Complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD), describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion.[1] Usually starting in a limb, it manifests as extreme pain, swelling, limited range of motion, and changes to the skin and bones. It may initially affect one limb and then spread throughout the body; 35% of affected people report symptoms throughout their whole bodies.[2] Two subtypes exist. Having both types is possible.[3]
Complex regional pain syndrome
Other names
Reflex sympathetic dystrophy (RSD), causalgia, reflex neurovascular dystrophy (RND)
Leg of an individual (left) with complext regional pain syndrome following tibial bone fracture.
Specialty
Neurology, Psychiatry, Physical Therapy
#Classification
The classification system currently in use by the International Association for the Study of Pain (IASP) divides CRPS into two types. It is recognised that people may exhibit both types of CRPS.
International Association for the Study of Pain Classification
Type Clinical findings Synonyms
Type I CRPS without evidence of nerve damage in the affected limb. Secondary to injury\trauma. This accounts for about 90% of CRPS. RSD, Sudeck’s atrophy
Type II CRPS with evidence of nerve damage in the affected limb. Causalgia
#Signs and Symptoms
Clinical features of CRPS have been found to be inflammation resulting from the release of certain proinflammatory chemical signals from the nerves, sensitized nerve receptors that send pain signals to the brain, dysfunction of the local blood vessels’ ability to constrict and dilate appropriately, and maladaptive neuroplasticity.[4]
The signs and symptoms of CRPS usually manifest near the injury site. The most common symptoms are extreme pain, including burning, stabbing, grinding, and throbbing. The pain is out of proportion to the severity of the initial injury.[5] Moving or touching the limb is often intolerable. With diagnosis of either CRPS types I or II, patients may develop burning pain and allodynia (pain to non-painfull stimuli). Both syndromes are also characterized by autonomic dysfunction, which presents with localized temperature changes, cyanosis, and/or edema.
The patient may also experience localized swelling; extreme sensitivity to nonpainful stimuli such as wind, water, noise, and vibrations; extreme sensitivity to touch (by themselves, other people, and even their clothing or bedding/blankets); abnormally increased sweating (or absent sweating); changes in skin temperature (alternating between sweaty and cold); changes in skin colouring (from white and mottled to bright red or reddish violet); changes in skin texture (waxy, shiny, thin, tight skin); softening and thinning of bones; joint tenderness or stiffness; changes in nails and hair (delayed or increased growth, brittle nails/hair that easily break); muscle spasms; muscle loss (atrophy); tremors; dystonia; allodynia; hyperalgesia; and decreased/restricted ability and painful movement of affected body part.[5] Drop attacks (falls), almost fainting, and fainting spells are infrequently reported, as are visual problems.
The symptoms of CRPS vary in severity and duration. One version of the McGill pain index, a scale for rating pain, ranks CRPS highest, above childbirth, amputation and cancer.[6] Since CRPS is a systemic problem, potentially any organ can be affected. Symptoms may change over time, and they can vary from person to person. Symptoms can even change numerous times in a single day.
The pain of CRPS is continuous, but varies in severity. It can be heightened by emotional or physical stress.[7]
Previously, CRPS was considered to have three stages however more recent studies suggest people affected by CRPS do not progress through sequential stages and the staging system is no longer in wide use.[8] Growing evidence instead points towards distinct sub-types of CRPS.[8]
#Cause
Inflammation and alteration of pain perception in the central nervous system are proposed to play important roles. The persistent pain and the perception of nonpainful stimuli as painful are thought to be caused by inflammatory molecules (IL-1, IL2, TNF-alpha) and neuropeptides (substance P) released from peripheral nerves. This release may be caused by inappropriate cross-talk between sensory and motor fibers at the affected site.[14] CRPS is not a psychological illness, yet pain can cause psychological problems, such as anxiety and depression. Often, impaired social and occupational function occur.[15]
