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Approach to the Patient with Disproportionate Pain.

Patients will at times complain of pain out of proportion to a given situation. The trauma was relatively mild; the surgery was uneventful; the x-rays were negative. The patient may have a low pain tolerance, be malingering or be suffering from a hysterical conversion; but a number of conditions need to be thoroughly considered first (Fig. 1). Acute spinal events (epidural hematoma and disc herniation), fractures (occult, stress, or insufficiency), and abnormal or expanding fluid collections can be diagnosed with magnetic resonance imaging (MRI)--a common tool in the setting of severe pain--while vascular insufficiency can initially be assessed by an examination. This article, therefore, focusses on compartment syndromes, necrotizing fasciitis, and reflex sympathetic dystrophy (also known as complex regional pain syndrome).

While orthopedic surgeons can easily recite the main features of these conditions, the reverse does not automatically apply: when treating a patient presenting with pain out of proportion to the presumptive initial diagnosis, the disorders in question will not always come to an orthopedist's mind. This is unfortunate as these conditions tolerate variable delays beyond which the results can be disabling to catastrophic.

The issue of a missed diagnosis can relate to fixation bias (i.e., the inability to see a problem from a fresh perspective). The orthopedist thinks he knows from past experience that his patient is malingering or drug seeking or has a low pain threshold and proceeds to overlook a serious condition.

How frequently does this occur? At our request, the Controlled Risk Insurance Company (CRICO) (*) investigated lawsuits pertaining to these diagnoses and found 184 cases between 2005 and 2014. Forty-one percent of the suits were due to a missed or delayed diagnosis. Forty-three cases came from an orthopedic surgery service. Most significantly, there were 41 cases of permanent severe and significant injury and 40 deaths. The most frequently cited factor in these instances of missed diagnosis or treatment (68%) was "clinical judgment." Within this category, common specific allegations were patient assessment issues (101 cases), selection and management of therapy (54 cases), and delay or failure to obtain appropriate consult or referral (35 cases). Fifty-five cases (30%) were attributed in part to a communication failure (e.g., a nurse, PA, or resident failing to alert an attending of a pain-out-of-proportion situation).

These statistics highlight the concept that these conditions continue to go unrecognized at a significant rate both by physicians and allied health care professionals.

Acute Compartment Syndrome

A compartment syndrome, first described by Volkmann in 1881, is an increase in the interstitial pressure within a closed fascial compartment resulting in vascular compromise and ischemia. (1) The potential sequelae are limb threatening. Reconstructive surgery can, to a certain extent, mitigate the complications of a missed compartment syndrome, but return of normal function or quality of life is rarely, if ever, achieved. In a series of missed compartment syndrome cases over a 10-year period, utilizing the NAIC severity scale (National Association of Insurance Commissioners), there was 1 death 1 permanent major disability, and 7 "permanent significant" disabilities.

Anatomy

The upper and lower limbs are separated into compartments by fascia. A compartment syndrome can occur in any of these, either singly or in combination. The arm is divided into 15 compartments: two in the upper arm [volar (flexor) and dorsal (extensor)], three in the forearm (volar, dorsal, and lateral), and 10 in the hand [hypothenar, thenar, abductor pollicis, dorsal interosseous (4), and volar interosseous (3)]. In the leg, the thigh features the anterior, medial and posterior compartment; the lower leg has the anterior, lateral, superficial and deep posterior compartments, while the foot consists of nine compartments [medial, lateral, interosseous (4), and central (3) compartments].

Etiology

Potential causes include fractures, soft tissue trauma (e.g., gunshot wounds), vascular injury, excessively tight casts or dressings, thermal injury (especially circumferential third-degree burns), and venous obstruction (e.g., post-ischemic swelling following tourniquet release and surgical positioning). (2-4) Open fractures and other penetrating trauma do not prevent the development of a compartment syndrome. Additionally, in a casted leg, neutral ankle flexion creates greater pressures in the anterior and deep posterior compartments than an ankle in plantar flexion. (5) In surgical patients, an epidural provides a partial sympathetic block with increased local blood flow and can exacerbate the swelling of an extremity; when combined with local anesthetics, the likelihood of a missed compartment syndrome increases. (6) Of the 28 cases of missed compartment syndrome leading to legal proceedings in the CRICO database, five were secondary to fractures, two to soft tissue injuries of an upper extremity, and three to other non-fracture orthopedic diagnoses (including even a torn meniscus).

