Red ear syndrome: a case series and review of the literature.

BACKGROUND: Red Ear Syndrome is a burning sensation and erythema of the ear, associated with a various number of disorders including migraine, trigeminal neuralgia, autoimmune disorders etc. Theories for RES pathophysiology have developed from current understandings of comorbid conditions. Characterizing the underlying mechanism of RES is crucial for defining effective treatments. CASE PRESENTATION: Three caucasian patients, ages 15, 47, and 67 years, with migraine, one with erythromelalgia are reported in this manuscript. RES pathophysiology is not fully understood due to its variable clinical presentation and numerous comorbid conditions, making it difficult to identify effective treatments. CONCLUSION: RES seems to be largely treatment-resistant, and most options involve treating the associated disorders and minimizing pain. Further investigation of future cases should lead to a more comprehensive understanding of the fundamental cause of RES and, hopefully, successful treatments.

Osimertinib­induced erythromelalgia: A case report.

The present study reports a case of osimertinib-induced erythromelalgia in a patient with metastatic lung adenocarcinoma. Osimertinib is an antineoplastic drug that irreversibly inhibits the epidermal growth factor receptor (EGFR) pathway by binding to the intracellular receptor tyrosine kinase site, thus preventing EGFR signal transduction. A 77-year-old female with a lung adenocarcinoma recurrence with secondary metastases was prescribed osimertinib therapy. The patient presented with painful erythema and warmth in the distal phalanges of all fingers on both hands, which worsened with heat and relieved with cold. Based on clinical data, erythromelalgia was diagnosed. Considering the age of onset, a primary erythromelalgia was ruled out. Further investigations excluded other secondary causes of erythromelalgia, therefore osimertinib was suspected as the cause. Although no cases of EGFR inhibitor-induced erythromelalgia have been reported, cutaneous adverse events induced by EGFR inhibitors have been documented. The present case may be the first evidence of osimertinib-induced erythromelalgia and may help clinicians to properly support patients who develop this EGFR inhibitor adverse event.

Painful Raynaud's mimics.

Raynaud's syndrome is a common finding in many autoimmune conditions. Accurately diagnosing Raynaud's, and differentiating it from mimicking conditions, is imperative in rheumatologic diseases. Raynaud's syndrome and Raynaud's mimickers, especially painful Raynaud's mimickers, can prove a diagnostic challenge for the practicing rheumatologist. Painful Raynaud's mimickers can lead to increased patient stress and unnecessary medical work up; Healthcare providers need to be aware of Raynaud's mimickers when evaluating patient concerns of skin color changes and pain. The present narrative review aims to highlight Raynaud's syndrome, important painful mimickers that may be seen, diagnosis, and updated management recommendations.

Treating Erythromelalgia with Interosseous Membrane Stimulation: An Autonomic Basis for the Condition and Its Treatment.

Background: Erythromelalgia, which has primary and secondary presentations, causes heat, pain, and redness in the skin. The condition seems to have an autonomic basis, with vasomotor dysfunction causing dilatation of some blood vessels and constriction of others. No consistently effective treatments have been reported. Anticonvulsant, antidepressant, antihistamine, anti-inflammatory, antihypertensive, analgesic, nutritional, and topical approaches have been tried as were lidocaine infusions, nerve blocks, and thoracic and lumbar sympathectomies. Interosseous membrane stimulation appears to affect the local autonomic milieu in the extremity being treated. This approach was used on a patient with erythromelalgia. Case: A 36-year-old woman with erythromelalgia was treated with interosseous membrane stimulation. Eight treatments were given over a 1-year timeframe at 1-3-month intervals. Results: This patient repeatedly experienced much relief from her burning paresthesias, swelling, diaphoresis, and ruddy discoloration of her extremities for 6-8 hours following each treatment. The intensity of her discomfort subsided gradually over time. Conclusions: Interosseous membrane stimulation is a safe, simple, and effective treatment for erythromelalgia, which is notoriously refractory to treatment. This patient's response to treatment might have been a result of localized derangement of her autonomic nervous system. It is possible that manipulation of the autonomic milieu of an extremity is a significant factor in the mechanism of action of interosseous membrane stimulation.

A novel cause of erythromelalgia due to pseudoephedrine.

