Overview: A rare vascular neurologic disorder of the distal extremities.
A rare vascular neurologic disorder of the distal limb often characterized by paroxysmal redness, elevated temperature, swelling, and severe burning pain of the distal limb. The cause of the disease is not entirely clear.
Definition
Erythromelalgia is a paroxysmal dilatation of blood vessels in the distal extremities.
It is characterized by paroxysmal elevation of temperature, redness, and swelling of the skin of the distal limb, and severe burning pain, usually most pronounced in the toes and soles of the feet.
Typing or Classification
The disease is clinically categorized as primary and secondary [1].
Primary erythema gangrenosum: genetic mutation is the main cause of the disease.
Secondary erythema gangrenosum: the onset of the disease is caused by immunity, metabolism, tumor, drugs and other reasons.
Pathogenesis
Erythema gangrenosum is a rare disease with an incidence of (0.36-2)/100,000 per year [2].
Primary erythema gangrenosum has its onset in childhood and adolescence and is more common in females than males.
Secondary erythema gangrenosum is more common in middle-aged and elderly people.
Etiology
Causes
The cause of erythema gangrenosum is not fully understood.
Primary erythema gangrenosum is an autosomal dominant disease, and SCN9A is the main cause of the gene mutation.
Secondary erythema gangrenosum is usually associated with the following diseases:
Myeloproliferative disorders: primary thrombocythemia, true erythrocytosis and myelofibrosis.
Connective tissue diseases: lupus erythematosus, rheumatoid arthritis, dry syndrome, mixed connective tissue disease, and vasculitis.
Tumors: colon cancer, breast cancer, thymoma, paraneoplastic syndrome, astrocytoma, and subcutaneous lipofuscinosis-like T-cell lymphoma.
Infections: influenza, syphilis, acquired immunodeficiency syndrome and recurrent bacterial infections.
Metabolic diseases: gout, diabetes mellitus and hypercholesterolemia.
Neurologic, musculoskeletal disorders: sciatica, neurofibromatosis, multiple sclerosis, carpal tunnel syndrome, various traumatic injuries and surgeries.
Vascular diseases: venous dystrophy, thromboembolism and atherosclerosis.
Poisoning: mushroom, lead and mercury poisoning.
Drugs: nicardipine, nifedipine, felodipine, cyclosporine, rosuvastatin, bromocriptine and iodine contrast media.
Predisposing factors
Prolonged standing, exercise, prolapse of limbs, increased ambient temperature, alcohol consumption, and eating spicy food can trigger the onset of the disease and exacerbation of symptoms [3].
Risk groups
People with family genetic history of erythema migrans.
People with autoimmune disease, myeloproliferative disease, tumor, gout, diabetes and other diseases.
People with long-term exposure to heavy metal substances such as lead and mercury.
People who use drugs such as nicardipine, nifedipine, felodipine, cyclosporine, bromocriptine and so on.
Pathogenesis
At present, the pathogenesis of this disease has not been completely clarified, and may be related to vascular, neurological and genetic factors.
It may be related to local vascular nerve dysfunction, microcirculatory dysfunction, local tissue ischemia and hypoxia, perivascular inflammation and so on.
These causes lead to dilation of small arteries in the extremities, which stimulates the neighboring nerve endings to produce symptoms [4].
Symptoms
Main symptoms
Skin redness, swelling, heat, and pain
It manifests as paroxysms of increased skin temperature, redness, swelling and severe pain.
The pain is a burning pain, evident at night, with intermittent episodes.
Symmetrical skin eruptions on both feet are most common, followed by eruptions on both hands, and a few patients may have unilateral eruptions only.
Individuals may also present with skin lesions on the face, neck, ears, and scrotum.
Nail changes
In patients with a long course of the disease, repeated episodes may lead to thickening of the skin and nails on the affected limbs.
Aggravation, Relief
Symptoms may be caused or aggravated by prolonged standing, exercise, drooping of the limb, elevated ambient temperatures, alcohol consumption, and eating spicy foods.
The use of cold water, ice, or being in a cold environment can reduce the redness, swelling, and pain of the skin.
Complications
Localized skin damage
Caused by repeated skin ischemia and hypoxia, malnutrition, and frequent immersion of the limb in cold or ice water.
Skin mucous membrane breakage, infection, and even the formation of ulcers, necrosis and gangrene occur.
Anxiety, depression state
Recurrent pain symptoms, affecting the patient’s sleep, normal life and social activities, quality of life is seriously reduced.
