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Erythromelalgia
Classification and external resources
ICD-10 I73.8
ICD-9 443.82
OMIM 133020
DiseasesDB 4476
eMedicine med/730 
MeSH 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. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings I00-I99 - Diseases of the Circulatory system (I00-I02 Acute rheumatic fever ( Rheumatic fever without mention of Heart The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books Silas Weir Mitchell ( January 15, 1829 – January 4, 1914) was an American Physician and Writer. 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 or mercury poisoning, and some autoimmune disorders. Small fiber peripheral neuropathy is a type of Neuropathy. It is also called small fiber neuropathy small fiber sensory neuropathy (SFSN and C fiber neuropathy Hypercholesterolemia (literally high blood cholesterol is the presence of high levels of Cholesterol in the blood. See also List of deadly fungi Mushroom poisoning, also known as mycetism, refers to deleterious effects from ingestion of Toxic substances present Mercury poisoning (also known as mercurialism, hydrargyria, Hunter-Russell syndrome, or acrodynia when affecting children is a Disease Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene SCN9A. Sodium channels are Integral membrane proteins that form Ion channels, conducting sodium ions ( Na+) through a cell's Plasma membrane The Nav17 Sodium ion channel protein is encoded by gene.Recent studies have associated a defect in SCN9A with Congenital insensitivity to pain.

Contents

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. [1]

Symptoms and signs

The most prominent symptoms of erythromelalgia are episodes of erythema, swelling, and a painful burning sensation primarily in the extremities. Erythema is redness of the Skin caused by Capillary congestion In medical parlance, swelling is the enlargement of organs caused by accumulation of excess fluid in tissues, called Edema. 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 alcohol or caffeine consumption. Caffeine is a bitter white crystalline Xanthine Alkaloid that acts as a Psychoactive Stimulant Drug and a mild Diuretic In some patients sugar and even melon consumption have also been known to provoke attacks. Melon is a term used for various members of the Cucurbitaceae family with fleshy fruit Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat this generates is known to produce erythromelalgia attacks. [1]

Cause

In general, erythromelalgia seems to consist of neuropathological and microvascular alterations. Neuropathology is the study of Disease of nervous system tissue usually in the form of either small surgical biopsies or whole autopsy brains Capillaries are the smallest of a body's Blood vessels measuring 5-10 μm in diameter which connect Arterioles and Venules and enable the interchange 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. 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 [1]

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. Structure and Anatomy Location C fibers are found in the peripheral nerves of the somatic sensory system. In Anatomy and Neurology, the dorsal root Ganglion (or spinal ganglion) is a nodule on a Dorsal root that contains cell bodies of Specifically, nociceptors (neurons responsible for the sensation and conduction of painful stimuli) appear to be the primarily affect neurons in these fibers. A nociceptor is a Sensory receptor that sends signals that cause the perception of Pain in response to a potentially damaging stimulus 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. The Sympathetic Nervous System ( SNS) is a branch of the Autonomic nervous system along with the Enteric nervous system and Parasympathetic nervous The skin is the outer covering of living tissue of an animal (or plant 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 In Physiology, Medicine, and Anatomy, muscle tone (aka residual muscle tension or tonus) is the continuous and passive partial In both cases, these changes in excitability are typically due to mutation of the sodium channel NaV1.7. Sodium channels are Integral membrane proteins that form Ion channels, conducting sodium ions ( Na+) through a cell's Plasma membrane The Nav17 Sodium ion channel protein is encoded by gene.Recent studies have associated a defect in SCN9A with Congenital insensitivity to pain. These differences in excitability alterations between the sympathetic nervous system and nociceptors is due to different expression of sodium channels other than NaV1. The Sympathetic Nervous System ( SNS) is a branch of the Autonomic nervous system along with the Enteric nervous system and Parasympathetic nervous A nociceptor is a Sensory receptor that sends signals that cause the perception of Pain in response to a potentially damaging stimulus Sodium channels are Integral membrane proteins that form Ion channels, conducting sodium ions ( Na+) through a cell's Plasma membrane 7 in them. [1]

Side effect of medication

Several medications including bromocriptine, verapamil, and nifedipine have been associated with medication-induced erythromelalgia. Bromocriptine (brand names include Parlodel an Ergoline derivative is a Dopamine agonist that is used in the treatment of Pituitary Tumors Verapamil (brand names Isoptin, Verelan, Calan, Bosoptin, Covera-HS) is an L-type Calcium channel blocker. Nifedipine (brand name Adalat, Nifedical, and Procardia) is a Dihydropyridine Calcium channel blocker.

