Case of the Month #9: Persistent Left Arm Pain by Dr Richard Wassall

CRPS is a chronic and debilitating pain condition that arises after trauma to a limb, usually occurring in the upper limbs more than lower limbs. CRPS has an incidence of 5.5 to 26.2 per 100,000 person-years and a 4:1 female:male ratio. However, CRPS may also occur spontaneously in up to 10% of cases, and it has also been reported in other body areas including face and trunk. It is characterized by disproportionate pain and variable combinations of signs and symptoms as described in the Budapest Criteria.

Here, our patient presented early in the course of the disease, which resulted in prompt management and referral to appropriate specialist care. Prognosis and outcomes of CRPS are difficult to predict, with resolution rates ranging between 74% in the 1st year to 36% after 6 years. She was lucky in that her symptoms improved quickly and started to resolve early with appropriate support from the local pain service. Return-to-work rates vary within the literature, with some studies describing a permanent inability-to-work rate of around 31% and a partial inability-to-work rate of 28%. Our patient had returned to part-time employment with the presumed intention of slowly increasing her exposure to full-time work guided by her symptoms and her ability to manage them.

The precise etiology of this enigmatic condition remains unexplained, but is liked to be multifactorial with both peripheral and central aberrant neuroinflammatory mechanisms playing a role in initiation, development, and maintenance of symptoms. Observational evidence of dysregulated inflammation, vasomotor dysfunction, peripheral nerve and cerebral cortical changes, have been proposed to cause the symptoms of CRPS, but may occur to a different extent depending on individual susceptibility, thereby accounting for the clinical heterogeneity of the condition. Familial forms of CRPS have implicated a genetic predisposition towards developing selective versions of the condition, and ongoing work is looking at various genetic loci involved e.g. HLA-DQ8 in both CRPS with and CRPS without dystonia, and HLA-B62 only with CRPS with dystonia.

In the initial ‘acute’ inflammatory phase of CRPS, the classic signs of an inflammatory response may occur, but inflammatory markers (CRP, WCC, ESR etc.) are frequently normal, or may only be mildly elevated. Local proinflammatory cytokines (IL-6 and TNF-alpha) have been implicated in this response, and may be involved in peripheral nociceptor activation and sensitization. Some studies have found increased levels of the neuropeptides substance-P and calcitonin gene-related peptide, which have been shown to cause plasma protein extravasation and neurogenic dilatation of arterioles, leading to the concept of neurogenically-mediated inflammation in CRPS. This dysregulation of the inflammatory process has led to the idea of deep-tissue microvascular ischaemia–reperfusion injury, which sensitizes the peripheral and central nervous system and maintains the ongoing inflammation.

Over time, as CRPS becomes chronic, cortical reorganization and changes in pain processing may also occur. Functional Magnetic Resonance Imaging studies show various changes in activity, including reduction in thalamic blood flow and functional cortical reorganization in the primary somatosensory cortex (S1), but changes in other areas including motor areas, prefrontal cortices, and insular cortices have been implicated. Some studies have suggested astrocyte over-activity may also play a role in chronicity of symptoms. Other central changes occur at the spinal and supraspinal levels linked to clinical signs of CRPS, whereby spinal nociceptive neurones become hyper-responsive to peripheral input, and increase nociceptive signalling to the cortex even in the absence of such input. In some cases, a shift from inhibition towards facilitation of nociceptive input was also found in the pain modulation pathways.

 In the peripheral nervous system, decreases in epidermal nerve fibres, and reduction in sweat gland and vascular innervation in patients with CRPS has been detected. Whether this small-fibre neuropathy is a result of CRPS rather than a cause of this disease remains to be elucidated. These features point to both a central and peripheral aetiology which is likely additive and synergistic. Most studies show no association between the onset of CRPS and psychological factors e.g. depression and anxiety, however these may develop as a result of CRPS, and may be extended to other neuropsychological changes including neglect, distorted image and representation, and asomatognosia (loss of ownership of the limb).