It may lead to anxiety and depression, and even self-harming behavior to the diseased limbs.
Consultation
Department of Medicine
Neurology
Paroxysmal elevation of skin temperature, redness, swelling and severe burning pain in both feet or hands are recommended to consult the Department of Neurology.
Functional Neurosurgery
Functional Neurosurgery is recommended for severe or prolonged symptoms, and surgery may be considered.
Preparation
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips
Protect the skin of the affected limb, especially during the first attack, to avoid skin breakdown, inflammation and infection, otherwise the inflammatory reaction will affect the diagnosis of the disease.
Avoid self-medication during the first attack, and avoid applying any medication on the skin by yourself, so as not to affect the diagnosis, delay or aggravate the disease.
Preparation Checklist for Medical Attention
Symptom checklist
Particular attention needs to be paid to the time of symptom onset, special manifestations, etc.
Are there paroxysms of redness, swelling, and increased temperature of the skin at the ends of the extremities?
Are there paroxysms of burning pain in the skin at the ends of the extremities?
Are the symptoms most noticeable at night?
Do these symptoms occur after prolonged standing, exercise, drooping of the limbs, or increased ambient temperature?
Can the burning pain be aggravated by localized heat or increased ambient temperature?
Can the skin pain be relieved when the affected limb is immersed in cold or icy water, or otherwise cooled?
Medical History Checklist
Have similar symptoms occurred in the past?
Has anyone in the family had similar symptoms or been diagnosed with erythematous limb pain?
Are there any myeloproliferative disorders, autoimmune disorders, tumors, infections, metabolic disorders, neuro-skeletal muscle disorders, vascular disorders?
Are you chronically exposed to heavy metals such as lead and mercury?
Any use of drugs such as nicardipine, nifedipine, felodipine, cyclosporine, bromocriptine, etc.?
Checklist
Test results of the last six months, which can be brought to the doctor’s office
Laboratory tests: blood routine, blood biochemistry, coagulation function, blood sedimentation, tumor markers, immune function and autoantibody tests.
Gene test: gene mutation detection and sequence analysis.
Ultrasound examination: bilateral upper limb and lower limb vascular ultrasound.
Neuroelectrophysiological examination: electromyography, nerve conduction velocity, small fiber neuropathy related examination.
Medication list
Medication use in the last 3 months, if available in boxes or packages, carry with you to the doctor’s office
For triggers of the disease: nicardipine, nifedipine, felodipine, cyclosporine, rosuvastatin, bromocriptine, and iodine contrast agents.
Medications for the treatment of the disease: e.g. aspirin enteric-coated tablets, propranolol, venlafaxine, misoprostol, amitriptyline, and Chinese herbs.
Diagnosis
Diagnosis is based on
Medical history
There is a history of recurrent episodes of redness, swelling, and pain in both feet or hands.
Patients with primary erythema gangrenosum may have a family history of the disease.
Secondary erythema gangrenosum
Often suffer from myeloproliferative diseases, autoimmune diseases, tumors, infections, metabolic diseases, neuro-skeletal muscle diseases, vascular diseases.
Long-term exposure to heavy metals, use of certain drugs.
Symptoms
Paroxysmal elevated skin temperature, redness, swelling and severe burning pain in both feet and hands, more pronounced at night.
Physical examination
Doctors mainly check the skin and arterial pulsation of the ends of the limbs during the attack, and carry out the skin critical temperature test.
Skin Appearance: During an attack, the skin is red, swollen and dilated, and the skin and nails are thickened if the disease is prolonged; the red color may subside temporarily when pressed, and the temperature may be elevated when touched.
Arterial pulsation: During the exacerbation period, when touching the dorsalis pedis and posterior tibial arteries of the affected limb, a slight increase in arterial pulsation can be detected.
Skin critical temperature test: immersing the affected limb in 32℃~36℃ water, if the induced symptoms appear and worsen, it is a positive test, supporting the diagnosis of the disease [5].
Examination tests
Laboratory tests
Including routine blood, blood sedimentation, blood biochemistry (liver and kidney function, blood lipids and glucose, electrolytes, etc.), coagulation function,, tumor markers, immune function and autoantibody tests.
The purpose is to find out the etiology related to secondary erythematous achalasia, such as erythrocytosis, accelerated blood sedimentation, the presence of antinuclear antibodies, rheumatoid factor, elevated blood glucose, and so on.
