Definition

Complex regional pain syndrome (CRPS) is a perplexing medical condition. CRPS begins when a patient has an injury—to a nerve, bone, soft tissue, or connective tissue. The injury heals as assessed by both clinical examination and imaging, yet the patient still has pain significantly out of proportion not only to the healed injury but at times even to the injury itself. In addition to pain, the patient can have hyperesthesia or allodynia at the site of the injury. Curiously, the temperature of the affected limb can be different from that of the other side, and there can be hair, nail, and skin changes. In some cases, these changes can spread beyond the injury site to the entire limb, and in the worst case, in addition to excruciating pain and hyperesthesia, the skin becomes pachydermic.

Before 1994, this bizarre disease and constellation of symptoms was known, among other names, as reflex sympathetic dystrophy. Despite this moniker, it was never proved that the sympathetic nervous system mediates all the components of the disease, nor was a peripheral reflex or feedback loop causing the disease found. In 1994, a conference was held to clarify the classification of the disease [1]. It was renamed CRPS with two classifications, CRPS II for apparent major nerve injury and CRPS I for no major nerve injury. The disease is complex, and it can often be regional rather than confined to a dermatome, myotome, or territory of a single peripheral nerve. Pain is the hallmark of the disease and, for a patient with history of an injury, the sine qua non of diagnosis. It is multifaceted.

The new name, interestingly, is less specific than the former name, expressing the current lack of a full understanding of the disease. More than a decade ago, one of us (V.S.R.) suggested that central remapping of sensory neurons in the cerebral cortex in response to a peripheral injury to the corresponding body area might be a root cause of pain and ultimately other problems in this condition [2]. This hypothesis has not only collected evidence since but led to new and potentially most useful treatments [3].

CRPS is relatively rare. Even with fracture, the most common inciting event, only 1% of patients develop CRPS [4]. The incidence has been estimated to be up to 26 per 100,000 person-years [5]. The incidence of CRPS type I is generally higher than that of CRPS type II. The lower extremity is more often affected than the upper extremity. Female sex, adult age, postmenopausal status, and smoking are all risk factors for its development [6]. In the pediatric population, the incidence of CRPS increases just before puberty [7].

The pathophysiologic mechanism of the disease is, again, poorly understood. There is emerging evidence that CRPS does not only affect the peripheral nervous system. Functional and structural reorganization [8] of the central nervous system has been demonstrated with functional magnetic resonance imaging [9], single-photon emission computed tomography, electroencephalography, and transcranial magnetic stimulation mapping. Neuroplasticity of both the cortical somatosensory [10] and motor [11] systems is implicated. Distorted sensory and motor mapping is hypothesized to promote spontaneous pain and neglect symptoms in CRPS.

Symptoms

CRPS is a clinical diagnosis. The diagnosis can be suggested by the history of present illness alone. An individual experiences an injury. The injury can come in a variety of forms, whether traumatic (e.g., crush injury, gunshot wound, burn, or protracted labor [12]) or nontraumatic (e.g., leprosy [13]). The “injury” can also be an otherwise uncomplicated surgery. While healing takes place, the individual develops pain variably progressive in intensity, area involvement, and duration. Patients with both CRPS type I and type II may report neuropathic pain that is often intense, constant, burning, and present even without stimulation or movement. Symptoms are not confined to a particular nerve or anatomic territory; CRPS can spread [14] to the contralateral limb and even progress to all four limbs. In addition to pain, motor complaints are common and include weakness, cramps, and stiffness. There may also be signs of neglect [15], or more subtly, some patients may refer to the affected limb in the third person (e.g., “it is not moving”). It is important to ask about abnormal sweating patterns, localized edema, and skin flushing as clues of autonomic dysfunction in the history.

Symptoms and signs of CRPS are historically grouped into three stages. Stage 1 consists of severe pain and inflammatory signs (e.g., pitting edema, rubor, increased hair and nail growth). Stage 2 is marked by more intense pain, brawny edema, pallor, ridged nails, and osteoporosis. Unyielding pain and irreversible skin and bone changes (e.g., dystrophy, contracture, and extensive osteoporosis) are the primary features of stage 3. Although CRPS does not always follow a stepwise progression, these stages are useful descriptively. Classifying the syndrome solely on the basis of the severity of pain (i.e., mild, moderate, and severe) may be appropriate to follow its clinical course over time. We also classify CRPS as irreversible (i.e., presence of pachydermic skin changes) or potentially fully reversible (i.e., absence of pachydermic skin changes).

