Introduction
Complex regional pain syndrome, also known as CRPS, is a type of chronic pain usually seen in the appendages following a complication like a stroke, injury, heart attack, or surgery. The pain is often unbearable and requires immediate medical attention. Early diagnosis and intervention can aid in quick remission.
What Are the Types of CRPS?
CRPS is broadly classified into two types based on the backdrop of nerve trauma:
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Type 1: Absence of nerve trauma (previously known as reflex sympathetic dystrophy).
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Type 2: Known history of nerve trauma (previously known as causalgia).
CRPS is further classified into:
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Warm: Patients with mechanical hyperalgesia (long and exaggerated pain response to minor mechanical stimulus).
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Cold: Patients with dystonia (involuntary muscle contraction).
CRPS is also classified as (based on the involvement of the sympathetic nervous system):
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Sympathetically maintained (SMP).
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Sympathetically independent (SIP).
Who Is Susceptible to CRPS?
CRPS is predominantly seen in women (four times more than males), with an average age predominance in the 40s. It is rarely seen in old or young ages, as the older do not show much inflammation after injury, and children or teenagers heal quickly and rapidly. Hence, either end of the age spectrum remains largely unaffected.
The incident was found to be geographically selective. Minnesota reported 5.46 per 1,00,000 individuals with an average age incidence of 46 years, and the Netherlands reported 26.2 cases per 1,00,000, with a peak age of 61 to 70 years, of their population. Minnesota study found four times the female dominance over male while the Netherland study found it to be three times. Upper appendage injury led to more CRPSs than lower. Fractures contributed to 44% to 46% of the CRPS cases.
What Are the Causes of CRPS?
CRPS is caused by various kinds and degrees of tissue trauma or in the presence of a prolonged lack of movement. The most common causes are -fractures, sprains, contusions, crush injuries, surgery, and innocuous interventions such as intravenous line placement.
1. Fractures: A fracture of the wrist, ankle, thumb, and pinky toe, about 49% of such cases, resulted in CRPS within the first eight weeks of the injury. Patients with rheumatoid arthritis, intra-articular ankle fractures, and dislocations are prone to CRPS with an equal incidence in the upper and lower limbs. With intervention, all patients showed great improvements at the 3-month mark, but at 1-year follow-up, they presented with persistent pain with no improvement. Sometimes, psychological stress and depression contribute to CRPS incidence. 32% of the patients undergoing closed reduction of distal radial fractures developed CRPS.
2. Surgery: About four of the patients who underwent foot or ankle surgery developed CRPS. Surgical management of fractures, carpal tunnel surgeries, and Dupuytren contracture surgery contribute to the development of CRPS.
3. Genetic: The role of genes in the development of CRPS is undetermined. Scientists suspect that human leukocyte antigen and tumor necrosis factor-alpha (TNF-α) polymorphism may play a role in the development of CRPs, with heredity being a contributing factor.
What Are the Stages of CRPS?
In 1990, Bonica suggested the presence of three stages:
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Acute.
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Subacute.
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Chronic.
Out of the three, the chronic stage lasts for about three months.
What Are the Symptoms of CRPS?
1. Type of Pain: Constant or fluctuating pain that may or may not be initiated by external stimuli resulting in burning, pricking, or squeezing-like sensations, which may involve the entire limb even though the region of the original injury was small. Sometimes due to the involvement of the secondary neurons of the spinal cord, less severe pain may occur in the opposite limb at a matching location, known as a “mirror pain.”
2. Reason for the Pain: Increased sensitivity to pain in the affected area (allodynia) is observed where a minor stimulus gives an exaggerated pain response (hyperalgesia). This is due to injury to the C-nerve fibers of the region resulting in abnormal blood flow, presenting a change of temperature and color of the limb compared to the opposite side. The limb may be warm or cool to the touch with a patchy appearance and varying colors like red, blue, purple, gray, or even pale.
3. Skin Symptoms: Insufficient oxygen delivery and hyperalgesia that prevents the patient from cleaning the affected area lead to changes in skin texture. The skin might become shiny and thin or even thick and scaly.
