Headache & Pain
Migraine: pathogenesis and pathophysiology
Nov. 18, 2022
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The authors have summarized erythromelalgia in this article. Discoveries of sodium channel mutations help our understanding of a variety of pain syndromes, including erythromelalgia. The authors further elaborate on its differential diagnosis, pathophysiology, and the current management options. Importantly, the role of aspirin in the diagnosis and management of secondary erythromelalgia has been emphasized.
• Erythromelalgia is characterized by episodic vasodilation associated with severe burning pain in the extremities.
• Primary erythromelalgia can be either familial or sporadic.
• Gain-of-function mutations of gene SCN9A (which encodes the Nav1.7 sodium channel) are present in many patients with primary erythromelalgia.
• Secondary erythromelalgia often presents as a symptom of underlying disease. It is often associated with myeloproliferative diseases; in these cases, it can be remarkably responsive to treatment with aspirin.
• Although many medications have been used for the treatment of erythromelalgia, the cornerstone of treatment is genetic counseling and avoidance of triggers.
Erythromelalgia, or “Mitchell disease,” was first described by Dr. Silas Wier Mitchell in 1878 (61). Erythromelalgia, which literally means red, painful extremities, describes an exceedingly rare, chronic condition that is characterized by the clinical triad of pronounced erythema, painful burning, and elevated skin temperature usually around the extremities (12; 83; 84). Clinically, erythromelalgia presents as intense redness (erythros) and severe pain (algia) in the extremities (melos). Erythermalgia, the alternative name of the condition, describes the elevated temperature (thermos) that is often noticed in the affected areas.
Although first described in 1878, the first major study reporting the incidence of erythromelalgia was conducted in 1932 at the Mayo Clinic. The study estimated the incidence of the disease to be in the range of one case per 40,000 patients (04). 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 (90). A comprehensive study undertaken in Norway in 1997 estimated the incidence of erythromelalgia to be 0.25/100,000 and prevalence 2/100,000, further strengthening the notion that the original Mayo Clinic study may have overreported the overall incidence of the disease (46; 43).
The genetic and molecular basis underlying primary erythromelalgia was not uncovered until the early 2000s; the inherited erythromelalgia susceptibility gene was first localized to the long arm of chromosome 2 based on a genomic analysis of one large kindred from the United States (20). Three years later, in 2004, linkage analysis identified mutations in the SCN9A gene, encoding the voltage-gated sodium channel NaV1.7, in a family with primary erythromelalgia. Studies in experimental animals have shown that the Nav1.7 sodium channel, which is preferentially expressed with dorsal root ganglion neurons and sympathetic ganglion neurons (77; 69), plays a major role in inflammatory pain (03; 64), but until the demonstration of mutations of Nav1.7 in patients with erythromelalgia, there was no definitive evidence for a role of this channel in pain in humans. Erythromelalgia is the first known human pain syndrome to be examined at a molecular level. Interestingly, primary erythromelalgia is also the first known human disease that involves the Nav1.7 sodium channel.
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 (59; 83; 84; 82). Occasional sporadic cases of juvenile-onset erythromelalgia have been reported to occur as a result of a de novo founder mutation in the SCN9A gene of the proband (35; 36). In these cases, although the mutation is present only in the proband and would be passed on to 50% of the offspring, it is not present in the proband’s parents.
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 (22; 49; 74; 42). 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 (43).
Although it is a chronic condition, symptoms tend to be more episodic than continuous and often occur following exposure to certain stimuli (05; 09). Attacks are described by patients as severe burning pain with accompanying redness in the extremities in response to warm stimuli or moderate exercise (78; 65). The lower extremities are more commonly involved than the upper extremities, and involvement is usually symmetrical (12; 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 (57).
There have been reports that the symptoms of this debilitating condition also tend to become worse as the patient ages (54). Furthermore, the affected areas may expand to include greater parts of the extremities, sometimes as far as the knee, as a person gets older (54). Increased age in patients with the condition correlates with significantly decreased survival when compared with individuals in the general population without the condition (15; 23; 70). 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 hot to the touch (16). 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, but in contrast to complex regional pain syndrome reflex sympathetic dystrophy, erythromelalgia is bilateral and symmetric (61; 78; 66).
Increases in environmental temperature seem to provoke exacerbation of the condition (34). Thus, exercise, exposure to warmth (including the summer months), and long periods of standing can possibly trigger attacks in at-risk individuals (78; 65; 34). Given this finding, exposure to environments with cooler temperatures tends to mitigate symptoms in individuals with erythromelalgia (13; 34). Environmental factors, including certain foods, alcoholic beverages, and spices, have been reported to aggravate symptoms in patients (66). Moreover, a characteristic feature is relief obtained by immersing the extremities in ice, which can lead to ulceration and gangrene. In the absence of a clear etiology, treatment has been empirical and only partially effective in most cases.
