Complex Regional Pain Syndrome (CRPS) is a disorder characterized by chronic disabling pain disproportionate to its inciting event. It usually develops after trauma; however there is no relation between severity of injury and development of this disorder and in some cases there is no precipitating event. This syndrome is characterized by regional pain with or without a specific nerve injury and does not necessarily need to follow a dermatomal pattern.1 Pain is associated with sensory, vasomotor disturbances, sudomotor disturbances, edema and/or trophic changes in various degrees, at various times during the course of the disease.
CRPS nomenclature has evolved through the years. It was previously referred to in the literature as Reflex Sympathetic Dystrophy, Algodystrophy, Causalgia, Sudeck’s atrophy among others. In 1993, the International Association for the study of Pain (IASP) established the current term CRPS. It has been subdivided in two types:2 CRPS type I (also known as Reflex Sympathetic Dystrophy) generally develops after minor trauma or surgery and does not involve a clinically identifiable peripheral nerve injury. CRPS type II, previously known as Causalgia, is associated with damage to a major nerve. 1
CRPS most often develops after acute tissue trauma including fractures, crushing injuries, sprains and surgeries. Patients may also develop CRPS after burns, stroke, frostbite, injections or local infections. However, it has been reported in cases without any identifiable precipitating event.3 There is currently no evidence that any particular injury regularly manifests as CRPS or that the severity of injury is related to the development of this syndrome.
Epidemiology including risk factors and primary prevention
Retrospective studies report an incidence of 26.2 cases of CRPS per 100,000 persons per year. 4 It is more common in female patients and with advanced age. The highest incidence is between the ages of 61-70 years old. CRPS may develop after any injury; however, the most common precipitating events reported are surgeries, fractures, crush injuries and sprains. 5 Fractures are mentioned as the most common precipitating event and the upper extremity is more frequently affected than the lower extremity.4
The pathophysiology of CRPS is not completely understood. There have been multiple proposed mechanisms that may contribute to the development of this disorder. These include peripheral and central sensitization, inflammation, altered sympathetic and catecholaminergic function, cortex reorganization, genetic factors, and psychophysiologic interactions. 6Peripheral mechanisms occur because nerve injury produces hyperexcitability of afferent nociceptors, which in turn causes changes in expression of neurotransmitters. These changes cause peripheral sensitization producing an increase in nociception and subsequently hypersensitivity. 7 Furthermore, this persistent hyperexcitability of nociceptors may trigger central sensitization by increased excitability of nociceptive neurons at the spinal cord. This produces an excitatory cascade, which finally results in exaggerated responses to nociceptive stimuli. 6
Other proposed mechanisms include classic and neurogenic inflammation. It has been found that patients with CRPS present with increased pro-inflammatory cytokines locally, in the bloodstream and in CSF.2 These substances may produce plasma extravasation and vasodilation, thereby producing localized edema, warmth and erythema characteristic of CRPS. 6
The sympathetic nervous system is also thought to play a role in the pathophysiology of CRPS, however it is not clearly understood. Sympathetic and catecholaminergic dysfunction may be responsible for autonomic manifestations in CRPS.
Neuroimaging studies suggest a reorganization of somatotopic maps in the cortex of patients with CRPS. The degree of somatotopic reorganization correlates significantly with pain intensity and degree of hyperalgesia. 6
The degree to which individual mechanisms contribute to CRPS may differ between patients and even within one patient over time. 6
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
CRPS usually occurs after a precipitating event, generally 6 weeks following the inciting event. 8,9 Initial symptoms may include pain, erythema, and edema at site of the lesion. During the course of the disease, pain and other symptoms may spread. 2 CRPS was historically thought to occur in the following 3 stages: (1) early or acute stage, characterized by pain and sensory abnormalities including hyperalgesia and allodynia, vasomotor and sudomotor dysfunction, and edema; (2) dystrophic stage, with worsened pain and sensory dysfunction, persistent vasomotor dysfunction, and significant motor and trophic changes over the next 3-6 months; and (3) atrophic stage, characterized by progressive vasomotor, motor, and trophic changes, but decreased pain and sensory dysfunction. 10
Currently, there is little support for these sequential stages, and there is new evidence supporting CRPS described as three different subtypes. Subtype 1 is characterized by vasomotor changes, subtype 2 by neuropathic pain and sensory disturbances, and subtype 3 by motor limitation and trophic skin changes. 10
Specific secondary or associated conditions and complications
Secondary complications from CRPS include sequelae of disuse including contractures as well as altered sensation of the affected limb. Infection, edema, dystonia, and myoclonus can also occur. Dystrophic changes of nails, skin, and hair, osteopenia (Sudeck’s atrophy), and small nerve fiber dropout may occur. Impaired sympathetic vasoconstriction may also occur and lead to presyncope or syncope.
