Raynaud Phenomenon and Vasomotor Syndromes




Episodic color changes of the hands and feet in response to cold or stress, known as Raynaud phenomenon (RP), are a frequent complaint among patients presenting to pediatric rheumatology clinics. The first description of vasomotor instability triggered by cold exposure, or “local asphyxia of the extremities,” is ascribed to A.G. Maurice Raynaud, a French medical student, whose name is eponymously linked with this disorder. Despite 150 years of clinical observation and basic research, it is only recently that significant inroads been made regarding the biological basis for this condition and establishing evidence-based therapeutic interventions.


Clinical Presentation


The clinical presentation of RP is characterized by recurrent episodes of vasospasm following exposure to cold or emotional stress. Episodes of RP typically occur as sudden onset of pallor (ischemia) of the digits, often triggered by changes in the ambient temperature or contact with cold surfaces, followed by blue (cyanosis) and then red (hyperemia) upon rewarming. Attacks commonly begin in a single finger or toe and then spread to other digits, symmetrically involving both hands and/or feet ( Fig. 31-1 ). The areas involved are often sharply demarcated and can be accompanied by sensations of pins and needles, aching, numbness, and/or clumsiness of the hands and feet. The index, middle, and ring fingers are the most frequently involved digits, whereas the thumb is often spared. Patients may also display symptoms of cutaneous vasospasm at other sites, including the ears, nose, face, knees, and nipples, and livedo reticularis involving the distal arms and legs. Vascular spasm within viscera, such as the esophagus or coronary arteries, may accompany peripheral symptoms, particularly in patients with systemic sclerosis (SSc).




FIGURE 31-1


A, Classic presentation of Raynaud phenomenon with symmetrical, sharply demarcated pallor affecting all fingers and sparing the thumbs. B, Cyanosis associated with Raynaud phenomena typically follows after pallor and represents deoxygenation of slow flowing blood.


The symptoms of RP attacks reflect transient arterial vasospasm that can last from minutes to hours and is typically readily reversed by mechanical warming measures. Upon warming, blood flow is often exaggerated: the skin appears reddened or flushed and the digits may swell or itch. With more severe episodes, tender, red subcutaneous nodules (pernio) and peeling or ulceration of skin overlying the involved areas may result from local tissue ischemia ( Fig. 31-2 ).




FIGURE 31-2


A, Digital ischemia secondary to Raynaud phenomenon resulting in painful erythematous plaques (pernio) on the tips of affected toes (from emedicine.medscape.com/article/1087946-media ). B, Necrosis of the fingertip and the proximal periungual area associated with Raynaud phenomenon (from asps.confex.com/asps/2006am/techprogram/paper_10931.htm ).


The triggers of RP in children are similar to those described in adults, with cold, emotional stress, and exercise as the most commonly reported initiators. Although exposure to absolute cold (e.g., air temperature below 0° C) is readily recognized as a stimulus, provocation may also occur upon transition from warmer to relatively cooler temperatures. In this way a seemingly modest cold exposure, such as entering an air-conditioned space or handling cold food, may cause an attack. A general body chill or exposure of the face can also trigger an episode, even if the hands or feet are kept warm. In some patients, RP occurs after nonspecific stimulation of the sympathetic nervous system (e.g., periods of intense emotional stress, startle response).


Primary RP, Raynaud sign, or idiopathic Raynaud disease are terms used to describe those patients without a definable cause for their symptoms beyond nonspecific vascular hyperreactivity ( Box 31-1 ). In this setting, RP is considered an exaggeration of the normal vasoconstriction response to cold exposure or stress, the clinical features are generally benign, and the symptoms are reversible with rewarming. Use of the word “disease” in this context may cause undue concern; thus, many clinicians prefer the term primary RP for otherwise healthy individuals. Secondary RP, or Raynaud syndrome , refers to patients in whom an associated disease or known cause of vascular injury drives the frequency and severity of symptoms.