During the course of treatment, some of the items may need to be reviewed periodically in order to assess the effectiveness of the treatment, as well as to monitor the physical condition and adjust the treatment program.
Microcirculation examination
Microcirculation examination of nail folds is mainly performed.
Observed under the microscope, it is seen that the outline of the nail fold capillary collaterals is blurred and dilated, and the pressure within them is increased, which is more serious when thermal stimulation is given [6].
Vascular ultrasonography
Vascular ultrasonography of both upper and lower extremities was performed.
It helps to understand the specifics of the blood vessels of the limbs, such as the presence of stenosis, occlusion, arteritis, etc., and is used to help in the differential diagnosis of thromboembolic vasculitis.
Genetic testing
Patients with primary erythromelalgia may be found to have a mutated SCN9A gene, which can be used to identify hereditary characteristics and differentiate from secondary erythromelalgia.
Cautions: Not used as a routine etiologic screen, but usually used when there is a high suspicion of primary erythema gangrenosum.
Other tests
Electromyography, nerve conduction velocity, small fiber neuropathy related tests: may be used to diagnose the presence of other neuromuscular disorders.
Diagnostic criteria
The following diagnostic criteria are generally used in current clinical practice [7]:
Burning pain in the extremities.
Pain aggravated by localized heat.
Pain relieves with cooling.
Skin lesions appear erythematous.
Elevated temperature of the involved skin.
Differential Diagnosis
Raynaud’s disease
Similarities: the congestive phase of Raynaud’s disease may also present with reddening of the skin and an increase in temperature, and the ischemic-hypoxic phase may be characterized by skin pain in the involved extremities.
Differences
Raynaud’s disease begins with symptoms of ischemia and hypoxia, with pale, cold skin on the extremities, decreased skin temperature, pain, and sensory abnormalities, and then changes to redness of the skin and increased temperature during the congestive phase.
Raynaud’s disease is susceptible to onset when the area is cold, and is relieved by a warm environment. In contrast, erythematous limb pain develops when the local temperature rises and is relieved in a cold environment.
Thromboembolic Vasculitis
Similarity: Thromboembolic vasculitis can also present with pain at the end of the limb.
Differences
Thromboembolic vasculitis is characterized by ischemic symptoms, including intermittent claudication, pale skin, cyanosis, and decreased or absent dorsalis pedis arterial pulsations, in addition to pain.
Ultrasound of the arteries of the lower extremities can detect inflammatory changes and arterial occlusion.
Treatment
Aim of treatment: reduce the number of attacks, alleviate the symptoms and improve the quality of life.
Treatment principle: avoiding triggering factors, combining medication with physical therapy and surgery. Secondary erythematous limb pain requires active treatment of the primary disease.
General treatment
Cooling therapy
Try to rest in bed and elevate the affected limbs during the attack.
Adopt local cold compresses or stay in the air-conditioned room to reduce pain symptoms.
In order to avoid frequent cooling of the limb skin damage, can be used sterile cold saline solution instead of tap water, wrapped in a plastic bag with the affected limb and then cooled with saline, and the time of each immersion should not be too long.
Thermal desensitization therapy
Let the patient repeatedly exposed to warm stimuli, so as to gradually reduce the sensitivity of the blood vessels of the limb to heat.
The affected limb is first immersed in water below the critical skin temperature, and then the water temperature is gradually increased until the patient experiences mild discomfort.
The water is immersed daily and gradually increased until the patient does not experience seizures in water temperatures above the critical skin temperature.
Medication
Improvement of microcirculation
Aim of treatment: Improve local microcirculation and relieve symptoms.
Commonly used drugs: propranolol, misoprostol, etc.
Precautions
Monitor the effect of various medications when used during an attack and choose the most sensitive medication as the first choice for subsequent attacks.
Start with a small dose and gradually increase the dose.
Pain relief
Treatment objective: to improve pain symptoms.
Commonly used drugs: Oxcarbazepine, Gabapentin, Pregabalin
Precautions: Adverse effects such as cardiac arrhythmia, atrioventricular block, bone marrow suppression, hepatic and renal impairment, hyponatremia, and skin rash may occur.
Inhibition of platelet aggregation
Give antiplatelet aggregation therapy to patients with blood disorders secondary to thrombocythemia.
Commonly used drugs: aspirin.
Caution: Observe the risk of gastrointestinal bleeding during oral aspirin therapy.
Other medications
Tricyclic antidepressants: amitriptyline, promethazine.
Calcium channel blockers: nimodipine, diltiazem.
