Reflex Sympathetic Dystrophy

                              DR KS Dhillon

Introduction

Complex Regional Pain Syndrome (CRPS) is a neuropathic pain disorder. It is characterized by persistent pain that is disproportionate to the degree of tissue injury and persists beyond the usual expected time for tissue healing [1].  Pain is accompanied by motor, sensory, and autonomic abnormalities. These abnormalities include hyperalgesia, allodynia, sudomotor, and vasomotor abnormalities, as well as trophic changes. The pain does not follow a particular dermatome or myotome but is rather regional. This disabling condition usually develops after a fracture, trauma, or surgery [2][3]. Some spontaneous cases have also been reported [4].

Ambroise Paré in the 16th century, reported cases with CRPS-like symptoms for the first time which developed following phlebotomy [5]. Silas Mitchell in 1864, observed this syndrome after gunshot wounds. In 1864 he used the term ‘causalgia’ to describe this syndrome. In 1946 James A. Evans coined the term ‘reflex sympathetic dystrophy’ to describe a similar condition. He suspected that the pain was sympathetically mediated [6]. In 1994, the International Association for the Study of Pain (IASP) named this condition ‘Complex Regional Pain Syndrome’. The IASP proposed a diagnostic criterion. Due to low specificity, a widely accepted revised criterion was proposed in 2010. It is commonly referred to as the "Budapest Criteria" [2,7].

CRPS has two subtypes. Type I was formerly known as reflex sympathetic dystrophy, and type II was formerly known as causalgia. In type I there is no nerve trauma. Type II occurs in the setting of known nerve trauma. Clinically they are indistinguishable. They follow a regional rather than a dermatomal or peripheral nerve distribution and favor the distal extremities. Spread outside of the initially affected area commonly occurs to the proximal or contralateral limb [6,8]. CRPS is further subdivided into "cold" versus "warm," and sympathetically maintained (SMP) versus sympathetically-independent (SIP), which may affect prognosis and treatment options [8].

CRPS not only affects sleep, function, and activities of daily living but also takes a significant mental and psychosocial toll on the patient [9,10,11]. Its diverse spectrum of clinical presentation and lack of clearly defined pathophysiology poses a challenge for optimal management. 

Etiology

CRPS usually occurs due to varying degrees or types of tissue trauma. It has been documented even in the absence of injury. It has been seen following periods of prolonged immobilization. A fracture is the most common injury associated with developing CRPS. Surgery is another common cause. Other inciting injuries or insults include contusions, sprains, and crush injuries. CRPS has even been reported after seemingly innocuous interventions such as intravenous line placement. Increased psychological distress experienced during the physical injury may affect the severity and prognosis of CRPS. 

Fracture

CRPS is commonly associated with extremity fractures. A large multicenter prospective study by Beerthuizen et al [12] found that 48.5% of patients developed CRPS (IASP criteria) after suffering a single fracture of the ankle, wrist, scaphoid, or the fifth metatarsal. All the patients remained symptomatic at 1-year follow-up. They found that rheumatoid arthritis and intraarticular ankle fractures and dislocations were risk factors for CRPS. There was no significant difference for disease onset between fractures of arms or legs.

Another prospective cohort study by Brunner et al [13] found that CRPS developed within 8 weeks after a noxious event. Symptoms improved in many patients at 3 months. There was no significant improvement noted at a year.

There are studies involving patients who developed CRPS after fracture of the distal radius that have identified higher age, social or psychological factors, and psychiatric comorbidities as risk factors [14,15].

There was, however, another prospective study that did not find any correlation between psychological factors or depression and the development of CRPS [16].

Surgery

Extremity surgeries are also more commonly associated with the development of CRPS. In a retrospective study by Rewhorn et al [17] of 390 patients who underwent foot and/or ankle surgeries, 4.36% developed CRPS. Surgical treatment of fractures has been found to have a higher risk of CRPS. 

A study by JelladIn et al [18] found that 32.2 % of their patients undergoing closed reduction of distal radius fracture, developed CRPS. Carpal tunnel surgeries were noted to have a 2 to 5% incidence of CRPS and Dupuytren contracture surgeries had a 4.5 to 40% incidence of CRPS [19]. 

