Complex regional pain syndrome

Editor-In-Chief: Robert G. Schwartz, M.D. [mailto:RGSHEAL@aol.com], Piedmont Physical Medicine and Rehabilitation, P.A.

Contributor: Cafer Zorkun M.D., PhD.

Overview
Complex Regional Pain Syndrome (CRPS) is a chronic progressive disease characterized by severe pain, swelling and changes in the skin. The International Association for the Study of Pain has divided CRPS into two types based on the presence of nerve lesion following the injury.

It is important to understand that not all complex regional pain syndromes are the same. Is quite possible for example to have a post phlebitic syndrome involving the leg that may present with skin color changes, excess pain and swelling, but has nothing to do with RSD.
 * Type I, also known as reflex sympathetic dystrophy (RSD), Sudeck's atrophy, Reflex neurovascular dystrophy (RND) or algoneurodystrophy, does not have demonstrable nerve lesions.
 * Type II, also known as causalgia, has evidence of obvious nerve damage.

The cause of this syndrome is currently unknown. Precipitating factors include underlying illness (especially vascular disease, an underlying rheumatic condition, a hidden infection or a coagulopathy in RSD cases), orthopedic injury and surgery. Although there are documented cases that have no identifiable injury to the original site in almost all cases of RSD there was an underlying event or injury.

History and nomenclature
The condition currently known as CRPS was originally described by Silas Weir Mitchell during the American Civil War, who named the condition causalgia. 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. 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.

Pathophysiology
The pathophysiology of CRPS remains unclear. However, recent research has suggested that oxidative damage (e.g. by free radicals) associated with one of the precipitating factors described earlier may play a role.

Susceptibility
CRPS can strike at any age, but is more common between the ages of 40 and 60. It affects both men and women, but is more frequently seen in women. The number of reported CRPS cases among adolescents and young adults is increasing.

Investigators estimate that two to five percent of those with peripheral nerve injury and 12 to 21 percent of those with hemiplegia (paralysis of one side of the body) will suffer from CRPS.

Research has demonstrated that the administration of Vitamin C after an injury may decrease one's susceptibility to developing CRPS.

Symptoms
The symptoms of CRPS usually manifest near the site of an injury, either major or minor, and usually [spread] beyond the original area. Symptoms may spread to involve the entire limb and, rarely, the opposite limb. The most common symptom is burning pain. The patient may also experience muscle spasms, local swelling, increased sweating, softening of bones, joint tenderness or stiffness, restricted or painful movement, and changes in the nails and skin.

The pain of CRPS is continuous and may be heightened by emotional stress. Moving or touching the limb is often intolerable. Eventually the joints become stiff from disuse, and the skin, muscles, and bone atrophy. The symptoms of CRPS vary in severity and duration. There are three variants of CRPS, previously thought of as stages. It is now believed that patients with CRPS do not progress through these stages sequentially and/or that these stages are not time-limited. Instead, patients are likely to have one of the three following types of disease progression:


 * 1) Type one (RSD)is characterized by severe, weather sensitive, burning pain at the site of the injury.  Muscle spasm, joint stiffness, restricted mobility, rapid hair and nail growth, and vasospasm (a constriction of the blood vessels) that affects color and temperature of the skin can also occur.
 * 2) Type two (RSD)is characterized by more edema.  Swelling spreads, hair growth diminishes, nails become cracked, brittle, grooved, and spotty, and contracture (loss of range of motion) occurs.  Joints can thicken and muscles atrophy.
 * 3) Type three is characterized by irreversible changes in the skin and bones(osteoporosis).  While bone changes can spread, they are most predominant at the injury site. With time the pain can spread to involve the entire limb or other limbs (so called stage four).  Most often with stage thee RSD there is marked muscle atrophy, severely limited mobility of the affected area,and flexor tendon contractions (contractions of the muscles and tendons that flex the joints)however not all cases of RSD progress classically from stage (or type) one through three.  Occasionally the limb is displaced from its normal position, and marked bone softening is more dispersed

Diagnosis
CRPS types I and II share the common diagnostic criteria shown below.
 * 1) Spontaneous pain or allodynia/hyperalgesia is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event.
 * 2) There is a history of edema, skin blood flow abnormality, or abnormal sweating in the region of the pain since the inciting event.
 * 3) No other conditions can account for the degree of pain and dysfunction.

