Erythromelalgia
Encyclopedia
Erythromelalgia, also known as Mitchell's disease (after Silas Weir Mitchell
), acromelalgia, red neuralgia, or erythermalgia, is a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities (or hands), are episodically blocked (frequently on and off daily), then become hyperemic and inflamed. There is severe burning pain (in the small fiber sensory nerves) and skin redness. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. Erythromelalgia can occur either as a primary or secondary disorder (i.e. a disorder in and of itself or a symptom of another condition). Secondary erythromelalgia can result from small fiber peripheral neuropathy
of any cause, essential thrombocytosis
, hypercholesterolemia
, mushroom
or mercury poisoning
, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene SCN9A
.
In 2004 Erythromelalgia became the first human disorder in which it has been possible to associate an ion channel mutation with chronic neuropathic pain; this became possible when a Yale neurologist spotted a Beijing geneticists team paper in the Journal of Medical Genetics titled "Mutations in SCN9A, Encoding a Sodium Channel Alpha Subunit, in Patients With Primary Erythromelalgia"; a connection was made that this sodium channel mutation was expressed primarily in peripheral pain sensing neurons. Conversely, in December 2006 a University of Cambridge team reported an SCN9A mutation that created a complete "lack of" pain sensation in the family of a Pakistan street performer. He felt no pain, walked on hot coals and stabbed himself to entertain crowds.
, swelling
, a painful deep-aching of the soft tissue (usually either radiating or shooting) and tenderness, along with a painful burning sensation primarily in the extremities. These symptoms are often symmetric and affect the lower extremities more frequently than the upper extremities. Symptoms may also affect the ears and face. For secondary erythromelalgia, attacks typically precede and are precipitated by the underlying primary condition. For primary erythromelalgia, attacks can last from an hour to months at a time and occur infrequently to frequently with multiple times daily. Common triggers for these episodes are exertion, heating of the affected extremities, and alcohol or caffeine consumption, and any pressure applied to the limbs. In some patients sugar and even melon
consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat this generates is known to produce erythromelalgia attacks. Raynaud's often coexists in patients with Erythromelalgia
and microvascular
alterations. How this occurs in secondary erythromelalgia is poorly understood and may be specific to the underlying primary condition. Primary conditions that have been shown to elicit erythromelalgia are listed in diagnosis, below.
Primary erythromelalgia is a better understood autosomal dominant disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of C-fibers
in the dorsal root ganglion
. Specifically, nociceptor
s (neurons responsible for the sensation and conduction of painful stimuli) appear to be the primarily affect neurons in these fibers. This hyperexcitability results in the severe burning pain experienced by patients. While the neuropathological symptoms are a result of hyperexcitability, microvascular alterations in erythromelalgia are due to hypoexcitability. The sympathetic nervous system
controls cutaneous vascular
tone
and altered response of this system to stimuli such as heat likely results in the observed microvascular symptoms. In both cases, these changes in excitability are typically due to mutation of the sodium channel NaV1.7
. These differences in excitability alterations between the sympathetic nervous system
and nociceptor
s is due to different expression of sodium channels other than NaV1.7 in them.
and pergolide, verapamil
, and nifedipine
have been associated with medication-induced erythromelalgia.
from Japan, and Clitocybe amoenolens
from France, has led to several cases of mushroom-induced erythromelalgia which lasted from 8 days to 5 months.
There are 10 known mutations in the voltage-gated sodium channel α-subunit NaV1.7 encoding gene, SCN9A
. This channel is expressed primarily in nociceptor
s of the dorsal root ganglion
and the sympathetic
ganglion neurons. 9 of these mutations have received further study and they have all shown to result in similar biophysical alterations, Table 1. As can be seen from table 1, the primary effect of erythromelalgia mutations is NaV1.7 channels that activate at more hyperpolarized potentials. NaV1.7 channels act largely as threshold sensors and initiate action potentials. Consequently, this shift in their activation profile results in channels that open closer to the resting membrane potential. In many mutations, this shift of activation is accompanied by shifts in the voltage sensitivity of fast and/or slow inactivation, often in the depolarized direction. This results in channels that are open for a longer of period of time, producing larger and more prolonged changes in membrane potential
.
