Complex Regional Pain Syndrome

Michael L. Weinberger

Thomas H. Brannagan III

INTRODUCTION

The complex regional pain syndrome has a long and changing history in medical practice. Veldman suggested that Ambrose Pare, in 1598, may have been the first to describe the syndrome of widespread limb pain with swelling, discoloration, and temperature change. Silas Weir Mitchell, a civil war era physician, discussed the relationship of the central and peripheral mechanisms and “reflex transfers” in the spinal cord along with his description of causalgia in soldiers who had intense nerve pain and autonomic dysregulation after gunshot wounds in battle. The term causalgia is attributed to Mitchell and the term reflex sympathetic dystrophy to Evans 80 years later. Other terms include the hand-shoulder syndrome, sympathalgia, algodystrophy, and Sudeck dystrophy. A consensus conference in 1993 led to a redefinition as the “complex regional pain syndrome” (CRPS). CRPS type 1 was intended to replace reflex sympathetic dystrophy (RSD) and CRPS type 2 to replace “causalgia.” These changes were an attempt to eliminate the implication that the sympathetic nervous system is involved in generating pain while agreeing that sympathetically maintained pain is a symptom.

EPIDEMIOLOGY

In two population-based studies, the incidence of CRPS was 5.46 to 26.2 per 100,000 person-years. The prevalence was estimated at 20.57 per 100,000 in Olmsted County. Women are three times more likely to be affected and postmenopausal women have the highest risk. The mean age at onset is 46 years, with the highest incidence between ages 61 and 70 years.

CLINICAL MANIFESTATIONS

CRPS 1 is a disorder with pain out of proportion to the severity of the injury, allodynia, vasomotor disturbances, motor disturbances, and trophic changes in the skin. Allodynia is defined as “pain resulting from a stimulus (such as a light touch of the skin) that would not normally provoke pain.” The symptoms typically follow trauma, which may be mild, but can occur after a myocardial infarction or varicella-zoster infection. A bone fracture is a common preceding event in about 45% of all patients. The arm is affected more commonly than the leg.

The pain is described as deep, sharp, sensitive, and hot. Patients are often sensitive to cold sensations and often guard their limbs to avoid physical contact. Swelling, edema, heat, and color changes occur in the affected limb, followed by osteoporosis and changes in hair, skin, and nail growth. The pain does not conform to nerve or root distribution and usually spreads beyond the area of injury. Some patients with CRPS 1 have dystonic postures of a hand or foot. Features similar to psychogenic movement disorders have been noted by some authors, including the difficulty initiating movement, abrupt onset, and dystonia at rest.

PATHOLOGY

CRPS 2 is defined by the presence of a nerve injury. In a single autopsy case of a CRPS 1 patient, pathologic changes included loss of posterior horn cells and activation of microglia and astrocytes. These changes were most prominent at the site of injury but extended throughout the length of the spinal cord. A study of amputated limbs noted microvascular changes with thickened basal membranes in capillaries in muscle and the loss of C fibers in some patients. In skin biopsy, CRPS 1, defined by the absence of an identified nerve injury, may show fewer small sensory epidermal nerve fibers than controls. Functional magnetic resonance imaging (fMRI) has demonstrated cortical reorganization with shrinkage of the contralateral primary somatosensory cortex, which can be reversed with pain relief.

PATHOBIOLOGY

There is little information about the pathophysiology of CRPS. Both peripheral and central neural mechanisms have been proposed. Human leukocyte antigen (HLA) associations have been described but not confirmed. Theories of the pathogenesis have centered on central sensitization, oxidative damage, and inflammation. After an injury, an initial barrage of C fiber afferent activity may result in central sensitization (see Chapter 57) of dorsal horn neurons, resulting in allodynia and expansion of the distribution of pain. Patients with CRPS have increased levels of proinflammatory cytokines and markers of glial cell activation in the cerebrospinal fluid (CSF). They also have increased markers for oxidative damage, including malondialdehyde. Loss of inhibitory dorsal horn neurons may be evident. More recently, an autoimmune mechanism has been proposed. Studies have demonstrated autoantibodies to autonomic nervous system autoantigens in 30% to 40% of CRPS patients but not in controls or neuropathy patients. Immunoglobulin G (IgG) antibodies to autonomic receptors (β2 adrenergic receptor and muscarinic-2 receptor) has been demonstrated. Also, α1 adrenoreceptors on nociceptive afferents has been shown to be upregulated in dermal nerves and epidermal cells, which may augment pain and neuroinflammation in CRPS.

DIAGNOSTIC CRITERIA

In addition to the changes in terminology, diagnostic criteria have also evolved. Early attempts to define diagnostic criteria were based on anecdotal accumulation of signs and symptoms. Kozin et al. established diagnostic criteria in 1976, including categories for definite, probable, and doubtful RSD. Gibbons proposed a diagnostic
scale based on clinical signs and symptoms and laboratory tests including response to sympathetic nerve block. Blumberg proposed a numeric grading scale based on autonomic symptoms, motor symptoms, and sensory symptoms.

The International Association for the Study of Pain (IASP) diagnostic criteria for CRPS from Merskey and Bogduk (1994) include the following:

The presence of an initiating noxious event or a cause of immobilization
Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event
Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain
This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction: type 1: without evidence of major nerve damage; type 2: with evidence of major nerve damage.

