Clinical manifestations

Presentation and course

Erythromelalgia may be either primary or secondary, depending on whether it is idiopathic or has a genetic cause (primary) or occurs in the setting of another disorder (secondary).

Primary erythromelalgia can further be subdivided into familial (inherited as an autosomal dominant trait) or sporadic forms. Moreover, familial and sporadic forms of erythromelalgia can be defined as juvenile (onset of symptoms occurring before the age of 20 years; often manifesting itself before the end of the first decade of life) or adult onset. These patients experience episodic vasodilation of the extremities in association with burning pain of the feet or lower extremities (57; 83; 84; 82). Occasional sporadic cases of juvenile-onset erythromelalgia have been reported to occur due to a de novo founder mutation in the SCN9A gene of the proband (34; 35).

Secondary erythromelalgia oftentimes presents as a symptom of an underlying disease. It is commonly associated with myeloproliferative diseases, such as polycythemia vera and essential thrombocythemia, but can also be seen in association with systemic conditions, including diabetes, rheumatoid arthritis, collagen vascular diseases, thrombotic thrombocytopenic purpura, hypertension, multiple sclerosis, cutaneous vasculitis, and gout, as well as with the use of certain drugs (21; 46; 72; 40). Patients with erythromelalgia in the setting of myeloproliferative disorders are often remarkably responsive to treatment with aspirin. As a corollary, any patient with erythromelalgia who responds to aspirin should be worked up for a hematological disorder. Interestingly, in the secondary form of erythromelalgia, a 2:1 predominance of females has been reported (41).

Although it is a chronic condition, symptoms tend to be more episodic than continuous and often occur following exposure to certain stimuli (05; 10). Attacks are described by patients as severe burning pain with accompanying redness in the extremities in response to warm stimuli or moderate exercise (76; 63). The lower extremities are more commonly involved than the upper extremities, and involvement is usually symmetrical (13; 82). In a published noninterventional study of 13 patients with inherited erythromelalgia, it was found that erythromelalgia pain attacks are both variable in duration (with a range of 5 minutes to 780 minutes) and in intensity (with a range of 1 to 10 and an average of 5 on the Numeric Rating Scale for pain). Interestingly, there was a large amount of variation, even in patients of the same family with the same mutation of the Nav1.7 sodium channel. Moreover, there was no consistent link between the number of attacks in a day and the severity of the pain during or between attacks (55).

There have been reports that the symptoms of this debilitating condition also tend to become worse as the patient ages (51). Furthermore, the affected areas may expand to include greater parts of the extremities, sometimes as far as the knee, as a person gets older (51). Increased age in patients with the condition correlates with significantly decreased survival when compared with individuals in the general population without the condition (15; 22; 68). Clinicians should raise their index of suspicion for the disorder in patients who present with burning pain in the extremities that are red or purple in color and warm to the touch (16).

Increases in environmental temperature seem to provoke exacerbation of the condition (33). Thus, exercise, exposure to warmth (including the summer months), and long periods of standing can possibly trigger attacks in at-risk individuals (76; 63; 33). Given this finding, exposure to environments with cooler temperatures tends to mitigate symptoms in individuals with erythromelalgia (15; 33). Environmental factors, including certain foods, alcoholic beverages, and spices, have been reported to aggravate symptoms in patients (64).

Prognosis and complications

Erythromelalgia is characterized by chronic neuropathic pain that can be difficult to treat (83; 84). Because a characteristic feature is relief obtained by immersing the extremities in ice, complications include ulceration and gangrene. In the absence of a clear etiology, treatment has been empirical and only partially effective in most cases. Early recognition and diagnosis remains the cornerstone of treatment. Therefore, it is crucial for clinicians to recognize characteristic clinical signs. The condition does remit spontaneously in occasional one third of patients (13; 83; 84).

Clinical vignette

Vignette 1: Primary inherited erythromelalgia. The patient was a 40-year-old male who presented to a neurologist with the complaint of episodic erythema, mild swelling, and painful burning sensations in his feet and hands bilaterally. He reported that his symptoms began when he was about 5 years of age, although his mother stated that he has had trouble with “red, hot feet” since he was about 1 or 2 years of age. His symptoms initially only affected his feet; however, he later had similar symptoms involving his hands. Over the years, the patient had noticed that his episodes had increased in frequency and severity. At the time of presentation, he experienced multiple daily episodes of burning, throbbing pain that lasted minutes to hours.