Pathophysiology

The initial rise in intra-compartmental pressure causes an increase in extravascular pressure leading the venules to collapse. Normal baseline myocyte metabolism requires a 5 to 7 mmHg oxygen tension, which can be easily maintained with the standard capillary perfusion pressure (CPP) of 25 mmHg and interstitial tissue pressure of 4 to 6 mmHg. (7) With the outflow blocked, the hydrostatic gradient drops sharply leading to reduced perfusion, increased edema, and eventually decreased arteriole perfusion pressure. When the critical threshold is reached, ischemia sets in. (8-10) Skeletal muscle reacts to ischemia by releasing histamine-like substances, which increase the vascular permeability of capillaries and leads to slowing of capillary flow, worsening ischemia. Furthermore, as myocytes lyse in response to ischemia, the released osmotically active particles attract further water that increases edema and adds to the worsening cycle of ischemia. Lack of oxygenated blood and accumulation of waste products leads to irritation of nerve endings, generating pain and decreased peripheral sensation. (11)

The most widely validated diagnostic criteria for a compartment syndrome is the difference between the compartment pressure and the diastolic blood pressure (delta-P) of < 30 mmHg. (10,12) A prospective series in patients with continuous compartment monitoring showed that when the difference between compartment pressure and diastolic blood pressure [greater than or equal to] 30 mmHg was maintained, patients had normal muscle function. (13) Anesthetic agents and narcotics can lower diastolic blood pressure, thus leading to a falsely normal delta-P. Therefore, when considering fasciotomies versus continued serial examinations in the intraoperative or otherwise intubated patient, it is important to use a preoperative diastolic pressure measurement to calculate the delta-P that most accurately assesses the status of the compartments. (10,14,15)

Diagnosis

Historically, the diagnosis of acute compartment syndrome has rested on the "5 P's"--pain, pallor, pulselessness, paralysis, and paresthesias--but some of these signs present too late. A complete lack of pulses is particularly rare, usually only occurring with concomitant arterial injury. (10) Additionally, several of the above signs and symptoms are difficult to impossible to elicit in an obtunded or altered patient. The hallmarks of a developing compartment syndrome are tense swollen compartments, pain out of proportion to the injury, and pain with passive stretching of the involved compartment. (10,16) These may not be present in all cases of compartment syndrome and conversely do not automatically reflect dangerous pressures. High clinical suspicion is necessary to avoid missing an atypical presentation. In a large retrospective study of 1,125 tibial fractures, the most common presenting symptom (71% of cases) was increasing pain requiring abnormal doses of medications. (8) In children, many now advocate observance for the "3 As": increasing analgesic requirement, anxiety, and agitation. In a series of 33 children with compartment syndrome, Bae et al. (17) determined that increased analgesic requirement was a more sensitive indicator in children and documented a mean of 7.3 hours before a change in vascular status.

A compartment syndrome is a clinical diagnosis, but in obtunded patients or atypical cases, confirmatory diagnosis can be made with objective compartment measurements. Compartment measurements can also help differentiate between an under-medicated patient and one who is developing a compartment syndrome. (9) However, if there is a high clinical suspicion, treatment should be initiated, especially if measurement delays can be expected. There are multiple methods described in the literature for measuring compartment pressures. Two of the most common are a side port needle or a slit catheter. The slit catheter attached to an arterial line and pressure transducer can be left in place to provide continuous pressure monitoring. (18) The Stryker Intracompartmental Pressure Monitor System (Stryker, Kalamazoo, Michigan) is a simple though not infallible alternative. (19) Pressures should be measured in close proximity to the fracture site and at multiple sites within all compartments. (9-10,12,14)

Historically, radiographic studies were not utilized for the diagnosis for compartment syndrome. However, a recent study by Allmon, et al. (20) indicated that in tibia fractures, there are several fracture characteristics that were more commonly associated with compartment syndromes. In their study, it most often occurred as a sequelae of tibial plateau fractures, particularly Schatzker type VI and when the fracture length was greater than 20% of the tibia length; it was not more common in segmental tibia fractures. (20)