Box 31-1

Clinical Features of Primary and Secondary Raynaud Phenomenon





  • Primary Raynaud phenomenon




    • Episodic vasospastic attacks precipitated by cold or emotional stress



    • Symmetrical involvement of distal extremities



    • No evidence of peripheral vascular disease



    • Absence of tissue necrosis, digital pitting, or gangrene



    • Normal nailfold capillary examination



    • Negative antinuclear antibody (ANA) test and normal erythrocyte sedimentation rate (ESR)




  • Secondary Raynaud phenomenon




    • Older age at onset



    • Male gender



    • Painful, asymmetric attacks with signs of digital ischemia (pernio or ulceration)



    • Ischemia proximal to the fingers or toes



    • Abnormal nailfold capillary examination with enlarged or distorted capillary loops



    • Abnormal laboratory parameters suggesting vascular or autoimmune disease (e.g., elevated ESR or CRP), autoantibodies (ANA, antitopoisomerase, anti-Smith antigen, antiphospholipid), decreased complement levels







Epidemiology


Primary RP is a common disorder that is frequently presented to rheumatologists because of concern for an underlying connective tissue disease. Estimates of the prevalence of RP range from 5% to 20% in women and 4% to 14% in men. The large variation between studies reflects, in part, the ethnic balance of the populations studied and the climate where the study patients live. For obvious reasons, patients living in colder climates are more likely to present for evaluation and at younger ages. A study of children 12 to 15 years old in Manchester, United Kingdom, reported an overall prevalence of 18% in females and 12% in males, with values increasing with age in this population. In general, RP is more common among women, adolescent, and young adult age groups, and family members of individuals with RP. Although the large majority of persons with RP do not have, nor will they develop, an associated rheumatological or vascular disorder, it is important to recognize that RP may herald significant rheumatic disease. RP occurs at high frequency (80% to 90%) in children with SSc or mixed connective tissue disease (MCTD) and is often the initial symptom of these disorders, preceding other manifestations of disease in some instances by years. New-onset RP should, therefore, prompt consideration and examination for signs and symptoms of systemic disease and, potentially, further rheumatological evaluation.




Etiology/Pathogenesis


In his thesis published in 1862, Raynaud ascribed the features he saw to “increased irritability of the central parts of the cord presiding over the vascular innervations.” Observing that local sympathectomy did not cure RP, Sir Thomas Lewis proposed in 1929 that RP was due to a “local fault,” rather than a defect in the central nervous system (CNS). Current data continue to support this view, suggesting that RP primarily represents exaggerated physiological vasomotor responses to cold temperature (i.e., lowering of blood flow to the skin, thereby reducing the loss of body heat and preserving core body temperature) and/or emotional stress. In broad terms, blood flow volume is regulated by an interactive system involving central and peripheral neural signals, cellular mediators, circulating hormones, and soluble vasoactive compounds. The inherent tone, or basal contractile activity, of vascular smooth muscle varies substantially between different arterial structures, ranging from relatively high in the coronary circulation to low or absent in the pulmonary circulation, and it can increase or decrease dramatically. Numerous mechanisms participate in the regulation of vascular tone, including both the intrinsic characteristics of vascular smooth muscle and endothelial cells, and extrinsic activities of local nerves, adjacent tissues, circulating cells, and soluble factors ( Box 31-2 ).


The pathophysiological mechanisms influencing RP can be segregated into three broad categories of abnormality: vascular, neural, and intravascular. The effects seen in primary RP are, by definition, fully reversible, whereas secondary RP may combine defective function and structural abnormalities, leading to irreversible tissue damage.


Endothelial cells play an active role in regulating vascular tone. Depending on their state of activation, endothelial cells can produce both potent vasodilating agents (e.g., prostacyclin and nitric oxide [NO]) and potent vasoconstricting agents (e.g., endothelins and angiotensin). Endothelial NO production, in particular, has a large effect on vascular tone, regulating vascular smooth muscle contraction, proliferation, and migration. NO also stimulates platelet disaggregation and hinders the adhesion of platelets, lymphocytes, and neutrophils to the endothelial surface, which can have secondary effects on vascular function. SSc-associated RP differs fundamentally from primary RP due to its associated vasculopathy involving fibrous intimal proliferation with associated intravascular thrombi. Endothelin-1 and angiotensin are potent vasoconstrictors with profibrotic activities that have been shown to be overexpressed in the skin of patients with SSc and other forms of secondary RP. These are but a few examples from a long list of agents and functions that may contribute to the pathogenesis of vascular abnormalities in SSc (summarized in Box 31-2 and discussed in greater detail in Chapter 27 ).



