Complex Regional Pain Syndrome (CRPS) consists of persistent pain that is disproportionately severe relative to the event that has triggered it, in association with autonomic disturbance. CRPS was previously known as reflex sympathetic dystrophy, causalgia, Sudeck's atrophy, algoneurodystrophy.
Complex regional pain syndrome begins as ongoing pain following an injury, bone fracture or surgery and continues despite the recovery of the initial injury. CRPS affects the extremities, particularly the upper limbs, with higher incidence in women. The condition is usually resolved within 12 months with exceptions where pain develops into a debilitating, chronic disorder impairing daily living activities and quality of life.
The pain is initially localised to the area of trauma but may subsequently spread to the entire limb and even to the opposite limb. In CRPS the sensation of pain is intensified by minor, non-noxious stimuli:
clothing touching the skin (allodynia)
noxious stimulus like pinprick (hyperalgesia)
The aetiology of CRPS is unknown and it is believed to be a multifactorial process. Both, the nervous system as well as the immune system contribute. Normally, a pain stimulus travels from the periphery to the dorsal horn of the spinal cord and then to the thalamus in the brain, where it is transferred to the cortex. In the thalamus, the pain sensation is transformed into perception followed by the release of hormones to suppress pain. The somatosensory cortex helps localise pain and process pain into consciousness.
However, an ongoing noxious stimulus leads to increased excitability of nociceptive neurons in the spinal cord, thus enhancing the response to pain in the brain and reducing the thresholds to non-noxious stimuli (sensitisation).
The stimulation of sensory nerves and the leads to release of (excitatory neurotransmitters, substance P, serotonin) and other chemicals (potassium, bradykinin, histamine, prostaglandins, leukotrienes) resulting in vasodilation, local inflammation (neurogenic inflammation) and swelling. These processes exacerbate nerve stimulation and neurogenic pain, creating a vicious cycle.
Neuroimaging studies of patients with CRPS have demonstrated brain changes, with a reduction of the somatosensory cortex area of the affected limb, indicating the pathology has a structural impact on the brain altering the perception of pain, a fact debunking the theory of CRPS being a psychological disease.
Persistent and exaggerated activation of the immune system, after tissue injury or ischaemic-reperfusion injury and consequent vascular damage, seem to play a significant role. Detection of autoantibodies against neuronal antigens substantiate the development of autoimmunity, a hypothesised contributing factor to CRPS.
The concept of CRPS progression divided into three stages (acute, dystrophic, atrophic) has now been essentially abandoned due to the wide variability of the symptom patterns among the patient population.
There are two types of CRPS:
Type I occurs after trauma and causes sensory, motor, autonomic and skin / bone changes in 95% of cases.
Type II also occurs after trauma but in the presence of a major nerve injury. Possible complications that may arise in long-standing CRPS include:
Swelling, atrophy, osteoporosis, pseudo-arthrosis, joint stiffness and tendon adhesions, which may lead to permanent functional disability. Secondary psychological complications include opiate drug dependence, depression and rarely suicide.
The exact causes of CRPS remain unknown. Trauma has to be present to make the diagnosis of CRPS, most commonly after surgery or major interventions, fractures, prolonged limb immobilisation or even following minor surgery. Psychological factors per se do not seem to trigger CRPS. However, there may be an association of CRPS with depression and anxiety when patients suffer from chronic pain. Major causes include:
Injuries: sprains, surgery, arthroscopy, wounds, fractures, crush trauma, burns
Prolonged limb immobilisation
The most commonly recognised risk factors for developing CRPS are:
History of CRPS
Prolonged limb immobilisation with a cast, splint or sling
Genetics (genes of major histocompatibility complex)
Psychological factors (high anxiety, still questioned but possible)
Symptomatic manifestations of CRPS apart from pain which is often very severe include elevated or reduced skin temperature, sweating, and oedema due to vascular abnormalities. Additional symptoms are abnormal posture of the limb, tremor and weakness. The common symptoms of CRPS are:
Spontaneous burning or aching pain of the affected extremity
Temperature changes (2/3 warmer, 1/3 colder)
In chronic CRPS, the main symptoms can become more severe. In the long term, patients may develop non-dermatomal sensory deficits, disturbances of the body perception, and motor deficits leading to:
Pain spread to the entire limb and often to the opposite limb
Severe muscle dystrophy
Reduced joint motion
The diagnosis of CRPS is based on medical assessment using both subjective symptom reports and objective signs on clinical assessment. Early diagnosis of CRPS is critical to prevent the transition into a chronic condition. The International Association for the Study of Pain (IASP) has established the Budapest diagnostic criteria of CRPS following the 2004 meeting in Budapest to achieve a higher specificity compared to previous definitions. The main criteria are:
A continuing pain that is disproportionate to the initial pathological event.