Genetics

The impact of genetic factors in the development of CRPS remains unclear. Tumor necrosis factor-alpha (TNF-α) polymorphism and human leukocyte antigen have been found to play a role in CRPS. When these factors are present there can be an earlier age of onset and more severe symptoms. A few retrospective reports have suggested familial inheritance [19].

Epidemiology

The incidence of CRPS appears to vary based on geographical location. A study by Sandroni et al. in Olmsted County Minnesota, that was reported in 2003, found an incidence of 5.46 per 100,000 person-years for CRPS type I and 0.82 per 100,000 person-years for CRPS type II [20]. Another study by Mos et al. in the Netherlands reported in 2006, found the incidence to be much higher at 26.2 cases per 100,000 person-years [21]. Both studies found that females were more often affected. The first study found that females were four times more likely to be affected than males, while the second study found that this disorder was at least three times more common in females [20,21].

The Netherlands study reported a peak incidence at 61–70 years of age. The American study found the median age of onset to be 46 years. Upper limbs were more commonly involved than lower limbs in both studies. Both studies used the IASP CRPS criteria for diagnosis of the disease. The most common trigger for the disease was found to be a fracture. A fracture was associated with 44 to 46% of the cases. Vasomotor symptoms of swelling, temperature, and color changes were most commonly reported [20,21].

The three-phase bone scans are most useful for making a diagnosis (85%). Autonomic testing is helpful in making a diagnosis in 80% of cases [20]. Asthma, menopause, angiotensin-converting enzyme (ACE) inhibitor use, osteoporosis, and history of migraine are risk factors for CRPS [21,22]. Cigarette smoking also increases the risk of developing CRPS [23].

Pathophysiology

Multiple pathophysiologic mechanisms have been described to explain CRPS. Scientific evidence does not point to a single main mechanism. The underlying mechanism seems to be multifactorial. Immunological, inflammatory, central, and peripheral sensitization, as well as autonomic changes, have been studied in CRPS [6].

Inflammatory Changes

Both the clinical presentation as well as the elevated inflammatory markers suggest that inflammation is a key mechanism underlying the development of CRPS. The basic features of inflammation, such as swelling, redness, increased temperature, pain, and functional impairment, are commonly associated with CRPS [24]. Elevated levels of pro-inflammatory cytokines such as TNF-α, Interleukin (IL)-1b, IL-2, and IL-6 have been found in both serum and cerebrospinal fluid of patients with CRPS [25,26,27,28]. As a result of tissue injury elevated levels of neuropeptides like calcitonin gene-related peptide (CGRP), bradykinin, and substance P are released from peripheral nerve endings. They trigger neurogenic inflammation. The elevated levels of inflammatory markers and neuropeptides cause vasodilation and tissue extravasation [22,29,30,31,32].

Immunological Changes

Autoimmune factors play a role in CRPS pathogenesis. Autoantibodies against beta-2-adrenergic receptors, muscarinic-2 receptors, and alpha -1a-adrenergic receptors, have been found in CRPS [33,34]. Goebel et al [35] found a significant improvement in pain following intravenous immunoglobulin treatment in CRPS patients. This further supports potential autoimmune pathophysiology.

Peripheral Sensitization

Peripheral nervous system sensitization is triggered by the release of pro-inflammatory markers after the injury. Markers such as TNF-α released reduce the stimulation threshold. This leads to local sensitization and hyperalgesia in CRPS. Catecholamine sensitivity of peripheral nerve fibers has also been seen in CRPS [6].

Central Sensitization and Neuroplasticity

In patients with CRPS, increased excitability of secondary dorsal horn neurons occurs. As a result of sensitization hyperalgesia and allodynia develops. The release of bradykinin, substance-P, and glutamate plays an important role in this process. Continued noxious primary afferent traffic into the dorsal horn leads to wind-up and central sensitization [24]. Based on the response to ketamine infusions in CRPS patients, activation of spinal N-methyl D-aspartate (NMDA) receptors seems to play an important role in the pathogenesis [36,37]. Improvement of CRPS symptoms with intrathecal baclofen suggests gamma-aminobutyric acid (GABA) involvement in sensitization [6].

Evidence of cortical reorganization has been noted in CRPS. A reduction in the somatosensory-cortex area corresponding to the affected extremity occurs [38]. The degree of neuroplasticity correlates with the intensity of pain and severity of hyperalgesia, both of which indicate central sensitization [39,40].

