Evaluation and Treatment of Complex Regional Pain Syndrome

Afferent Mechanisms

Some of the symptoms of CRPS are similar to those of inflammation, such as pain, redness, warmth, and swelling. Sudeck suggested more than 100 years ago that CRPS could be a form of bone inflammation, but this idea could not be confirmed because CRPS is not associated with fever, increased blood sedimentation rate, increased C-reactive protein (CRP), and leukocytosis.

However, over the past 20 years, several studies have shown that inflammation is an important mechanism in the development and maintenance of CRPS. Increased levels of two neuropeptides, C-gene related peptide and substance-P, have been demonstrated in the serum of CRPS patients.

Levels of the pro-inflammatory cytokines, interleukin-6 (IL-6), and tumor necrosis factor (TNF)-α, measured in artificial blisters on the skin of CRPS patients, were found to be elevated in the affected extremity. TNF-α and IL-6 levels in skin biopsies from fracture patients with and without CRPS were higher in patients with CRPS. Serum levels of soluble TNF receptors, and the pro-inflammatory cytokines TNF-α, IL-1, and IL-8 are increased in patients with early CRPS. In contrast, the levels of anti-infla­mmatory cytokines such as IL- 4, IL-10, and transforming growth factor β-1 are reduced.

Artificial blisters on the skin of CRPS patients have also been found to contain more tryptase in the affected extremity. Tryptase is a marker of mast cell activity. Therefore it seems likely that mast cells are involved in the release of pro-inflammatory cytokines in CRPS.

The involvement of T lymphocytes in CRPS has recently been demonstrated in a study in which levels of the soluble interleukin two receptor (sIL-2R) were higher in serum from CRPS patients. The level of sIl-2R is a biomarker of inflammatory activity. However, it is important to realize that it is not a disease-specific biomarker; sIL-2R may also be increased in other syndromes. It is a specific measure of inflammatory activity. Signs and symptoms remain the cornerstone for the diagnosis of CRPS.

In patients with CRPS, signs of hypoxia, such as increased lactate levels, muscle acidosis, and specific histopathologic features, have been found in local tissue. A decrease in the capillary oxygenation of the skin was observed with micro-light-guided spectroscopy.

In other studies, an imbalance between the vasodilating nitric oxide (NO) and the vasoconstricting endothelin-1 (ET-1) has been shown, in artificial blisters on the skin of patients with cold CRPS, the NO level is lower, and the ET-1 level is higher in the affected extremity. This is probably a direct consequence of persistent inflammation.

Skin biopsies showed an increase in α receptors. It was previously believed to be because of an autonomic nervous system disorder. Recent research has also shown a direct influence of persistent inflammation on the increase in α receptors. In the affected extremities of CRPS-1 patients, histopathologic examination of skin biopsies revealed a loss of C and Aδ fibers and abnormal branching nerve endings. In one study, axonal density was found to be 29% lower in CRPS patients. This is probably the result of ongoing inflammation.

According to the IASP definition, CRPS-1 does not show nerve damage in classic neurophysiologic research. The fact that CRPS1 may have an unrecognized small fiber neuropathy makes the distinction between CRPS-1 and CRPS-2 somewhat artificial.

Efferent Mechanisms

Chronic stimulation of nociceptors can lead to central sensitization, pain, and sensory disturbances. Previously, these signs and symptoms have been termed neuropathic. Today, we use the term nociplastic pain, which is a pain that arises from altered nociception despite the absence of clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence of a disease or lesion of the somatosensory system causing pain.

The sensory disturbances in CRPS are related not only to the pathology at the affected site but also to disturbances at the spinal or supraspinal level. Changes in the central nervous system, central sensitization, and neuroplasticity can lead to hypersensitivity to normal stimuli (allodynia) and painful stimuli (hyperalgesia). The exact mechanisms have not yet been fully elucidated. The action of neurotransmitters on postsynaptic receptors for N-methyl-d-aspartate, aminomethylphosphonic acid (AMPA), and neurokinin-1 (NK1) are involved. CRPS is also referred to as sympathetic reflex dystrophy because of the signs and symptoms of autonomic dysfunction. In the acute phase of CRPS, both phasic and tonic sympathetic reflexes in the affected extremity are disturbed. Noradrenaline levels in the affected extremity are lower. Changes in the spinal cord or higher centers of the central nervous system are likely to play a role in the dysregulation of the autonomic nervous system. In the past, dysfunction of the sympathetic nervous system has been used to explain the increased blood flow in warm CRPS. With today’s knowledge, it makes more sense to relate this increased blood flow to inflammation. Cold CRPS was thought to be caused by an increase in α-adrenergic receptors because of the depletion of local catecholamines. As previously described, the upregulation of α-adrenergic receptors can also be explained by continuing inflammation. The motor system may also be affected. A decrease in the range of motion is common and cannot always be explained by pain alone but is also likely to be of spinal or supraspinal origin. Severe dystonia may occur, characterized by flexion of the fingers, wrist, elbow, and sometimes shoulder, and plantar flexion or extension of the foot. This is typical of a more chronic phase. Since dystonia responds to intrathecal administration of baclofen, spinal g-aminobutyric acid (GABA) receptors are likely to play a role in its development.