Some of these mutant channels have been expressed in dorsal root ganglion
(DRG) or sympathetic
neuron
s. In DRG neurons expressing the F1449V mutation, a lower threshold is required for action potential
creation (93.1 ± 12.0 pA
) than those expressing wild-type channels (124.1 ± 7.4 pA). Furthermore, while DRG neurons expressing wild-type channels only respond with a few action potentials, those expressing F1449V channels respond with a high-frequency train of action potentials. There is a similar effect in DRG neurons expressing the L858H and A863P mutants. Here, there is also a notable change in resting membrane potential, being depolarized by 4-7 mV
versus wild-type channel expressing cells. The situation is different, however, in sympathetic neurons expressing the L858H mutation. While L858H expressing sympathetic ganglion are depolarized ~5mV relative to wild-type expressing neurons, their threshold for action potential initian is notably higher. Furthermore, while current injection of 40pA for 950ms provokes an average of 6 action potentials in sympathetic neurons expressing wild-type channels this stimulation evokes only approximately 2 action potentials with reduced overshoots in sympathetic neurons expressing L858H mutant channels. Further investigation has demonstrated that the differences in response between DRG and sympathetic neurons is due to expression of NaV1.8 in the former. Consequently, expression of NaV1.8 channels in sympathetic neurons also expressing L858H mutant NaV1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.
An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels is unaffected by cooling. L858F mutant channels, however, are activated at more depolarized potentials when cooled than at normal body temperature. At 16°C the activation V½ of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35°C. Fast inactivation is affected in a similar manner in both wild-type and L858F mutant channel and is, thus, unlikely to contribute to symptom resolution due to cooling. While such cooling is unlikely to affect neuronal cell bodies, axon
s and termini express NaV1.7 and are present in the skin.
Once it has been established that it is not secondary erythromelalgia — see below — then a programme of management can be put in place.
Some diseases present with symptoms similar to erythromelalgia. Complex regional pain syndrome
(CRPS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely or primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CRPS.
Erythromelalgia is sometimes caused by other disorders. A partial list of diseases known to precipitate erythromelalgia is below.
may reduce symptoms of erythromelalgia. Mechanical cooling of the limbs by elevating them, placing in cool water, or managing the ambient environment frequently is often necessary constantly as flares occur due to sympathetic autonomic dysfunction of the capillaries. The pain that accompanies it is severe and treated separately (the pain is similar to CRPS, phantom limb or thalamic pain syndrome).
Primary erythromelalgia management is symptomatic, i.e. treating painful symptoms only. Specific management tactics include avoidance of attack triggers such as: heat, change in temperature, exercise or over exertion, alcohol and spicy foods. This list is by no means comprehensive as there are many triggers to set off a 'flaring' episode. Whist a cool environment is helpful in keeping the symptoms in control, the use of cold water baths is discouraged as such since erythromelalgia sufferers pain is extreme. In pursuit of added relief sufferers can inadvertently cause tissue damage or death, i.e., necrosis. One clinical study has demonstrated the efficacy of IV
lidocaine
or oral mexilitine, though it should be noted that differences between the primary and secondary forms was not studied. Another trial has shown promise for misoprostol
, while other have shown that gabapentin
, venlafaxine
, and oral magnesium
may also be effective.
Anecdotal evidence shows that a combination of drugs such as duloxetine
and pregabalin
is an effective way of reducing the symptoms of erythromelalgia in conjunction with analgesia. Most people with erythromelalgia do not go into remission and the symptoms are ever present at some level.
Again, anecdotally, many of those suffering with EM are prescribed ketamine
topical creams as a way of managing pain on a long term basis.
Living with erythromelalgia can result in a deterioration in quality of life resulting in the inability to function in a work place, lack of mobility, depression and is socially alienating; greater education of medical practitioners is needed. As with many rare diseases, many people with EM end up taking years to get a diagnosis and to receive appropriate treatment.
