NEWSLETTER 13: COMPLEX REGIONAL PAIN SYNDROME
Needlestick IV Insertion-induced
Formerly: RSD; Causalgia; Sudeck's Atrophy or Algodystrophy

CRPS (Complex Regional Pain Syndrome) is a chronic pain condition believed to be the result of dysfunction in the central or peripheral nervous systems. Typical symptoms include dramatic changes in the color and temperature of the skin over the affected limb or body part, accompanied by intense burning pain, skin sensitivity, sweating, and swelling.

CRPS may be a result of negligent medical care especially if there were unnecessary delay in diagnosis or treatment as early diagnosis and treatment are critically time sensitive in this ubiquitous disorder that is well understood by a minority of physicians and potentially present even with relatively minor trauma. There have been cases of medical malpractice lawsuits that have been won where the plaintiff alleged painful and debilitating CRPS as a result of a negligent blood draw as described by a San Diego attorney. The problem is in presenting CRPS to the jury in such a fashion that the expert witness from opposing counsel doesn't make it seem like a whiplash injury that is hard to prove and codify and easy to claim by malingers. ExpertMD and Dr. Saponaro have the knowledge, expertise and the experience of teaching CRPS in a fashion that you feel like a medical school student who is easily learning:

1. What is CRPS
2. How to diagnose it dependently and reliably
3. How to tell when a patient does not have it (differential diagnosis)
4. How to treat it
5. The ability to teach legal colleagues and jurors the medical intricacies

CRPS has been in the medical literature over one hundred years. In 1900 Paul Sudeck first described it (Sudeck's atrophy). J. Doupe [35] and his colleagues studied and treated injured WW II servicemen in 1944, which was a real value to the advancement of the diagnosis and treatment of then called RSD (CRPS). Claude Bernard, "a great physiologist" doing prolific research in the mid-1800s, was the first scientist to emphasize the importance of experimental techniques in obtaining valid clinical observations in reference to the sympathetic nervous system in association with sensibility and motor function. (36). In an experiment, he removed the superior cervical ganglion (mimicking CRPS) in the cat and described the effects on skin sensation and blood flow in the affected organ (just like occurs in humans with CRPS). [37]. The authors Ross (1932), Kwan (1935) and Livingston (1943) contributed to the idea that the relief of pain following sympatholysis is fundamental to a diagnosis of causalgia and reflex sympathetic dystrophy; two older names for CRPS [38].

We strive to communicate effectively on the level of the jurors and lawyers the complex medical literature surrounding CRPS. Obviously it would be not prudent to address them as if they were doctors who specialize in CRPS; although these days with Google everyone including my Mother are becoming more informed and conversant with complex medical issues than I remember I was as a freshman. What follows is some basic knowledge of the pathophysiology of CRPS.

CRPS type I is frequently triggered by tissue injury; the term describes all patients with the above symptoms but with no underlying nerve injury.

Patients with CRPS type II experience the same symptoms, but their cases are clearly associated with a nerve injury.

Older terms used to describe CRPS include RSD (Reflex Sympathetic Dystrophy) and Causalgia (Sudeck's atrophy). Causalgia was the term first used during the Civil War to describe the intense, hot pain felt by some veterans long after their wounds had healed. CRPS can strike at any age but is more common between the ages of 40 and 60 years. However, the number of CRPS cases among adolescents and young adults is increasing. CRPS affects both men and women.

Chronic pain from Complex Regional Pain Syndrome (CRPS) presents a myriad of diagnostic and therapeutic challenges to the treating physician. The disease involves multiple organ systems, including neural, vascular, bony, and soft tissue structures [1] [2] [3] [4] [5] . CRPS is a descriptive term defining a complex disorder or group of disorders that may develop as a consequence of trauma affecting the limbs, with or without an identifiable nerve lesion. To differentiate the presence or absence of nerve trauma, CRPS is divided into two types:

1. Type 1 CRPS has no identifiable nerve injury. Formerly termed Sudeck's atrophy and Causalgia.
2. Type 2 CRPS has an identifiable nerve injury present.

