Complex Regional Pain Syndrome Part 1: Essentials of Assessment and Diagnosis

Disease/Disorder

Definition

Complex Regional Pain Syndrome (CRPS) is a disorder characterized by continued debilitating regional pain that is inordinate to the provoking event, with or without a specific nerve injury and does not need to follow a dermatomal pattern.¹ It usually develops after trauma; however there is no relation between severity of injury and development of this disorder and in some cases there is no precipitating event. The pain is often associated with a combination of sensory and motor deficits, vasomotor disturbances, sudomotor disturbances, edema and/or trophic changes all of which tend to present at distinct times throughout the course of the syndrome.

It was originally classified by the International Association for the Study of Pain (IASP) in 1994 and formally updated to the Budapest Criteria (2003), and now to the Valencia consensus (2019) due to its higher sensitivity and specificity; however CRPS remains a diagnosis of exclusion.^1,2

CRPS is further classified into: a) CRPS type I (previously Reflex Sympathetic Dystrophy) which typically develops after trauma or injury and does not involve a specific peripheral nerve; and b) CRPS type II (previously Causalgia) which develops after peripheral nerve injury.¹ It can be further subdivided into “warm” (sympathetically maintained) or “cold” (sympathetically independent).

CRPS nomenclature has evolved through the years. It was previously referred to in the literature as Reflex Sympathetic Dystrophy, Algodystrophy, Causalgia, Sudeck’s atrophy among others.

Etiology

CRPS type I has a higher propensity to develop after an injury and can be due to several precipitating events ranging from sprains, fractures, visceral disease or even immobilization, while CRPS type II is known to occur after obvious peripheral nerve damage and can be related to a multitude of initial events.³

CRPS most often develops after acute tissue trauma including fractures, crushing injuries, sprains and surgeries. Patients may also develop CRPS after burns, stroke, frostbite, injections or local infections.  However, it has been reported in cases without any identifiable precipitating event.⁶ There is currently no evidence that any particular injury regularly manifests as CRPS or that the severity of injury is related to the development of this syndrome.

The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS.⁴ Evidence for dysfunction of both the innate and adaptive immune systems in CRPS is presented, through measured cytokines and other inflammatory mediators in the skin of affected limbs. Additional results from studies of mediator levels in animal models are evaluated in this context. Similarly, the production of autoantibodies and the potential targets of those antibodies from human, animal, and translational studies is reviewed. Compelling evidence of autoinflammation in skin and muscle of the affected limb has been collected from CRPS patients and laboratory animals. Cytokines including IL-1β, IL-6, TNFα, and others are reliably identified during the acute phases of the syndrome. More recently, autoimmune contributions have been suggested by the discovery of self-directed pain-promoting IgG and IgM antibodies in CRPS patients and model animals. Both the autoimmune and the autoinflammatory components of CRPS appear to be regulated by neuropeptide-containing peripheral nerve fibers and the sympathetic nervous system.⁵

Earlier age at CRPS onset and more severe symptoms have been found in patients with some human leukocyte antigen and tumor necrosis factor-alpha (TNF-α) polymorphisms.⁶ A recent study identified four single nucleotide polymorphisms in genes expressed in peripheral nervous system neurons and immune cells that were associated with CRPS type 1 development, and more common in men.⁷ Several case reports and retrospective studies suggest a familial inheritance; however, no clear inheritance pattern has been established.⁸

Epidemiology including risk factors and primary prevention

Literature reports a frequency of 26.2 per 100,000 persons per year for CRPS type I and 5.5 per 100,000 persons per year for CRPS type II.^9,10 Females have a higher propensity compared to males at a 4:1 ratio, and there is an increased incidence in the fourth decade and from 61 to 70 years old.⁹ No racial differences have been noted. Fractures are the most common precipitating event, particularly in the upper extremity.¹⁰

The development of CRPS following surgery is a major cause of concern as this complicates post-operative management and has significant clinical ramifications. Operative procedures of the shoulder (incidence 0.9-11%), distal radius (22-39%), carpal tunnel (2-5%) Dupuytren’s contracture (4.5-40%), foot and ankle surgery (4.36%) have been associated with the manifestation of CRPS.⁸ In a prospective study of patients with tibial fractures, the incidence of CRPS following surgical repair was documented at 31%; 33.3% of patients treated with intramedullary nailing, 28.6% of patients treated with nails and screws and 28.6% of patients treated with external fixation.¹¹

Other risk factors include asthma, history of migraine, angiotensin-converting enzyme inhibitor use, menopause, osteoporosis, cigarette smoking.^9,12,13

