AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1994, the International Association for the Study of Pain (IASP), after development of consensus by a group of pain medicine experts, suggested that the term complex regional pain syndrome (CRPS) should replace reflex sympathetic dystrophy (RSD) and causalgia—CRPS type 1 for RSD, and CRPS type 2 for causalgia. However, the IASP diagnostic criteria were never fully validated, and several pain specialists raised concerns about their clinical and scientific value. The criteria have poor diagnostic specificity and may result in overdiagnosis of CRPS.

RSD is a descriptive term meaning a complex disorder or a group of disorders that may develop as a consequence of trauma affecting the limbs, with or without an obvious nerve lesion. RSD also may develop after visceral diseases or CNS lesions or, rarely, without an obvious antecedent event. It consists of pain and related sensory abnormalities, abnormal blood flow and sweating, abnormalities in the motor system, and changes in structure of both superficial and deep tissues ("trophic" changes). Not all components need be present.

The term "reflex sympathetic dystrophy" is intended to be used in a descriptive sense and does not imply specific underlying mechanisms. Most of the definition of RSD can be applied equally well to causalgia; however, CRPS type 1 (ie, RSD) occurs without a definable nerve lesion, while type 2 (ie, causalgia) refers to cases in which a definable nerve lesion is present.

Evans described RSD as a syndrome with the following manifestations:

• Pain and swelling at a site remote from the inciting injury
• No obvious local tissue damage
• Altered skin color
• Altered sweat production

On the basis of the description by Veldman et al, diagnosis of RSD can be made if the following clinical grounds are met:

• At least 4 of the following 5 symptoms/signs are present: unexplained diffuse pain, altered skin color, altered skin temperature, edema, reduced active range of motion
• Symptoms aggravated by activity of the extremity
• Symptoms present in an area much larger than and also distal to the primary injury

IASP diagnostic criteria for CRPS are the following:

• The presence of an initiating noxious event, or a cause for immobilization
• Continuing pain, allodynia, or hyperalgesia that is disproportionate to any inciting event in severity
• Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain
• Exclusion of conditions that would otherwise account for the degree of pain and dysfunction. The distinction between CRPS with (type 2) and without (type 1) nerve injury is based on findings on electromyography (EMG) and nerve conduction studies (NCS). The clinical validation of these criteria still is being debated.

Associated signs and symptoms of CRPS listed in IASP taxonomy but not used for diagnosis are as follows:

• Atrophy of hair, nails, and other soft tissues
• Alterations of hair growth
• Loss of joint mobility
• Impairment of motor function, including weakness, tremor, and dystonia
• Sympathetically maintained pain - May be present

Staging has no clinical value, but for historical interest the authors would like to mention that the course commonly was divided into the following 3 stages:

• Acute or hyperemic
• Dystrophic or ischemic
• Atrophic

Pathophysiology

No consensus exists regarding the pathogenic mechanisms involved in RSD. Hypotheses include (1) sympathetic nervous system (SNS) dysfunction leading to sympathetically maintained pain (SMP), (2) peripheral dysfunction, (3) central dysfunction, and (4) inflammatory process.

SNS involvement in the mechanism of RSD/CRPS type 1 is supported clinically by the presence of abnormal temperature and color of the skin as well as altered sweat excretion in the affected extremities. Surgical and chemical sympathectomy can relieve pain in some cases. The prevailing hypothesis is that posttraumatic sympathetic-afferent interaction can be established, so that sympathetic efferents can enhance primary afferent nociceptor activity. The coupling of sympathetic and afferent neurons can occur peripherally or at the level of dorsal root ganglia. Experimental studies have demonstrated that within 2 weeks of a nerve lesion that spares a significant number of axons, electrical stimulation of the sympathetic trunk and injections of catecholamines can activate or sensitize C-nociceptors.

The peripheral dysfunction is related to peripheral denervation and/or sympathetic denervation. Initially, vasodilatation is present in the denervated area. Later, the vasculature may develop increased sensitivity to circulating catecholamines due to up-regulation of adrenoreceptors.

The central dysfunction may be related to the effect of high levels of discharge originating in sensory fibers within the affected extremity. These discharges may induce changes in the autonomic CNS and subsequently an alteration in central autonomic control. Clinically, hyperhidrosis is found in many patients with RSD but cannot be explained by a peripheral mechanism, because unlike blood vessels, sweat glands do not develop denervation hypersensitivity.