There are few laboratory tests that are useful in the diagnosis of compartment syndrome. Indicators of muscle necrosis such as serum creatine phosphokinase have been used for diagnosing and monitoring the resolution of the compression. Myoglobin can be seen in the urine, but must be differentiated from hematuria. Myoglobinuria is evidence of muscle cell lysis and is toxic to glomeruli; if myoglobinuria is detected, aggressive fluid treatment to prevent renal failure should be considered. (3,9,10,14)

Treatment

Most critical to the outcome of a compartment syndrome is the delay in treatment. In one study comparing fasciotomies before and after 12 hours of symptoms, 68% of patients treated early had normal function versus only 8% of patients treated late. In another study, of five patients who underwent fasciotomy after 35 hours, one patient died of multi-organ failure and amputation was necessary in the other four. (21,22)

Casts or other circumferential or occlusive dressings should be split or released completely. The affected limb should be elevated above the level of the patient's heart, which minimizes swelling and maximizes perfusion. (9,16,17) If the symptoms do not improve, the treatment of choice is urgent complete fasciotomy of all affected compartments. The length of the skin incision necessary for an adequate fasciotomy remains debatable. While some advocate limited incisions pointing to a lower morbidity, others feel that a long incision is best considering the reports of recurrent compartment syndromes due to the intact skin itself. A study by Cohen et al. (23) reported that in the post-traumatic compartment syndrome of the lower extremity treated with a two-incision technique, the incisions needed to be 16 [+ or -] 4 cm in length to achieve complete decompression. In the thigh, a lateral approach can address the anterior and posterior compartments, but may require a second medial incision; in the lower leg, all four compartments can be reached by a long anterolateral incision or two separate medial and lateral approaches. There are proponents of both the one and two incision techniques for releasing all four compartments of the leg, but neither has been established as the superior approach as long as all involved compartments are reached. Following surgical fasciotomy, incisions are generally left open to prevent recurrence. However, if one chooses to perform a secondary closure, care must be taken to not do so at the expense of increased pressures. (24) On return to the operating room, if there is any sign of new or remaining muscle necrosis, it should be debrided and closure not attempted until a later date. If direct skin edge apposition cannot be achieved easily, split thickness skin grafts can be used for coverage. A retrospective study by Weaver et al. (25) showed that the majority of wounds that could not be closed at the first post-fasciotomy closure could never be closed primarily. Wounds that were closed aggressively with split thickness skin grafts at the first post-fasciotomy surgery led to significant shorter hospital stays (12.2 versus 17.4 days). (25) Long term, patients may complain of decreased sensation, recurrent ulcerations, or other issues at the site of fasciotomy. (26) Nevertheless, the overall morbidity of a missed compartment syndrome or incompletely released compartment is far more significant. Once muscle death has occurred, treatment can only restore limited function.

Necrotizing Fasciitis

Necrotizing fasciitis (NF) is a life-threatening bacterial infection of the skin, soft tissue, and muscle with high morbidity and mortality; the diagnosis and treatment are extremely time sensitive. In the CRICO database, nine cases specifically related to underlying orthopedic diagnoses (three fractures, two sprains, one following a traumatic compartment syndrome, and three with unspecified injuries to the hand, shoulder region, and knee and leg). Of 103 NF cases, 29 resulted in death, five in permanent major disability, and 19 in permanent significant disability.

The first known report of necrotizing fasciitis, also known colloquially as a disease of "flesh-eating bacteria," dates to 500 BC by Hippocrates. (27) In 1871, Joseph Jones, a military surgeon during the American Civil War, reported over 2,600 cases of "hospital gangrene" with a mortality rate of 46%. (28) The moniker "necrotizing fasciitis" dates from 1952. (29) Its prevalence is often reported to be approximately 0.4 per 100,000 (30) In the United States, approximately 500 to 1,500 cases are reported each year. (31) Some studies show a predilection for males (with a ratio of 3:1), mostly attributed to the increased incidence in males of the genital and perineal version of this affliction. Patients over 50 years of age are at greater risk. (31-33) In a review of the literature, Goh et al. (34) found that median mortality ratio was 21.5%, but its rate varies greatly within the literature (8.7% to 76%) and is thought to be slightly lower in the extremities. (32,33,35) Comorbidities include diabetes mellitus in 40% to 60% of patients, liver cirrhosis, chronic heart failure, and alcohol abuse. (35,36) The use of NSAIDs has been shown to worsen mortality since they suppress fever and can thereby delay diagnosis. (35,37)

