eMedicine Specialties > Neurology > Headache and Pain

Complex Regional Pain Syndromes

Author: Anthony H Wheeler, MD, Pain and Orthopedic Neurology, Charlotte, North Carolina
Contributor Information and Disclosures

Updated: Dec 17, 2009

Introduction

Background

In 1994, a consensus group of pain medicine experts gathered by the International Association for the Study of Pain (IASP) agreed on diagnostic criteria for reflex sympathetic dystrophy and causalgia, and renamed them complex regional pain syndrome (CRPS) types I and II respectively. These groups were determined according to the type of inciting event, rather than any difference in clinical presentation or pathophysiology. Many experts felt that the IASP diagnostic criteria were ambiguous; however, these criteria were developed as a starting point, and the IASP fully intended to validate these criteria through clinical research studies.^1,2

CRPS type I requirements included causation by an initiating noxious event, such as a crush or soft tissue injury; or causation by immobilization, such as due to a tight cast or frozen shoulder. CRPS type II is characterized by the presence of a defined nerve injury. Both types demonstrate continuing pain, allodynia, or hyperalgesia that is usually disproportionate to the inciting event. At some time during the process, both show evidence of edema; changes in skin blood flow as manifested by color change and skin temperature changes greater than 1.1°C from the homologous body part; or abnormal sudomotor activity in the painful region. Both types require exclusion of the existence of any condition that might otherwise account for the degree of pain and dysfunction.^1,3

Since their inception, experts and pain medicine specialists have communicated their concerns regarding the clinical and scientific value of the IASP criteria claiming that they exhibit poor diagnostic specificity and may result in overdiagnosis of CRPS. A small single center empirical validation study demonstrated that the 1994 CRPS criteria did indeed demonstrate overdiagnosis of the syndrome.³ Other studies have confirmed the lack of any uniform consensus and thorough validation of IASP criteria has not yet been achieved.

Pathophysiology

Hypothetical mechanisms

In most cases, experts believe that the development of CRPS results when persistent noxious stimuli from an injured body region leads to peripheral and central sensitization; whereby, primary afferent nociceptive mechanisms demonstrate abnormally heightened sensitization, including spontaneous pain and hyperalgesia. Allodynia and hyperalgesia occur when central nervous system (CNS) somatosensory processing of normal nonpainful mechanical stimuli, such as light touching of the skin, are perceived as painful. Therefore, skin in the injured area becomes more sensitive to all stimuli, even nonpainful stimuli. Sensory impairment and hyperalgesia evolve through sensitization and altered central processing such that aberrant perception of pain spreads beyond the original injury site and beyond the area of spontaneous pain.

A similar impairment of CNS processing leads to motor aberrancies, such as weakness in the affected area or tremor. Sensitization peripherally and centrally within the nervous system associated with impaired CNS processing is linked to proposed disturbances within the sympathetic nervous system that lead to the appearance of sympathetic hyperactivity that adversely affects the injured area. Studies suggest that an augmented inflammatory response coupled with impaired healing further contribute to the refractory nature of the malevolent CRPS.^4,2,5,6,7

Peripheral and central sensitization

Mechanical, thermal, and chemical stimuli activate peripheral nociceptors that transmit pain messages through lightly myelinated A-delta fibers and unmyelinated C fibers. Algogenic substances that are typically involved in tissue damage and capable of inducing transduction centripetally include potassium, serotonin, bradykinin, histamine, prostaglandins, leukotrienes and substance P (SP). Neuropeptides, such as SP and CGRP, are transported to the endings of nociceptive afferents where they can instigate ortho- and retrograde actions, including, but not limited to, neurogenic inflammation, which can incite a host of additional hostile algogenic mechanisms.

Pain messaging is transmitted through C fibers and A-delta fibers that project to Rexed layers I, II, and V in the spinal cord. Peripheral sensitization occurs when persisitant or repetitive noxious stimulation of high threshold polymodal C fibers causes enhanced sensitivity, lower stimulus thresholds, and prolonged enhanced activation of dorsal horncells, especially those with glutamate receptors. Peripheral transmission of pain stimuli through A-delta fibers and C fibers leads to the release of excitatory amino acids, such as glutamine and asparagine, which then act upon N -methyl-D -aspartic acid (NMDA) receptors, causing release of the neuropeptide SP. NMDA-activated release of substance P lowers the threshold for synaptic excitability in these normally silent second order interspinal synapses.^4,2,5,6,7

CNS sensitization and chronicity are fostered through afferent processing by second-order nociceptive-specific neurons and wide-dynamic-range (WDR) neurons in the spinal cord. WDR neurons contribute more significant sensitivity than nociceptor-specific neurons, because both nociceptive and non-nociceptive afferents converge to synapse on a single WDR neuron, and WDR neurons respond with equal intensity regardless of whether the neural signal is noxious (hyperalgesia).

