Complex regional pain syndrome (CRPS), sometimes referred to by the hyponyms reflex sympathetic dystrophy (RSD) or reflex neurovascular dystrophy (RND) (type 1) or causalgia (type 2), is a rare and severe form of neuroinflammatory and dysautonomic disorder causing chronic pain, neurovascular, and neuropathic symptoms. Although it can vary widely, the classic presentation occurs when severe pain from a physical trauma or neurotropic viral infection outlasts the expected recovery time, and may subsequently spread to uninjured areas. The symptoms of types 1 and 2 are the same, except type 2 is associated with nerve injury.

Usually starting in a single limb, CRPS often first manifests as pain, swelling, limited range of motion or partial paralysis, or changes to the skin and bones. It may initially affect one limb and then spread throughout the body; 35% of affected individuals report symptoms throughout the body. Two types are thought to exist: CRPS type 1 (previously referred to as reflex sympathetic dystrophy) and CRPS type 2 (previously referred to as causalgia). It is possible to have both types.

Amplified musculoskeletal pain syndrome, a condition that is similar to CRPS, primarily affects pediatric patients, falls under rheumatology and pediatrics, and is generally considered a subset of CRPS type 1.

Classification The classification system in use by the International Association for the Study of Pain (IASP) divides CRPS into two types based on the presence or absence of measurable nerve pathophysiology. +International Association for the Study of Pain ClassificationTypeClinical findingsSynonymsType ICRPS without evidence of neuropathology in the affected limb. This accounts for about 90% of CRPS.reflex sympathetic dystrophy, RSD, Sudeck's atrophyType IICRPS with evidence of neuropathology in the affected limb.causalgia

Signs and symptoms

Clinical features of CRPS have been found to be inflammation resulting from the release of certain pro-inflammatory chemical signals from surrounding nerve cells; hypersensitization of pain receptors; dysfunction of local vasoconstriction and vasodilation; and maladaptive neuroplasticity.

The signs and symptoms of CRPS usually manifest near the injury site. The most common symptoms are extreme pain, including burning, stabbing, grinding, and throbbing. The pain is out of proportion to the severity of the initial injury. Moving or touching the limb is disproportionately painful (allodynia). Other findings are aspects of disuse including swelling, stiffness (limited range of motion), and disuse related changes to the skin (temperature, color, sweating, texture) and bones (disuse osteoporosis).

A prior concept of CRPS having three stages is no longer in wide use. The trend is now to consider distinct sub-types of CRPS.

Cause Complex regional pain syndrome is uncommon, and its cause is unclear. CRPS typically develops after an injury, surgery, heart attack, or stroke. Investigators estimate that 2–5% of those with peripheral nerve injury, and 13–70% of those with hemiplegia (paralysis of one side of the body) will develop CRPS. In addition, some studies have indicated that tobacco smoking is more often present in CRPS patients. Smoking may be involved in its pathophysiology among tobacco users by enhancing sympathetic activity, vasoconstriction, or other unknown neurotransmitter-related mechanism. This hypothesis was based on a small 1993 retrospective analysis of 53 patients with RSD, which showed that 68% of patients were smokers, compared to only 37% of the control population. The results are preliminary and are limited by their retrospective nature. A minority (7%) of individuals with CRPS in a single limb go on to develop it in another.

Pathophysiology

Inflammation and alteration of pain perception in the central nervous system are proposed to play important roles. The persistent pain and the perception of nonpainful stimuli as painful are thought to be caused by inflammatory molecules (IL-1, IL-2, TNF-alpha) and neuropeptides (substance P) released from peripheral nerves. This release may be caused by inappropriate cross-talk between sensory and motor fibers at the affected site. CRPS is not a psychological illness, yet pain can cause psychological problems, such as anxiety and depression. Often, impaired social and occupational function occur.

Complex regional pain syndrome is a multifactorial disorder with clinical features of neurogenic inflammation (inflammation mediated by nerve cells), nociceptive sensitisation (which causes extreme sensitivity or allodynia), vasomotor dysfunction (blood flow problems which cause swelling and discolouration) and maladaptive neuroplasticity (where the brain changes and adapts with constant pain signals); CRPS is the result of an "aberrant [inappropriate] response to tissue injury". The "underlying neuronal matrix" of CRPS is seen to involve cognitive and motor as well as nociceptive processing; pinprick stimulation of a CRPS affected limb was painful (mechanical hyperalgesia) and showed a "significantly increased activation" of not just the S1 cortex (contralateral), S2 (bilateral) areas, and insula (bilateral) but also the associative-somatosensory cortices (contralateral), frontal cortices, and parts of the anterior cingulate cortex. In contrast to previous thoughts reflected in the name RSD, it appears that there is reduced sympathetic nervous system outflow, at least in the affected region (although there may be sympatho-afferent coupling). Wind-up (the increased sensation of pain with time) and central nervous system (CNS) sensitization are key neurologic processes that appear to be involved in the induction and maintenance of CRPS.