CRPS consists of: pain with its related sensory abnormalities; abnormal blood flow and sweating; abnormalities in the motor system; changes in structure in both superficial and deep tissues (trophic changes); or functional impairment. It does not exist in the absence of pain. The following four criteria were established by IASP (International Association for the Study of Pain), all of which are required to be present to confirm a clinical diagnosis of CRPS:

1. An inciting noxious event (or nerve injury for type 2) resulting in immobilization of an extremity.
2. Disproportionate degree of pain, allodynia, and/or hyperalgesia.
3. Edema, alteration in blood flow, or abnormal sudomotor (sweating) activity in the region of pain.
4. Exclusion of underlying conditions that would otherwise account for these symptoms.

CRPS is further divided depending on its relationship of the Pain to the Sympathetic Nervous System: Independent vs. Maintained

1. Independent of (SIP)
2. Maintained by (SMP)

CRPS may be classified as having either: Sympathetically Independent (SIP) or Sympathetically Maintained (SMP) [6] [7]. Sympathetically Maintained Pain (SMP) is defined as significant pain decreased or relieved after sympathetic intervention by oral medications (eg, amitriptyline) or parenteral intervention (eg, IV phentolamine, stellate ganglion block). SMP is more completely characterized than SIP, is more responsive to treatment, and has a better prognosis. A hallmark feature of SMP is thermoregulatory and vasomotor instability responding to sympatholytic intervention. A mechanical or neural precipitating or exacerbating event is termed a nociceptive stimulus.

The exact cause of CRPS is unknown. In some cases, the sympathetic nervous system plays an important role in sustaining the pain. The most recent theories suggest that pain receptors in the affected part of the body become responsive to a family of catecholamines. Animal studies indicate that norepinephrine, a catecholamine released from sympathetic nerves, acquires the capacity to activate pain pathways after tissue or nerve injury. The incidence of SMP (Sympathetically Maintained Pain) in CRPS is not known. Some researchers believe that the importance of the sympathetic nervous system depends on the stage of the disease.

Another theory is that CRPS type II (with identifiable nerve injury) is caused by a triggering of the immune response, which leads to the characteristic inflammatory symptoms of redness, warmth, and swelling in the affected area. Therefore, CRPS may represent a disruption of the healing process. In all likelihood, CRPS does not have a single cause but is rather the result of multiple causes that produce similar symptoms.

Because the single best prediction of success in the management of CRPS is early treatment, the prompt diagnosis of CRPS, identification of the nociceptive focus, determination of physiologic staging (hot/cold, SMP versus SIP), and prompt treatment provide palliation and allow for recovery.

