Introduction

Erythromelalgia is a rare, chronic condition that is characterised by periodic symptom flares. This happens when there is excessive increased blood flow to the affected area(s). The condition typically affects the feet and hands, but can also affect many other regions of the body.

Common symptoms include redness on the skin and intense burning sensations, which make daily tasks difficult.¹ However, symptoms of Erythromelalgia tend to come and go, thus making diagnosis more difficult and leading to delays. The intermittent nature of this condition not only makes it hard to pinpoint the diagnosis but also often causes it to be misdiagnosed as another nerve or skin condition.²

This article will focus on both skin and nerve testing in Erythromelalgia and how effective they are as diagnostic tools. We will also explore what these diagnostic tools entail, when they are recommended, and why they matter.

Section 1: Understanding erythromelalgia

Erythromelalgia occurs when the nerves that control the body’s blood vessels do not function properly. As a result of this, blood flow regulations become disrupted and cause an increase in blood flow to certain areas in the body. This excessive blood flow then causes pain, redness and swelling in the affected regions.  

There are two main types of erythromelalgia: 

• Primary erythromelalgia - Caused by changes (mutations) in specific genes that affect how pain nerves function
• Secondary erythromelalgia - Rare and develops later in life (usually between ages 40 - 60 years) and tends to be linked to another condition³

Common symptoms that occur in erythromelalgia are:¹

• Mild to severe pain
• Redness on the skin
• Itchiness
• Cold skin between flares
• Swelling
• Tingling sensations
• Sweating

Although the diagnosis of erythromelalgia is made up of well-recognised signs and symptoms, the intermittent pattern of symptom presentation means there are difficulties when diagnosing this condition. This is why, sometimes taking photographs during flare-up episodes may be recommended to help document the disease progression and aid diagnosis.⁴

Typically, the patient is questioned on their medical history, and may be asked about symptoms such as: 

• Fever 
• Recent trauma 
• Joint pain

Knowing this can help doctors rule out conditions such as cellulitis, systemic lupus erythematosus and rheumatoid arthritis, which can cause erythromelalgia.⁴

Section 2: What is a skin biopsy?

A skin biopsy is a procedure that is used as a diagnostic tool to identify skin conditions. This procedure involves having a small sample of skin tissue removed and sent to the lab so that it can be examined under a microscope.⁵ Utilising a skin biopsy can help to identify conditions such as rashes, infections, psoriasis or skin cancer. 

There are different types of skin biopsies:

• Punch biopsy
• Shave biopsy
• Excisional biopsy

Deciding which type of biopsy to use is dependent on the size and location of the skin flare-up. Although due to its lack of specificity, a skin biopsy is not typically used as a first-choice diagnostic tool for erythromelalgia. 

However, a skin biopsy can still be useful in detecting a range of conditions, such as: 

• Different types of skin rashes
• Inflammation
• Epidermal and perivascular nerve density changes

This is something scans and blood work cannot provide, proving skin biopsy as an effective diagnostic tool for distinguishing erythromelalgia from other skin/nerve conditions.⁸

Section 3: What is nerve testing?

Nerve testing is typically used to help doctors evaluate how well the nerves and muscles are working. Understanding this can help determine any diagnoses and conditions that are affecting the nerves. There are three common types of nerve testing:

Nerve conduction studies (NCS)

This is a test which measures how fast an electrical impulse travels through the nerve. This means it can also detect if there is any nerve damage. NCS are typically used in conjunction with electromyography (EMG) in order to differentiate between a nerve disorder and a muscle disorder.⁹

Electromyography (EMG)

This test is used to measure the muscle response or electrical activity during rest, movement and nerve stimulation. In other terms, it helps to identify any neuromuscular conditions.¹⁰

Quantitative sensory testing (QST)

This is a set of non-invasive tests that determines how well the nerve endings work. QST measures the sensation and pain thresholds for temperature, touch, pressure and vibrations. This helps to find signs of damage to the nerve endings.¹¹

Nerve testing is important in the diagnosis of erythromelalgia because it helps to identify and assess small fibre nerve dysfunction. Identifying abnormalities in these small nerve fibres is particularly useful as they are involved in sensing pain and temperature changes. 

