Erythromelalgia: Symptoms, Types, Causes and Treatment

Erythromelalgia is a rare but often debilitating condition that can dramatically impact an individual’s quality of life. Characterized primarily by episodes of burning pain and redness in the extremities, it can be challenging to diagnose and even more difficult to manage. Recent advances have shed light on the underlying mechanisms and potential treatments, but for many patients, the journey remains complex. In this article, we’ll break down the key symptoms, types, causes, and treatment options for erythromelalgia, providing a comprehensive and evidence-based overview.

Symptoms of Erythromelalgia

Living with erythromelalgia means contending with a constellation of symptoms that can disrupt daily routines, comfort, and even social participation. The classic presentation centers on burning pain, redness, and warmth—usually in the feet and hands. These episodes are typically triggered by heat, exercise, or even seemingly minor environmental changes, and are often alleviated by cooling.

Symptom	Description	Typical Areas	Source(s)
Pain	Burning, severe, episodic	Usually feet/hands	2 3 4 5 7
Redness	Marked erythema of affected areas	Extremities	2 3 4 5
Warmth	Increased skin temperature	Extremities	2 3 4 5
Swelling	Variable, often during episodes	Hands/feet	4 5
Triggers	Heat, exercise, dependency, spicy food, alcohol	Hands/feet	2 4 5
Relief	Cooling, elevation, rest	Hands/feet	2 3 4 5
Impact	Impaired mobility, QOL, school/work absence	General	4 5

Table 1: Key Symptoms of Erythromelalgia

Hallmark Symptoms

The cardinal symptoms of erythromelalgia are episodes of:

• Burning pain: This is often described as severe, sometimes excruciating, and can last from minutes to hours or even persist without treatment 2 3 4 5.
• Redness and warmth: The affected areas become noticeably red and hot to the touch during episodes 2 3 4.
• Swelling: In some cases, swelling accompanies the pain and redness, making movement uncomfortable or impossible 4 5.

Typical Patterns and Distribution

• The feet are most commonly affected, followed by the hands. Some individuals may also experience symptoms in other areas, such as the face or ears, but this is less frequent 2 3 4 5.
• Episodes are often symmetrical and may involve both sides of the body simultaneously 7.

Triggers and Relief

• Heat is the most common trigger: warm environments, physical activity, or even wearing warm socks can precipitate attacks 2 4 5.
• Other triggers include alcohol, spicy foods, and dependency of the limb (letting it hang down) 2 4.
• Cooling—such as immersing the affected limb in cold water—provides relief, but overuse can lead to skin damage or immersion injury 3 4 5 15.
• Elevation of the extremity can also help, although relief is often temporary 2 3 4.

Impact on Quality of Life

• The pain can be so intense that daily activities, such as walking or wearing shoes, become impossible 4 5.
• Many patients experience significant reductions in quality of life, with some unable to attend school or maintain employment due to their symptoms 4 5.
• Despite these challenges, a large proportion of individuals with erythromelalgia remain undiagnosed for years 5.

Types of Erythromelalgia

Erythromelalgia is not a single disease but a syndrome that encompasses several forms, each with distinct features, underlying causes, and responses to treatment. Recognizing the type is crucial, as it guides both diagnosis and management.

Type	Age of Onset	Main Features	Source(s)
Primary	Childhood/Teens	Idiopathic or genetic, symmetric	3 6 7 8 9 10
Inherited	Childhood/Adult	Familial, SCN9A mutation	6 7 10 16
Secondary	Adult	Associated with other diseases	2 3 8 9
Aspirin-responsive	Adult	Linked to thrombocythemia	1 2 3 8 11

Table 2: Types of Erythromelalgia

Primary Erythromelalgia

• Definition: Occurs in the absence of an associated disease; often idiopathic or genetic 7 8 9.
• Onset: Typically in childhood or adolescence, but adult-onset forms also exist 3 6 7.
• Features: Bilateral, symmetric burning pain, redness, and warmth, usually in the lower limbs 7 8.
• Genetic Link: Many cases are familial and caused by mutations in the SCN9A gene, which encodes the Nav1.7 sodium channel 6 7 10 16.
• Aspirin Response: Usually poor; childhood forms often resistant to aspirin 3 7.