Etiology

There are two classic types of necrotizing fasciitis. The most common, Type I, is a polymicrobial infection with two or more pathogens that is usually found in the trunk or perineum and that typically affects patients with several underlying comorbidities. Type II, is an infection with beta-hemolytic streptococcus pyogenes typically occurring in the extremities of younger, healthy subjects. The tissue necrosis is caused by the virulence factors of this group A streptococcus. (31) It is increasingly seen in association with Staphylococcus aureus, which also secretes toxins that cause leukocyte destruction and tissue necrosis. Methicillin-resistant Staphylococcus aureus (MRSA) has been reported in 10% to 30% of all cases, complicating treatment. (32,33) The more rare Type III is a monobacterial infection with a Clostridium series or other anaerobic organism. Clostridium perfringens is most commonly seen in IV drug users. (35) InAsia, Vibrio vulnificus, a marine bacterium, is common (36) Type IV, the most rare, is due to fungal infections and is usually seen in immuno-compromised patients. Wound cultures are positive in 80% of cases, but blood cultures are positive in only 25%. (37) The infection spreads along the superficial fascia, destroying fascia and adipose tissue. Necrosis of the superficial fascia and fat produces a thin, watery, malodorous fluid. In an evolving spiral, bacteria cause thrombosis of the nutrient vessels to the hypodermis causing tissue ischemia, worsening edema, and skin necrosis; ischemia then promotes the dissemination of the infection. The intense pain has been attributed to the tissue ischemia affecting local nerves branches, but the area may later become anesthetic as cutaneous nerves are destroyed. (31,33,38)

Diagnosis

Necrotizing fasciitis classically presents with a triad of pain, swelling, and erythema. The severe pain is out of proportion to an otherwise benign, cellulitis-appearing presentation. Fevers are sometimes present, but not necessary for diagnosis. Tachycardia greater than 100 beats per minute, hypotension (mean arterial pressure less than 100) and tachypnea can also be present in the hours following initial presentation. (33) On exam, the skin may be just slightly erythematous or can already present with evidence of necrosis and hemorrhagic bullae. The area of tenderness extends far beyond the visibly abnormal area, as the infection spreads through the deep fascia. (313338) Patients can be stable on presentation but then rapidly decompensate into septic shock. If there is a suspicion of necrotizing fasciitis on initial exam, resuscitation and surgical planning should be initiated immediately.

Leukocytosis greater than 20,000/L is suspicious for necrotizing fasciitis over cellulitis. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) Score was developed to differentiate necrotizing fasciitis from other soft-tissue infections based on laboratory results commonly performed in the initial evaluation of a soft tissue infection, factors in the CRP, white blood cell count, hemoglobin, sodium, creatinine, and blood glucose. (3940) A score above 6 is considered diagnostic (Tables 1 and 2).

Imaging is not particularly helpful. Like other entities that present most significantly with dramatically disproportionate pain, necrotizing fasciitis is a clinical diagnosis. X-rays can show subcutaneous gas formation that can be present in approximately half of cases, but otherwise have low sensitivity and specificity. (41) Computed tomography (CT) or magnetic resonance imaging (MRI) can show the soft tissue extent of the infection via fascial edema, inflammation, and gas. However, these tests, particularly MRI, are not always readily accessible on moment's notice and not necessary for diagnosis. The literature discusses a bedside "finger" test with frozen sections whereby a 2 cm skin incision is made and a finger inserted down to the deep fascia. Confirmatory signs of NF include malodorous grayish purulent fluid, "dishwater pus" which is pathognomonic for NF, as well as lack of bleeding or tissue resistance to blunt dissection (32,-34) Infection disease consults for appropriate broad-spectrum antibiotics are considered by some to be imperative, and general surgery or vascular surgery co-management may also be necessary depending on extent or anatomic distribution of disease.