2. ESSENTIALS OF ASSESSMENT
A detailed history of present illness is essential. The most common complaints are hyperesthesia and/or allodynia. Pain is often described as hot, burning, and ache-like, which can either follow a dermatomal or a non-dermatomal distribution. It is relieved with medication and rest, and is exacerbated by temperature changes, limb movement, stress and physical activity.
History of recent surgery or trauma, including sprains, crush injuries and fractures should be thoroughly assessed as this may be a trigger for CRPS.
To make a clinical diagnosis of CRPS, the following criteria (the Budapest criteria) must be met: 11
• The patient must have continuing pain, which is disproportionate to any inciting event.
• The patient must have at least one symptom in 3 of the 4 following categories:
|Sensory||Sensory reports of hyperesthesia and/or allodynia|
|Vasomotor||Report of temperature asymmetry and/or skin color changes|
|Sudomotor/edema||Report of edema and/or sweating changes and/or sweating asymmetry|
|Motor/trophic||Report of decreased range of motion and/or motor dysfunction (weakness, tremor, or dystonia) and/or trophic changes (hair, nail, or skin)|
• The patient must display at least one sign during the physical exam in 2 of the 4 categories:
|Sensory||Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement)|
|Vasomotor||Evidence of temperature asymmetry between limbs and/or skin color changes/asymmetry|
|Sudomotor/edema||Evidence of edema and/or sweating changes/asymmetry|
|Motor/trophic||Evidence of decreased range of motion and/or motor dysfunction (manual muscle testing weakness, tremor, or dystonia) and/or trophic changes (hair, nail, skin)|
• There is no other diagnosis that better explains the symptoms and signs.
• A diagnostic subtype called CRPS-not otherwise specified (NOS) was created that would capture those patients who did not meet the new clinical criteria but whose signs and symptoms could not be better elucidated by any other diagnosis .1
The patient must display quasi-objective findings on exam in at least 2 of the 4 categories. Examination tools should include pin, temperature tape or infrared thermometer, von Frey testing or weighted pin, algometer, and goniometer.
Sensory signs are elicited through light touch and pinprick. Light touch can be performed with a cotton-tipped swab or soft brush. Motor changes can present as reduced range of motion and tremors. Trophic changes may manifest as growth or loss of hair and nail changes.
Vasomotor signs can be detected by assessing skin color and measuring skin temperature in affected and contralateral limbs. CRPS may spread to other extremities, and it may be important to measure skin temperature in arms and legs. The examiner must also assess for sudomotor changes (sweating changes/asymmetry) and edema. Trophic changes manifest as shiny, edematous, and erythematous skin findings with loss of hair.
There are isolated findings in CRPS, which are more suggestive of other conditions on the differential. Limited and painful joint range of motion can be found with adhesive capsulitis. Skin warmth and swelling around the joints may be the first finding for inflammatory arthritis. Red, hot, and painful extremities can be found in erythromelalgia, although this condition is frequently symmetric, while CRPS is at least initially unilateral. Cold limbs might indicate vascular insufficiency. Neuropathic pain can be exquisite in postherpetic neuralgia and shingles. In each of these cases, other physical examination findings may assist in organizing the differential when considering CRPS.
