High Yield Topics

Complex Regional Pain Syndrome

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Ovid: 5-Minute Sports Medicine Consult, The


Complex Regional Pain Syndrome
Andrew R. Peterson
David T. Bernhardt
Basics
Description
  • Exaggerated response to injury manifested by 4 clinical characteristics:
    • Intense and/or prolonged pain
    • Vasomotor disturbances
    • Delayed functional recovery
    • Various associated trophic changes
  • 1995 consensus statement grouped several previously identified syndromes as “complex regional pain syndrome” (CRPS):
    • Complex regional pain syndrome type I
    • Complex regional pain syndrome type II (previously “causalgia”)
  • Reflex sympathetic dystrophy
  • Shoulder-hand syndrome
  • Sudeck atrophy
  • Neurovascular dystrophy
  • Pain dysfunction syndrome
  • Transient osteoporosis
  • Acute atrophy of bone
Epidemiology
  • Adult:
    • Female: Male, 4:1
    • Median age at onset: 46 yrs
    • Upper limb twice as common as lower limb
    • Most report a triggering event
    • Fracture most common trigger (46%)
    • Distal radius most common triggering fracture, but only 1% of radius fractures develop CRPS
    • Incidence following peripheral nerve injury: 2–14%
  • Children:
    • Female: Male lower than in adults, but majority are female (67–86%)
    • Symptoms typically start just prior to puberty:
      • Mean age 12.4 in girls
      • Mean age 13.4 in boys
    • Lower limb more likely to be involved than upper limb (5:1)
    • Often less clear inciting event
    • Higher recurrence rate
    • More responsive to treatment than adults
Incidence
5.46 per 100,000 person-years at risk
Prevalence
20.57 per 100,000 person-years
Risk Factors
  • Precipitating event (adults):
    • Usually painful, but not always
    • Fracture
    • Surgery (especially arthroscopic procedures)
    • Sprain
    • Myocardial infarction
    • Hemiplegia
    • Immobilization following stroke
    • Placement of arteriovenous graft for hemodialysis
    • Peripheral nerve injury
    • Up to 35% have no history of precipitating event.
  • Precipitating event (children):
    • 50% have a vague, minor, or no precipitating event:
      • Sprains
      • Strains
      • Minor contusions
    • Surgery (especially arthroscopic procedures of the knee)
    • Henoch-Schönlein purpura
    • Emotional stress
    • Hepatitis B vaccination
  • Constitutional or psychiatric predisposition:
    • Suspected by many clinicians, but no evidence to support
    • Clearly not present in most patients with CRPS
    • “Sympathetic hyper-reactors” described as those with a history of increased sweating in the palms, poor cold tolerance, and emotional liability
Genetics
Human leukocyte antigen (HLA) type:
  • Increased incidence in those with HLA-A3, B7, and DR2 (15)
  • HLA-DR2 (15) may predict poor treatment outcome.
  • HLA testing has no role in clinical management of CRPS.
  • No specific single-gene polymorphisms have been clearly linked to CRPS.
General Prevention
  • Stroke:
    • Early mobilization following stroke decreases risk of developing CRPS (1)[A].
    • Limited evidence supports early mobilization following injury and myocardial infarction.
  • Fracture:
    • Vitamin C supplementation (500 mg/day in most studies, but 200 mg and 1,500 mg have also shown effect) decreases rate of CRPS following distal radius fractures (2)[A].
    • Mechanism is unclear
  • Regional anesthesia:
    • IV regional anesthesia (IVRA) is commonly used to provide anesthesia during extremity surgery.
    • IVRA with or without clonidine may decrease the chance of developing postsurgical CRPS (3)[B].

