The most significant way to improve care of patients with complex regional pain syndrome is with an early diagnosis.
By Gary W. Jay, MD
Complex regional pain syndrome (CRPS) is a heterogeneous group of disorders that generally develop after trauma to soft tissue but also may develop after visceral diseases or nerve lesions, or rarely without an obvious antecedent event. This debilitating neurologic syndrome is characterized by pain and hypersensitivity, vasomotor skin changes, and functional impairment. Structural changes in both the deep and superficial tissues may occur.
The precise cause of the syndrome is not known, and treatments are not curative. However, emerging research is helping to further understanding of the pathogenesis and treatment of this challenging syndrome.
CRPS is grouped into 2 categories (CRPS type I and CRPS type II) based on the absence or presence, respectively, of peripheral nerve damage. The International Association for the Study of Pain (IASP) defines CRPS type I as “a syndrome that usually develops after an initiating noxious event, is not limited to the distribution of a single peripheral nerve, and is apparently disproportionate to the inciting event. It is associated at some point with evidence of edema, changes in skin blood flow, abnormal sudomotor activity in the region of the pain, or allodynia or hyperalgesia.”1 CRPS type II is characterized by clinical signs of peripheral nerve injury, such as abnormalities found on nerve conduction study.2
Signs and Symptoms
CRPS is a spectrum disorder with clinical features varying in intensity and clinical presentation. The symptoms and diagnostic features of CRPS types I and II are identical. They include severe pain or uncomfortable sensations, as well as limb swelling, hair growth changes (most typically hair falling out, as well as possible development of coarser, darker hair and/or rapid hair growth), nail changes (faster growth, distorted shape), as well as muscle atrophy, increased sweating, and skin changes (thin and shiny, or skin lesions).3 Symptoms may be acute or last for many years.
In addition, patients may experience a spreading of symptoms to other parts of the body—most commonly in a contralateral or ipsilateral pattern. Diagonal spread is rare but also may occur.4Spread of symptoms typically occurs spontaneously without a secondary trauma, except in the case of diagonal spread, which generally occurs in the context of a new trauma and is more common in patients with a younger age at onset of CRPS and a more severely affected phenotype.4 Although the cause of spreading CRPS symptoms is not clear, researchers have speculated that CRPS may spread by spinally or cortically mediated mechanisms.4
A recent study examining the clinical characteristics of patients with CRPS found that approximately 73% of CRPS patients were female, and the mean age at onset of symptoms was 43 years.5The investigators also found a greater predominance of left-handedness (21.8% vs 10% in the general population) and multiple limb involvement (13%, 83% of whom had contiguous spread). The median time from symptom onset to diagnosis was 6 months, but ranged up to 129 months.
Warm and Cold Subtypes
Bruehl et al recently provided evidence to support the concept of warm and cold subtypes of CRPS in an international, multicenter study.6 Their evaluation of the signs and symptoms of CRPS in 152 patients revealed a warm CRPS patient cluster characterized by a warm, red, edematous, and sweaty extremity, and a cold CRPS patient cluster characterized by a cold, blue, and less edematous extremity.
Median pain duration was significantly shorter in the warm subtype than in the cold subtype (4.7 vs 20 months; P < 0.001), but pain intensity was comparable.6 A measure of inflammation was significantly elevated in the warm subtype (P < 0.001), but this measure decreased significantly the first year after injury (P < 0.001). The investigators suggested that inflammatory mechanisms may contribute most prominently to the acute phase of the warm subtype but diminish over time.
Pain catastrophizing, depression, and anxiety are commonly found in patients with CRPS and are linked with poorer outcomes.7,8 Notably, patients are at high risk for suicidal ideation (74%), underscoring the need for psychiatric evaluation and early intervention for psychiatric disorders in the overall management of CRPS.9 (see Patient Advocacy for Complex Regional Pain Syndrome.)
Pathophysiology of CRPS
The origins of the disease remain largely unclear. CRPS most likely is developed and maintained by both the central and peripheral nervous system. Possible contributors to CRPS include:
- Ischemic reperfusion injury or oxidative stress10-13
- Peripheral and central sensitization14-18
- Altered sympathetic nervous system function or sympatho-afferent coupling19-23
- Nerve injury24-26
- Neurogenic inflammation and autoimmune dysfunction, including activated glial cells27-31
- Brain plasticity32-35
- Genetic and psychological factors/disuse36-40
The Role of Glial Cells
Over the past decade, research on CRPS has focused on the role of glial cell activation in the perpetuation of CRPS. Increased glial cell activation has been demonstrated in patients with CRPS.30,31In addition, data from animal studies supports the hypothesis that limb fracture triggers afferent C-fiber substance P release, which signals chronic neuroglial activation. That glial activation, in turn, may contribute to the ongoing central nociceptive sensitization in CRPS.41 Evidence suggests that microglial activation triggers proinflammatory responses—including release of cytokines—that leads to neuronal hyperexcitability, neurotoxicity, and chronic inflammation.42
This research has led to investigation of pharmacotherapies to block glial cell activation in CRPS, including use of low-dose naltrexone and minocycline.
Brain Imaging Findings
Brain imaging research had vastly improved our understanding of CRPS and has demonstrated that CRPS is associated with abnormal brain system morphology. These morphologic changes result in dysregulation of pain processing in motor, sensory, affective pain, and autonomic systems.
For example, a 2014 study by Barad et al illustrated that patients with CRPS have a decreased volume of gray matter in pain-related affect regions in the brain including the dorsal insula, left orbitofrontal cortex, and several areas of the cingulate cortex.32Patients also had a greater volume of gray matter in the bilateral dorsal putamen and right hypothalamus.
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