Objective: Erythromelalgia is a rare, highly debilitating disorder characterised by severe episodes of discomfort, erythema, and desquamation of the extremities. Its causes include genetic factors, medications, and several underlying medical conditions. This paper describes a novel cause of erythromelalgia through a case report and literature review. Case description: A 47-year-old Caucasian man presented with a two-year history of intermittent pain, redness and desquamation of the hands. He experienced several such episodes, each lasting 3-4 weeks. A skin biopsy confirmed the diagnosis of erythromelalgia. After several recurrences, he admitted to the intermittent use of pseudoephedrine as a nasal decongestant, which coincided with the episodes of erythromelalgia. Complete resolution of symptoms was reported on cessation of this medication. Conclusion: Pseudoephedrine has been reported to cause a wide range of cutaneous reactions but has not been known to precipitate erythromelalgia. Recognition of this rare side effect may offer early diagnosis and reduced morbidity.

Erythromelalgia Secondary to Anti-Tumor Necrosis Factor (TNF) Alpha Therapy: A Report of Two Cases.

Erythromelalgia is a rare syndrome with a generally unknown etiology. Whether primary or secondary, this condition is characterized by paroxysmal episodes of erythema, pain, and heat in the extremities. We report two cases of erythromelalgia occurring after the initiation of treatment with infliximab. The first case involves a 38-year-old patient who had been followed since August 2022 for ileocolonic Crohn's disease classified as A2L3B3 according to the Montreal classification, which was resistant to treatment and required infliximab therapy. Two months after the first infusion of infliximab, the patient developed symptoms of erythromelalgia. After ruling out other potential causes through an etiological assessment and conducting a pharmacological investigation, infliximab was considered the most likely cause. Infliximab was discontinued, and symptomatic treatment was initiated, including vascular laser sessions. The patient showed significant clinical improvement. In the second case, a 16-year-old patient with ileocolonic Crohn's disease classified as A1L3B3 according to the Montreal classification was treated with ileocecal resection and received an infusion of infliximab. Sixteen days after the second infusion, she developed clinical symptoms of erythromelalgia. The etiological assessment was inconclusive. Due to a strong suspicion of erythromelalgia secondary to tumor necrosis factor (TNF) alpha inhibitor therapy, infliximab was replaced with ustekinumab. The patient also received symptomatic treatment, and her clinical condition improved, marked by the disappearance of pain.

Erythromelalgia. Part II: Differential diagnoses and management.

The management of erythromelalgia is challenging and requires multidisciplinary effort. Patient education is crucial as unsafe self-administered cooling techniques can lead to significant morbidity, including acral necrosis, infection, and amputation. The goal of management is pain control, reduction of flare frequency, and prevention of complications. This text is focused on the management of erythromelalgia and several other incompletely understood and under-recognized neurovascular disorders such as red scrotum syndrome, red ear syndrome, facial flushing, and complex regional pain syndrome.

Erythromelalgia. Part I: Pathogenesis, clinical features, evaluation, and complications.

Erythromelalgia is a rare pain disorder that is underrecognized and difficult-to-treat. It is characterized by episodes of extremity erythema and pain that can be disabling; it may be genetic, related to an underlying systemic disease, or idiopathic. Considering the prominent cutaneous features characteristic of the condition, dermatologists can play an important role in early recognition and limitation of morbidity. The first article in this 2-part continuing medical education series reviews the epidemiology, pathogenesis, clinical manifestations, evaluation, and complications.

Erythromelalgia caused by the missense mutation p.Arg220Pro in an alternatively spliced exon of SCN9A (NaV1.7).

Erythromelalgia (EM), is a familial pain syndrome characterized by episodic 'burning' pain, warmth, and erythema. EM is caused by monoallelic variants in SCN9A, which encodes the voltage-gated sodium channel (NaV) NaV1.7. Over 25 different SCN9A mutations attributed to EM have been described to date, all identified in the SCN9A transcript utilizing exon 6N. Here we report a novel SCN9A missense variant identified in seven related individuals with stereotypic episodes of bilateral lower limb pain presenting in childhood. The variant, XM_011511617.3:c.659G>C;p.(Arg220Pro), resides in the exon 6A of SCN9A, an exon previously shown to be selectively incorporated by developmentally regulated alternative splicing. The mutation is located in the voltage-sensing S4 segment of domain I, which is important for regulating channel activation. Functional analysis showed the p.Arg220Pro mutation altered voltage-dependent activation and delayed channel inactivation, consistent with a NaV1.7 gain-of-function molecular phenotype. These results demonstrate that alternatively spliced isoforms of SCN9A should be included in all genomic testing of EM.