Research into the genetic mutations continues but there is a paucity of clinical studies focusing on living with erythromelalgia. There is much urgency within pharmaceutical companies to provide a solution to those who suffer with pain such as that with erythromelalgia.
Silas Weir Mitchell
Silas Weir Mitchell was an American physician and writer.He was son of a physician, John Kearsley Mitchell , and was born in Philadelphia, Pennsylvania....
), acromelalgia, red neuralgia, or erythermalgia, is a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities (or hands), are episodically blocked (frequently on and off daily), then become hyperemic and inflamed. There is severe burning pain (in the small fiber sensory nerves) and skin redness. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. Erythromelalgia can occur either as a primary or secondary disorder (i.e. a disorder in and of itself or a symptom of another condition). Secondary erythromelalgia can result from small fiber peripheral neuropathy
Small fiber peripheral neuropathy
Small fiber peripheral neuropathy is a type of neuropathy that occurs from damage to the small unmyelinated peripheral nerve fibers. These fibers, categorized as C fibers, are present in skin, peripheral nerves and organs. The role of these nerves is to innervate the skin and help control...
of any cause, essential thrombocytosis
Essential thrombocytosis
Essential thrombocythemia is a rare chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause. In some cases this disorder may be progressive, and rarely may evolve into acute myeloid leukemia or myelofibrosis...
, hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
, mushroom
Mushroom poisoning
Mushroom poisoning refers to harmful effects from ingestion of toxic substances present in a mushroom. These symptoms can vary from slight gastrointestinal discomfort to death. The toxins present are secondary metabolites produced in specific biochemical pathways in the fungal cells...
or mercury poisoning
Mercury poisoning
Mercury poisoning is a disease caused by exposure to mercury or its compounds. Mercury is a heavy metal occurring in several forms, all of which can produce toxic effects in high enough doses...
, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene SCN9A
Nav1.7
Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons, the nociceptive neurons at dorsal root ganglion and trigeminal ganglion, and sympathetic ganglion neurons, which are part of the autonomic nervous system.-...
.
In 2004 Erythromelalgia became the first human disorder in which it has been possible to associate an ion channel mutation with chronic neuropathic pain; this became possible when a Yale neurologist spotted a Beijing geneticists team paper in the Journal of Medical Genetics titled "Mutations in SCN9A, Encoding a Sodium Channel Alpha Subunit, in Patients With Primary Erythromelalgia"; a connection was made that this sodium channel mutation was expressed primarily in peripheral pain sensing neurons. Conversely, in December 2006 a University of Cambridge team reported an SCN9A mutation that created a complete "lack of" pain sensation in the family of a Pakistan street performer. He felt no pain, walked on hot coals and stabbed himself to entertain crowds.
Classification
Primary erythromelalgia may be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Both of these may be further classified as either juvenile or adult onset. Juvenile onset occurs prior to age 20 and frequently prior to age 10. While the genetic cause of the juvenile and sporadic adult onset forms is often known, this is not the case for the adult onset familial form.Incidence
Recent research in the U.S. found the incidence of EM (the number of people a year diagnosed with EM) to be 1.3 per 100,000. The rate for women was higher — 2.0 per 100,000 per year — than men, which was just 0.6. The median age at diagnosis was 61. These rates were five times higher than those estimated by an earlier Norwegian study — the only other known research describing EM incidence. Approximately five percent of those with EM have the autosomal dominant (Primary-Inherited) form of the disease.Symptoms and signs
The most prominent symptoms of erythromelalgia are episodes of erythemaErythema
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...
, swelling
Swelling (medical)
In medical parlance, swelling is the transient enlargement or protuberance in the body and may include tumors. According to cause, it may be congenital, traumatic, inflammatory, neoplastic or miscellaneous....
