CRPS is becoming the great imitator in pain medicine. This article discusses the symptomatology of the disease, including atypical presentations.
Recent studies of neuropathic pain have helped delineate the major features of CRPS. It is now clear that most patients with CRPS have suffered either an injury to terminal twigs (peripheral fibers) of C and A-δ nociceptive afferents in soft tissue, or have a frank nerve injury, bone fracture, or have undergone a surgical procedure.2,3 Cluster analysis has revealed that the signs and symptoms of the syndrome may be separated into distinct factors (Table 1).4 The clinical diagnosis requires at least one symptom in each of the factors and one sign in at least two of the factors.5
Over time, changes occur in the central nervous system’s (CNS) control of the autonomic, somatosensory, and motor systems.6 Major mechanisms underlying the pathophysiology of the disease include peripheral sensitization of the C and A-δ afferent terminal nerves in the area of injury; central sensitization of pain transmission neurons (PTNs) in all components of the pain matrix; immune mechanisms; and a maladaptive response of physiologic pain mechanisms.7-15 There are subtypes of CRPS rather than specific clinical stages through which the syndrome evolves. This review focuses on the severe subtype, which is manifested by pain that has spread from the site of original injury, is longstanding, comprises all components of the syndrome, and may be generalized to the entire body.16,17
Chest Pain in CRPS
A common cause of atypical chest pain in CRPS patients, which is more frequent in women than men, is irritation and sensitization of the intercostobrachial (ICB) nerve.16,17 The source of the ICB nerve arises from the second intercostal nerve root (T2) and has variable contributions from T3 and T4 nerve roots.18,19 It innervates the axilla, medial, and anterior arm, and contributes to the innervation of the upper anterior chest wall from its connection with the long thoracic nerves.19,20 It also contributes to the innervation of the posterior forearm from its connections with the posterior antebrachial cutaneous nerve and occasionally innervates the pectoralis major and minor muscles.20
A recent prospective study using pressure algometry to evaluate the sensitivity of the chest wall in CRPS patients and normal controls revealed that the majority of patients with upper extremity CRPS (94%) reported a history of chest pain, compared to 19% of controls.17 Of the CRPS patients with chest pain, 66% had bilateral pain; 79% reported pain that was above the breast and deep in nature; 51% of patients had pain that radiated to their jaw/head/neck; and 46% had shoulder/arm pain. In 65% of the patients, chest pain was elicited by elevation of the arms.
CRPS has developed in patients following modified radical mastectomy and other breast surgeries, as well as in patients with invasive cancers.21-23 Following mastectomy, patients have described an ever present pain in the medial and posterior arm.21 The pain is described as dull, aching, or burning, with superimposed episodes of lancinating pain. It is increased with movement and can be elicited by pressure on the second intercostal space of the anterior axillary line. Presenting symptoms of Pancoast’s syndrome (lung tumors) include chest pain and allodynia in the medial upper arm and shoulder from metastatic invasion of the ICB nerve.24
Systemic Medical Complications of CRPS
It generally has been accepted that over time CRPS affects the somatosensory, autonomic, and limbic components of the pain matrix in a majority of severely affected patients.6 The systemic complications of the syndrome are not as well appreciated.25
Cluster analysis of 500 patients with severe CRPS demonstrated 3 distinct groups: neuropsychologically normal patients (36%); patients with mild dysexecutive deficits (42%); and patients who had cognitive impairment in executive function, naming, and memory (22%).26 The memory deficits demonstrated in these latter patients suggested executive (retrieval) rather than amnestic (encoding) dysfunction. The evaluation of this large cohort of >500 patients suggests that a dysexecutive syndrome is the underlying deficit. Depression, extent, and duration of illness did not correlate with these cognitive changes.26,27
Functional magnetic resonance imaging (fMRI) studies of CRPS patients with hand involvement demonstrate activity-dependent neuroplasticity. There is clear alteration of a patient’s hand representation in the primary somatosensory cortex, which reverts to normal with recovery.28-31 CRPS patients have demonstrated tactile and proprioceptive deficits and also report as if their hands feel “foreign or strange” or not belonging to their bodies.32-34 In addition to the impaired cognitive function and plastic aberrations of the body schema demonstrated in CRPS patients, there may be structural brain changes, as demonstrated in other severe neuropathic pain states.35
Almost all severely affected CRPS patients complain of lethargy, tiredness, and weakness. As the illness progresses, there is an increase of proinflammatory cytokines in the serum and cerebrospinal fluid and a decline in anti-inflammatory cytokines.8,36-38 These inflammatory cytokines act both peripherally at the site of injury and centrally in the pain matrix. In patients with severe, longstanding CRPS, the extent of CD14+ and CD16+ monocyte/macrophage proinflammatory activity in the serum increases, whereas the total monocyte count remains normal.39 The initial nonspecific immune activation following injury or infection occurs within hours and is called the sickness response. The increase in inflammatory cytokines leads to brain interactions that trigger a cascade of behavioral responses, including pain facilitation.40 The severe fatigue suffered by the majority of CRPS patients at all stages of their illness may result in part from engagement of the sickness response circuitry.41
Cardiac Complications of CRPS
Approximately 2,500 CRPS patients with disease duration of longer than 2 years and at least 2 involved extremities have been evaluated at the Drexel University Pain Clinic. Of these, 800 had electrocardiogram (EKG), echocardiogram, and clinical cardiac evaluations prior to the administration of subanesthetic ketamine protocols for refractory pain. There were no specific EKG abnormalities other than a slightly higher than normal pulse rate, ranging from 80 to 100 beats per minute. The ejection fraction ranged from 50% to 65%, not differing from controls. Approximately 10% of this cohort described palpitations, syncope, or presyncope during the course of their illness.42