A consensus workshop in 2003 proposed changes because of the concern that the aforementioned criteria lack specificity in the face of high sensitivity. Validation studies of these criteria suggest that overdiagnosis may be a problem and the inclusion of objective data beyond the subjective and historic data currently called for may improve specificity with modest diminishment in sensitivity.

The Budapest criteria have been accepted by the IASP for the third revision of formal taxonomy and diagnostic criteria of pain states. Clinical diagnostic criteria for CRPS include an array of painful conditions characterized by continuing (spontaneous 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 shows distal predominance of abnormal sensory, motor, sudomotor vasomotor, or trophic findings, all with variable progression over time.

CLINICAL DIAGNOSTIC CRITERIA

Continuing pain disproportionate to an inciting event
Must include at least one symptom in three of the four following categories:
- Sensory: hyperesthesia, allodynia, or both
- Vasomotor: temperature asymmetry, skin color changes, skin color asymmetry, or all of these
- Sudomotor/edema: edema, sweating, sweating asymmetry, or all three
- Motor/trophic: decreased range of motion, motor dysfunction (weakness tremor, dystonic posture), trophic changes (hair, nail, skin), or all three
Must display at least one sign at the time of evaluation in two or more categories:
- Sensory: hyperalgesia (to pinprick), allodynia (to light touch, temperature sensation, or deep somatic pressure or joint movement), or combinations of these
- Vasomotor: evidence of temperature asymmetry (>1°C), skin color changes or asymmetry, or combinations
- Sudomotor/edema: edema, sweating changes, or sweating asymmetry
- Motor/trophic: decreased range of motion, motor dysfunction (weakness, tremor, dystonia), or trophic changes (hair, skin, nails)
No other diagnosis better explains the sign and symptoms.

These criteria have no implications of etiology or pathophysiology. Tests of these criteria demonstrated lower rates of overdiagnosis with little loss of sensitivity.

Published data report that the clinical criteria result in a sensitivity of 85% and sensitivity of 69% and the research criteria, 70% and 96%, respectively.

Other diagnostic tests have included thermography, bone scans, and quantitative sensory testing. Schurmann et al. studied patients with acute radial fracture who met the 1994 IASP criteria and the 1999 Bruehl research criteria. They found a high specificity but low sensitivity for bone scans. Thermography demonstrated poor sensitivity and specificity. Magnetic resonance imaging (MRI) showed high specificity but poor sensitivity. Plain x-rays showed high specificity but low sensitivity with a positive predictive value of 58% and a negative predictive value of 86%. The authors suggest that these tests are not useful for screening but bone scan and MRI have high specificity; however, clinical criteria are still the gold standard.

Historically, three stages of CRPS have been described. Recent analyses have not supported this theory but have suggested three possible subtypes: (1) limited syndrome with predominance of vasomotor signs, (2) limited syndrome with predominance of neuropathic pain/sensory abnormalities, and (3) full blown CRPS with greatest degree of motor/trophic and disuse-related changes.

TREATMENT

Because the etiology of CRPS is uncertain and treatment proposals for CRPS have been untested in placebo-controlled trials but based on historic precedent and anecdotal reports, therapy is debated. Physical therapy and functional restoration have played a major role in the treatment of CRPS. Current guidelines have been developed by consensus. The focus is gradual and progressive movement and use of the limb with increased load bearing as well as desensitization to sensory stimuli. Nerve block, psychotherapy, cognitive behavioral techniques, and pharmacotherapy are added to allow a patient to participate in occupational and physical therapy. Edema must also be addressed with active motion or special garments. The goal is to progress through desensitization, increasing flexibility, edema control, increased range of motion, stress loading, normal postures and balance, and then to normal usage, with vocational and functional rehabilitation.

Few placebo-controlled randomized trials of drug therapy for CRPS have been carried out, and current therapy is largely based on treatment of neuropathic pain. Biphosphonates, including clodronate and alendronate, have been shown to provide effective pain relief in placebo-controlled trials (Table 56.1) [Level 1].1,2 IV ketamine in anesthetic doses over 5 to 10 days has also been reported in open-label controlled trials to be effective in producing symptom reduction or remission in a subgroup of patients refractory to other therapies [Level 1].3,4 A study of subanesthetic doses of ketamine in refractory CRPS patient was not effective [Level 1].5 A recent Cochrane Review concluded that there is moderate to low quality evidence supporting its use in the treatment of CRRPS [Level 1].1 Oral steroids (methylprednisolone 32 mg for 2 weeks, then tapering off for 2 weeks or prednisone 30 mg for 12 weeks) have been reported to be more effective than placebo, but the weight of current evidence indicates that overall there is no evidence for their effectiveness [Level 1].1,3 Intravenous (IV) phentolamine (0.5 g/kg) has shown no significant pain relief but sympatholytic agents (also including phenoxbenzamine and clonidine) have been used despite lack of supportive data from clinical
studies. Other treatments that have been used without clear evidence of efficacy include topical agents such as dimethyl sulfoxide (DMSO) and lidocaine, thalidomide (doses ranging from 50 mg twice a week to 400 mg a day), calcitonin, and gabapentin (600 mg titrated up to 1,800 mg a day).

Only gold members can continue reading. Log In or Register to continue