Evidence exists that vitamin C supplementation may reduce the risk of CRPS type I for wrist fractures, in foot and ankle trauma, and following total knee replacement or lumbar spine surgery at a 12 month follow up.¹⁴ The oral vitamin C dosage varied from 200 to 1,500 mg in a meta-analysis; however generally ≥500mg is considered optimal. Duration of supplementation is typically 45-50 days.¹⁵ The most common side effects of supplementation are fatigue and lethargy, along with increased risk for nephrolithiasis for higher doses. In addition, intravenous supplementation or inclusion of vitamin C in regional blocks may reduce the risk of CRPS.^14,16 The exact mechanism of action for the effects of vitamin C on CRPS are unknown, but are believed to be due to its anti-oxidant capabilities and improvement of bone density, and physical performance.

In the pediatric population, CRPS is more common among early adolescent females with CRPS type 1 affecting the lower extremity.¹⁷

Patho-anatomy/physiology

The physiological process of CRPS is not completely delineated. Several theoretical mechanisms have been proposed, which include sympathetically maintained pain, sensory and motor dysfunction, peripheral and central sensitization, and protective disuse. A large majority believe that continued noxious stimuli related to damaged areas may lead to sensitization of the peripheral and central nervous system. Peripheral injured nociceptors lead to an overexpression of neurotransmitters and eventual hypersensitivity due to repetitive stimulation. 

The overstimulation of the peripheral nervous system leads to increased nociceptive awareness in the central nervous system. A distorted perception of nociceptive stimuli causes a continuous torrent of downstream ramifications and an ongoing exaggerated response to the initial stimuli.

The involvement of the sympathetic nervous system is not fully understood and has lost some of its significance over time.⁶ There may be a relation to increased catecholamine concentrations and subsequent interactions among nociceptive neurons.^18,19 Additional mechanisms revolve around the body’s active inflammatory response in an attempt to heal injured areas. Inflammatory markers released into the bloodstream and injured tissue lead to vasodilation and eventual engorgement, presenting as edema, warmth, or signs of inflammation.¹⁸

Whilst many observations have been made of physiological abnormalities, how these explain the condition and who does and doesn’t develop CRPS remains unclear. A new overarching hypothesis that may explain the condition invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy.²⁰

Other proposed mechanisms include classic and neurogenic inflammation. It has been found that patients with CRPS present with increased pro-inflammatory cytokines locally, in the bloodstream and in CSF.³ These substances may produce plasma extravasation and vasodilation, thereby producing localized edema, warmth and erythema characteristic of CRPS.⁶

Neuroimaging studies suggest a reorganization of somatotopic maps in the cortex of patients with CRPS. The degree of somatotopic reorganization correlates significantly with pain intensity and degree of hyperalgesia.⁶

The degree to which individual mechanisms contribute to CRPS may differ between patients and even within one patient over time.⁶

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Initial symptoms of CRPS typically develop within 6 weeks of the precipitating event.¹⁸ Early symptoms tend to include edema, sensory changes, distal vasomotor changes, and pain at the area of insult. Over time, symptoms become less localized.

CRPS was historically divided into three stages, with initial stages lasting up to 6 months.

• Stage 1 (acute): edema, vasomotor dysregulation, severe tenderness, and allodynia.   
• Stage 2 (dystrophic): skin and muscle atrophy, brittle nails and atrophy, intense proximal pain, mottled skin, and brawny edema.
• Stage 3 (atrophic): skin becomes pale, smooth, shiny, and cyanotic, contractures and flexion deformities, pain decreases, and vasomotor changes stop.

However, evidence to date suggests that the evolution of CRPS is unlikely to be sequential.

Another CRPS classification is to “warm” and “cold”, with individuals sometimes exhibiting early warm symptoms but transitioning to cold later on.

• Warm: warm, red, dry and edematous extremity, shorter duration (4.7 months)¹
• Cold: cold, blue, sweaty and less edematous extremity, longer duration (20 months)¹

Pain in itself has a multitude of different features or presentations, from burning, stabbing, or a dragging character, to throbbing and constricting. A large proportion of pain is located in deeper structures (muscles, tendons, bones) as compared to the more superficial locations.

Autonomic and trophic changes have a propensity for hyperemic or livid features and a larger majority of individuals show no alteration in the growth of hair and nails. Edema or areas of swelling present most of the time and changing in sweating patterns are inconsistent among individuals. Reduced strength is more prevalent than normal strength and almost half have some form of movement disorder. Sensory disorders tend to be the most consistent deficit and could be increased or decreased at the time of exam.¹⁶

Specific secondary or associated conditions and complications

Secondary complications from CRPS include sequelae of disuse including contractures as well as altered sensation of the affected limb. Infection, edema, dystonia, and myoclonus can also occur. Dystrophic changes of nails, skin, and hair, osteopenia (Sudeck’s atrophy), and small nerve fiber dropout may occur. Impaired sympathetic vasoconstriction may also occur and lead to presyncope or syncope.

