Pediatric Complex Regional Pain Syndrome

By Galaxy Li, MD and Jason Wells, MD
Division of Pain Medicine
Dept. of Anesthesiology
Nemours Children's Specialty Care
Jacksonville, Florida

Complex Regional Pain Syndrome (CRPS) is a neuropathic pain disorder that has continued to challenge children, pain researchers, and pediatric clinicians since the early 1970s.1 Divided into two subtypes, CRPS 1 was formerly known as Reflex Sympathetic Dystrophy (RSD) while CRPS 2 was known as causalgia.  These two subtypes were joined under the CRPS heading in 1993 by the International Association for the Study of Pain (IASP).  While similar in presentation, the distinction between CRPS 1 and 2 is the absence (type 1) or presence (type 2) of documented nerve injury.  CRPS patients will commonly present to their care provider with a burning neuropathic pain exhibiting hyperalgesia and/or allodynia in a specific site on the body, most commonly a limb, usually following a minor traumatic incident.  Other signs and symptoms may include edema, changes in temperature, differences in hair or distal nail bed growth, or limited range of motion.  The disease affects both adults and children with a predisposition towards girls. In children, the lower extremity is more often affected than the upper, and mean age of diagnosis is around 12 years old.2-3  

While diagnostic criteria are no different than in the adult population, pediatric patients may not relate symptomatology as effectively, and thus careful histories and physical examinations must be obtained.  During diagnostic workup, disorders that may present with similar symptoms of CRPS include neuropathy of the central nervous system such as multiple sclerosis, radiculopathy, plexopathy, focal or multifocal neuropathy, vascular disorders such as Raynaud syndrome, leukemia, thyroid dysfunction, vitamin deficiencies, myofascial pain, and fibromyalgia. Rare conditions such as Fabry disease and erythromelalgia may be considered as well.  

When CRPS was initially coined by the IASP, diagnostic criteria included the following:4

CRPS 1

  1. Presence of inciting noxious event or cause of immobilization*
  2. Continued disproportional pain, hyperalgesia, or allodynia from noxious event
  3. Evidence at some time of edema, skin changes, blood flow, or abnormal sudomotor function in region of pain
  4. Diagnosis is excluded from other conditions that may explain pain and dysfunction

*not required for diagnosis

CRPS 2

  1. The presence of continuing pain, hyperalgesia, or allodynia after nerve injury, not necessarily limited to distribution of injured nerve
  2. Evidence at some time of edema, skin changes, blood flow, or abnormal sudomotor function in region of pain
  3. Diagnosis is excluded from other conditions that may explain pain and dysfunction

As the first criterion for CRPS 1 is optional for its diagnosis, many children are diagnosed with no known history of nerve injury or inciting noxious event.  Those who recall a noxious event at all may categorically describe it as mild at best, compared to the eventual pain severity at diagnosis. This has historically mystified families and clinicians who seek a cause for the constellation of symptoms in contrast to those with CRPS 2 where there is known nerve injury.   

In 2007, the Budapest criteria for CRPS were created:5

  1. Presence of continued disproportional pain from inciting event
  2. At least one symptom in three of the four following categories
      • Sensory: hyperesthesia, allodynia
      • Vasomotor: temperature asymmetry, changes in skin color
      • Sudomotor/edema: edema, changes in sweating, sweating asymmetry
      • Motor/trophic: decreased range of motion, motor dysfunction (tremor, weakness, dystonia), trophic changes (hair, skin, nails)
  1.  Report one sign in two or more of the following categories at time of presentation
      • Sensory: hyperalgesia to pinprick, allodynia to touch or joint movement
      • Vasomotor: temperature asymmetry, color asymmetry
      • Sudomotor/edema: edema, changes in sweating, sweating asymmetry
      • Motor/trophic: decreased range of motion, motor dysfunction, trophic changes
  2.  No other condition that can explain pain and dysfunction