Box 31-2

Factors Influencing Vascular Reactivity





  • Arterial smooth muscle cells




    • Transmural pressure (autoregulation)



    • Oxygen tension/ischemia



    • Temperature (decreased temperature selectively increases response to norepinephrine)




  • Endothelial cell products




    • Nitric oxide (vasodilation)



    • Prostacyclin (vasodilation)



    • Endothelin-1 (vasoconstriction)




  • Sympathetic nervous system




    • Norepinephrine (vasoconstriction)




  • Neuropeptides




    • Substance P (vasodilation)



    • Vasoactive intestinal peptide (vasodilation)



    • Calcitonin gene-related peptide (vasodilation)



    • Neurokinin A (vasodilation)



    • Somatostatin (vasoconstriction)



    • Neuropeptide Y (vasoconstriction)




  • Other




    • Shear stress



    • Platelet products (thromboxane, serotonin)



    • Blood viscosity



    • Blood cell deformability



    • Estrogen





Neurotransmitters from both autonomic and sensory afferent nerves also influence digital vascular tone. Blood vessels can receive innervation from three main classes of neurons: sympathetic vasoconstrictor neurons, sympathetic or parasympathetic vasodilator neurons, and sensory neurons that mediate vasodilation. Although the sympathetic nervous system, via release of norepinephrine, is considered a major mediator of vasoconstriction in the skin, local nerve endings can produce both vasodilating (substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, neurokinin A) and vasoconstricting (somatostatin, neuropeptide Y) neuropeptides in response to local microenvironmental effects. Although many patients report stress as a trigger for RP, suggesting CNS influence on local vasospasm, studies that investigated the differential effects of mental stress in patients with RP have produced mixed results and have failed to clarify the role of the CNS in the pathogenesis of this disorder.


Vascular reactivity is also affected by shear stress, vasoactive substances released by platelets (thromboxane, serotonin), changes in blood viscosity, and changes in the rheological properties of blood (e.g., altered red blood cell deformability), which highlights the complexity of regulatory mechanisms involved.


The marked sensitivity to cold in both primary and secondary RP appears to be mediated, at least in part, by an enhanced response to stimulation of alpha adrenergic receptors in the digital and cutaneous vessels of patients with RP. Alpha adrenergic receptors are increased in small vessels relative to larger vessels in normal subjects, and are particularly numerous in cutaneous arteries and veins relative to other tissue beds. In humans, the administration of “selective” alpha-1 and alpha-2 adrenergic agonists causes a reduction in skin or finger blood flow. Cold exposure has been shown to selectively amplify the vascular smooth muscle constriction response to norepinephrine mediated through alpha adrenergic receptors. Estrogen has also recently been shown to increase expression of alpha-2 adrenergic receptors in vascular smooth muscle and to increase cold sensitivity, which may explain the greater prevalence of RP among postpubertal females. Within the alpha-2 adrenergic receptor family, individual subtypes (e.g., alpha-2a, -2b, and -2c) have been shown to display differing sensitivity to cold in both humans and mice. Under normal conditions (37°C), alpha-2c adrenoreceptors in cutaneous arteries are stored within the Golgi apparatus. Cooling induces activation of Rho/Rho kinase signaling pathways, prompting translocation of alpha-2c adrenoreceptor from the Golgi complex to the plasma membrane and augmenting sensitivity of contractile proteins to calcium ions. One trigger for Rho/Rho kinase signaling may be a rapid increase of reactive oxygen species (ROS) seen in smooth muscle cells following cold exposure (below 28° C). Ischemia and reperfusion, in turn, induce production of additional ROS by mitochondria, leading to further activation of the Rho/Rho kinase pathway and provoking repeated or persistent cycles of vasospasm. Selective inhibition of alpha-2 adrenergic receptors abolishes cold-induced vasoconstriction of isolated blood vessels in vitro, and inhibition of Rho kinase signaling pathways prevents translocation of alpha-2 adrenoreceptors from the Golgi to the cell surface in response to cooling.


Increased contractile protein responses to alpha-2 adrenergic agonists and cooling, and the associated changes in Rho/Rho kinase and protein tyrosine kinase activity, are observed in both primary and secondary RP compared to healthy controls. These findings provide a possible unifying explanation for cold-induced vascular reactivity in primary and secondary RP, identify a family of targets through which mutations may contribute to familial and ethnic clustering, and highlight opportunities for the development of new therapeutic agents.


