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Erythromelalgia

by Stephen M. Pribut, D.P.M.

Introduction:

Erythromelalgia is a rarely seen clinical disorder. The name of this clinical entity comes from the Greek for red (erythros), extremity (melos), and pain (algos). While erythromelalgia has often been considered as a "disease" it is likely better viewed as a "clinical entity" or a clinical condition which the most predominant feature is the redness resulting from a pathological response of the shunting of blood to the skin microvascular vessels. The characteristics overall are red, warm, and painful feet and/or hands.

Erythromelalgia is most commonly seen in the secondary form which usually occurs in conjunction with myeloproliferative disorders. Along with the myeloproliferative disorder other hematological abnormalities such as polycythemia and thrombocytosis are often seen. Studies have reported erythromelalgia to occur in from 3 to 65% of patients with myeloproliferative disorders. A comprehensive listing of causes of secondary erythromelalgia would include: polycythemia vera, essential thrombocythemia, myelofibrosis and chronic myelogenous leukemia. Some reports have also ascribed this condition to being related to rheumatoid arthritis, gout, vasculitis, pernicious anemia, SLE and possibly drug induced (bromocriptine, nicardipine, nifedipine, pergolide and verapamil).

The features of erythromelalgia include lower extremity vasodilatation, redness, burning pain and increase in temperature. This may last from minutes to days or longer. Itching may accompany the other symptoms. Usually the episodes are triggered by exposure to warmth. Warm ambient temperature will trigger the reaction which will abate with cooling of the extremities.

Several other factors which have been reported to trigger the response in some people include exercise, tight shoes, alcohol, spicy foods, and vasodilating agents.

The soles of the feet and toes are most often affected, but it may affect the lower extremity up to the knee. I have seen this occur clinically in conjunction with a myeloproliferative disorder and as a primary erythromelalgia without any other associated disease.

The symptoms of erthromelalgia often occur up to 2.5 years before the myeloproliferative disorder is diagnosed. A workup for other causes such as these disorders is critical and it is often desirable to periodically test again.

“...redness, heat, and pain are the most often seen symptoms of erythromelalgia.”

In cases with thrombocythemia the platelets have a decreased time of survival and hyperaggregability. Prostaglandins and cyclooxygenase may play a vital role in the pathogenesis of this specific form of the disorder.

Recent research in therapy has extended to medicines with an impact on the nervous system. While SSI (selective serotonin inhibitors) recent therapy has also addressed the NMDA receptor sites in the form of medications that may have an impact on these sites. Neuroscience is a rapidly changing field and while science never progresses as rapidly as we would like, it does progress and new therapeutic options may appear within the next 3 to 5 years. However, the current options are in the course of being refined with improved protocols and individualization of therapy.

Several cases of primary familial erythromelalgia have involved gain of function mutations of the SCN9A gene which is responsible for the voltage-gated sodium channel Nav1.7. Voltage-gated sodium channels are important for neuron excitation and also in neuron signalling. Nav1.7, Nav1.8, and Nav1.9 are found in peripheral neurons. These voltage-gated sodium channels are vital components of pain pathways. Arch Neurol. 2005;62(10):1587-1590. doi:10.1001/archneur.62.10.1587. ßWWW.ARCHNEUROL.COM
Pedigree structure, sequencing data, and phenotype. The pedigree and electrophoretograms of part of SCN9A exon 6 are shown (SCN9A is the gene that encodes the voltage-gated sodium channel 􏰂 subunit Nav1.7). The DNA sequence
for the affected family members revealed a heterozygous substitution of serine for threonine
at position 721.

Loss of function mutation of the Nav1.7 results in a congenital abscence of pain sensation. Mutations resulting in a gain of function, for example F1449V and L858H, can contribute to primary erythromelalgia. These mutations result in a lower threshold for action potentials and a higher frequency of firing.

In short more than one component of the nervous system seems to be involved. Primary erythermalgia includes what seems to be a neuropathic disorder of the small peripheral sensory and sympathetic neurons. And in some cases hyperexcitability of Nav1.7 is a feature caused by a enhance function mutation.

Synonyms:

Erythromelalgia, erythermalgia

Classification and Types:

Primary:

Often idiopathic, but may be inherited as an autosomal dominant. Research is ongoing in this area and has been helped tremendously by the human genome project. See above for a discussion on SCN9A-related inherited erythromelalgia . Sequence analysis of SCN9A should be performed.

Two differing systems of classification exist today. Drenth and Michiels (1994, 1995) proposed using the terms erythromelalgia for a platelet-mediated form that is responsive to aspirin and use the terms primary and secondary erythermalgia for non-aspirin sensitive forms of the disorder.

Kurzrock and Cohen (1991) subdivide the disorder into adult-onset idiopathic and adult-onset secondary along with early-onset idiopathic and early-onset childhood forms. The early onset form has a male to female ratio of 1:2.5. Secondary erythromelalgia caused by myeloproliferative disorders seem to occur in a male to female ratio of 3:2.

Secondary:

Secondary erythromelalgia is associated with other disorders such as myeloproliferative disorders and thrombocytosis.

Smith and Allen in 1938 used the term erythermalgia to place an emphasis on the warmth noted with this disorder. They were the first to subdivide the disorder into primary and secondary.

