Complex, which denotes the dynamic and varied nature of the clinical presentation, within a single person over time and among persons with seemingly similar disorders. It also includes the autonomic, cutaneous, motor, inflammatory, and dystrophic changes that distinguish this syndrome from other forms of neuropathic pain.

Regional, which describes the wider distribution of the clinical symptoms and findings beyond the area of the original lesion. This is considered a key characteristic of this syndrome. The distal part of a limb is usually affected, but occasionally it occurs in other parts of the body (e.g., the face, torso) and may spread to other body parts.

Pain, the hallmark of CRPS, is out of proportion to the initiating event. The designation refers to spontaneous burning pain and thermally or mechanically induced allodynia (i.e., pain from stimuli that are not normally painful).

• CRPS type 1 follows an inciting noxious event.

• Spontaneous pain or hyperalgesia/allodynia exists beyond the territory of a single peripheral nerve and is disproportionate to the initiating event.

• Edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain has developed since the initiating event.

• The diagnosis is excluded by the presence of conditions that otherwise would account for the degree of dysfunction and pain.

• CRPS type 2 is a syndrome that results specifically from a nerve injury; otherwise, it is similar in all other aspects to CRPS type 1. Spontaneous allodynia or pain occurs that is not necessarily limited to the region of the injured nerve.

• Since the original nerve injury, edema, temperature and skin blood flow changes, abnormal sudomotor activity, and motor dysfunction in the region of the pain have developed.

• The diagnosis is excluded by the presence of conditions that would otherwise account for the degree of dysfunction and pain.

Exaggerated Local Inflammatory Response Theory and Neurogenic Inflammation

Several authorities have suggested that CRPS can occur secondary to an exaggerated local inflammatory response to injury, resulting in disruption of the autoregulation of blood flow and in turn giving rise to the classic phases of CRPS.¹⁹ It has been suggested that some of the clinical features of CRPS in its early stage can be explained by an inflammatory process. This theory was originally proposed by Sudeck.²⁰ The painful affected limb is usually hot, red, swollen, and with reduced function, which are signs of inflammation. Studies have shown that inflammatory mediators (e.g., tumor necrosis factor-α, interleukin-6) are elevated in blister fluid and blood samples obtained from affected limbs.²¹ This theory is supported by the fact that corticosteroids are often successful in the treatment of patients with acute CRPS.²² The reported efficacy of low-dose intravenous immune globulins could be due to an anti-inflammatory effect.²³ Bisphosphonates, which have immune modulatory properties, were also effective in four small randomized controlled trials involving CRPS of less than 6 months in duration.¹⁹

Neurogenic inflammation has been implicated further on the basis of studies of calcitonin gene–related peptide, which was found to be elevated in the sera of CRPS patients.²¹ It has been suggested that a localized neurogenic inflammation may be involved in the production of vasodilatation, acute edema, and increased sweating. Neuropeptides released from sensory neurons cause skin reddening and swelling, which are seen in affected limbs. When C fibers in affected and to a lesser degree in unaffected limbs are experimentally activated, CRPS patients respond with much stronger neuropeptide-mediated skin reddening and swelling than control patients do.¹⁹

The importance of neuropeptides in the pathophysiologic process of CRPS is further underlined by the finding that CRPS is associated with angiotensin-converting enzyme inhibitor therapy.¹⁹ Angiotensin-converting enzyme metabolizes the neuropeptide substance P and bradykinin to inactive forms; thus angiotensin-converting enzyme inhibitors may lead to higher tissue levels of these neuropeptides. These findings have not yet been translated into clinical management of CRPS.