An impaired limb can be disabling. Inquiry into how patient minimizes discomfort while pursuing activities of daily living, including bathing and dressing, can guide functional restoration efforts. Because upper extremities are more frequently affected by CRPS, dominant hand function may be affected. Physical impairment may exceed those found with limb amputations and patients may demonstrate distress similar to that found with other chronic pain conditions.
At this time, no laboratory studies are used for the assessment of CRPS. Testing to exclude other diagnoses on the differential, including vascular studies to evaluate compromised limb perfusion, electrodiagnostics for specific neuropathies, and rheumatologic laboratory studies to evaluate for arthritis, may be helpful.
Although plain films may reveal patchy osteoporosis at periarticular region in the affected limb, imaging studies are not routinely used for the diagnosis of CRPS due to low sensitivity. Magnetic resonance imaging (MRI) is occasionally performed to evaluate for other muscle, joint, or soft tissue etiologies of pain. There is some evidence that triple-phase bone scans may provide better sensitivity and specificity than MRI and plain films for ruling out aspects of the differential, but bone scans show no diagnostic utility in CRPS per se, since a negative bone scan does not rule out CRPS.12
Supplemental assessment tools
Historically, the diagnosis of CRPS required abrupt and transient relief from pain and dysesthesia with a systemic chemical sympatholysis (Bier Block) and/or a diagnostic sympathetic block with a stellate ganglion block or a lumbar paravertebral block.13 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. 13
Autonomic tests such as resting sweat output (RSO), the resting skin temperature (RST), and the quantitative sudomotor axon reflex test (QSART) have been used to evaluate CRPS.13 Quantitative sweat tests and sudomotor axons reflex are sometimes used to assess sudomotor dysfunction, but are rarely used and have limited availability. Electrodiagnostic testing may be useful in the diagnosis of CRPS type II to demonstrate nerve injury, although tolerance to this examination may be limited.
Early predictions of outcomes
Early diagnosis and intervention in CRPS is associated with improved outcome and function. Although pain may decrease over time, detrimental changes arise from neuroplasticity. Additionally, long-term deficits in muscles, bones, and nerves are seen if the syndrome advances or goes undiagnosed and untreated. Recurrence of CRPS is not uncommon; estimates of recurrence range from about 10 to 30 percent, with the higher rates occurring in younger patients, including children.14,15
Weather may exacerbate CRPS symptoms. Tobacco and alcohol use is reported in 56% and 78% of patients with CRPS, respectively.
Social role and social support system
The most pragmatic assessment of pain must include biological, psychological, and sociological aspects.1 Secondary psychologic responses and dysfunction are ubiquitous. Addressing psychologic and social factors can improve outcome. The role of psychologic and social factors must be viewed with caution. It is critical to identify and aggressively treat all spheres of the pain experience.1 Plasma levels of epinephrine and norepinephrine were elevated in a sample of CRPS patients compared with healthy control subjects. While theoretically, stress and emotional distress could elevate these catecholamines, a causal relationship between social and environmental influences and the development of CRPS is far from proven.
3. REHABILITATION MANAGEMENT AND TREATMENTS
For Expanded Details, See Complex regional pain syndrome Part 2: Management and Treatment
Coordination of care
CRPS syndrome is not only biologically complex, due to its unclear pathophysiological background, but also frequently contains social and psychological components which makes successful treatment even more difficult to achieve.1 Functional restoration is best achieved through an interdisciplinary model and includes physical therapy, occupational therapy, recreational therapy, vocational rehabilitation, cognitive behavioral therapy, and medical oversight. This program emphasizes physical activity (“reanimation”), desensitization, and normalization of sympathetic tone in the affected limb and involves a steady progression from the most gentle, least invasive interventions to the ideal of complete rehabilitation in all aspects of the patient’s life.1
Patient & family education
CRPS patients must be personally committed to health improvement. Functional restoration is difficult without lifestyle modification, as well as integration of rehabilitative techniques. Families must also be educated in supportive efforts to restore function.
