A. Nervous system insult. The initial insult, including local tissue injury, pain, and immobilization, is thought to cause functional and structural alterations at peripheral, spinal, and even cortical levels of the nervous system, resulting in spontaneous pain and exaggerated painful responses to mildly noxious or non-noxious stimuli. Changes at the spinal level include a decrease in descending inhibitory influences, hyperexcitability, increase in size of receptive fields of neurons, and reorganization of pain reflexes, including those involving sympathetic neurons. An alteration of a wide range of dynamic neurons has been proposed as an important occurrence, resulting in their signaling pain in response to ordinarily non-noxious stimuli. The decrease in normal sensory input resulting from the decreased activity of the affected region "opens the gate" to ongoing pain and leads to further neural reorganization.
In the peripheral nervous system, nociceptors begin to generate ectopic or exaggerated discharges. These may result from microscopic injury and alterations in the milieu, including edema, decreased nutrient flow, and release of products by activated sensory neurons themselves (e.g., substance P).
The sympathetic nervous system, which is normally linked to pain by spinal and more central reflexes, assumes a more prominent role in pain generation and becomes less able to regulate vascular tone, sweating, and other functions normally. One component of sympathetically mediated pain is the development in nociceptors of a-adrenergic receptors and synaptic connections with sympathetic neurons, so that they become inappropriately activated by sympathetic neuronal activity and circulating catecholamines.
B. Sympathetic dysfunction. Sympathetic function, including sudomotor and vasomotor activity, may be both increased and decreased abnormally (i.e., the key abnormality is instability and dysregulation). Periods of sympathetic hypofunction may lead to receptor hypersensitivity. This is why, in most patients, the affected region may at different times be warm and red (hypervasular), blue and cold (hypoperfused), or mottled. It should be noted that even in areas of hypervascularity nutrient flow will often be diminished (because of dysregulation of microvasculature and arteriovenous anastomoses), which contributes to pain and weakness. These changes explain both the effectiveness of treatments designed to decrease sympathetic nervous activity and the variability of the response.
C. Edema occurs when venous outflow is compromised either mechanically or in response to the products of sympathetic or sensory neurons (e.g., prostaglandins, substance P). Edema itself can cause pain through nerve compression, interference with blood flow and diffusion of nutrients, and interference with motion. All of these in turn can further increase edema and lead to dystrophic changes.
The synergistic effects of substance P and prostaglandins with abnormal blood flow patterns cause the rapid development of osteopenia. Atrophic changes result from the above abnormalities and disuse.
D. Movement disorders result from the effects of sympathetic hyperactivity and of neuropeptides released by nociceptors on motor neurons in the spinal cord and preganglionic sympathetic nerves. These, in turn, affect muscle spindles and muscle itself and nociceptor function in the affected region. Tremor is the movement abnormality most tightly linked to sympathetic activity. Changes at the cortical level may also play a role, particularly in neglect.
E. Mechanical derangements. The injury triggering RSD or the changes resulting from RSD can lead to "mechanical derangements" and secondary nerve injuries (e.g., compression and neuromas); these cause pain and further perpetuate the disorder.
A major and still unanswered question is why RSD develops in a particular person—in other words, what is the diathesis? Psychiatric components have been suggested but have never been convincingly demonstrated. It has been suggested that sympathetic reactivity as evidenced by a personal history of vasomotor instability, blushing or blanching, palmar perspiration in response to emotions, or a family history of Raynaud's syndrome may be a marker of susceptibility, but this remains to be firmly established.
V. Diagnosis. The diagnosis is clinical and based primarily on the development of the symptoms and signs described above in an appropriate temporal relation to an inciting event. The time required for symptoms to develop ranges from a day or two to 2 weeks or longer. In the early phase, the excessive pain may be attributed to the injury, whereas in the delayed presentation, the original injury may have been forgotten, especially if minor. Because the early signs and symptoms are vague and nonspecific, the clinician must have a high index of suspicion for RSD in the setting of conditions associated with it.
There are no diagnostic tests specific for RSD. Levels of acute-phase reactants are abnormal only if they are secondary to an associated illness. Hence, they may alert the clinician to consider alternative diagnoses. Radiographs and technetium bone scans are the modalities most commonly used in routine clinical practice. Increasing attention is being given to the incorporation of more sophisticated tests of blood flow and sympathetic function.
Most series emphasize the frequency with which diagnosis is delayed. The earlier the treatment is initiated, the better the response, because neural changes and osteopenia may take a while to reverse and RSD is perpetuated by the vicious cycle of pain and immobilization. There is some uniformity in the marked decrease in response to treatment after RSD has been present for a year or even 6 months.
A. Differential diagnosis includes the large number of conditions that in themselves cause pain, immobility, and swelling with or without inflammation. These include injuries (crush wounds, fractures, stress fractures, osteonecrosis); infections of both bone and soft tissue, which, like RSD, may result from injuries; thromboangiitis obliterans; Raynaud's syndrome; and inflammatory disorders, including crystal-induced and other arthritides. Pain and swelling may of course result from an injury per se, but their duration and severity and the associated vasomotor and sudomotor changes help in the differentiation. Thoracic outlet syndrome and cervical or thoracic spine disorders must be considered. It has been suggested that the former, particularly if associated with prominent subclavian stenosis, may be associated with true RSD. RSD may also be confused with scleroderma in cases that initially present with skin changes late in stages 2 or 3.
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