Erythromelalgia is a painful inherited neuropathy that can be difficult to treat (83; 84). Early recognition and diagnosis remains the cornerstone of treatment. Crucial to achieving this end is the ability of clinicians to recognize characteristic clinical signs. Diagnostic confirmation in suspected patients can be achieved via full neurologic examination, which tends to be normal, and verification with tests such as MRI scan of the brain, skin biopsy, nerve conduction studies, and electromyography to rule out other disorders (13; 66). The condition does remit spontaneously in occasional one third of patients (12; 83; 84).
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; he slept uncovered and often kept the room cool through the use of an air conditioner. 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; therefore, he began to avoid these things as well.
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. Of note, due to the severity of her symptoms, his aunt had decided not to have children. 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 scan 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. In fact, she stated that bathing in her Jacuzzi, a favorite pastime, always triggered the symptoms. 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.
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 (20; 87). 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 (77). 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 (which makes it easier to activate the channel) and slowed deactivation (which keeps the channel open longer than normal). In other words, a mutation that hyperpolarizes the activation of NaV1.7 channels makes it easier for a depolarizing stimulus to activate, or turn on, the channel. Because sodium channel activation results in an inward electrical current that depolarizes neurons, NaV1.7 mutations that cause erythromelalgia render DRG neurons hyperexcitable. At the cellular level, 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 (10; 83; 84; 82). Primary erythromelalgia is an autosomal dominant disorder; penetrance appears to be 100% for inherited mutations (87; 17). In addition to pain signaling DRG neurons, sympathetic peripheral fibers have also been recognized as being adversely affected by the mutations (49; 44). At a physiological level, erythromelalgia mutations in Nav1.7 typically result in hyperexcitability of the nociceptive DRG neurons in which Nav1.7 is normally present, causing these cells to generate inappropriate action potentials that are relayed to the brain, signaling the presence of a painful stimulus even when one is not there (17; 84). Dynamic clamp studies of the L858H IEM mutation have definitely shown that hyperexcitability of small DRG neurons, including nociceptors, is directly linked to amplification of net sodium influx (26; 79). However, these same mutations produce hypoexcitability within sympathetic ganglion neurons, which also express Nav1.7 (69), providing a basis for the abnormality of sympathetic vasomotor control that is seen in these patients (69).
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 (73). 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 (39). 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 (18).
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 (28). 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 (28). 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 (87). In fact, secondary erythromelalgia is a distinct, acquired disorder whose development is believed to be associated with rheumatologic and autoimmune factors (72). 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 (24; 51; 21; 63; 49). Unlike primary erythromelalgia, which is associated with alterations of critical sodium channels on the molecular level, secondary erythromelalgia has been suggested to be associated with acquired vascular changes that eventually lead to local hypoxia-induced symptoms in affected areas (63). Studies suggest that the condition arises in the setting of systemic disorders as a result of 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 (63). 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 (43; 63; 52).
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 overall incidence of both primary and secondary erythromelalgia is thought to be in the range of one case per 40,000 or 3.3 cases per million depending on the study (04; 63). A study suggested that the annual prevalence of the condition ranges between 18 and 20 cases per million (43; 63). Although primary erythromelalgia is familial and often presents early in life, the secondary subset of the disorder can occur at any age and affects both genders equally. A comprehensive study undertaken in Norway in 1997 estimated the incidence of erythromelalgia to be 0.25/100,000 and a prevalence of 2/100,000, further strengthening the notion that the original Mayo Clinic study may have overreported the overall incidence of the disease (46; 43).
Given that erythromelalgia is precipitated via exposure to elevated temperatures, strict future avoidance of such environments should be encouraged (63; 12). For example, exercise regimens that require exposure to arid environments such as beaches or deserts should be avoided. Furthermore, recreational activities such as Jacuzzi or sauna bathing should be minimized on account of the contributory role they play in exacerbating symptoms. 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 (63). However, patients should be cautioned not to immerse their limbs in ice water, which can cause gangrene and life-threatening hypothermia (55), but rather to use a fan.
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)
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 (63).