Glucocorticoid: Dexamethasone.
Neurologic function regulators: glutamine, methylcobalamin, vitamin B12, etc.
Topical topical drugs: 5% lidocaine, capsaicin, gabapentin, diclofenac, compound midodrine, etc.
Oral high-dose magnesium, rifampicin combined with chlorpromazine, intravenous lidocaine, and intravenous immunoglobulin can also improve the symptoms of the disease [5].
Physical therapy.
Treatment with ultrasound or ultrashort wave, and short-wave ultraviolet irradiation methods can also be used [8].
Closed treatment
Closure therapy can be performed in cases where the pain is severe and cannot be relieved by lowering the temperature of the affected limb or oral medication.
The main methods are: supra-ankle ring closure, sacral epidural closure, lumbar sympathetic ganglion block [9].
Surgical treatment
Surgical treatment can be chosen in individual cases where various treatments are ineffective and pain is obvious.
Commonly used surgical procedures: lumbar sympathetic ganglion disruption or severance, and spinal cord electrical stimulation may also be considered in patients with intractable pain.
Prognosis
Cure
Primary erythema gangrenosum is not cured by specific medications, but it is not a life-threatening condition and can be treated to minimize the number of attacks and reduce symptoms.
The cure of secondary erythema gangrenosum is related to the type of primary disease.
Prognostic factors
Patients with the following characteristics have a relatively good prognosis.
Timely receipt of regular treatment.
No complications such as distal limb infection, necrosis, or gangrene.
No psychoemotional abnormalities such as anxiety or depression.
Harmfulness
Patients may have skin and mucous membrane ulceration, infection, and even the formation of necrosis, gangrene and even amputation.
Recurrent attacks of erythematous limb pain affect patients’ night sleep and normal working life, which can seriously affect the quality of life and aggravate the burden of family and society.
Some patients suffer from depression, anxiety and other psychological problems, and in serious cases, there is a risk of self-harm and suicide.
Daily
Daily Management
Dietary management
Balanced nutrition, with high-quality protein, low-fat, low-salt, low oil, high-fiber diet, such as eggs, fish and poultry, fresh fruits and vegetables.
Abstain from smoking, alcohol, and avoid drinking large amount of coffee and strong tea.
Avoid eating spicy food, such as chili peppers, onions, curry, etc.
Patients with secondary erythematous limb pain, adjust their diet according to their various primary diseases, such as diabetic patients pay attention to low sugar diet, gout patients pay attention to low purine diet.
Life management
Avoid prolonged prolapse of the limbs.
Avoid working and living in high ambient temperatures [10].
Avoid prolonged standing, especially in higher ambient temperatures.
Exercise management
Suitable forms of exercise such as walking, tai chi, etc. can be chosen on the advice of a doctor.
Exercise appropriately, avoid strenuous exercise, and avoid exercise in higher ambient temperatures.
Psychological support
Maintain an optimistic and positive mindset and avoid large mood swings.
When the patient has low mood, depression, anxiety, the family should cooperate with the doctor to guide the patient to correctly understand the disease, correctly understand the purpose of the treatment of this disease.
If the state of depression and anxiety is serious, seek help from medical personnel in time to avoid self-inflicted limb injuries due to psychological problems.
Disease monitoring
Monitor the triggers of erythema migrans and avoid them as much as possible.
Monitor the skin changes of the affected limb to avoid ulceration, infection, etc. If there are changes such as skin blisters and purplish color, it should be taken seriously.
In patients with secondary erythema erythematosum, monitor changes in the corresponding primary disease.
Follow-up
Follow up and review regularly as prescribed by the doctor. If there is any change in the condition, it is necessary to go to the hospital at any time.
Prevention
Primary erythema gangrenosum is a hereditary disease and is difficult to prevent. Secondary erythema gangrenosum is a hereditary disease and is difficult to prevent effectively. Prevention of secondary erythema gangrenosum focuses on active treatment of the primary disease.
The following measures have the potential to reduce the risk of onset and flare-ups.
Regular screening tests are recommended for people with a family history of the disease.
Avoid prolonged standing and strenuous exercise.
Avoid working and living in higher ambient temperatures.
Avoid contact with higher-temperature water or other substances when washing your face, feet, bathing, and in other work-life situations.
Quit smoking and drinking. Non-smokers should stay away from smoking environments and smokers should quit smoking.
Avoid eating too much spicy food.
Maintain an optimistic mindset, live a regular life, and ensure sleep.