Pediatrics

Complex Regional Pain Syndromes

OVERVIEW: What every practitioner needs to know

Are you sure your patient has complex regional pain syndrome? What are the typical findings for this disease?

Complex regional pain syndrome (CRPS) is an amplified musculoskeletal pain syndrome characterized by (1) severe limb pain that is disproportionate to the inciting event along with (2) signs of autonomic dysfunction (abnormal skin color, temperature change, and/or edema) (See Figure 1). Regional sensory disturbances such as allodynia (pain produced by normally non-noxious stimulation) and hyperalgesia in addition to motor dysfunction are common signs and symptoms.

Figure 1.

Complex regional syndrome. The foot was cold and cyanotic and she could not move the foot or toes.

Children with CRPS report pain out of proportion to the history and physical findings. Symptoms often begin following a trauma but often the trauma seems trivial compared to the extreme nature of the patients signs and symptoms. However, 10-35% experience no preceding trauma.

Children with CRPS report pain out of proportion to history and physical findings and have at least one finding of autonomic dysfunction. Pain typically occurs in a lower extremity but may occur in an upper extremity or at multiple sites. Most patients experience allodynia and are unable to tolerate even light touch due to severe pain.

Patients typically have an incongruent affect and report a maximum pain score while appearing otherwise cheerful. Pain may spread beyond the initial site or may be migratory. Autonomic signs include cool skin, cyanosis, edema, and/or increased sweating. Less common clinical findings include dystrophic skin changes, bony edema, osteoporosis, and abnormal hair growth.

Nomenclature:

Alternative names for CRPS in the literature include reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy (RND) causalgia, Sudeck's atrophy, algodystrophy, transient osteoporosis, and acute atrophy of the bone. A consensus development conference in 1995 grouped these disorders under a single heading of complex regional pain syndrome (CRPS).

CRPS is divided into two categories:

a. Type I occurs in patients with no identifiable nerve lesion. The overwhelming majority of children with CRPS present with Type I.

b. Type II, formerly called causalgia, occurs where a clearly identified nerve lesion is present.

Do children have stages of CRPS?

The stages of CRPS that some authors discuss in adults with CRPS are controversial and do not exist in children.

Other ways CRPS varies in children compared to adults include:

- Children are less likely than adults to have a history of inciting injury.

- The leg is more often involved, and skin temperature of the involved limb is often cooler in children.

- Neurologic symptoms are less pronounced in children.

- Co-morbid psychological issues are more prevalent in children than adults.

- The duration of CRPS does not predict outcome in children.

What other disease/condition shares some of these symptoms?

Trauma

Juvenile idiopathic arthritis

Osteomyelitis

Soft tissue or bony tumor

Erythromelalgia

Angioedema

Venous Thrombosis

What caused this disease to develop at this time?

The pathogenesis of CRPS is poorly understood, but likely involves the formation of an abnormal reflex arc, secondary to local, central nervous system (CNS), and genetic factors. The reflex arc follows the sympathetic nervous system, through the cortical centers, and produces peripheral vascular disturbance. There can be significant variation in signs and symptoms between patients, and even temporal change within the same subject.

Psychological stress and other comorbid psychological disorders are commonly reported in pediatric CRPS cases. It is not clear whether the psychological disorders are due to the same CNS arc that contributes to CRPS or if these symptoms are a result of the pain and stress secondary to CRPS. Children with CRPS often report pain out of proportion to exam findings, and conversion symptoms are not an uncommon association. Children with CRPS are often described as bright, accomplished overachievers.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There are no laboratory studies that confirm or exclude the diagnosis of CRPS. Complete blood count, serum electrolytes, BUN, creatinine, and erythrocyte sedimentation rate (ESR) are typically normal.

Would imaging studies be helpful? If so, which ones?

Radiographs and other imaging do not reliably differentiate CRPS from other disease processes.

Radiographs of the affected extremity may be obtained to evaluate for occult fracture, though a normal radiograph does not entirely exclude fracture.

