Abstract
Complex regional pain syndrome (CRPS) is an enigmatic condition that is often difficult to treat. CRPS type I does not involve injury to a nerve, whereas type II does involve nerve injury. With both types, the patient presents with pain out of proportion to the original injury. The pain can spread in a limb well beyond the injury site. There can be hair, nail, and skin changes, and in severe cases may progress to pachydermia. The etiology of CRPS remains unknown; however, central cortical and subcortical sensory and motor remapping after injury may play a role. Treatment is a challenge. No medication has been shown significantly beneficial in controlled studies. Nerve blocks help in some cases. Return of active movement and weight bearing, along with decreased pain, are clearly the therapeutic goals. If appropriate, a trial of pain medications, nerve blocks, and physical modalities can be used as adjuvants along with physical or occupation therapy to manage symptoms. Mirror therapy may also be a useful active assist adjuvant and has shown promise in case reports and initial studies.
Keywords
Causalgia, central pain, chronic pain, chronic regional pain syndrome, mirror therapy, reflex sympathetic dystrophy
| Synonyms | |
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| ICD-10 Codes | |
| G90.511 | Complex regional pain syndrome I of right upper limb |
| G90.512 | Complex regional pain syndrome I of left upper limb |
| G90.519 | Complex regional pain syndrome I of unspecified upper limb |
| G90.521 | Complex regional pain syndrome I of right lower limb |
| G90.522 | Complex regional pain syndrome I of left lower limb |
| G90.529 | Complex regional pain syndrome I of unspecified lower limb |
| G90.59 | Complex regional pain syndrome I of other specified site |
| G56.40 | Causalgia of unspecified upper limb |
| G56.41 | Causalgia of right upper limb |
| G56.42 | Causalgia of left upper limb |
| G57.70 | Causalgia of unspecified lower limb |
| G57.71 | Causalgia of right lower limb |
| G57.72 | Causalgia of left lower limb |
| G58.9 | Mononeuropathy, unspecified |
Definition
Complex regional pain syndrome (CRPS) is a perplexing medical condition that begins when someone 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. It was renamed CRPS with two classifications: CRPS I with no major nerve injury and CRPS II for an apparent 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. The new name, interestingly, is less specific than the former name, expressing the current lack of a full understanding of the disease. It is theorized 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. This hypothesis has led to new and potentially useful treatments.
CRPS is relatively rare. Even with fracture, the most common inciting event, only 1% of patients develop CRPS. The incidence has been estimated to be up to 26 per 100 000 person-years. 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. In the pediatric population, the incidence of CRPS increases just before puberty.
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 of the central nervous system has been demonstrated with functional magnetic resonance imaging, single-photon emission computed tomography, electroencephalography, and transcranial magnetic stimulation mapping. Neuroplasticity of both the cortical somatosensory and motor 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, and it is important to document an injury, including whether there is an apparent injury to a nerve. The injury can come in a variety of forms, whether traumatic (e.g., crush injury, gunshot wound, burn, or protracted labor ) or nontraumatic (e.g., leprosy ). 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 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, 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.
There are three stages that occur with CRPS, and although it does not always follow a stepwise progression, these stages are useful descriptively. 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. 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 find it useful to classify CRPS as reversible (i.e., absence of pachydermic skin changes) or irreversible (i.e., presence 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; by the sixth month, all patients will exhibit varying degrees of depression, sleep disturbance, and anxiety.
Physical Examination
Inspect the skin 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. 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, 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. 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.
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. Patients may stop or severely limit use of their dominant upper extremity. 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. 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
There is no “gold standard” for diagnosis of CRPS, and it is a diagnosis of exclusion. Several sets of diagnostic criteria exist, and none have been shown to be superior. 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. IASP criteria are notably limited by poor inter-rater reliability and a specificity of only 36%. They have been revised as the Budapest criteria, which boast an increased specificity. 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.
Workup should focus on excluding other diagnoses. Frequently ordered tests include routine blood tests to screen for infection and acute inflammation, plain radiographs to screen for fracture, and electrodiagnostics to screen for coexisting nerve injury and muscle fiber loss.
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. A meta-analysis supports the use of triple-phase bone scan for assessment owing to its high sensitivity and negative predictive value. Musculoskeletal ultrasonography is an additional diagnostic modality being considered.
Cellulitis
Lymphedema
Occult or stress fracture
Acute synovitis
Septic arthritis
Septic tenosynovitis
Scleroderma
Plexitis, peripheral neuropathy
Postherpetic neuralgia
Peripheral vascular disease, arterial insufficiency
Deep venous thrombosis, phlebitis
Vasculitis
Treatment
Initial
A series of studies have suggested that a 50-day regimen of daily vitamin C of at least 500 mg, started immediately after extremity trauma or surgery, may prevent the development of CRPS. Although there is not universal consensus regarding this recommendation, it has been adopted into the American Academy of Orthopaedic Surgeons clinical guideline.