Essential thrombocythemia - resulting from a myeloproliferative disorder is the most frequent cause of secondary erythromelalgia. It has been reported to occur in up to 25% of individuals with erythromelalgia.

Diagnostic Studies:

It is important to rule out myeloproliferative disorders. Among other tests a CBC and differential should be performed. Look for a high platelet count and/or a high hematocrit (larger then 50%). A rheumatological workup may also be performed. A neurological examination will look for evidence of peripheral neuropathy.

Differential Diagnosis:

Course:

The prognosis and course vary widely. One does not necessarily experience a downward spiral. It is imperative to determine if there is an associated disorder and if the erythromelalgia is secondary. The symptoms will vary between staying the same, improving, or in some cases becoming more severe.

Treatment:

Many years ago primary erythromelalgia was only treatmented with was aspirin, elevation, and intermittent applications of ice. Aspirin, elevation and intermittent applictions of cold compresses are still often used but other treatments have become available as thinking about neural function has progressed and more research has been done.

Gapabentin has been used.

Lyrica and Lyrica in combination with Cymbalta has also been found to be useful in some patients.

Topical Application of a combination of Amitryptaline 1% with Ketamine 0.5% was found to be helpful in 75% of patients in a small study reported by the Mayo Clinic. This was compounded as a gel in the study, but has also may be compounded in a cream which may lead to improved absorption.

Intermittent ice application, daily aspirin (500 mg po each day), elevation.

Mexiletene a non-selective sodium channel inhibitor, has been used for gain of function mutation L858F NaV1.7 in primary erythromelalgia.

Other therapies directed to the primary condition associated with erythromelalgia

Chemotherapy to lower platelet count.

Phlebotomy in patients with polycythemia vera.

In general avoid over-warming the extremities. Elevate legs often throughout the day.

What Does The Future Hold

Future research will help define the differences among patients. Better protocols for evaluation of related diseases in secondary erythromelalgia will be estabilished and disseminated. Cross disciplinary teams will be helpful, although referral protocols will also work. Primary erythromelalgia research will continue on neuron function and channelopathies will become better understood. Defining which symptoms come from what neural elements is also important. The contributions of the peripheral and autonomic nervous system will ultimately become better understood.

There are an increasing number of options available now, as the understanding that a channelopathy of NaV1.7 is often a factor. As this is being written there are experimental approaches being made with specific targeting of the NaV1.7 gated-sodium channel. Delivery of the treatment will also lead to different approaches. And one day in the distant future CRISPR technology may specifially alter genetic expression of the channel proteins.

References and additional resources:

Cregg R, Cox J, Bennett D et. al.: Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV1.7 sodium channels, British Journal of Pharmacology Volume 171, Issue 19, pages 4455–4463, October 2014

Drenth JP, van Genderen PJ, Michiels JJ: Thrombocythemic erythromelalgia, primary erythermalgia, and secondary erythermalgia: three distinct clinicopathologic entities. Angiology 1994 Jun; 45(6): 451-3[Medline].

Merc Manual. Erythromelalgia. http://www.merck.com/pubs/mmanual/section16/chapter212/212f.htm

Michiels JJ, Abels J, Steketee J: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med 1985 Apr; 102(4): 466-71[Medline].

Michiels JJ, Drenth JP, Van Genderen PJ: Classification and diagnosis of erythromelalgia and erythermalgia. Int J Dermatol 1995 Feb; 34(2): 97-100[Medline].
Nardino, RJ, et. al.. Erythromelalgia: eMedicine Topics. http://www.emedicine.com/med/topic730.htm

Michiels J, Morsche R et. al: Autosomal Dominant Erythermalgia Associated With a Novel Mutation in the Voltage-Gated Sodium Channel α Subunit Nav1.7 . Arch Neurol. 2005;62(10):1587-1590. doi:10.1001/archneur.62.10.1587

Stadler, T (03/06/2015). "Erythromelalgia mutation Q875E Stabilizes the activated state of sodium channel Nav1.7". The Journal of biological chemistry (0021-9258), 290 (10), 6316.

Organizations:

NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
1 AMS Circle
Bethesda, MD 20892-3675
Tel: (301)496-8188
Fax: (301)718-6366
Tel: (877)226-4267
TDD: (301)565-2966
Email: NAMSIC@mail.nih.gov
Internet: http://www.nih.gov/niams/

Erythromelalgia Association
4343 Roosevelt Way, NE
#305
Seattle, WA 98105
Tel: (206)632-0894
Fax: (206)632-1894
Email: jeanmilt@prodigy.net
Internet: http://www.erythromelalgia.org

 


About Dr. Pribut: Dr. Pribut is a member of the Advisory Board of Runner's World magazine. He is a past president of the American Academy of Podiatric Sports Medicine (AAPSM). He served as chair of the AAPSM Athletic Shoe Committee for 5 years and has served on the Education Committee, the Research Committee, the Public Relations Committee and also chaired the Annual Meeting Committee. Dr. Pribut is a past president of the District of Columbia Podiatric Medical Association, serving in that post for 4 years. Dr. Pribut has served as a member of the American Podiatric Medical Association's Clinical Practice Advisory Committee and their Internet Committee. Dr. Pribut is a Clinical Assistant Professor of Surgery at the George Washington University Medical Center.

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