The two types differ only in the nature of the inciting event. Type I CRPS develops following an initiating noxious event that may or may not have been traumatic, while type II CRPS develops after a nerve injury.

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. Three phase bones scans have been thought of as one of the most specific diagnostic studies for RSD, but they are not very sensitive and therefor delay recognition of cases. 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
Thermography is a diagnostic technique for measuring blood flow by determining the variations in heat emitted from the body. Thermographic images are direct measurements of sympathetic skin galvonic impedance. A color-coded "thermogram" of a person in pain often shows an altered blood supply to the painful area, appearing as a different shade (abnormally pale or violet) than the surrounding areas of the corresponding part on the other side of the body. A difference of 1.0°C between two symmetrical body parts is considered significant, especially if a large number of asymmetrical skin temperature sites are present. The affected limb may be warmer or cooler than the unaffected limb. Thermography is felt to be the most sensitive objective diagnostic study for RSD. It is very important for the doctor to understand sympathetic galvonic skin responses when interpreting a thromographic image and to keep in mind other syndromes that are RSD look a likes. Thermography is the only test that allows for vasomotor mapping and therefor also provides information as to both the distribution of that patient's RSD and its underlying generator.

Sweat testing
Abnormal sweating can be detected by several tests. A powder that changes color when exposed to sweat can be applied to the limbs; however, this method does not allow for quantification of sweating. Two quantitative tests that may be used are the resting sweat output test and the quantitative sudomotor axon reflex test. These quantitative sweat tests have been shown to correlate with clinical signs of CRPS.

Radiography
Patchy 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. Bone densitometry can also be used to detect changes in bone mineral density. It can also be used to monitor the results of treatment, as bone densitometry parameters improve with treatment.

Electrodiagnostic testing
The nerve injury that characterizes type II CRPS can be detected by electromyography. In contrast to peripheral mononeuropathy, the symptoms of type 2 CRPS extend beyond the distribution of the affected peripheral nerve.

Prevention
Vitamin C has been shown to reduce the prevalence of complex regional pain syndrome after wrist fractures. A daily dose of 500 mg for fifty days is recommended.

Treatment
Physicians use a variety of drugs to treat CRPS, including antidepressants, anti-inflammatories such as corticosteroids and COX-inhibitors such as piroxicam, vasodilators, GABA analogs such gabapentin and pregabalin, and alpha- or beta-adrenergic-blocking compounds.

Elevation of the extremity and physical therapy are also used to treat CRPS.

Injection of a local anesthetic such as lidocaine is often the first step in treatment. Injections are repeated as needed. However, early intervention with non-invasive management may be preferred to repeated nerve blockade. In most cases it is best to have blocks done above the highest level of vasomotor abnormality. The use of topical lidocaine patches has been shown to be of use in the treatment of CRPS-1 and -2. .

Neurostimulation (spinal cord stimulators) may also be surgically implanted to reduce the pain by directly stimulating the spinal cord. These devices place electrodes either in the epidural space (space above the spinal cord) or directly over nerves located outside the central nervous system. Implantable drug pumps may also be used to deliver pain medication directly to the cerebrospinal fluid which allows powerful opioids to be used in a much smaller dose than when taken orally.

Surgical, chemical, or radiofrequency sympathectomy &mdash; interruption of the affected portion of the sympathetic nervous system &mdash; can be used as a last resort in patients with impending tissue loss, edema, recurrent infection, or ischemic necrosis. However, there is little evidence that these permanent interventions alter the pain symptoms of the affected patients.

Physical therapy is the most important part of treatment, though it should be noted that many patients are incapable of participating in physical therapy due to muscular and bone problems. People struggling with CRPS often develop guarding behaviors where they avoid using or touching the affected limb. Unfortunately, inactivity can exacerbate the disease and perpetuate the pain cycle. Physical therapy works best for most patients, especially goal-directed therapy, where the patient begins from an initial point, regardless of how minimal, and then endeavors to increase activity each week. Therapy should be directed at facilitating the patient to engage in physical therapy, movement and stimulation of the affected areas.

