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Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis

Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Jun 22, 2022.

INTRODUCTION — Complex regional pain syndrome (CRPS) is a disorder of a body region, usually of the distal limbs, which is characterized by pain, swelling, limited range of motion, vasomotor instability, skin changes, and patchy bone demineralization. It frequently begins following a fracture, soft tissue injury, or surgery.

The etiology, pathophysiology, clinical manifestations, and diagnosis of CRPS in adults are reviewed here. Other aspects of CRPS in adults and children are presented separately.

(See "Complex regional pain syndrome in adults: Treatment, prognosis, and prevention".)

(See "Complex regional pain syndrome in children".)

DEFINITION AND TERMINOLOGY — The consensus definition of CRPS is as follows [1]: "CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time."

There are many older alternative names for CRPS in the literature, including reflex sympathetic dystrophy, algodystrophy, causalgia, Sudeck atrophy, transient osteoporosis, and acute atrophy of bone. Upper extremity involvement following stroke or myocardial infarction was sometimes referred to as the "shoulder-hand syndrome." In the modern era, these disorders are grouped under the single heading of CRPS [2].

Two subtypes of CRPS have been recognized [1,2]:

Type I (the form also known as reflex sympathetic dystrophy) corresponds to patients with CRPS without evidence of peripheral nerve injury and represents approximately 90 percent of clinical presentations.

Type II was formerly termed "causalgia" and refers to cases in which peripheral nerve injury is present.

However, the pathophysiologic basis for and clinical utility of the distinction between these two subtypes of CRPS is uncertain [1,3-5]. The term "sympathetically maintained pain" is considered to be a variable phenomenon associated with a variety of disorders, including CRPS types I and II.

Some investigators also recognize "warm" and "cold" subtypes of CRPS [6]:

"Warm" CRPS is distinguished by increased skin temperature at the onset of symptoms, further suggesting this as an inflammatory type.

"Cold" CRPS is differentiated by decreased skin temperature at the onset of symptoms.

Others have proposed central, peripheral, and mixed phenotypes based on symptom-clustering analysis [7].

PATHOGENESIS — The pathogenesis of CRPS is unknown. Proposed mechanisms involve both the peripheral and central nervous system and include classic inflammation, neurogenic inflammation, and maladaptive changes in pain perception [8-12].

Proinflammatory cytokines (eg, interleukin [IL-]1beta, IL-2, IL-6, and tumor necrosis factor [TNF]-alpha) appear to have a role in CPRS [13-16]. Among the mechanisms proposed for the persistent pain and allodynia that are a hallmark of CRPS is the release of inflammatory mediators and pain-producing peptides by peripheral nerves [12,17,18]. Neuropeptides that produce pain and signs of inflammation when experimentally administered include substance P, neuropeptide Y, and calcitonin gene-related peptide. In a process known as neurogenic inflammation, nerve impulses that propagate in an antidromic fashion (that is, from proximal to distal in a sensory, particularly nociceptive, nerve axon) could lead to the release of neuropeptides. There may also be cross-talk between afferent and efferent nerves at a site of nerve injury. This model also offers a possible explanation for the phenomenon of allodynia, in which a normally painless stimulus to the affected limb, such as light touch, produces significant pain.

Central sensitization is another possible explanation for pain and allodynia in CRPS. Increased activity in nociceptive afferents due to peripheral noxious stimuli, tissue damage, or nerve injury leads to increased synaptic transmission at somatosensory neurons in the dorsal horn of the spinal cord [12]. Cortical reorganization in sensory and motor regions of the brain [19-22] and evidence of glial activation [11,23-25] may lead to persistent activity of primary nociceptive neurons to cause central sensitization [19].

The role of the sympathetic nervous system in CRPS is unclear; however, autonomic manifestations previously ascribed to sympathetic overactivity could be due to catecholamine hypersensitivity [26] and may involve the formation of a reflex arc after an inciting event [4]. The arc follows the routes of the sympathetic nervous system and is modulated by cortical centers to produce peripheral vascular disturbances. The pain sensation in response to injury may lead to increased sensitivity of injured axons to epinephrine and other substances released by local sympathetic nerves. The enhanced sensitivity can be blocked by the intravenous administration of sympatholytic agents.