 
Despite these criteria and attempts at its validation, there remains no gold standard for diagnosis, as its pathophysiology is unclear.  A qualified pain specialist will usually make the diagnosis of CRPS based on history and physical exam, although a variety of imaging modalities and lab studies to rule out other diseases and quantitative sensory testing, thermoregulatory sweat tests, and bone scintigraphy may have already been ordered.  The mechanism of the disease process is likely multifactorial, with sympathetic and central components.  Following a triggering event, an exaggerated inflammatory response with pain mediated though C-type and Aδ-type neurons has been described.  Pro-inflammatory cytokines may lead to the initial tissue damage and alterations in cutaneous innervation, including reduced numbers of C-and Aδ-type neurons with increased aberrant neurons.  With repeated noxious stimuli, central sensitization occurs with increased excitability of secondary central nociceptive neurons in the spinal cord mediated by substance P, bradykinin and glutamate.  This increased excitability may manifest in the hyperalgesia, allodynia, and wind-up phenomenon seen in those with CRPS.  The acute phase of CRPS (approximately first three months) is characterized by reduced levels of norepinephrine in the affected region with a subsequent up-regulation of sympathetic nervous system receptors.  This may account for the trophic and thermoregulatory changes observed with disease progression.  Maladaptive neuroplasticity occurs with disease progression as functional MRI studies have shown decreased and reorganized somatosensory cortices correlating with the affected limb/region.  Ongoing inflammation, psychological stressors, and genetic predispositions may also play a role in the disease progression.6-7

Treatments originally described in adult CRPS consist of:

  • Physical / occupational therapy- desensitization, transcutaneous electrical nerve stimulation, exercise, massage, contrast baths
  • Membrane stabilizers
  • Antidepressants
  • Bisphosphonates
  • Oral / parenteral / topical / epidural opioids
  • Ketamine
  • Corticosteroids
  • Sympathetic nerve blocks
  • Spinal cord stimulation
  • Peripheral nerve stimulation
  • Intrathecal drug delivery: local anesthetics with adjuvants, opioids, baclofen, ziconitide

Compared to adults, children with CRPS are more likely to have spontaneous resolution of symptoms and show a greater response to early noninvasive treatment.  Dietz et al. found that 89% of 51 pediatric CRPS patients had no or minimal residual pain following instruction of a self-administered mobilization program with massage and no medications, no sympathectomies, no nerve blocks, no formal physical therapy, nor pain management referrals.8  Sherry et al. described 92% of 103 children with CRPS 1 becoming symptom-free after initial treatment of an intensive exercise program with initial psychological evaluation but without modalities or medications. Of the 49 children followed through five years, 88% were symptom-free while 31% had experienced a relapse of symptoms that resolved with reinstitution of physical therapy.9 This is consistent with previous studies showing advantageous outcomes with early physical and occupational therapy modalities.

Psychological therapy is advocated for both children with CRPS and for their families.  Though no CRPS-specific studies have been conducted, a 2014 Cochrane review by Eccleston et al found that psychological therapies were effective at reducing recurrent and chronic pediatric pain.10  Palermo et al. described that internet-based cognitive behavior therapy leads to increased activity levels, improved sleep quality, and decreased need for parental help and protective behaviors in children with chronic pain.11  In a retrospective review of 32 children with CRPS treated with intensive inpatient physical rehabilitation therapy by Brooke et al., 34% experienced resolution at time of discharge and 89% of those who followed up eventually had resolution of symptoms.12

Although pharmacologic treatment is common in adult practice, there are no official recommendations for pediatric CRPS. Although its role is unclear in pediatric CRPS, vitamin C serves as prophylaxis from CRPS in adults with wrist fractures.13  Over-the-counter nonsteroidal anti-inflammatory drugs and acetaminophen are the usual first adjuncts used in concert with physical therapy as they tend to be readily available to parents.  While possibly useful in allowing patients to cooperate with physical therapy, Wilder et al. did not find any significant reductions in pain scores with OTC medication use in children.3 Low et al. describe the utility of gabapentin and amitriptyline in aiding children with CRPS to participate in physical therapy but no chronic use studies have been performed.2  As research surfaces on potential pathophysiologic mechanisms involving cytokines and neuropeptides for CRPS, there may be a role for immunomodulatory agents.  One of the emerging treatment modalities in adult CRPS is parenteral ketamine.  While current evidence has only shown benefits on the scale of weeks to months, there have not been any large-scale pediatric studies yet.  Everett et al. presented a case report of a combination of a continuous sciatic nerve block and parenteral ketamine infusion providing significant relief for a seventeen year-old patient with CRPS 1 who did not previously experience relief with a lumbar sympathetic block.14 Sheehy et al. described significant reduction in pain scores of hospitalized children with specific pain conditions following sub-anesthetic ketamine infusions consistent with prior studies in adult populations.15

