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1 Continuing Education Column Complex Regional Pain Syndrome: Mechanism, Diagnosis and Treatment Chan Kim, MD Department of Anesthesiology & Pain Medicine, Ajou University College of Medicine E mail : kimchan@ajou.ac.kr J Korean Med Assoc 2008; 51(6): Abstract Complex regional pain syndromes (CRPS, formerly reflex sympathetic dystrophy and causalgia) are neuropathic pain disorders of one or more extremities developing inadequately after traumas or lesions in the peripheral or central nervous system (CNS). However, CPRS may also develop spontaneously. CRPS is clinically characterized by sensory (pain, hyperalgesia, and allodynia), autonomic (disturbances of skin temperature, color change, and presence of sweating abnormalities), and motor (paresis, tremor, and dystonia) disturbances. There have been growing evidences for that CRPS is a systemic disease involving the CNS and peripheral nervous system. The diagnosis is mainly based on clinical symptoms and signs, so that it could be under or over diagnosed. However, careful clinical evaluation and additional tests should lead to an adequate diagnosis. The goal of treatment is to improve functions, relieve pain, and achieve remission. The early diagnosis and multidisciplinary treatments, which include pain management, rehabilitation, and psychological therapy, are the most important elements for solving the patients problems. Keywords : Complex regional pain syndrome; Neuropathic pain; Central nervous system 553

2 Kim C Table 1. IASP (Orlando) diagnositc criteria for complex regional pain syndrome The presence of an initiating noxious event, or a cause of immobilization Continuing pain allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction Type I: without evidence of major nerve damage Type II: with evidence of major nerve damage Table 2. Summary of decision rules considered Criteria/Decision Rules for Proposed Criteria 2+sn categories & 2+ sx categories Sensitivity 0.94 Specificity sn categories & 3+ sx categories sn categories & 4+ sx categories sn categories & 2+ sx categories sn categories & 3+ sx categories sn categories & 4+ sx categories

3 Complex Regional Pain Syndrome Table 3. Revised CRPS criteria proposed by the budapest consensus group General Features of the Syndrome CRPS describes an array of painful conditions that are characterized by a continuing spontaneous and/or evoked regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor and/or trophic findings. The syndrome shows variable progression over time. There are two versions of the proposed diagnostic criteria: a clinical version meant to maximize diagnostic sensitivity with adequate specificity, and research version meant to more equally optimal sensitivity and specificity. These proposed criteria are described in Table 3A and Table 3B, respectively. Table 3A. Clinical Diagnostic Criteria for CRPS Continuing pain, which is disproportionate to any inciting event Must report at least one symptom in three of the four following categories: Sensory: Reports of the hyperesthesia 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, nail, skin) Must display at least one sign* at time of evaluation in two or more of the following categories: Sensory: Evidence of hyeralgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement) Vasomotor: Evidence of temperature asymmetry (>1 ) and/or skin color changes and/or asymmetry Sudomotor/Edema: Evidence of 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, nail, skin) There is no other diagnosis that better explains the signs and symptoms *A sign is counted only if it is observed at time of diagnosis. Table 3B. Research Diagnostic Criteria for CRPS Continuing pain, which is disproportionate to any inciting event Must report at least one symptom in each of the four following categories: Sensory: Reports of the hyperesthesia 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, nail, skin) Must display at least one sign* at time of evaluation in two or more of the following categories: Sensory: Evidence of hyeralgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement) Vasomotor: Evidence of temperature asymmetry and/or skin color changes and/or asymmetry Sudomotor/Edema: Evidence of 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, nail, skin) There is no other diagnosis that better explains the signs and symptoms 555

4 Kim C Figure 1. A CRPS patient with 7 months of pain duration. The patient suffered from the right leg pain, especially, below the ankle after the right knee contusion and arthroscopy. 556

Sweat drops are seen around the left great toe and right foot shows no sweating. Figure 3.

5 Complex Regional Pain Syndrome Figure 2. A CRPS patient with 8 months pain duration. Left foot shows reddish and swelling. Sweat drops are seen around the left great toe and right foot shows no sweating. Figure 3. A CRPS patient with 4 months of pain duration. The patient developed CRPS of the right upper extremity after the right wrist sprain followed by falling down. Right hand shows severe swelling. 557

6 Kim C 558

Complex Regional Pain Syndrome Figure 4. Possible couplings between sympathetic neurons and afferent neurons.

mediated indirectly via the blood vessels (blood flow). It can occur in the periphery, in the dorsal root ganglion, or, possibly, in the lesioned nerve (A).