Complex regional pain syndrome is a multifactorial disorder with clinical features of neurogenic inflammation (swelling in the central nervous system), nociceptive sensitisation (which causes extreme sensitivity or allodynia), vasomotor dysfunction (blood flow problems which cause swelling and discolouration) and maladaptive neuroplasticity (where the brain changes and adapts with constant pain signals); CRPS is the result of an “aberrant [inappropriate] response to tissue injury”.[4] The “underlying neuronal matrix” of CRPS is seen to involve cognitive and motor as well as nociceptive processing; pinprick stimulation of a CRPS affected limb was painful (mechanical hyperalgesia) and showed a “significantly increased activation” of not just the S1 cortex (contralateral), S2 (bilateral) areas, and insula (bilateral) but also the associative-somatosensory cortices (contralateral), frontal cortices, and parts of the anterior cingulate cortex.[16] In contrast to previous thoughts reflected in the name RSD, it appears that there is reduced sympathetic nervous system outflow, at least in the affected region (although there may be sympatho-afferent coupling).[17] Wind-up (the increased sensation of pain with time)[18] and central nervous system (CNS) sensitization are key neurologic processes that appear to be involved in the induction and maintenance of CRPS.[19]
Compelling evidence shows that the N-methyl-D-aspartate (NMDA) receptor has significant involvement in the CNS sensitization process.[20] It is also hypothesized that elevated CNS glutamate levels promote wind-up and CNS sensitization.[19] In addition, there exists experimental evidence demonstrating the presence of NMDA receptors in peripheral nerves.[21] Because immunological functions can modulate CNS physiology, a variety of immune processes have also been hypothesized to contribute to the initial development and maintenance of peripheral and central sensitization.[22][23] Furthermore, trauma related cytokine release, exaggerated neurogenic inflammation, sympathetic afferent coupling, adrenoreceptor pathology, glial cell activation, cortical reorganisation,[24] and oxidative damage (e.g., by free radicals) are all factors which have been implicated in the pathophysiology of CRPS.
The mechanisms leading to reduced bone mineral density (up to overt osteoporosis) are still unknown. Potential explanations include a dysbalance of the activities of sympathetic and parasympathetic autonomic nervous system [26][27][28] and mild secondary hyperparathyroidism.[29] However, the trigger of secondary hyperparathyroidms has not yet been identified.
In summary, the pathophysiology of complex regional pain syndrome has not yet been defined; CRPS, with its variable manifestations, could be the result of multiple pathophysiological processes.[17]
Diagnosis
Diagnosis is primarily based on clinical findings. The original diagnostic criteria for CRPS adopted by the International Association for the Study of Pain (IASP) in 1994 have now been superseded in both clinical practice and research by the ‘‘Budapest Criteria” which were created in 2003 and have been found to be more sensitive and specific.[30] They have since been adopted by the IASP. The criteria require there to be pain as well as a history and clinical evidence of Sensory, Vasomotor, Sudomotor and Motor or Trophic changes. It is also stated that it is a diagnosis of exclusion.
To make a clinical diagnosis all four of the following criteria must be met:
Continuing pain, which is disproportionate to any inciting event
Must report at least one symptom in three of the four following categories…
Sensory: Reports of hyperesthesia and/or allodynia
Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
Sudomotor/Edema: Reports of edema and/or sweating changes and/or sweating asymmetry
Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
Must display at least one sign at time of evaluation in two or more of the following categories
Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)
Vasomotor: Evidence of temperature asymmetry (>1 °C) and/or skin color changes and/or asymmetry
Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry
Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
There is no other diagnosis that better explains the signs and symptoms
#Diagnostic #adjunctive
No specific test is available for CRPS, which is diagnosed primarily through observation of the symptoms. However, thermography, sweat testing, X-rays, electrodiagnostics, and sympathetic blocks can be used to build up a picture of the disorder. Diagnosis is complicated by the fact that some patients improve without treatment. A delay in diagnosis and/or treatment for this syndrome can result in severe physical and psychological problems. Early recognition and prompt treatment provide the greatest opportunity for recovery.