Treatment

Prompt wide-spectrum antibiotic administration is important, but the treatment of necrotizing fasciitis is emergent surgical debridement. Failure to improve on broad spectrum antibiotics alone is further diagnostic of a necrotizing fasciitis picture. (34) Empiric recommendations for a polymicrobial infection, once confirmed on cultures, consists of ampicillin/ampicillin-sulbactam with metronidazole or clindamycin; adequate anaerobic coverage is important for this type of NF. (3342) For S. pyogenes or S. aureus infections, first or second-generation cephalosporins are recommended for methicillin-sensitive Staphylococcus aureus (MSSA) and vancomycin for MRSA. However, tissue hypoxia impairs the delivery of antibiotics to the infected tissue, another reason for urgent surgical debridement. Delay in surgery by more than 12 hours can be fatal, especially in acute, fulminant NF; the mortality rate is 9 times greater when surgery is not performed within 24 hours after symptom presentation. (43) Altered mental status, vital signs abnormalities, metabolic acidosis, or other signs of sepsis reflect an immediate need for surgery, the mortality rate in this group still being 70%. (44) Debridement also minimizes the spread of infection, overall tissue loss, and the risk of amputation. The initial debridement needs to be radical. The relative risk of death was 7.5 times higher if the first debridement was limited. (45) Repeat debridement should be considered within 24 hours, and many patients require repeated returns to the operating room. Tang et al. (46) recommended criteria for amputation including extensive soft tissue necrosis with underlying muscle involvement and rapidly progressing infection, high anesthesia risk, and presence of shock necessitating more than one inotropic agent. Amputation is a more expeditious procedure with less blood loss than debridement and reduces the number of procedures a critically ill patient would have to endure. In a systematic review of 451 patients with NF, limb loss was reported in 22%, and an equal number died; mean hospitalization length with 25 days with time in the ICU ranging 1 to 46 days. (47)

Reflex Sympathetic Dystrophy (Complex Regional Pain Syndrome)

Reflex sympathetic dystrophy (RSD), previously known as shoulder-hand syndrome, causalgia, Sudek's atrophy, and also most recently as complex regional pain syndrome (CRPS), is an umbrella term for a collection of clinical signs and symptoms reflecting painful neurological dysfunction. It is most strongly identified by unexplained disproportionate pain out of proportion with the inciting injury, though there need not have been trauma. The name "reflex sympathetic dystrophy" reflects an uncontrolled neurological response ("reflex") that may or may not involve the sympathetic system. If left untreated, CRSD can lead to neuromuscular compromise ("dystrophy"). The term "complex regional pain syndrome" has been in existence since 1994. Current epidemiological data suggest an incidence ranging from 5.5 to 26.2 per 100,000 per year, a prevalence 2 to 4 times higher in women, and a median age of onset between 40 and 53 years. (48) The CRICO database revealed 53 cases of litigation surrounding missed CRPS; 13 cases resulting in permanent significant disability; 30 were primarily attributed to underlying orthopedic conditions, including eight instances of CRPS following fractures of the hand or wrist, three related to carpal tunnel syndrome, and 11 due to other unspecified sprains, strains, synovitis, or joint disorders.

Presentation

Complex regional pain syndrome comprises four primary features: severe pain, (initial) swelling, stiffness, and vasomotor instability defined as color, temperature, and sudomotor changes. The upper extremity is most commonly affected. (49) There are numerous diagnostic criteria purported to aid the diagnosis of CRPS, but none are evidence-based. Broadly, it is divided into two types: CRPS I occurs where there is no obvious nerve damage by the original injury, while CRPS II reflects identifiable nerve damage. While some divide the presentations of CRPS into "warm" or "high flow" CRPS to describe the hot, painful extremity, and "cold" or "low flow" CRPS for the cool, atrophic limb, the warm presentation may simply precede the cold. (48) In another it was found that some patients with CRPS for more than 10 years still have "warm" limbs. (50) The International Association for the Study of Pain(IASP) adapted Budapest criteria (Table 3) are the most recent and the only ones to have been validated for diagnosis of CRPS. (51) However, they do not differentiate between levels of severity, elucidate the prognosis, or aid in the treatment, and they are difficult to use in the clinical setting; we refer the reader to the paper by Harden et al. (51) for further information. This Budapest criteria revealed 99% sensitivity with 68% specificity. (51) In some cases, patients recover quickly while others have more severe symptoms that slowly resolve or that do not resolve at all, thus becoming a chronic refractory CRPS. (49,51) The IASP diagnostic criteria are often not utilized by many clinicians. Complex regional pain syndrome is an over-diagnosed condition. If the patient does not manifest the time-related physical manifestation of disease, then the diagnosis may be just neuropathic pain instead.

