Michael Stanton-Hicks Pain Management Department, Centre for Neurological Restoration; Children’s Hospital CCF Shaker Pediatric Pain Rehabilitation Program, Cleveland Clinic, Cleveland, Ohio, USA Complex Regional Pain Syndrome (CRPS), synonymous with Reflex Sympathetic Dystrophy (RSD), has a long history. Ambrose Pare′, surgeon to King Charles IX, provided one of the earliest descriptions of this syndrome in the 16th century after bloodletting in the arm of the Monarch who was suffering from smallpox [1]. Denmark in 1813 provided a similar description following amputation in a soldier during the Peninsula War [2]. In 1900, Sudeck, a German surgeon in Eppendorf, described radiologic changes that were associated with the putative syndrome that bears his name in German‐speaking countries [3]. The next major and perhaps the most complete description came from Silas Weir Mitchell, who described what he named causalgia (causa ‐ heat, algia ‐ pain) that developed following a musket shot wound in an extremity of soldiers during the American Civil War [4]. Symptoms were the same; extremely severe burning pain and shiny, red, hot skin. During World War II, James Evans introduced the term RSD [5]. In 1994, a consensus group under the auspices of the International Association for the Study of Pain (IASP) developed the initial criteria that make up the acronym CRPS (Complex Regional CRPS is a painful condition that is invariably a consequence of a sprain, fracture or surgery of an extremity that tends to be distal, but can, less frequently, occur at other sites of the body (e.g. the knee) or, rarely, without any recorded history. In fact, the trigger may be as inconsequential as an insect bite. Two distinct subtypes are described: CRPS I (formally RSD) in which there is no obvious nerve injury and CRPS II (formerly causalgia), where nerve injury has occurred. The clinical presentation includes inflammatory changes, autonomic dysfunction, nervous system sensitization, spontaneous pain, allodynia/hyperalgesia and motor disturbances that are out of proportion with what would be expected from each inciting event. In most cases, the foregoing clinical features are usually found in one extremity but, in a smaller number of patients, they may be expressed in another or multiple extremities [8, 9]. Early or acute CRPS is generally associated with “warm” skin, but a few patients may present with so called‐called “cold” CRPS, normally a feature of the chronic syndrome. Secondary structural changes in superficial and deep tissues may develop over time [10]. While our understanding of CRPS epidemiology has improved considerably, there are still distinct anomalies between study populations, data gathering and countries that highlight the current gaps in our knowledge. The first study of 85 patients from a small community in Rochester, MN, USA, gathered by Sandroni et al in 2003 using IASP criteria, found a prevalence of 21:100,000 with females predominating 3:1 and expression in the upper extremity occurring in more than 60% of all patients [11]. A more recent study of 1043 patients in a regional community in Germany by Ott and Maihöfner has corroborated these results [12]. Most recently, however, Kim et al. used data from the National Health Insurance Service of Korea (74,349 patients) and found a much narrower ratio of female to male prevalence, a reversal of the upper vs. lower limb incidence and a higher age incidence. It should be pointed out, however, that many of the patients in this study were diagnosed using the Persistent Disability and Assessment Guidelines of the American Medical Association (AMA) and not the IASP criteria. In addition, the study population included individuals who were both older and on workers compensation, thereby increasing the proportion of those with lower extremity injuries. These data are not directly comparable because of the different criteria used and the nature of the populations studied [13] In adolescents and children, where the data are more certain, females outnumber males by a ratio of 4:1 [14]. This chapter describes the diagnostic assessment and subsequent management of CRPS based on the best evidence approach. A number of mechanisms underlying sensory, motor, inflammatory, immune/auto immune, autonomic and genetic influences are addressed in the context of treatment and management strategies. Table 37.1 Diagnostic critera “Budapest” for CRPS. Patients must exhibit at least 1 SYMPTOM in 3 of 4 categories and 1 SIGN in 2 or more categories (sens. 0.99; spec. 0.68)” Whereas the initial International Association for the Study of Pain (IASP) diagnostic criteria that were introduced in 1999 lacked clinical validation, their introduction was meant to provide a common descriptive set of clinical signs and symptoms without the suggestion of a purported mechanism that could be applied to the diagnosis of CRPS [6]. Their subsequent validation and acceptance as the Budapest Criteria by the IASP in 2010 now provides a universal clinical tool with a high degree of specificity while still maintaining adequate sensitivity that will avoid the underdiagnosis of CRPS [15, 16]. The phenomenon of Sympathetically Maintained Pain (SMP), previously a requirement for the diagnosis of CRPS, is now acknowledged as