#Thermography
Presently, established empirical evidence suggests against thermography’s efficacy as a reliable tool for diagnosing CRPS. Although CRPS may, in some cases, lead to measurably altered blood flow throughout an affected region, many other factors can also contribute to an altered thermographic reading, including the patient’s smoking habits, use of certain skin lotions, recent physical activity, and prior history of trauma to the region. Also, not all patients diagnosed with CRPS demonstrate such “vasomotor instability” — particularly those in the later stages of the disease.[31] Thus, thermography alone cannot be used as conclusive evidence for—or against—a diagnosis of CRPS and must be interpreted in light of the patient’s larger medical history and prior diagnostic studies.[32]
In order to minimise the confounding influence of external factors, patients undergoing infrared thermographic testing must conform to special restrictions regarding the use of certain vasoconstrictors (namely, nicotine and caffeine), skin lotions, physical therapy, and other diagnostic procedures in the days prior to testing. Patients may also be required to discontinue certain pain medications and sympathetic blockers. After a patient arrives at a thermographic laboratory, he or she is allowed to reach thermal equilibrium in a 16–20 °C, draft-free, steady-state room wearing a loose fitting cotton hospital gown for approximately twenty minutes. A technician then takes infrared images of both the patient’s affected and unaffected limbs, as well as reference images of other parts of the patient’s body, including his or her face, upper back, and lower back. After capturing a set of baseline images, some labs further require the patient to undergo cold-water autonomic-functional-stress-testing to evaluate the function of his or her autonomic nervous system’s peripheral vasoconstrictor reflex. This is performed by placing a patient’s unaffected limb in a cold water bath (approximately 20 °C) for five minutes while collecting images. In a normal, intact, functioning autonomic nervous system, a patient’s affected extremity will become colder. Conversely, warming of an affected extremity may indicate a disruption of the body’s normal thermoregulatory vasoconstrictor function, which may sometimes indicate underlying CRPS.[33]
#Radiography
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Scintigraphy, plain radiographs, and magnetic resonance imaging may all be useful diagnostically. Patchy osteoporosis (post-traumatic osteoporosis), which may be due to disuse of the affected extremity, can be detected through X-ray imagery as early as two weeks after the onset of CRPS. A bone scan of the affected limb may detect these changes even sooner and can almost confirm the disease. Bone densitometry can also be used to detect changes in bone mineral density. It can also be used to monitor the results of treatment since bone densitometry parameters improve with treatment.
#Ultrasound
Ultrasound-based osteodensitometry (ultrasonometry) may be potential future radiation-free technique to identify reduced bone mineral density in CRPS.[29] Additionally, this method promises to quantify the bone architecture in the periphery of affected limbs.[29] This method is still under experimental development.
#Electrodiagnostic #testing
Electromyography (EMG) and nerve conduction studies (NCS) are important ancillary tests in CRPS because they are among the most reliable methods of detecting nerve injury. They can be used as one of the primary methods to distinguish between CRPS types I and II, which differ based on evidence of actual nerve damage. EMG and NCS are also among the best tests for ruling in or out alternative diagnoses. CRPS is a “diagnosis of exclusion”, which requires that no other diagnosis can explain the patient’s symptoms. This is very important to emphasise because patients otherwise can be given a wrong diagnosis of CRPS when they actually have a treatable condition that better accounts for their symptoms. An example is severe carpal tunnel syndrome (CTS), which can often present in a very similar way to CRPS. Unlike CRPS, CTS can often be corrected with surgery to alleviate the pain and avoid permanent nerve damage and malformation.[34]
Both EMG and NCS involve some measure of discomfort. EMG involves the use of a tiny needle inserted into specific muscles to test the associated muscle and nerve function. Both EMG and NCS involve very mild shocks that in normal patients are comparable to a rubber band snapping on the skin. Although these tests can be very useful in CRPS, thorough informed consent must be obtained prior to the procedure, particularly in patients experiencing severe allodynia. In spite of the utility of the test, these patients may wish to decline the procedure to avoid discomfort.
#Classification
Type I, formerly known as reflex sympathetic dystrophy (RSD), Sudeck’s atrophy, or algoneurodystrophy, does not exhibit demonstrable nerve lesions. As the vast majority of patients diagnosed with CRPS have this type, it is most commonly referred to in medical literature as type I.
Type II, formerly known as causalgia, has evidence of obvious nerve damage. Despite evidence of nerve injury, the cause or the mechanisms of CRPS type II are as unknown, as the mechanisms of type I.