The pain episodes were triggered by exercise or an increase in the ambient temperature. Summer months seemed to cause an increase in the frequency of painful attacks, especially if the day was hot and humid. The pain was relieved by cooling the affected extremities by using a fan or submerging the areas in ice water. In fact, during the winter months, the patient often walked outside without shoes to help relieve his pain. He preferred to wear open-toed shoes or to ambulate barefoot, even in the winter months. Because physical exertion, such as walking uphill or running, triggered his symptoms, the patient avoided most physical activities. He also felt that his symptoms could be triggered by alcohol or caffeine consumption, spicy foods, and sometimes, melon.

A review of systems was unrevealing. A review of his family history revealed that over three generations, multiple relatives had experienced similar symptoms beginning approximately at the same age. This included two of his children, his mother, his brother, his maternal aunt and uncle, and his uncle’s son and daughter. He had one maternal uncle without any symptoms.

Physical examination showed diffuse erythema over the patient’s feet and hands, extending to the ankles or wrists respectively. Neurologic examination, including motor, reflex, and sensory examinations, was normal.

Evaluation of this patient included an MRI brain, as well as sensory and motor nerve conduction studies of the right arm and leg, all of which were normal. Complete blood count, platelet count, blood chemistries, and antinuclear antibodies were within normal range. Testing for Fabry disease was negative. Evaluation of the SCN9A gene in this patient revealed a single amino acid substitution, which was also present in all of the tested affected family members.

On the basis of the patient’s clinical presentation, his family history, and the negative work-up, he was given the diagnosis of primary inherited erythromelalgia. Management included a trial of symptomatic pharmacological relief, as well as pain counseling. He was advised to not submerge his extremities in cold water. He was counseled on how to maintain a cool environment, how to safely cool his affected extremities, and how to avoid triggers.

Vignette 2: Adult onset, sporadic erythromelalgia. The patient was a 41-year-old female who presented with an 8-month history of intermittent tingling, and erythema as well as painful throbbing, burning sensations in her lower extremities. Her symptoms extended to approximately mid-calf, bilaterally. She noticed that her symptoms began approximately 8 months prior to presentation, while driving home from her first day at an aerobics class she had recently joined. She had never noticed any pain or erythema on her hands or face. Her symptoms were intermittent, lasting minutes to hours, and occurred approximately two or three times per week. She occasionally had multiple episodes during the span of 24 hours.

Her pain episodes were triggered by exercise or an increase in environmental temperature. She preferred to sleep without blankets covering her feet and often had a fan blowing on her lower extremities during the night hours. She often wore sandals and avoided any tight-fitting pants or hosiery in an attempt to prevent the start of her symptoms.

On review of systems, she had diet-controlled hyperlipidemia. She had no history of orthostatic hypotension, gastroparesis, labile blood pressure, palpitations, or other signs of autonomic dysfunction. There were no family members with similar symptoms over the last four generations.

The patient had a normal neurologic examination. No abnormalities were seen on nerve conduction studies or electromyography. No abnormalities were noticed on laser Doppler flow examination. Subsequent quantitative sudomotor axon reflex test yielded normal findings. All of the patient’s blood work was within normal limits.

On the basis of the patient’s clinical presentation and negative work-up, the patient was given the diagnosis of adult onset, sporadic erythromelalgia. Management for this patient is the same as the above patient.

Biological basis

Etiology and pathogenesis

The SCN9A gene on 7.94 cM interval of chromosome2q has been identified as the locus of mutations that cause the primary, hereditary form of erythromelalgia (19; 88). The SCN9A gene encodes the alpha subunit of the Nav1.7 voltage-gated sodium channel, which is predominantly expressed within both sensory and sympathetic neuronal cells (75). Primary erythromelalgia is due to missense mutations of the Nav1.7 sodium channel, which result in single amino acid substitutions in the channel alpha subunit protein and cause gain-of-function changes in channel function, most notably a hyperpolarization of activation and slowed deactivation. Because sodium channel activation results in an inward electrical current that depolarizes neurons, NaV1.7 mutations that cause erythromelalgia render dorsal root ganglion (DRG) neurons hyperexcitable. The mutant Nav1.7 channels lead to hyperexcitability in small DRG neurons by reducing the threshold for action potential firing, enabling spontaneous action potential firing, or enhancing the response to small stimuli (11; 83; 84; 82). In addition to pain signaling DRG neurons, sympathetic peripheral fibers have also been recognized as being adversely affected by the mutations (46; 42).