Genetic factors also may be involved in the pathogenesis of CRPS. One case-control study reported a significantly increased frequency of HLA-DQ1 among patients affected by CRPS type I [27]. The results of another study suggested that the phenotype of CRPS that progressed to develop multifocal or generalized dystonia was associated with HLA-DR3 [28].

CRPS can be considered a type of autoimmune syndrome due to the presence of antinuclear antibodies and immunoglobulin G autoantibodies against surface antigens on autonomic neurons [29-33].

EPIDEMIOLOGY — Population-based studies estimate an incidence between 5 and 26 per 100,000 per year [34-36]. The female-to-male ratio of CRPS is 2:1 to 4:1 [34-38]. The incidence appears to be highest in females who are postmenopausal [35].

Inciting events — The most common inciting events leading to CRPS are fractures, crush injuries, sprains, and surgery. However, no precipitating factors are identified in up to 10 percent of patients [34-36]. In a large retrospective cohort of 1043 patients with CRPS at a single-center referral clinic, the most common inciting events were fractures (44 percent), blunt traumatic injuries including sprains (21 percent), surgery (12 percent), and carpal tunnel syndrome (7 percent) [36]. The distribution of inciting events varied by subtype, particularly for carpal tunnel syndrome, which was significantly more common in type II cases compared with type I (36 versus 3 percent).

Several earlier reports suggested that psychosocial issues and personality traits acted as predisposing factors for CRPS [39-42]. However, this notion remains controversial because subsequent studies have not confirmed such an association [43-45].

CLINICAL MANIFESTATIONS — The main clinical symptoms of CRPS are pain, sensory changes, motor impairments, autonomic symptoms, and trophic changes in the affected limb [46]. The onset of CRPS generally occurs within four to six weeks of the inciting event [46,47](see 'Inciting events' above). The initial symptoms usually include pain, erythema, and swelling of the affected limb [17]. In most cases, the limb is warm initially, though some are cold at presentation or evolve from warm to cold.

CRPS in adults more commonly occurs in the upper limbs [34,36]. Involvement of both upper and lower limbs in the same patient is unusual [48]. However, the symptoms of CRPS may spread over time to involve adjacent areas of the affected limb or, occasionally, other ipsilateral or contralateral limbs [49,50].

Pain — Pain is typically the most prominent and debilitating symptom of CRPS. The pain of CRPS is described as a burning, stinging, or tearing sensation that is felt deep inside the limb in most cases, though it may be superficial in some [41]. The pain is most often continuous and undulating but can be paroxysmal. Pain may be worse at night and exacerbated by limb movement, contact, temperature variation, or stress [36,46].

Sensory abnormalities — Various types of sensory abnormalities are common in CRPS. Some patients have evidence of hyperalgesia, allodynia, or hypesthesia on examination [41]. Sensory disturbances are usually distal in the limb, sometimes in a stocking/glove pattern.

Motor symptoms — Approximately two-thirds of patients with CRPS have functional motor impairments related to pain [36,41,46]. Impairment is typically manifest by a reduction of complex muscle strength in handgrip or during tiptoe standing. Limb movement may be limited by edema, pain, or contractures. Some patients develop central motor manifestations such as tremor, myoclonus, dystonic postures, or impaired initiation of movement [51].

Autonomic changes — Differences in skin temperature, skin color, sweat, or edema (comparing the affected with the unaffected side) are common symptoms of CRPS [46]. Of note, edema may be a result of inflammation, endothelial, and/or autonomic dysfunction [52,53]. In one large cohort of patients, the most common autonomic signs were skin color change (74 percent, mostly livido or hyperemia), edema (70 percent), and increased sweating (40 percent) [36]. The mean temperature difference between affected and unaffected sides was 0.08°C; half of patients had an absolute difference in skin temperature of ≥1°C.

Skin changes — Trophic changes affecting the connective tissue in CRPS may include increased hair growth, increased or decreased nail growth, contraction and fibrosis of joints and fascia, and skin atrophy [46].

Clinical stages — Though some early reports described three sequential clinical stages of CRPS [54-59], this concept has been largely abandoned by most experts for lack of evidence to support the existence of discrete stages [3,60]. Nevertheless, staging is still considered useful by a declining proportion of clinicians.

The purported stages are as follows:

Stage 1 – Either after an event or without apparent cause, the patient develops pain in a limb. The essential features include burning, throbbing pain; diffuse, uncomfortable aching; sensitivity to touch or cold; and localized edema [61]. The distribution of the pain is not compatible with a single peripheral nerve, trunk, or root lesion. Vasomotor disturbances occur with variable intensity, producing altered color and temperature. The radiograph is usually normal but may show patchy demineralization.

