Erythromelalgia 853501 220842273 2008-06-21T21:43:35Z DOI bot 6652755 Citation maintenance. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{DiseaseDisorder infobox | Name = Erythromelalgia | Image = | Caption = | DiseasesDB = 4476 | ICD10 = {{ICD10|I|73|8|i|70}} | ICD9 = {{ICD9|443.82}} | ICDO = | OMIM = 133020 | MedlinePlus = | eMedicineSubj = med | eMedicineTopic = 730 | MeshID = D004916 | }} '''Erythromelalgia''', also known as Mitchell's disease (after [[Silas Weir Mitchell]]), red neuralgia, or erythermalgia, is a rare disorder in which blood vessels, usually in the lower extremities, are episodically blocked and inflamed. There is severe burning pain and skin redness associated with this blood vessel blockage. The attacks are periodic and are commonly triggered by heat, alcohol consumption, or exertion. 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, [[hypercholesterolemia]], [[mushroom poisoning|mushroom]] or [[mercury poisoning]], and some [[autoimmune disorder]]s. Primary erythromelalgia is caused by mutation of the voltage-gated [[sodium channel]] α-subunit gene ''[[Nav1.7|SCN9A]]''. ==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.<ref name="Novella_2007">{{cite journal |author=Novella SP, Hisama FM, Dib-Hajj SD, Waxman SG |title=A case of inherited erythromelalgia |journal=Nature clinical practice. Neurology |volume=3 |issue=4 |pages=229–34 |year=2007 |pmid=17410110 |doi=10.1038/ncpneuro0425}}</ref> ==Symptoms and signs== The most prominent symptoms of erythromelalgia are episodes of [[erythema]], [[swelling (medical)|swelling]], and a painful burning sensation primarily in the extremities. These symptoms are usually 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 minutes to hours and occur infrequently to multiple times daily. Common triggers for these episodes are exertion, heating of the affected extremities, and [[ethanol|alcohol]] or [[caffeine]] consumption. 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.<ref name="Novella_2007"/> ==Cause== In general, erythromelalgia seems to consist of [[neuropathology|neuropathological]] and [[capillary|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 [[erythromelalgia#Diagnosis|diagnosis]], below.<ref name="Novella_2007"/> Primary erythromelalgia is a better understood [[autosomal dominant]] disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of [[group C nerve fiber|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 smooth muscle|vascular]] [[muscle tone|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|Na<sub>V</sub>1.7]]. These differences in excitability alterations between the [[sympathetic nervous system]] and [[nociceptor]]s is due to different expression of [[sodium channel]]s other than Na<sub>V</sub>1.7 in them.<ref name="Novella_2007"/> ===Side effect of medication=== Several medications including [[bromocriptine]], [[verapamil]], and [[nifedipine]] have been associated with medication-induced erythromelalgia. ===Mushroom poisoning=== The consumption of two species of related fungi, ''[[Clitocybe acromelalga]]'' from Japan,<ref>{{cite journal |last=Ichimura |first=J |year=1918|title=A new poisonous mushroom |journal=Bot Gaz (Tokyo) |volume=65 |pages=10911}}</ref> and ''[[Clitocybe amoenolens]]'' from France,<ref>{{cite journal|author=Saviuc PF, Danel VC, Moreau PA, Guez DR, Claustre AM, Carpentier PH, Mallaret MP, Ducluzeau R |year=2001|title=Erythromelalgia and mushroom poisoning |journal=J. Toxicol Clin Toxicol |volume=39 |issue=4 |pages=403–07|doi=10.1081/CLT-100105162}}</ref> has led to several cases of mushroom-induced erythromelalgia which lasted from 8 days to 5 months.<ref>{{cite journal |last=Diaz |first=James H.