Early RSD/CRPS type 1 has an inflammatory component. Substance P and other neuropeptides are considered to be the cardinal mediators of neurogenic inflammation. Analyses of joint fluid and synovial biopsies in patients with RSD have shown an increase in protein concentration, synovial hypervascularity, and neutrophil infiltration. Response of RSD/CRPS type 1 to steroids further supports the notion of an inflammatory process.

Frequency

United States

Surveys of veterans suggest that the incidence of causalgia following injury to a peripheral nerve is 1-5%. Little is known about the epidemiology of CRPS type 1 in the United States or internationally. The reported incidence of CRPS type 1/RSD is 1-2% after various fractures, 2-5% after peripheral nerve injury, and 7-35% in prospective studies of Colles fracture. The likelihood of developing CRPS/RSD is higher if the lesion is distal or if the sciatic nerve is affected.

Mortality/Morbidity

• Despite treatment, many patients are left with varying degrees of chronic pain, atrophic changes, and disability. Pain is the most important factor leading to disability.
• Some have suggested that aggressive treatment of pain in an acute setting could reduce the incidence of CRPS type 1/RSD, although further studies are needed to support this observation. Remissions followed by relapse also have been described.
• The frequency of the HLA-DQ1 antigen appears to be higher in patients with CRPS type 1 than in controls. However, no genetic marker is known for CRPS type 1/RSD.

Race

RSD affects all races; no racial predilection is observed.

Sex

A female predominance exists; female-to-male ratio is 2:1.

Age

• Mean age of patients at their initial evaluation in pain centers is approximately 40-42 years.
• The highest incidence of the disease appears to be in adults aged 40-49 years; it appears frequently in almost every age group except children. RSD/CRPS type 1 has been described in children, but the incidence is much lower than in adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Often symptoms of CRPS type 1 begin immediately, days or weeks after an injury, usually in a distal extremity. Rarely, the onset can be months after the injury. Usually one limb is involved, but rarely the involvement can be bilateral (4-5%), and very rarely 3 or 4 extremities can be affected. CRPS type 1 can be acute (first 2 months) or chronic (after 2 months). Approximately half of patients with CRPS type 1 report it to be related to an on-the-job injury.

• Clinical features of CRPS type 1/RSD are influenced by the following:
• • Duration: As many as 80% of patients with initial symptoms of CRPS type 1/RSD are cured within 18 months from onset, spontaneously or with treatment. Greater duration of CRPS is related to significantly greater likelihood of abnormalities of sensation and less likelihood of sweating abnormalities or edema.
  • Location: The pain and other symptoms can be located virtually located anywhere in the body. Extremities are involved most often, although locations such as external genitalia or nose may be involved. Patients may have pain at the ulnar styloid process after Colles fracture or at the lateral malleolus after a sprain. Frozen shoulder and/or tendinitis of biceps often accompany CRPS type 1/RSD in the hand.
• Symptoms of CRPS type 1 include the following:
• • Spontaneous pain: Pain that is not limited to the territory of a single peripheral nerve is the cardinal feature of CRPS. The character of pain can be burning (most often), aching, throbbing, or tingling. The pain is aggravated by activity of the extremity, and its severity is typically disproportionate to the inciting event.
  • Difficulty/inability in using the affected extremity
  • Neglect-like symptoms: These include "cognitive neglect" in which the limb may feel foreign and "motor neglect" in which directed mental and visual attention are needed to move the limb.
  • Altered skin temperature: This often is noted as a difference in skin temperature between the affected and unaffected limbs. At onset, the affected extremity is warmer in two thirds of cases and colder in one third. Many patients give a history of warmer extremities at onset and colder extremities later in the evolution of the disease. Some authors describe "primarily cold RSD" and "primarily warm RSD."
  • Rapid fatigability: This is almost invariably present in late stages.