CRPS (Complex Regional Pain Syndrome) type I (without identifiable nerve injury) causes chronic, poorly controllable pain, autonomic, sensorimotor disorders, and serious trophic alterations in the later stages. It develops in the distal extremities mostly after minimal trauma or surgical intervention and rarely spontaneously. The severity of symptoms is disproportionate to the causative event. The latest scientific findings show that the previously called RSD (Reflex Sympathetic Dystrophy), which was supposed to be a result of a hyperreactive autonomic nervous system, is a very complex syndrome that occurs on different integration levels of the nervous system. SMP (Sympathetically Maintained Pain) may be facultatively characteristic, but is not to be misunderstood as an underlying mechanism. A neurogenic inflammation reaction has recently been discussed, just as had been postulated by Paul Sudeck long before. That was the reason why the ISAP (International Association for the Study of Pain) introduced the more descriptive term "Complex Regional Pain Syndrome" (CRPS) type I back in 1994. Due to the complexity of the process necessitating qualified knowledge, it is important to immediately refer patients to a specialized pain clinic. The diagnosis of CRPS type I is based upon a carefully taken case history and a clinical examination by an experienced practitioner. Imaging diagnostic tools and laboratory findings are of no or only low predicative value. The question of whether SMP exists after diagnosing CRPS type I is of eminent value for planning therapy. Therefore, diagnostic regional anesthetics along with a trial of Elavil are still important in spite of their uncertain prognostic relevance. Physical therapy, occupational therapy, medical treatment, and psychotherapy play an important role in the primary treatment of CRPS type I as noninvasive procedures. Despite heavy criticism, invasive sympathetic block (ie: stellate ganglion block for upper extremity involvement), subsequent to adequate diagnostics, is an important part of the therapeutic concept. A multimodal therapeutic concept, which includes all available possibilities, is absolutely necessary to avoid grave permanent disabilities caused by insufficient or failed therapy. Nevertheless, already established as well as new treatment modalities have to be critically observed by further randomized, prospective control trials. Perception of pain is complex and is dependent upon the initiating event, afferent input, efferent modulation, and cortical interpretation. Nociceptive or painful events secondary to cellular damage produce a secondary inflammatory cascade, which includes the activation of polymodal afferent neurons (pain receptors) that input through the dorsal horn of the spinal cord to higher cortical centers. If nociceptive signals are inappropriately intense or ineffectively modulated by descending pathways, symptoms may escalate beyond the magnitude of the cellular insult. In the extremity, increased receptor-neurotransmitter activity potentiates sympathetically maintained pain through one or more of the following: microvascular control, direct neural input, or central sensitization [8] [9] [10] [11]. Following trauma, lower-extremity physiology is altered by the magnitude of the insult, subsequent internal responses, and external occurrences. How an individual perceives pain depends upon a complex interplay of physiological occurrences and psychological adaptations. In the majority of cases, return to "normal," or a premorbid functional steady state, occurs in a predictable manner [1] [12].

The key symptom of CRPS is continuous, intense pain out of proportion to the severity of the injury (if an injury has occurred) that worsens over time. CRPS most often affects one of the extremities (arms, legs, hands, or feet) and is also often accompanied by other symptoms, including the following:

• "burning" pain
• increased skin sensitivity
• changes in skin temperature (warmer or cooler compared with the opposite extremity)
• changes in skin color (often blotchy, purple, pale, or red)
• changes in skin texture (shiny, thin, and sometimes excessively sweaty)
• changes in nail and hair growth patterns
• swelling and stiffness in affected joints
• motor disability, with decreased ability to move the affected body part.

Often the pain spreads to include the entire arm or leg, even though the initiating injury might have been only to a finger or toe. Pain can sometimes travel to the opposite extremity and may be heightened by emotional stress. The symptoms of CRPS vary in severity and length. Some experts believe 3 stages are associated with CRPS, marked by progressive changes in the skin, muscles, joints, ligaments, and bones of the affected area, though this progression has not yet been validated by clinical research studies.

Stage 1 is thought to last from 1 to 3 months and is characterized by severe, burning pain, along with muscle spasm, joint stiffness, rapid hair growth, and alterations in the blood vessels that cause the skin to change color and temperature.

Stage 2 lasts from 3 to 6 months and is characterized by intensifying pain; swelling; decreased hair growth; cracked, brittle, grooved, or spotty nails; softened bones; stiff joints; and weak muscle tone.

In stage 3, the syndrome progresses to the point where changes in the skin and bone are no longer reversible. Pain becomes unyielding and may involve the entire limb or affected area. Marked muscle loss, severely limited mobility, and involuntary contractions of the muscles and tendons that flex the joints may be found. Limbs may become contorted.