Autonomic Changes

Sympathetic-afferent coupling occurs in CRPS. It is due to the upregulation of sympathetic receptors on nociceptive nerve fibers. As a result of this sympathetic hyperactivity, there is increased pain and sympathetic sensitivity of nociceptive nerves. The local swelling, color changes, and temperature variations associated with this disorder suggest an involvement of the autonomic nervous system [41]. Widespread autonomic dysregulation in CRPS can affect the heart rate and can lead to orthostatic dysfunction [42]. In warm CRPS, vasodilation occurs as a result of reduced catecholamine release. The opposite phenomenon occurs in cold CRPS [6].

History and Physical Examination

Patients can have sensory, motor, or autonomic symptoms. Sensory symptoms include allodynia where non-painful stimuli cause pain and hyperalgesia where painful stimuli cause exaggerated pain. Patients can also have autonomic symptoms. These include skin color and temperature changes (vasomotor dysfunction) and swelling and sweating changes (sudomotor dysfunction). Motor symptoms include weakness, tremors, reduced range of motion, and even dystonia (involuntary muscle contraction) in the affected extremity [43].

CRPS can be associated with worsening depression, poor function, anxiety, and diminished quality of life. A systematic review by Lohnberg et al [11] examined psychosocial factors associated with CRPS and they concluded that there is no support in the literature for specific personality or psychopathology predictors of CRPS [11]. Patients with a significant comorbid psychological burden and/or poor coping mechanisms can demonstrate pain-related behavior and catastrophic thinking. 

CRPS can also be associated with systemic medical conditions such as neuropsychological deficits that include executive functioning, memory, word retrieval, constitutional symptoms such as lethargy, weakness, disruptions in sleep architecture, cardiopulmonary involvement which includes neurocardiogenic syncope, atypical chest pain, chest wall muscle dystonia leading to shortness of breath, endocrinopathies which include impaired hypothalamic-pituitary-adrenal axis with low serum cortisol, hypothyroidism, urologic dysfunction with increased urinary frequency and urgency, urinary incontinence, and gastrointestinal dysmotility with nausea, vomiting, diarrhea, constipation, indigestion [44,45,46,42,47,48].

Evaluation

The pathophysiologic mechanism for CRPS has yet to be identified. There is no gold standard diagnostic test for CRPS [8]. The diagnosis is clinical. It is based on the widely accepted Budapest criteria. As compared to the previous IASP criteria, the Budapest criteria have similar sensitivity (0.99) but higher specificity (0.68) [7].

The Budapest Criteria [6] includes the following:

A. There should be continuing pain that is disproportionate to the inciting event.

B. There should be at least one symptom in three of the following four categories:

• Sensory: Reports of hyperalgesia and/or allodynia.

• Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry.

• Sudomotor/edema: Reports of edema 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, skin, nails).

C. They must display at least one sign at the time of evaluation in two or more of the following categories:

• Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch or deep somatic pressure),

• Vasomotor: Evidence of temperature asymmetry and/or skin color changes and/or asymmetry,

• Sudomotor/edema: Edema 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, skin, nails).

D. There is no other diagnosis that better explains the signs and symptoms.

Various objective testing measures such as thermography, triple-phase bone scan, and the quantitative sudomotor axon reflex test have been utilized. They are, however, not necessary to make the diagnosis of CRPS. The diagnosis of CRPS is largely clinical. The differential diagnosis of CRPS includes small or large fiber sensorimotor neuropathy, vasculitis, vascular insufficiency, lymphedema, cellulitis, erythromelalgia, deep vein thrombosis, and Reynaud’s phenomenon. Diagnostic tests in CRPS are done to screen for other potential differential diagnoses.

Management

Patients with CRPS can improve spontaneously. In some patients, the symptoms can be debilitating. It is good to institute aggressive management as soon as possible since a delay may result in an unfavorable outcome. Compared to chronic CRPS, early CRPS is less resistant to treatment and has a better prognosis [49]. The aim of treatment is not only to improve pain and discomfort but also to restore function and prevent disability. The most optimal treatment would include an interprofessional approach including physical and occupational therapy, pharmacotherapy, behavioral therapy, and interventions [6].

