Complex regional pain syndrome: diagnosis and treatment

Key points•Complex regional pain syndrome (CRPS) is a post-traumatic disorder characterized by a non-dermatomal distributed, severe, continuous pain in the affected limb and is associated with sensory, motor, vasomotor, sudomotor, and trophic disturbances.•CRPS is a clinical diagnosis and is diagnosed using the new International Association for the Study of Pain (IASP) clinical diagnostic criteria. There is no diagnostic test specific for CRPS.•The pathophysiology of CRPS is multifactorial, with recent studies pointing towards CRPS being an exaggerated inflammatory response as a result of trauma or surgery.•CRPS should be treated in a multidisciplinary fashion with treatment consisting of adequate pain management, physiotherapy, and psychological evaluation and intervention.•In the future, we expect a shift from a symptomatic to a more mechanism-based treatment of CRPS. •Complex regional pain syndrome (CRPS) is a post-traumatic disorder characterized by a non-dermatomal distributed, severe, continuous pain in the affected limb and is associated with sensory, motor, vasomotor, sudomotor, and trophic disturbances.•CRPS is a clinical diagnosis and is diagnosed using the new International Association for the Study of Pain (IASP) clinical diagnostic criteria. There is no diagnostic test specific for CRPS.•The pathophysiology of CRPS is multifactorial, with recent studies pointing towards CRPS being an exaggerated inflammatory response as a result of trauma or surgery.•CRPS should be treated in a multidisciplinary fashion with treatment consisting of adequate pain management, physiotherapy, and psychological evaluation and intervention.•In the future, we expect a shift from a symptomatic to a more mechanism-based treatment of CRPS. Complex regional pain syndrome (CRPS) is a clinical disorder that is characterized by severe, continuous pain in the affected extremity, which is accompanied by sensory, vasomotor, sudo-motor/oedema, and motor/trophic changes.1Harden RN Bruehl S Perez RS et al.Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for complex regional pain syndrome.Pain. 2010; 150: 268-274Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar. The pain is regionally restricted (i.e. cannot be related to a specific dermatome) and disproportionate to the inciting event.1Harden RN Bruehl S Perez RS et al.Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for complex regional pain syndrome.Pain. 2010; 150: 268-274Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar,2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar CRPS is usually precipitated by trauma (mostly fractures) or surgery.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar The upper extremity is affected more often than the lower extremity.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar, 3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar, 4van Eijs F Stanton-Hicks M Van Zundert J et al.Evidence-based interventional pain medicine according to clinical diagnoses. 16. Complex regional pain syndrome.Pain Pract. 2011; 11: 70-87Crossref PubMed Scopus (117) Google Scholar CRPS is usually limited to one extremity, though cases of CRPS in multiple extremities have been described.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar The incidence of CRPS has been reported to range from 5.5 to 26.2 per 100 000 person-years.3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar,5Sandroni P Benrud-Larson LM McClelland RL Low PA Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study.Pain. 2003; 103: 199-207Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar Women are more frequently affected than men, with studies reporting a three- to four-fold higher incidence in women.3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar,5Sandroni P Benrud-Larson LM McClelland RL Low PA Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study.Pain. 2003; 103: 199-207Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar The highest incidence was found in women aged 61–70 yr.3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar Two distinctive forms of CRPS are currently described in the literature: CRPS type I where there is no demonstrable nerve lesion and CRPS type II where there is demonstrable nerve lesion.1Harden RN Bruehl S Perez RS et al.Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for complex regional pain syndrome.Pain. 2010; 150: 268-274Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar,4van Eijs F Stanton-Hicks M Van Zundert J et al.Evidence-based interventional pain medicine according to clinical diagnoses. 16. Complex regional pain syndrome.Pain Pract. 2011; 11: 70-87Crossref PubMed Scopus (117) Google Scholar,6Merskey H Bogduk N Classification of Chronic Pain (Revised). 2nd Edn. IASP, Seattle, WA2011: 4-7Google Scholar CRPS types I and II do not differ in clinical presentation and the choice of treatment.7Bruehl S An update on the pathophysiology of complex regional pain syndrome.Anesthesiology. 