When prevention is ineffective, aggressive management of CRPS early in the course of disease may minimize long-term impairment. Pharmacotherapy, physical and/or occupational therapy, interventional pain procedures, and neuromodulation are common management options.
Anti-Inflammatory Medications
Inflammation is implicated at least in the early development of CRPS; nonsteroidal anti-inflammatory drugs are thus often employed as first-line agents. There is no definitive evidence supporting this practice. Topical formulations of dimethyl sulfoxide and N -acetylcysteine, both free radical scavengers thought to buffer the excess byproducts from inflammatory processes, are viable options to consider. Three randomized controlled trials (RCTs) found topical dimethyl sulfoxide 50% and N -acetylcysteine formulations somewhat effective at reducing pain and improving function in CRPS type I. Corticosteroids have also been used to manage inflammation with mixed success, with existing RCTs often suggesting that a short course of oral prednisone may improve inflammatory symptoms initially, but this often does not translate into functional gains.
Neuropathic Medications
There is good evidence demonstrating effectiveness of antidepressants and anticonvulsants in treating neuropathic pain, but their effect of CRPS remains poorly investigated. Two RCTs demonstrated some efficacy of gabapentin, yet no statistical significance was found in another study. The sedating side effects of both medication classes can provide the added benefit of treating sleep disturbance. In contrast, clonidine does not appear to be effective in CPRS management.
Opioids and N -Methyl- d -Aspartate Receptor Antagonists
Opioids may be useful in the acute stages of CRPS for control of pain, but this is controversial, especially with regard for addiction potential. Methadone may be considered for opioid-tolerant patients with severe neuropathic pain because of its N -methyl- d -aspartate (NMDA) receptor antagonist activity, which attenuates pain transmission through dorsal horn cells to the central nervous system.
Intravenous and 10% topical formulations of ketamine, a noncompetitive NMDA receptor antagonist, have been shown to weakly improve pain. However, intravenous administration of ketamine warrants close monitoring, given a risk of psychedelic crisis, and repeated administrations have been associated with acute transaminitis. Memantine is another noncompetitive NMDA receptor antagonist; its effectiveness when it is used alone has to be validated.
Bisphosphonates
Focal demineralization is a notable radiographic feature of CRPS, with a small contribution from disuse. Bisphosphonates are used to treat pathologic bone metabolism. A handful of RCTs have suggested that both oral and intravenous bisphosphonate formulations can improve pain in the acute inflammatory phase. More research is necessary to determine the optimum formulation, dosage, and duration.
Novel Medications
A handful of novel medications have been studied in recent years. These studies are small and report only short-term outcomes, but they represent the continued effort of the medical community to find a better pharmacologic agent to treat CRPS. Tadalafil, a phosphodiesterase inhibitor aimed at reversal of the vasoconstrictive effect of CRPS, is one such medication under investigation and may provide pain reduction for patients with cold CRPS in the lower limbs. Intravenous immune globulin may improve pain for selected patient populations ; a multi-centered, placebo-controlled RCT is currently underway to ascertain its effects. Two case series suggest that maintenance plasma exchange may be helpful for a subset of chronic CRPS patients.
Many agents have proved ineffective, including lenalidomide and infliximab. Intravenous magnesium is now yielding mixed results in the last of two RCTs. For more details on additional medications that have been examined—including baclofen, lidocaine, and intranasal calcitonin—refer to the systematic review by Van Zundert et al.
Rehabilitation
Physical and Occupational Therapy
Physical and occupational therapies may be effective at improving pain and functional level. Relative to occupational therapy, physical therapy may provide quicker pain reduction at a lower cost. Studies are generally unable to detect greater benefit with varying the frequency or programs of therapy. The focus of physical and occupational therapy should be encouraging and improving active movement, weight bearing, and ambulation. Physical modalities, as long as otherwise not contraindicated, should be utilized as adjuvants to assist in improving active movement.
Qigong may provide long-term anxiety relief for chronic, refractory CRPS.
Mirror Therapy
Mirror therapy was first devised as a therapeutic tool to relieve pain in amputees from a poorly mobile or spasmodic phantom limb. In mirror therapy, a patient moves both limbs—the affected limb as best as possible—while watching the reflection of the good limb ( Fig. 100.1 ). Visual feedback from the reflection of the good limb—which looks like the affected limb moving normally—feeds into and improves the motor control loop of the affected limb, ideally improving movement of the affected limb. RCTs, case reports, and a systematic review have since affirmed the benefit of mirror therapy in CRPS.