Dynamic clamp studies of the L858H IEM mutation have shown that hyperexcitability of small DRG neurons, including nociceptors, is directly linked to amplification of net sodium influx (25; 77). However, these same mutations produce hypoexcitability within sympathetic ganglion neurons, which also express Nav1.7 (67), providing a basis for the abnormality of sympathetic vasomotor control that is seen in these patients (67). Aging h male and female mice possessing L858 Na1.7 channels experience a significant reduction in sodium conductance. This represents a functional loss, which is probably due to age-related changes in transcription and cellular compensation (86). A study has shown that stimulating hyperpolarization-activated cyclic nucleotide-gated channels leads to a reduction in the excitability and firing frequency of DRG neurons, both in those expressing the wild type and those with the L858H mutation. This effect is due to an increase in hyperpolarization-activated currents (78). These studies are indicative of the complex biology of sodium channels, the pathology of which can result in different phenotypes (erythromelalgia, small fiber neuropathy, and paroxysmal extreme pain syndrome), depending on the expression of other genes as well as epigenetic and environmental factors.

In addition to the variable effect on neurons, IEM mutations have also been linked to more complex clinical phenotypes. The G856R mutation of Nav1.7 was found in two siblings, both of whom have the typical symptoms of IEM, albeit to different intensities, as well as underdevelopment of their limbs (71). Although the study could show that the mutation caused a gain-of-function phenotype as is normally seen in IEM mutations, the precise link between the mutation and limb underdevelopment is not well understood. In addition to this, Huang and colleagues characterized the Nav1.7 I234T mutation from patients that not only exhibit symptoms of IEM but also have an impaired ability to sense pain (38). These patients have experienced painless fractures and corneal anesthesia. Current and dynamic clamp analyses of the channel revealed that the mutation could cause drastic membrane depolarization of a small percentage of DRG cells, resulting in a loss of excitability, which in turn results in a clinical loss-of-function phenotype. A list of Nav1.7 mutations shown to cause erythromelalgia as of 2013 is available (17).

Although paroxysmal pain disorder (previously known as familial rectal pain syndrome) has also been shown to involve mutations in the SCN9A gene, findings have concluded that the characteristic phenotypes of erythromelalgia and paroxysmal pain disorder are distinctive and easily distinguishable clinically (27). Whereas erythromelalgia most often presents as episodic vasodilation of the extremities in association with burning pain of the feet and lower extremities, paroxysmal pain disorder most often presents as recurrent bouts of burning rectal and ocular pain in association with tonic, nonepileptic seizures (27). It has been suggested that the different clinical presentations are related to different physiological effects of erythromelalgia mutations (which enhance Nav1.7 channel activation) and paroxysmal pain disorder mutations (which impair Nav1.7 inactivation).

In contrast to primary erythromelalgia, no genetic basis has been identified thus far in secondary erythromelalgia (88). In fact, secondary erythromelalgia is a distinct, acquired disorder whose development is believed to be associated with rheumatologic and autoimmune factors (70). Secondary erythromelalgia is seen in association with a myriad of systemic conditions, most particularly with myeloproliferative disorders. Its development may be related to the release of humoral components from platelets or ischemic tissues that tend to be exacerbated in the presence of certain conditions and after ingestion of various drugs, including nicardipine, verapamil, bromocriptine, nifedipine, and pergolide (23; 48; 20; 61; 46). Unlike primary erythromelalgia, which is associated with alterations of critical sodium channels, secondary erythromelalgia has been suggested to be associated with acquired vascular changes that eventually lead to local hypoxia-induced symptoms in affected areas (61). Studies suggest that the condition arises due to physiological responses to stimuli caused by systemic conditions that result in maldistribution of skin microvascular blood flow, leading to inadequate nutritive perfusion at the extremities. This presumably results in hypoxic conditions and is believed to lead to the symptoms of intense burning, unremitting pain, and other symptoms that have come to distinguish the condition (61). Thus, findings point to a common pathogenetic mechanism prevalent in all cases of secondary erythromelalgia, namely, microvascular arteriovenous shunting secondary to systemic insults, some of which occur during exacerbations of systemic diseases (41; 61; 49).