A large number of diseases, disorders, medications, and chemical agents have been associated with secondary RP, presumably reflecting a common end point of vascular injury and the complex mechanisms responsible for control of vessel reactivity ( Box 31-3 ). As noted previously, changes in the microvascular system are seen in association with intimal fibrosis and endothelial dysfunction in SSc. Endothelial cell dysfunction appears at an early stage and is associated with increased platelet adhesion, decreased storage of von Willebrand factor, and decreased adenosine uptake. Ischemic reperfusion injury results in increased production of ROS, which further alters vascular tone. However, not all increased vascular reactivity in patients with SSc can be attributed to endothelial injury or fibrosis. These mechanisms may occur with, or even induce, the increase in alpha-2 adrenergic receptor reactivity discussed previously. Other observations in SSc include enhanced endothelial cell proliferation, reduced activity of NO, increased circulating levels of endothelin-1, and increased expression of endothelin receptors.



Box 31-3

Conditions Associated with Secondary Raynaud Phenomenon in Children





  • Rheumatological disorders




    • Systemic sclerosis



    • Mixed connective tissue disease (MCTD)



    • Systemic lupus erythematosus (SLE)



    • Juvenile dermatomyositis (JDMS)



    • Vasculitides



    • Sjögren syndrome



    • Antiphospholipid syndrome




  • Primary vasospastic disorders




    • Migraine




  • Mechanical/obstructive disorders




    • Primary vasculopathies



    • Recurrent trauma/frostbite



    • Thoracic outlet syndrome



    • Repetitive motion injury/carpal tunnel syndrome




  • Hyperviscosity/thromboembolic disorders




    • Cryoglobulinemia



    • Polycythemia



    • Sickle cell disease



    • Essential thrombocythemia



    • Hyperlipidemia




  • Endocrine disorders




    • Carcinoid



    • Pheochromocytoma



    • Hypothyroidism




  • Infectious disorders




    • Parvovirus B19



    • Helicobacter pylori




  • Chemical/drug exposures




    • Chemotherapeutic agents (bleomycin, vinblastine)



    • Vasoconstrictive agents (amphetamines, antihistamines, pseudoephedrine, phenylephrine)



    • CNS stimulants/ADHD therapeutics (methylphenidate, dextroamphetamine)



    • 5-hydroxtryptamine receptor antagonists (ergotamine, methysergide)



    • Polyvinyl chloride



    • Mercury



    • Street drugs (cocaine, LSD, ecstasy, psilocybin)




  • Other




    • Down syndrome



    • Arteriovenous malformation



    • Anorexia nervosa



    • Reflex sympathetic dystrophy





Intravascular or circulating factors have also been implicated in the pathogenesis of RP, in particular in patients with SSc. Abnormal platelet activation, defective fibrinolysis, and oxidant stress have also been reported. Although their actions are not fully understood, intravascular factors may exacerbate the effect of digital vasospasm by reducing basal blood flow in the microvasculature and promoting coagulation.




Diagnosis


History


Patients with primary RP are frequently referred to rheumatologists due to concerns that they might have an underlying rheumatological disorder. A detailed patient history should be collected, including the distribution of affected sites; frequency, severity, and duration of attacks; color pattern; triggers; seasonality; and associated symptoms (i.e., numbness, paresthesia, pain). Patients should also be questioned for any features suggestive of connective tissue disease (CTD) such as unexplained fever, fatigue, rash, morning stiffness, arthralgia, myalgia, dysphagia, peripheral edema, lymphadenopathy, or oral ulcers; about changes in digits, such as nail pitting, ulcers, or poor healing; and about the incidence of infection. Potential associated or precipitating factors should also be assessed, including frostbite, drug or toxin exposure, infection, vibration injury, personal and family history of RP or CTD, migraines, weight loss or eating disorders, and cardiovascular disease.