These nerve tests can also reveal less common symptoms in people with erythromelalgia and help rule out and differentiate erythromelalgia from other large fibre neuropathies or neuromuscular diseases.¹²

Section 4: When are these tests recommended? 

Due to its characteristic symptoms, in many cases, healthcare professionals may not turn to additional tests for an erythromelalgia diagnosis. However, sometimes nerve testing and skin biopsies may be recommended for specific situations, including cases where:^5,11 

• Symptoms are particularly severe
• Further investigation is needed
• The clinical presentation needs to be distinguished from other conditions with overlapping symptoms involving nerve irritation

In addition, utilising skin biopsies has been proven to help distinguish between primary and secondary erythromelalgia, as well as detect decreased nerve density.¹⁴

When used together, skin biopsies and nerve testing can help confirm nerve involvement and aid medical professionals in determining tailored treatments that reduce nerve pain and improve blood flow.^4,12

Section 5: Why these tests matter

There are many benefits associated with the usage of skin biopsies and nerve testing, such as:

• Providing clearer and earlier diagnoses of nerve-related pain^15,16
• Assessing both sensory and autonomic nerve fibres^15,16
• Distinguishing other nerve-related disorders that have similar symptomology¹¹

Together, these findings can guide more effective treatment options. For instance, if nerve damage is found, neuropathic pain medications (like pregabalin) may work better than drugs that only target the vasculature.¹⁷ This increased effectiveness in medication may help provide more clarity and hope to families and those suffering from erythromelalgia.

However, there are also limitations to using these diagnostic tools:

• Skin biopsies and nerve testing are encouraged to be used in combination
  As often, results may vary, with one test showing abnormalities while another test appears normal e.g. abnormal skin biopsy but normal QST¹⁸
• Skin biopsies are not widely available as they require specialised labs and pathologists
  This can increase costs and waiting times
• Skin biopsies tend to be more invasive in comparison to basic clinical tests¹⁵

Section 6: What patients can expect

Below is a brief step-by-step of what happens during a skin biopsy and nerve tests.

Skin biopsy

Skin biopsies tend to be quite fast. 

• A healthcare professional will clean the chosen area of skin
• A local anaesthetic is then injected into the cleaned area to numb it
• A small sample of the skin is then removed (typically via a punch biopsy)
• The sample is sent to the lab for analysis

There is no need for stitches, as biopsies take a superficial layer off.⁵

Nerve testing/nerve conduction test

• Two electrodes are placed on the skin over the nerves or muscle
• Mild electrical pulses are used to stimulate the nerves
• The electrodes measure the speed and strength of the nerve responses following stimulation

The speed of nerve conduction is calculated by measuring the distance between the electrodes and the time it takes to move between the two electrodes.⁹

Following a nerve test, you may feel some brief tingling or muscle twitching, but overall discomfort is mild and is usually outpatient care.

Both procedures have low risk and are routine, safe procedures that provide valuable information for diagnosis and treatment.

Summary

Erythromelalgia is a lifelong, rare condition. This condition is caused by excessive increased blood flow that results in periodic symptom flares. Diagnosis tends to be difficult to identify and can lead to delays. This is because of the condition’s intermittent nature, making it a condition that is often misunderstood.^1,2 

Both skin biopsy and nerve testing are useful diagnostic tools for gaining an earlier and more accurate diagnosis of neuropathy and neuropathic pain conditions. These tests can also be used to assess the sensory and autonomic fibres of the nerves.^15,16 

Although tests are not recommended as the first choice of diagnosis, nerve testing and skin biopsies may be recommended for specific situations, such as when the symptoms are severe or need further investigation. They are also particularly useful for ruling out other conditions that have similar symptoms that irritate the nerves, making these tests very useful in clarifying the condition.^5,11