Hyperalgesia and allodynia initially develop at the injury site; however, when central sensitization occurs through WDR neural activity, the area of pain expands beyond the initial region of tissue pathology. The peripheral changes described eventually cause an injury environment, whereby primary afferents, including nociceptors, demonstrate an increased sensitivity to circulating or experimentally injected subcutaneous norepinephrine.^{8,2,5,6,7,9,10,11,12,13,14}

Sympathetically maintained pain (SMP)

For decades, CRPS was thought to be caused by sympathetic nervous system (SNS) hyperactivity. SNS involvement in CRPS is supported clinically by the presence of abnormal temperature and color of the skin and altered sweating in the affected extremities. Surgical and chemical sympathectomy can relieve pain in some cases. However, under normal physiologic circumstances, there is no interaction between sympathetic and peripheral afferent nociceptive neurons.^8,2,15,16,17 Furthermore, multiple discrepancies contradict an SNS role. Some of these discrepancies include the following: (1) plasma catecholamine concentrations are lower in CRPS-affected limbs^18,19 , (2) most patients diagnosed with CRPS do not obtain significant or durable pain relief from sympathetic blocks^20,21 , and (3) skin temperature does not correlate with the activity of sympathetic vasoconstrictor neurons.²²

To explain this incongruity, the pathophysiology of SMP was hypothesized to result from an abnormal coupling between sympathetic efferent and nociceptive afferent neurons.²³ Two possible conditions may lead to pathological coupling: interaction of between sympathetic efferents and intact or regenerating peripheral nociceptive C-fiber neurons or interaction with sympathetic vasoconstrictor neurons and afferent somata within the dorsal root ganglion (DRG).²⁴

This coupling is mediated by norepinephrine, which is released from sympathetic terminals and adrenoreceptors that are newly expressed on afferent nociceptive neurons. Thus, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury.²⁵ Therefore, an increased number of targeted and functionally upregulated alpha-receptors on lesioned nociceptive afferents, which has been demonstrated, would explain how reduced sympathetic activity in CRPS is capable of maintaining pain.^16,2

Evidence suggests that early autonomic symptoms and signs of CRPS are indicative of CNS dysfunction.²⁶ Wasner et al suggest that warmth of the affected extremity in the early stages of CRPS I is caused by functional inhibition of central cutaneous vasoconstrictor activity that leads to cutaneous vasodilation.¹⁷ However, over time, functional inhibition of vasoconstrictor activity may lead to adrenergic hypersensitivity from peripheral denervation and/or sympathetic denervation.

Initially, vasodilatation is present in the denervated area, but later, the vasculature may develop increased sensitivity to circulating catecholamines due to upregulation of cutaneous adrenoreceptors. In fact, research has revealed that the nerve lesion in CRPS II leads to an increased sensitivity to circulating catecholamines. Initially, vasodilation is present within the denervated area causing the skin adjacent and on the same side to become abnormally warm at first and then change to a chronically cold status. This occurrence mimics the course of chronic or progressive CRPS due to vasoconstriction caused by vascular hypersensitivity to catecholamines. Other mechanisms include an increased density of cutaneous alpha-adrenoreceptors and pathological upregulation of alpha-adrenergic receptors.^{8,2,21,15,23,24,25,26,17}

Sensory and motor dysfunction

In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous pain and hyperalgesia.²⁷ Clinical findings in patients consistently show sensory impairments that spread beyond the injured territory and spontaneous pain, often engulfing a quadrant or hemisensory region. These abnormal patterns are due to altered central afferent processing and have been demonstrated on functional imaging studies.^28,29,30

Likewise, evidence to date supports the presence of similar mechanisms involving abnormalities of CNS motor processing that are responsible for causing impairments of muscle strength affecting the involved distal extremity, rather than pain, edema, disuse, trophic changes, or nerve injury. Kinematic analysis studies suggest that motor deficits are probably due to impaired integration of visual and sensory afferent input within the parietal cortex.³¹ Also, increased amplitude of physiologic tremor due to CNS mechanisms is common, occurring in about 50% of patients under observation.³²

Aberrant healing and exaggerated inflammation

After tissue injury, the body is programmed to respond in a manner that would promote healing toward regaining full use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant healing response including exaggerated and persistent inflammation and guarding.