being a symptom that may be present in many other neuropathic disorders that is not exclusive to CRPS [17]. The Budapest criteria are shown in Table 37.1. To improve the integrity of the Budapest criteria and provide both a catalogue of the presenting symptoms from which temporal changes during the course of the syndrome can be quantified, it was necessary to develop a scale that includes elements of the Budapest criteria that express severity of the condition at any time point. Of the previous severity scales, the Impairment Level SumScore (a validated instrument) is one the best and most comprehensive, but does not contain some of the elements in the Budapest Criteria and therefore would not be appropriate in this case. To address this issue, Harden et al, 2010 developed the CRPS Severity Score (CSS). The study based on the same 16 signs and symptoms that was subsequently validated was published by Harden et al. in 2017 [18] (Figure 37.1). A number of recent reports have identified predisposing factors, the nature of injuries and possible biomarkers that would seem to make the development of CRPS more likely. Fractures of the forearm, the so‐called antebrachial region or similar injuries of the lower extremity (ankle fracture) are more susceptible to the development of CRPS [19, 20]. Severe fractures and high energy trauma, musculoskeletal disease, rheumatoid arthritis and prolonged general anesthesia (but not regional anesthesia) are all associated with a higher incidence of CRPS [21]. Immobilization is a risk factor for the development of CRPS. Studies of immobilization in humans shown the development of sensitivity to heat and pressure without pain [22]. Finally, the question of whether there is a genetic association in CRPS has been raised. Some smaller studies have described polymorphisms in potential mediators of inflammation such as cytokines and the α1a‐adrenoceptor [23]. Many diseases with associated inflammation, such as multiple sclerosis and celiac disease, also have a genetic association with the human leukocyte antigen (HLA) system [24]. Mailis and Wade were the first to implicate the HLA and CRPS (RSD) and drew attention to multiple sclerosis and narcolepsy, which also share the DR2(15) antigen. The HLA‐DR13 antigen is associated with dystonia in CRPS and, in a study of genome‐wide profiling, certain genes including HLA‐related genes are differentially expressed [25]. Another aspect of genetic studies is the identification of specific micro RNAs. As such, these non‐coding RNA molecules are “master regulators” that control many proteins and are responsible for translational processes involved in cell‐to‐cell communication and could ultimately be biomarkers for CRPS soon after injury [26]. A definite genetic underpinning with CRPS therefore remains to be confirmed. Figure 37.1 CRPS) Severity Score – CSS. Temperature measurement, preferably by thermography, is one of the most useful objective signs and is also a component of the CSS [27]. For some years, bone scintigraphy (3‐phase) has been promoted as a useful adjunct to confirm a diagnosis of CRPS. However, although its specificity is high, its sensitivity in relation to the Budapest criteria is poor [28]. Furthermore, a recent metanalysis of bone scintigraphy does not support its use in the diagnosis of CRPS [29]. As a diagnostic tool, electromyography is useful to identify a nerve lesion (CRPS 2). More recently, electromyography has been suggested as a tool to distinguish myoclonus in CRPS patients from other causes [30]. However, because this sign is present in only 11 ‐ 36 % of cases, it lacks sensitivity to support a clinical diagnosis of CRPS. No unitary pathology is available to explain the onset of CRPS. In fact, it seems to be a combination of an abnormal inflammatory response and peripheral nervous system dysfunction [31]. Underlying the typical features of inflammation, is a complex immune response that includes the proliferation of keratinocytes releasing inflammatory cytokines (an innate‐immune response) [32]. Cytokines (including TNFα, IL‐6 and IL‐8) found in the first 3 months after onset amongst other inflammatory reactions also evoke the release of osteoblasts and osteoclasts that are responsible for the bony changes (osteoporosis) and the proliferation of connective tissue cells that ultimate lead to contractures [33, 34]. The peripheral nervous system both manifests and is impacted by the inflammatory response. Neurogenic inflammation (the term used to describe the release from nociceptors of substance P (SP) and calcitonin gene‐related peptide (CGRP), which are neuropeptides that supplement the classical signs of inflammation) added to nociceptor sensitization by inflammatory cytokines leads to pain and hyperalgesia [35]. Additionally, SP underlies increased hair growth, a frequent accompaniment of CRPS and CGRP that can cause hyperhidrosis [36]. CRPS has also been ascribed as having a small‐fiber neuropathic etiology [37]. Intraepidural neurites are reduced by 29% in affected skin compared with unaffected control sites [38]. Axonal loss can have far reaching effects in sub‐served tissues and absent nervi vasorum can affect the microcirculation indiscriminately causing mismatch between arteriolar and venular flows and increasing the bypass of blood flow via arteriovenous shunts (AVS), resulting in tissue hypoxia and edema. Other neuropeptides that are released from small fibers activate macrophages, mast cells and other immune cells that then exaggerate the inflammatory response [39. 