The persistence of abnormal extremity physiology beyond normal time frames, with concomitant pain and functional impairment, is pathologic. The presence of transient dystrophic pain is normal, but the abnormally prolonged persistence of that dystrophic pain is pathologic and is termed causalgia, reflex sympathetic dystrophy, algodystrophy, or complex regional pain syndrome. Persistence of pathologic responses can result in permanent structural or functional damage within the extremity, the central nervous system, or both. Because of individual variability in the natural history of the dystrophic process, time frames for staging CRPS often are inappropriate. Physiologic responses are influenced by the magnitude of damage from the initiating injury, the structures damaged, variability in premorbid physiology, existing extremity adaptability, and the effects of partial treatment [1] [12] [13] [14] [15] [16]. Abnormal extremity physiology is an expected occurrence following trauma. Prolonged or persistent abnormal physiology may characterize a dystrophic response. Over time, irreversible events may occur. CRPS, a series of complex physiologic events, must include pain in combination with impaired function, trophic change, and autonomic dysfunction [17]. The distinction between SMP (Sympathetically Maintained Pain) and SIP (Sympathetically Independent Pain) is important [7] [10] [11] because early recognition and treatment of CRPS is the single most important predictor of functional recovery and pain relief. Objective techniques to diagnose the syndrome are crucial [12] [18]. Pain is manifest in a variety of presentations. Hyperalgesia and increased intensity of pain are common and may be primary, affecting the area of injury, or secondary, affecting nontraumatized surrounding regions. Allodynia, pain produced by normally nonpainful stimuli, is frequently a characteristic of SMP (Sympathetically Maintained Pain). The use of standardized questionnaires or scales such as the Visual Analog Scale [19], the McGill Pain Questionnaire [20], the Rand Corporation short form (SF-36) [21] [22] [23], or a self-administered questionnaire for assessment of symptom severity and functional status are useful tests for conversion of subjective complaints of pain into objective scores [19] . Trophic changes are common in the dystrophic process and include stiffness, edema, osteopenia, and atrophy of hair, nails, and skin. Edema may be followed with volumetric studies; however, most trophic changes are difficult to qualify. Osteopenia, unless severe, may not be documented by plain roentgenograms and, for quantitative analysis, must be analyzed by dual photon absorptiometry or quantitative scintigraphy [24] [25]. Endurance testing using computerized equipment may detect subtle functional changes that may reflect extremity stiffness or atrophy [12] [18].

Autonomic function controls sweating, piloerection, and microvascular perfusion in the digits. It may be evaluated by an assessment of: (1) total digital blood flow, which is composed of both thermoregulatory and nutritional components; and (2) sudomotor activity (sweating). Total digital perfusion and its components can be analyzed by indirect measures such as temperature, laser Doppler fluxmetry, and plethysmography, and by direct techniques such as vital capillaroscopy [26]. Sweating may be analyzed by changes in galvanic skin response, which measures skin resistance using Ag/AgCl (silver/silver chloride) electrodes. Changes in electrical conductance/resistance (galvanic skin response) are related to the rate of sweating, which in turn is under sympathetic control [12] [20]. Quantitative analysis of thermoregulatory and nutritional microvascular flow allows physiologic staging of CRPS and provides a mechanism to evaluate the effects of interventions and time upon the process [12] [15] [18] [26] [27] [28]. Use of physiologic stress in some form is a necessary component of extremity testing for reproducible analysis of dynamic physiologic events [12] [15]. Cold stress testing using digital temperature and laser Doppler fluxmetry provides a physiologic assessment of autonomic function in patients with reflex sympathetic dystrophy. The effects of exposure to a mild thermal challenge (cold) can be observed and digital temperatures and laser Doppler fluxmetry can be analyzed from computer-generated plots before, during, and after stress. Vital capillaroscopy allows the direct evaluation of the cutaneous nutritional papillary capillaries and a direct measure of nutritional blood flow—a component of total digital blood flow. The presence of abnormal capillary morphology associated with post-traumatic events or systemic disease may be diagnostic. Differentiation of SIP (Sympathetically Independent Pain) from SMP (Sympathetically Maintained Pain) is important diagnostically. SIP implies a more central process, often with irreversible end-organ adaptations and the presence of central pain. Prognosis for recovery in SIP is guarded.