, a painful deep-aching of the soft tissue (usually either radiating or shooting) and tenderness, along with a painful burning sensation primarily in the extremities. These symptoms are often symmetric and affect the lower extremities more frequently than the upper extremities. Symptoms may also affect the ears and face. For secondary erythromelalgia, attacks typically precede and are precipitated by the underlying primary condition. For primary erythromelalgia, attacks can last from an hour to months at a time and occur infrequently to frequently with multiple times daily. Common triggers for these episodes are exertion, heating of the affected extremities, and alcohol or caffeine consumption, and any pressure applied to the limbs. In some patients sugar and even melon
Melon
thumb|200px|Various types of melonsThis list of melons includes members of the plant family Cucurbitaceae with edible, fleshy fruit e.g. gourds or cucurbits. The word "melon" can refer to either the plant or specifically to the fruit...
consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat this generates is known to produce erythromelalgia attacks. Raynaud's often coexists in patients with Erythromelalgia
Cause
In general, erythromelalgia seems to consist of neuropathologicalNeuropathology
Neuropathology is the study of disease of nervous system tissue, usually in the form of either small surgical biopsies or whole autopsy brains. Neuropathology is a subspecialty of anatomic pathology, neurology, and neurosurgery...
and microvascular
Capillary
Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...
alterations. How this occurs in secondary erythromelalgia is poorly understood and may be specific to the underlying primary condition. Primary conditions that have been shown to elicit erythromelalgia are listed in diagnosis, below.
Primary erythromelalgia is a better understood autosomal dominant disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of C-fibers
Group C nerve fiber
-Location:C fibers are found in the peripheral nerves of the somatic sensory system. They are afferent fibers, conveying input signals from the periphery to the central nervous system.-Structure:...
in the dorsal root ganglion
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
. Specifically, nociceptor
Nociceptor
A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.-History:...
s (neurons responsible for the sensation and conduction of painful stimuli) appear to be the primarily affect neurons in these fibers. This hyperexcitability results in the severe burning pain experienced by patients. While the neuropathological symptoms are a result of hyperexcitability, microvascular alterations in erythromelalgia are due to hypoexcitability. The sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
controls cutaneous vascular
Vascular smooth muscle
Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood vessels.Vascular smooth muscle contracts or relaxes to both change the volume of blood vessels and the local blood pressure, a mechanism that is responsible for the...
tone
Muscle tone
In physiology, medicine, and anatomy, muscle tone is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting state. It helps maintain posture, and it declines during REM sleep.-Purpose:Unconscious nerve impulses maintain the...
and altered response of this system to stimuli such as heat likely results in the observed microvascular symptoms. In both cases, these changes in excitability are typically due to mutation of the sodium channel NaV1.7
Nav1.7
Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons, the nociceptive neurons at dorsal root ganglion and trigeminal ganglion, and sympathetic ganglion neurons, which are part of the autonomic nervous system.-...
. These differences in excitability alterations between the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
and nociceptor
Nociceptor
A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.-History:...
s is due to different expression of sodium channels other than NaV1.7 in them.
Side effect of medication
Several medications including ergot derivatives like bromocriptineBromocriptine
Bromocriptine , an ergoline derivative, is a dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease , hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.- Indications :Amenorrhea, female infertility, galactorrhea, hypogonadism, and acromegaly...
and pergolide, verapamil
Verapamil
Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
, and nifedipine
Nifedipine
Nifedipine is a dihydropyridine calcium channel blocker...
have been associated with medication-induced erythromelalgia.
Mushroom poisoning
The consumption of two species of related fungi, Clitocybe acromelalgaClitocybe acromelalga
Clitocybe acromelalga is a basidiomycete fungus of the large genus Clitocybe found in Japan. It was discovered to be poisonous in 1918, when symptoms of occurred within 3 days of consumption. It had been mistaken for the edible blewit Lepista inversa.Consumption of a related species, C. amoenolens...
from Japan, and Clitocybe amoenolens
Clitocybe amoenolens
Clitocybe amoenolens, commonly known as the paralysis funnel, is an agaric fungus of the large genus Clitocybe. It was originally described from Morocco in 1975 by the French mycologist Malençon. It was discovered to be poisonous after several people had consumed specimens all found in the alpine...
from France, has led to several cases of mushroom-induced erythromelalgia which lasted from 8 days to 5 months.