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Etiology
Pathogenesis is unclear, but several theories exist:
  • Reflex arc following inciting event
  • Sympathetic nerve reflex arc causes central sympathetic dysfunction, causing peripheral vascular dysfunction
  • Increased sensitivity of injured nerves to endocrine and paracrine substances
  • Inappropriate inflammatory mediator control (especially IL-6, IL-1β, TNF-alpha, substance P, neuropeptide, and calcitonin gene-related peptide)
  • Several studies have demonstrated CNS modulation as cause of CRPS.
  • A recent model of “neurogenic inflammation” attempts to tie the above theories together into a unifying theory of pathogenesis.
Commonly Associated Conditions
  • Precipitating injury or event
  • Possible psychiatric or personality disorders
  • Other pain syndromes have been reported as associated conditions:
    • May represent heterogeneity of a single disease or susceptible phenotype
    • Fibromyalgia most commonly associated pain syndrome
Diagnosis
  • Clinical diagnosis
  • Laboratory and imaging studies are only indicated if diagnosis is uncertain.
History
  • Stage 1: Early disease following inciting event or spontaneous:
    • Progressive limb pain
    • Burning pain
    • Occasional throbbing
    • Diffuse aching
    • Sensitivity to cold and/or touch
    • Localized edema
  • Stage 2: Progressive physical changes (see “Physical Exam”)
  • Stage 3: Severe disease:
    • Worsening pain
    • Increasingly dramatic physical findings (see “Physical Exam”)
  • Other symptoms (not stage-specific): Urinary urgency, frequency, and/or incontinence
Physical Exam
  • Stage 1:
    • Localized edema
    • Vasomotor disturbances:
      • Color changes
      • Temperature changes (usually cool, but can be warm)
  • Stage 2:
    • Progressively worsening soft tissue edema
    • Thickening of the skin
    • Muscle wasting
  • Stage 3:
    • Joint contractures
    • Waxy appearance to skin
    • Brittle nails
  • Other findings (not stage-specific):
    • Allodynia
    • Hyperhidrosis
    • Abnormal hair growth (patchy, sparse, or excessive hair)
    • Urinary retention
Diagnostic Tests & Interpretation
  • CRPS is a clinical diagnosis.
  • The tests and imaging studies listed below should only rarely be performed when the diagnosis is uncertain.
Lab
Tests to exclude other systemic causes of pain:
  • CBC
  • ESR
  • Fasting blood glucose
  • Serum ionized calcium level
  • Thyroid-stimulating hormone and free T4 levels
Imaging
  • Bone scan (triple-phase technitium-99m bone scintigraphy):
    • Increased uptake in 2/3 of adult patients with reflex sympathetic dystrophy
    • Findings vary by phase:
      • 30 sec: Increased flow, but decreased tracer uptake in affected limb
      • 3 min: Capillary leak around affected joint
      • 3 hr: Increased uptake of tracer at periarticular bone of affected joint
    • Findings less reliable in pediatric patients:
      • 1/3 exhibit increased uptake (usually in late stages of disease).
      • 1/3 exhibit normal findings.
      • 1/3 exhibit decreased uptake (usually in early stages).
    • Can also be used to help rule out other diagnoses, such as stress fracture or tumor
  • Plain radiography (x-ray):
    • Initially normal
    • After 3 mos, may show patchy subchondral osteopenia
    • Late stages show profound bone demineralization.
    • X-ray findings are less common in children.
  • MRI:
    • Multiple nonspecific changes (edema, skin thickening)
    • Useful to rule out constant stimulants (such as meniscal tear or loose body)
  • Thermography:
    • Significant skin temperature asymmetry
    • Cold challenge may increase sensitivity and specificity
  • CT scan:
    • Focal areas of osteoporosis
    • Swiss cheese appearance of bone in stage 3 CRPS can be dramatic.
    • Costs, radiation dose, and poor sensitivity and specificity limit use

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Diagnostic Procedures/Surgery
  • Autonomic testing:
    • Resting sweat output (RSO)
    • Resting skin temperature (RST)
    • Quantitative sudomotor axon reflex test (QSART)
    • Abnormal RSO and QSART are highly sensitive for CRPS.
    • Use of these tests should be limited to patients with uncertain diagnosis
  • Sympathetic blockade:
    • Typically causes abrupt improvement in symptoms
    • In those with cool affected limbs, typically have increase of 1–3°C in skin temperature
    • Lack of response has high negative predictive value.
    • Relief is typically transient.
    • Stellate or lumbar sympathetic blocks more diagnostically useful than regional blocks (eg, Bier block), although both may provide relief of symptoms
Differential Diagnosis
  • Fracture/stress fracture
  • Infection
  • Tumor (especially Pancoast syndrome)
  • Nerve root impingement
  • Vasculitis
  • Rheumatoid arthritis
  • Peripheral neuropathy
  • Deep vein thrombosis
  • Angioedema
  • Other pain syndromes
Treatment
  • Usually more effective early in disease (4)[A]
  • Follow a stepwise approach, starting with least risky/invasive and progressing to more invasive as needed (3)[C]
  • An interdisciplinary program seems to be the most effective approach to CRPS (3)[B]:
    • Physical therapy
    • Occupational therapy
    • Psychotherapy
    • Medications
    • Interventional procedures
Medication
First Line
  • Vitamin C 500 mg daily for prevention in patients with distal radius fractures (2)[A]
  • Tricyclic antidepressants have been shown to decrease pain in multiple studies and should be considered in all patients with CRPS (3)[A].
Second Line
  • Antiepileptic drugs:
    • Thoroughly tested for other pain syndromes, but cannot extrapolate results to CRPS.
    • Gabapentin most widely used, but studies have demonstrated variable efficacy
    • Pregabalin is also widely used, but has not been studied for treatment of CRPS.
  • Selective serotonin and norepinephrine reuptake inhibitors have not been studied for treatment of CRPS.
  • Systemic glucocorticoids may be useful for improving the clinical course of CRPS early in the disease (3)[B].
  • Bisphosphonates are effective for preventing bone loss in CRPS, but they have an unclear effect on the overall disease course:
    • Widely used
    • Several clinical studies have demonstrated variable efficacy.
    • Pamidronate, alendronate, and clodronate have been most studied.
  • Topical capsaicin cream is effective in other types of neuropathic pain. It is generally safe and may be a useful adjuvant treatment for CRPS (3)[C].
  • Opioid use should be limited [C].
  • Several other medications have been reported to be effective in small trials, but are rarely used:
    • Free radical scavengers (dimethylsulfoxide and N-acetylcysteine)
    • Topical clonidine
    • Ketamine
    • Baclofen
Additional Treatment
Additional Therapies
  • Physical therapy mainstay of RSD treatment
  • Tactile desensitization is most effective if used early.
  • Joint mobilization, progressive weight-bearing, strengthening, and return to daily activities are important aspects of care directed by physical therapy.
  • Transcutaneous electrical nerve stimulation can be beneficial.
  • Behavioral management
  • Relaxation techniques
  • Stress management