SMP (Sympathetically Maintained Pain) is diagnosed in patients who experience an improvement during or after treatment with sympathetic medications. Classically, SMP must respond to an epidural, intrathecal, or lumbar plexus block or peripheral nerve block. Rapid response to such blocks supports the concept of receptor-mediated CRPS and has led to the suggestion that pain relief following intravenous phentolamine, a mixed ?1 and ? 2 antagonist, is pathognomonic for SMP [29] [30]. Not all patients with clinical SMP who respond to other forms of sympathetic intervention report relief with phentolamine, however. Although clinical signs and symptoms of CRPS and pain relief following pharmacologic interventions that affect sympathetic controls can combine to support the diagnosis of SMP, it must be stressed that there is no single pathognomonic test for SMP. This is no way implies that this is not a real codified disease.

Once a sympathetic component of pain is verified, it is important to determine the presence or absence of a mechanical or a neurologic focal trigger or nociceptive event. If an identifiable focus can be corrected, surgical treatment should be performed once optimal nonoperative relief has been obtained. In the foot, ankle, and lower extremity, posterior tibial nerve entrapment or compression, contusion of superficial sensory nerves in the dorsum of the foot, peroneal nerve entrapment, or injury to the intrapatellar branch of the saphenous nerve are common nerve irritants. Mechanical nociceptive conditions include entrapment of the peroneal tendons, intra-articular abnormalities such as cartilage flaps, arthrofibrosis, and others. In general, these conditions require pharmacologic palliation preoperatively and pharmacologic protection postoperatively. Identifiable peripheral nerve lesions include neuroma, neuroma-in-continuity, and compression neuropathy. Neural involvement may have been primary (ie, part of an initiating injury), or secondary (ie, caused by altered extremity physiology). In either situation, the compromised and irritated nerve serves as a nociceptive focus. Surgical intervention is indicated if symptoms persist after nonoperative intervention. Although surgery can precipitate a dystrophic flare, it still can be performed safely in patients with active or latent CRPS [12] [18] [31].

CRPS is diagnosed primarily through observation of the signs and symptoms. However, many other conditions have similar symptoms. It can be difficult for physicians to make a firm diagnosis of CRPS early in the course of the disorder when symptoms are few or mild. On the other hand, a simple nerve entrapment can sometimes cause pain severe enough to resemble a type-2 CRPS. Diagnosis is further complicated by the fact that some cases will improve gradually over time without treatment. No specific diagnostic tests exist for CRPS, and the most important role for testing is to rule out other conditions. Some clinicians apply a stimulus (such as touch, pinprick, heat, or cold) to the area to determine whether it causes pain. Physicians may also use triple-phase bone scans to identify changes in the bone and in blood circulation. The prompt use of pharmacologic management is integral to optimal outcome. Narcotic medications are less effective in managing dystrophic symptoms than sympatholytic interventions that:

1. decrease nerve hyperexcitability (eg, membrane stabilizers such as steroids or anticonvulsives)
2. diminish receptor upregulations (eg, phentolamines, ?2 agonists, tricyclic antidepressants)
3. block or decrease neural transmission (eg, peripheral nerve blocks, intrathecal medications)
4. improve nutritional flow (eg, calcium channel blockers).