At the site of injury, peripheral C-fiber nociceptors transmit pain messages that cause ortho- and retrograde release of substance P and CGRP into damaged tissues, which result in vasodilation, extravasation of pro-nociceptive mediators, reactivation and further sensitization of C-fiber afferents, and increased tissue comorbidity in the injured area.^8,5 These neuropeptides lead to the physical findings associated with inflammation, including redness, warmth, and swelling, which are also commonly present in early CRPS. Also, algogenic substances are released, which increases nociception and initiates the process of peripheral sensitization previously discussed. Skin sensitivity and tenderness spreads into adjacent regions, which are thought to be caused by secondary hyperalgesia from CNS alterations that are consistent with the described sensitization process.

Protective disuse

Decreased use of an injured body part would appear to be a normal postinjury reaction. After injury, the organism protects and guards the injured body part to optimize healing and prevent reinjury. The normal healing organism gradually increases the use of the injured region, which aids in the potential for recovery and reintegration of the body part into the organism’s normal sense of self. However, excessive protection and guarding, such as casting or splinting, is commonly promoted by medical recommendations and increases the patient’s volitional disuse of the extremity and promotes fear-avoidance, which may progress into a neurologic neglectlike syndrome.

This phenomenon has been postulated as causative in some patients with CRPS.³² Many of the symptoms and signs of CRPS are consistent with those that would naturally develop from lack of use. For example, an unused dependent limb eventually develops swelling (dependent edema), coolness (decreased blood flow), and trophic changes (decreased blood flow).^8,2,33

Frequency

United States

A population-based study by Sandroni et al showed an incidence of approximately 5.5 per 100,000 person-years at risk and a prevalence of about 21 per 100,000 for CRPS type I.³⁴ The same study showed an incidence of 0.8 per 100,000 person-years at risk and a prevalence of about 4 per 100,000 for CRPS type II.^34,8 Therefore, the incidence of CRPS type I is higher than CRPS type II.^34,8 The reported incidence of CRPS type I is 1-2% after various fractures⁸ , while the incidence of CRPS type II approximates 1-5% after peripheral nerve injury.^8,35 The incidence of CRPS is 12% after a brain injury³⁶ and 5% after myocardial infarction.³⁷

Mortality/Morbidity

Despite treatment, many patients are left with varying degrees of chronic pain, trophic 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 I, however, further studies are needed to support this observation. Remissions followed by relapse have also been described. The frequency of the HLA-DQ1 antigen appears to be higher in patients with CRPS than in controls, and HLA-DR13 is associated with progression towards multifocal or generalized dystonia.^38,39 Recently a new HLA I locus was detected that may predict spontaneous onset of CRPS.⁴⁰

Race

CRPS affects all races; no racial predilection is observed.

Sex

Females experience CRPS more commonly than males by a ratio that varies from 2:1-4:1.^{8,41,34,42,43,44,45}

Age

CRPS is distributed across age groups, with a mean age peek between 37 and 50 years.^{8,41,34,42,43,44,45} CRPS occurs in children with increased incidence following puberty, with females affected more frequently at a ratio of 4:1 and increased occurrence in the lower extremity by a ratio of 5.3:1. The mean age of onset is 12.5 years in a cohort of 396 children.

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. CRPS type 1 has been described in children, but the incidence is much lower than in adults.

Clinical

History

Often symptoms of complex regional pain syndrome (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 are influenced by the following:
  • Duration: As many as 80% of patients with initial symptoms of CRPS type 1 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 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 reflex sympathetic dystrophy" and "primarily warm reflex sympathetic dystrophy."
  • 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 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.
• Hyperpathia (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 CRPS," "primarily warm CRPS," or "secondarily cold CRPS." 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 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 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.

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