Synonyms (often used interchangeably but not all the same entity): reflex sympathetic dystrophy, causalgia, Sudeck's atrophy, post-traumatic dystrophy, shoulder hand dystrophy, reflex neurovascular dystrophy

In 1979 the International Association for the Study of Pain (IASP) stated that pain is: "An unpleasant sensory and emotional experience associated with actual or potential tissue damage or, is described in terms of such damage".

In 1994, it went on to specify that: "Pain is always subjective. Each individual learns the applications of the word through experiences relating to injuries in early life".¹

Complex regional pain syndrome (CRPS) is a complex and poorly understood condition.

It is typically characterised by segmental limb pain after a (usually) relatively minor injury to a limb but is more severe and lasts much longer than would normally be expected given the injury.² It may also encompass a range of problems involving one or more of the nerves, skin, muscles, blood vessels and bone. Occasionally, it affects parts of the body other than the limbs and it may also arise in the absence of injury.

It is thought to arise as a result of abnormal sympathetic nerve healing following trauma, although the exact pathophysiology still remains very much a mystery. In theory, it can be divided into two disease entities of differing aetiologies:

• CRPS I - formerly known as reflex sympathetic dystrophy (RSD), this is pain which develops in the absence of identifiable nerve injury.
• CRPS II - formerly known as causalgia (literally meaning 'hot pain'), this develops after injury to a major peripheral nerve.

However, the difference may be academic for patients who experience the same pain in both conditions and for whom treatment options are the same.

Epidemiology

Incidence

Complex regional pain syndrome (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.³

Prevalence

Based on the single population study available, it seems to be more common in females (male:female is 1:4) with an estimated prevalence of 20.57 cases per 1,000,000. However, the true prevalence is hard to establish as many cases are not diagnosed and resolve spontaneously.

Presentation

The word 'complex' was added to the terms reflex sympathetic dystrophy (RSD) and causalgia to reflect the variety of symptoms and signs that these patients can present with, in addition to pain.

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 nonpainful stimulus.
• Swelling.
• Abnormal vasomotor activity - spontaneous temperature changes.
• Abnormal sudomotor activity - spontaneous sweating.
• Abnormal pilomotor activity - 'goose bumps'.

The symptoms of complex regional pain syndrome (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, e.g. 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.

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 (particularly in complex regional pain syndrome I (CRPS I)).

Generally, the diagnostic criteria are accepted as being a history of a noxious event or immobilisation (CRPS I) or a nerve injury (CRPS II) of the affected area, associated with pain that is disproportionate to the inciting event³ plus one or more of the following:

• Abnormal function of the sympathetic nervous system.
• Evidence of swelling at some point in time since injury.
• Movement disorder.
• Changes in tissue growth (dystrophy and atrophy).
• Absence of any condition that could cause this degree of pain or dysfunction.

However, patients may present in complex and varied ways, the one common factor being pain. This may result in the patient being labelled as a malingerer or there may be suspicion that it is a ploy to obtain opiate analgesia. The bizarre nature of the movement disorders can be erroneously diagnosed as psychogenic. Diagnosis may be aided by the spreading nature of the problems but on the other hand, if a mirror image type spread occurs, there is no normal limb to compare to. There are often psychological sequelae (see below) which may be interpreted as the cause rather than the consequence of the symptoms. Careful history taking and a systematic look for evidence of the signs outlined above are crucial as early diagnosis and intervention are important for a positive outcome.

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 technecium 99m.³
• Thermography may detect changes in body temperature that are common in complex regional pain syndrome (CRPS).

Associated diseases

There has been some debate over whether these patients have a predisposing personality disorder. The current general consensus is that this is not the case but that the severity of the pain and the disruption that it can cause to a patient can lead to depression and anxiety which may resemble a personality disorder.⁵

Staging

Traditionally, complex regional pain syndrome (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.