Clinical Criteria


The complaint of cold hands or feet is very common and must be distinguished from RP, which involves both cool skin and cutaneous color changes. Normal individuals may have cool skin and digital pallor or skin mottling on cold exposure. However, unlike RP, onset is not abrupt, the recovery phase of vascular flow is not delayed, and there is no prolonged or sharp demarcation of color changes in skin. A diagnosis of RP may be made if the patient provides a history of symptoms characteristic of a Raynaud episode; history alone is accepted as diagnostic in general practice, because no simple clinical test consistently triggers an attack. If necessary, or for research studies, digital arteriolar blood flow can be documented by Doppler flow ultrasound. Characteristic changes have also been reported by plethysmography and arteriography, although the latter is not usually necessary or indicated and is performed with some danger of precipitating acute catastrophic arteriolar spasm in patients with severe RP. In practice, digital artery ultrasound is readily available and interrogates the same anatomical structures as angiography, and it is cheaper, faster, and noninvasive. Although measurement of digital blood pressure, digital blood flow, or skin temperature responses to cooling may be predictive in a research setting, attempts to induce and measure attacks in an office setting are not consistent, even in patients with definite RP. A simple approach employing the use of standard questionnaires and color photos of typical features has proven useful in clinical trials and epidemiological studies.


Specific criteria for the diagnosis of RP were first proposed in 1932. Several modifications designed to improve the differentiation of primary and secondary RP have been proposed and validated (see Box 31-1 ). The diagnosis of RP is fundamentally based on a history of episodic vasospastic attacks precipitated by cold or stress. Characteristic features include sharply demarcated lesions; bilateral symptoms; and white, blue, and/or red color changes, although the spectrum of symptoms observed is broad. Maricq and colleagues have reported that, among adults who were cold sensitive, only 1% had triphasic color changes, and 37% had white or blue color only. In a retrospective review of 123 pediatric patients, Nigrovic and colleagues reported that 24% of children with primary RP and 19% of children with secondary RP reported triphasic color changes, whereas 40% to 50% had only monophasic color changes. An interesting cross-sectional study of patients in the Netherlands indicated that reactive hyperemia at the end of an attack and discoloration of the earlobes and nose were more highly associated with primary RP than with secondary RP.


Significant factors differentiating primary from secondary RP are the absence of evidence for vascular disease by clinical examination (including blood pressure, pulses, and nailfold capillaroscopy) in primary RP, and the presence of abnormal nailfold capillaries and/or laboratory findings suggesting systemic disease in secondary RP. Primary RP attacks typically involve all fingers in a symmetrical pattern and are not commonly associated with significant pain. Asymmetrical finger involvement and severe pain, by contrast, are suggestive of an underlying pathology and should prompt a more vigorous evaluation. Although patients with primary RP are, by definition, generally healthy, comorbid conditions, including hypertension, atherosclerosis, cardiovascular disease, and diabetes mellitus, can increase the frequency or severity of symptoms. Anatomical variants, such as incomplete palmar arterial arch (clinical positive Allen test), can augment the symptoms of vasospasm, leading to earlier and more severe presentations. An issue important in the evaluation of children with RP is the use of stimulants for attention deficit disorder, which may exacerbate vasospasm and vascular dysfunction.


As discussed, the regulation of regional blood flow is complex and susceptible to a variety of insults. Also, the number of disorders associated with RP is extensive (see Box 31-3 ). As research progresses, the border between idiopathic and “disease”-associated symptoms blurs. Ultimately, primary RP is a diagnosis of exclusion supported by lack of progression over time toward development of an associated disorder. Although extensive special testing is not always necessary, every patient with a diagnosis of RP should be carefully evaluated for features of concurrent or incipient disease. Among these, the rheumatological diagnoses most often associated with secondary RP are SSc, MCTD, and other CTD (e.g., systemic lupus erythematosus [SLE], overlap syndromes, polymyositis, dermatomyositis, Sjögren syndrome, and vasculitis). Other conditions that must be considered include occlusive vascular disease, drug effects, hematological or coagulation abnormalities, and other vasospastic syndromes (see Box 31-3 and later discussion).


Nailfold Capillary Microscopy


Nailfold capillary microscopy is a simple, yet powerful diagnostic tool shown to significantly improve the predictive power of clinical evaluation. The examination can be performed at the bedside using a handheld magnifier (e.g., DermLite) or with a low-power microscope ( Fig. 31-3 ). Enlarged or distorted capillary loops, telangiectasias, and a relative paucity or loss of capillary loops strongly suggest a concurrent or incipient CTD. The presence of these features in a patient with RP should prompt a vigorous search for related findings.




