Complex Regional Pain Syndromes I and II (Reflex Sympathetic Dystrophy, Causalgia)

Introduction

The definitions of reflex sympathetic dystrophy (RSD) and causalgia syndromes have been revised recently to avoid implicating the sympathetic nervous system in treatment or mechanism; the syndromes have been renamed with the clinically descriptive terms of complex regional pain syndrome types I and II (CRPS type I and CRPS type II). Given the incomplete understanding of these syndromes, restructuring the diagnostic criteria of RSD to CRPS nomenclature was based on a consensus of the contemporary knowledge about the nature of the disorder revised by international expert clinicians and scientists. According to the International Association of Study of Pain (IASP) and the National Institute of Neurological Disorders and Stroke, CRPS is a chronic pain condition that is probably due to dysfunction in the central and/or peripheral nervous systems. The initial consensus-based diagnostic criteria described a collection of clinical symptoms and signs affecting a region of the body, most commonly after trauma ( Table 48.1 ). CRPS is characterized by abnormal sensory, autonomic, cutaneous and bone changes restricted to commonly distal limb regions. These new diagnostic criteria stimulated additional research to ensure their adequacy. The diagnostic accuracy of these criteria were further improved in a series of controlled trials by comparison to well-defined neuropathic conditions such as diabetic neuropathy ( Table 48.1 ). These revised criteria do not demonstrate high reliability and are not useful clinically in assessing the severity and prognosis or in treating subcategories of symptoms and signs.

Despite the standardization of the diagnostic criteria in adults, there are relatively few data on the validation of the clinical presentation in children. In children both the diagnosis and treatment remain challenging for any clinician. A multidisciplinary approach is often crucial for successful outcome, particularly in severe cases where the child is assessed and managed as an individual as well as a family and community member.

CRPS-I and CRPS-II, like their respective predecessors RSD and causalgia, raise a major question about possible mechanism(s). Cardinal symptoms of CRPS-I and CRPS-II are pain with allodynia (pain from an innocuous stimulus), hyperalgesia (more pain than expected from a painful stimulus), or both. CRPS-II develops following a distinct peripheral nerve injury, whereas CRPS-I usually follows a minor noxious event without obvious nerve injury and with the symptoms spread across multiple peripheral nerve territories ( Figure 48.1 ). It is not clear whether CRPS-I and CRPS-II are different syndromes or represent different features in a continuum of nerve injury. Three stages (acute, dystrophic, and chronic atrophic) of CRPS are described in adults based on the severity or time course of the disorder. In children, the duration of CRPS-I is usually shorter than in adults and so trophic changes are not a common presentation, although such changes are observed. This chapter summarizes the current understanding of childhood CRPS type I (CRPS-I) assessment and management.

Incidence and Prevalence

There is evidence that CRPS in children is more common than was previously thought but is rare and the true incidence is unknown. In a rural population of 106,470 in the USA, the incidence of CRPS-I in children between the ages of 10 and 19 years was 1.6 per 10 ⁵ and was nonexistent in younger age children. In adults, depending on how data are gathered and how diagnoses are made, as many as 5.5 per 10 ⁵ person-years are at risk in a rural area of USA based on IASP diagnostic criteria, with a prevalence of 20.6 per 10 ⁵ . The estimated overall incidence rate of adult CRPS is much higher in a large cross-section Dutch population, 26 per 10 ⁵ person-years, using different diagnostic criteria. In contrast to adult CRPS, childhood CRPS is marked by (1) predominance of preadolescent females (5–7:1 male); (2) predominance of lower extremity involvement (4–6:1 upper extremity) particularly the ankle and foot; (3) less frequently preceded by surgery or major trauma (in less than 10% spontaneous onset); (4) greater stress in family and school environment; and (5) favorable response to physical therapy.

