Complex regional pain syndrome

Complex regional pain syndrome (CRPS) is any of several 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 types exist: reflex sympathetic dystrophy (RSD) and causalgia. Having both types is possible.[3]

Complex regional pain syndrome
Other namesalgodystrophy; hyponym: reflex sympathetic dystrophy (RSD); hyponym: causalgia; hyponym: reflex neurovascular dystrophy (RND)
Leg of an individual (left) with complex regional pain syndrome following tibial bone fracture.
SpecialtyNeurology, Psychiatry, Anesthesiology
TreatmentPhysical therapy (more effective with early diagnosis); medications (e.g. anti-seizure for nerve pain, opioids, muscle relaxers etc.); Sympathetic Nerve Blocks; ketamine infusions; lidocaine infusions; implanted opioid pump; in rare cases amputation
MedicationAnti-seizure medications for nerve pain (e.g. Gabapentin); muscle relaxers (e.g. Baclofen), opioids (may be administered orally, via patch, or implanted intrathecal pump); ketamine or lidocaine infusions

Classification

The classification system 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.[4]

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. reflex sympathetic dystrophy, RSD, Sudeck's atrophy
Type II CRPS with evidence of nerve damage in the affected limb. causalgia

Signs and symptoms
Severe CRPS of right arm
CRPS visible on hands and wrists

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.[5]

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.[6] Moving or touching the limb is often intolerable. With diagnosis of either CRPS types I or II, patients may develop burning pain and allodynia. Both syndromes are also characterized by autonomic dysfunction, which presents with temperature changes (usually localized, but can be global), 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 light clothing or bedding/blankets); abnormally increased sweating (or absent sweating); changes in skin temperature (alternating between overly warm 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.[6] Drop attacks (falls), almost fainting, and fainting spells are infrequently reported, as are visual problems.

The symptoms of CRPS vary in severity and duration. 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. The more dynamic symptoms, especially vascular aspects (edema, temperature) and location of pain, can change numerous times a day.[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

Complex regional pain syndrome is uncommon, and its cause is not clearly understood. CRPS typically develops after an injury, surgery, heart attack, or stroke.[6][9] Investigators estimate that 2–5% of those with peripheral nerve injury,[10] and 13-70% of those with hemiplegia (paralysis of one side of the body)[11] will develop CRPS. In addition, some studies have indicated that cigarette smoking was strikingly present in patients and is statistically linked to RSD. This may be involved in its pathology by enhancing sympathetic activity, vasoconstriction, or by some other unknown neurotransmitter-related mechanism. This hypothesis was based on a retrospective analysis of 53 patients with RSD, which showed that 68% of patients and only 37% of controls were smokers. The results are preliminary and are limited by their retrospective nature.[12] 7% of people who have CRPS in one limb later develop it in another limb.[13]

Pathophysiology

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".[5] 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.[25] In addition, autoantibodies are present in a wide number of CRPS patients and IgG has been recognized as one of the causes of hypersensitivity that stimulates A and C nociceptors, attributing to the inflammation.[26]

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[27][28][29] and mild secondary hyperparathyroidism.[30] However, the trigger of secondary hyperparathyroidism 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.[31] 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.[32]

To make a clinical diagnosis all four of the following criteria must be met:[33]

  1. Continuing pain, which is disproportionate to any inciting event
  2. Must report at least one symptom in three of the four following categories..
    • Sensory: Reports of hyperesthesia
    • 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)
  3. 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)
  4. There is no other diagnosis that better explains the signs and symptoms

Diagnostic adjuncts

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.[34] 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.[35]

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 their 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.[36]

Radiography

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.[30] Additionally, this method promises to quantify the bone architecture in the periphery of affected limbs.[30] 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.[37]

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.[38] 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.[38] 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".[39]

Prevention

Vitamin C may be useful in prevention of the syndrome following fracture of the forearm or foot and ankle.[40]

Treatment

Treatment of CRPS often involves a number of modalities.[41]

Therapy

Physical and occupational therapy have low-quality evidence to support their use.[42] Physical therapy interventions may include transcutaneous electrical nerve stimulation, progressive weight bearing, graded tactile desensitization, massage, and contrast bath therapy. In a retrospective cohort (unblinded, non-randomised and with intention-to-treat) of fifty patients diagnosed with CRPS, the subjective pain and body perception scores of patients decreased after engagement with a two-week multidisciplinary rehabilitation programme. The authors call for randomised controlled trials to probe the true value of multidisciplinary programs for CRPS patients.[43]

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.[42] However, beneficial effects of mirror therapy in the long term is still unproven.[44]

Graded motor imagery

Graded motor imagery appears to be useful for people with CRPS-1.[45] Graded motor imagery is a sequential process that consists of (a) laterality reconstruction, (b) motor imagery, and (c) mirror therapy.[41][46]

Transcutaneous Electrical Nerve Stimulation (TENS)

Transcutaneous Electrical Nerve Stimulation (TENS) is a therapy that uses low voltage electrical signals to provide pain relief through electrodes that are placed on the surface of the skin. Evidence supports its use in treating pain and edema associated with CRPS although it does not seem to increase functional ability in CRPS patients.[47]

Medications

Tentative evidence supports the use of bisphosphonates, calcitonin, and ketamine.[42][48] Nerve blocks with guanethidine appear to be harmful.[42] Evidence for sympathetic nerve blocks generally is insufficient to support their use.[49] Intramuscular botulinum injections may benefit people with symptoms localized to one extremity.[50]

Ketamine

Ketamine, a dissociative anesthetic, appears promising as a treatment for CRPS.[51] It may be used in low doses if other treatments have not worked.[52][53] No benefit on either function or depression, however, has been seen.[53]