CRPS as a Sympathetically Mediated Syndrome

The role of the sympathetic nervous system in CRPS remains controversial. Evidence in favor of a role for this system is in part based on color, temperature, and sweating differences between CRPS-affected and unaffected limbs. These differences are thought to be mediated by sympathetic dysregulation. There is a low centrally mediated sympathetic outflow to cutaneous vasoconstrictors in an affected limb, which may produce a red and warm extremity.¹⁹ Local anesthetic application to the sympathetic ganglia (e.g., stellate or lumbar sympathetic block) can relieve pain for the short term in selected patients,^19,24 although repeated applications do not necessarily prolong the effect.²⁵ The sympathetically maintained pain can be reduced by sympathetic blockade, particularly in the early stage of CRPS, but this is rare in long-standing CRPS.²⁶

Evidence that does not support a primary role for the sympathetic system includes the finding that other vasomotor signs, such as bluish discoloration and cold temperature, may be due to supersensitivity or upregulation of receptive adrenal receptors rather than a dysregulation of the sympathetic outflow.¹⁹ The vasomotor and sudomotor signs often diminish with time. It has been suggested that the permanent cold temperature in some cases of late CRPS may be due to endothelial rather than sympathetic dysfunction.¹⁹ Hannington-Kiff ²⁷ noted that agents that deplete the limb autonomic nerve endings of norepinephrine (e.g., regional guanethidine) should therefore be effective; however, all four randomized controlled trials conducted to assess this therapy have been negative.¹⁹ Many clinicians using this method (i.e., intravenous regional sympathetic block) have demonstrated that it reduced pain in some patients,¹⁹ and one wonders whether this effect was the result of the application of a tourniquet. Intravenous regional sympathetic block may be more effective with saline than with guanethidine.¹⁹

CRPS as the Result of Limb Ischemia-Reperfusion Injury

Some investigators believe that CRPS type 1 is an abnormal inflammatory response to a deep tissue injury, producing a picture of a compartment syndrome with resultant oxygen free radical–induced microvascular dysfunction, further ischemia and inflammation, and nociceptor excitement.¹⁹ Coderre et al²⁸ reported in an animal model that transient application of limb ischemia produced a syndrome similar to CRPS. Koban et al²⁹ showed that there was some evidence for low oxygen tension in the superficial skin layers of affected limbs, potentially enhancing the idea that ischemia might also be present in deeper tissues. The use of vitamin C in preventing the development of CRPS after radius fracture has been thought to be due to the scavenging of free oxygen radicals.¹⁹ Groeneweg et al,³⁰ in a pilot study, showed that tadalafil (a phosphodiesterase inhibitor) reduced pain in some CRPS patients with cold limbs. This was thought to be secondary to its vasodilator property and may also explain the mechanism of sympathetic blocks in these patients.

Central sensitization is the physiologic manifestation of severe peripherally induced pain.³¹ It is the molecular process that corresponds to the observation that after a period of repeated or intense noxious or innocuous stimuli, the involved extremity or site of pain becomes painful and remains so even after the initial stimulation has subsided.¹⁹ This theory is thought to be important in most chronic pain.¹⁹ It is believed that N-methyl D-aspartate (NMDA) receptors may play an important role in central sensitization. In two randomized clinical trials, low-dose intravenous ketamine (an NMDA antagonist) dramatically reduced CRPS pain, which may indicate an important role for such central sensitization.¹⁹ Ketamine strongly reduced the average pain intensity for several weeks, independent of the duration of CRPS syndrome, but without improving function. One limitation of ketamine infusion is its potential for neurotoxicity.¹⁹ The current protocols of ketamine treatment are also cumbersome and expensive; they are given during a 5-day hospital in-patient stay or a consecutive 10–working day outpatient therapy. Intravenous magnesium therapy, which is similar to ketamine therapy, may reduce central sensitization.¹⁹

CRPS Secondary to Nerve Damage

Permanent dysfunction of small-diameter primary afferent nociceptor axons distal to a site of trauma is associated with CRPS. The similarity of CRPS to small fiber–predominant polyneuropathy stimulated the idea that regionally restricted small nerve fiber damage may occur in CRPS, rather than sympathetic dysfunction, and may be responsible for CRPS signs.¹⁹ Studies of CRPS amputated limbs and skin biopsy specimens showed small fiber loss.¹⁹ Therefore, it is postulated that CRPS type 1 syndrome may, in fact, represent a neuropathic pain syndrome.