Physical

• The impairment of motor function is present in about 80-90% of patients at some point in the disease and consists of paresis or pseudoparalysis or clumsiness.
• Range of motion often is limited secondary to motor deficit and/or pain.
• Tremor of the affected limb is present in about half of the patients in late stages.
• Dystonia of the affected foot or hand is described in 10% of patients in late stages.
• Muscle spasms are present in 25% of patients in CRPS type 1/RSD of longer duration.
• Hypoesthesia is described in about 70% of patients and most often is present in a glovelike or stockinglike distribution. Hemihypoesthesia also is described; hypothermesthesia and loss of proprioception are described in some cases.
• Anesthesia dolorosa is sometimes present; this means the sensitivity to touch is absent while severe pain is present in that area.
• Allodynia (ie, pain to touch) is described in 70-80% of patients.
• Hyperpathy (ie, exaggerated response to painful stimuli) is present in 70-80% of patients.
• Abnormal sweating is a sign of autonomic dysfunction. About half of the patients have hyperhidrosis.
• Edema is secondary to autonomic dysfunction. Sometimes persistent edema is caused by infection of the atrophic soft tissues.
• Altered skin color is related to vasomotor changes. Skin discoloration and atrophy can occur later. Brown-gray scaly pigmentation of the skin in the affected limb is described in some studies.
• Atrophy of soft tissue, muscles, and bones also can occur. The trophic changes are not included in the IASP criteria because so far the pathophysiology is unknown and they might result from simple disuse of the extremity.
• Altered skin temperature reflects vasomotor instability and leads to "primarily cold RSD," "primarily warm RSD," or "secondarily cold RSD." At the time of assessment by a physician, approximately 5-10% do not have a significant difference in skin temperature, about 40-45% have a warmer affected extremity, and 40-45% have a colder affected extremity.
• Hypotrichoses often is noticed in the affected area. Sometimes hypertrichosis is present, and this is considered a sign of sympathetic dysfunction. However, hypotrichosis or hypertrichoses is irrelevant for establishing the diagnosis.
• Altered nail growth is also a sign of sympathetic dysfunction; however, it is not reliable for diagnostic purposes.

Causes

Most often CRPS type 1 is initiated by trauma to an extremity. Such injuries account for more than 90% of patients with RSD/CRPS type 1.

• Injuries precipitating the development of CRPS in decreasing order of frequency are as follows: (1) sprain/strain, (2) surgical wounds, (3) fractures, (4) contusion/crush injury, and (5) rarely, other injuries such as venipuncture, lacerations, burns, inflammatory processes, electric shock, and spinal cord injuries.
• Spontaneous cases/unknown causes account for approximately 5% of patients and often may be explained by minor injuries that have been forgotten.
• Unusual precipitating events supposedly accounting for RSD/CRPS type 1 include visceral lesions, CNS lesions (eg, stroke, tumors, brain injury, amyotrophic lateral sclerosis, meningitis, syringomyelia), peripheral vascular bypass procedures, arteriovenous graft for hemodialysis, carpal tunnel surgery, and spinal cord injury.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Causalgia
Chronic arterial insufficiency
Hysterical conversion
Irritative lesions of peripheral nerve
Malingering
Neurotic compulsive postures
Peripheral nerve entrapment
Peripheral nerve neuroma
Phlebothrombosis
Plexopathies
Polyneuropathies
Raynaud disease
Rheumatologic disease
Soft-tissue infection

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No specific blood workup is indicated for RSD/CRPS type 1. The following tests are used for routine screening to rule out infections or rheumatologic disease:
• • CBC
  • Complement fixation
  • Erythrocyte sedimentation rate
  • Antinuclear antibody
  • Rheumatoid factor

Imaging Studies

• Plain radiographs show patchy demineralization of the epiphyses of long bones and also of the bones of the hands and feet. These findings cannot be appreciated until the syndrome is advanced. The sensitivity and specificity have been reported to be 69% and 71%, respectively.
• Three-phase bone scanning enables evaluation of total extremity perfusion, which typically is increased in stage 1, normalized in stage 2, and decreased in stage 3. The sensitivity and specificity are reported to be 60% and 86%, respectively.

Other Tests

• Thermography has a debatable value in the evaluation of RSD/CRPS type 1.
• EMG/NCS can help differentiate early phases of CRPS type 1 and type 2.
• Quantitative sudomotor axon reflex test demonstrates abnormal function of sudomotor reflex loops in RSD. Abnormal findings on this test are highly predictive of a positive response to sympathetic blocks.
• Laser Doppler flowmetry may demonstrate changes in the skin blood flow.

Histologic Findings

Skeletal muscles demonstrate (1) decrease in type 1 fibers, (2) increase in lipofuscin pigment, (3) atrophic fibers with a slight angular appearance, and (4) severely thickened basal membrane layers of the capillaries.

Peripheral nerve: Efferent nerve fibers are unaffected histologically; from afferent fibers, only C-fibers have demonstrated histopathologic abnormalities consisting of denervation of Schwann cell stacks, miniature axon sprouts, and an obvious increase of collagen pockets. Loss of C-fibers can be noted as well. Sometimes, multiple basal membranes surround the small endoneural vessels.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Acute treatment of RSD/CRPS type 1 should include steroids and, if needed, opioids. Patients with recurrent or refractory symptoms are best treated in a multidisciplinary pain clinic, as they need more invasive and intensive treatment.