Management

General principles

• The key approach is to provide adequate pain relief in order to undertake rehabilitation with the primary aim of restoring function.
• Good progress can be made in treating complex regional pain syndrome (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 below).
• It will usually resolve spontaneously. However, if treatment is required but delayed, the disorder can quickly spread to the entire limb and changes in bone and muscle may become irreversible.
• Therapeutic goals should include:
  • Minimisation of pain and determination of the contribution of the sympathetic nervous system to the patient's pain.
  • Physical therapy to encourage normal use of the limb.
  • Education and psychological support.

Referral

Referral is best done early. The Royal National Hospital for Rheumatic Diseases in Bath is one of the only national centres to offer specialist CRPS rehabilitation service to people from across the UK. They provide an inpatient rehabilitation programme to those who are assessed as being appropriate. See referral leaflet included in the 'Internet and further reading' section, below. Other specialists across the UK, with a special interest in the condition, include:

• Dr Andreas Goebel, The Walton Centre for Neurology and Neurosurgery NHS trust, Fazakerley, Liverpool, L9 7LJ.
• Dr Richard Haigh, Department of Rheumatology, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW.
• Dr Arianne Herrick or Alison Dwyer, Rheumatology or Anaesthetic Department, Hope Hospital, Salford, Manchester, M6 8HD.
• Dr Douglas Justins, Pain Clinic, St Thomas' Hospital, London, SE1 7EH.
• Dr Nicholas Shenker, Department of Rheumatology, Addenbrooke's Hospital, Cambridge, CB2 0QQ.

Pain control

1. Drug therapy^6,7 - introduction of analgesic drugs is done gradually and sequentially with an optimal dose determined on an individual patient basis. Drugs tend to be prescribed for pain that is:
   • Constant.
   • Causing sleep problems.
   • Inflammatory or due to recent tissue injury.
   • Spontaneous and jabbing in nature (paroxysmal dysaesthesias and lancinating pain).
   • Sympathetically maintained pain (SMP).
   • Due to muscle cramps.
   Drugs used include non-steroidal anti-inflammatory drugs (NSAIDs) for mild-to-moderate pain, anticonvulsants or other sodium-channel blockers for significant allodynia or hyperalgesia, antidepressants and opiates. The latter are debated owing to the obvious disadvantages but are useful where pain is refractory to less aggressive therapies, particularly during flare-ups.³ Sympathetically mediated pain responds well to clonidine patching and benzodiazepines may be used in muscle cramps. Steroids may be used in swelling and inflammation and calcitonin or bisphosphonates may be added where osteopenia and trophic changes have occurred.
   
   
2. Sympathetic blockade - generally, sympathetic nerve blocks are used less commonly as they only provide an effective medium-term analgesic effect for some, no benefit to others and can exacerbate the pain in certain cases. However, sympathetic blockade may provide a solution in some individuals and selective blockade provides a further insight into the cause of the pain. There is the added benefit that it has a prognostic value as the patient's response will help to determine the likely success of other treatment modalities.
   • Reversible blockade: injections - these can be performed with or without intravenous sedation and are performed in a setting where vital signs can be monitored throughout the block. A sympathetic block of the upper extremity is called a stellate ganglia block. A sympathetic block of the lower extremity is called a lumbar sympathetic block. Intravenous regional nerve blocks and somatic nerve blocks may also be carried out, although there is little evidence to support the effectiveness of the former.^8,9 If there is a significant decrease in pain following the sympathetic block, the patient is said to have sympathetically maintained pain (SMP). Those who do not are said to have sympathetically independent pain (SIP).
   • Surgical sympathectomy - only those patients with SMP are considered for surgical treatment. Surgical intervention will only provide as much relief as a chemical block (with the benefit that it is permanent) so those who have only experienced a modest improvement may not be suitable as it is a relatively invasive procedure with potential complications. Post-sympathectomy pain (neuralgia) is one potential complication. Motor cortex stimulation is another surgical option that is being investigated.⁶
3. Other treatment modalities - spinal cord stimulation may be a useful treatment for some of the more severely affected patients (it is costly and can have technical drawbacks).¹⁰ Acupuncture has been investigated and found to work well in children.³ Some patients respond to placebo treatment but the beneficial effect tends to be weaker and last less long.