CRPS as an Autoimmune Disorder

Goebel¹⁹ showed evidence for antineuronal autoantibodies in 30% of patients in one study of CRPS patients. In another study, Blaes et al³² demonstrated these antibodies in 90% of the study group. Both groups of investigators demonstrated that passive transfer of patient serum immunoglobulin G antibodies elicits abnormal motor functions and behavior in mice similar to that found in CRPS, suggesting a functional effect.¹⁹ Goebel also demonstrated, in a randomized clinical trial, that a single infusion of low-dose intravenous immune globulin effectively reduces pain in patients with long-standing CRPS. It has been postulated that if autoantibodies are involved, therapeutic strategies such as plasmapheresis or reverse vaccination may be beneficial.¹⁹

Cortical Reorganization Theory

Functional magnetic resonance imaging (MRI) studies during the last several years have shown that sensory representations of CRPS-affected limbs are altered, that the degree of this alteration corresponds to pain intensity, and that reduction in pain is associated with normalization.¹⁹ There are also changes in the motor cortex. CRPS patients often feel alienation toward their affected limb; the limb can feel strange and disfigured. Computer-based graded motor imagery, which consists of exercise to train the brain in better recognition of the affected limb, can decrease swelling and pain in some CRPS patients.¹⁹ Mirror therapy (advocated by McCabe; see later) for the treatment of CRPS requires that the patient hide the affected limb behind a mirror placed perpendicular to the body midline. When the patient looks into the mirror and performs bilateral synchronized gentle movement, the affected limb (in actuality the reflection of the unaffected limb in the mirror) appears and moves normally. This therapy has been shown to minimize both early and late pain in some patients with CRPS³³ and strongly suggests that signs such as swelling are, in part, under cortical control.

Genetic and Other Theories

A genetic association has been implicated in patients with CRPS. Most studies have examined HLA associations,¹⁹ but the data have not been robust. A few investigators have suggested that CRPS has a psychological origin.¹⁹ However, a systematic investigation did not confirm this association.³⁴

Stage 1, acute (0-3 months): Stage 1 is characterized by warmth, erythema, burning, edema, hyperalgesia, hyperhidrosis, and, after a few months, patchy osteoporosis. At this stage, a good result can be expected with Bier’s block or chemical sympathectomy, one that often lasts longer than the normal duration of the block. Spontaneous resolution may occur in this stage, and the clinical course is reversible.

Stage 2, dystrophic (3-6 months): Stage 2 is marked by a good response to sympathetic block; symptoms are present for a fixed interval, but spontaneous resolution is rare. Characteristics include coolness, mottling of the skin, cyanosis, brawny edema, dry brittle nails, continuous pain, and diffuse osteoporosis. A bone scan is positive, and changes in bone structure are observed on radiographs.

Stage 3, atrophic (≥6-12 months): In this most advanced stage, pain always extends beyond the area of injury and florid trophic changes occur, including atrophy of the skin and its appendages and fixed joint contractures. Radiographs show severe demineralization and ankylosis.

Pain is a necessary symptom for the diagnosis of CRPS. It is located in the affected extremity and is disproportionate to what would be expected from the initial event. It may be spontaneous or evoked and is usually reported as diffuse. It is not consistent with the distribution of a peripheral nerve, even if the initial injury involved such a nerve. This important feature distinguishes CRPS from pain of other causes and from more specific neuropathic pain disorders. The pain may be reported as burning, throbbing or aching, intermittent or continuous, and exacerbated by physical or emotional stresses. The patient often adopts a protective posture to protect the affected extremity.

Sympathetic dysfunction is reported as a sudomotor or vasomotor instability in the affected extremity compared with the unaffected extremity. This dysfunction may vary in severity from time to time, and the patient may report that the extremity is warm and red or cold and blue, purple, or mottled. Veldman et al³⁸ reported that 92% of patients had altered skin temperature. Sweating, particularly in the palms or soles, may be reported as increased, decreased, or unchanged. Normal sympathetic function may be present at certain times. Swelling may be reported at any stage of the syndrome and is typically peripheral. It may be intermit­tent or continuous and may be exacerbated by the dependent position of the extremity. There can also be pitting or brawny edema.

