Epidemiology

Incidence

Incidence rates of 26 per 100,000 patient years are reported in Europe.^[1] 

CRPS can affect any age but is more common between the ages of 40 and 60 years with a mean age of onset of 46 years, although the number of CRPS cases among adolescents and young adults is increasing. It may occur as often as in 5% of all injuries. It occurs in up to 15% of peripheral nerve injuries and following 10-30% of fractures.^[2]

Presentation

The word 'complex' reflects the variety of symptoms and signs that these patients can present with, in addition to pain. Symptoms usually begin within one month following the inciting event or immobilisation. As the signs and symptoms vary widely, patients can present to various specialties - eg, orthopaedics, neurologists, dermatologists or rheumatologists. This can lead to a delay in diagnosis; thus, a thorough history and examination are crucial from the initial consultation.^[1]

Symptoms

The characteristic symptom is that of pain - typically burning in nature and out of proportion to the severity of the injury. It is chronic, gets worse rather than better with time and the affected area may have associated features such as:

• Sensitivity to touch.
• Allodynia - perception of pain from a non-painful stimulus.
• Swelling.
• Abnormal vasomotor activity - spontaneous temperature changes.
• Abnormal sudomotor activity - spontaneous sweating.
• Abnormal pilomotor activity - 'goosebumps'.

The symptoms of CRPS vary in severity and duration. There is often a history of trauma - this may be very minor such as a cut to the finger. The symptoms do not appear to be related to the magnitude of the injury, which may not be remembered (if it occurred at all). Other entities that have led to CRPS include:

• Head injury.
• Stroke.
• Polio.
• Amyotrophic lateral sclerosis (ALS).
• Myocardial infarction.
• Polymyalgia rheumatica.
• Operative procedures - eg, carpal tunnel release.
• Brachial plexus pathology.
• Cast/splint immobilisation.
• Prolonged bedrest.

Signs

There are not always objective findings in these patients, who may be accused of malingering. However, the following may occur:

• About 80% of cases have temperature differences between opposite sides. They may be warmer or cooler and this may be a fluctuating sign (sometimes occurring within a few minutes) depending on room temperature, local temperature of the skin and emotional state. Occasionally, it may occur spontaneously. This may be associated with a change in skin colour.
• Other skin changes include a shiny, dry or scaly appearance. Hair may be coarse initially, then become thin, nails become brittle and grow faster (initially) then slower and there may be associated rashes, ulcers or pustules which may become infected. Abnormal and spontaneous vasomotor, sudomotor and pilomotor activity, as described above, also occur.
• Hard, pitting oedema may occur diffusely over the painful region. There is often a well-demarcated boundary along the skin line - almost diagnostic of the condition, although similar findings occur when patients tie a band around the limb for comfort.
• Movement may be limited, both because of the pain and because joints are often described as stiff, particularly with difficulty in initiating movements. (The stiffness disappears after a sympathetic nerve block.) Disuse atrophy can ensue. Other muscular disorders include sudden and severe spasms, tremors and involuntary severe jerking and dystonia.

Symptoms and signs may spread over time in one of three ways:

• Continuity type spread - the symptoms gradually spread out from the initial source.
• Mirror image type spread - the symptoms spontaneously start up in the opposite limb.
• Independent type spread - this may be spontaneous or following another trauma.

It is also important to look for psychological symptoms which may need to be treated.

Diagnosis

The diagnosis is clinical and may be difficult, particularly in the early stages of the syndrome where there may be little, if any, physical evidence of a problem. The Royal College of Physicians recommends the use of the "Budapest criteria" to make a diagnosis.^[1] This requires all of the following four to be present:

• Presence of pain which is disproportionate to the initial causative event.
• Presence of one sign in two or more of the categories listed below.
• Presence of at least one symptom in three or more of the categories listed below.
• No other diagnosis would better fit the signs and symptoms.