Emerging research suggests including the early stages of movement (activation of premotor and primary motor cortices) through graded motor imagery (GMI) or mirror visual feedback (MVF) therapy in treatment of CRPS.1 The mechanism of action of these therapies is still unclear.1 MVF therapy first asks the patient to close his/her eyes and describe both the affected and unaffected limb (i.e., size, location, and any perceived differences), followed by imagined movements of both extremities.16 The movements for the program are focused on painful joints and those that are just proximal and distal to the joint.1 The participant is then invited to look at the mirrored limb without movement in order to try to achieve ownership. 1
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Practice strategies, which recognize the subjective and objective features of this heterogeneous, biopsychosocial disease, can guide performance improvement. In the absence of larger randomized controlled trials, an empirical approach is appropriate. In recent years, the role of occupational therapy has become more important as it can lead the multidisciplinary treatment focus of functional restoration. It has integrated new skills such as GMI, which include novel techniques for treatment.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Research is ongoing in the realm of immune testing, genotypic, and phenotypic testing (e.g. functional MRI) to investigate whether these areas can contribute to the diagnosis of chronic pain conditions, including CRPS. Sympathetic adrenergic nerves travel along arteries and nerves and are found in the adventitia (outer wall of a blood vessel). In view of this some clinicians are performing sonographically guided peripheral nerve blocks and peripheral perivascular sympathetic blocks for CRPS management in patients. Currently, there is ongoing research about this management. At the moment, the diagnosis of CRPS still relies mostly on clinical evaluation and no particular laboratory or imaging study alone can provide a diagnosis.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Controversies and gaps in the evidence-based knowledge of CRPS are significant. There is hope that larger randomized controlled trials will begin to integrate fundamentals of CRPS diagnosis, while employing rigorous methodology, and monitoring of functional outcomes.
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- Bussa M, Guttilla D, Lucia M, Mascaro A, Rinaldi S. Complex regional pain syndrome type I: a comprehensive review. Acta Anaesthesiologica Scandinavica 2015;59(6): 685-97
- T. Borchers, M.E. Gershwin. Complex Regional Pain Syndrome: A Comprehensive and Critical Review. Autoimmunity Reviews 2013;13: 242–265.
- de Mos M, de Bruijn AG, Huygen FJ, et al. The incidence of complex regional pain syndrome: a population-based study. Pain 2007;129: 12.
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- Bruehl S. An update on the pathophysiology of complex regional pain syndrome. Anesthesiology 2010;113: 713.
- Gierthmühlen, J. Binder A. and Baron, R. Machanism-based treatment in complex regional pain syndromes. Nature Reviews. Neurol. 2014;10(9): 518-28
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- Thomson McBride AR, Barnett AJ, Livingstone JA, Atkins RM. Complex regional pain syndrome (type 1): a comparison of 2 diagnostic criteria methods. Clin J Pain 2008;24: 637.
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- Harden RN, Bruehl S, Perez RS, et al. Validation of proposed diagnostic criteria (the “Budapest Criteria”) for complex regional pain syndrome. 2010;150: 268-274.
- Cappello ZJ, Kasdan ML, Louis DS. Meta-analysis of imaging techniques for the diagnosis of complex regional pain syndrome type I. J Hand Surg. 2012;37: 288-296.
- Abdi, S. Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on March 31, 2016.)
- Zyluk, A. Complex regional pain syndrome type I. Risk factors, prevention and risk of recurrence. J Hand Surg Br. 2004Aug;29(4): 334-7.
- Veldman PH, Goris RJ. Multiple reflex sympathetic dystrophy. Which patients are at risk for developing a recurrence of reflex sympathetic dystrophy in the same or another limb. Pain. 1996 Mar;64(3): 463-6.
- McCabe C. Mirror visual feedback therapy. A practical approach. J. Hand Ther. 2011;24: 170–8, quiz 79.
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Original Version of the Topic:
Sunjay Mathur, MD. Complex regional pain syndrome Part 1: Essentials of Assessment and Diagnosis. Publication Date:2012/08/09.
Luis Baerga-Varela, MD
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Rafael Arias-Berrios, MD
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Shirley Grigg, MD
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Natalia M. Betances Ramírez, MD
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Juan Galloza Otero, MD
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