Nerve growth factor (NGF) released during inflammation reacts with the high-affinity receptor trka for NGF in the membrane of the sympathetic varicosities, inducing

7 Complex Regional Pain Syndrome Figure 4. Possible couplings between sympathetic neurons and afferent neurons. Coupling with primary afferent neurons depends on activity in the sympathetic neurons and the expression of functional adrenoceptors by the afferent neurons, or is mediated indirectly via the blood vessels (blood flow). It can occur in the periphery, in the dorsal root ganglion, or, possibly, in the lesioned nerve (A). The inflammatory mediator bradykinin (BK) reacts with B2 receptors in the membrane of the sympathetic varicosities, inducing release of prostaglandin E2 (PGE2; B). Nerve growth factor (NGF) released during inflammation reacts with the high-affinity receptor trka for NGF in the membrane of the sympathetic varicosities, inducing release of an inflammatory mediator or inflammatory mediators (C). Activation of the adrenal medulla (AM) by sympathetic preganglionic neurons leads to release of a hormone (possibly adrenaline) (D). (adopted from Janig w 2000). A B C D 559

8 Kim C Activation : AMPA/KAI receptor fast EPSPs Activation : Slow EPSPs, plateau potentials, summation & windup Modulation : Post translational processing and central sensitization Modulation : Altered connectivity and cell death Figure 5. Modes of neural plasticity at synapses onto nociceptive transmission neurons in the dorsal horn of the spinal cord. The neurons are activated by fast EPSPs and enhanced by slow EPSPs, plateau potentials, and windup. Modulation through intracellular kinase/phosphatase signaling cascades produces central sensitization through facilitating AMPA/kainate and NMDA receptor function or cell surface expression. Modification is mediated by induced expression of gene products, loss of inhibitory interneurons, and establishment of aberrant excitatory synaptic connections (adopted from Woolf CJ 2003). 560

9 Complex Regional Pain Syndrome Figure 6. Schematic diagram of sensory, autonomic, and somatomotor changes in patients with CRPS I. Changes are triggered and possibly maintained by the nociceptive afferent input from the somatic and visceral body domains. Whether these central changes are reversible in patients with chronic CRPS I is unclear. The central changes possibly affect the endogenous control system of nociceptive impulse transmission. Coupling between the sympathetic neurons and the afferent neurons in the periphery (open arrow) is one component of the pain in patients with SMP. However, it seems to be unimportant in those without SMP. Note that SMP and pain that is not dependent on the sympathetic nervous system can exist in parallel in the same patient (adopted from Janig w 2000). 561

$calcaneus fracture.$

10 Kim C A B C Figure 7. Three phase bone scan image of CRPS patient with pain duration of 13 months. Precipitating event was operation of right calcaneus fracture. Right ankle and whole metatarsophalangeal joints show hot uptake in blood pool and delayed image. 562

11 Complex Regional Pain Syndrome Diagnosis CRPS Care Continuum Psychological Treatment Assess for Axis I Disorders Pain Coping Skills Biofeedback / Relaxation Training Cognitive Behavioral Therapy for Treatment of Axis I Disorders Inadequate or Partial Response Increase Frequency / Intensity of Psychatherapy Failure to Progress in Rehab Pain Management with Oral and Topical Drugs Psychological Treatment with Educational Focus Rehabilitation Pathway Progress Reactivation Desensitization Isometrics Flexibility Edema Control Peripheral E-stim Treat Secondary MFP ROM (gentle!) Stress Loading Isotonic Strengthening Aerobic Conditioning Postural Normalization Ergonomics Movement Therapies Normalization of Use Vocational / Functional Rehab EXCELLENT RESPONSE FOLLOW UP Progress Interventional Pain Management Minimally Invasive Sympathic Nerve Block (s) IV Regional Block (s) Somatic Nreve Block (s) Failure to Progress in Rehab Inadequate or Partial Response More Invasive Epidural and Plexus Catheter Blocks Neurostimulation Intrathecal Drug Therapy (e.g. Baclofen) Inadequate or Partial Response Surgical or Experimental Therapies Sympathectomy Motor Cortex Stimulation RELAPSE REPEAT PATHWAY Figure 8. Treatment algorithm for CRPS (adopted from Stanton Hicks M 2002). 563

well as strong analgesics for 3 months, however his pain and swelling did not

12 Kim C A B C Figure 9. A CRPS patient suffering with 4 months of pain duration shows severe swelling of right hand (A). He had various interventional treatment including the sympathetic ganglion block as well as strong analgesics for 3 months, however his pain and swelling did not disappear. Spinal cord stimulation (SCS) was tried 5 months after the pain onset, his symptom was gradually improved. One month after the SCS his right hand swelling marked diminished (B) and he could get right hand grip (C). 564

13 Complex Regional Pain Syndrome 565

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5.Æ¯Áýb71®µ¿¾ðÆ88~700 J KMA Special Issue Diagnosis and Treatment of Complex Regional Pain Syndrome Dong Eon Moon, MD Department of Anesthesiology and Pain Medicine, Catholic University College of Medicine Email : demoon@catholic.ac.kr