The categories include:^[1] 

• Sensory category - allodynia (to light touch, temperature, deep somatic pressure or joint movement) and/or hyperalgesia (to pinprick). These count whether they are present as symptoms or signs; hyperesthesia can also qualify but only as a symptom.
• Vasomotor category - signs or symptoms of temperature differences (as a sign the difference needs to be >1°C) and/or skin colour changes and/or skin colour asymmetry.
• Sudomotor/oedema category - sign or symptoms of oedema and/or sweating and or sweating asymmetry.
• Motor/trophic category - reduction in range of motion and/or motor dysfunction (including weakness, tremor or dystonia) and/or trophic changes (of the hair, nail or skin).

This classification means that CRPS can only be diagnosed if there are limb signs. Furthermore, some changes may abate over time - eg, swelling and sweating. In these patients a diagnosis of CRPS-NOS (not otherwise specified) should be given.^[1] 

The diagnosis should be made without delay, as early treatment will prevent the complications which occur from limb disuse. 

The diagnosis can be made not only by doctors but by therapists too.

Differential diagnosis

• Poorly placed splint or cast.
• Nerve entrapment.
• Deep vein thrombosis.
• Thrombophlebitis.
• Thoracic outlet syndrome.
• Carpal tunnel syndrome.

Investigations

• No blood tests support or exclude the diagnosis.
• It is worth noting that X-rays, electromyography (EMG), nerve conduction studies, CT scans and MRI studies may all be entirely normal. However, X-rays can show patchy osteoporosis in due course in up to 70% of cases (Sudeck's atrophy or post-traumatic osteoporosis) and a bone scan may show increased or decreased uptake of technetium ^99mTc.^[2]
• Thermography may detect changes in body temperature that are common in CRPS.
• The diagnosis is clinical and over-reliance on investigations is unnecessary.^[1] 

Staging

Traditionally, CRPS was seen as a three-stage disease; however, these stages are increasingly being seen as theoretical, as all the features may not be present and the speed of progression varies hugely between patients. Some patients never actually progress to stage III whilst others get to stage III and lose some of the symptoms of the earlier stages.

For the purposes of management, assessment of severity is divided as follows:^[1] 

• Mild CRPS: few signs of pain-related disability or distress. Pain can be managed with simple analgesics or neuropathic medications.
• Moderate to severe CRPS:
  • Moderate to severe signs and/or symptoms at presentation.
  • Dystonia.
  • Failure of response to treatment.
  • Continued deterioration or only short-lived improvements.

Management

General principles

• The key approach is a multidisciplinary one but should be centred around the GP and pain teams. 
• Care has to be taken so that the patient's care does not become fragmented, as they may end up seeing several different specialties.
• Good progress can be made in treating CRPS if treatment is begun early, ideally within three months of the first symptoms.
• Early treatment often results in remission, so consider early referral (see 'Referral', below).
• Pain flares may occur but usually settle over a few weeks. Medications should be continued with a temporary reduction in intensity of physical therapy.
• The Royal College of Physicians provide four 'pillars' of therapy: education, pain reduction, physical rehabilitation and attention to psychological needs, aiming to improve the quality of life.^[1] 

Referral

Referral from primary care is necessary for the following:^[1] 

• Confirmation of CRPS.
• Exclusion of other causes of the symptoms/signs.
• Helping to control difficult symptoms including pain, distress and associated disability.
• Functional rehabilitation.

Confirmed cases can be managed in primary care provided symptoms are mild and responding to treatment.

Mild cases can be referred to multidisciplinary pain clinics, whereas moderate to severe CRPS can be referred to either multidisciplinary pain clinics or specialist units.^[1] 

Medications^[1] 

• Simple analgesics to begin with and gradually up-titrate - eg, non-steroidal anti-inflammatory drugs (NSAIDs).
• If pain is not reduced to a mild level by 3-4 weeks then use medication for neuropathic pain - eg, tricyclic antidepressants or gabapentin.
• Limb use should also be encouraged with gentle exercise, frequent attention to the affected limb, and desensitisation (using various fabric modalities whilst observing the limb).
• Medications may also be needed for associated depression if present.
• Pamidronate as a one-off treatment can be given to patients with CRPS of less than six months duration.