The traditional invasive treatments of CRPS include single sympathetic blocks, epidural catheters, continuous sympathetic blocks, spinal cord stimulation, and pain-directed surgeries.  These modalities are also utilized in the pediatric population with sympathetic blocks and epidural catheters being the most commonly reported.  While anecdotal evidence has shown reductions in pain scores and improvement in function following repeated sympathetic blocks, Zernikow et al. determined that evidence for invasive treatments of CRPS in pediatric patients is weak.16  None of the three Cochrane Database reviews on CRPS recommend cervicothoracic or lumbar sympathectomy, local anesthetic sympathetic blockade, or spinal cord stimulation in adult CRPS because of a lack of evidence.17-19  However, Cucchiaro G. et al. found a 68% resolution of pain within four days following continuous nerve blockade via local anesthetic infusion combined with intense physical therapy in thirty children with CRPS.20 Less invasive treatments such as transcutaneous electrical nerve stimulation and acupuncture in pediatric CRPS have been described with relatively small case series.21-22  More randomized controlled trials with standardized outcomes may definitively reveal a potential role for invasive treatments in pediatric CRPS towards delineating a treatment algorithm.

Multidisciplinary and interdisciplinary pediatric pain management centers are popular as what is believed to be a more comprehensive approach to CRPS, both in the inpatient and outpatient settings.23-25  This may stem from evidence and proposed mechanisms of efficacy in the multidisciplinary approach towards chronic pain in adults.26-27  With nine nonrandomized treatment studies and one randomized controlled study consisting of 1,020 children with chronic pain who underwent intensive interdisciplinary pain treatment, Hechler et al. conducted a meta-analysis on disability, pain intensity, and depressive symptoms.  The group found relatively large improvements in disability compared to those in pain intensity and depressive symptoms. However, study design limitations and substantial heterogeneity in other measures restricted the ability to solely attribute positive treatment effects to intensive interdisciplinary pain treatment. One of the studies in the meta-analysis incorporated regional anesthesia techniques such as epidural catheters and peripheral nerve blocks.27

Diagnostic and therapeutic components of pediatric CRPS continue to evolve as research advances towards a clearer understanding of its pathophysiology. Trends in adult CRPS research also serve as reference points for pediatric CRPS management.  More randomized controlled studies are required to further develop our diagnostic criteria, streamline therapeutic options for prolonged relief, and minimize relapse.

References

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  2. Low AK, Ward K, Wines AP. Pediatric complex regional pain syndrome. J Pediatr Orthop. 2007;27(5):567–72.
  3. Wilder RT, Berde CB, Wolohan M, et al. Reflex sympathetic dystrophy in children. Clinical characteristics and follow-up of seventy patients. J Bone Joint Surg Am. 1992;74(6):910–9.
  4. Merskey H, Bogduk N. Classification of chronic pain : descriptions of chronic pain syndromes and definitions of pain terms. 2. Seattle: IASP Press; 1994.
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  6. Lebel A, Becerra L, Wallen D, et al. fMRI reveals distinct CNS processing during symptomatic and recovered complex regional pain syndrome in children. Brain. 2008;131: 1854-79.
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  8. Dietz FR, Compton SP. Outcomes of a simple treatment for complex regional pain syndrome type I in children. Iowa Orthop J. 2015;35:175–80.
  9. Sherry DD, Wallace CA, Kelley C, et al. Short- and long-term outcomes of children with complex regional pain syndrome type I treated with exercise therapy. Clin J Pain. 1999;15(3):218–23.
  10. Eccleston C, Palermo TM, de C Williams AC, et al. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst Rev. 2014;5:1–94.
  11. Palermo TM, Law EF, Fales J, et al. Internet delivered cognitive-behavioral treatment for adolescents with chronic pain and their parents: a randomized controlled multicenter trial. Pain. 2016;157(1):174–85.
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  13. Aïm F, Klouche S, Frison A, et al. Efficacy of vitamin C in preventing complex regional pain syndrome after wrist fracture: a systematic review and meta-analysis. Orthop Traumatol Surg Res. 2017;103:465–70.
  14. Everett A, Mclean B, Plunkett A, et al. A unique presentation of complex regional pain syndrome type I treated with a continuous sciatic peripheral nerve block and parenteral ketamine infusion: a case report. Pain Med. 2009;10(6):1136–9.
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  21. Kesler RW, Saulsbury FT, Miller LT et al. Reflex sympathetic dystrophy in children: treatment with transcutaneous electric nerve stimulation. Pediatrics. 1988;82(5):728–32.
  22. Lin K, Tung C. Acupuncture for Pediatric Complex Regional Pain Syndrome. Med Acupuncture. 2016; 28(3): 156-161.
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