FIGURE 31-3


Nailfold capillaroscopy. A, Normal nailfold capillary size and distribution. B, Early changes of scleroderma showing dilation, tortuosity, and disorganization. C, Active stage scleroderma showing increasingly disorganized architecture, giant capillaries and hemorrhage, decreased number of vessels, and increased frequency of abnormal vessels. D, Late-stage scleroderma showing severe dropout and abnormal vessels with arborization.



Laboratory Testing


If the history and physical examination, including nailfold capillary microscopy, are not suggestive of a cause for secondary RP, a diagnosis of primary RP may be made, and there is no need for further specialized testing. In particular, blood tests such as the erythrocyte sedimentation rate and antinuclear antibody (ANA) are not necessary and may be misleading. If, however, there is a moderate or higher clinical suspicion of a secondary cause of RP, then special testing as indicated by the clinical assessment is appropriate. Recommended laboratory studies for possible connective tissue disorders include a complete blood count, a general blood chemical analysis with tests for renal and liver function, urinalysis, complement (C3 and C4), and ANA. If the ANA is positive, tests for specific autoantibodies may assist with formulating a diagnosis (e.g., anti-double-stranded DNA, anti-SSA [Ro], anti-SSB [La], antiribonucleoprotein, antitopoisomerase [anti-Scl 70], and antiphospholipid antibodies). Anticentromere pattern ANA and anti-Scl 70 antibodies have the highest sensitivity for predicting evolution to SSc and risk for development of digital ischemia. It is important to recognize that while most pediatric patients with secondary RP will have a positive ANA (85% to 100%), a significant number of pediatric patients with primary RP will have nonspecific elevation of ANA titer without evidence for an associated rheumatic disorder. Conversely, in a cohort of 1039 adult patients monitored prospectively, only 6.3% of patients with negative autoantibody studies developed CTD over more than 10 years of follow-up, whereas nearly 60% of patients with RP and a positive ANA were ultimately diagnosed with a CTD. About 30% of pediatric patients with primary or secondary RP were also found to have antiphospholipid antibodies, although none of the patients had features of systemic antiphospholipid syndrome.


Although anticentromere and antitopoisomerase antibodies are associated with development of SSc, the combination of autoantibodies and nailfold capillary microscopy may be more informative than either finding alone. In a 20-year prospective study of 586 patients with RP who had no known CTD at enrollment, the overall incidence of limited (CREST variant) or diffuse SSc was 13%. In patients with one or more related autoantibodies or abnormal nailfold capillary microscopy, the incidence of SSc was 47%, whereas in those with both an autoantibody and abnormal nailfold capillary microscopy, the incidence of SSc was nearly 80%. Further discussion of the clinical evaluation of systemic rheumatological disorders and the significance of autoantibodies in the prognosis of SSc are included elsewhere in this text ( Chapter 27 ).


Differential Diagnosis


The differential diagnosis for RP includes the extensive list of conditions in Box 31-3 . In patients who present with prolonged peripheral vascular obstruction, it is particularly important to distinguish whether they are experiencing a thrombotic event rather than transient vasospasm. Although an exhaustive discussion of these possibilities is beyond the scope of this chapter, the following paragraphs represent disorders commonly considered in the differential diagnosis of nonclassic RP.


Acrocyanosis is an uncommon, painless, vasospastic disorder causing persistent coldness and bluish discoloration of the hands (and less commonly of the feet). Patients with acrocyanosis have cold and diffusely cyanotic color changes that can involve the entire hand and foot, extending proximally without a sharp demarcation between affected and unaffected tissue. Mild diaphoresis may be present, creating a clammy feel to the extremities. Mild capillary abnormalities may exist but do not show the avascular regions or giant capillaries found in patients with scleroderma. Both acrocyanosis and RP are more common in individuals with low body weight or who have anorexia nervosa. Evaluation for cyanotic heart disease, celiac disease, eating disorders, or GI malabsorption should be considered.


Perniosis, or chilblains, is a cold-induced condition marked by the appearance of painful, erythematous, papular, or nodular lesions, usually located on the fingers, toes, thighs, and/or buttocks. As with RP, pernio may present as an idiopathic process or in association with systemic disease (e.g., SLE). It is distinguished from RP by the lack of blanching and absence of a sharp line of demarcation. Although clinically and histologically distinct from RP, the treatment paradigms are similar and based primarily on nonpharmacological lifestyle modifications. Although definitive data are lacking, many of the agents used for RP can be considered for pernio if pharmacological intervention is necessary.


