erythromelalgia erythromelalgia erythromelalgia or mitchell's disease (after silas weir mitchell) is a rare vascular 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. erythromelalgiaerythromelalgia in left handspecialtycardiology 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 link to the scn9a gene was initially published in the journal of medical genetics. later that year, in an article in the journal of neuroscience, cummins et al., demonstrated, using voltage clamp recordings, that these mutations enhanced the function of nav1.7 sodium channels, which are preferentially expressed within peripheral neurons. one year later, in an article in brain, dib-hajj et al., demonstrated that nav1.7 mutants channels, from families with inherited erythromelalgia (iem), make dorsal root ganglion (drg, peripheral and sensory), neurons hyper excitable, thereby demonstrating the mechanistic link between these mutations and pain, thereby firmly establishing nav1.7 gain-of-function mutations as the molecular basis for iem. 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. by 2013, nearly a dozen gain-of-function mutations of nav1.7 had been linked to iem. the multi-decades search which identified gene scn9a as the cause of inherited erythomelalgia is documented in a book by stephen waxman, chasing men on fire: the story of the search for a pain gene. 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. 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. the disease is characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients may have fever, palpitations, headache, and joint pain. in the 1987 epidemic in hubei, 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. billing codes systems and other systems erythromelalgia can be found in several billing codes systems and other systems. erythromelalgia is generally classified as a disease of the circulatory system, falling under the class of other peripheral vascular disease, as the following two billing code systems will show: icd-9-cm according to the icd-9-cm database (international classification of diseases, ninth revision, clinical modification), erythromelalgia is listed under diseases of the circulatory system and is identified by number 443.82. icd-10-cm according to the icd-10-cm database (international classification of diseases, tenth revision, clinical modification), erythromelalgia is listed under diseases of the circulatory system and is identified by i73.81. mesh according to the mesh database (medical subject headings), erythromelalgia is classified under the unique id number of d004916. omim according to the omim database (ncbi - online mendelian inheritance in man), primary erythromelalgia is listed under the number: 133020. symptoms and signs erythromelalgia in hands of a scandinavian male, 52, after holding a book). 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. attacks most frequently occur at night, thus having the potential to greatly interfere with sleep. common triggers for daytime 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. the coexistence of erythromelalgia and raynaud's phenomenon is rare, but case studies of patients with both diagnoses have been reported in medical journals. 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. epidemic erythromelalgia is characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients may have fever, palpitations, headache, and joint pain. in the 1987 epidemic in hubei, 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. cause toes during an em flareup 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 affected 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 from two different seasons. side effect of medication several medications, including verapamil and nifedipine, as well as ergot derivatives such as bromocriptine and pergolide, have been associated with medication-induced erythromelalgia. mushroom poisoning 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 school students in rural areas of china. a large epidemic erythromelalgia was occurred in hubei province of china in 1987 and the disease was characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients had fever, palpitations, headache, and joint pain. 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. subsequently, a virus - erythromelalgia-related poxvirus (erpv) - was repeatedly isolated from throat swabs of six separate patients from two different counties and wuhan city in hubei province. the genome of this virus has been sequenced and it appears that this virus is related to a strain of mousepox. serological characterization can easily distinguish human erpv from ectromelia virus and vaccinia virus by cross-neutralization and plaque reduction assays since this virus has not yet been isolated from other outbreaks in other parts of southern china to date this putative association needs to be further investigated. the finding of the specific antibody conversion to atis of erpv in patients' paired sera strengthens the evidence for a possible aetiological role of human erpv in epidemic erythromelalgia. pathophysiology 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 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. table 1. summary of mutations nav1.7 associated with primary erythromelalgia mutation region shift of activation v½ shift of inactivation (fast and/or slow) v½ other effects