Inherited (Familial) Erythromelalgia

• Genetics: Autosomal dominant inheritance, SCN9A gene mutations 6 7 10 16.
• Phenotype: Early-onset, severe, often refractory to standard treatments 7 10.
• Onset Variability: Early-onset typically more severe; delayed-onset mutations cause milder disease 6.

Secondary Erythromelalgia

• Definition: Occurs as a result of another medical condition 2 3 8 9.
• Common Associations: Myeloproliferative disorders (essential thrombocythemia, polycythemia vera), diabetes, autoimmune diseases, certain drugs 2 3 8.
• Aspirin Response: Many cases, especially those linked to myeloproliferative disease, respond dramatically to aspirin 1 2 3 8 11.
• Course: Sometimes precedes the diagnosis of the underlying disease by years; regular blood counts are recommended for adult patients 2 3.

Aspirin-Responsive Erythromelalgia

• Distinct Entity: Defined by dramatic response to low-dose aspirin, usually linked to high platelet counts in conditions like essential thrombocythemia or polycythemia vera 1 2 3 8 11.
• Mechanism: Platelet-mediated arteriolar inflammation and thrombosis 1 11.

Causes of Erythromelalgia

Understanding what causes erythromelalgia is crucial for both diagnosis and management. While the condition can arise in different contexts, advances in research have clarified some common mechanisms.

Cause	Mechanism/Pathway	Associated Type	Source(s)
Genetic (SCN9A)	Nav1.7 sodium channel gain-of-function	Primary/Inherited	6 7 10 16
Platelet-mediated	Arteriolar inflammation/thrombosis	Secondary/Aspirin-resp.	1 2 3 8 11
Microvascular	Arteriovenous shunt dysfunction	Primary/Secondary	12 13
Other diseases	Myeloproliferative, autoimmune, diabetes	Secondary	2 3 8 9
Drug-induced	Medications (e.g., CCBs, bromocriptine)	Secondary	8 17

Table 3: Causes and Mechanisms of Erythromelalgia

Genetic and Channelopathies

• Nav1.7 Sodium Channel Mutations: Many cases of primary and familial erythromelalgia are caused by gain-of-function mutations in the SCN9A gene, resulting in hyperexcitability of pain-sensing neurons (nociceptors) 6 7 10 16.
  • This leads to abnormal firing in peripheral nerves and the characteristic burning pain 10.
  • Mutations with greater effects on sodium channel activation cause earlier and more severe disease 6.

Platelet-Mediated Microvascular Changes

• Thrombocythemia and Myeloproliferative Disorders: In adults, erythromelalgia is often secondary to blood disorders such as essential thrombocythemia or polycythemia vera 1 2 3.
  • Pathology involves platelet activation and microvascular occlusion, leading to local inflammation and tissue ischemia 1 11.
  • Aspirin is highly effective in this subtype due to its action on platelet cyclooxygenase 1 2 3 11.

Microvascular Dysfunction and Shunting

• Vascular Dynamics: Both primary and secondary forms show evidence of dysfunctional microvascular responses, including abnormal arteriovenous shunting, which increases blood flow and skin temperature during attacks 12 13.
  • This supports the idea that erythromelalgia is a syndrome of vascular dysregulation, not just a single disease 13.

Secondary to Other Diseases or Drugs

• Systemic Illnesses: Secondary erythromelalgia can be associated with diabetes, autoimmune diseases, infections, or be induced by certain drugs (e.g., calcium channel blockers, bromocriptine) 2 3 8 9.
  • Treating the underlying condition or stopping the offending medication often leads to symptom improvement 8 17.

Treatment of Erythromelalgia

Erythromelalgia can be a formidable therapeutic challenge. While some individuals respond well to simple measures, others may require advanced interventions. No single treatment works for everyone, and management is often individualized.