The patient must report at least one CRPS symptom in three of the four categories:
Sensory symptoms: hyperalgesia (noxious stimulus) and allodynia (non-noxious stimulus)
Vasomotor symptoms: skin temperature asymmetry, skin colour changes, skin colour asymmetry to opposite side
Sudomotor symptoms/oedema: swelling/oedema, sweating changes, sweating asymmetry to opposite side
Motor & trophic symptoms: Reduced range of motion, motor dysfunction (weakness, tremor), trophic alterations of the skin, nail, hair.
At time of clinical evaluation, the patient must display at least one sign in two or more of the above categories.
Diagnosis of CRPS is confirmed if no other diseases fit the array of symptoms identified on clinical examination.
Additional diagnostic methods may support the findings of the clinical examination or be used for differential diagnosis:
Electromyography & nerve conduction studies (CRPS II)
Triple phase bone scintigraphy (increased bone metabolism)
MRI of extremity looking for bone oedema
Quantitative sudomotor axon reflex test
Trial of sympathetic ganglion block
X-rays and MRI to exclude nerve compression at the spine
Other tests to rule out alternative conditions such as deep vein thrombosis, arthritis, diabetes or infection.
The treatment of CRPS remains a challenge. Because of the lack of consensus on a standardised treatment for CRPS, several strategies are currently recommended mostly based on a multidisciplinary management. Some of these are not proven to be efficacious:
Physical/occupational therapy (especially for CRPS Type I)
Oral corticosteroids (acute phase)
Opioid analgesics (morphine derivatives)
Anti-convulsant drugs (pregabalin, gabapentin, topiramate)
Local injection of anaesthetics early in the disease
Calcitonin (calcium modulation)
Calcium channel blockers
Mirror box therapy (restore correct image of affected limb)
Hyperbaric oxygen therapy (emerging therapy)
Surgical intervention is used in case conservative treatment fails but it may not resolve the symptoms. Surgical approaches include:
Spinal cord stimulation: small electrodes are implanted along the spine with the purpose of delivering mild electric impulses to the affected sensory nerves
Pain pump implantation: it consists of the implantation near the abdomen of a small device that releases analgesic medications directly to the spinal cord
Radiofrequency ablation: destruction of the sympathetic ganglion either via radiofrequency ablation or using chemicals
High frequency and repetitive transcranial magnetic stimulation: may reduce pain when combined with medical treatment
Amputation: in rare cases, amputation of the affected limb may be the last option.
Physical and occupational therapy can be very effective in treating pain and reduced function caused by CRPS. Psychological counseling may be recommended if these therapeutic strategies are not successful. Common rehabilitative strategies include:
Stretching / fine motor exercises
Pilates / Yoga
The main strategy for preventing CRPS is to treat pain at the onset of the first symptoms especially after injury or trauma. It is essential to maintain regular physical activity of the affected limb to avoid muscle wasting, joint stiffness and ultimately disability.
Vitamin C is the most efficacious preventative therapy after a fracture or surgery due to its antioxidant properties, which may reduce inflammation.
Minimising the duration of the tourniquet use to block blood flow during limb surgery to reduce ischaemic-reperfusion injury mediated by oxidative stress when blood flow is restored
Bisphosphonate administration may help to restore bone metabolism
Topical ketamine for analgesia