Aetiology
The vast majority of patients develop CRPS as a consequence of trauma, including soft-tissue injuries, sprains, surgeries, and fractures. Immobilisation also plays a significant role.
Mild type 1 CRPS may follow 30% to 40% of fractures and surgical trauma; severe and chronic type 1 CRPS occurs with up to 4% of fractures.[7][8][9] There is a relationship between the severity of the injury and the risk of developing persistent pain. There are rare reported cases following visceral illness. Type 2 CRPS has been reported to occur with approximately 4% of peripheral nerve injuries.[10]
Pathophysiology
The pathophysiology of CRPS is unknown but is likely to be multifactorial.[11]
Mixed peripheral nerves contain small nociceptive nerve fibres (A delta and C fibres) that are pain-sensing. Dysfunction of these nerve fibres can result in reduced pain thresholds, increased responsiveness to peripheral stimuli (peripheral sensitisation), and central nervous system changes that amplify and extend symptoms (central sensitisation). Central sensitisation results in increased responsiveness to ordinarily innocuous mechanical stimuli (mechanical allodynia) and spread of pain to non-involved areas (primary and/or secondary hyperalgesia).[12] Although, by definition, type 1 CRPS has no identifiable nerve injury, small-fibre abnormalities in A delta and C fibres have been detected in biopsies from patients with type 1 CRPS.[13][14][15] This is distinct from type 2 CRPS, when the nerve injury occurs to a defined nerve. However, the clinical utility of distinguishing between type 1 and type 2 CRPS remains unclear.[16]
Autonomic nerve dysfunction, both peripheral and central, has long been thought to underlie vasomotor, sudomotor, and trophic changes that can vary over hours or days. In 80% of patients, skin temperature is increased with erythema and oedema in the first 6 months, decreasing thereafter with bluish discoloration and thinning of the skin.[17]
Some of these features may be secondary to neurogenic inflammation. Nociceptor activation releases neuropeptides (e.g., calcitonin gene-related peptide, substance P, and pro-inflammatory cytokines such as tumour necrosis factor-alpha [TNF-alpha]) in the periphery. This induces neurogenic inflammation and consequent vasodilation, protein extravasation, and oedema.[17][18][19][20] One meta-analysis concluded that CRPS is associated with a pro-inflammatory state in blood, blister fluid, and spinal fluid, and that inflammatory profiles differ between acute and chronic CRPS states.[21] The immune response differs in acute and chronic CRPS,[21] with increased mast cell accumulation and activation of epidermal keratinocytes and increased TNF-alpha and interleukin-6 (IL-6) expression in acute CRPS, whereas the reverse occurs in chronic CRPS.[22]
It has been hypothesised that underlying neuroinflammation, at least in some cases of CRPS, is a unique regional autoimmune response to the presence of neoantigens, initiated or activated by trauma.[23] Several lines of experimental evidence support the presence of autoimmunity, with roles for B cells, mast cells, keratinocytes, IgM and IgG antibodies, transforming growth factor, IL-6, nerve growth factor, and histamines.[24][25] In both type 1 and type 2 CRPS there is evidence for the presence of serum autoantibodies against cell surface antigens in autonomic neurons, but the exact epitope has not been isolated. Whether this is an epiphenomenon or has pathogenic significance is uncertain.[26]
Other central nervous system adaptive changes occur; these may explain motor findings, hyperreflexia, cutaneous sympathetic dysfunction, and the therapeutic potential of motor cortex stimulation.[27][28][29][30] The motor cortex has been shown to be involved in the pathophysiology of chronic pain. There is evidence of defective intracortical disinhibition and hyperactivity of thalamic neurons in chronic neuropathic pain states.[30][31]
Classification
CRPS is defined as continuing pain disproportionate to any inciting event. The classification of CRPS by the International Association for the Study of Pain (IASP) in 1994 was subsequently updated by the Budapest criteria in 2004 and the Valencia adaptation to the Budapest criteria in 2019.[1][2][3]
Confirmed CRPS based on diagnostic criteria:
Type 1 (CRPS-I): CRPS in the absence of an identifiable nerve lesion
Type 2 (CRPS-II): CRPS in the presence of an identifiable nerve lesion
CRPS with remission of some features: for patients previously documented as having fully met CRPS criteria (either type 1 or type 2) but who currently display CRPS features insufficient to fully meet the diagnostic criteria
CRPS-NOS (not otherwise specified): for patients who have never met the CRPS criteria: they display some but not all features of CRPS required for formal diagnosis, but no other diagnosis better explains the features.
Budapest diagnostic criteria[1][3]
CRPS is defined as continuing pain disproportionate to any inciting event. A patient must have at least one symptom in three of the four following categories.[1]
Sensory: hyperaesthesia and/or allodynia.
Vasomotor: temperature asymmetry and/or skin colour changes and/or skin colour asymmetry.
Sudomotor/oedema: oedema and/or sweating changes and/or sweating asymmetry.
Motor/trophic: decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin).
At least one sign must be present at the time of evaluation in two or more of the following categories.[1]
Sensory: hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement).
Vasomotor: temperature asymmetry and/or skin colour changes and/or asymmetry.
Sudomotor/oedema: oedema and/or sweating changes and/or sweating asymmetry.
Motor/trophic: decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin).
No other diagnosis can explain the signs and symptoms.[1]
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