Mushroom poisoning

The consumption of two species of related fungi, Clitocybe acromelalga from Japan,[2] and Clitocybe amoenolens from France,[3] has led to several cases of mushroom-induced erythromelalgia which lasted from 8 days to 5 months. Clitocybe acromelalga is a Basidiomycete Fungus of the large genus Clitocybe found in Japan Clitocybe amoenolens, commonly known as the poison dwarf bamboo mushroom, is a Basidiomycete Fungus of the large genus Clitocybe [4]

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. Sodium channels are Integral membrane proteins that form Ion channels, conducting sodium ions ( Na+) through a cell's Plasma membrane 7 encoding gene, SCN9A. The Nav17 Sodium ion channel protein is encoded by gene.Recent studies have associated a defect in SCN9A with Congenital insensitivity to pain. This channel is expressed primarily in nociceptors of the dorsal root ganglion and the sympathetic ganglion neurons. A nociceptor is a Sensory receptor that sends signals that cause the perception of Pain in response to a potentially damaging stimulus In Anatomy and Neurology, the dorsal root Ganglion (or spinal ganglion) is a nodule on a Dorsal root that contains cell bodies of The Sympathetic Nervous System ( SNS) is a branch of the Autonomic nervous system along with the Enteric nervous system and Parasympathetic nervous 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. The Membrane potential, or better Membrane Voltage, is the difference of Electric potentials between two Aqueous solutions separated by a ( 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 (or transmembrane potential) is the Voltage difference (or Electrical potential difference between the interior and exterior of a

Some of these mutant channels have been expressed in dorsal root ganglion (DRG) or sympathetic neurons. In Anatomy and Neurology, the dorsal root Ganglion (or spinal ganglion) is a nodule on a Dorsal root that contains cell bodies of The Sympathetic Nervous System ( SNS) is a branch of the Autonomic nervous system along with the Enteric nervous system and Parasympathetic nervous Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information In DRG neurons expressing the F1449V mutation, a lower threshold is required for action potential creation (93. In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal 1 ± 12. 0 pA) than those expressing wild-type channels (124. The ampere, in practice often shortened to amp, (symbol A is a unit of Electric current, or amount of Electric charge per second 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. [5] 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 volt (symbol V) is the SI derived unit of electric Potential difference or Electromotive force. [6][7] 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. [6]

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 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. An axon or nerve fiber is a long slender projectionof a nerve cell or Neuron, that conducts electrical impulses away from the neuron's Cell 7 and are present in the skin. [8]

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 References
I136V D1S1 [9]
F216S D1S4 Hyperpolarized Hyperpolarized Faster entry into fast-inactivation [10], [11], [12]
S241T D1S4-5 Hyperpolarized Hyperpolarized [13], [14]
N395K D1S6 Hyperpolarized Depolarized Creation of a large window current, decreased lidocaine sensitivity [10], [12]
I848T D2S4-5 Hyperpolarized Slowed deactivation and inactivation [10], [15], [16]
L858F D2S4-5 Hyperpolarized Depolarized Slowed deactivation, faster recovery from inactivation, cooling depolarizes activation and hyperpolarizes inactivation V½ [10], [17], [8]
L858H D2S4-5 Hyperpolarized Slowed deactivation, enhanced slow inactivation, [6], [10], [15], [16]
A863P D2S5 Hyperpolarized Depolarized Creation of a window current, slowed deactivation [7]
F1449V D3-4 Hyperpolarized [5]
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. Lidocaine ( INN) (ˈlaɪdoʊkeɪn or lignocaine (former BAN) (/ˈlɪgnoʊkeɪn/ is a common Local anesthetic and antiarrhythmic drug

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. Complex Regional Pain Syndrome (CRPS is a chronic progressive disease characterized by severe pain swelling and changes in the skin 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. [1]

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 myeloproliferative diseases ("MPD"s are a group of diseases of the Bone marrow in which excess cells are produced Hypercholesterolemia (literally high blood cholesterol is the presence of high levels of Cholesterol in the blood. Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues Small fiber peripheral neuropathy is a type of Neuropathy. It is also called small fiber neuropathy small fiber sensory neuropathy (SFSN and C fiber neuropathy Fabry disease (also known as Anderson-Fabry disease, Angiokeratoma corporis diffusum, Ruiter-Pompen-Wyers syndrome, Ceramide trihexosidosis Mercury poisoning (also known as mercurialism, hydrargyria, Hunter-Russell syndrome, or acrodynia when affecting children is a Disease See also List of deadly fungi Mushroom poisoning, also known as mycetism, refers to deleterious effects from ingestion of Toxic substances present Sciatica is a set of symptoms including Pain that may be caused by general compression and/or irritation of one of five nerve roots that give rise to the Sciatic nerve Bromocriptine (brand names include Parlodel an Ergoline derivative is a Dopamine agonist that is used in the treatment of Pituitary Tumors Pergolide is an Ergoline -based Dopamine receptor Agonist used for the treatment of Parkinson's disease. Verapamil (brand names Isoptin, Verelan, Calan, Bosoptin, Covera-HS) is an L-type Calcium channel blocker. Ticlopidine (trade name Ticlid) is an Antiplatelet drug in the Thienopyridine family Aspirin, or acetylsalicylic acid (ASA (əˌsɛtɨlsælɨˌsɪlɨk ˈæsɨd is a Salicylate drug, often used as an Analgesic to relieve