Pathophysiology

The pathophysiological mechanisms of CRPS-I are not well understood. In adult trials, no unifying pathophysiological mechanisms have been identified to explain CRPS in all patients. In children, the data are very limited because pain testing trials that invoke pain with repeated application of noxious stimuli are objectionable ethically and are frequently opposed by patients and parents. Several mechanisms are postulated for the generation and/or maintenance of CRPS-I such as small fiber nociceptor axons dysfunction, sympathetic dysregulation, tissue hypoxia and reperfusion injury, inflammation, autoimmune antibodies, and central and cortical reorganization. Several studies have shown that immobilization impairs tactile perception and may shrink somatosensory cortical (S1) representation. Mobilization of the affected limb reverses these changes; however, whether pain and/or mobilization causes these cortical reorganizations or the cortical changes cause the pain remains an open question. A preliminary study in children with CRPS showed that allodynic stimulation of the affected limb and comparison to the contralateral unaffected limb and to normal controls resulted in significant changes in CNS circuitry in children with CRPS and having features similar to those described in adults with CRPS. These changes improved after treatment and symptoms resolution.

The precise mechanisms of CRPS-I remain a research challenge. However, they may involve somatosensory and motor and sympathetic nervous systems in a subgroup of CRPS patients in whom the pain could be sympathetically maintained. The latter mechanism may explain why in a few CRPS patients a series of temporary sympathetic ganglia blockades with local anesthetics leads to pain relief lasting beyond the pharmacological duration of the local anesthetic action.

A recent controlled trial in children with CRPS, ages 7–17 years, demonstrated that thermal and mechanical quantitative sensory abnormalities are strongly suggestive of central sensitization. A follow-up double blind placebo-controlled crossover trial by the same investigators compared intravenous versus lumbar sympathetic blockade with lidocaine in a small number of children (ages 10–18 years) and found that a single lumbar sympathetic blockade produced significant reduction in pain intensity in response to evoked dynamic and static mechanical stimulation, mechanical temporal summation, and spontaneous pain scores in approximately 40% of the patients. The findings of this study provide support for the concept that in some patients a component of pain involves a sympathetic efferent and somatic afferent cycle of activities and suggest that selective sympathetic ganglia blockade can alleviate pain. The long-term benefit of sympathetic blockade in children and adults has not been investigated or demonstrated.

Other contributory factors have been proposed to influence the development of CRPS, such as genetic association with different human leukocyte antigens (HLA), and hereditary patterns among members of families. An observational study of 31 families identified two to five affected families and found that the phenotype of CRPS was more severe in the familial cases compared to sporadic cases. Other studies suggest mitochondrial (female transmission) inheritance in families. These preliminary reports suggest that the association of CRPS with genetic factors is multifactorial without a distinct inheritance pattern. The DNA profiling is yet to be determined.

Several psychological conditions have been advanced to explain the triggers and/or maintenance of the CRPS both in children and adults, but no consistent relationship has been demonstrated. As with adults, the psychological aspects are strongly associated with a wide range of chronic disorders in children. Many coexisting factors such as emotional stress, anxiety, depression, fear of movement, and other psychological disturbances have been reported in children with CRPS, as have other behavioral elements such as reinforcing effects of responses to pain, pseudoneurologic presentation, and major life events. However, most existing studies have been conducted in samples of children already experiencing chronic pain, thus preventing a thorough understanding of whether psychological distress precedes or follows the onset of the pain symptoms.

In the pediatric literature, research has not examined the role of psychological factors in CRPS as widely or as systematically as in the adult literature. Clinically, however, there exist similar viewpoints and assumptions that CRPS in children may represent primarily a manifestation of psychological distress. This dichotomized view of CRPS as either a biological or nonbiological (i.e. psychological) entity is at odds with current conceptualizations of chronic pain as a biopsychosocial phenomenon—that is, an experience that is shaped by a confluence of integrated factors in biological, psychological and social realms. Multiple case reports have focused on children with features of CRPS with comorbid psychiatric illness, including conversion disorder, post-traumatic stress disorder, somatization disorder, and anorexia. A majority of these case reports implicate a psychiatric disorder as primary to the development of CRPS symptoms; however, these reports lack prospective data to support this claim, use single subject designs, rely solely on clinical interview, and fail to apply specific diagnostic criteria when labeling patients as having CRPS. These reports do underscore that psychological distress is a hallmark of pediatric CRPS.