Some treating physicians have even initiated physical therapy under light general anesthesia, in an attempt to remobilize the extremity. While the unpredictability of this illness often causes a frustrating pattern of progress and regress. Physical therapy can be very dangerous too, if bone and tissue damage has already occurred. It should only be used with extreme caution.

A study in 2007 indicated that Collateral Meridian Therapy was effective in lowering CRPS patient's VAS pain score.

EEG Biofeedback, various forms of psychotherapy , relaxation techniques and hypnosis are adjunctive treatments which assist coping.

Ketamine Therapy
Ketamine, a potent anesthetic, is being used as an experimental and controversial treatment for Complex Regional Pain Syndrome. The theory of ketamine use in CRPS/RPS is primarily advanced by neurologist Dr Robert J. Schwartzman of Drexel University College of Medicine in Philadelphia, and researchers at the University of Tübingen in Germany. The hypothesis is that ketamine manipulates NMDA receptors which might reboot aberrant brain activity.

There are two treatment modalities; the first consist of a low dose ketamine infusion of between 25-90 mg per day, delivered over five days either in hospital or as an outpatient. This is called the awake technique.

Open label, prospective, pain journal evaluation of a 10-day infusion of intravenous ketamine (awake technique) in the CRPS patient concluded that "A four-hour ketamine infusion escalated from 40-80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation".

The second treatment modality consists of putting the patient into a medically-induced coma, then administering an extremely high dosage of ketamine; typically between 600-900 mg. This version, currently not allowed in the United States, is most commonly done in Germany but some treatments are now also taking place in Monterrey, Mexico.

According to Dr Schwartzman, 14 cases out of 41 patients in the induced-coma ketamine experiments were completely cured. "We haven't cured the original injury," he says, "but we have cured the RSD or kept it in remission. The RSD pain is gone."

"No one ever cured it before," he adds. "In 40 years, I have never seen anything like it. These are people who were disabled and in horrible pain. Most were completely incapacitated. They go back to work, back to school, and are doing everything they used to do. Most are on no medications at all. I have taken morphine pumps out of people. You turn off the pain and reset the whole system."

No trials have been done for the coma induced method to date.

This method gained attention in pop culture through season 3 of the FOX television drama House, M.D., which opens a few months after the title character, Gregory House, was placed into a ketamine coma to treat ongoing neuropathy in his right leg. House is shown to have recovered significant use of his right leg (he even goes running regularly), but the treatment eventually wears off and House is once more left in pain and significantly disabled.

Prognosis
Good progress can be made in treating CRPS if treatment is begun early, ideally within 3 months of the first symptoms. Early treatment may even result in remission. Detailed assessment for an underlying perpetrator and addressing those factors that impact blood flow and never recovery cna have a tremendous clinical impact. If treatment is delayed, however, the disorder can quickly spread to the entire limb and changes in bone and muscle may become irreversible. In 50 percent of CRPS cases, pain persists longer than 6 months and sometimes for years. In teens and younger patients with CRPS, the prognosis is excellent. Even without invasive therapy, upwards of 75% of children have full recovery with virtually 100% of the patients having marked improvement. The prognosis is not always good. The limb, or limbs, can experience muscle atrophy, loss of use and functionally useless parameters that require amputation. 

Similar disorders
CRPS has characteristics similar to those of other disorders, such as shoulder-hand syndrome, which sometimes occurs after a heart attack and is marked by pain and stiffness in the arm and shoulder; Sudeck syndrome, which is prevalent in older people and women and is characterized by bone changes and muscular atrophy, but is not always associated with trauma; and Steinbrocker syndrome, which includes symptoms such as gradual stiffness, discomfort, and weakness in the shoulder and hand. Erythromelalgia also shares many components of CRPS (burning pain, redness, temperature hypersensitivity, autonomic dysfunction, vasospasm)they both involve small fiber sensory neurosympathetic components. Interestingly Erythromelalgia involves a lack of sweating, whereas CRPS often involves increased sweating. Subvariations of both exist.

Current research
The National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health (NIH), 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 RSDS 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 RSDS 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 RSDS 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 affective way then progress on to using mirrors to rewrite the faulty signals in the brain that appear responsible for this condition.

CRPS in animals
CRPS has also been described in non-human animals.