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. Necrosis (in Greek Νεκρός = "dead" is the name given to unnatural Death of cells and living tissue. 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. Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. Lidocaine ( INN) (ˈlaɪdoʊkeɪn or lignocaine (former BAN) (/ˈlɪgnoʊkeɪn/ is a common Local anesthetic and antiarrhythmic drug Mexiletine ( INN, sold under the trade name Mexitil) belongs to the Class IB anti-arrhythmic group of medicines Another trial has shown promise for misoprostol, while other have shown that gabapentin, venlafaxine, and oral magnesium may also be effective. Misoprostol is a drug that is FDA -approved in the United States for the prevention of non-steroidal anti-inflammatory drug ( NSAID)-induced Gabapentin (brand name Neurontin) is a medication originally developed for the treatment of Epilepsy. Venlafaxine (Effexor Efexor is an Antidepressant of the Serotonin-norepinephrine reuptake inhibitor (SNRI class first introduced by Wyeth in 1993 Magnesium (mægˈniːziəm is a Chemical element with the symbol Mg, Atomic number 12 Atomic weight 24 [1]

External links

Footnotes

  1. ^ a b c d e f Novella SP, Hisama FM, Dib-Hajj SD, Waxman SG (2007). "A case of inherited erythromelalgia". Nature clinical practice. Neurology 3 (4): 229-34. doi:10.1038/ncpneuro0425. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17410110.  
  2. ^ Ichimura, J (1918). "A new poisonous mushroom". Bot Gaz (Tokyo) 65: 10911.  
  3. ^ Saviuc PF, Danel VC, Moreau PA, Guez DR, Claustre AM, Carpentier PH, Mallaret MP, Ducluzeau R (2001). "Erythromelalgia and mushroom poisoning". J. Toxicol Clin Toxicol 39 (4): 403-07.  
  4. ^ Diaz, James H. (February 2005). "Syndromic diagnosis and management of confirmed mushroom poisonings". Critical Care Medicine 33 (2): 427-36. doi:10.1097/01.CCM.0000153531.69448.49. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  5. ^ a b Dib-Hajj SD, Rush AM, Cummins TR, et al (2005). "Gain-of-function mutation in Nav1. 7 in familial erythromelalgia induces bursting of sensory neurons". Brain 128 (Pt 8): 1847-54. doi:10.1093/brain/awh514. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15958509.  
  6. ^ a b c Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG (2006). "A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons". Proc. Natl. Acad. Sci. U. S. A. 103 (21): 8245-50. doi:10.1073/pnas.0602813103. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16702558.  
  7. ^ a b Harty TP, Dib-Hajj SD, Tyrrell L, et al (2006). "Na(V)1. 7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons". J. Neurosci. 26 (48): 12566-75. doi:10.1523/JNEUROSCI.3424-06.2006. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17135418.  
  8. ^ a b Han C, Lampert A, Rush AM, et al (2007). "Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1. 7". Molecular pain 3: 3. doi:10.1186/1744-8069-3-3. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17239250.  
  9. ^ Lee MJ, Yu HS, Hsieh ST, Stephenson DA, Lu CJ, Yang CC (2007). "Characterization of a familial case with primary erythromelalgia from Taiwan". J. Neurol. 254 (2): 210-4. doi:10.1007/s00415-006-0328-3. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17294067.  
  10. ^ a b c d e Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB (2005). "SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels". J. Invest. Dermatol. 124 (6): 1333-8. doi:10.1111/j.0022-202X.2005.23737.x. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15955112.  
  11. ^ Choi JS, Dib-Hajj SD, Waxman SG (2006). "Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy". Neurology 67 (9): 1563-7. doi:10.1212/01.wnl.0000231514.33603.1e. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16988069.  
  12. ^ a b Sheets PL, Jackson JO, Waxman SG, Dib-Hajj SD, Cummins TR (2007). "A Nav1. 7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity". J. Physiol. (Lond. ) 581 (Pt 3): 1019-31. doi:10.1113/jphysiol.2006.127027. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17430993.  
  13. ^ Michiels JJ, te Morsche RH, Jansen JB, Drenth JP (2005). "Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1. 7". Arch. Neurol. 62 (10): 1587-90. doi:10.1001/archneur.62.10.1587. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16216943.  
  14. ^ Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG (2006). "Size matters: Erythromelalgia mutation S241T in Nav1. 7 alters channel gating". J. Biol. Chem. 281 (47): 36029-35. doi:10.1074/jbc.M607637200. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17008310.  
  15. ^ a b Yang Y, Wang Y, Li S, et al (2004). "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia". J. Med. Genet. 41 (3): 171-4. doi:10.1136/jmg.2003.012153. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14985375.  
  16. ^ a b Cummins TR, Dib-Hajj SD, Waxman SG (2004). "Electrophysiological properties of mutant Nav1. 7 sodium channels in a painful inherited neuropathy". J. Neurosci. 24 (38): 8232-6. doi:10.1523/JNEUROSCI.2695-04.2004. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15385606.  
  17. ^ Han C, Rush AM, Dib-Hajj SD, et al (2006). "Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1. 7". Ann. Neurol. 59 (3): 553-8. doi:10.1002/ana.20776. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16392115.  
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