|year=2005 |month=February |title=Syndromic diagnosis and management of confirmed mushroom poisonings |journal=Critical Care Medicine |volume=33 |issue=2 |pages= 427–36|doi=10.1097/01.CCM.0000153531.69448.49}}</ref> ==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 Na<sub>V</sub>1.7 encoding gene, ''[[Nav1.7|SCN9A]]''. This channel is expressed primarily in [[nociceptor]]s of the [[dorsal root ganglion]] and the [[sympathetic nervous system|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 Na<sub>V</sub>1.7 channels that activate at more hyperpolarized potentials. Na<sub>V</sub>1.7 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 nervous system|sympathetic]] [[neuron]]s. In DRG neurons expressing the F1449V mutation, a lower threshold is required for [[action potential]] creation (93.1 ± 12.0 [[ampere|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.<ref name="Dib-Hajj_2005">{{cite journal |author=Dib-Hajj SD, Rush AM, Cummins TR, ''et al'' |title=Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons |journal=Brain |volume=128 |issue=Pt 8 |pages=1847–54 |year=2005 |pmid=15958509 |doi=10.1093/brain/awh514}}</ref> 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 [[volt|mV]] versus wild-type channel expressing cells.<ref name="Rush_2006">{{cite journal |author=Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG |title=A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=21 |pages=8245–50 |year=2006 |pmid=16702558 |doi=10.1073/pnas.0602813103}}</ref><ref name="Harty_2006">{{cite journal |author=Harty TP, Dib-Hajj SD, Tyrrell L, ''et al'' |title=Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons |journal=J. Neurosci. |volume=26 |issue=48 |pages=12566–75 |year=2006 |pmid=17135418 |doi=10.1523/JNEUROSCI.3424-06.2006}}</ref> 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 Na<sub>V</sub>1.8 in the former. Consequently, expression of Na<sub>V</sub>1.8 channels in sympathetic neurons also expressing L858H mutant Na<sub>V</sub>1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.<ref name="Rush_2006"/> An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels in 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 V<sub>½</sub> 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 Na<sub>V</sub>1.7 and are present in the skin.<ref name="Han_2007">{{cite journal |author=Han C, Lampert A, Rush AM, ''et al'' |title=Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7 |journal=Molecular pain |volume=3 |issue= |pages=3 |year=2007 |pmid=17239250 |doi=10.1186/1744-8069-3-3}}</ref> {| class="wikitable" style="text-align:center" |+'''Table 1.''' Summary of mutations Na<sub>V</sub>1.7 associated with primary erythromelalgia |- valign="bottom" ! Mutation ! Region ! Shift of activation V<sub>½</sub> ! Shift of inactivation (fast and/or slow) V<sub>½</sub> ! Other effects ! References |- ! I136V | D1S1 | | | | <ref name="Lee_2007">{{cite journal |author=Lee MJ, Yu HS, Hsieh ST, Stephenson DA, Lu CJ, Yang CC |title=Characterization of a familial case with primary erythromelalgia from Taiwan |journal=J. Neurol. |volume=254 |issue=2 |pages=210–4 |year=2007 |pmid=17294067 |doi=10.1007/s00415-006-0328-3}}</ref> |- ! F216S | D1S4 | Hyperpolarized | Hyperpolarized | Faster entry into fast-inactivation | <ref name="Drenth_2005">{{cite journal |author=Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB |title=SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels |journal=J. Invest. Dermatol. |volume=124 |issue=6 |pages=1333–8 |year=2005 |pmid=15955112 |doi=10.1111/j.0022-202X.2005.23737.x}}</ref>, <ref name="Choi_2006">{{cite journal |author=Choi JS, Dib-Hajj SD, Waxman SG |title=Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy |journal=Neurology |volume=67 |issue=9 |pages=1563–7 |year=2006 |pmid=16988069 |doi=10.1212/01.wnl.0000231514.33603.1e}}</ref>, <ref name="Sheets_2007">{{cite journal |author=Sheets PL, Jackson JO, Waxman SG, Dib-Hajj SD, Cummins TR |title=A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity |journal=J. Physiol. (Lond.) |volume=581 |issue=Pt 3 |pages=1019–31 |year=2007 |pmid=17430993 |doi=10.1113/jphysiol.2006.127027}}</ref> |- ! S241T | D1S4-5 | Hyperpolarized | Hyperpolarized | | <ref name="Michiels_2005">{{cite journal |author=Michiels JJ, te Morsche RH, Jansen JB, Drenth JP |title=Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7 |journal=Arch. Neurol. |volume=62 |issue=10 |pages=1587–90 |year=2005 |pmid=16216943 |doi=10.1001/archneur.62.10.1587}}</ref>, <ref name="Lampert_2006">{{cite journal |author=Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG |title=Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating |journal=J. Biol. Chem. |volume=281 |issue=47 |pages=36029–35 |year=2006 |pmid=17008310 |doi=10.1074/jbc.M607637200}}</ref> |- ! N395K | D1S6 | Hyperpolarized | Depolarized | Creation of a large window current, decreased [[lidocaine]] sensitivity | <ref name="Drenth_2005"/>, <ref name="Sheets_2007"/> |- ! I848T | D2S4-5 | Hyperpolarized | | Slowed deactivation and inactivation | <ref name="Drenth_2005"/>, <ref name="Yang_2004">{{cite journal |author=Yang Y, Wang Y, Li S, ''et al'' |title=Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia |journal=J. Med. Genet. |volume=41 |issue=3 |pages=171–4 |year=2004 |pmid=14985375 |doi=10.1136/jmg.2003.012153}}</ref>, <ref name="Cummins_2004">{{cite journal |author=Cummins TR, Dib-Hajj SD, Waxman SG |title=Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy |journal=J. Neurosci. |volume=24 |issue=38 |pages=8232–6 |year=2004 |pmid=15385606 |doi=10.1523/JNEUROSCI.2695-04.2004}}</ref> |- ! L858F | D2S4-5 | Hyperpolarized | Depolarized | Slowed deactivation, faster recovery from inactivation, cooling depolarizes activation and hyperpolarizes inactivation V<sub>½</sub> | <ref name="Drenth_2005"/>, <ref name="Han_2006">{{cite journal |author=Han C, Rush AM, Dib-Hajj SD, ''et al'' |title=Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7 |journal=Ann. Neurol. |volume=59 |issue=3 |pages=553–8 |year=2006 |pmid=16392115 |doi=10.1002/ana.20776}}</ref>, <ref name="Han_2007"/> |- ! L858H | D2S4-5 | Hyperpolarized | | Slowed deactivation, enhanced slow inactivation, | <ref name="Rush_2006"/>, <ref name="Drenth_2005"/>, <ref name="Yang_2004"/>, <ref name="Cummins_2004"/> |- ! A863P | D2S5 | Hyperpolarized | Depolarized | Creation of a window current, slowed deactivation | <ref name="Harty_2006"/> |- ! F1449V | D3-4 | Hyperpolarized | | | <ref name="Dib-Hajj_2005"/> |- | colspan="6" | Region nomenclature: D'''A'''-'''B''', linker between domains '''A''' and '''B'''; D'''A'''S'''B''', transmembrane segment '''B''' in domain '''A'''; and D'''A'''S'''B'''-'''C''', the linker between transmembrane segments '''B''' and '''C''' in domain '''A'''. |} ==Diagnosis== Some diseases present with symptoms similar to erythromelalgia. [[Complex regional pain syndrome]] (CPRS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CPRS. Erythromelalgia is often a secondary condition for other disorders that must be ruled out for a diagnosis of primary erythromelalgia. A partial list of diseases known to precipitate erythromelalgia is below.<ref name="Novella_2007"/> :*[[Myeloproliferative disease]] :*[[Hypercholesterolemia]] :*[[Autoimmune disorder]] :*[[Small fiber peripheral neuropathy]] :*[[Fabry's disease]] :*[[Mercury poisoning]] :*[[Mushroom poisoning]] :*[[Sciatica]] :*Some medications, such as [[bromocriptine]], [[pergolide]], [[verapamil]] and [[ticlopidine]] ==Treatment/Management== For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment, though [[aspirin]] may reduce symptoms of erythromelalgia. The primary method of primary erythromelalgia management is the avoidance of attack triggers, such as heat, over-exertion and alcohol consumption. While a cool environment is helpful in guarding against symptoms, the use of cold water baths is discouraged as such use may cause skin [[necrosis]]. One clinical study has demonstrated the efficacy of [[intravenous therapy|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.<ref name="Novella_2007"/> ==External links== * [http://www.erythromelalgia.org/ The Erythromelalgia Association] ==Footnotes== {{Reflist|2}} {{Vascular diseases}} [[Category:Channelopathy]] [[Category:Neurological disorders]] [[Category:Genetic disorders]] [[de:Erythromelalgie]] [[fr:Érythromelalgie primaire familiale]] [[nl:Erythromelalgie]] [[pl:Bolesny rumień kończyn]]