Erythromelalgia in a 77-year-old woman with longstanding polycythemia vera
|Classification and external resources|
Erythromelalgia, formerly 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 may 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, polycythemia vera, 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; when its pathophysiology was initially published in the Journal of Medical Genetics. Conversely, in December 2006 a University of Cambridge team reported an SCN9A mutation that resulted in a complete lack of pain sensation in a Pakistani street performer and some of his family members. He felt no pain, walked on hot coals and stabbed himself to entertain crowds.
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. The juvenile onset form 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.
In rural areas of southern China, outbreaks of erythromelalgia have occurred during winter and spring at 3-5 year intervals among secondary school students. This epidemic form of erythromelalgia has been viewed as a different form of non-inherited primary erythromelalgia and affects mainly teenage girls in middle schools.
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 erythema, 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 phenomenon often coexists in patients with Erythromelalgia. Symptoms may present gradually and incrementally, sometimes taking years to become intense enough for patients to seek medical care. In other cases symptoms emerge full blown with onset.
In general, erythromelalgia seems to consist of neuropathological 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, nociceptors (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 nociceptors is due to different expression of sodium channels other than NaV1.7 in them.
What causes epidemic erythromelalgia in southern China remains unknown although several erythromelalgia-associated poxviruses were isolated from throat swabs of several patients at different counties and two different seasons.
Side effect of medication
The consumption of two species of related fungi, Clitocybe acromelalga from Japan, and Clitocybe amoenolens from France, has led to several cases of mushroom-induced erythromelalgia which lasted from 8 days to 5 months.
Possible infectious cause
An epidemic form of this syndrome occurs in secondary students in rural China. In 1987 a virus - erythromelalgia-associated poxvirus - was reported to have been recovered from throat swabs from such an outbreak. The genome of this virus has been sequenced and it appears that this virus is a strain of ectromelia virus.
Since this virus has not yet been isolated from other outbreaks in other parts of southern China to date this putative association should be treated with circumspection.
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. This channel is expressed primarily in nociceptors of the dorsal root ganglion and the sympathetic ganglion neurons. Nine 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 neurons. 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 initiation[clarification needed] 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, axons and termini express NaV1.7 and are present in the skin.
|Mutation||Region||Shift of activation V½||Shift of inactivation (fast and/or slow) V½||Other effects||References|
|F216S||D1S4||Hyperpolarized||Hyperpolarized||Faster entry into fast-inactivation|||
|N395K||D1S6||Hyperpolarized||Depolarized||Creation of a large window current, decreased lidocaine sensitivity|||
|I848T||D2S4-5||Hyperpolarized||Slowed deactivation and inactivation|||
|L858F||D2S4-5||Hyperpolarized||Depolarized||Slowed deactivation, faster recovery from inactivation, cooling depolarizes activation and hyperpolarizes inactivation V½|||
|L858H||D2S4-5||Hyperpolarized||Slowed deactivation, enhanced slow inactivation,|||
|A863P||D2S5||Hyperpolarized||Depolarized||Creation of a window current, slowed deactivation|||
|Region nomenclature: DA-B, linker between domains A and B; DASB, transmembrane segment B in domain A; and DASB-C, the linker between transmembrane segments B and C in domain A.|
Erythromelalgia is a difficult condition to diagnose as there are no specific tests available. However, reduced capillary density has been observed microscopically during flaring; and reduced capillary perfusion is noted in the patient. Another test that can be done is to have the patient elevate their legs, and note the reversal(from red to pale) in skin color. Tests done at universities include quantitative sensory nerve testing, laser evoked potentials, sweat testing and epidermal sensory nerve fiber density test(which is an objective test for small fiber sensory neuropathy) 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 (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.
For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment, though aspirin has been thought to reduce symptoms of erythromelalgia it is rare to find evidence that this is effective. Mechanical cooling of the limbs by elevating them can help 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). Patients are strongly advised 'NOT to place the affected limbs in cold water to relieve symptoms when flaring occurs. It may seem a good idea but it precipitates problems further down the line causing damage to the skin and ulceration often intractable due to the damaged skin. A possible reduction in skin damage may be accomplished by enclosing the flaring limb in a commonly available, thin, heat transparent, water impermeable, plastic food storage bag. The advice of a physician is advised depending on specific circumstances.
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 that are inexplicable. Whilst a cool environment is helpful in keeping the symptoms in control, the use of cold water baths is strongly discouraged.In pursuit of added relief sufferers can inadvertently cause tissue damage or death, i.e., necrosis. See comments at the end of the preceding paragraph regarding possible effectiveness of plastic food storage bags to avoid/reduce negative effects of submersion in cold water baths.
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. but no further testing was carried out as newer research superseded this combination
Strong anecdotal evidence from EM patients shows that a combination of drugs such as duloxetine and pregabalin is an effective way of reducing the stabbing pains and burning sensation symptoms of erythromelalgia in conjunction with the appropriate analgesia. In some cases, antihistamines may give some relief. Most people with erythromelalgia never go into remission and the symptoms are ever present at some level, whilst others get worse, or the EM is eventually a symptom of another disease such as systemic schleroderma.
Some suffering with EM are prescribed ketamine topical creams as a way of managing pain on a long term basis. Feedback from some EM patients has led to reduction in usage as they believe it is only effective for short periods.
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; much 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.
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Mild sufferers may find sufficient pain relief with tramadol or amitriptyline. Sufferers of more severe and widespread EM symptoms, however, may obtain relief only from opioid drugs. Opana ER, which is a combined opiod of Oxycodone and Hydromorphone(Dilaudid) has been found to be effective for many in the USA, whilst in the UK slow-release morphine has proved to be effective. These powerful and potentially-addictive drugs may be prescribed to patients only after they have tried almost every other type of analgesia to no avail. (This delay in appropriate pain management can be a result of insurer-mandated or legally-required step therapy, or merely overly-cautious prescribing on the part of sufferers' doctors.)
The combination of Cymbalta (duloxetine) and Lyrica (pregabalin) has also proven to be useful in controlling pain, but many EM patients have found this combination has side effects that they are unable to tolerate.
Erythromelalgia remains a rare condition that most doctors are completely unaware of; consequently, it may take years before EM patients receive proper pain control. As with many other rare conditions, management of EM is frequently patient-led, as they are in many cases more knowledgeable about their condition and what tests and treatments are appropriate.
The first reported case was in 1878 by Silas Weir Mitchell who suggested the term 'erythromelalgia.' It is derived from the Greek words erythros ("red"), melos ("limb") and algos ("pain").
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- Erythromelalgia at eMedicine