• Steroids have demonstrated good analgesic efficacy in controlled clinical trials in early CRPS. Prednisone 30 mg/day has significant effects at 12 weeks. Methylprednisolone 32 mg/day for 2 weeks followed by tapering over 2 weeks provides 65% relief at 4 weeks.
• Opioids are an effective treatment for acute and chronic pain in CRPS/RSD. Aggressive treatment of pain in the acute phase may help prevent chronicity. Opioids can be given PO, IV, or as patient- controlled IV analgesia.
• Calcitonin intranasal spray 200 IU per day in alternating nostrils has been demonstrated to be an effective treatment for pain in CRPS/RSD.
• Vitamin C could have some efficacy related to the vitamin's antioxidant properties. One double-blind, placebo-controlled study showed that vitamin C given to patients with wrist fractures reduced the incidence of RSD.
• Adjuvant drugs that can be tried, although clinical trials still have to provide stronger evidence for efficacy. Drugs that may be effective include (1) antiepileptic drugs such as gabapentin, carbamazepine, lamotrigine, and topiramate; (2) antidepressants; (3) GABA-B receptor antagonists such as baclofen; (4) local anesthetics such as lidocaine patch (Lidoderm), creams containing lidocaine, or mexiletine PO; (5) topical analgesics such as capsaicin; and (6) topical clonidine, an alpha2-adrenergic agonist that can be tried if SMP is present.
• Other modalities should be used in conjunction with the medication, such as the following:
• • Physical therapy (PT) is recommended widely as a first-line therapy for CRPS. Early PT treatment has been advocated, since earlier treatment correlates with better outcome. If occupational therapy (OT) is added to PT, results are even better. Despite widespread use of PT in the treatment of CRPS, large controlled trials examining its efficacy are lacking.
  • Psychotherapy is aimed at helping patients cope with pain, and sometimes at treating depression, which often is associated with chronic pain.
• Clinical experience supports early intervention with sympatholytic procedures (pharmacologic or nerve block techniques), but further scientific data are required to confirm the appropriate timing and relative efficacy of different procedures. These have a place in treatment of CRPS only if SMP is demonstrated and improvement in pain and function are noted after each block.
• • Sympathectomy, chemical or surgical, has a role only in cases of RSD/CRPS in which SMP is demonstrated and SNS is involved in the pathogenesis. However, readers should keep in mind that the change of terminology from RSD to CRPS was made mainly to avoid the unwarranted assumption that SNS is always involved in the pathogenesis of RSD. A dysesthetic syndrome can occur after sympathectomy; it usually is transient but sometimes can be persistent.
  • Chemical sympathectomy is transient and should be used initially for diagnostic purposes to establish the involvement of SNS and hence inhibition of sympathetic activity (eg, increased limb temperature or ocular Horner signs) without evidence of sensory somatic blockade (eg, hypoesthesia to pinprick and cold stimuli). Early diagnosis of SMP and therefore prompt treatment may prevent chronicity. A series of chemical sympathectomy procedures is recommended only if clinical evidence of progressive improvement in pain and function is noted after each procedure. For chemical sympathectomy, 2 basic techniques are used.
    • Injections of local anesthetic around sympathetic paravertebral ganglia that project to the affected body part (sympathetic ganglion block): This will affect all components of the sympathetic outflow to an extremity (adrenergic vasoconstrictor, cholinergic sudomotor, and adrenergic pilomotor). The most common procedures are lumbar, axillary, or stellate ganglion blockades.
    • Intravenous regional block: This will prevent the release of only norepinephrine from the sympathetic terminals within the region of application (ie, distal to the tourniquet). Guanethidine, bretylium, and ketanserine have demonstrated some efficacy in this procedure. The technique involves application of a tourniquet on the affected limb and intravenous (IV) administration of the substance distal to the cuff for a limited period of time, after which the tourniquet is removed.
  • Epidural injection of clonidine (an alpha2-adrenergic receptor agonist) and/or baclofen (a GABA-B receptor antagonist) and/or opioids has an analgesic effect in chronic RSD/CRPS type 1, but also raises significant sedation and hypotension issues. Continuous epidural infusion can be complicated by infections.
  • A single local infiltration with local anesthetic relieves or improves the pain if tendinitis is present (most often the scapular tendon of biceps is involved). In many patients, tendinitis is relieved permanently by local infiltration of a corticosteroid.
  • Intrathecal baclofen can be used for the treatment of dystonia in patients with RSD/CRPS type 1 syndrome.
  • Posterior column stimulator has been demonstrated to reduce pain and improve health-related quality of life in patients with RSD/CRPS.
  • Peripheral nerve stimulation has been advocated for use in patients with CRPS II, with symptoms entirely or mainly in the distribution of a single major peripheral nerve, and who have been unresponsive to other therapeutic modalities.