2010; 113: 713-725Crossref PubMed Scopus (277) Google Scholar Consequently, CRPS will be used as a general term in this article referring to both CRPS type I and CRPS type II. CRPS can have a severe impact on the quality of life of patients and can lead to substantial physical and social disability.8de Mos M Sturkenboom MC Huygen FJ Current understandings on complex regional pain syndrome.Pain Pract. 2009; 9: 86-99Crossref PubMed Scopus (120) Google Scholar,9Kemler MA Furnee CA The impact of chronic pain on life in the household.J Pain Symptom Manage. 2002; 23: 433-441Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar It is therefore important for clinicians to recognize and diagnose this disorder in order to provide appropriate care and guidance to patients suffering from this debilitating disease. The purpose of this educational article is to provide clinicians with concise information regarding the pathophysiology, diagnosis, and treatment of CRPS. Patients generally present themselves with severe, continuous pain that typically takes on a glove- or stocking-like distribution.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar Injury or surgery usually precede the symptoms.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar The pain is often accompanied by sensory, vasomotor, sudomotor/oedema, and motor/trophic symptoms. These signs and symptoms can vary during the course of the disease. Patients may report (hyper)sensitivity to painful and non-painful stimuli (hyperaesthesia and/or allodynia). Differences in skin temperature between the affected and contralateral limb may be reported. Sweating patterns between the affected and contralateral limb may be altered. Swelling of the affected limb can be reported. Symptoms of motor dysfunction, such as loss of range of motion, tremor, and dystonia, can be described. Patients may also report changes in hair and nail growth of the affected limb.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar Patients may further report increase of symptoms after exercise.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar Findings during physical examination include, but are not limited to, allodynia and/or hyperalgesia, differences in colour and skin temperature between the affected and contralateral limb, and oedema of the affected limb.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar Functional tests may reveal a reduction in the range of motion of the affected limb in comparison with the contralateral limb.3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar Tremor, dystonia, and altered nail and hair growth of the affected limb can also be observed.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,3de Mos M de Bruijn AG Huygen FJ Dieleman JP Stricker BH Sturkenboom MC The incidence of complex regional pain syndrome: a population-based study.Pain. 2007; 129: 12-20Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar CRPS patients are often described as having warm, intermediate, or cold CRPS based on reported and measured skin temperature differences between the affected and contralateral limb.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,10Wasner G Schattschneider J Heckmann K Maier C Baron R Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value.Brain. 2001; 124: 587-599Crossref PubMed Scopus (264) Google Scholar Current research suggests the existence of different phenotypes of CRPS based on the signs and symptoms deemed most prominent during history taking and physical examination.11Bruehl S Harden RN Galer BS Saltz S Backonja M Stanton-Hicks M Complex regional pain syndrome: are there distinct subtypes and sequential stages of the syndrome?.Pain. 2002; 95: 119-124Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar These signs and symptoms could reflect the underlying pathophysiological mechanism (i.e. inflammation, pain/sensory disturbances, vasomotor disturbances, motor disturbances, and psychological disturbances). When assessing signs and symptoms of CRPS patients, it is important for physicians to recognize which pathophysiological mechanism is most prominent. By determining the most prominent mechanism, physicians can use specific therapies to target these mechanisms (Fig. 1). It is our hypothesis that in the majority of patients, especially patients with warm (acute) CRPS, inflammation is the most prominent mechanism. All the other mechanisms are a result of the ongoing inflammation. During the course of the disease, inflammation disappears in some of the patients, resulting in different forms of rest damage. There is currently no gold standard for the diagnosis and treatment of CRPS. History and physical examination are the cornerstones for appropriate diagnosis and management.1Harden RN Bruehl S Perez RS et al.Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for complex regional pain syndrome.Pain. 2010; 150: 268-274Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar Various criteria exist for the diagnosis of CRPS.1Harden RN Bruehl S Perez RS et al.Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for complex regional pain syndrome.Pain. 2010; 150: 268-274Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar,2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar Currently, the most commonly used criteria for the diagnosis of CRPS are the new International Association for the Study of Pain (IASP) clinical diagnostic criteria1Harden RN Bruehl S Perez RS et al.Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for complex regional pain syndrome.Pain. 2010; 150: 268-274Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar (Table 1). These criteria are based on observed and patient-reported signs and symptoms.1Harden RN Bruehl S Perez RS et al.Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for complex regional pain syndrome.Pain. 2010; 150: 268-274Abstract Full Text Full Text PDF PubMed Scopus (689) Google ScholarTable 1New International Association for the Study of Pain (IASP) clinical diagnostic criteria1Harden RN Bruehl S Perez RS et al.Validation of proposed diagnostic criteria (the ‘Budapest Criteria’) for complex regional pain syndrome.Pain. 2010; 150: 268-274Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar 1.Continuing pain, which is disproportionate to any inciting event.2.Must report at least one symptom in three of the four of the following categories: •Sensory: reports of hyperaesthesia and/or allodynia•Vasomotor: reports of temperature asymmetry and/or skin colour changes and/or skin colour asymmetry•Sudomotor/oedema: reports of oedema and/or sweating changes and/or sweating asymmetry•Motor/trophic: reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)3.Must display at least one sign at time of evaluation in two or more of the following categories: •Sensory: evidence of hyperalgesia (to pinprick) and or allodynia (to light touch and/or deep somatic pressure and/or joint movement)•Vasomotor: evidence of temperature asymmetry and/or skin colour changes and/or asymmetry•Sudomotor/oedema: evidence of oedema and/or sweating changes and/or sweating asymmetry•Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail skin)4.There is no other diagnosis that better explains the signs and symptoms. Open table in a new tab CRPS has an extensive differential diagnosis, which can be summarized into the following categories: neuropathic pain-like syndromes, myofascial pain syndromes, inflammation, vascular diseases, and psychological disorders (Table 2).4van Eijs F Stanton-Hicks M Van Zundert J et al.Evidence-based interventional pain medicine according to clinical diagnoses. 16. Complex regional pain syndrome.Pain Pract. 2011; 11: 70-87Crossref PubMed Scopus (117) Google Scholar Most of these disorders have similar presentations, occasionally making the diagnosis of CRPS a challenge.Table 2Differential diagnosis of complex regional pain syndrome.4van Eijs F Stanton-Hicks M Van Zundert J et al.Evidence-based interventional pain medicine according to clinical diagnoses. 16. Complex regional pain syndrome.Pain Pract. 2011; 11: 70-87Crossref PubMed Scopus (117) Google Scholar Copyright © 2012 John Wiley & Sons, Ltd.Neuropathic pain syndromes •Peripheral (poly) neuropathy •Nerve entrapment •Radiculopathy •Post-herpetic neuralgia •De-afferentation pain post-cerebrovascular accident•Plexopathy•Motor neuron diseaseVascular diseases •Thrombosis •Acrocyanosis •Atherosclerosis •Raynaud's phenomenon •ErythromelalgiaInflammation •Erysipelas •Inflammation-not otherwise specified •Bursitis •Seronegative arthritis •Rheumatologic diseasesMyofascial pain syndromes •Overuse •Disuse •Tennis elbow •Repetitive strain injury •FibromyalgiaPsychiatric problems •Somatoform pain disorders •Munchhausen syndrome Open table in a new tab As the pathophysiology of CRPS is still not completely understood, there is limited use for additional clinical and laboratory tests in the diagnosis of CRPS.4van Eijs F Stanton-Hicks M Van Zundert J et al.Evidence-based interventional pain medicine according to clinical diagnoses. 16. Complex regional pain syndrome.Pain Pract. 2011; 11: 70-87Crossref PubMed Scopus (117) Google Scholar Diagnostic tests can, however, be used to exclude other disorders that could explain the observed signs and symptoms or to monitor the signs and symptoms of CRPS. An example of the latter is quantitative sensory testing, which is mostly used in research settings to quantify sensory disturbances found during physical examination. The exact pathophysiology of CRPS is still unknown.12Birklein F Schlereth T Complex regional pain syndrome-significant progress in understanding.Pain. 2015; 156: S94-103Crossref PubMed Scopus (110) Google Scholar Both peripheral and central mechanisms are thought to play a role in the initiation and maintenance of CRPS.12Birklein F Schlereth T Complex regional pain syndrome-significant progress in understanding.Pain. 2015; 156: S94-103Crossref PubMed Scopus (110) Google Scholar Various studies point towards CRPS being an exaggerated inflammatory response as a result of trauma or surgery.