Epidemiology

Given the fact that few reported cases of primary erythromelalgia have appeared in the medical literature, accurately assessing the incidence and prevalence of the condition can pose a challenge. Despite the exceedingly rare nature of the primary subset, secondary erythromelalgia is less rare and has been suggested to appear in as many as 65% of all patients with myeloproliferative disorders.

The first major study reporting the incidence of erythromelalgia was conducted in 1932 at the Mayo Clinic (04). The study estimated the incidence of the disease to be in the range of one case per 40,000 patients. In the mid-1980s, an epidemic outbreak of erythromelalgia occurred among rural inhabitants in China, prompting medical professionals to investigate the characteristic distribution of the disorder (91). A comprehensive study undertaken in Norway in 1997 estimated the incidence of erythromelalgia to be 0.25 out of 100,000 and prevalence 2 out of 100,000. Another study suggested that the annual prevalence of the condition ranges between 18 and 20 cases per million (41; 61).

Prevention

Given that erythromelalgia is precipitated via exposure to elevated temperatures, strict future avoidance of such environments should be encouraged (61; 13). For example, exercise regimens that require exposure to arid environments should be avoided. Furthermore, recreational activities such as sauna bathing should be minimized. In cases of secondary erythromelalgia, immediate withdrawal of offending agent or treatment of underlying conditions is a prerequisite to mitigating symptoms and minimizing risk of future exacerbation. Cooling the affected area has been shown to minimize pain and associated symptoms (61). However, patients should be cautioned not to immerse their limbs in ice water, which can cause gangrene and life-threatening hypothermia, but rather to use a fan (53).

Differential diagnosis

The initial diagnosis of erythromelalgia can be challenging, particularly given the many other causes of painful erythematous extremities such as:

• Complex regional pain syndrome (reflex sympathetic dystrophy) • Causalgia (only pain is the main finding) • Thromboangiitis obliterans • Raynaud phenomenon (primary and secondary forms) • Burning hands and feet syndrome (idiopathic small-fiber neuropathy of elderly) • Restricted forms of myofascial pain syndrome (fibromyalgia) • Fabry disease (especially in males with associated clinical findings) • Vasculitic neuropathies • Diabetic neuropathy • Vitamin deficiency (B12/ B1) • Vitamin excess (pyridoxine) • Hypothyroidism • Collagen vascular disease (systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, vasculitis) • Paraneoplastic syndrome • Medications (amiodarone, cisplatinum, colchicine, verapamil, nifedipine, bromocriptine, ticlopidine) • Toxin or heavy metals (acrylamide, ethylene oxide, arsenic, thallium, mercury) • Human immunodeficiency virus neuropathy • Small-fiber neuropathy • Sciatica

Thus, considering an appropriate differential diagnosis in at-risk patients can help eliminate misdiagnoses associated with this condition. Arriving at an accurate diagnosis necessitates paying careful attention to relevant medical history and clinical findings because no definitive laboratory criteria are currently available (61). Due to the difficulty with diagnosis, the average time from presentation to diagnosis is 5 years (06)

It is important for clinicians to remember that erythromelalgia shares a number of clinical features with, and is often confused with, complex regional pain syndrome (reflex sympathetic dystrophy) because both are characterized by severe pain and vasomotor disturbances. In contrast to complex regional pain syndrome, erythromelalgia is bilateral and symmetric (59; 76; 64).

Diagnostic workup

Although early recognition and treatment of the condition represent the best probability for successfully managing erythromelalgia, diagnosis can present a challenge for clinicians (05; 64). Although the diagnosis should be guided by thorough history and physical examination, other diagnostic testing may assist in arriving at a definitive diagnosis.