Compelling evidence shows that the N-methyl-D-aspartate (NMDA) receptor has significant involvement in the CNS sensitization process. It is also hypothesized that elevated CNS glutamate levels promote wind-up and CNS sensitization. In addition, there exists experimental evidence demonstrating the presence of NMDA receptors in peripheral nerves. Because immunological functions can modulate CNS physiology, a variety of immune processes have also been hypothesized to contribute to the initial development and maintenance of peripheral and central sensitization. Furthermore, trauma-related cytokine release, exaggerated neurogenic inflammation, sympathetic afferent coupling, adrenoreceptor pathology, glial cell activation, cortical reorganisation, and oxidative damage (e.g., by free radicals) are all factors which have been implicated in the pathophysiology of CRPS. In addition, autoantibodies are present in a wide number of CRPS patients and IgG has been recognized as one of the causes of hypersensitivity that stimulates A and C nociceptors, attributing to the inflammation.

The mechanisms leading to reduced bone mineral density (up to overt osteoporosis) are still unknown. Potential explanations include a dysbalance of the activities of sympathetic and parasympathetic autonomic nervous system and mild secondary hyperparathyroidism. However, the trigger of secondary hyperparathyroidism has not yet been identified.

In summary, the pathophysiology of complex regional pain syndrome has not yet been defined; CRPS, with its variable manifestations, could be the result of multiple pathophysiological processes.

Diagnosis Diagnosis is primarily based on clinical findings. The original diagnostic criteria for CRPS adopted by the International Association for the Study of Pain (IASP) in 1994 have now been superseded in both clinical practice and research by the "Budapest Criteria" which were created in 2003 and have been found to be more sensitive and specific. They have since been adopted by the IASP. The criteria require there to be pain as well as a history and clinical evidence of sensory, vasomotor, sudomotor, and motor or trophic changes. It is also stated that it is a diagnosis of exclusion.

To make a clinical diagnosis all four of the following criteria must be met:

Continuing pain, which is disproportionate to any inciting event Must report at least one symptom in three of the four following categories. Sensory: Reports of hyperesthesia Vasomotor: Reports of temperature asymmetry or skin color changes or skin color asymmetry Sudomotor/Edema: Reports of edema or sweating changes or sweating asymmetry Motor/Trophic: Reports of decreased range of motion or motor dysfunction (weakness, tremor, dystonia) or trophic changes (hair, nail, skin) Must display at least one sign at time of evaluation in two or more of the following categories Sensory: Evidence of hyperalgesia (to pinprick) or allodynia (to light touch or temperature sensation or deep somatic pressure or joint movement) Vasomotor: Evidence of temperature asymmetry (>) or skin color changes or asymmetry Sudomotor/Edema: Evidence of edema or sweating changes or sweating asymmetry Motor/Trophic: Evidence of decreased range of motion or motor dysfunction (weakness, tremor, dystonia) or trophic changes (hair, nail, skin) There is no other diagnosis that better explains the signs and symptoms

Diagnostic adjuncts No specific test is available for CRPS, which is diagnosed primarily through observation of the symptoms. However, thermography, sweat testing, X-rays, electrodiagnostics, and sympathetic blocks can be used to build up a picture of the disorder. Diagnosis is complicated by the fact that some patients improve without treatment. A delay in diagnosis or treatment for this syndrome can result in severe physical and psychological problems. Early recognition and prompt treatment provide the greatest opportunity for recovery.

Thermography Presently, established empirical evidence suggests against thermography's efficacy as a reliable tool for diagnosing CRPS. Although CRPS may, in some cases, lead to measurably altered blood flow throughout an affected region, many other factors can also contribute to an altered thermographic reading, including the patient's smoking habits, use of certain skin lotions, recent physical activity, and prior history of trauma to the region. Also, not all patients diagnosed with CRPS demonstrate such "vasomotor instability"—particularly those in the later stages of the disease. Thus, thermography alone cannot be used as conclusive evidence for—or against—a diagnosis of CRPS and must be interpreted in light of the patient's larger medical history and prior diagnostic studies.