Technetium-99m bone scan may show decreased uptake in some cases of CRPS, but may be normal in others; rarely will it show a hot-spotty pattern as seen in adults with CRPS. A normal bone scan can help exclude osteomyelitis, bone tumor, and stress fracture, but does not exclude CRPS.

Ultrasound should be performed if there is high suspicion for thrombus.

Magnetic resonance scan frequently shows bony or soft tissue edema that cannot be readily distinguished from the findings in trauma or a small fracture.

Other studies such as electromyographic or nerve conduction studies are usually normal in children with CRPS, but may show nonspecific slowing of nerve conduction.

Autonomic testing such as measures of resting sweat output, resting skin temperature, and quantitative sudomotor axon reflex test are used in adults, but have no role in children. Thermography is unhelpful in the diagnosis of CRPS.

Confirming the diagnosis

There is not an algorithm for the diagnosis of complex regional pain syndrome.

Several attempts have been made to validate and approve uniform diagnostic criteria, but this is primarily in adult population. There is currently no diagnostic gold standard criterion for CRPS in children.

If you are able to confirm that the patient has complex regional pain syndrome, what treatment should be initiated?

Once a diagnosis is established, further laboratory and imaging investigations should cease and medications for pain withdrawn. A multi-disciplinary approach to treatment should begin early and include physical therapy, occupational therapy, and psychological and behavioral therapy. The goals of therapy are to return and maintain full physical function and provide the child tools to cope with pain while working toward restoration of function.

A physical rehabiliation and desensitization regimen should focus on using the affected limb as much as possible and reestablishing function, aerobic training and strengthening. The exercise requirement varies from 45 minutes per day in a home exercise program to 6 hours daily for 2-6 weeks in a day hospital program. 5 to 10 minute blocks of desensitization (i.e. rubbing, patting, brushing) multiple times throughout the day is encouraged.

Cognitive behavioral therapy to develop coping strategies and skills is imperative. Most patients should also have individual or family therapy, or both. Since children with CRPS are more likely to have comorbid psychological stressors or disorders than adults with the condition, addressing underlying psychodynamics is paramount.

What are the adverse effects associated with each treatment option?

When starting an intense exercise program, care is taken to avoid injury, especially overuse injuries.

More overt psychopathology may emerge when the child is confronted with getting better. This may manifest with conversion symptoms, suicidality, or oppositional behavior. Rarely, sexual abuse is revealed which is always met with psychological repercussions.

What are the possible outcomes of complex regional pain syndrome?

The majority of children with CRPS have a favorable prognosis. In a large pediatric case series of 103 patients, complete remission was achieved in 92% of patients. 30% of patients relapsed, and most relapsed within the first 6 months of presenation and typically responded to reintroduction of physical and occupational therapy. The psychological effects of a relapse must be addressed as these children are more likely to develop other stress-related conditions such as depression, anxiety disorder, and non-limb pain.

What causes this disease and how frequent is it?

Overall incidence in adult studies report 5.5 to 26.2 per 100,000 person years and prevalence of 20.6 per 100,000. The majority of pediatric reported cases occur in girls (70%). The mean age of presentation is 13 years of age. CRPS is unusual below 7 years of age, although has been reported in children as young as 2 years.

Significant preceding trauma is uncommon in children, but CRPS can follow fractures, surgery, motor vehicle accidents, and injections.

The role of the CNS is supported by functional magnetic resonance imaging (MRI) in children, demonstrating change in basal ganglia and parietal lobe activation that persist after CRPS resolution. Findings suggest pain-induced activation of endogenous pain mediating systems. CNS involvement is also suggested by hemisensory impairment extending beyond the painful area, and increased frequency of both allodynia and movement disorders with sensory defects.

Genetic factors may be involved in the pathogenesis of CRPS, but little is known about the role of these factors. 31 families were identified with two or more affected members, and a family history of CRPS predicted disease development at a younger age and had more severe findings than sporadic cases. HLA associations with CRPS in adults have also been identified. A twofold increase of HLA-A3, B7, and DR2(15) MHC antigens was observed compared to controls among 15 women with CRPS.

How do these pathogens/genes/exposures cause the disease?