Stage 2 – The second stage is marked by progression of the soft tissue edema, thickening of the skin and articular soft tissues, muscle wasting, and the development of brawny skin. This may last for three to six months.

Stage 3 – The third stage is most severe and is characterized by limitation of movement, the shoulder-hand syndrome (capsular retraction producing a frozen shoulder), contractures of the digits, waxy trophic skin changes, and brittle, ridged nails. Bone radiography reveals severe demineralization.

EVALUATION AND DIAGNOSIS — The diagnosis of CRPS is based upon the clinical features as determined by the history and physical examination. The diagnosis is suspected in the following circumstances [46]:

Symptoms (eg, pain, sensory changes, motor symptoms, autonomic dysfunction, or trophic changes) develop after limb trauma, usually within four to six weeks.

Symptoms are no longer fully explained by the initial trauma.

Symptoms affect the distal limb, go beyond the region involved in the trauma, or extend beyond the territory innervated by a single nerve or nerve root.

The diagnosis can be made if patients with these symptoms fulfill the clinical diagnostic criteria for CRPS discussed in the next section below. (See 'Clinical diagnostic criteria' below.)

There is no "gold-standard" test or method for confirming the diagnosis. However, some investigators assert that certain investigations are useful for the diagnosis of CRPS, particularly three-phase bone scintigraphy showing increased radiotracer uptake in joints distant from the trauma site. Other tests with some possible utility include side-by-side radiographs (eg, both hands imaged on the same radiograph) showing spotty bone decalcification, and long-term or repetitive skin temperature measurements showing >1°C difference for the affected versus unaffected side [46].

Clinical diagnostic criteria — The Budapest consensus criteria for the clinical diagnosis of CRPS are as follows [1,3]:

Continuing pain, which is disproportionate to any inciting event.

For the clinical diagnosis of CRPS, the patient must report at least one symptom in three of the following four categories (the more stringent research criteria require at least one symptom in all four categories):

Sensory: Reports of hyperesthesia and/or allodynia

Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry

Sudomotor/edema: Reports of edema and/or sweating changes and/or sweating asymmetry

Motor/trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

For the clinical diagnosis of CRPS, the patient must display at least one sign at the time of evaluation in two of the four following categories (the more stringent research criteria require at least one sign in three of the four categories):

Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)

Vasomotor: Evidence of temperature asymmetry (>1°C) and/or skin color changes and/or asymmetry

Sudomotor/edema: Evidence of edema and/or sweating changes and/or sweating asymmetry

Motor/trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

There is no other diagnosis that better explains the signs and symptoms.

The Budapest criteria do not explicitly incorporate certain key features of CRPS, including involvement of the limbs but not the head or trunk, the predominant occurrence of symptoms and signs in the distal part of the limb, and the presence of symptoms and signs that do not correspond to the territory of a nerve or nerve root [46]. However, these concepts are encapsulated in the definition of CRPS provided by the Budapest consensus group conference [1] as noted above. (See 'Definition and terminology' above.)

The Budapest criteria appear to be equally sensitive and more specific compared with earlier CRPS consensus criteria [2,62] for differentiating patients with CRPS from patients with other types of neuropathic pain [63]. In a cohort of over 700 patients with a clinical diagnosis of either CRPS (n = 609) or other chronic pain disorders (n = 104) in which various diagnostic criteria were applied, the Budapest criteria had the best combination of sensitivity and specificity (82 and 68 percent, respectively) [36]. A proposed weighted CRPS prediction score was developed from the cohort, which, if validated, may be useful as a screening tool.

Adjunctive diagnostic testing — Diagnostic imaging and autonomic testing are used when clinical features are atypical to support the diagnosis of CRPS and to exclude alternative causes to symptoms.

Bone scintigraphy — Bone scintigraphy (ie, bone scan) is a sensitive technique for the detection of any of a large variety of bone, joint, and periarticular disorders, including fracture, infection, tumor, arthritis, and metabolic bone disease. Triple-phase bone scintigraphy is useful for detecting alterations in bone metabolism in patients with CRPS who have active bone resorption. Although CRPS is a clinical diagnosis that does not depend upon the results of imaging studies, bone scintigraphy performed within the first five months after onset of symptoms can support the diagnosis if there is increased (ipsilateral >1.32 compared with contralateral) radiotracer uptake by a quantitative region-of-interest evaluation during the mineralization (ie, third) phase in joints distant from the trauma site [46,64]. Of note, a negative bone scan does not rule out the diagnosis of CRPS [46].