23, 40]. One particular enzyme, tryptase, from mast cells found in CRPS 1 in the affected local tissue together with other pro‐inflammatory cytokines promotes inflammation [41]. During the onset and acute (3‐ 4‐month) phase of the syndrome, an adaptive‐immunity develops after which there is a tendency for some of the early clinical signs to normalize. However, in many cases temporal changes in the pathophysiology of CRPS can be identified as the syndrome passes through an intermediate (15 month) timeframe before becoming chronic. Some of these reflect autoimmune aspects such as serum autoantibodies against adrenergic and cholinergic receptors [42, 43]. These findings will be discussed below. Although the clinical inflammatory signs are less obvious in cold CRPS, recent studies underscore a continuing but changed type of local inflammation [44]. A disturbance of the sympathetic component of the autonomic nervous system has always been associated with CRPS [45]. The alteration in sweating, vasoconstriction, related fluctuations of temperature and the phenomenon of Sympathetically Maintained pain (SMP) have been considered synonymous with CRPS. Although this viewpoint has taken a back seat to the enormous progress that has been made in our understanding of the combined inflammatory and complex immune processes that constitute CRPS, the recent discovery of agonistic serum auto‐antibodies against adrenergic and cholinergic receptors (SNS) suggestive of an autoimmune involvement gives one pause for thought [46]., The relief of pain after sympathetic block suggests a direct or indirect interruption of the SNS [47]. The failure to relieve pain after a sympathetic block however is termed sympathetically independent pain (SIP) and may reflect reorganization of the central nervous system (CNS) [48]. However, dysfunction of the SNS is consistent with the both acute and chronic CRPS. In fact, Gradl et al determined that hypoactivity of the SNS was systemic‐wide and not exclusive to the ipsilateral extremity [49]. Their work underscores not just continuing inflammation, but also ongoing SNS dysfunction as found by Vogl et al. [50]. At the height of the acute phase of CRPS when hypofunction of the SNS and impairment of vasoconstrictor reflexes are at their peak, local vasodilatation is due to a number of factors including neurogenic inflammation (above), abnormal endothelin‐1/NO ratio and inflammatory cytokines IL‐1β, !L‐6, TNFα. Antigen‐presenting cells (APC) such as dendritic cells (epidermal synonymous with Langerhans cell) are another source of inflammatory cytokines, above [51]. These cells express α1‐ adrenoceptors, which are also found on lymphoid tissue [52. 53]. The sub‐type α1A‐adrenoceptor is driven by the expression of inflammatory cytokines TNFα or IL‐1β [54]. The two phenotypes, warm and cold CRPS represent not just differences in temperature, but also reflect dissimilar risk factors or mechanisms. Warm CRPS is associated with mechanical hyperalgesia while sensory loss, cold‐induced pain and dystonia are clinical features found in cold CRPS [55]. A history of prior chronic pain or severe life events are also more common in patients who present with cold CRPS [47]. Twenty percent of patients with early CRPS present with a cold extremity [56]. The change in temperature and blood flow from acute to chronic CRPS reflects a continuum of vasoactivity and inflammation throughout the early course of the syndrome that trends in most cases toward a cold extremity. In a few patients, however, the limb will remain warm, sometimes for years. We know from studies that the up‐regulation and increasing density of alpha‐1 adrenoceptors (α‐1 AR’s) is also responsible for vasoconstriction and a cold extremity [57, 58]. Beta‐2 adrenoceptors (β‐2 AR) activated by norepinephrine have also been shown to liberate interleukin‐6 (IL‐6), which sensitizes nociceptors and thereby amplifies CRPS symptoms, an indirect adrenergic action [59]. Whereas the noradrenergic system in the CNS is normally antinoceptive, with alpha‐2 adrenoceptors (α‐2 AR) having an inhibitory function at the dorsal horn, this system is compromised after peripheral nerve injury, thereby enhancing excitatory transmission [59]. During the past decade, much interest has been generated by autoimmune aspects of CRPS. In their studies of immunoglobulins such as IgG in both animals and patients, Goebel and coworkers have characterized CRPS as a “novel kind of autoimmune disease” [60, 61]. Agonistic autonomic receptor autoantibodies are prevalent in CRPS. Translational studies in rodents have shown that human serum immunoglobulins from patients with long‐standing CRPS activate α1A adrenoceptors or muscarinic receptors with high binding affinity [62]. Flow cytometric and spectrofluorometric studies would suggest an antibody‐induced α1A adrenoceptor activation. Many CRPS patients also suffer from visceral conditions such as voiding difficulties (Interstitial cystitis (IS)) and irritable bowel syndrome (IBS) ‐ suggestive