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Complementary and Alternative Medicine
Acupuncture:
  • Popular complementary therapy
  • High patient satisfaction
  • Well-designed studies have shown no difference when compared to placebo (4).
  • May have a role as part of an interdisciplinary approach to CRPS
Surgery/Other Procedures
  • Nerve blockade:
    • Sympathetic nerve blockade can be both therapeutic and diagnostic.
    • Lumbar sympathetic block for lower extremity
    • Stellate ganglion blocks for upper extremity
    • Unclear which patients are good candidates for sympathetic blocks
    • Unpredictable response to repeated sympathetic blocks
  • Other interventional procedures:
    • Used less frequently and less proven than sympathetic blockade
    • Peripheral nerve stimulation
    • Spinal cord stimulation
    • Chemical and surgical sympathectomy
    • Implanted spinal infusion pumps and/or intrathecal injections:
      • Baclofen may be useful if significant dystonia.
      • Clonidine has frequent side effects, such as hypotension and significant sedation.
    • Deep brain stimulation
Ongoing Care
Follow-Up Recommendations
A strong partnership with the patient and all participating caregivers is essential.
Patient Monitoring
  • Weekly or biweekly follow-up is appropriate.
  • Have a flexible treatment plan:
    • Stepwise approach to care
    • Therapeutic trials of only 1–2 wks before moving on to the next treatment modality
Prognosis
  • Early diagnosis and treatment can lead to resolution by 6–12 mos.
  • Late diagnosis is associated with permanent residual symptoms.
  • Children are more likely to relapse than adults.
  • 3 distinct phases (described above):
    • Patients in stage 1 and 2 respond better to therapy.
    • Stage 3 disease is often more refractory to treatment.
References
1. Petchkrua W, Weiss DJ, Patel RR. Reassessment of the incidence of complex regional pain syndrome type 1 following stroke. Neurorehabil Neural Repair. 2000;14:59–63.
2. Stevermer JJ, Ewigman B. Give vitamin C to avert lingering pain after fracture. J Fam Pract. 2008;57:86–89.
3. Hsu ES. Practical management of complex regional pain syndrome. Am J Ther. 2009;16:147–154.
4. Dowd GS, Hussein R, Khanduja V, et al. Complex regional pain syndrome with special emphasis on the knee. J Bone Joint Surg Br. 2007;89:285–290.
Additional Reading
Barbier O, Allington N, Rombouts JJ. Reflex sympathetic dystrophy in children: review of a clinical series and description of the particularities in children. Acta Orthop Belg. 1999;65:91–97.
Codes
ICD9
  • 337.20 Reflex sympathetic dystrophy, unspecified
  • 337.22 Reflex sympathetic dystrophy of the lower limb
  • 355.9 Mononeuritis of unspecified site
Clinical Pearls
  • Clinical diagnosis of an exaggerated response to injury of a limb with intense prolonged pain, vasomotor disturbances, delayed functional recovery, and trophic changes
  • Pathology is unclear, but there is an obvious central sympathetic disregulation that causes or modulates peripheral symptoms.
  • Diagnostic tests should be reserved for unclear cases and to rule out other diagnoses.
  • Treatment should be initiated immediately at diagnosis and follow a rapid stepwise approach from least to most invasive.
  • A partnership between providers, therapists, and the patient is essential for effective treatment.


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