth muscle cells; enhancement
of procoagulant activity and reduction of fibrinolysis promote the for-
Raynaud phenomenon may also be a reflection of a more general-
mation of intravascular microthrombi, and the release of chemotactic
ized vasospastic disorder (e.g., migraine headache or Prinzmetal and adhesion factors activates local inflammatory processes.20
angina).15,16
HISTORY AND PHYSICAL EXAMINATION
Once a diagnosis of Raynaud phenomenon has been estab-
lished—or, at least, strongly suspected—a thorough history and “hairpin” capillary loops. However, the pattern seen in patients
physical examination can help distinguish between primary and with Raynaud phenomenon secondary to an underlying cause
secondary forms of the condition.The presence of specific symp- (e.g., scleroderma, dermatomyositis, or undifferentiated connec-
toms of connective tissue disease (particularly arthralgia, myalgia, tive tissue disease) often includes enlarged capillary loops , with
and dry mucous membranes), extended exposure to vibrating evidence of angiogenesis, architectural derangements, and areas
machinery, or antecedent use of certain medications is suggestive of decreased vascularity.19 Serologic markers provide additional
of secondary Raynaud phenomenon. The earliest specific diag- support for the diagnosis of secondary Raynaud phenomenon:
nostic criteria for primary Raynaud phenomenon were described the anti-Smith antibody is specific for SLE, and the anti-topoiso-
by Allen and Brown in 1932.17 More current criteria take advan- merase and anti–RNA polymerase antibodies are highly specific
tage of modern diagnostic tools and serologic testing. Primary for scleroderma-spectrum disorders. Among experts, there is lit-
Raynaud phenomenon is suspected when attacks are symmetrical tle doubt that patients with Raynaud phenomenon who test pos-
and episodic, when the history and the physical examination itive for autoantibodies are at higher risk for the eventual devel-
reveal no evidence of tissue gangrene or a possible underlying opment of a connective tissue disease.20
causative condition, when antinuclear antibody titers and eryth-
rocyte sedimentation rates are normal, and when nailfold capil-
Management
lary examination yields unremarkable results.18
Management of Raynaud phenomenon generally consists of
TESTING FOR SUSPECTED SECONDARY RAYNAUD lifestyle modification and medical treatment, with surgical
PHENOMENON options limited to severe or refractory cases. Nonpharmacologic
If secondary Raynaud phenomenon is suspected on the basis treatment generally suffices for primary Raynaud phenomenon,
of the history and the physical examination, more specific testing but it is often inadequate for management of secondary Raynaud
is appropriate. A particularly helpful test is nailfold capillaroscopy. phenomenon, which is usually more severe. Mild forms of Raynaud
The bases of the fingernails of the fourth and fifth digits are phenomenon are managed with lifestyle modification, including
examined with a handheld ophthalmoscope set to 10 to 40 maintenance of total body warmth (as well as warmth of hands
diopters after a drop of immersion oil is placed on each nailfold. and fingers), avoidance of cold and emotional stress, cessation of
The normal vascular pattern, seen in healthy control subjects and smoking, discontinuance of the use of vibrating tools, and avoid-
patients with primary Raynaud phenomenon, consists of delicate ance of vasoconstricting substances (e.g., caffeine, cocaine, beta
- 3. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 24 RAYNAUD PHENOMENON — 3
blockers, and decongestants). Biofeedback training has also been plasminogen activator and with low-molecular-weight heparin;
shown to be of some utility in reducing symptoms of Raynaud however, these agents were found to carry significant bleeding
phenomenon, though several studies have questioned its value, risks and thus have not been widely accepted for treatment of
especially in comparison to that of medical management.21,22 Raynaud phenomenon.28,33
Calcium channel blockers are the vasodilators most commonly For refractory, severe Raynaud phenomenon, surgical manage-
used to treat Raynaud phenomenon. Nifedipine, diltiazem, felodi- ment, most often involving some form of sympathectomy, is rec-
pine, and amlodipine are all effective, though they tend to be more ommended. Both central and distal sympathectomy have been
effective in patients with the primary form of the condition than in employed for this purpose; initial success rates are good, but there
those with the secondary form. One meta-analysis found short-act- is a high incidence of recurrent symptoms.