Although early recognition and treatment of the condition represent the best probability for successfully managing erythromelalgia, diagnosis can present a challenge for clinicians (05; 66). Although the diagnosis should be guided via a thorough history and physical examination, a battery of other interventions 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; 66). Furthermore, use of full neurologic examination, MRI scan of the brain, skin biopsy, nerve conduction studies, and electromyography and microneurography are useful in preventing misdiagnosis (16; 66). 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). In such patients, meticulous recording of skin temperature in affected areas along with transcutaneous oximetry and laser Doppler flow can be instrumental in arriving at an accurate diagnosis (16). Furthermore, because small-fiber neuropathy has been reported in some patients with erythromelalgia, thermoregulatory sweat testing can be a sensitive and effective marker in diagnosing patients with the disease (13).
Erythromelalgia secondary to myeloproliferative disease can respond dramatically to aspirin (58). 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 (66).
Although developing a broad, reflective differential is important, a thorough history and diagnostic evaluation are critical to prevent misdiagnosis. This is especially true of other neurologic syndromes that tend to mimic erythromelalgia such as complex regional pain syndrome, chronic mountain sickness, Anderson-Fabry disease, autosomal dominant burning feet syndrome, and chronic idiopathic axonal polyneuropathy. 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 (53). In fact, sensorineural deafness can be seen in as many as 78% of patients with Anderson-Fabry disease (53). Erythromelalgia rarely affects visceral organs and tends to primarily affect the distal extremities, primarily on a superficial level. Perhaps the disorder that most closely mimics erythromelalgia is chronic mountain sickness, which can only be distinguished via nerve biopsy (76). Like erythromelalgia, the most prominent clinical finding in chronic mountain sickness tends to be burning in the distal extremities (76). Nerve biopsy in a patient with chronic mountain sickness will demonstrate demyelination as well as the reduction of unmyelinated axons, whereas no such reduction in myelin is demonstrable in patients with erythromelalgia (76; 13). Chronic idiopathic axonal polyneuropathy presents with burning pain in the distal extremities, but unlike erythromelalgia, idiopathic axonal polyneuropathy most commonly affects disabled elderly men (40).
As a result of the lack of studies on the condition, erythromelalgia was characterized as refractory to medical management (72). Although researchers have made great strides in understanding the condition, many cases of erythromelalgia remain difficult and frustrating undertakings (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 (63). Importantly, in patients with primary erythromelalgia, genetic counseling and counseling on the chronic nature of the disease is essential (38). 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 (75). 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 (41). 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 (67). Interestingly, 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 (11), with intravenous immunoglobulin (62) 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 (70; 68). Further, 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 (19; 29).
Medical management is currently the most effective method of treating primary erythromelalgia and should include genetic counseling and symptomatic management of exacerbations (66). 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 (08). 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) (37). 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 (50). 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 (45). 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.
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 exciting work focusing on the gene as a molecular target for pain treatment and future therapies (83; 80; 81; 07; 18).
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; 30; 88). 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 (06). 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 (71). These are early studies, but they show promise for improved erythema multiforme treatment through selective Nav1.7 blockade in the future.
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) (31).
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 atomic proximity to previously predicted carbamazepine-responsive S241T mutation in the folded channel structure (86). 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 (60). 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 (89). 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 (59). 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 (48). Thus, prophylactic use of low-dose aspirin is recommended to all patients with secondary erythromelalgia, particularly those with polycythemia vera-induced erythromelalgia (48).
Separate from medical management, it has been suggested that operative procedures may provide some level of relief in select patient populations. Spinal cord stimulation has been previously described as a potentially efficacious pain-management modality in case reports of both adult and pediatric patients (32; 67; 56; 25; 27; 47). Dorsal root ganglion stimulation has also been suggested as a potential therapeutic option, trialed in one adult patient with medication-refractory erythromelalgia (33). This may provide some relief in selected cases of inherited erythromelalgia, where the primary driver of pain is a gain-of-function mutation in NaV1.7 channels at the dorsal root ganglion level.
Matthew Alsaloum PhD
Dr. Alsaloum of Yale School of Medicine has no relevant financial relationships to disclose.See Profile
Philip R Effraim MD PhD
Dr. Effraim of Yale University has no relevant financial relationships to disclose.See Profile
Stephen G Waxman MD PhD
Dr. Waxman of Yale University has no relevant financial relationships to disclose.See Profile
Emma Ciafaloni MD FAAN
Dr. Ciafaloni of the University of Rochester received personal compensation for serving on advisory boards and/or as a consultant for Alexion, Avexis, Biogen, PTC Therapeutics, Ra Pharma, Strongbridge Biopharma PLC, and Wave; and for serving on a speaker’s bureau for Biogen. Dr Ciafaloni also received research and/or grant support from Orphazyme, Santhera, and Sarepta.See Profile
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