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,13Huygen FJ De Bruijn AG De Bruin MT Groeneweg JG Klein J Zijlstra FJ Evidence for local inflammation in complex regional pain syndrome type 1.Mediators Inflamm. 2002; 11: 47-51Crossref PubMed Scopus (275) Google Scholar This inflammatory response has long been a topic of debate, as general markers of inflammation, such as C-reactive protein, white blood cell count, interleukin 6 (IL-6), and erythrocyte sedimentation rate, are usually not elevated in plasma of CRPS patients.2Veldman PH Reynen HM Arntz IE Goris RJ Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients.Lancet (London, England). 1993; 342: 1012-1016Abstract PubMed Scopus (945) Google Scholar,14Schinkel C Gaertner A Zaspel J Zedler S Faist E Schuermann M Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome.Clin J Pain. 2006; 22: 235-239Crossref PubMed Scopus (164) Google Scholar However, when considering the symptoms of (acute) CRPS, ‘classic signs of inflammation’, such as pain, redness, increase in temperature, swelling, and loss of function, are often displayed.8de Mos M Sturkenboom MC Huygen FJ Current understandings on complex regional pain syndrome.Pain Pract. 2009; 9: 86-99Crossref PubMed Scopus (120) Google Scholar Recent studies focusing on inflammatory processes in CRPS have found higher levels of pro-inflammatory cytokines in blister fluid [IL-6, tumor necrosis factor alpha (TNF-α)] of the affected extremity compared with the unaffected extremity. This suggests a role for local inflammatory processes in CRPS.13Huygen FJ De Bruijn AG De Bruin MT Groeneweg JG Klein J Zijlstra FJ Evidence for local inflammation in complex regional pain syndrome type 1.Mediators Inflamm. 2002; 11: 47-51Crossref PubMed Scopus (275) Google Scholar Elevated levels of pro-inflammatory cytokines have further been found in serum, plasma, and cerebrospinal fluid of patients with CRPS.14Schinkel C Gaertner A Zaspel J Zedler S Faist E Schuermann M Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome.Clin J Pain. 2006; 22: 235-239Crossref PubMed Scopus (164) Google Scholar, 15Alexander GM van Rijn MA van Hilten JJ Perreault MJ Schwartzman RJ Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS.Pain. 2005; 116: 213-219Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 16Alexander GM Peterlin BL Perreault MJ Grothusen JR Schwartzman RJ Changes in plasma cytokines and their soluble receptors in complex regional pain syndrome.J Pain. 2012; 13: 10-20Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Pro-inflammatory cytokines have been suggested to be involved in peripheral nociceptor activation and sensitization, which in turn could cause symptoms such as pain and hyper-algesia that are experienced in CRPS.17Sommer C Kress M Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia.Neurosci Lett. 2004; 361: 184-187Crossref PubMed Scopus (664) Google Scholar Apart from the ‘classic’ form of inflammation, studies have proposed neurogenic inflammation as an underlying mechanism for symptoms such as oedema, vasodilation, and increased sweating that are observed in CRPS.18Birklein F Schmelz M Schifter S Weber M The important role of neuropeptides in complex regional pain syndrome.Neurology. 2001; 57: 2179-2184Crossref PubMed Scopus (228) Google Scholar Studies have found increased levels of calcitonin-gene-related peptide (CGRP) and substance P (SP) in serum of patients with CRPS versus healthy controls.14Schinkel C Gaertner A Zaspel J Zedler S Faist E Schuermann M Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome.Clin J Pain. 2006; 22: 235-239Crossref PubMed Scopus (164) Google Scholar,18Birklein F Schmelz M Schifter S Weber M The important role of neuropeptides in complex regional pain syndrome.Neurology. 2001; 57: 2179-2184Crossref PubMed Scopus (228) Google Scholar These neuropeptides have been shown to lead to neurogenic dilatation of arterioles (CGRP) and plasma protein extravasation (SP).19Holzer P Neurogenic vasodilatation and plasma leakage in the skin.Gen Pharmacol. 1998; 30: 5-11Crossref PubMed Scopus (382) Google Scholar This in turn could explain the redness and swelling that are observed in CRPS.18Birklein F Schmelz M Schifter S Weber M The important role of neuropeptides in complex regional pain syndrome.Neurology. 2001; 57: 2179-2184Crossref PubMed Scopus (228) Google Scholar,19Holzer P Neurogenic vasodilatation and plasma leakage in the skin.Gen Pharmacol. 