ing nifedipine, 10 to 20 mg three or four times a day, to be moder- For many years, open cervicothoracic sympathectomy was
ately effective at reducing symptoms in patients with Raynaud phe- commonly performed for symptomatic treatment of Raynaud
nomenon and scleroderma.23 A large clinical study found sustained- phenomenon (which was thought to result from an overactive
release nifedipine to be useful as well.22 Despite some variability in sympathetic response), but the results were mixed.34,35 The open
the published reports, calcium channel blockers remain the first form of the procedure was associated with substantial morbidity
choice for medical treatment after failure of nonmedical treatment. and frequent recurrence of symptoms, and as a result, it has now
Other vasodilators have also been shown to be effective. In one been largely abandoned. Some surgeons have advocated perform-
study, losartan, an angiotensin receptor blocker, proved to be more ing thoracoscopic sympathectomy[see 4:10 Video-Assisted Thoracic
effective than nifedipine in reducing the frequency and severity of Surgery] to treat severe Raynaud phenomenon that is refractory
episodes of both primary and secondary Raynaud phenomenon.24 to medical management, but the benefits and durability of this
Topical nitrates provide a degree of benefit as well.20 Because sero- approach have not been established. In this procedure, the ipsilat-
tonin may be partially involved in the pathogenesis of Raynaud eral pleural space is approached thoracoscopically, with the patient
phenomenon, a number of studies have focused on the use of sero- under general anesthesia. The sympathetic chain is identified as it
tonin reuptake inhibitors and serotonin receptor antagonists.25 In a courses down the ribs near the costovertebral junction, and the
small open-label trial that included both patients with primary second through fourth thoracic sympathetic ganglia lying be-
Raynaud phenomenon and patients with the secondary form of the tween the ribs are cauterized. Bilateral sympathectomy may be
condition, fluoxetine was more effective than nifedipine in reduc- performed in a sequential fashion during the same operation. Ap-
ing the severity and frequency of attacks over a 6-week period; the proximately 90% of patients experience immediate relief of symp-
effect was most pronounced in female patients and in patients with toms after thoracoscopic sympathectomy, but the majority also
primary Raynaud phenomenon.26 In another study, ketanserin, a experience recurrence of symptoms.36,37 Proponents of this proce-
selective serotonin receptor antagonist that is no longer available in dure argue that these recurrent symptoms are not as severe as the
the United States, significantly reduced the number of attacks over original preoperative symptoms and that patients who undergo the
a 3-month period.27 Intravenous prostaglandins have also been operation as treatment of ulceration exhibit continued long-term
used with success. In one report, iloprost, given as a 5-day infusion, healing. Nonetheless, in our view, it is advisable to reserve thora-
was beneficial in severe cases of Raynaud phenomenon, mitigating coscopic sympathectomy for selected cases of Raynaud phenome-
symptoms and enhancing the healing of ischemic ulcers28; unfor- non that are refractory to medical management.
tunately, iloprost is also unavailable in the United States. Of the I.V. At present, localized digital sympathectomy using microsurgical
prostaglandins currently available in the United States, alprostadil techniques is generally preferred to proximal sympathectomy for
(prostaglandin E1 [PGE1]) and epoprostenol (PGI2) have achieved, treatment of nonhealing ulcerations in patients with severe, refrac-
at best, mixed results,29,30 whereas prazosin has been employed tory Raynaud phenomenon.38 This procedure involves stripping the
with some success against primary and secondary Raynaud phe- adventitia, along with digital sympathetic fibers, from the involved
nomenon (though its effectiveness seems to be limited in patients digital arteries, with the patient under either regional or general
with scleroderma).31 anesthesia. In one small study of seven patients, it was suggested
Some authors have advocated low-dose aspirin therapy for that this digital sympathectomy could be extended to include the
Raynaud phenomenon, but to date, trials of antiplatelet therapy palmar arch, the radial and ulnar arteries proximal to the wrist,
have yielded disappointing results.28 In a placebo-controlled, ran- and the nerve of Henle, which is responsible for the sympathetic
domized trial published in 2003, cilostazol increased blood vessel innervation of the distal ulnar artery.39 The investigators found
diameter in patients with primary and secondary Raynaud phe- that by 1.5 years after adventitial stripping of the proximal radial
nomenon but did not bring about any improvement in symp- and ulnar arteries with resection of the nerve of Henle, all ischemic
toms.32 In smaller studies, some success was achieved with tissue ulcerations had resolved.
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