Abstract
Complex regional pain syndrome (CRPS) is a complex neuropathic pain syndrome. It is a challenging clinical entity, and the name for this illness as well as the classification system has evolved over time. Pain is the hallmark of this illness, particularly when disproportionate to what should be expected, along with atypical symptoms that may or may not include autonomic dysfunction. The disease course has been described as having an “acute” initial stage with progression to a “chronic” or “trophic” stage, although more recent data suggest that there may actually be three different subtypes of CRPS with different clinical features. Both a central and a peripheral sensitization component are believed to be involved in the pathophysiology of CRPS, although the exact mechanism is not well known. Clinical presentations for CRPS may vary from patient to patient, and characteristic signs and symptoms can be classified as sensory, vasomotor, sudomotor/edema, and motor/trophic. A thorough history and physical examination are critical to evaluate for findings that may correlate with diagnostic criteria. The burden of illness for patients with CRPS is significant and may require long-term medical treatment. Resolution may occur in some cases; complications of pain, limited range of motion, atrophy, contractures, and abnormal sensation may develop.
Keywords
Causalgia, Complex regional pain syndrome, Reflex sympathetic dystrophy, Sympathetic pain, CRPS
Introduction
Complex regional pain syndrome (CRPS) is a challenging neuropathic pain syndrome characterized by severe pain with atypical features. Continuing regional pain that is seemingly disproportionate to the usual course of illness/injury, in time or severity, is a key sign of this disease process. As a clinical entity it has been known by many names. They have evolved from terms such as “causalgia” and “reflex sympathetic dystrophy” (RSD) to the current nomenclature of CRPS type I and type II. Similarly, diagnostic criteria for this complex condition have evolved over time.
Claude Bernard is noted to have documented the first sympathetic pain syndrome in the 1800s, and “causalgia” was first described in American Civil War veterans by Silas Weir-Mitchell. Paul Sudeck described a pain syndrome known as “acute inflammatory bone atrophy” that could spread beyond the initial site of injury and was given the name “Sudeck atrophy.” In the 1940s the term “reflex sympathetic dystrophy” was used for a sympathetic pain syndrome and entered common clinical usage. RSD fell out of favor as a term, as dystrophy was seen in a small percentage of patients and sympathetic and autonomic changes were not consistently delineated as causative factors. Furthermore, the role of a “reflex” in the syndrome was not well identified. In 1994 the International Association for the Study of Pain (IASP) changed the terminology to CRPS type I and type II.
CRPS often involves a trauma, but it can occur spontaneously. The development of CRPS is not related to the severity of a trauma/injury. CRPS type I has been associated with an inciting event (often an injury such as a crush injury or soft tissue injury), whereas type II (similar to the entity previously called “causalgia”) has an association with a documented nerve injury, whether penetrating trauma or iatrogenic or surgical in nature.
Classically, syndromes mediated by the sympathetic nervous system had a presenting component of autonomic dysfunction (abnormalities in diaphoresis, perfusion, and trophic changes) and some degree of improvement with neural blockade of the sympathetic supply to the affected area. More recently, pain disproportionate to what should be expected of the injury is the hallmark of this illness, along with atypical symptoms that include disuse, hypersensitivity, sudomotor changes (edema, sweating), and vasomotor changes (skin color/temperature). The pain must not be better explained by another diagnosis, and it need not be restricted to a specific nerve territory or dermatome. CRPS symptoms may “spread” over time to other body regions. The variety of symptoms (sensory, motor, autonomic, trophic, and others) in patients with CRPS contributes to resistance to typical pharmacologic therapies for other similar/related neuropathic pain syndromes. A multimodal approach to clinical treatment is generally employed.
Although our understanding of CRPS continues to improve and evolve, deficiencies in the methodology of published studies have been a limiting factor. Evidence-based reviews of the CRPS literature have cited a need for more high-quality research.
Epidemiology and Demographics
CRPS is often, but not always, associated with a traumatic injury. It is more commonly associated with fractures, followed by sprain injuries and then elective surgery. There is no one particular injury that regularly or reliably leads to the development of CRPS and there is not a direct correlation with the severity of an injury and the onset of CRPS. The upper limb is more affected by CRPS than the lower limb. Data on the incidence are variable, ranging from 5.46 new cases per 100,000 persons per year to 26.2 new cases per 100,000 persons per year. Women are more affected than men. Peak incidence is 61–70 years old (possibly related to elderly patients having a greater fracture risk).
As a disease entity, CRPS has a relatively low prevalence; this and variable clinical presentations may contribute to limited epidemiologic data.
Regarding risk factors, immobilization may be the greatest risk factor and may explain the “shoulder-hand syndrome” that has been described after a stroke without a traumatic injury. Postmenopausal women have also been found to be at increased risk for CRPS type I. One literature review also concluded that female sex (postmenopausal females in particular), ankle intradislocations or intraarticular fractures, distal radius fractures, immobilization, and intense pain in the early phases after trauma may be risk factors for CRPS type I. CRPS more commonly occurs after a wrist fracture, with a reported incidence of 1%–37%.
Prior studies and recent literature reviews do not demonstrate an association of psychiatric conditions with CRPS 1.
Course/Prognosis
CRPS generally develops within 6 weeks after an inciting event. It has previously been described as having an initial acute stage (“warm” or “hot”) of up to 6 months and then a later “cold” stage. The acute stage, lasting less than 6 months, presents with a painful, red, warm, sweaty, and swollen affected limb with increased hair growth. Over time the chronic stage develops; the swelling resolves, the skin becomes thin and cold, and the nails become brittle and pitted with decreased hair growth (trophic changes). Muscle atrophy with contractures and fibrosis can occur.