Frostbite is relatively common in cold climates and can have prolonged sequelae including tissue loss and persistent cold sensitivity. In a study of 30 individuals who had suffered moderate (second degree) frostbite, Ervasti and colleagues reported subjective symptoms at 4 to 11 years after injury in 63% of the subjects, including hypersensitivity to cold, numbness, and decreased touch sensitivity. Cold air provocation testing revealed an increased tendency for vasospasm in these individuals, including white fingers in 20%.


Carpal tunnel syndrome is relatively rare in children and is more often idiopathic or secondary to metabolic disorders (e.g., lysosomal storage diseases), rather than related to overuse as is seen in adults. Symptoms are more characteristically numbness and reduced manual dexterity, rather than color changes, and are generally not related to cold exposure. Although the wrist-flexion test (Phalen maneuver) and the nerve compression or percussion test (Tinel sign) can be informative, they are often nondiagnostic in pediatric patients, and electrophysiological testing is indicated to confirm a diagnostic suspicion.


Brachial or lumbosacral plexus neuropathies are also rare in children, outside of those related to birth injury, but may be present in older adolescents and young adults presenting for evaluation in pediatric clinics. The typical presentation of idiopathic brachial plexus neuritis (Parsonage–Turner syndrome) or lumbosacral plexopathy includes acute onset of shoulder or proximal leg pain, respectively, associated with weakness and muscle wasting in the extremity and without restricted passive range of motion. Numbness and color changes in the extremity are variable, but gradual in onset, fixed in nature, and typically less prominent a complaint than pain and neuromuscular symptoms. Idiopathic plexus neuropathies often follow an upper respiratory infection and may be recurrent. Electromyographic findings are characteristic and diagnostic. Prognosis is generally good, though recovery may be protracted and may require intensive physical therapy to reduce contractures and restore muscle strength.


Erythromelalgia is a relatively rare condition of paroxysmal vasodilation. Erythromelalgia can be thought of as the opposite of RP. Symptoms manifest as episodic burning pain accompanied by erythema, warmth, and swelling of the hands and/or feet; symptoms are brought on by heat, exercise, or friction, and affected patients report dramatic relief with application of ice or cold water. Erythromelalgia also presents in both primary and secondary forms. Primary erythromelalgia (also termed erythermalgia ) appears in childhood and can be familial (autosomal dominant) or sporadic. It affects girls more than boys, and symptoms are most often symmetrical; it is frequently resistant to treatment. Recent studies have attributed a majority of both familial and sporadic cases to gain-of-function mutations of SCN9A, the gene that encodes the voltage-gated sodium channel Na(v)1.7. Loss-of-function mutations in the same gene are associated with congenital insensitivity to pain. Secondary erythromelalgia is more common and typically presents in older children and adults. The majority of cases are associated with essential thrombocytosis and are characteristically responsive to low-dose aspirin therapy. Erythromelalgia can also develop in individuals with small fiber neuropathies of various etiologies, including multiple sclerosis, hypercholesterolemia, mercury and other heavy-metal poisoning, and a variety of autoimmune diseases. These patients are not responsive to aspirin, but the condition typically responds to treatment of the underlying disorder. Management of erythromelalgia includes avoidance of triggers (heat, friction) and application of cold during acute attacks. Although controlled studies are lacking, if aspirin or treatment of associated conditions is unsuccessful, case studies have reported successful use of a range of approaches: pharmacological (e.g., nifedipine, verapamil, propranolol, nitroprusside), nonpharmacological (e.g., biofeedback, hypnosis), and surgical (sympathectomy, amputation, stereotactic destruction of regions of the hypothalamus).


Complex regional pain syndrome (CRPS), or reflex sympathetic dystrophy, will often present with altered temperature and coloration of the involved extremity. Persons with CRPS usually have unilateral distal limb involvement, with the affected area showing differences in temperature (warmer or colder) and color (red, pale, or mottled) compared with the unaffected side. These individuals typically display severe diffuse allodynia; paresthesia, causalgia, or other abnormal sensations; refusal to move the affected region; and unusual positioning of the affected extremity. A detailed discussion of CRPS can be found elsewhere in this text ( Chapter 52 ).

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