Physical and occupational therapy

One of the cornerstones of therapy is re-establishing use of the affected limb. Physical therapy exercises, occupational therapy interventions, use of hydrotherapy and a transcutaneous electrical nerve stimulation (TENS) machine can all be key in this process.

Patient education and psychological support⁶

A useful initial approach is to establish a written protocol covering various aspects of the patient's care: procedures (e.g. nerve blocks), medications, physical/occupational therapy, psychosocial issues and new laboratory tests or consultations. A psychological evaluation by an expert in chronic pain should be carried out 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.

Complications

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

Prognosis

The duration of complex regional pain syndrome (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. Some patients experience periods of remission and exacerbation. Periods of exacerbation may last for weeks, months (50% of cases have pain for >6 months) or years. Paediatric cases tend to do better.³

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.¹¹ Cases with relatively minor symptoms, may resolve spontaneously.

There are no studies showing that reflex sympathetic dystrophy (RSD)/CRPS affects the patient's lifespan.

Prevention

Investigators are studying new approaches to treat complex regional pain syndrome (CRPS) and intervene more aggressively after traumatic injury to lower the patient's chances of developing the disorder. Scientists are studying how signals of the sympathetic nervous system cause pain in CRPS patients and there is evidence that there might be a role for sympathetic blocks in preventing CRPS. Researchers hope to discover the mechanism that causes the spontaneous pain of CRPS and 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.¹²

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.

Document references

1. Neurological Disorders: public health challenges, World Health Organization, 2006
2. Ornetti P, Maillefert JF; Reflex sympathetic dystrophy: still a poorly defined entity, Rev Prat. 2004 Jan 31;54(2):123-30. [abstract]
3. Parrillo SJ; Complex Regional Pain Syndrome, eMedicine, Mar 2010
4. Lewis JS, Kersten P, McCabe CS, et al; Body perception disturbance: a contribution to pain in complex regional pain syndrome (CRPS). Pain. 2007 Dec 15;133(1-3):111-9. Epub 2007 May 16. [abstract]
5. Schwartzman RJ; New treatments for reflex sympathetic dystrophy. N Engl J Med. 2000 Aug 31;343(9):654-6.
6. National Clearinghouse Guidelines; Complex regional pain syndrome: treatment guidelines (third edition), April 2008
7. Ribbers GM, Geurts AC, Stam HJ, et al; Pharmacologic treatment of complex regional pain syndrome I: a conceptual framework. Arch Phys Med Rehabil. 2003 Jan;84(1):141-6. [abstract]
8. Systematic review of intravenous regional sympathectomy for reflex sympathetic dystrophy, Bandolier, April 2007
9. Straube S, Derry S, Moore RA, et al; Cervico-thoracic or lumbar sympathectomy for neuropathic pain and complex Cochrane Database Syst Rev. 2010 Jul 7;7:CD002918. [abstract]
10. Kemler MA, De Vet HC, Barendse GA, et al; The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years' follow-up of the randomized controlled trial. Ann Neurol. 2004 Jan;55(1):13-8. [abstract]
11. Lee J, Nandi P; Early aggressive treatment improves prognosis in complex regional pain syndrome. Practitioner. 2011 Jan;255(1736):23-6, 3. [abstract]
12. Zollinger PE, Tuinebreijer WE, Breederveld RS, et al; 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. 2007 Jul;89(7):1424-31. [abstract]

Internet and further reading

• Hsu ES; Practical management of complex regional pain syndrome. Am J Ther. 2009 Mar-Apr;16(2):147-54. [abstract]
• Complex regional pain syndrome, Bath Royal National Hospital for Rheumatic Diseases