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: A Review of Medical Management Options and Our Approach to Management.

Erythromelalgia (EM) is a rare disorder characterized by episodic, burning pain associated with erythema and warmth of the extremities. The feet and hands are most commonly affected. The pain can be so severe that patients may engage in behaviors, sometimes extreme, to cool the affected areas and change their lifestyle to avoid precipitating factors, such as exercise and increased ambient heat. A literature search was performed with PubMed and MEDLINE with the search term erythromelalgia. Inclusion criteria were studies on EM published after 1985 until January 1, 2022, in the English language and studies that provided information on medical treatment of EM. Studies were excluded if they were duplicates or did not include treatment data. No guidelines exist for the treatment of this complex disorder. Lifestyle modifications and pharmacologic treatments (topical and systemic) are discussed in this article, which provides a comprehensive review of published medical management options for erythromelalgia and a proposed approach to management.

Life-threatening hypothermia in a child with primary erythromelalgia.

Primary erythromelalgia is a rare autosomal-dominant condition due to pathogenic variant in the SCN9A gene, characterized by childhood onset of excruciating pain, redness, and warmth of acral sites. Patients often resort to ice water baths and other cooling measures to manage the discomfort. Hypothermia is a rare complication, reported only twice previously. We report a child with primary erythromelalgia due to a confirmed pathogenic variant admitted with life-threatening hypothermia. Although the overuse of cooling mechanisms may have contributed, we postulate that the SCN9A mutation may lead to thermodysregulation and make patients with primary erythromelalgia particularly susceptible to this complication.

High frequency dorsal column spinal cord stimulation for management of erythromelalgia.

Erythromelalgia is a rare hereditary channelopathy affecting the Nav1.7 sodium channel. Patients afflicted with this condition suffer from pain in their hands and feet, with vasomotor changes including flushing and redness to the distal upper and lower extremities. Current treatment modalities for this condition include pharmacological therapies (neuropathic medications), behavioural interventions, lumbar epidural infusions with local anaesthetics and sympathetic nerve blocks. Despite these treatments, many patients may have refractory pain. In these situations, there may be a role for dorsal column spinal cord stimulation for management of their pain. Here, we present the case of a 21-year-old man with 9-year history of refractory erythromelalgia successfully treated with paresthesia-free dorsal column spinal cord stimulation.

Dorsal Root Ganglion Stimulation for Erythromelalgia Related Foot Pain: A Case Report and Review of the Literature.

Erythromelalgia is a rare neurovascular disorder characterized by erythema, warmth, and episodic burning pain, often felt in the face, hands, and feet. Symptoms are typically worse with heat, exercise, stress, and during the overnight hours. Management often requires a multidisciplinary approach, including pain trigger avoidance, cool water baths, and topical and oral neuropathic medications. The use of spinal cord stimulation has been described in multiple case reports with success reported out to 24 months. To our knowledge, the use of dorsal root ganglion (DRG) stimulation for erythromelalgia-related pain has not been described. Herein, we present a case of erythromelalgia-related pain at the bilateral plantar surfaces of the feet, which was treated successfully with bilateral sacral S1 nerve root DRG stimulation.

Spinal Cord Stimulation in the Treatment of Pediatric Erythromelalgia.

BACKGROUND: In children, erythromelalgia is a rare but difficult to manage condition that results in bilateral episodic pain and redness in distal extremities. It is heat intolerant and relieved by cooling. Management of erythromelalgia is difficult and requires a complex multidisciplinary approach. CASE DESCRIPTION: We present a case of successful treatment of erythromelalgia with short-term spinal cord stimulation in a 12-year-old girl. The patient had severe burning pain, having undergone trials of multiple medical therapies before presenting to our department. Dual-lead spinal cord stimulator electrodes were successfully implanted without complication, leading to excellent pain control, now 8 months postimplant. CONCLUSIONS: This case spurs interest for future research in neuromodulation as part of the multimodal regimen to treat pediatric erythromelalgia.

[Erythromelalgia: skin redness and pain]. / Erythromelalgie: rote Haut und Schmerz.

Erythromelalgia is a rare disease that is associated with hemato-oncological diseases or after taking certain drugs and toxins, but it can also occur as an independent clinical picture, for example, due to mutations in the sodium channel NaV1.7. Clinically, there is a characteristic triad of attack-like burning pain and skin redness in the area of the distal extremities, which can be alleviated by excessive cooling. The attacks are triggered by heat, exertion, and stress. The diagnosis is primarily made clinically and can be confirmed by genetic testing if a sodium channel NaV1.7 mutation is present. Important differential diagnoses are complex regional pain syndrome, the non-freezing cold injury, and small fiber neuropathies. Therapy is multidisciplinary and has to be planned individually and include physical therapy and psychotherapy as well as drug therapy as integral components.