Studying Erythromelalgia Using Doppler Flowmetry Perfusion Signals and Wavelet Analysis-An Exploratory Study.

Erythromelalgia (EM) is a rare disease, which is still poorly characterized. In the present paper, we compared the hand perfusion of one female EM patient, under challenges, with a healthy control group. Using a laser Doppler flowmeter (LDF) with an integrated thermal probe, measurements were taken in both hands at rest (Phase I) and after two separate challenges-post-occlusive hyperemia (PORH) in one arm (A) and reduction of skin temperature (cooling) with ice in one hand (B) (Phase II). The final measurement periods corresponded to recovery (Phases III and IV). The control group involved ten healthy women (27.3 ± 7.9 years old). A second set of measurements was taken in the EM patient one month after beginning a new therapeutic approach with beta-blockers (6.25 mg carvedilol twice daily). Z-scores of the patient's LDF and temperature fluctuations compared to the control group were assessed using the Wavelet transform (WT) analysis. Here, fluctuations with |Z| > 1.96 were considered significantly different from healthy values, whereas positive or negative Z values indicated higher or lower deviations from the control mean values. Cooling elicited more measurable changes in LDF and temperature fluctuations, especially in higher frequency components (cardiac, respiratory, and myogenic), whereas PORH notably evoked changes in lower frequency components (myogenic, autonomic, and endothelial). No significant Z-score deviations were observed in the second measurement, which might signify a stabilization of the patient's distal perfusion following the new therapeutic approach. This analysis involving one EM patient, while clearly exploratory, has shown significant deviations in WT-derived physiological components' values in comparison with the healthy group, confirming the interest in using cold temperature as a challenger. The apparent agreement achieved with the clinical evaluation opens the possibility of expanding this approach to other patients and pathologies in vascular medicine.

A case of erythromelalgia with gastrointestinal dysautonomia treated with immunoglobulin: A case report.

An 18-year-old female with a history of atopic march, hyperhidrosis, and eosinophilic esophagitis was diagnosed with erythromelalgia and gastrointestinal dysautonomia secondary to presumed autoimmune small fiber neuropathy. The patient experienced significant clinical improvements after the initiation of intravenous immunoglobulin therapy, supporting an underlying autoimmune disorder.

Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain.

We show here that hyperpolarization-activated current (Ih ) unexpectedly acts to inhibit the activity of dorsal root ganglion (DRG) neurons expressing WT Nav1.7, the largest inward current and primary driver of DRG neuronal firing, and hyperexcitable DRG neurons expressing a gain-of-function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain. In this study we created a kinetic model of Ih and used it, in combination with dynamic-clamp, to study Ih function in DRG neurons. We show, for the first time, that Ih increases rheobase and reduces the firing probability in small DRG neurons, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih . Our results show that Ih , due to slow gating, is not deactivated during action potentials (APs) and has a striking damping action, which reverses from depolarizing to hyperpolarizing, close to the threshold for AP generation. Moreover, we show that Ih reverses the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. In the aggregate, our results show that Ih unexpectedly has strikingly different effects in DRG neurons as compared to previously- and well-studied cardiac cells. Within DRG neurons where Nav1.7 is present, Ih reduces depolarizing sodium current inflow due to enhancement of Nav1.7 channel fast inactivation and creates additional damping action by reversal of Ih direction from depolarizing to hyperpolarizing close to the threshold for AP generation. These actions of Ih limit the firing of DRG neurons expressing WT Nav1.7 and reverse the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. KEY POINTS: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, the molecular determinants of hyperpolarization-activated current (Ih ) have been characterized as a 'pain pacemaker', and thus considered to be a potential molecular target for pain therapeutics. Dorsal root ganglion (DRG) neurons express Nav1.7, a channel that is not present in central neurons or cardiac tissue. Gain-of-function mutations (GOF) of Nav1.7 identified in inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, produce DRG neuron hyperexcitability, which in turn produces severe pain. We found that Ih increases rheobase and reduces firing probability in small DRG neurons expressing WT Nav1.7, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih . We also demonstrate that Ih reverses the hyperexcitability of DRG neurons expressing a GOF Nav1.7 mutation (L858H) that causes IEM. Our results show that, in contrast to cardiac cells and CNS neurons, Ih acts to stabilize DRG neuron excitability and prevents excessive firing.

Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders.

BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.

Clinical Characterization of Pediatric Erythromelalgia: A Single-Center Case Series.

Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates. There was a female predominance (2.5:1), and the median onset age was 12 years (IQR = 3-14). Patients saw a median of three specialists (IQR = 2-3) for a diagnosis. The majority (90%) reported bilateral symptoms. Cooling methods usually provided partial relief, while heat and exercise exacerbated pain. No medication appeared to be consistently effective; commonly prescribed medications included sodium channel blockers (n = 37), topical analgesics (n = 26), gabapentin (n = 22), and aspirin (n = 15). Based on the currently published literature, we believe this cohort is the largest pediatric study of erythromelalgia to date. Many findings are consistent with those of previously published case series. Work is in progress to establish a prospective cohort and multi-center registry.

Case report: Spinal cord stimulation in the treatment of pediatric erythromelalgia.

Introduction: In children, erythromelalgia is a rare chronic pain syndrome characterized by erythema, severe burning pain, and itching of affected feet. Unfortunately, there is no definitive therapy available currently. Case report: Here, we report a case of primary erythromelalgia and the treatment response in a 10-year-old boy, whose genetic findings for mutations in the SCN9A gene were positive and skin biopsy results were diagnosed as small fiber neuropathy, while he has suffered from excruciating burning pain, itching, erythema, and recurrent infections over the past 3 years. He did not respond well to conventional treatment, and the only way to receive minimal relief was to immerse his feet in ice water. After a successful trial of spinal cord stimulation (SCS), the implantable pulse generator (IPG) was successfully implanted without complications, and it proved partial response to therapy. Conclusion: There is no specific, efficient treatment for pediatric erythromelalgia currently, but this case demonstrates neuromodulation serves as part of the multimodal regimen to treat pediatric erythromelalgia.

[Simultaneous Analysis of Paralepistopsis acromelalga Applied to Cooked and Processed Foods].

The applicability of a method for simultaneous analysis of Acromelic acids A, B, and Clitidine, which are venomous constituents of Paralepistopsis acromelalga, was assessed for three simulations: tempura, chikuzenni, and soy sauce soup. All components were detectable for all cooking methods. No interfering peak affecting the analysis was observed. The findings indicate that samples of leftover cooked products can be used to ascertain causes of food poisoning by Paralepistopsis acromelalga. Additionally, results showed that most of the toxic components were eluted into the soup broth. This property is useful for rapid screening for Paralepistopsis acromelalga in edible mushrooms.

Endoscopic lumbar sympathectomy as a treatment option for primary erythromelalgia - case report and review.

Erythromelalgia is a rare disease, involving pain, edema, redness, and hyperthermia in the limbs. It is extremely refractory to drugs, has no defined treatment, and causes psychological comorbidities in the patient. We describe a case of erythromelalgia involving a 17-year-old boy who had been suffering from the disease for almost 4 years prior to finding an effective treatment. A bilateral endoscopic lumbar sympathectomy was performed, limited to L2 and L3 resections. Four weeks after the procedure, the patient's symptoms were significantly mitigated and at 8 months follow-up he remained almost asymptomatic. Endoscopic lumbar sympathectomy was an effective treatment for primary erythromelalgia in this teenager, with exceptional reduction of his symptoms.

Eritromelalgia é uma doença rara caracterizada por dor, edema, eritema e hipertermia nos membros. É extremamente refratária a medicamentos e não tem um tratamento definido, causando comorbidades psicológicas para o paciente. Descrevemos o caso de um menino de 17 anos que possuía eritromelalgia há quase 4 anos antes de ser submetido a um tratamento efetivo. Foi realizada simpatectomia lombar endoscópica bilateral limitada à ressecção dos gânglios L2 e L3. Após 4 semanas do procedimento, o paciente teve diminuição significativa dos seus sintomas e, com 8 meses de seguimento, permanece praticamente assintomático. A simpatectomia lombar endoscópica foi um tratamento eficaz para eritromelalgia primária em um adolescente, com redução excepcional dos seus sintomas.