A disease course that involves three distinct phases of CRPS has also been described. Again, an acute stage with pain and sensory abnormalities with allodynia, hyperalgesia, and vasomotor/sudomotor dysfunction has been postulated. This is followed by a dystrophic stage with persistent sensory and vasomotor symptoms and motor and trophic changes over the next 3–6 months and finally an atrophic stage , where there are progressive vasomotor, motor, and trophic changes but the pain and sensory abnormalities seem to decrease (“burn out”). More recently, these “phases” have not been validated clinically. Instead, more recent subgroup analysis has demonstrated that it is more likely that there are instead three different subtypes of CRPS: (1) a vasomotor-predominant, relatively limited syndrome, (2) a similarly limited syndrome with sensory abnormalities and pain predominating, and (3) a subtype that more closely resembles “classic” RSD. The second subtype may be a synonym for CRPS type II (“causalgia”), and the third subtype may have the greatest degree of trophic change and bone-density change despite having a shorter pain duration.
Overall the burden of illness with CRPS is large and can be quite limiting for patients. CRPS generally requires long-term intensive medical treatment with a significant negative impact on the quality of life. Prognostic factors are not well defined. Resolution does occur, and it is less probable to do so over time. Resolution rates of up to 74% during the first year and up to 36% within the first 6 years have been reported. Complications (other than pain and the associated sequelae) often include limited range of motion and/or contractures, and abnormal sensation.
Pathophysiology
The exact mechanism underlying CRPS as an illness is unknown, but the knowledge gap seems to be narrowing. The disease process seems to be elusive and complicated and likely multifactorial. A repeated hypothesis for this illness involves a central sensitization component and a peripheral sensitization component.
The inciting event, when present, provokes an acute stage reaction with a “classic” inflammatory response, but perhaps more importantly a “neurogenic” inflammatory response. Patients with CRPS have increased proinflammatory cytokines locally and systemically (including cerebrospinal fluid) that are responsible for localized edema, warmth, and erythema. The role of inflammation is supported by mechano-heat-insensitive C-fibers, which have been found to have a neurosecretory role, where the nociceptors actually release neuropeptides via an axon reflex. Substance P release may correlate with swelling/edema, and calcitonin-gene-related peptide can induce vasodilation. Serum markers of sedimentation rates, autoimmune antibody titers, and cell counts are generally normal.
Chronic activation of the afferent C-fibers from a noxious stimulus has been proposed as a mechanism for subsequent peripheral sensitization and reduction in the threshold for activation. It has been postulated that peripheral sensitization may be related to chronic neurogenic inflammation. Markers such as interleukin (IL)-6 and tumor necrosis factor α were elevated in the affected limb, and increased serum levels of substance P and IL-8 were also found in patients with CRPS.
The neurotransmitter N -methyl d -aspartate (NMDA) has been implicated as a factor in central sensitization. NMDA receptors may make afferent nerves more sensitive to transmitter release and thus may cause action potentials to be produced with lower levels of neurotransmitters, resulting in enhanced nociceptive transmission. In this theory, the NMDA receptors can change the plasticity of the neural tissues.
Central sensitization has also been shown in a study that demonstrated cortical somatosensory organizational changes in patients with CRPS ; these changes were reversible with resolution of symptoms. Functional MRI changes have demonstrated a difference in side-to-side cortical processing of mechanical stimuli. These maladaptive features are some of the functional and structural changes identified in CRPS. The presence of well-recognized features of the disease, including myoclonus/dystonia/tremor, malperceptions of one’s own limb, paresis/weakness, and diffuse, nondermatomal sensory loss, also support a central nervous system (CNS) component.
A study evaluating for “spread” of CRPS type I identified different patterns of spread (contiguous, independent/diffuse, and mirror imaging) and also postulated that localized pathology could be a likely explanation for contiguous spread. A CNS component (including aberrant CNS regulation of neurogenic inflammation) along with increased susceptibility was postulated to contribute to independent or mirror-image spread of the disease process.
CRPS is considered a type of autonomically mediated pain, which often has a sympathetic component to it, although CRPS can be sympathetically independent. CRPS with sympathetically mediated pain can be diagnosed by a positive response (pain relief) with sympathetic neural blockade. Autonomic symptoms (particularly the sudomotor changes in the affected body part, with initial warmth and edema and later cooling) are likely due to an inability of the vessels to constrict or dilate. Enhanced sympathetic activity may be a factor in the excitation of nociceptive fibers and development of pain; however, the association of sympathetic and afferent coupling is not well understood.
History and Physical Examination Findings
As the diagnosis of CRPS is largely based on clinical findings, a thorough history and physical examination is critical, specifically in terms of findings that may correlate with diagnostic criteria. Signs and symptoms in CRPS that are important on examination, particularly for diagnostic purposes, are classified as (1) sensory, (2) vasomotor, (3) sudomotor/edema, and (4) motor/trophic. History and physical examination should focus on an evaluation of these systems and help ensure that a key criterion to diagnose CRPS, the absence of a better explanation for symptoms, is met. In addition, the clinical presentation of CRPS is variable from patient to patient and a complete assessment is necessary to make a correct diagnosis (see Boxes 4.1 and 4.2 ).
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