Essentials of Assessment

History

A detailed history of present illness is essential. The most common complaints are hyperesthesia and/or allodynia. Pain is often described as hot, burning, and ache-like, and can either follow a dermatomal or a nondermatomal distribution.  It is relieved with medication and rest, and is exacerbated by temperature changes, limb movement, stress and physical activity. Signs and symptoms are highly variable between patients, and often change over time.

History of recent surgery or trauma, including sprains, crush injuries and fractures should be thoroughly assessed as this may be a trigger for CRPS.

To make a clinical diagnosis of CRPS, the following criteria (the Budapest criteria) must be met.²

• The patient must have continuing pain, which is disproportionate to any inciting event.
• The patient must have at least one symptom in 3 of the 4 following categories:

• The patient must display at least one sign during the physical exam in 2 of the 4 categories:

• There is no other diagnosis that better explains the symptoms and signs.
• A diagnostic subtype called CRPS-not otherwise specified (NOS) was created that would capture those patients who did not meet the new clinical criteria but whose signs and symptoms could not be better elucidated by any other diagnosis.²

The Budapest criteria has been reported to have sensitivity of 0.99 and specificity of 0.79.²¹

Specific diagnostic criteria for the pediatric population are currently in development. Diagnostic accuracy of the Budapest criteria in children is somewhat limited as 37% of pediatric CRPS patients do not qualify as having CRPS.²²

Physical examination

The patient must display quasi-objective findings on the exam in at least 2 of the 4 categories. Examination tools should include pin, temperature tape or infrared thermometer, von Frey testing or weighted pin, algometer, and goniometer.

Sensory signs are elicited through light touch and pinprick. Light touch can be performed with a cotton-tipped swab or soft brush. Motor changes can present as reduced range of motion and tremors. Trophic changes may manifest as growth or loss of hair and nail changes.

Vasomotor signs can be detected by assessing skin color and measuring skin temperature in affected and contralateral limbs. CRPS may spread to other extremities, and it may be important to measure skin temperature in arms and legs. The examiner must also assess for sudomotor changes (sweating changes/asymmetry) and edema. Trophic changes manifest as shiny, edematous, and erythematous skin findings with loss of hair.

There are isolated findings in CRPS, which are more suggestive of other conditions on the differential. Limited and painful joint range of motion can be found with adhesive capsulitis. Skin warmth and swelling around the joints may be the first finding for inflammatory arthritis. Red, hot, and painful extremities can be found in erythromelalgia, although this condition is frequently symmetric, while CRPS is at least initially unilateral. Cold limbs might indicate vascular insufficiency. Neuropathic pain can be exquisite in postherpetic neuralgia and shingles. In each of these cases, other physical examination findings may assist in organizing the differential when considering CRPS.

Functional assessment

An impaired limb can be disabling. Inquiry into how patients minimize discomfort while pursuing activities of daily living, including bathing and dressing, can guide functional restoration efforts. Because upper extremities are more frequently affected by CRPS, dominant hand function may be affected. Physical impairment may exceed those found with limb amputations and patients may demonstrate distress similar to that found with other chronic pain conditions. Additionally, neuropsychological changes such as asomatognosia, or “neglect-like” changes, in the absence of any brain lesion have been reported.²³

Laboratory studies

At this time, no laboratory studies are used for the assessment of CRPS. Testing to exclude other diagnoses on the differential, including vascular studies to evaluate compromised limb perfusion, electrodiagnostics for specific neuropathies, and rheumatologic laboratory studies to evaluate for arthritis, may be helpful. While multiple biomarkers have been studied with varied results, currently none are accepted for routine clinical use.²⁴

Imaging

Various imaging modalities have been used for CRPS and could potentially be used to help diagnosis and monitoring; however at this time there are no radiologic diagnostic criteria established and the diagnosis is primarily clinical.²⁵ Triple phase bone scans are generally considered the most useful; however a meta-analysis demonstrated that it has no added value to CRPS diagnosis and should not be used for confirmation. However, a negative bone scan may help to exclude the disease or rule out other etiologies.²⁶

Plain films may reveal patchy osteoporosis at periarticular regions in the affected limb. Magnetic resonance imaging (MRI) is occasionally performed to evaluate for other muscle, joint, or soft tissue etiologies of pain.²⁰ Some data regarding use of functional MRI, CT, PET-CT and diffusion tensor imaging exist; however their use tends to be more experimental.²⁵