Current understanding of erythromelalgia suggests that the best diagnostic results can be achieved during a painful episode rather than during periods of remission (05; 64). Because the symptoms of erythromelalgia are often similar to and can overlap with those of small fiber neuropathy, it's advisable to include autonomic testing and assessment of intraepidermal nerve fiber density (IENFD) through a skin biopsy in the diagnostic process. In a study, only about five (approximately 10%) out of 52 patients who were clinically diagnosed with erythromelalgia showed abnormally low intraepidermal nerve fiber density in a skin biopsy taken from the distal leg (52). All had other causes for abnormal intraepidermal nerve fiber density: ie, two had diabetes, and in another two, numbness in the feet preceded the diagnosis of erythromelalgia. Conversely, quantitative sensory testing, Q sweat, and thermoregulatory sweat tests showed abnormalities in 50%, 46%, and 60% of the patients, respectively. This study reveals a mismatch between functional impairment and the loss of small fibers in patients with erythromelalgia. Watabe and colleagues identified a new SCN9A mutation that was associated with severe erythromelalgia and small fiber neuropathy (80). This was evidenced by an abnormal density of epidermal nerve fibers in a length-dependent manner.

Of note, clinical genetic testing for the condition remains primarily a research tool at this time. Although it has been clearly demonstrated that some mutations in gene SCN9A produce an amino acid substitution in the Nav1.7 resulting in gain-of-function changes in the channel that produces hyperexcitability of dorsal root ganglion neurons, other amino acid substitutions may be functionally tolerated by the channel, do not change its physiology, and are of unclear clinical significance. A mutation of SCN9A/Nav1.7 can only be considered pathogenic if it segregates with diseases phenotype, ie, is present in multiple affected family members and not in unaffected family members, or has been shown by functional profiling to produce gain-of-function changes in the channel (85). At this time, demonstration of a missense mutation does not have therapeutic implications.

In patients who cannot be evaluated during a painful crisis, it is recommended that nerve function and vascular function tests be conducted after provoking symptoms via exercise or increases in local temperature (16).

Erythromelalgia secondary to myeloproliferative disease can respond dramatically to aspirin (56). In fact, patients typically report pain relief for several days after a single dose. Patients who respond to aspirin should be worked-up for an associated myeloproliferative disorder (64).

Other neurologic syndromes that tend to mimic erythromelalgia include complex regional pain syndrome, chronic mountain sickness, Anderson-Fabry disease, autosomal dominant burning feet syndrome, and chronic idiopathic axonal polyneuropathy (74). Unlike erythromelalgia, complex regional pain syndrome is usually unilateral and often associated with trauma-related cytokine release resulting in exaggerated neurogenic inflammation and pain in the affected extremities (02). The recognition of such differences is critical to arriving at an accurate diagnosis in the setting of suspected erythromelalgia. Anderson-Fabry disease describes a condition that results in neuropathic pain in association with cerebrovascular, renal, and sensorineural deficits (50). In fact, sensorineural deafness can be seen in as many as 78% of patients with Anderson-Fabry disease (50). Erythromelalgia rarely affects visceral organs and tends to primarily affect the distal extremities, primarily on a superficial level. Chronic idiopathic axonal polyneuropathy presents with burning pain in the distal extremities, but unlike erythromelalgia, does not cause erythema or vasodiliatory changes.

Management

Although there has been a great progress in understanding erythromelalgia, many patients remain difficult to treat (83; 84). This is especially true of primary erythromelalgia, for which a myriad of medications including nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, tricyclic antidepressants, corticosteroids, calcium channel antagonists, and other drugs have been used, all with varying responses (61). Importantly, in patients with primary erythromelalgia, genetic counseling and counseling on the chronic nature of the disease is essential (37). Patients must be advised to avoid triggers, as well as how to properly cool painful extremities. Patients need to be warned against submerging their extremities in ice or in icy water due to the possibility of developing skin necrosis and ulceration. A safer option is using a fan to cool the skin. However, patients should be warned against overcooling the extremities. In a published case report, a 6-year-old girl with the L858F Nav1.7 mutation, developed refractory hypothermia likely because of overcooling (73). Of note, prior to the event, her parents had controlled her IEM pain episodes by maintaining the ambient temperature at 15 ºC, and they continuously cooled her lower extremities with either a fan or air conditioner. She had a complicated 4-week course in the pediatric ICU. Attempts to raise her temperature led to excruciating lower limb pain, and normalization of her temperature was only successfully accomplished after the patient was heavily sedated with ketamine.

Of note, in a report a 19-year-old man with genetically verified erythromelalgia (L136V) who had failed multiple medical therapies underwent behavioral therapy by a psychiatrist and a clinical psychologist (39). In this therapy, he was taught how to use breathing techniques to alleviate his pain and eliminate his dependence on cold water immersion. The authors report that after treatment, although he still has burning pain in his legs, he feels no urge to immerse his limbs in cold water.