Physical and Occupational Therapy

Manual therapy and exercises are part of the treatment regime for CRPS. Other treatment modalities include ultrasound, laser, pain education, transcutaneous electrical nerve stimulation, mirror therapy, and graded motor imagery (GMI). Manual therapy and exercise improve the function, and range of motion, as well as reduce disability through endorphin release as well as other central and peripheral analgesic mechanisms [3,50]. Pain education influences pain perception and behavior by improving understanding of pain pathophysiology [3]. The GMI and mirror therapy remediate maladaptive cortical neuroplastic changes that are associated with chronic pain conditions like CRPS [51].

A 2016 Cochrane review found that GMI and mirror therapy may improve pain as well as function in CRPS. The quality of the evidence, however, was poor. Two clinical trials each for mirror therapy and GMI therapy have demonstrated improvement in pain and function at 6 months. Low-quality evidence was also found for the improvement of impairment in CRPS with multimodal physiotherapy [3].

Pharmacotherapy

There are several medications that are used in the management of CRPS. These include anti-inflammatory medications, antidepressants, transdermal lidocaine, anticonvulsants, opioids, bisphosphonates, and NMDA antagonists. Using a multimodal pharmacologic regimen can lead to superior outcomes. 

Anti-inflammatory Medications

Since inflammation is thought to play a role in disease pathogenesis, oral corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) have been used in CRPS. There were three trials that compared oral corticosteroids to placebo in CRPS. Based on these trials a 2013 Cochrane review concluded that oral steroids do not significantly reduce pain. This, however, was supported by very low-quality evidence. The Cochrane review also found that oral corticosteroids do seem to improve composite pain scores [52]. Another study compared piroxicam (NSAID) to oral prednisone. The study found that oral prednisolone seemed to be more effective in improving composite CRPS scores in post-stroke patients [53]. A study by Kalitamore et al [54] found that a 2-month treatment with low-dose oral prednisone was safe and effective in post-stroke CRPS.

Bisphosphonates

Bisphosphonates such asrisedronate (Actonel), alendronate (Fosamax), ibandronate (Boniva), zoledronic acid (Reclast), and pamidronate (Aredia) are routinely used in bone-related problems as it inhibits osteoclastic activity. There are several mechanisms of action of bisphosphonates in CRPS. The more commonly accepted mechanism includes inhibition of bone marrow cell proliferation and migration. It also inhibits inflammation modulation [55]. A 2017 meta-analysis concluded that bisphosphonates reduce pain in CRPS I [56]. A Cochrane review in 2013 found that there is low-quality evidence that also seemed to suggest the same response in CRPS. It is more so in those with concomitant evidence of osteopenia or osteoporosis [52].

Anticonvulsants and Antidepressants

Gabapentin, an anticonvulsant, is the most widely studied medication in this class. Its mechanism is via inhibition of the alpha 2-delta subunit of voltage-gated calcium channels. It is widely used in the treatment of CRPS, although the quality of evidence regarding its effectiveness in treating CRPS is very low [52]. A study in 2016 compared amitriptyline and gabapentin for CRPS I and pediatric neuropathic pain. The study found that both the medications reduced pain intensity and disability significantly. However, there was no significant difference in effect between the two [57].

Opioids

The effectiveness of opioids for the treatment of CRPS has not been studied. Therefore no evidence-based conclusions can be drawn [41].

NMDA Antagonists

NMDA receptor antagonists such as ketamine have been hypothesized to reverse central sensitization and maladaptive cortical neuroplastic changes in patients with CRPS [24]. There is low-quality evidence which suggests that intravenous ketamine infusion may improve pain in CRPS for up to 4-11 weeks [52,52]. Side effects and psychomimetic properties of ketamine have prevented its widespread use [24].

Behavioral Therapy

In patients with depression, the levels of catecholamines are elevated and this can worsen CRPS by inducing central sensitization through adrenergic mechanisms. Psychotherapy can help reverse this effect. There is only one small trial that has evaluated the efficacy of behavioral interventions in CRPS. Despite the lack of clear evidence supporting the use of behavioral therapy in CRPS, behavioral therapy has been recommended as part of comprehensive treatment [58].

Interventions

Sympathetic Blocks

Sympathetic hyperactivity is believed to cause CRPS [41]. Therefore, lumbar sympathetic nerve blocks are used to treat lower extremity symptoms, and stellate ganglion sympathetic blocks are used to treat upper extremity symptoms of this syndrome. A 2013 Cochrane review found that sympathetic blocks with local anesthetic were ineffective at reducing CRPS related pain. The quality of evidence was, however, low [52]. Another Cochrane review in 2016 failed to draw any definitive conclusions on the efficacy of such treatment in CRPS due to paucity of evidence [59].

