Erythromelalgia

Co-Editors In Chief: Tanya Greenberg, M.D. and Duane Pinto, M.D.

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 or mercury poisoning, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene 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.

Symptoms and signs
The most prominent symptoms of erythromelalgia are episodes of erythema, 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 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.

Cause
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 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 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.

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 NaV1.7 encoding gene, SCN9A. This channel is expressed primarily in nociceptors of the dorsal root ganglion and the 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 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 &#177; 12.0 pA) than those expressing wild-type channels (124.1 &#177; 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 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.

An affective, 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&#186;C the activation V½ of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35&#186;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.

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.
 * 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 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 affective.