of a much more widespread autonomic dysregulation [63]. Another example of an autoimmune‐related mechanism in CRPS are the results of recent studies by Tajerian et al. who used liquid crystal mass spectrometry to detect increased levels of a large protein Krt16, which is a biomarker for conditions like rheumatoid arthritis. The finding of increased binding of Krt16 on mRNA and protein in mouse skin in their murine fracture immobilization model is suggestive of an autoimmune reactivity in animals and humans with CRPS. These results corroborate the association of CRPS with the HLA system already mentioned above [64]. The observation of neuronal plasticity in the CNS during the course of CRPS been greatly facilitated by almost two decades of extraordinary advances in neuro imaging. Cumulative evidence of both structural and functional changes in somatosensory and somatomotor cortical representations, subcortical and autonomic brain regions are reflected during CRPS [65]. The prevalence of motor symptoms including paresis, tremor, dystonia, myoclonus and exaggerated tendon reflexes in CRPS patients is associated with morphological and functional alterations in the primary somatosensory cortex [66, 67]. Weakness, poor coordination and reduced distal arm mobility followed by tremor are the most common impairments [68] and dystonia occurs in more than 50% of patients [69]. Dystonia is related to neuropathological defects in basal ganglia and is manifested by posturing involving the wrist and fingers in the upper extremity with plantar flexion or inversion as the most common signsI in the lower extremity [70]. Dystonia may occur not just in the acute phase, but also during the chronic phase. The disease may spread to involve more than one extremity and dystonia may also occur in more than one limb. fMRI imaging of CRPS patients has revealed bilateral reduction of putaminal and nucleus acumbens volumes [71]. Similar changes in the ventral striatum would also be consistent with corresponding changes of functional connectivity between these subcortical structures and the ipsilateral somatosensory and association cortices. Such alterations of somatosensory networks have been described in children who avoid movement due to fear of pain. Other CRPS CNS changes that have benefited from brain imaging are the cingulate and amygdala (emotional function), perirhinal and hippocampus (memory). As a research tool, understanding the clinical course of CRPS has benefitted from observing changes in connectivity after different therapeutic interventions [72]. Another direct consequence of somatosensory reorganization is the body midline‐shift to the healthy side – distorted image of the affected extremity [73]. Similarities in the perception of their affected extremity are found between patients who have CRPS or stroke. After crossing the unaffected limb to the ipsilateral side, any tactile information will be perceived as arising from the unaffected limb [74]. Application of this phenomenon to the use of mirror therapy will be discussed under clinical management. Central sensitization (e.g. onset of allodynia) is demonstrated by activation of the “brain matrix” and has been demonstrated by fMRI [75]. Although several studies and one large metanalysis have not found any predisposing psychological morbidity that might influence the onset and maintenance of CRPS, some factors such as posttraumatic stress disorder (PTSD) after previous injury have been shown to influence the onset of CRPS [76, 77]. Additionally, while there is no evidence to suggest that patients with CRPS are more anxious or more depressed than other patients after trauma, the comparatively severe and relentless nature of symptoms and depersonalization (an attributive behavioral state) has recently undergone evaluation in patients who have continuing chronic pain following trauma. An instrument, the Cambridge Depersonalization Scale, has been used to compare patients with limb trauma and CRPS. Recent results have shown a greater number of depersonalization phenomena in CRPS patients. An exaggerated negative psychological response to painful stimuli (catastrophizing) could influence the onset of CRPS, although distinguishing this from its natural history is difficult [78]. Catastrophizing in children is associated with altered somatosensory brain volumes leading to chronic pain and impaired motor function [79]. During the past decade several recent studies have addressed how social factors can adversely influence the onset or course of CRPS. These include social status, workers compensation and litigation related to the source of injury [80, 81].
Chapter 37
Complex regional pain syndrome
History
Introduction
Category
Symptom
Sign
SENSORY
Hyperesthesia,
allodynia
hyperalgesia (PP)
allodynia – mech. /
thermal / deep
VASOMOTOR
Δ skin / color
Δ temperature
> 1˚ C / Δ skin color
SUDOMOTOR
EDEMA
Δ sweating / edema
Δ sweating / edema
MOTOR
TROPHIC
motor dysfunction 
ROM
Δ trophic
motor dysfunction 
ROM (weak,
dystonia, tremor) /
trophic
Diagnosis and Influencing Factors
Adjuncts to Diagnosis
Pathophysiology
Autonomic Nervous System and the Immune Response
Autoimmunity
Central Nervous System
Behavioral Aspects
Management of CRPS
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