Surgical Care

• Surgical sympathectomy is likely to bring complete pain relief only in patients demonstrating transient complete relief with paravertebral sympathetic ganglion blockade.
• • The reported incidence of complete relief ranged from 58-100%, whereas the duration of follow-up in these studies varied from 6 months to 17 years.
  • Surgical sympathectomy should not be recommended routinely because the SMP component may resolve spontaneously over time or play a minimal role, if any, in the complicated pathogenesis of CRPS.
  • In some patients who experience complete relief for a while, the pain starts again.
• Amputation of the affected limb as a treatment is an extreme option and is very rarely recommended. In the past, it used was sometimes advised for patients who had RSD with severe hyperpathy in combination with a nonfunctional limb or recurrent severe infections in the limb. However, there is a significant risk of complex regional pain syndrome developing in the stump.

Consultations

• Pain specialist: This should be the consultation of choice.
• Physical medicine and rehabilitation
• Neurology
• Anesthesiology
• Psychiatry/psychology
• Neurosurgery

Diet

• No special diet has been effective in the treatment of RSD/CRPS type 1.
• Anecdotal reports suggest that vitamin C can improve outcome.

Activity

No restriction on activity is recommended. The only limitations in activity are related to what the patient cannot do because of pain or decreased range of motion, and also to what the patient is not supposed to do because of associated conditions (eg, fracture, sprain, strain).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Clinical trials strongly suggest that steroids are effective when given in the acute phase of CRPS type 1/RSD. This probably is related to their effect on neurogenic inflammation. Opioids can bring relief in acute as well in chronic pain. Intranasal calcitonin has been used successfully in treatment of pain associated with CRPS/RSD.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties. They can cause profound and varied metabolic effects and modify the body's immune response to diverse stimuli.

Drug Category: Analgesics

Pain control is essential to quality patient care. Analgesics ensure patient comfort. They can have side effects such as sedation, constipation or, rarely, respiratory depression.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• In CRPS type 1/RSD, inpatient care typically is reserved for patients with refractory pain or infections of the atrophic limb, patients requiring surgery, and sometimes patients requiring procedures.

Further Outpatient Care

• Patients with CRPS type 1/RSD should receive care in a pain clinic in which appropriate evaluation and treatment can minimize discomfort and degree of disability.

Transfer

• Patients should be referred to a pain clinic as soon as CRPS type 1 is suspected on clinical grounds.

Deterrence/Prevention

• Early treatment of pain appears to decrease the frequency of chronic disease and later complications.

Complications

• Osteoporosis
• Limitation of active movement in joints
• Infections
• Nodular fasciitis of the palmar or plantar skin

Prognosis

• Approximately 80% of the patients with CRPS type 1/RSD have complete spontaneous relief of signs and symptoms within 18 months; however, no criteria have been established to predict from the very beginning who will have a spontaneous cure and who will not. Some of the patients whose symptoms do not resolve spontaneously still may be cured by treatment.
• Of patients who develop refractory CRPS type 1/RSD, 50-80% have disability secondary to pain and/or limited range of motion. The main disabilities are limitations in activities of daily living (ADL).
• Long duration of symptoms and signs, the presence of trophic changes, and the presence of primarily cold RSD are associated with higher chances of poor outcome and disability.

Patient Education

• Patients should be informed that, even while wearing a cast, they will undergo mild passive range of motion exercises. After the cast is removed, physical therapy and occupational therapy should be started early, and some ADLs should be resumed as soon as possible following the recommendations of the physical therapist and occupational therapist.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Underestimating symptoms that suggest CRPS type 1/RSD is risky, because they sometimes could be associated with emotional load or depression. Patients' complaints should always be taken seriously and appropriate referral performed.

Special Concerns

• Diagnosis is based on the clinical picture, with additional information regarding the presence of SMP or autonomic dysfunction provided by carefully performed and interpreted supplemental tests.
• The diagnosis of conversion disorder or malingering should be a diagnosis of exclusion made only after careful evaluation by a pain specialist.
• Opinions that CRPS type 1/RSD occurs mainly in people with psychiatric problems, although never proven, have done patients a lot of harm because their complaints often are not taken seriously.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Apr 18, 2006