Pathophysiology
N.B. This section pertains solely to primary erythromelalgia as the secondary form is too poorly understood.There are 10 known mutations in the voltage-gated sodium channel α-subunit NaV1.7 encoding gene, SCN9A
Nav1.7
Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons, the nociceptive neurons at dorsal root ganglion and trigeminal ganglion, and sympathetic ganglion neurons, which are part of the autonomic nervous system.-...
. This channel is expressed primarily in nociceptor
Nociceptor
A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.-History:...
s of the dorsal root ganglion
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
and the sympathetic
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
ganglion neurons. 9 of these mutations have received further study and they have all shown to result in similar biophysical alterations, Table 1. As can be seen from table 1, the primary effect of erythromelalgia mutations is NaV1.7 channels that activate at more hyperpolarized potentials. NaV1.7 channels act largely as threshold sensors and initiate action potentials. Consequently, this shift in their activation profile results in channels that open closer to the resting membrane potential. In many mutations, this shift of activation is accompanied by shifts in the voltage sensitivity of fast and/or slow inactivation, often in the depolarized direction. This results in channels that are open for a longer of period of time, producing larger and more prolonged changes in membrane potential
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
.
Some of these mutant channels have been expressed in dorsal root ganglion
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
(DRG) or sympathetic
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. In DRG neurons expressing the F1449V mutation, a lower threshold is required for action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
creation (93.1 ± 12.0 pA
Ampere
The ampere , often shortened to amp, is the SI unit of electric current and is one of the seven SI base units. It is named after André-Marie Ampère , French mathematician and physicist, considered the father of electrodynamics...
) than those expressing wild-type channels (124.1 ± 7.4 pA). Furthermore, while DRG neurons expressing wild-type channels only respond with a few action potentials, those expressing F1449V channels respond with a high-frequency train of action potentials. There is a similar effect in DRG neurons expressing the L858H and A863P mutants. Here, there is also a notable change in resting membrane potential, being depolarized by 4-7 mV
Volt
The volt is the SI derived unit for electric potential, electric potential difference, and electromotive force. The volt is named in honor of the Italian physicist Alessandro Volta , who invented the voltaic pile, possibly the first chemical battery.- Definition :A single volt is defined as the...
versus wild-type channel expressing cells. The situation is different, however, in sympathetic neurons expressing the L858H mutation. While L858H expressing sympathetic ganglion are depolarized ~5mV relative to wild-type expressing neurons, their threshold for action potential initian is notably higher. Furthermore, while current injection of 40pA for 950ms provokes an average of 6 action potentials in sympathetic neurons expressing wild-type channels this stimulation evokes only approximately 2 action potentials with reduced overshoots in sympathetic neurons expressing L858H mutant channels. Further investigation has demonstrated that the differences in response between DRG and sympathetic neurons is due to expression of NaV1.8 in the former. Consequently, expression of NaV1.8 channels in sympathetic neurons also expressing L858H mutant NaV1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.
An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels is unaffected by cooling. L858F mutant channels, however, are activated at more depolarized potentials when cooled than at normal body temperature. At 16°C the activation V½ of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35°C. Fast inactivation is affected in a similar manner in both wild-type and L858F mutant channel and is, thus, unlikely to contribute to symptom resolution due to cooling. While such cooling is unlikely to affect neuronal cell bodies, axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s and termini express NaV1.7 and are present in the skin.
Diagnosis
Erythromelalgia is a difficult condition to diagnose as there are no specific tests available. To get a diagnosis can take many months and the patient will often have seen 6 or 7 specialists before finding out what is wrong with them.Once it has been established that it is not secondary erythromelalgia — see below — then a programme of management can be put in place.
Some diseases present with symptoms similar to erythromelalgia. Complex regional pain syndrome
Complex regional pain syndrome
Complex regional pain syndrome is a chronic progressive disease characterized by severe pain, swelling and changes in the skin. It often affects an arm or a leg and may spread to another part of the body.Though treatment is often unsatisfactory, early multimodal therapy can cause dramatic...
(CRPS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely or primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CRPS.
Erythromelalgia is sometimes caused by other disorders. A partial list of diseases known to precipitate erythromelalgia is below.