Mood disturbance is common in the chronic stages of the illness. Patients often report anxiety as the disease progresses beyond the second month; and by the sixth month, all patients will exhibit varying degrees of depression, sleep disturbance, and anxiety [16].

Physical Examination

Begin the examination by inspecting for signs of injury at or near the affected site. The injury may have been long ago and only a scar remains. If possible, compare all findings with the contralateral side to identify subtle asymmetry. Look for evidence of autonomic disturbances that are manifested as localized edema, skin color changes, and abnormal sweating pattern; note that skin color is best observed under natural light. Late-stage CRPS is characterized by trophic changes, such as abnormal hair and nail growth, thin and shiny skin, and fibrosis. At rest, disuse atrophy is the most apparent motor disturbance, but spontaneous muscle fasciculation, tremor, and cramp in the supporting muscles of the limb may also be observed.

Proceed to gentle palpation of the affected area. Make note of marked temperature asymmetry. Studies have shown that a clinician can adequately identify temperature and limb circumference asymmetry without special instruments [17]. Nonetheless, an infrared thermometer or a surface-probe thermometer can give more precise measurements. A temperature difference of more than 1.1° C between the affected area and a nonaffected, homologous body part is significant [1], but clinicians should have a low index of suspicion for CRPS such that even a small temperature change may be clinically relevant. Next, estimate the extent of involvement by sensory disturbances, such as increased sensitivity (hyperesthesia), exaggerated pain response to a painful stimulus (hyperalgesia), pain to an innocuous stimulus (allodynia), and paradoxically in some patients, hypoesthesia [18]. Ascertain abnormal findings with repeated testing. The sensory examination includes tests for light touch, pinprick, temperature, vibration, and proprioception. Consider testing the forehead because sensory disturbances on the ipsilateral side have been described [19].

Have the patient actively range the affected joints. Make note of difficulty with initiation of motion and range of motion deficits, which in turn require passive range to assess for contracture. The clinician can then perform a thorough musculoskeletal and neurologic examination including strength, stability, and reflexes to assess for deficits, be they related or unrelated to the CRPS.

Functional Limitations

The most immediate effects are dysfunction in activities of daily living from disuse of the affected limb. Lower limb involvement results in gait impairment. Even properly treated patients may continue to experience disability and decreased quality of life in the long term [20]. Permanent disability may ensue if contracture develops over time. Chronic pain also leads to the well-known syndrome of deconditioning, sleep disturbance, anxiety, and depression. With inadequate treatment, quality of life can be severely affected, often with devastating social, recreational, financial, and vocational consequences.

Diagnostic Studies

Several sets of diagnostic criteria (e.g., Bruehl and Veldman) exist, and none has been shown to be superior [21]. The International Association for the Study of Pain (IASP) criteria are most widely referenced in the literature and made up of the following four components: (1) presence of an identifiable noxious event or cause of immobilization; (2) persistent pain, allodynia, or hyperalgesia, disproportionate to any inciting event; (3) edema, changes in skin blood flow, or abnormal sudomotor activity; and (4) exclusion of other diagnoses as the cause of these symptoms [1]. IASP criteria are notably limited by poor inter-rater reliability and a specificity of only 36% [22]. They were subsequently revised in 2003 and published in 2007 as the Budapest criteria, which boast an increased specificity [23]. The Budapest criteria replace the second and third components of IASP criteria with at least one symptom and one sign in three of the following four categories: sensory, vasomotor, sudomotor or edema, and motor or trophic changes.

There is no “gold standard” for diagnosis of CRPS. It is a diagnosis of exclusion. Electromyography and nerve conduction studies can help identify nerve injury, if there is clinical suspicion. Doppler flowmeter, vascular scintigraphy, and vital capillaroscopy evaluate for vasomotor changes. Quantitative sudomotor axon reflex testing measures sweat output after mild electrical stimulation.

Plain films are often normal early in the course. Demineralization may become evident by the second month. Magnetic resonance imaging demonstrates nonspecific marrow edema, soft tissue swelling, and joint effusion. Even bone scintigraphy, in which the most suggestive finding is increased periarticular activity in the affected limb, has variable sensitivity and specificity [24]. A recent meta-analysis supports the use of triple-phase bone scan for assessment owing to its high sensitivity and negative predictive value [25].