Plain film radiography — Plain radiographs often demonstrate patchy osteoporosis, but the sensitivity of this finding for CRPS is very low [46]. Some experts suggest that imaging both hands on the same radiograph can be supportive of the diagnosis of CRPS if there is patchy bone osteoporosis involving the affected hand [46].

Autonomic testing — Autonomic tests that have been used to evaluate patients with suspected CRPS include the resting sweat output (RSO), the resting skin temperature (RST), and the quantitative sudomotor axon reflex test (QSART). Some experts advocate serial measurement of skin temperatures [46], based upon evidence from one small study that a 2°C difference for the affected versus unaffected side was supportive of the diagnosis of CRPS [65]. However, this method requires monitoring for five to eight hours with recording of skin temperature at one-minute intervals using temperature sensors applied to the index fingers. Thus, it is not practical as a routine clinical test [66].

Other tests and interventions — There is no clear role for magnetic resonance imaging (MRI) or computed tomography (CT) scanning in the evaluation of suspected CRPS nor is there any role for the response to sympatholysis to confirm the diagnosis of CRPS.

MRI may be useful for excluding some conditions in the differential diagnosis (see 'Differential diagnosis' below) but is not useful for confirming the diagnosis of CRPS [46]. Limited data suggest that CT scanning can show focal areas of osteoporosis in a Swiss cheese-like appearance [67]. However, weighing the cost, radiation dose, and limited experience with use of CT scanning in evaluation of patients with CRPS, we suggest not using CT as a diagnostic test.

Historically, abrupt transient relief from pain and dysesthesia with a systemic chemical sympatholysis (ie, intravenous regional anesthesia, also termed a "Bier block," and/or a regional sympathetic nerve block such as stellate ganglion or lumbar sympathetic nerve blocks) was considered necessary to make the diagnosis of CRPS. However, as the role of the sympathetic nervous system in the pathogenesis of CRPS remains unclear and contradictory, it is now widely accepted that a positive response to sympathetic block is not diagnostic of CRPS. Rather, such a response is an important indicator of sympathetically maintained pain.

DIFFERENTIAL DIAGNOSIS — Conditions that can have some of the clinical features of CRPS include the following [68]:

Infection of skin, muscle, joint, or bone – Infections are characterized by redness (erythema), swelling (edema), warmth, and pain. Laboratory tests that are indicators of an infection, such as increases in the erythrocyte sedimentation rate (ESR) or in the C-reactive protein (CRP) and elevations in the peripheral blood white blood cell count, are unremarkable in CRPS. (See "Synovial fluid analysis" and "Infectious tenosynovitis" and "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis" and "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Compartment syndrome – Increased pressure within an anatomic compartment bounded by unyielding fascial membranes causes the pain and swelling in compartment syndrome. Acute compartment syndrome is a surgical emergency that usually develops soon after significant trauma, particularly involving long bone fractures of the lower leg or forearm. Acute compartment syndrome may also occur following minor trauma or from nontraumatic causes such as ischemia-reperfusion injury, coagulopathy, certain animal envenomations and bites, extravasation of intravenous fluids, injection of recreational drugs, and prolonged limb compression. Early symptoms include progressive pain out of proportion to the injury; signs include tense swollen compartments and pain with passive stretching of muscles within the affected compartment. (See "Acute compartment syndrome of the extremities".)

Peripheral vascular disease – Chronic hypoperfusion of the feet and legs results in cold feet with discoloration, leg cramps, or pain that is worse with activity and better with rest (ie, vascular claudication). (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

Deep vein thrombosis – Deep vein thrombosis can lead to swelling, redness, and pain of the extremity involved. However, this problem generally can be distinguished from CRPS by history and physical examination together with Doppler ultrasound vascular testing. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

Peripheral neuropathy – Several causes of peripheral neuropathy, including diabetic neuropathy, can also present with hypersensitivity and dystrophic changes of the extremities. (See "Overview of polyneuropathy" and "Screening for diabetic polyneuropathy".)

