Total knee arthroplasty (TKA) has been shown to be a successful and cost-effective procedure for decreasing pain and restoring function in patients with end-stage osteoarthritis.1–5 However, patient dissatisfaction has been reported to be as high as 50%,6 with residual pain being the most common factor contributing to dissatisfaction.3,7 Rates of pain between 9% and 14% have been reported at 10-year follow-up of TKA.1,2,6
Determining the causes of the pain is often a diagnostic challenge, and there are multiple potential etiologies for residual pain following TKA, such as low-grade infection, midflexion instability, and component malalignment with patellar maltracking.8 Less common causes of residual knee pain include crepitation and patellar clunk syndrome, patellofemoral symptoms, early aseptic loosening, hypersensitivity to component materials, and complex regional pain syndrome (CRPS).8 Complex regional pain syndrome can cause disabling pain, stiffness, and prolonged recovery, but it is often overlooked because available diagnostic modalities are not specific.8,9
Complex regional pain syndrome is a potential cause of persistent pain after TKA. A retrospective study of patients diagnosed with CRPS affecting the knee found TKA to be the second most common inciting event, behind arthroscopy.10 However, the condition following TKA is less well characterized.11 This article reviews the current literature regarding CRPS after TKA, explains the diagnosis, and discusses treatment algorithms.
Pathophysiology of Complex Regional Pain Syndrome
Complex regional pain syndrome is a chronic pain condition with autonomic and inflammatory features that affects limbs after injury.12 It is a complex neurological disease with a variable characterization, but CRPS mainly presents with spontaneous or stimulus-induced pain that is out of proportion to the initial injury, autonomic instability, motor and sensory dysfunction, trophic and ischemic changes, and prolonged recovery time.13–16
There are many historic synonyms for this condition, including reflex sympathetic dystrophy, Sudeck's atrophy, causalgia, algodystrophy, and algoneuro-dystrophy.17,18 However, the International Association for the Study of Pain consolidated the terms into CRPS to encompass the wide variety of disorders of previous terminologies and descriptions.18,19 Complex regional pain syndrome is further divided into type I and type II. Type I includes reflex sympathetic dystrophy and related conditions without nerve injury, whereas type II includes the development of causalgia following peripheral nerve damage.20 Despite simplified nomenclature, CRPS continues to be misdiagnosed due to the heterogeneity of patient presentations. This has led to multiple proposed pathophysiological mechanisms and varying diagnostic criteria of the syndrome.
Complex regional pain syndrome mostly develops after an inciting injury, such as a sprain, a fracture, or surgical trauma.12 The severity of the injury does not predict development of CRPS, as even minor trauma can lead to the symptoms.21 Numerous theories have been proposed regarding the pathophysiology of CRPS, including changes in central regulation of sympathetic activity, hyper-sensitivity of peripheral catecholamine receptors at target organs, abnormal synapses between sensory and sympathetic fibers, atypical neurotransmitter release by severed nerves, and disrupted auto-regulation of blood flow.13–15,22–24 Psychogenic factors may also play a role in development of the syndrome.25 Overall, the pathophysiological mechanisms of CRPS and related conditions remain poorly understood, but the available evidence suggests that the disease process takes place at multiple integrated levels of the nervous system, with observed changes in somatosensory, sympathetic, and somatomotor systems.16
Complex regional pain syndrome is an uncommon complication after TKA. However, given the heterogeneous diagnostic criteria employed by studies, its true incidence is difficult to assess. In a study by Katz et al26 of 662 primary TKAs, 5 (0.8%) patients developed CRPS. In a study by Nielsen et al27 including 247 TKAs, 3 patients (0.012%) had CRPS. In a study by Ritter,28 439 posterior cruciate-retaining total condylar knee arthroplasties were performed during 9 years, and 6 patients had a diagnosis of reflex sympathetic dystrophy (0.014%). The largest retrospective study—1280 TKAs—conducted by Burns et al9 found the incidence of CRPS following TKA to be 0.7% (Table 1).
Summary of Results From Studies Examining Complex Regional Pain Syndrome Following Total Knee Arthroplasty
In a prospective study performed by Harden et al,25 the prevalence of CRPS after TKA using older International Association for the Study of Pain diagnostic criteria (Orlando criteria) was 21.0% at 1 month, 13.0% at 3 months, and 12.7% at 6 months. However, the authors conceded that temperature and swelling found in patients could be attributed to normal inflammatory processes. Comparatively, no cases of CRPS were identified in a prospective study of 100 TKAs using newer, more accurate criteria (Budapest criteria); however, 8 patients were identified when applying the older, less specific and less stringent criteria (Orlando criteria).11 The true incidence is likely less than 1%, as demonstrated by previous retrospective analyses and the prospective study performed by Kosy et al.9,11,26–28 However, a larger prospective study using contemporary diagnostic criteria is necessary to determine the true incidence.