Bisphosphonate treatment

As of 2013, high-quality evidence supports the use of bisphosphonates (either orally or via IV infusion) in the treatment of CRPS.[48] Bisphosphonates inhibit osteoclasts which are cells involved in the resorption of bone. Bone remodeling, via osteoclast activity in resorption of bone, is thought to sometimes be hyperactive in CRPS. It is hypothesized that bone resorption causes acidification of the intercellular milieu and this activates nerves involved in nociception that densely innervate bone causing pain; therefore inhibiting bone resorption and remodeling is thought to help with regards to pain in CRPS.[48] CRPS involving high levels of bone resorption, as seen on bone scan, is more likely to respond to bisphosphonate therapy.[48]

Opioids

Opioids such as oxycodone, morphine, hydrocodone, and fentanyl have a controversial place in treatment of CRPS. These drugs must be prescribed and monitored under close supervision of a physician, as these drugs will lead to physical dependence and can lead to addiction.[54] Thus far, no long-term studies of oral opioid use in treating neuropathic pain, including CRPS, have been performed. The consensus among experts is that opioids should not be a first line therapy and should only be considered after all other modalities (non-opioid medications, physical therapy, and procedures) have been trialed.[55]

Spinal cord stimulators

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).[56] While they improve pain and quality of life, evidence is unclear regarding effects on mental health and general functioning.[57]

Dorsal root ganglion stimulation is type of neurostimulation that is effective in the management of focal neuropathic pain. The FDA approved its use in February 2016. The ACCURATE Study demonstrated superiority of dorsal root ganglion stimulation over spinal (dorsal column) stimulation in the management of CRPS and causalgia.[58]

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.[59] 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.[60] Since this is the ultimate treatment of a painful extremity, it should be left as a last resort.

Prognosis

The prognosis in CRPS is improved with early and aggressive treatment; with the risk of chronic, debilitating pain being reduced with the early treatment.[61] 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 worse with the chronic "cold" form of CRPS and with CRPS affecting the upper extremities.[61] Disuse of the limb after an injury or psychological distress related to an injury are also associated with a poorer prognosis in CRPS.[61] Some cases of CRPS may resolve spontaneously (with 74% of patients undergoing complete resolution of symptoms (often spontaneously) in a population based study in Minnesota), but others may develop chronic pain for many years.[61] Once one is diagnosed with CRPS, 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.[62]

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,[63] with a recent observational study finding an incidence of 1.16/100,000 among children in Scotland.[64]

History

The condition currently known as CRPS was originally described during the American Civil War by Silas Weir Mitchell, who is sometimes also credited with inventing the name "causalgia".[65] However, this term was actually coined by Mitchell's friend Robley Dunglison from the Greek words for heat and for pain.[66] Contrary to what is commonly accepted, it emerges that these causalgias were certainly major by the importance of the vasomotor and sudomotor symptoms but stemmed from minor neurological lesions. In the 1940s, the term reflex sympathetic dystrophy came into use to describe this condition, based on the theory that sympathetic hyperactivity was involved in the pathophysiology.[67] In 1959, Noordenbos observed in causalgia patients that "the damage of the nerve is always partial."[68] Misuse of the terms, as well as doubts about the underlying pathophysiology, led to calls for better nomenclature. In 1993, a special consensus workshop held in Orlando, Florida, provided the umbrella term "complex regional pain syndrome", with causalgia and RSD as subtypes.[69]

Research

The National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health, supports and conducts research on the brain and central nervous system, including research relevant to RSDS, through grants to major medical institutions across the country. NINDS-supported scientists are working to develop effective treatments for neurological conditions and ultimately, to find ways of preventing them. Investigators are studying new approaches to treat CRPS and intervene more aggressively after traumatic injury to lower the patient's chances of developing the disorder. In addition, NINDS-supported scientists are studying how signals of the sympathetic nervous system cause pain in CRPS patients. Using a technique called microneurography, these investigators are able to record and measure neural activity in single nerve fibers of affected patients. By testing various hypotheses, these researchers hope to discover the unique mechanism that causes the spontaneous pain of CRPS, and that discovery may lead to new ways of blocking pain. Other studies to overcome chronic pain syndromes are discussed in the pamphlet "Chronic Pain: Hope Through Research", published by the NINDS.

Research into treating the condition with mirror visual feedback is being undertaken at the Royal National Hospital for Rheumatic Disease in Bath. Patients are taught how to desensitize in the most effective way, then progress to using mirrors to rewrite the faulty signals in the brain that appear responsible for this condition.[70] However, while CRPS can go into remission, the chance of it reoccurring is significant.

The Netherlands has the most comprehensive program of research into CRPS, as part of a multimillion-Euro initiative called TREND.[71] German and Australian research teams are also pursuing better understanding and treatments for CRPS.

In other animal species

CRPS has also been described in animals, such as cattle.[72]

Notable cases
  • Nia Frazier, Dance Moms star[73]
  • Paula Abdul, singer, actor, TV personality[74]
  • Jill Kinmont Boothe, US ski slalom champion[75]
  • Gemma Collis-McCann, British paralympic fencer[76]
  • Shin Dong-wook, South Korean actor and model[77]
  • Howard Hughes, American business tycoon, aviator, inventor, filmmaker, and philanthropist[78]
  • Rachel Morris, British paralympic cyclist.[79]
  • Cynthia Toussaint, author and media personality[80]
  • Danielle Brown, British paralympic archer[81]
  • Radene Marie Cook, former Los Angeles radio broadcaster, artist, and advocate[82]
  • Marieke Vervoort, Belgian Paralympic athlete[83]
  • Bruno Soriano, Spanish footballer[84]

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