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 thrombocythemia, 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 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 Na_V1.7 sodium channels, which are preferentially expressed within peripheral neurons. One year later, in an article in Brain, Dib-Hajj et al., demonstrated that Na_V1.7 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 Na_V1.7 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 Na_V1.7 had been linked to IEM. The multi-decades search which identified gene SCN9A as the cause of inherited erythromelalgia is documented in a book by Stephen Waxman, Chasing Men on Fire: The Story of the Search for a Pain Gene.

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.

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.^{[citation needed]}

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.

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 Na_V1.7. These differences in excitability alterations between the sympathetic nervous system and nociceptors is due to different expression of sodium channels other than Na_V1.7 in them.