Pediatric red ear syndrome: A case report of an erythromelalgia type and review of the literature.

Red ear syndrome has been reported in the literature to have similarities to erythromelalgia with auricular involvement; however, the distinction between the two is controversial. Red ear syndrome has previously been classified as idiopathic (primary) or secondary, with headaches being the most common association in the idiopathic or primary form. We present a case of pediatric red ear syndrome with hand and foot involvement that we believe represents auricular erythromelalgia. In this report, we propose a classification system to unify the diagnoses of red ear syndrome and erythromelalgia and review the literature on pediatric cases of red ear syndrome.

Review of primary and secondary erythromelalgia.

Erythromelalgia is a condition characterized by episodic pain, erythema and temperature of the extremities, which is relieved by cooling and aggravated by warming. It is useful to review this topic in light of recent discoveries of the genetic mutations that now define primary erythromelalgia, as opposed to secondary erythromelalgia, which is often associated with underlying medical disorders.

Chemical lumbar sympathectomy in the treatment of recalcitrant erythromelalgia.

OBJECTIVE: Erythromelalgia is highly disabling and treatment is often very challenging. There have been solitary case reports that it might benefit from sympathectomy. This study sought to evaluate the short-term and long-term efficacy of chemical lumbar sympathectomy (CLS) for treatment of recalcitrant erythromelalgia and try to identify a CLS-responsive subset. METHODS: Patients with recalcitrant erythromelalgia were recruited from a tertiary hospital over a 10-year period. L3 to L4 CLS was performed using 5% phenol. The pain intensity score (visual analog scale [VAS] 0-10) was assessed before CLS and at 1 day, 1 week, 3 months, 6 months, 1 year, and 2 years after CLS. A VAS decrease of 90%-100% is defined as complete response, 60%-89% as major partial response. Relapse was defined by a return of a VAS score of 5 or higher. SCN9A gene mutations were screened. RESULTS: Thirteen patients were enrolled, with a median age of 15 years. The mean follow-up was 6.2 ± 3.8 years. SCN9A gene mutation was identified in five patients having family histories. The VAS was 8.2 ± 2.0 at baseline; it decreased to 4.9 ± 2.7 at 1 day and 1.9 ± 3.0 at 1 week after CLS. Nine patients (69.2%) achieved complete response at 1 week after CLS, including three patients with SCN9A gene mutation. Among the three complete response patients having the gene mutation, two reverted to major partial response and one relapsed at 2 years after CLS. Among the six complete response patients without mutation, five maintained complete response and one relapsed. Among the four patients who did not achieve complete response, one patient died at 3.5 months and one patient had an amputation performed at 4 months after CLS. CONCLUSIONS: CLS provides a valid option for the treatment of recalcitrant erythromelalgia. It takes about 1 week to achieve full efficacy. Relapse may occur, especially in patients with an SCN9A gene mutation.

Erythromelalgia.

Erythromelalgia is a rare syndrome characterized by the intermittent or, less commonly, by the permanent occurrence of extremely painful hyperperfused skin areas mainly located in the distal extremities. Primary erythromelalgia is nowadays considered to be a genetically determined neuropathic disorder affecting SCN9A, SCN10A, and SCN11A coding for NaV1.7, NaV1.8, and NaV1.9 neuronal sodium channels. Secondary forms might be associated with myeloproliferative disorders, connective tissue disease, cancer, infections, and poisoning. Between the pain episodes, the affected skin areas are usually asymptomatic, but there are patients with typical features of acrocyanosis and/or Raynaud's phenomenon preceding or occurring in between the episodes of erythromelalgia. Diagnosis is made by ascertaining the typical clinical features. Thereafter, the differentiation between primary and secondary forms should be made. Genetic testing is recommended, especially in premature cases and in cases of family clustering in specialized genetic institutions after genetic counselling. Multimodal therapeutic intervention aims toward attenuation of pain and improvement of the patient's quality of life. For this purpose, a wide variety of nonpharmacological approaches and pharmacological substances for topical and systemic use have been proposed, which are usually applied individually in a step-by-step approach. Prognosis mainly depends on the underlying condition and the ability of the patients and their relatives to cope with the disease.

Between fire and ice: refractory hypothermia and warmth-induced pain in inherited erythromelalgia.

Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Nav1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury. We describe a patient from a family with IEM due to the L858F mutation of Nav1.7 who presented with refractory hypothermia due to overcooling. This presentation of refractory hypothermia necessitating warming strategies, complicated by severe warmth-induced pain, posed a substantial therapeutic challenge. We report our experience in overcoming hypothermia lasting 3 weeks in a child with IEM, discuss possible pathophysiological mechanisms underlying this unusual complication and suggest potential therapeutic interventions.

[Pain and analgesia : Mutations of voltage-gated sodium channels]. / Schmerz und Schmerzlosigkeit : Mutationen spannungsabhängiger Natriumkanäle.

Voltage-gated sodium channels (Navs) are crucial for the generation and propagation of action potentials in all excitable cells, and therefore for the function of sensory neurons as well. Preclinical research over the past 20 years identified three Nav-isoforms in sensory neurons, namely Nav1.7, Nav1.8 and Nav1.9. A specific role for the function of nociceptive neurons was postulated for each. Whereas no selective sodium channel inhibitors have been established in the clinic so far, the relevance of all three isoforms regarding the pain sensitivity in humans is currently undergoing a remarkable verification through the translation of preclinical data into clinically manifest pictures. For the last ten years, Nav1.7 has been the main focus of clinical interest, as a large number of hereditary mutants were identified. The so-called "gain-of-function" mutations of Nav1.7 cause the pain syndromes hereditary erythromelalgia and paroxysmal extreme pain disorder. In addition, several Nav1.7 mutants were shown to be associated with small-fiber neuropathies. On the contrary, "loss-of-function" Nav1.7 mutants lead to a congenital insensitivity to pain. Recently, several gain-of-function mutations in Nav1.8 and Nav1.9 have been identified in patients suffering from painful peripheral neuropathies. However, another gain-of-function Nav1.9 mutation is associated with congenital insensitivity to pain. This review offers an overview of published work on painful Nav mutations with clinical relevance, and proposes possible consequences for the therapy of different pain symptoms resulting from these findings.

[Erythromelalgia: Diagnosis and therapeutic approach]. / L'érythromélalgie : approche diagnostique et thérapeutique actuelle.

Erythromelalgia is a rare intermittent vascular acrosyndrome characterized by the combination of recurrent burning pain, warmth and redness of the extremities. It is considered in its primary form as an autosomal dominant neuropathy related to mutations of SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Secondary erythromelalgia is associated with myeloproliferative disorders, drugs (bromocriptine, calcium channel blockers), or clinical conditions such as rheumatic diseases or viral infection. Primary familial erythromelalgia include genetics and sporadic forms associated with small fibers neuropathy. Aspirin is a useful treatment of erythromelagia associated with myeloproliferative disorders. Treatment of primary erythromelalgia is difficult, individualized, with sodium channel blockers such as lidocaine, carbamazepine and mexiletine.

Lumbar Sympathetic Pulsed Radiofrequency Treatment for Primary Erythromelalgia: A Case Report.

Erythromelalgia is often refractory and resistant to many forms of treatment. Numerous therapeutic options have been tried, but effective treatment remains elusive. The sympathetic nervous system has been involved in various painful conditions of neuropathic, vascular, and visceral origin. Sympathetic block is helpful in making a diagnosis and managing pain. We report a case of excellent pain relief after lumbar sympathetic pulsed radiofrequency treatment in a patient with primary erythromelalgia of the lower extremities. This case suggests the viability of pulsed radiofrequency treatment in patients with erythromelalgia.

Small fiber neuropathy: Getting bigger!

Etiological and clinical heterogeneity of small fiber neuropathy (SFN) precludes a unifying approach and necessitates reliance on recognizable clinical syndromes. Symptoms of SFN arise from dysfunction in nociception, temperature, and autonomic modalities. This review focuses on SFN involving nociception and temperature, examining epidemiology, etiology, clinical presentation, diagnosis, pathophysiology, and management. Prevalence of SFN is 52.95 per 100,000 population, and diabetes and idiopathic are the most common etiologies. Dysesthesia, allodynia, pain, burning, and coldness sensations frequently present in a length-dependent pattern. Additional autonomic features in gastrointestinal, urinary, or cardiovascular systems are frequent but poorly objectified. SFN is diagnosed by intraepidermal nerve fiber density and quantitative sensory and autonomic tests in combination with normal nerve conduction. Pathophysiological understanding centers on sodium channel dysfunction, and genetic forms are beginning to be understood. Treatment is directed at the underlying etiology supported by symptomatic treatment using antidepressants and anticonvulsants. Little is known about long-term outcomes, and systematic cohort studies are needed.