Spinal Cord Stimulation

Spinal cord stimulation (SCS) is carried out by delivering electric stimulation to the dorsal column of the spinal cord by the placement of electrodes in the epidural space. The electrodes are connected to an implanted pulse generator to power the electrode. In some devices, an external pulse generator is used.

Several mechanisms of action of SCS have been proposed. This includes inhibition of nociceptive neural conduction in the spinal cord, vasodilation, adrenergic inhibition, and reversal of cortical maladaptive neuroplastic changes. There was a systematic review in 2017 that studied the effectiveness of SCS in CRPS. The authors of the review concluded that a high level of evidence supports the use of SCS for the improvement of pain scores, quality of life as well as the perception of pain relief in CRPS [59].

Dorsal Root Ganglion Stimulation

Targeting the dorsal root ganglion (DRG) instead of the spinal cord is a new and novel neuromodulation modality for the treatment of chronic pain. This allows a more focused application of neurostimulation than traditional SCS. DRG stimulation was approved by the United States Food and Drug Administration in 2016 for the treatment of lower extremity pain in CRPS.

A pooled analysis study by Huygen et al [60] concluded that DRG stimulation was safe and effective for CRPS with a 4.9-point mean reduction of pain intensity in CRPS-I. The ACCURATE study compared SCS and DRG stimulation in 152 subjects with CRPS. The study results were published in 2017. This randomized trial found that DRG stimulation was more effective than traditional SCS in reducing pain and improving quality of life in CRPS [61].

Differential Diagnosis

The differential diagnosis of CRPS includes:

• Arterial insufficiency

• Gillian Barre syndrome

• Hysteria

• Phlebothrombosis

• Porphyria

• Poliomyelitis

• Tabes dorsalis

• Monometric amyotrophy

• Multiple sclerosis

• Peripheral atherosclerotic disease

Staging

In 1990 Bonica proposed 3 stages of CRPS. Bruehl et al [62] studied the validity of the 3 stages in a series of 113 patients and they found no significant difference in duration of symptoms among the stages. This suggests that clear generalized disease stages don't exist in CRPS.

Prognosis

The prognosis of CRPS is variable. Spontaneous remission and refractory clinical presentation have been seen in CRPS. However early treatment may improve the prognosis.

Complications

Some of the complications seen in patients with long-standing CRPS include:

• Dystonia

• Cognitive executive dysfunction

• Irritable bowel syndrome 

• Adrenal insufficiency

• Gastroparesis

Deterrence 

It has been hypothesized that oral supplementation of vitamin C lowers the risk of the development of CRPS after fractures due to its antioxidant properties. In 2015, a meta-analysis of 3 trials found that the available evidence failed to demonstrate a definitive preventive role of vitamin C in CRPS development after distal radial fractures. The level of evidence was, however, low [63]. In 2017 another meta-analysis and systemic review evaluated the efficacy of vitamin C in the prevention of CRPS development after wrist fractures. Five hundred mg daily vitamin C therapy for 50 days seemed to reduce the risk of CRPS at 1 year in this study [64].

Conclusion

Complex regional pain syndrome (CRPS) is a neuropathic pain disorder. It is defined by the presence of distinct clinical features, that include hyperalgesia, allodynia, sudomotor and vasomotor abnormalities, and trophic changes. The pain experienced is disproportionate to the degree of tissue injury and it persists beyond the normal expected time for tissue healing.

The pathophysiology is multifactorial. It involves pain dysregulation in the sympathetic and central nervous systems, with likely inflammatory, genetic, and psychological contributions.

There are two subtypes. Type I was formerly known as reflex sympathetic dystrophy. Type II was formerly known as causalgia. Type I occurs in the absence of nerve trauma. Type II occurs in the setting of known nerve trauma. Clinically they are indistinguishable. They follow a regional rather than dermatomal or peripheral nerve distribution. CPRS occurs in the distal extremities. Spread beyond the initially affected area commonly occurs in the proximal or contralateral limb. CRPS is further subdivided into "warm" versus "cold" and sympathetically maintained versus sympathetically independent, which may affect prognosis and treatment options. 

An interdisciplinary team approach is required to maximize recovery and limit disability. Early advanced pain management is key to improved outcomes.

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