Demographics and Risk Factors
The risk factors for developing CRPS postoperatively remain relatively unknown.25,29 In a systematic literature review evaluating risk factors for all causes of CRPS, Pons et al30 identified female, particularly postmenopausal female, immobilization, and higher than usual levels of pain in early stages following trauma. However, following TKA, Burns et al9 found no significant difference regarding age, sex, and follow-up period between patients who developed CRPS after TKA and those who did not.
Proposed risk factors for CRPS also include psychological conditions. Several studies have suggested that greater preoperative pain and psychological factors, such as depression, anxiety, neuroticism, or anger, predispose patients to the development of CRPS following injury or surgery. In a prospective study investigating predisposing factors influencing the development of CRPS after TKA, greater preoperative anxiety modestly predicted CRPS symptomatology at 1 month, which later diminished, while higher preoperative pain intensity predicted longer-term (3 to 6 months) development of CRPS.25 In contrast, a systematic review performed by Beerthuizen et al31 demonstrated no correlation between psychological factors and the development of CRPS from all causes.
The classic presentation of CRPS is commonly a burning pain out of proportion to the inciting event in a regional distribution with an intolerance to temperature.15 The quality of pain can vary, and deep pain localizing to the bone has been increasingly observed.15 Allodynia and hyperalgesia are also common features. Patients frequently have autonomic dysfunction exhibited by vasomotor and sudomotor instability as color changes, temperature changes, hyperhidrosis, and edema.32 Limited range of motion and muscle weakness are also present in the majority of patients. Complex regional pain syndrome typically involves an acute phase characterized by vasomotor changes and hyperesthesia, followed by a chronic phase with trophic skin changes and allodynia (warm and dystrophic phases).14,22,24,33 However, it has been reported that the classic clinical presentation and progression of CRPS are not always present when it affects the knee.15,22
In the early period following TKA, disproportionate pain, stiffness, delayed recovery, and cutaneous hypersensitivity could signify CRPS; classic indications of CRPS, such as vasomotor signs, may be unreliable given postoperative hyper-emia.9,26 It has been reported that the most reliable clinical indicator of CRPS affecting the knee is pain out of proportion to the inciting event (Table 1).10,22,26,34,35
Considering that the pathophysiological mechanism of CRPS and its subsets are unknown, there is no gold standard diagnostic test nor objective standardized tools. The diagnosis is typically made clinically and is one of exclusion.20 Multiple diagnostic criteria have been developed, with the Budapest criteria being the most recent and accepted by the International Association for the Study of Pain. In a validation study, the Budapest criteria for the diagnosis of CRPS were found to greatly improve on existing International Association for the Study of Pain criteria, yielding a sensitivity of 0.99 and specificity of 0.68.36 Using these new diagnostic criteria, a prospective study of 100 patients performed by Kosy et al11 found no cases of CRPS after TKA. However, there were 17 cases of excessive pain, and the most common signs were sensory and sudomotor, with motor/trophic changes not being observed.11 The authors argued that the newer diagnostic criteria should be used because overdiagnosis of CRPS based on isolated signs and symptoms could have negative effects by delaying management for more common causes of pain, such as neuropathic pain.11
Although CRPS is a clinical diagnosis, certain procedures and imaging modalities such as plain radiographs may help in confirming it. However, their utility is often limited after TKA. After a few months, plain radiographs often demonstrate patchy subchondral osteopenia; in later stages, profound bone demineralization can be observed.14,22,24 Unfortunately, these subtle findings are often difficult to interpret after TKA, considering preoperative disuse atrophy.26 Technetium-99 bone scintigraphy is sensitive but not specific for identifying CRPS13,22 because of diffuse uptake following TKA, limiting its usefulness in supporting a diagnosis of CRPS.9
Nerve-conduction studies can assist in ruling out causes of neuropathic pain, such as neuromas, nerve entrapment, and neuropathies.15,37 Magnetic resonance imaging can also help identify and rule out other disorders causing persistent pain, but it may yield normal findings in CRPS.15,22,38 Bone edema and occult fractures have been visible on magnetic resonance imaging in patients with CRPS of the foot; thus, magnetic resonance imaging cannot be used to rule out CRPS.38 The usefulness of metal artifact reduction sequence or multi-acquisition variable-resonance image combination magnetic resonance imaging in the detection of small nerves is not clear. Thermography detecting temperature differences between legs has been documented to have high sensitivity and specificity for determining CRPS in limbs.39 However, it likely lacks specificity following TKA and could be unreliable given postoperative hyperemia.9,26 Overall, these studies may be sensitive but are not specific in diagnosing CRPS.9
A positive response to sympathetic blockade in patients with vasomotor and sudomotor changes can be key to diagnosis and management.26,32 Some authors even consider an improvement in pain and increase in temperature after sympathetic blockade to be the gold standard test for diagnosis.22,26 Sympatholysis can also be used as a treatment modality.16,40 Complex regional pain syndrome remains a clinical diagnosis; it may be more difficult to diagnose after TKA. Clinicians should have suspicion for CRPS in patients with excessive pain, stiffness, and delayed recovery after more common diagnoses have been excluded.