Vascular thoracic outlet syndrome – Patients with thoracic outlet syndrome may present with swelling (often a sensation of swelling without visible change), paresthesia, and erythema. (See "Overview of thoracic outlet syndromes".)

Rheumatoid arthritis – Chronic rheumatoid arthritis affects the synovium of the joints and can have signs and symptoms similar to those in CRPS. However, the symptoms of rheumatoid arthritis are present in various joints (eg, wrists, knees, shoulders, hands, and feet), as opposed to just a region of the body. Furthermore, laboratory bloodwork is helpful in diagnosing rheumatoid arthritis. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

Raynaud phenomenon – Raynaud phenomenon is an exaggerated vasoconstrictive response to cold temperature and emotional stress. The phenomenon is manifested clinically by sharply demarcated color changes of the skin of the digits. The diagnosis of Raynaud phenomenon is made if the fingers are unusually sensitive to cold and change color (to white, blue, or both) when exposed to cold temperatures. Abnormal vasoconstriction of digital arteries and cutaneous arterioles due to a local defect in normal vascular responses is thought to underlie the disorder. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

Erythromelalgia – Erythromelalgia is an acquired or (rarely) inherited clinical syndrome characterized by the intermittent occurrence of red, hot, painful extremities. The syndrome usually affects the legs (predominantly the feet) but may also involve arms (predominantly hands) and rarely involves the face. (See "Erythromelalgia".)

Functional neurological symptom disorder (conversion disorder) – Patients with functional neurological symptom disorder (conversion disorder) may report neurologic symptoms such as pain, sensory abnormalities, and weakness. Functional neurological symptom disorder (conversion disorder) is an involuntary condition featuring symptoms that occur in the absence of a neurologic disease but are not feigned. (See "Functional neurological symptom disorder (conversion disorder) in adults: Terminology, diagnosis, and differential diagnosis".)

Factitious disorder – Factitious disorder describes an intentional production of physical or psychologic symptoms or findings to assume the "sick role." (See "Factitious disorder imposed on self (Munchausen syndrome)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Complex regional pain syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Complex regional pain syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition – Complex regional pain syndrome (CRPS) is defined as a disorder of the extremities characterized by regional pain that is disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is not restricted to a specific nerve territory or dermatome and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time. (See 'Definition and terminology' above.)

Pathogenesis – The etiology and pathophysiology of CRPS are unknown. Proposed mechanisms include classic inflammation, neurogenic inflammation, and maladaptive changes in pain perception at the level of the central nervous system. (See 'Pathogenesis' above.)

Epidemiology – CRPS is more common in females than in males. The most frequent inciting events for CRPS are fractures and soft tissue injuries. CRPS seldom occurs in the absence of an identifiable trigger. (See 'Epidemiology' above.)

Clinical features – The main clinical symptoms of CRPS are pain, sensory changes, motor impairments, autonomic symptoms, and trophic changes in the affected limb. Of these, pain is typically the most prominent and debilitating symptom. (See 'Clinical manifestations' above.)

Diagnosis – The diagnosis of CRPS is made by the history and physical examination when clinical features fulfill diagnostic criteria. (See 'Evaluation and diagnosis' above.)

Clinical diagnostic criteria – Diagnostic criteria are based upon four symptom/sign categories (sensory, vasomotor, sudomotor/edema, and motor trophic) and require that the patient reports one symptom in three of the four categories and displays one sign at the time of evaluation in two of the four categories. The criteria require that no other diagnosis better explains the symptoms and signs. (See 'Clinical diagnostic criteria' above.)

Diagnostic testing – Bone scintigraphy, plain film radiography, and autonomic testing are used when clinical features are atypical to support the diagnosis of CRPS and to exclude alternative causes to symptoms. (See 'Bone scintigraphy' above and 'Plain film radiography' above and 'Autonomic testing' above.)

Differential diagnosis – The differential diagnosis of CRPS includes a large number of conditions that can have some of the clinical features of CRPS, including (see 'Differential diagnosis' above):

Infection of skin, muscle, joint, or bone

Compartment syndrome

Peripheral vascular disease

Deep vein thrombosis

Peripheral neuropathy

Vascular thoracic outlet syndrome

Rheumatoid arthritis

Raynaud phenomenon

Erythromelalgia

Conversion and factitious disorders

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert Sheon, MD, who contributed to an earlier version of this topic review.

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Topic 5628 Version 34.0

References

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