Patients are frequently classified into two groups based upon temperature: “warm” or “hot” CRPS in one group and “cold” CRPS in the other group. The majority of patients (about 70%) have the “hot” type, which is said to be an acute form of CRPS.[35] Cold CRPS is said to be indicative of a more chronic CRPS and is associated with poorer McGill Pain Questionnaire scores, increased central nervous system involvement, and a higher prevalence of dystonia.[35] Prognosis is not favourable for cold CRPS patients; longitudinal studies suggest these patients have “poorer clinical pain outcomes and show persistent signs of central sensitisation correlating with disease progression”.[36]
#Prevention
Vitamin C may be useful in prevention of the syndrome following fracture of the forearm or foot and ankle.[37]
#Treatment
Treatment of CRPS often involves a number of modalities.[38]
#Therapy
Physical and occupational therapy have low-quality evidence to support their use.[39] Physical therapy interventions may include transcutaneous electrical nerve stimulation, progressive weight bearing, graded tactile desensitization, massage, and contrast bath therapy. Both pain and body perception disturbance in CRPS have been shown to decrease after a structured multidisciplinary rehabilitation programme.[40]
#Mirror #box #therapy
Mirror box therapy uses a mirror box, or a stand-alone mirror, to create a reflection of the normal limb such that the patient thinks they are looking at the affected limb. Movement of this reflected normal limb is then performed so that it looks to the patient as though they are performing movement with the affected limb. Mirror box therapy appears to be beneficial at least in early CRPS.[39] However, beneficial effects of mirror therapy in the long term is still unproven.[41]
Graded motor imagery Edit
Graded motor imagery appears to be useful for people with CRPS-1.[42] Graded motor imagery is a sequential process that consists of (a) laterality reconstruction, (b) motor imagery, and © mirror therapy.[38][43]
#Medications
Tentative evidence supports the use of bisphosphonates, calcitonin, and ketamine.[39] Nerve blocks with guanethidine appear to be harmful.[39] Evidence for sympathetic nerve blocks generally is insufficient to support their use.[44] Intramuscular botulinum injections may benefit people with symptoms localized to one extremity.[45]
#Ketamine
Ketamine, a dissociative anesthetic, appears promising as a treatment for CRPS.[46] It may be used in low doses if other treatments have not worked.[47][48] No benefit on either function or depression, however, has been seen.[48]
#Bisphosphonate #treatment
As of 2013, low-quality evidence supports the use of bisphosphonates.[39] A 2009 review found “very limited data reviewed showed that bisphosphonates have the potential to reduce pain associated with bone loss in patients with CRPS I, however, at present evidence is not sufficient to recommend their use in practice”.[49]
#Opioids
Opioids such as oxycodone, morphine, hydrocodone, and fentanyl are effective in reducing pain. These drugs must be prescribed and monitored under close supervision of a physician, as these drugs are addictive.[50] Thus far, no long-term studies of oral opioid use in treating neuropathic pain, including CRPS, have been performed. Even without solid scientific support, though, most experts believe that opioids should be given as part of a comprehensive pain treatment program for CRPS. Opioids should be prescribed immediately if other medications do not provide sufficient analgesia.[51]
#Surgery
Spinal cord stimulators Edit
Spinal cord stimulator appears to be an effective therapy in the management of patients with CRPS type I (level A evidence) and type II (level D evidence).[52] While they improve pain and quality of life, evidence is unclear regarding effects on mental health and general functioning.[53]
#Sympathectomy
Surgical, chemical, or radiofrequency sympathectomy — interruption of the affected portion of the sympathetic nervous system — can be used as a last resort in patients with impending tissue loss, edema, recurrent infection, or ischemic necrosis.[54] However, little evidence supports these permanent interventions to alter the pain symptoms of the affected patients, and in addition to the normal risks of surgery, such as bleeding and infection, sympathectomy has several specific risks, such as adverse changes in how nerves function.
#Amputation
No randomized study in medical literature has studied the response with amputation of patients who have failed the above-mentioned therapies and who continue to be miserable. Nonetheless, on average, about half of the patients will have resolution of their pain, while half will develop phantom limb pain and/or pain at the amputation site. As in any other chronic pain syndrome, the brain likely becomes chronically stimulated with pain, and late amputation may not work as well as it might be expected. In a survey of 15 patients with CRPS type 1, 11 responded that their lives were better after amputation.[55] Since this is the ultimate treatment of a painful extremity, it should be left as a last resort.
#Prognosis
Good progress can be made in treating CRPS if treatment is begun early, ideally within three months of the first symptoms. If treatment is delayed, however, the disorder can quickly spread to the entire limb, and changes in bone, nerve, and muscle may become irreversible. The prognosis is not always good. Johns Hopkins Hospital reports that 77% of sufferers have spreads from the original site or flares in other parts of the body. The limb, or limbs, can experience muscle atrophy, loss of use, and functionally useless parameters that require amputation. RSD/CRPS will not “burn itself out”, but if treated early, it is likely to be manageable. Once one is diagnosed with ite, should it go into remission, the likelihood of it resurfacing after going into remission is significant. Taking precautions and seeking immediate treatment upon any injury is important.[citation needed]
Epidemiology
CRPS can occur at any age, with the average age at diagnosis being 42.[10] It affects both men and women; however, CRPS is three times more frequent in females than males.[10]
CRPS affects both adults and children, and the number of reported CRPS cases among adolescents and young adults has been increasing,[56] with a recent observational study finding an incidence of 1.16/100,000 among children in Scotland.