4. Nail and Hair Symptoms: An abnormal pattern of nail and hair growth and sweating may be seen, varying from none at all to excessive growth and sweat in contrasting degrees.
5. Manifestation of the Limbs: The limbs become rigid, leading to the tendons and ligaments losing their flexibility. These connective tissues impinge on the nerve fiber and may internally provoke CRPS.
6. Bone Symptoms: If the nerve supplying the bones gets affected in the injury, a demarcated change is observed in the X-ray, which helps the specialist pinpoint the exact region of nerve damage. Rough or enlarged or malunion of bones or bone cysts can initiate or prolong CRPS.
7. Change in Movement: CRPS rarely involves motor nerves. The inability to freely move the limb is mostly due to the pain, abnormality, poor circulation, and inflation of the sensory input of muscle movement. Sometimes patients complain of involuntary jerks, reflexes, and movements.
CRPS is also associated with:
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Worsening depression.
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Diminished quality of life.
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Catastrophic thinking.
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Neurological deficits (executive functioning, memory, word retrieval).
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Non-specific symptoms (lethargy, weakness, disruptions in sleep architecture).
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Cardiopulmonary conditions (neuro-cardiogenic syncope, atypical chest pain, chest wall muscle dystonia.
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Endocrinopathies (an impaired hypothalamic-pituitary-adrenal axis with low serum cortisol, hypothyroidism).
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Kidney-related disorders - increased urinary frequency and urgency, urinary incontinence.
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Gastrointestinal disorders (nausea, vomiting, diarrhea, constipation, indigestion).
What Is the Pathophysiology of CRPS?
There is no evidence that points to a single mechanism of causality, rather suggests a multifactorial origin-inflammatory, immunological, central, peripheral sensitization, as well as autonomic changes together or individually contribute towards the pathophysiology of CRPS.
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Inflammatory Changes: Inflammation is the key mechanism for the development of CRPS, with increased temperature, swelling, redness, pain, and functional impairment as major indicators.Elevated levels of pro-inflammatory cytokines such as TNF-α, interleukin (IL)-1b, IL-2, and IL-6 have been isolated from serum and CSF (cerebrospinal fluid). Neurogenic inflammation is triggered by neuropeptides like calcitonin gene-related peptide (CGRP), bradykinin, and substance P released from peripheral nerve endings. Both of these cytokines and neuropeptides together cause vasodilation and tissue extravasation.
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Immunological Changes: Autoantibodies against the β-2-adrenergic receptor, α -1a-adrenergic receptor, and muscarinic-2 receptor have been observed, and intravenous immunoglobulin therapy has resulted in relief from pain. This supports the idea of immunological pathophysiology.
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Peripheral Sensitization: TNF-α (tissue necrosing factor) markers released during injury diminish the stimulation threshold leading to hyperalgesia and allodynia. Catecholamine sensitivity of peripheral nerve fibers is also marked.
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Central Sensitization and Neuroplasticity: The release of substance-P, bradykinin, and glutamate after injury increases the excitability of secondary dorsal horn neurons, which activates central sensitization resulting in hyperalgesia and allodynia.Cortical reorganization (neuroplasticity) with a reduction in the somatosensory-cortex area corresponding to the affected limb is observed, which in turn correlates with the intensity of pain and severity of hyperalgesia.
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Autonomic Changes: Physiologic upregulation of sympathetic receptors during trauma on the nociceptive nerves (pain receptors) initiates sympathetic hyperactivity, which leads to increased pain and sympathetic sensitivity of nociceptive nerves. Autonomic dysfunction is evident as localized swelling, color, and temperature variations, varying heart rates, and orthostatic dysfunction (development of symptoms during change of posture). Warm CRPS decreases catecholamine activity resulting in vasodilation, while in cold CRPS, results are reversed.
How to Evaluate CRPS?
There are no laboratory diagnostic criteria to confirm the CRPS due to the unavailability of a definite conclusion on its pathophysiology. The diagnosis is based on Budapest criteria, 2003, which is a revised edition of the IASP criteria of 1994.
Budapest criteria consist of four symptoms and four sign categories.