- Myeloproliferative diseaseMyeloproliferative diseaseThe myeloproliferative diseases are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than...
- HypercholesterolemiaHypercholesterolemiaHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
- Autoimmune disorder
- Small fiber peripheral neuropathySmall fiber peripheral neuropathySmall fiber peripheral neuropathy is a type of neuropathy that occurs from damage to the small unmyelinated peripheral nerve fibers. These fibers, categorized as C fibers, are present in skin, peripheral nerves and organs. The role of these nerves is to innervate the skin and help control...
- Fabry's diseaseFabry's diseaseFabry disease is a rare X-linked recessive lysosomal storage disease, which can cause a wide range of systemic symptoms...
- Mercury poisoningMercury poisoningMercury poisoning is a disease caused by exposure to mercury or its compounds. Mercury is a heavy metal occurring in several forms, all of which can produce toxic effects in high enough doses...
- Mushroom poisoningMushroom poisoningMushroom poisoning refers to harmful effects from ingestion of toxic substances present in a mushroom. These symptoms can vary from slight gastrointestinal discomfort to death. The toxins present are secondary metabolites produced in specific biochemical pathways in the fungal cells...
- SciaticaSciaticaSciatica is a set of symptoms including pain that may be caused by general compression or irritation of one of five spinal nerve roots that give rise to each sciatic nerve, or by compression or irritation of the left or right or both sciatic nerves. The pain is felt in the lower back, buttock, or...
- Some medications, such as bromocriptineBromocriptineBromocriptine , an ergoline derivative, is a dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease , hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.- Indications :Amenorrhea, female infertility, galactorrhea, hypogonadism, and acromegaly...
, pergolidePergolidePergolide is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease....
, verapamilVerapamilVerapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
and ticlopidineTiclopidineTiclopidine is an antiplatelet drug in the thienopyridine family. Like clopidogrel, it is an adenosine diphosphate receptor inhibitor. It is used in patients in whom aspirin is not tolerated, or in whom dual antiplatelet therapy is desirable...
Treatment/Management
For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment, though aspirinAspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
may reduce symptoms of erythromelalgia. Mechanical cooling of the limbs by elevating them, placing in cool water, or managing the ambient environment frequently is often necessary constantly as flares occur due to sympathetic autonomic dysfunction of the capillaries. The pain that accompanies it is severe and treated separately (the pain is similar to CRPS, phantom limb or thalamic pain syndrome).
Primary erythromelalgia management is symptomatic, i.e. treating painful symptoms only. Specific management tactics include avoidance of attack triggers such as: heat, change in temperature, exercise or over exertion, alcohol and spicy foods. This list is by no means comprehensive as there are many triggers to set off a 'flaring' episode. Whist a cool environment is helpful in keeping the symptoms in control, the use of cold water baths is discouraged as such since erythromelalgia sufferers pain is extreme. In pursuit of added relief sufferers can inadvertently cause tissue damage or death, i.e., necrosis. One clinical study has demonstrated the efficacy of IV
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
lidocaine
Lidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
or oral mexilitine, though it should be noted that differences between the primary and secondary forms was not studied. Another trial has shown promise for misoprostol
Misoprostol
Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...
, while other have shown that gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
, venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
, and oral magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
may also be effective.
Anecdotal evidence shows that a combination of drugs such as duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
and pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
is an effective way of reducing the symptoms of erythromelalgia in conjunction with analgesia. Most people with erythromelalgia do not go into remission and the symptoms are ever present at some level.
Again, anecdotally, many of those suffering with EM are prescribed ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
topical creams as a way of managing pain on a long term basis.
Living with erythromelalgia can result in a deterioration in quality of life resulting in the inability to function in a work place, lack of mobility, depression and is socially alienating; greater education of medical practitioners is needed. As with many rare diseases, many people with EM end up taking years to get a diagnosis and to receive appropriate treatment.
Research into the genetic mutations continues but there is a paucity of clinical studies focusing on living with erythromelalgia. There is much urgency within pharmaceutical companies to provide a solution to those who suffer with pain such as that with erythromelalgia.