The sodium channel blockers lidocaine and mexiletine have been reported to be helpful in some patients, although the beneficial effects are transient. A case study reported treatment with a combination of spinal cord stimulation and mexiletine (65). The spinal cord stimulator eradicated the pressure and throbbing pain the patient experienced, but not the burning pain. It was only with addition of the mexiletine that the burning pain was treated. Moreover, the use of mexiletine alone was tried in this patient, but it was not as efficacious as when used in combination with the spinal cord stimulator. There have also been case reports of successful treatment of erythromelalgia with local administration of botulinum toxin A (12), with intravenous immunoglobulin (60) and topical midodrine (a selective α1-agonist) (14). However, it is unknown whether these treatment modalities could be widely used.

Promising results have been reported from controlled trials using a topical gel compound containing amitriptyline and ketamine; further studies are required before this therapeutic option becomes more widely accepted by clinicians (68; 66). Studies of serotonin-reuptake inhibitors such as venlafaxine have provided promising results both in the immediate alleviation of symptoms associated with erythromelalgia and in reducing their occurrence (18; 28).

Medical management is currently the most effective method of treating primary erythromelalgia and should include genetic counseling and symptomatic management of exacerbations (64). There have been several case reports, mostly in pediatric cases, demonstrating success in using epidural infusions to treat erythromelalgia pain. A case report has demonstrated success in a 34-year-old woman (09). In this study, she received a 3-day infusion of 0.0625% ropivacaine with 2 mcg/ml fentanyl after failing treatment with aspirin. Her pain was reportedly reduced from 10/10 to 0-1/10 during the treatment. Upon follow-up 9 months after treatment, she reported her pain as 0-2/10. During this time, the ulcers on her lower extremities healed and erythema resolved. She did not require opioids during this time. Although there are only a few case reports demonstrating success with this technique in adults, this suggests that lumbar epidural infusion might have broad efficacy in treating the symptoms of erythromelalgia in both pediatric and adult populations.

Although attempts at surgical sympathectomies have yielded conflicting results, there has been a steadily increasing number of case reports reporting apparently successful treatment of refractory erythromelalgia pain with lumbar sympathetic ganglion blockade (LSGB) (36). In two reports, LSGB, undertaken via slightly different approaches, was reported as resulting in immediate reduction in pain scores. In the first study, two rounds of fluoroscopically-guided pulsed radiofrequency treatments were used in conjunction with 0.375% ropivacaine in a 22-year-old patient (47). This patient reported consistently lower pain scores (2 to 3, down from 6 to 8 out of 10 on the Visual Analogue Scale) for the duration of the 12 weeks she was followed in the pain clinic. In the second study, three pediatric patients (aged 5 to 17) with confirmed SCN9A mutations underwent CT fluoroscopy-guided LSGB at the L3 or L4 level with a mixture of 0.2% ropivacaine, clonidine, and triamcinolone (43). Although there was some variation in the patients’ response, all three reported immediate and marked reduction in pain scores, with greatly reduced pain medication requirements. Also of note, these patients reported prolonged symptom relief ranging from 3 to 4 months to over 9 months. A caveat is that the number of patients reported in these studies is small and long-term follow-up is needed. Nevertheless, taken together, these reports provide some suggestive evidence that LSGB may show promise in some patients. Additional studies will be needed to determine the best way to achieve prolonged pain relief.

Spinal cord stimulation has been previously described as a potentially efficacious pain-management modality in case reports of both adult and pediatric patients with treatment refractory erythromelalgia (31; 65; 54; 24; 26; 44; 92). Dorsal root ganglion stimulation has also been suggested as a potential therapeutic option, trialed in one adult patient with medication-refractory erythromelalgia (32).

Given the fact that the sodium channel gene SCN9A has been identified as the source of pain and inflammation in primary erythromelalgia, there has been investigative work focusing on the gene as a molecular target for pain treatment and future therapies (83; 79; 81; 08; 17).