1. The patient should report continuing pain disproportionate to the pain stimulus.
2. The patient should report at least one symptom in three of the four following categories:
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Sensory: Hyperalgesia and/or or allodynia.
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Vasomotor: Changes in temperature or color of the skin.
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Sudomotor or Edema: Swelling or disproportionate sweating pattern.
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Motor or Trophic: Weakness, tremor, dystonia, or changes to hair, skin, and nails.
3. The patient should exhibit at least one sign during physical examination in more than two of the following categories:
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Sensory: Hyperalgesia (to pricks) and/or allodynia (to light touch or pressure).
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Vasomotor: Changes in temperature or color of the skin.
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Sudomotor or Edema: Swelling or disproportionate sweating pattern.
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Motor or Trophic: Weakness, tremor, dystonia, or changes to hair, skin, and nails.
4. No better diagnosis suits the set of signs and symptoms exhibited by the patient.
To summarize, Budapest criteria check and correlate the chief complaints, basic signs, and symptoms of CRPS with the clinical presentation of the patient during physical examination.
How to Treat or Manage CRPS?
Early intervention and aggressive management are the keys to treating CRPS, as acute cases tend to be less resistant to treatment than chronic CRPSs. Hence, delivering a better prognosis. The best management is to follow an interdepartmental approach, including physical and occupational therapy, pharmacotherapy, behavioral therapy, and interventions.
1. Physical and Occupational Therapy
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Manual therapy.
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Exercises.
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Transcutaneous electrical nerve stimulation.
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Ultrasound.
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Laser.
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Pain education.
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Mirror therapy.
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Graded motor imagery (GMI).
2. Pharmacotherapy
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Anti-inflammatory medications: Oral corticosteroids and Non-steroidal anti-inflammatory drugs (NSAIDs). Piroxicam (NSAID) is found to be better than oral Prednisone.
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Anticonvulsants and antidepressants: Gabapentin, which affects the calcium channels; and Amitriptyline.
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Transdermal lidocaine.
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Opioids.
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NMDA antagonists: Ketamine may reverse central sensitization and maladaptive cortical neuroplastic changes but carry major side effects and psychomimetic effects.
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Bisphosphonates: These drugs inhibit bone marrow proliferation and migration as well as inflammation.
3. Behavioral Therapy:
The increase of catecholamines in depression can activate or worsen CRPS by inducing central sensitization. Behavioral therapy may be introduced in the management protocol for comprehensive treatment.
4. Interventions:
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Sympathetic blocks.
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Spinal cord stimulation.
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Dorsal root ganglion stimulation.
What Are the Complications of CRPS?
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Dystonia (involuntary muscle contraction).
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Cognitive executive dysfunction (problems in planning, problem-solving, time, and task management).
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Adrenal insufficiency (deficiency of hormones from the adrenal gland).
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Gastroparesis (muscles of the stomach lose motility).
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Irritable bowel syndrome (pain arising from the large intestine).
What Is the Differential Diagnosis of CRPS?
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Arterial insufficiency (restricted blood flow in arteries).
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Gillian Barre syndrome (immune system attacks the nerves).
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Hysteria (psychic disturbance).
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Monomelic amyotrophy (progressive degeneration of motor neurons).
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Multiple sclerosis (immune cells erode the myelin sheath-nerve coverings).
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Peripheral atherosclerotic disease (reduced blood flows to appendages and digits).
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Phlebothrombosis (blood clot in veins).
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Porphyria (over-accumulation of porphyrin).
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Tabes dorsalis (degeneration of the sensory nerves to the brain).
What Is the Prognosis of CRPS?
The prognosis of CRPS is fairly variable, which indicates that the pain associated can undergo spontaneous remission and may even recur at a later stage. Despite the inconsistency of the prognosis, early treatment is the key to managing the condition.
Conclusion
CRPS is a condition that brings extreme pain, often beyond the normally perceived threshold, along with intense physical and mental agony, due to which the patient becomes vulnerable, requiring the utmost attention of both professionals and family members. Early intervention in all disciplines is required to decrease the recovery time and get the patient back onto the rails.