Central Mechanisms

Functional MRI has shown that in CRPS patients, a reorganization can occur in the cerebral cortex. Possibly altering blood flow to the thalamus plays a role, resulting in changes in activation patterns and sensory mapping.

It has been frequently suggested in the past that CRPS is an imaginary disease that typically occurs in women who somatize and have secondary gains because of chronic disabilities. In a systematic review of the literature, Beerthuizen et al. refuted this view and demonstrated that a link between psychological and/or psychiatric determinants and the development of CRPS could only be found in poorly conducted research and not in methodologically sound research. A potentially important explanation for this misconception is that CRPS is regularly used as an embarrassment diagnosis. Another reason is that the natural course of a chronic pain syndrome such as CRPS easily gives rise to anxiety, depression, and catastrophizing. Therefore patients with chronic CRPS can also develop such symptoms. The cause and effect should not be confused.

Certain experiences and/or behaviors can influence the course of CRPS. Extreme fear of pain can lead to kinesiophobia and disuse. Therefore immobilization of the affected extremity takes longer than necessary, the blood flow decreases, and the final result is increased rigidity and muscle atrophy. This was confirmed in a study in which the forearm of healthy volunteers was immobilized with a plaster splint. This immobilization has been shown to cause various symptoms of CRPS, such as temperature changes and changes in mechanical and thermal sensitivity. It is striking that the participants had no pain. The symptoms disappeared after the cast was removed. Several activation mobilization treatments have been developed for this mechanism that can play a role in CRPS, varying from regular physiotherapy to graded exposure.

Interactions Between the Different Mechanisms

CRPS appears to be the result of a complex cascade. The trigger is usually tissue or nerve damage. This leads to sterile inflammation, which is initially physiologic. For unclear reasons, this inflammation runs out of control and does not normally stop after healing. Continuing inflammation leads to spinal and supraspinal changes in sensory and motor skills. Continuing inflammation can also lead to endothelial dysfunction, an increase in α receptors, and small fiber neuropathy. In many patients, inflammatory symptoms are prominent in the early stages. Often, but not always, these symptoms disappear over time, and neuropathic/nociplastic, vasomotor, and/or motor dysregulation become more prominent. However, there are also patients in whom the affected extremity is cold from the start.

In this respect, patients with CRPS can be divided into subtypes, although this is difficult because there is a lot of overlap. Such a classification is relevant because it makes the treatment more mechanically oriented and better tailored to the individual patient. Bruehl distinguished several subtypes in a cluster analysis:

• a relatively limited syndrome in which vasomotor symptoms are prominent

• a relatively limited syndrome in which neuropathic/nociplastic pain and/or sensory disturbances are prominent

• a profuse CRPS syndrome in accordance with the classic description

An important question remains as to why some develop and others do not get CRPS and, even more remarkably, how someone who has experienced major trauma does not advance to the pain syndrome while others progress into a thunderous CRPS after minor trauma. The process is likely determined by a combination of intrinsic factors, such as genetic susceptibility or an autoimmune disease that is acquired or not, extrinsic factors such as the type of trauma and treatment, and environmental factors.

Medical History

The condition often develops distally in one extremity. The affected area was often more extensive than ​​the original damage. The complaints are characterized by a combination of pain, sensory, vasomotor, sudomotor, motor, and trophic symptoms. The pain is continuous.

The skin is hypersensitive to touch. Asymmetry can occur in temperature, color, edema, and/or sweating. Sometimes the range of motion is decreased, and sometimes there are motor impairments such as weakness, tremor, or dystonia. Changes in hair and/or nail growth may also occur. Often, the symptoms are not constant over time. CRPS can worsen with the exertion of the affected extremities.

The diagnosis of CRPS is based on these criteria. The criteria most commonly used today were originally initiated by Harden and Bruehl. These were later called the Budapest criteria. After acceptance by the IASP, they are referred to as the new IASP criteria for CRPS. (See Table 35.1 . )

Physical Examination

Vasomotor, sudomotor, and trophic signs may be present on inspection. There may be a difference in skin color, edema, hair, and nail growth between the affected and unaffected extremities. Sensory and vasomotor symptoms may be present on palpation. There may be allodynia, hyperalgesia, and skin temperature differences between the affected and contralateral extremities. Motor abnormalities such as loss of function, loss of strength, stiffness, and pain, involuntary movements, tremor, and dystonia may occur during motor function tests.

There are no specific clinical tests for the diagnosis of CRPS. Additional neurologic examination of sensitivity, strength, and reflexes did not reveal any other abnormalities besides the abnormalities previously mentioned.

Additional Research

Several additional studies are possible, but none are pathognomonic. Sometimes supplemental testing is necessary to rule out other diagnoses. Several methods have been developed to classify and quantify the clinical signs and symptoms of CRPS. These can be used in the context of research or to assess whether a patient meets the CRPS criteria. However, they have no additional value for clinical diagnosis. Examples are:

• infrared temperature measurements

Quantitative Sensory Tests

• Volumetry and finger diameter in edema of the extremities

Differential Diagnosis

Many symptoms that can occur with CRPS also occur under other conditions. Therefore CRPS has an extensive differential diagnosis (see Table 35.2 ). In addition to inflammation, neuropathic, myofascial pain syndromes, degenerative disorders, vascular disease, and psychogenic disorders can be distinguished.