1998; 30: 5-11Crossref PubMed Scopus (382) Google Scholar CRPS has previously been described as an autoantibody-mediated autoimmune disease.20Goebel A Blaes F Complex regional pain syndrome, prototype of a novel kind of autoimmune disease.Autoimmun Rev. 2013; 12: 682-686Crossref PubMed Scopus (78) Google Scholar,21Goebel A Leite MI Yang L et al.The passive transfer of immunoglobulin G serum antibodies from patients with longstanding Complex Regional Pain Syndrome.Eur J Pain. 2011; 15: 504.e1-504.e6Google Scholar Passive transfer of CRPS patient serum–immunoglobulin G has been shown to induce behavioural changes in mice, and serum from CRPS patients has been shown to stain rodent sympathetic ganglia.20Goebel A Blaes F Complex regional pain syndrome, prototype of a novel kind of autoimmune disease.Autoimmun Rev. 2013; 12: 682-686Crossref PubMed Scopus (78) Google Scholar,22Blaes F Schmitz K Tschernatsch M et al.Autoimmune etiology of complex regional pain syndrome (M. Sudeck).Neurology. 2004; 63: 1734-1736Crossref PubMed Scopus (69) Google Scholar Furthermore, a small group of CRPS patients experienced pain relief after treatment with low-dose intravenous immunoglobulin.21Goebel A Leite MI Yang L et al.The passive transfer of immunoglobulin G serum antibodies from patients with longstanding Complex Regional Pain Syndrome.Eur J Pain. 2011; 15: 504.e1-504.e6Google Scholar A study conducted by Dirckx et al.23Dirckx M Schreurs MW de Mos M Stronks DL Huygen FJ The prevalence of autoantibodies in complex regional pain syndrome type I.Mediators Inflamm. 2015; 2015: 718201Crossref PubMed Scopus (25) Google Scholar showed a significantly higher proportion of CRPS patients with positive anti-nuclear antibody test results as compared to a population of healthy blood bank donors. There are thus many findings supporting this theory of autoimmunity.20Goebel A Blaes F Complex regional pain syndrome, prototype of a novel kind of autoimmune disease.Autoimmun Rev. 2013; 12: 682-686Crossref PubMed Scopus (78) Google Scholar,23Dirckx M Schreurs MW de Mos M Stronks DL Huygen FJ The prevalence of autoantibodies in complex regional pain syndrome type I.Mediators Inflamm. 2015; 2015: 718201Crossref PubMed Scopus (25) Google Scholar However, to define a disease as an autoimmune disorder certain criteria (Witebsky's criteria) must be met.24Rose NR Bona C Defining criteria for autoimmune diseases (Witebsky's postulates revisited).Immunol Today. 1993; 14: 426-430Abstract Full Text PDF PubMed Scopus (626) Google Scholar These criteria have not yet been fulfilled in the case of CRPS which gives rise to the question whether CRPS is more an auto-inflammatory than an autoimmune disease.23Dirckx M Schreurs MW de Mos M Stronks DL Huygen FJ The prevalence of autoantibodies in complex regional pain syndrome type I.Mediators Inflamm. 2015; 2015: 718201Crossref PubMed Scopus (25) Google Scholar Another hypothesis on the pathophysiology of CRPS is that of deep-tissue microvascular ischaemia–reperfusion injury.25Laferriere A Millecamps M Xanthos DN et al.Cutaneous tactile allodynia associated with microvascular dysfunction in muscle.Mol Pain. 2008; 4: 49Crossref PubMed Scopus (55) Google Scholar This hypothesis, which was tested in a chronic post-ischaemia pain animal model, proposes a state of deep-tissue ischaemia and inflammation caused by a microvascular ischaemia–reperfusion injury as the cause for abnormal pain sensations, such as allodynia, in CRPS.25Laferriere A Millecamps M Xanthos DN et al.Cutaneous tactile allodynia associated with microvascular dysfunction in muscle.Mol Pain. 2008; 4: 49Crossref PubMed Scopus (55) Google Scholar,26Coderre TJ Bennett GJA Hypothesis for the cause of complex regional pain syndrome-type I (reflex sympathetic dystrophy): pain due to deep-tissue microvascular pathology.Pain Medicine (Malden, Mass). 2010; 11: 1224-1238Crossref PubMed Scopus (95) Google Scholar Genetics seems to play a role in the predisposition to CRPS. A Dutch cohort study showed the frequency of human leucocyte antigen (HLA)-DQ1 to be significantly higher in CRPS patients than in the controls.27Kemler MA van de Vusse AC van den Berg-Loonen EM Barendse GA van Kleef M Weber WE HLA-DQ1 associated with reflex sympathetic dystrophy.Neurology. 1999; 53: 1350-1351Crossref PubMed Google Scholar There is evidence that HLA-B62 and HLA-DQ8 are associated with CRPS with fixed dystonia.28de Rooij AM Florencia Gosso M Haasnoot GW et al.HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia.Pain. 2009; 145: 82-85Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Another study showed HLA-DR13 to be associated with multifocal or generalized tonic dystonia of CRPS.29van Hilten JJ van de Beek WJ Roep BO Multifocal or generalized tonic dystonia of complex regional pain syndrome: a distinct clinical entity associated with HLA-DR13.Ann Neurol. 2000; 48: 113-116Crossref PubMed Scopus (95) Google Scholar These findings indicate that certain HLA loci may be involved in the susceptibility to certain phenotypes of CRPS.28de Rooij AM Florencia Gosso M Haasnoot GW et al.HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia.Pain. 2009; 145: 82-85Abstract Full Tex