A few studies have been published using larger samples of children with CRPS incorporating psychiatric clinical interviews or standardized assessments of psychological distress. All but one of these interview-based studies concluded that children and adolescents with CRPS had a high prevalence of elevated emotional distress compared to healthy peers and tended to be high-achievers living in high-stress families, citing these as factors that contribute to the syndrome. Conversely, results from studies utilizing standardized assessment measures indicated that children with CRPS routinely displayed normative levels of emotional distress, depressive symptoms, intelligence, and family functioning. A study by Logan and colleagues compared children with CRPS to children with other chronic pain disorders and found similar levels of psychological distress across groups, offering some evidence against the view that CRPS differs from other pediatric chronic pain problems in the severity of accompanying psychological distress.

Clearly, psychological factors are important facets of the overall biopsychosocial experience of CRPS and should be thoroughly assessed and identified as targets of treatment when relevant. Importantly, however, many children presenting for tertiary evaluation of CRPS report having previously been told that the condition is due to stress, or is “all in their heads.” While psychological factors in the child and family likely do influence the expression of CRPS in terms of its course, severity, and/or response to treatment, assuming that children fit a particular personality type or have significant psychiatric involvement in the presentation of their pain condition based on a CRPS diagnosis alone is unfounded and may be detrimental to children and their families seeking to understand an often difficult and confusing diagnosis. Certainly, the identification and treatment of psychological concomitants, such as symptoms of depression or anxiety, and of interpersonal factors that can influence the course of the disorder, such as family dynamics and parental responses to pain behaviors, are important goals in managing pediatric CRPS. Yet it is crucial to recognize that CRPS presents as a multifaceted biopsychosocial phenomenon; consequently, treatment should entail coordinated interdisciplinary efforts that address the biological, physical, and psychosocial aspects and sequelae of this complex condition.

A recent comprehensive review of literature of epidemiological, genetic, and experimental studies in adults with CRPS concluded that CRPS is a complex disorder and implicated multiple mechanisms in the pathophysiology that results in maladaptive neuroplasticity in most patients.

Diagnosis

CRPS is a clinical diagnosis based on the medical history and signs and symptoms listed by IASP criteria ( Table 48.1 ). The symptoms and signs indicate a multifactorial disorder associated with aberrant inflammatory response to tissue injury, vasomotor dysfunction, and maladaptive neuroplasticity. At present there are no specific pathologic, histologic, or biochemical markers for its diagnosis. The laboratory tests and radiological imaging studies are helpful to exclude underlying causes or conditions that might mimic the CRPS presentation, e.g. infection, stress fracture, ligaments or meniscal tear, arthritis, erythromelalgia, etc. Over time, the disorder may spread to adjacent noninjured areas, and ipsilateral and/or contralateral limb.

Quantitative sensory testing has recently been introduced to assess the functioning of cutaneous somatic small fibers in adults with neuropathy and painful conditions, including CRPS. In a preliminary study in children with CRPS, the investigators found various abnormalities, which suggest considerable heterogeneity of evoked mechanical and thermal sensory abnormalities among children presenting with CRPS-related pain. As with adult CRPS, the thermal and mechanical sensory abnormalities appear in different combinations in different patients with similar clinical presentations. In a majority of patients, the pathogenesis of pain is seemingly of central origin. A large-scale adult study compared healthy adults with patients with various neuropathic pain syndromes and CRPS; it noted that although most patients with CRPS exhibited gain in sensory function (hyperesthesia, allodynia, hyperalgesia, hyperpathia) a number of patients presented with a mixed gain and loss of sensory function.

Early diagnosis may improve prognosis and mitigate the unnecessary suffering from delayed diagnosis or misdiagnosis that may stigmatize the patient’s condition as not “real” or “all in the head,” and avoid disuse atrophy, poor physical functioning, and in some cases exposures to unwarranted and potentially harmful interventional procedures that have not clearly shown to provide additional benefit.