Rehabilitation^[1] 

• This should be considered in all cases. and started early, regardless of which specialty the patient is seeing when the initial diagnosis is made. 
• Again, a multidisciplinary approach is needed.
• This can be outpatient or inpatient.
• Pain management programmes which are run in groups may be available in specialised settings.
• Psychosocial factors may lead to reduced response to rehabilitation and should be actively looked for and corrected. This includes previous negative experiences, poor coping, and depression.
• Treatment approaches used in rehabilitation for CRPS are wide and include education and support, desensitisation, postural control and oedema control. In addition to this, specialised units may also undertake more specialised therapeutic strategies - eg, mirror visual feedback and graded motor imagery.

Other treatments^[1] 

• Spinal cord stimulation is used in specialist centres for patients who have not responded to a multidisciplinary approach.  The effects of this treatment reduce over time.
• Specialist centres may also use clonidine and local anaesthesia injection into the epidura, local anaesthetic injection into the sympathetic chain, intravenous regional sympathetic blocks or interscalene indwelling catheters. The evidence for their use is inconclusive but they can reduce pain. 
• Dystonia which fails rehabilitation is treated with intrathecal baclofen or serial splinting in certain centres.

Other specialty team involvement^[1] 

• Orthopaedics - up to 25% of cases follow limb fractures and orthopaedic surgery. Patients may have been discharged but it may be necessary to re-refer to rule out organic pathology - eg, compression of nerves by scar tissue. Surgery should be avoided if possible, as it may lead to further CRPS, although it is usually mild. There is no role for amputation.
• Rheumatology, neurology and neurosurgery - to rule out other potential causes of pain.
• Dermatologists - precipitating factors can be skin conditions, such as herpes zoster, vasculitis and leg ulcers. CRPS may also present with skin changes including skin atrophy, hypertrichosis, bullae and leukonychia.

Patient education and psychological support

A useful initial approach is to establish a written protocol covering various aspects of the patient's care: procedures (eg, nerve blocks), medications, physical/occupational therapy, psychosocial issues and new laboratory tests or consultations. A psychological evaluation by an expert in chronic pain may be necessary  to outline contributory factors which might be addressed. Patients with CRPS commonly report the following psychological issues:

• Difficulty relaxing.
• Low self-esteem.
• Inappropriate/ineffective coping strategies.
• Difficulty accessing/accepting social support.
• Suicidal ideation.

Psychological interventions (including cognitive behavioural therapy and relaxation techniques) can help the patient to address these issues.

Complications

• Depression is common.
• Immobilisation may aggravate pain and stiffness.
• Skin infections can occur and occasionally may be very severe.

Prognosis

The duration of CRPS varies: in mild cases it may last for weeks followed by remission; in many cases the pain continues for years and, in some cases, indefinitely. It is estimated that 15% have unrelenting pain and physical disability at two years. Some patients experience periods of remission and exacerbation. Periods of exacerbation may last for weeks, months (50% of cases have pain for more than six months) or years. Paediatric cases tend to do better.^[2]

If undiagnosed and untreated, CRPS can spread to all extremities. This makes the rehabilitation process more difficult. Apart from the significant morbidity experienced by the patient, this also leads to a very costly process of managing chronic pain and permanent deformities. There are also significant psychosocial and psychiatric problems, as well as potential dependency on narcotics to manage; the patient may be completely incapacitated by the disease. The treatment of patients with advanced CRPS is a challenging and time-consuming task. However, if diagnosed early and treated aggressively, prognosis is improved.^[3] Cases with relatively minor symptoms, may resolve spontaneously.

There are no studies showing that CRPS affects the patient's lifespan.

Prevention

Investigators are studying new approaches to treat CRPS and intervene more aggressively after traumatic injury to lower the patient's chances of developing the disorder. Researchers hope to discover the mechanism that causes the spontaneous pain of CRPS; that discovery may lead to new ways of blocking pain. Meanwhile, it would appear that patients suffering from fractures are well advised to maintain a good intake of vitamin C.^[4]

The authors would like to thank Dr Jenny Lewis and Dr Karen Rodham from the Royal National Hospital for Rheumatic Diseases for their advice and contributions to this article.