Diagnosis

Complex regional pain syndrome is a diagnosis of exclusion and cannot be suspected if other diagnoses that could be responsible for the signs and symptoms are present. It most commonly develops progressively over 1 month following an inciting event that undergoes expected healing. In the initial months, hypoesthesia and hyperalgesia are common, as is ongoing anesthesia dolorosa. (50) The pain may be poorly responsive to anti-inflammatory or narcotic medications. In comparison to the pain of the acute presentation, the pain of later phases is more frequently present at rest and resistant to treatment. (52) The patient develops a behavioral pattern of constant guarding or avoidance of the painful region. Active movement of the limb is avoided secondary to the severe pain, promoting the development of debilitating contractures. A hallmark of chronic CRPS is the development of orthopedic or neuropathic findings due to altered biomechanics, tissue dystrophy, and atrophy of the affected limb. (52) Swelling can occur early with patchy discoloration of the involved region that the patient cannot or is unwilling to move, furthering the loss of function. Even after CRPS subsides, the patient may still perceive the hand as being severely swollen and larger than the contralateral side. (51) Though many cases do not adhere to any published staging, following the onset of pain, muscle weakness, tremor, allodynia (painful response to non-painful stimuli), hyperalgesia (heightened pain response), hyperhidrosis, and ultimately contractures, hair and nail abnormalities and atrophy and dystrophy develop to various degrees depending on the success of the treatment, the patient's willingness to engage the involved extremity in rehabilitation, and presence of disease. (48)

Complex regional pain syndrome is initially a clinical diagnosis of exclusion; there are no pathognomonic physical examination findings, laboratory studies, or imaging studies. Radiographs sometimes show diffuse or periarticular disuse osteopenia of the affected limb. An MRI is an excellent tool for excluding other diagnoses, but not for diagnosing CRPS. The bone edema it reveals is neither sensitive nor specific. A three-phase bone scan can demonstrate increased uptake in the affected joints but is not sensitive or specific. (53) Other tests, such as thermography, isolated cold stress tests, or sweat testing have all been investigated but are not specific for CRPS and thus rarely used.

Pathophysiology

The root causes of CRPS continues to elude investigators. It is commonly thought to be triggered by minor or major trauma; fractures underlie 60% of cases in some reports and surgery is the precipitating event in 20%. (50,51) Other reported etiologies include injections, venipuncture, infections, burns, cerebrovascular accidents, or myocardial infarctions. (50,54) In up to 10% of cases, there is no identifiable precipitating event. There are reports of CRPS occurring in identical twins, and possibly a hereditary component in families with HLA-DR 13 or 15, but no consistent links have been identified. (55) Multiple studies have shown an absence of correlation between CRPS and anxiety, depression, personality disorders, or other psychiatric conditions. In many, it starts as an "excessive post-traumatic inflammation" that neither resolves as expected nor correlates with the severity of the trauma. (56) The incidence following distal radius fractures has been reported to be as high as 25%, and it has also been reported following carpal tunnel decompressions (up to 5%) and Dupuytren's contracture releases (5% to 25%). (57) The joint contractures, the activation of osteoblasts and osteoclasts causing high-turnover osteoporosis, the increased hair growth, and hyperhidrosis can all be secondary to this pathologic inflammatory state. (58) Laboratory markers of inflammation, such as TNF-alpha, IL-2, and substance P have been isolated acutely but with no causative link. (58) Skin biopsies taken from patients with fewer than 6 months of symptoms have high levels of THA-alpha that return to normal as the disease transitions from acute to chronic. (58) Central nervous system involvement in CRPS Type I is supported by symptoms that cannot be a purely peripheral process. For example, pain can be felt in the contralateral limb or in non-synchronous areas of the body, such as genital pain in CRPS of lower extremity. (51) Higher neurological reorganization or "maladaptive neuroplasticity" is also seen. Magnetic resonance imaging and advanced magnetoencephalopathy (MEG) reveal that the representation of the affected limb on the primary somatosensory cortex has been altered afteryears of CRPS-type pain, and that reduction in pain reverses the change. (59) Ongoing research in this area centers on damage to small fragile nerve fibers, both myelinated and un-myelinated. Small fiber damage can result in the trophic changes. (51)

Treatment

Many cases of CRPS resolve or go into prolonged remission with multi-disciplinary treatment strategies. The reported success rates range from a high of 90% at 2 years to a low of 74% at 12 months, but a significant percentage of cases do not resolve. (48) Zyluk et al. (60) reported spontaneous recurrence in 5 of 250 cases over 15 years, and Veldman et al. (61) showed a recurrence rate of 9% of 1,183 cases over 20 years with 3% in the ipsilateral and 6% actually occurring in the contralateral side. Following the resolution of an episode, it is thought that repeat trauma can reactivate one's CRPS, but not all recurrences have been correlated to traumatic events or surgical interventions.