Treatment of CRPS is primarily achieved with a multimodal approach that includes physical therapy and pharmacological agents. Nonsteroidal anti-inflammatory drugs, analgesics, steroids, and anti-neuropathic drugs such as gabapentin are typical agents administered to control patients' pain.15 Gentle range of motion by physical therapy is advised to avoid overstimulation and is focused on gaining full extension while not aggressively forcing flexion (Table 1).9,11,16
The most important factor in predicting improvement has been shown to be early administration of treatment after onset of symptoms (within 6 months), while late identification has been associated with refractory symptoms.13,21,34,41 In the study performed by Burns et al,9 this was demonstrated when formal physiotherapy was suspended and non-steroidal anti-inflammatory drug or opiate analgesia was started, Fifty percent of the patients required manipulation under anesthesia, and final range of motion was hindered (97° compared with 114° in the control group) (Table 1). The final mean maximal degrees of knee flexion achieved in patients with TKA complicated by CRPS was similar to those previously reported.26,40 Burns et al9 found that patients who developed CRPS after TKA still improved compared with their preoperative assessments. Considering the importance of early recognition, patients with persistent pain could benefit from physical therapy and standard analgesic regimens throughout the diagnostic process.11 If these modalities are ineffective, regional anesthetic and sympathetic blockade are typically administered.
Sympathetic blockade appears to be the most effective treatment option for patients who develop CRPS in the knee. In a study performed by O'Brien et al,10 92% of patients with CRPS of the knee treated with sympathetic blockade had resolution of symptoms. These findings were compared with those of 29 patients who developed CRPS after total knee replacement; a lumbar sympathetic block was performed with local anesthesia. Thirteen (44.8%) had complete resolution of symptoms, 12 had complete or partial relief of symptoms that was not sustained, and 3 had no improvement.40 In a study by Cooper et al,42 epidural block anesthesia was administered with an indwelling catheter following extensive physical therapy and medical treatment, resulting in complete resolution of CRPS symptoms in 78.5% of patients (11 of 14 patients, all diagnosed by positive symptomatic response to lumbar sympathetic block). Patients were treated for an average of 4 days and also received continuous passive motion, manipulation as necessary, muscle stimulation, and alternating hot and cold soaks.42 Cooper et al22 later concluded that the most effective treatment for CRPS of the knee after failure of conservative management was an indwelling epidural block for up to 7 days combined with functional rehabilitation. The proposed protocol included bupivacaine with early manipulation if flexion was less than 90°, followed by a narcotic epidural agent for pain control after the patient regained pain-free motion with physical therapy and continuous passive motion.22 Surgical sympathectomy was also reported to be successful, but the authors advised that it should only be employed after failure of repeated lumbar sympathetic blockade or a failed trial of inpatient epidural block.22 Thus, if early noninvasive management is ineffective, sympathetic blockade can be administered with good efficacy.
Complex regional pain syndrome is an uncommon cause of persistent pain following TKA, having a true incidence likely below 1%. Its presentation can be atypical following knee replacement, often involving just excessive pain, stiffness, and prolonged recovery. Further, classic vasomotor signs such as erythema and edema are distorted in the context of normal postoperative changes, making diagnosis more difficult. Clinicians should have suspicion for CRPS if patients continue to experience persistent pain and delayed improvements after more common etiologies, such as component malposition and infection, have been excluded.
Intervention with physiotherapy and pharmacological agents should proceed in the early phases of disease progression (within 6 months) to avoid long-term symptoms refractory to treatment. When noninvasive approaches have failed, sympathetic blockade has been shown to be effective.
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Summary of Results From Studies Examining Complex Regional Pain Syndrome Following Total Knee Arthroplasty
|Study||Study Design||Total No. of TKA||Cases of CRPS After TKA||Diagnosis||Signs and Symptoms||Treatment||After Intervention|
|Katz et al26||Retrospective||662||5 (0.7%)||Clinical, improvement of symptoms after sympathetic blockade||Greater than expected pain, cutaneous hypersensitivity, cold sensation, limited knee flexion||Physical therapy, analgesic support, manipulation under anesthesia, sympathetic block||Average increase in knee score: 35|
|Harden et al25||Prospective||77||16 (21.0%) at 1 month, 9 (13.0%) at 3 months, 7 (12.7%) at 6 months||Orlando criteria||Hyperesthesia, hyperalgesia, allodynia increased temperature, erythema, edema||Not reported||Not reported|
|Burns et al9||Retrospective||1280||8 (0.6%)||Clinical||Marked post-operative stiffness, disproportionately high pain levels, swelling, increased vasomotor and sudomotor changes||Physical therapy, analgesic support, manipulation under anesthesia in quiescent phase||Average increase in knee ROM: 33°|
|Kosy et al11||Prospective||100||8 (8.0%), 0 (0%)||Orlando criteria, Budapest criteria||Excessive pain levels, sensory symptoms, edema||Not reported||Not reported|