Treatment Type	Example/Drug	Best for	Source(s)
Lifestyle	Cooling, avoiding triggers	All types	4 5 13 17
Aspirin	Low-dose aspirin	Secondary, platelet-related	1 2 3 8 11
Sodium channel blockers	Mexiletine, carbamazepine	Primary, genetic	7 15 16
Anticonvulsants	Gabapentin	Primary, refractory	14 15 16 17
Vasodilators	Sodium nitroprusside	Refractory, select cases	15 17
Topical therapies	Lidocaine, compounded creams	Various	7 15 17
Other meds	Antidepressants, beta-blockers	Various	14 17
Underlying disease	Treat primary illness	Secondary	2 8 17

Table 4: Common Treatments for Erythromelalgia

Lifestyle and Non-Pharmacologic Measures

• Cooling: Most patients obtain relief by cooling the affected area, such as immersing it in cold water or using fans 4 5 13.
  • Caution is needed to avoid immersion injuries or frostbite, especially in children 3 15.
• Trigger Avoidance: Staying in cool environments, wearing loose clothing, and avoiding warm baths or spicy foods can help minimize attacks 4 5 17.

Aspirin and Platelet Modulation

• Aspirin: Highly effective for erythromelalgia associated with myeloproliferative disorders or high platelet counts 1 2 3 8 11.
  • A single daily dose can dramatically reduce symptoms.
  • Ineffective in idiopathic/primary forms, especially in children 3 7.

Sodium Channel Blockers and Anticonvulsants

• Mexiletine and Carbamazepine: Particularly effective in cases linked to SCN9A mutations; they block Nav1.7 sodium channels and reduce neuronal excitability 7 15 16.
• Lidocaine: Both intravenous and topical forms can be useful, especially in severe or refractory cases 7 15.
• Gabapentin: An anticonvulsant that has shown benefit in some patients, particularly those who do not respond to other therapies 14 15 16.
  • Can be combined with other agents like carbamazepine for additional benefit 16.

Other Pharmacologic Options

• Vasodilators: Agents like sodium nitroprusside may be used in severe, refractory cases but come with significant side effects and monitoring requirements 15 17.
• Topical Therapies: Compounded creams containing lidocaine, amitriptyline, or ketamine are sometimes used for localized relief 7 15 17.
• Other medications: Beta-blockers, antidepressants, and tricyclics have been used with variable success 14 17.

Treating Underlying Causes

• Secondary erythromelalgia: Addressing the primary disease (e.g., controlling diabetes, stopping causative drugs, treating autoimmune disease) often improves symptoms 2 8 17.
  • For drug-induced cases, discontinuing the offending medication is key 8 17.

Individualized and Multidisciplinary Care

• No established guidelines exist, so treatment is tailored to each patient’s type, severity, and response to medications 7 17.
• Multidisciplinary care (neurology, dermatology, hematology, pain management) is often needed for optimal outcomes 7 17.

Conclusion

Erythromelalgia is a complex, heterogeneous syndrome with significant impact on patient well-being and quality of life. Advances in our understanding have improved classification and management, but many patients still struggle with refractory symptoms.

Key Points:

• Symptoms: Burning pain, redness, warmth, and swelling—worsened by heat, improved by cooling 2 3 4 5.
• Types: Primary (idiopathic/genetic), inherited (familial), secondary (disease/drug-related), and aspirin-responsive (platelet-mediated) 3 6 7 8.
• Causes: Genetic mutations (SCN9A/Nav1.7), platelet-mediated microvascular changes, vascular dysregulation, systemic diseases, and drugs 1 2 3 6 7 8 10 11 12 13 16.
• Treatment: Lifestyle modification, aspirin (for platelet-related cases), sodium channel blockers, anticonvulsants, and treatment of underlying conditions; management is highly individualized 1 2 3 7 13 14 15 16 17.

For patients and clinicians alike, awareness of erythromelalgia’s varied presentations and causes is essential for timely diagnosis and effective management. Continued research and multidisciplinary collaboration remain vital to improving outcomes for those affected by this challenging condition.