The possibility of Nav1.7-specific sodium channel blockers, which target Nav1.7, but leave other sodium channel subsets unblocked thereby minimizing off-target side effects, is also being explored (81; 29; 89). In a placebo-controlled, double-blind study, five patients with erythromelalgia were treated with single doses of an arylsulfonamide Nav1.7 blocker, resulting in decreased heat-induced pain in at least one of two trials in most of the patients (07). In the same study, induced pluripotent stem cells (iPSC) from patients with erythromelalgia were successfully differentiated into sensory neurons. These iPSC-derived sensory neurons reproduce the hyperexcitability, elevated spontaneous firing frequency, and heat sensitivity seen in the clinical phenotype of erythromelalgia. Application of the selective Nav1.7 channel blocker successfully reduced the frequency of spontaneous firing, increased the action potential rheobase, and reversed the elevated heat sensitivity in the iPSC-derived sensory neurons in a manner that parallels the patients’ responses.

A published report has described a second generation of Nav1.7 selective antagonists (01). These acylsulfonamide compounds have much slower dissociation from Nav1.7 when compared to the first generation arylsulfonamide blockers. In addition, with repeat dosing, the study demonstrated approximately 10-fold increased potency relative to first generation compounds. When these compounds were tested in mice, they showed robust analgesic and antinociceptive activity (69). These show promise for targeted treatment of erythromelalgia through selective Nav1.7 blockade.

Genomic analysis together with atomic-level structural modeling has been used to predict susceptibility of patients carrying an inherited erythromelalgia mutation, S241T of Nav1.7, to treatment with carbamazepine. In a double-blind crossover study of two patients with erythromelalgia from the same family carrying the S241T mutation, both patients reported a reduction in overall time in pain and duration of erythromelalgia episodes after treatment with carbamazepine. These patients also underwent fMRI scans to assess brain activity during treatment with carbamazepine and placebo. The reduction in pain was accompanied in the fMRI scans by a shift in activity away from valuation and pain areas of the brain (areas that are activated in association with chronic pain) toward somatosensory and parietal association cortex (areas activated by acute pain) (30).

In a 2017 study by Yang and colleagues, the effects of carbamazepine on Nav 1.7 I234T, a known erythromelalgia-causing mutation, were characterized. The study showed that the I234T mutation was in close proximity to previously predicted carbamazepine-responsive S241T mutation in the folded channel structure (87). The study also demonstrated that the I234T mutation causes a large hyperpolarizing shift in the V1/2 of activation, making the channel easier to open, and the I234T mutation increases the firing of DRG sensory neurons across physiological temperatures. When carbamazepine was applied at a clinically relevant concentration, there was a partial correction of the hyperpolarized V1/2 of activation and a reduction in the firing of DRG sensory neurons. This study provides verification of the utility of the pharmacogenomic approach to the treatment of patients.

One of the major conundrums regarding treatment of erythromelalgia, as has been described extensively here, is the individual-to-individual variations in the efficacy of treatment. In an extension of the pharmacogenomic approach, Mis and colleagues have published a proof of principle study using iPSCs from members of the same family with different intensity of IEM symptoms and whole exome sequencing, which demonstrates that the relative sensitivity to pain can be captured in an iPSC model, that in some cases mechanisms active in peripheral sensory neurons can contribute to differences in pain between individuals, and that genetic variants in other genes can modulate the excitability of sensory neurons (58). This proof of principle study was followed by Yuan and colleagues two years later, who showed, also in an iPSC-derived sensory neuron cell background, that the concept of “pain resilience mutations” generalizes and may contribute to observed inter-individual differences in pain sensation (90). Gaining a better understanding of these subtle variations between patients with IEM, even when they carry the same Nav1.7 mutation, moves us closer to individualized medicine and more efficacious treatment for patients with IEM.

In secondary erythromelalgia, the key to treatment is identification of the underlying cause. Treatment of this often mitigates the symptoms and leads to remission of outbreaks. For example, phlebotomy in patients with polycythemia and effectively normalizing platelet counts in patients with essential thrombocytopenia can initiate a commensurate decrease in secondary erythromelalgia symptoms (57). In cases where an external stimulus such as heat is the suspected exacerbation trigger, strict future avoidance of such stimuli should be recommended. In the event that a certain medication yields an eruption of symptoms, immediate withdrawal of offending agent is recommended. Low doses of aspirin have been shown to reduce the incidence of both arterial and venous thrombosis, thereby improving symptoms associated with the disorder (45). Thus, prophylactic use of low-dose aspirin is recommended to all patients with secondary erythromelalgia, particularly those with polycythemia vera-induced erythromelalgia (45).