Oral medications should be initiated early in the presence of "burning," "tearing," or "searing" pain that does not respond to analgesic medications (non-narcotic or narcotic). First-line agents include nonsteroidal anti-inflammatory drugs (NSAIDS), tricyclic antidepressants, (eg, low-dose amitriptyline), anticonvulsant (eg, phenytoin, gabapentin or Lyrica), or steroids. Because of concerns over the development of avascular necrosis, steroids are often avoided by orthopaedic surgeons but are commonly employed by internists. The judicious use of steroids is appropriate. If identifiable and manageable by surgery, dystrophic foci should be corrected after optimal pharmacologic protection has been obtained. Injury to peripheral nerves is the most common source of nociceptive (dystrophic) irritation; it may be associated with osseous and nonosseous derangements. Nerves may require neurolysis, neurorrhaphy, neuroma resection, and if necessary, environmental modification of the nerve bed [12] [31]. When CRPS is suspected, a combination of NSAIDS may be combined with combination sympatholetics. For example, burning dysesthetic hyperpathic foot pain after a sprain associated with swelling would be treated with physical therapy, contrast baths, NSAIDs, low dose amitriptyline (25 mg tid); and either phenytoin (100 mg tid) or gabapentin (starting at 100 mg tid), Lyrica (staring at 75 mgm BID) or a calcium channel blocker (eg, Norvasc at 5mg qd) may be employed. Drugs are tapered or actively increased depending on the patient's response. If symptoms are not alleviated, a short course of high-dose steroid or continuous blocks should be considered. In the presence of edema and localized hyperalgesia, an alpha2 agonist (eg, clonidine, 0.1 mg patch) may be applied to the hyperalgesic area. If the extremity is painful, cool, and early trophic changes are present, physical therapy, physical modalities (eg, contrast baths), a tricyclic antidepressant, and a calcium channel blocker may be effective.

If the patient shows no appropriate response, intermittent or continuous autonomic blocks should be considered. Consider continuous epidural blocks for 5 to 7 days, combined with outpatient therapy. Optimal management of CRPS is multimodal and requires titration of interventions and drugs, modifications of intervention based upon response, and art as well as science. General principles of treatment include:

1. use of physical modalities such as range of motion, intermittent stress (eg, weight bearing, impact), or contrast baths (should be initiated early)
2. oral medications based upon staging (hot/cold, edema/trophic) and adjusted depending on response
3. use of the least invasive, least expensive, and safest interventions first, with an increase in complexity of treatment until adequate response occurs
4. identification of any nociceptive foci and surgical intervention if necessary
5. the use of pain consultants for intermittent or continuous autonomic blocks in refractory patients. Oral and parenteral drugs used in treatment of CRPS including: NSAIDs; Steroids; Tricyclic Antidepressants; SSRIs; Anticonvulsants; CCBs; Alpa-2 Agonists; and, Bretylium. Sympathetic blocks including Stellate Ganglion blocks for upper limb are a key element in controlling CRPS. They offer at times spectacular, instantaneous relief. Response to such blocks is in fact one of the diagnostic criteria for CRPS. These injections may be repeated if improvement is satisfactory for a period of time.

Summary

The management of CRPS can be approached using objective criteria in a logical and systematic fashion. Frustration during treatment is common because: (1) the pathophysiology of CRPS is incompletely understood, (2) there is significant variation in presentation due to disparate premorbid anatomy and physiology, and (3) the natural history may be affected by incomplete treatment. Therapeutic efforts that should be effective may fail, and a trial-and-error approach to treatment is often mandatory. Early recognition of CRPS and prompt intervention, however, provide the best opportunity for clinical improvement.

References

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C.L. Bernard, Influence du Grand Sympahique Sur La Sensitibilité et Sur La Calorification, 3 R. SOC. BIOL. (Paris) 163-64 (1851), cited in STANTON-HICKS, supra note 1, at 217.
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36. STANTON-HICKS, supra note 1, at 217 (referring to S.T. Kwan, The Treatment of Causalgia by Thoracic Sympathetic Gaglionectomy, 101 ANN. SURG. 222-27 (1935); J.P. Ross, Causalgia, 65 ST. BARTHOLOMEW HOSP. REP. 103 (1932); W.K. LIVINGSTON, PAIN MECHANISMS: A PHYSIOLOGIC INTERPRETATION OF CAUSALGIA AND ITS RELATED STATES (MacMillan 1943)).

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Member, ACFEI (American College of Forensic Examiners Institute of Forensic Science)
Expert Medical Witness, ExpertMD
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