Supplemental assessment tools

Historically, the diagnosis of CRPS required abrupt and transient relief from pain and dysesthesia with a systemic chemical sympatholysis (Bier Block) and/or a diagnostic sympathetic block with a stellate ganglion block or a lumbar paravertebral block. However, as the role of the sympathetic nervous system in the pathogenesis of CRPS remains unclear and contradictory, it is now widely accepted that a positive response to sympathetic block is not diagnostic of CRPS. Furthermore, there is low evidence to support or recommend against use of local anesthetic sympathetic blockade is effective for reducing pain in CRPS.²⁷

Autonomic tests such as resting sweat output (RSO), the resting skin temperature (RST), and the quantitative sudomotor axon reflex test (QSART) have been used to evaluate CRPS.²⁸ Quantitative sweat tests and sudomotor axon reflex are sometimes used to assess sudomotor dysfunction but are rarely used and have limited availability. Electrodiagnostic testing may be useful in the diagnosis of CRPS type II to demonstrate nerve injury, although tolerance to this examination may be limited.

Early predictions of outcomes

Early diagnosis and intervention in CRPS is associated with improved outcome and function. Although pain may decrease over time, detrimental changes arise from neuroplasticity. Additionally, long-term deficits in muscles, bones, and nerves are seen if the syndrome advances or goes undiagnosed and untreated.

In a study with a mean follow up of 5.8 years, 30% of patients considered themselves fully recovered, 54% were stable and 16% reported progressive disease.²⁹ Cold CRPS and CRPS involving the upper extremity are associated with worse outcomes.²⁹ Female sex, greater baseline pain, anxiety and disability were associated with worse CRPS severity long term.³⁰ Among older adults with distal radius fractures, higher BMI, immobilization time, and lower physical activity were associated with lower functional outcomes at 6 week and 1 year follow-up.³¹

Recurrence of CRPS is not uncommon; estimates of recurrence range from about 10 to 30%, with the higher rates occurring in younger patients, including children.^32,33

Environmental

Weather may exacerbate CRPS symptoms. Tobacco and alcohol use is reported in 56% and 78% of patients with CRPS, respectively.

Social role and social support system

The most pragmatic assessment of pain must include biological, psychological, and sociological aspects.¹ Secondary psychological responses and dysfunction are ubiquitous.

A 2020 cross-sectional study showed patients with CRPS with more negative disease perceptions experienced greater pain, disability, and kinesiophobia. Psychological stress may influence disease progression as patients with higher levels of anxiety, perception of disability, and pain-related fear have been shown to have a worsened disease course. Plasma levels of epinephrine and norepinephrine were elevated in a sample of CRPS patients compared with healthy control subjects. While theoretically, stress and emotional distress could elevate these catecholamines, a causal relationship between social and environmental influences and the development of CRPS is far from proven. Further, catastrophizing, commonly seen in CRPS, has been shown to increase pro-inflammatory cytokines which may also be linked to disease progression.^1,34,35This psychosocial distress among CRPS patients may result in higher pain intensity compared to similar distress in a non-CRPS chronic pain patient.¹

Addressing psychologic and social factors may improve outcomes; however, neither have been proven as the cause of CRPS.¹ The role of psychologic and social factors must be viewed with caution. It is critical to identify and aggressively treat all spheres of the pain experience.¹

Rehabilitation Management and Treatments

See Complex Regional Pain Syndrome Part 2: Management and Treatment

Cutting Edge/Emerging and Unique Concepts and Practice

See Complex Regional Pain Syndrome Part 2: Management and Treatment

Gaps in the Evidence-Based Knowledge

See Complex Regional Pain Syndrome Part 2: Management and Treatment

References

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Bibliography

Goebel A. Complex regional pain syndrome in adults. Rheumatology. 2011;50:1739-1750.

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Original Version of the Topic

Sunjay Mathur, MD. Complex Regional Pain Syndrome Part 1: Essentials of Assessment and Diagnosis. 8/9/2012.

Previous Revision(s) of the Topic

Luis Baerga-Varela, MD, Rafael Arias-Berrios, MD, Shirley Grigg, MD, Natalia M. Betances Ramírez, MD, Juan Galloza Otero, MD. Complex Regional Pain Syndrome Part 1: Essentials of Assessment and Diagnosis. 8/16/2016.

Laurentiu Dinescu, MD, Justin Faye, MD, Alec Guerzon, MD, Michael Mosier, MD. Complex Regional Pain Syndrome Part 1: Essentials of Assessment and Diagnosis. 1/7/2021

Author Disclosures

Michael Sein, MD
Nothing to Disclose

Rosalynn Conic, MD
Nothing to Disclose