It is thought that in a susceptible host (stressed adolescent) that a minor insult will manifest with sympathetic overdrive of the autonomic system, leading to central sensitization and the perpetuation of intense sensation of pain along with physical findings of autonomic abnormality (temperature change, color change, edema).

Other clinical manifestations that might help with diagnosis and management

It is imperative to educate the family about complex regional pain syndrome. This includes acknowledging the existence of pain, but that pain does not represent damage even though it may be severe and in conjunction with autonomic changes. Families must trust that there is no "quick fix" and that remission is probable with hard work. They should be instructed not to go to the emergency department for severe exacerbations unless there are extenuating circumstances such as fever, but rather take a warm bath, walk, and continue functional activities.

What complications might you expect from the disease or treatment of the disease?

CRPS may spontaneously resolve, however, there is a high likelihood of continued refractory chronic pain into adulthood possibly leading to disability if left untreated. Most severe complications and treatment difficulties are exhibited in children with stress related symptoms such as eating disorders and suicide attempts. These children will avoid addressing underlying psychological and behavioral issues, leading to increased stress, and perpetuating the pain arc.

How can complex regional pain syndrome be prevented?

An older woman with a fractured wrist has a 10% chance to get CRPS, but if she takes vitamin C, the risk falls to 2%. Likewise, the incidence of CRPS following carpel tunnel surgery is reduced if one takes vitamin C. In children with CRPS it is not known whether vitamin C would be similarly beneficial, but it is relatively risk free and inexpensive so we recommend 500 mg to 1000 mg of vitamin C for 2 months following a fracture or severe injury and to start it 2 days before elective surgery.

What is the evidence?

Sherry, DD, Wallace, DA, Kelly, C. "Short- and long term-term outcomes of children with complex regional pain syndrome type I treated with exercise therapy". Clin J Pain. vol. 15. 1999. pp. 218-223.

(103 children were treated with physical and occupational therapy, without drugs, and 95 resolved all signs and symptoms. 88% were fine 5 years later.)

Bernstein, BH, Singsen, BH, Kent, JT. "Reflex neurovascular dystrophy in childhood". J Pediatr. vol. 93. 1978. pp. 211.

(This is the first large paper in children. 23 children (24 episodes) were treated with physical therapy (none were treated with sympathetic blockade) and all regained normal function; 12 of 20 had no symptoms at follow-up and 5 had occasional discomfort [mean 2.4 years later]).

Sherry, DD, Weisman, R. "Psychologic aspects of childhood reflex neurovascular dystrophy". Pediatrics. vol. 81. 1988. pp. 572.

(21 families were studied and most were overly cohesive with high expectations and high achievement even though most had average intelligence. Marital discord was common. The children were seen as significantly sicker than children with arthritis.)

deRooij, AM, de Mos, M, Sturkenboom, MC. "Familial occurrence of complex regional pain syndrome". Eur J Pain. vol. 13. 2009. pp. 171.

(31 families with multiple members with CRPS were identified [2 with 5, 4 with 4, 8 with 3 and 17 with 2 affected relatives]. CRPS occurred in younger patients when familial but they did not find a clear inheritance pattern.)

Zollinger, PE, Tuinebreijer, WE, Breederveld, RS, Kreis, RW. "Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study". J Bone Joint Surg Am. vol. 89. 2007. pp. 1424-1431.

(416 patients with 427 wrist fractures were randomized. CRPS following wrist fracture was reduced from 10% to 2% in those taking vitamin C. They recommended 500 mg for 50 days post fracture.)

Ongoing controversies regarding etiology, diagnosis, treatment

The use of medication or medical procedures are not recommended by this author. There are no prospective randomized clinical trials of pharmacologic agents in the treatment of CRPS in children. The role of pharmacologic agents in the treatment of children with CRPS remains unknown and controversial. Similarly there are not randomized trials to support the use of transcutaneous electrical nerve stimulation (TENS), regional sympathetic nerve block, epidural and intrathecal anesthetics, or sympathectomy, and are not required in the majority of children with CRPS.

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