Trophic and Motor Changes

Trophic changes of the skin may be reported later in the course of the syndrome. The nails may be atrophic or hypertrophic. Hair growth and texture may be decreased or increased, and the skin may become atrophic. Motor dysfunction may include dystonia, tremor, and loss of strength of the affected muscle groups. Joint swelling and stiffness may also be reported, particularly of the digits.

Budapest Diagnostic Criteria

The Budapest diagnostic criteria were published to facilitate the clinical diagnosis³⁹ and were updated in 2007.^19,40 They are as follows:

Sensory impairment can include allodynia, mechanical or thermal hyperalgesia, hyperesthesia, or hypalgesia. These sensory impairments can be localized (glove-like) or generalized. Quantitative sensory testing to confirm the clinical findings of sensory abnormalities can be applied; however, this is not specific for patients with CRPS.⁴¹

Sudomotor Sympathetic Examination

Resting heat output may be estimated by skin impedance⁴²; by quinizarin or cobalt blue testing⁴³; or as part of the quantitative sudomotor axon reflex test,⁴⁴ which measures resting sweat output by hygrometry and changes evoked by iontophoresis of acetylcholine into the skin.⁴⁵ These tests are useful diagnostic tools for CRPS; however, they are difficult to conduct and are not generally recommended for the routine diagnosis of CRPS.^41,46

Vasomotor Examination

Simultaneous temperature measurements of both the affected and unaffected extremities are taken at corresponding anatomic sites. The temperature of the digit pads, palms and soles, and forearms and calves can be measured with non­contact thermometry or thermography. Serial measurements should be taken because peripheral temperatures vary widely under normal circumstances. Skin perfusion can be evaluated visually or by pulse oximetry.

Edema

Edema is judged clinically by comparing one extremity with the other because most volume displacement methods are cumbersome.

Trophic Changes

The skin, hair, and nails of the two sides are compared.

Motor Dysfunction

The presence of dystonia, tremor, and changes in strength can be measured. Objective measurements should be taken (e.g., apposition and opposition pinch strength, grip, and weight bearing on lower extremity).

Psychological Testing

Psychological testing has been used to rule out concomitant mental illness but has not been validated in CRPS.³⁴

Neurophysiologic Testing

The diagnosis of CRPS type 2 requires documentation of a peripheral nerve lesion. CRPS may also develop after central nervous system lesions (brain tumor or brain infarct); therefore, it is important to confirm or to exclude peripheral nerve or central nervous system lesions. Nerve conduction studies may show discrete abnormalities secondary to edema or peripheral vasoconstriction.⁴¹ Distinct abnormalities of more than 20% of normal values should be observed in CRPS type 2. Somatosensory evoked potentials after ulnar/median or tibial nerve stimulation testing can also be abnormal in patients with CRPS type 2, although they are usually normal in patients with CRPS type 1. Overall, these tests can be useful in the diagnosis of CRPS types 1 and 2, confirming peripheral nerve or central nerve system lesions. However, the findings are not specific.

Electromyography recordings are not frequently used in patients with CRPS because they are painful and may exaggerate the pain of CRPS.

Inflammatory Parameter Assessment

Neuroinflammatory mediators such as substance P, bradykinin, and calcitonin gene–related peptide are usually increased in patients with CRPS. Other systemic inflammatory markers (e.g., C-reactive protein, erythrocyte sedimentation rate, and leukocyte count) are not elevated.⁴⁷

Three-Phase Bone Scans

Three-phase bone scans have been used for the diagnosis of CRPS during the past 3 decades.^48,49 Accelerated blood flow into the diseased limb, combined with an increased diffuse activity during the blood pool phase and an increased periarticular uptake in the delayed static phase, is considered to be pathognomonic for CRPS (Fig. 85-2). In a meta-analysis of 24 studies analyzing imaging techniques for the diagnosis of CRPS type 1, Cappello et al⁵⁰ supported the use of the triple-phase bone scan to rule out CRPS type 1 owing to its greater sensitivity and higher negative predictive value compared with both MRI and plain film radiography.