Data support early intervention, ideally within 3 months of the presentation of symptoms. If delayed, there is a high risk of conversion to chronic CRPS and the damage may be irreversible. (62) Studied treatments include various physical therapy modalities, mirror-box therapy (see below), medications, and surgery. Physical therapy modalities, including transcutaneous electrical nerve stimulation (TENS), progressive motion and weightbearing, tactile desensitization, and contrast bath therapy, are critical to help patients avoid joint contractures, diminish skin sensitivity, and restore function. (63) Mirror feedback therapy is especially helpful to those with an inability to participate in physical therapy due to touch intolerance severe tactile pain. (64) The patient exercises their normal hand in front of a mirror so that the sides are reversed. As such the impaired limb appears to the patient to be moving normally, ideally helping the brain to reorganize its neural network. (60,64)

Medication trials have included anti-inflammatories, anticonvulsants, neuropathic agents, anti-depressants, and anesthetics. Acetaminophen, non-steroidal anti-inflammatories, and amitriptyline have not shown any benefit. One study of gabapentin demonstrated efficacy, but only during the first 8 weeks of symptoms. (65) Free-radical scavengers, topical or oral (DMSO, N-acetyl-cysteine, respectively), have been shown to be more useful in acute cases of "warm" CRPS. Glucocorticoids reduce post-traumatic inflammation and have been shown to help acutely, but the optimal dosage is unknown. (48,62) Small studies have suggested that bisphosphonates may also help to improve pain though the mechanisms are unknown. (66) Some theorize that the bisphosphonates help to improve the pain associated with osteolytic bone loss. (66-68) A recent study showed that patients with less than 6 months of symptoms treated with IV neridronate had improved pain control at 1 year. (5268) Sympathetic blockades with local anesthetics agents are considered to be diagnostic, but questions have been raised regarding their treatment benefits. A recent Cochrane analysis of local anesthetic sympathetic blocks found the data lacking with regards to the efficacy of local anesthetic blockade. (69) However, some practitioners continue to endorse a limited course of blocks administered over a few weeks if an initial experimental block relieves symptoms. (48) Intravenous regional anesthesia with guanethidine is no longer recommended, and recent studies emphasize the risk of significant adverse effects. (70) Ketamine, a potent NMDA antagonist that alters the central nervous system's processing of pain signals, has shown some promise in moderate to severe CRPS. Many different formulations such as topical, low-dose infusions, and ketamine-induced comas have been tried. Sigtermans et al. (71) reported a double-blind, randomized placebo-controlled trial of a 4.2 day continuous low-dose infusion of ketamine that lead to a 12-week sustained reduction in the pain. A study of a 5-day infusion of anesthesia-dose ketamine also showed complete remission in all patients. (72)

Although there is great resistance to surgery for CRPS patients, some practitioners believe that pain resolution may be achieved through nerve decompression or denervation, neuroma resection, and neurolysis in those patients who are properly indicated by diagnostic nerve blocks. (52) Surgical release of contractures has not been successful. Surgical release of finger contractures has at best a 50% improvement in symptoms. (62) A recent systematic review by Bodde et al. (73) stated that the existing data, all from level IV evidence, were not sufficient to provide conclusions on the benefits or adverse affects of amputation for CRPS. Indirect surgical intervention with spinal cord stimulator placement is an option, particularly for CRPS of the lower extremities, but data on the success of this are also lacking. In a prospective randomized study comparing physical therapy alone to physical therapy with a spinal cord stimulator, patients in both groups had equal results. (74) In another study, spinal cord stimulators were shown to be more cost-effective over a patient's lifetime compared with physical therapy and medical management. (75)

As there are no predictably successful treatment modalities, the correct intervention may be prevention. Avoidance of prolonged immobilization and early physical or occupational therapy may be helpful. (76) Oral vitamin C is the most recognized medical therapy. Doses of 1 g/day for 50 days following surgery have been shown to significantly reduce postoperative incidence of CRPS. (77) Although other recent studies have not supported its use as strongly, (78) a recent validity study supported the idea of vitamin C preventing CRPS after distal radius fracture. Considering also its low cost and safety, Malay et al. (79) confirmed that the AAOS recommendation of vitamin C in these fractures had merit.

Conclusion

In short, the best policy with regard to these three conditions remains early detection and cognizance of the potentially serious conditions underlying a patient's "excessive pain." The morbidity, or mortality, of a missed compartment syndrome can be truly life-altering if the limb dysfunction is permanent or if reperfusion leads to renal failure or death. Similarly, necrotizing fasciitis has a high mortality rate if not diagnosed early and treated both aggressively and expeditiously. Complex regional pain syndrome, while not dependent on aggressive surgical intervention, has shown the best outcomes in patients with early diagnosis and intervention.

Disclosure Statement

None of the authors have a financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.

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Diana C. Patterson, MD, and Ronald P. Grelsamer, MD

Diana C. Patterson, MD, and Ronald P. Grelsamer, MD, Department of Orthopaedic Surgery, Mount Sinai Health System, New York, New York, USA.

Correspondence: Diana Patterson, MD, Department of Orthopedic Surgery, One Gustave L. Levy Place, 5 East 98th Street, 9th Floor, New York, New York 10029, USA; diana.patterson@mountsinai.org.

(*) Controlled Risk Insurance Company (CRICO) is the medical professional liability insurer for the Harvard medical community.

Caption: Figure 1 Pain out of proportion diagnostic algorithm created by authors.
Table 1 Six Different Variables Included in the Laboratory Risk
Indicator for Necrotizing Fasciitis (LRINEC) Score to Help Discriminate
Between Necrotizing and Non-Necrotizing Soft-Tissue Infections

Variable                   Value      LRINEC Score

C-reactive protein, mg/L   < 150          0
                           > 150          4
WBC count, cells/mm (3)     < 15          0
                              15-25       1
                            > 25          2
Hemoglobin level, g/dL      > 13.5        0
                              11-13.5     1
                            < 11          2
Sodium level, mmol/L       > 135          0
                           < 135          2
Creatinine level, mg/dL      < 1.6        0
                             > 1.6        2
Glucose level, mg/dL       < 180          0
                           > 180          1

Table 2 Patient Categories Within the Laboratory Risk Indicator for
Necrotizing Fasciitis (LRINEC) Score According to the Likelihood of
Necrotizing Soft-Tissue Infection

Risk Category  LRINEC Score                 Probability of NSTI

Low            [less than or equal to]5     < 50%
Intermediate   6-7                            50%-75%
High           [greater than or equal to]8  > 75%

Table 3 The International Association for the Study of Pain (IASP)
Adapted Budapest Criteria for the Diagnosis of CRPS

At the time of examination,
the patient must report:

1. Continuing pain             Disproportionate to inciting event
2. Symptoms                    At least 1 in 3 of the following 4
                               categories:
                               Sensory
                               Vasomotor
                               Sudomotor
                               Motor or Trophic
3. Signs                       At least 1 in 2 of the following 4
                               categories:
                               Sensory
                               Vasomotor
                               Sudomotor
                               Motor or Trophic

4. No other diagnosis
explaining symptoms and signs

At the time of examination,
the patient must report:

1. Continuing pain
2. Symptoms
                               Hyperaesthesia or allodynia
                               Temperature or color changes--asymmetry
                               Edema or sweating changes--asymmetry
                               Decreased ROM, weakness, tremor, or
                               dystonia; trophic changes in skin,
                               hair, or nails
3. Signs                       At least 1 in 2 of the following
                               categories:
                               Hyperaesthesia to pin prick
                               Allodynia to light touch
                               Evidence of temperature or color
                               asymmetry
                               Evidence of edema or sweating asymmetry
                               Evidence of decreased ROM, weakness,
                               tremor or dystonia; trophic changes to
                               skin, hair, or nails
4. No other diagnosis
explaining symptoms and signs


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Author:Patterson, Diana C.; Grelsamer, Ronald P.
Publication:Bulletin of the NYU Hospital for Joint Diseases
Article Type:Report
Date:Apr 1, 2018
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