Dermatology: Practical and Conceptual
Original Article | Dermatol Pract Concept. 2023;13(3):e2023191 1
Clinical Challenges in Primary Erythromelalgia:
a Real-Life Experience from a Single Center and
a Diagnostic-Therapeutic Flow-Chart Proposal
Andrea Michelerio1,2, Carlo Tomasini1,2, Eloisa Arbustini3, Camilla Vassallo2
1 Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
2 Dermatology Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
3 Centre for Inherited Cardiovascular Diseases, IRCCS Policlinico San Matteo, Pavia, Italy
Key words: erythromelalgia, SCN9A protein, NAV1.7 Voltage-Gated Sodium Channel, mexiletine, treatments
Citation: Michelerio A, Tomasini C, Arbustini E, Vassallo C. Clinical Challenges in Primary Erythromelalgia: A Real-Life Experience From
A Single Center and a Diagnostic-Therapeutic Flow-Chart Proposal. Dermatol Pract Concept. 2023;13(3):e2023191. DOI: https://doi.
org/10.5826/dpc.1303a191
Accepted: February 27, 2023; Published: July 2023
Copyright: ©2023 Michelerio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Camilla Vassallo, MD, PhD, Dermatology Clinic, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi,
19, 27100 Pavia, Italy. Phone: + 39 0382-503492 E-mail: c.vassallo@smatteo.pv.it
Statement of Informed Consent: Written informed consent was obtained from the patients for their anonymized infor-
mation to be published in this article.
Introduction: Primary erythromelalgia (EM) is a rare clinical syndrome characterized by recurrent
erythema, burning pain and warmth of the extremities. The symptoms greatly compromise the pa-
tients’ quality of life leading to severe disability. SCN9A mutations can be the cause of the disease.
Dermatologists are often the specialists these patients turn to for assistance.
Objectives: To describe the demographic and clinical characteristics of patients with primary EM,
to assess the presence and mutation types in the SCN9A gene, to evaluate the effectiveness of several
therapeutic approaches, and to propose a diagnostic algorithm with therapeutic implications.
ABSTRACT
2 Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
Introduction
Erythromelalgia (EM) is a rare clinical syndrome character-
ized by the triad of recurrent erythema, burning pain and
warmth of the extremities. The burning sensation is the most
predominant symptom and is usually triggered and exacer-
bated by heat, ambulation, physical activity, emotional stress,
fever, sitting, leg dependence, and covering of extremities [1].
The symptoms may occur intermittently or, in rare cases, con-
tinuously [2]. Rest, cold temperatures and elevation of the af-
fected limbs alleviate symptoms. Indeed, pain is often relieved
by putting affected parts in ice cold water, which results in
immersion injury of the affected parts, uncovering their feet
during sleep or walking barefoot in winter [1-3]. The lower
limbs are more commonly affected than the upper limbs, usu-
ally with bilateral and symmetrical involvement [2,3]. Occa-
sionally, the face, nose, ears, neck, and the genital area may
be affected [2,4-6]. Despite not being always considered of
dermatologic competence, EM patients are often referred to
a dermatologist due to these symptoms.
EM may be primary or secondary. As a primary disease, EM
can be inherited (familial) or non-inherited (sporadic) [3,4].
As a secondary disease, EM is usually associated with my-
eloproliferative disorders such as polycythemia vera and
thrombocytopenia, however paraneoplastic, drug-induced,
connective-tissue diseases, hypertension, poxviruses and vac-
cinations associated cases have also been described [2,7-19].
The primary form has an estimated annual incidence of
1.1 cases per 100,000, with a female predominance [2,5].
The discovery of a gain-of-function missense mutations in
SCN9A, a gene encoding the voltage-gated sodium chan-
nel alpha subunit Na(v)1.7, in primary familial EM has
provided insights into this disorder [20]. Yet, the patho-
genesis remains complex, involving both neurological and
vascular mechanisms, and resulting in a challenging patient
management.
As a consequence of the disease, patients’ quality of life is
greatly compromised, with patients avoiding school, work-
ing and limiting social activities. Disability is not uncommon
as a result of intolerable pain, secondary tissue damage, or
self-mutilation, leading in some cases to suicide [2,4]. As
symptoms and signs of EM are subtle, especially in early
stage, and/or mimicking other diseases, diagnosis is often de-
layed [21]. Thus, early recognition of the affection is crucial
in order to establish an effective treatment. Further, despite
the significant clinical impact, no clinical guidelines are cur-
rently available for EM management or treatment.
Objectives
The aims of this study were i) to describe the demographic
and clinical characteristics of a series of patients with primary
EM in our Center, ii) to assess the presence and mutation
types in the SCN9A gene, iii) to evaluate the effectiveness of
several therapeutic approaches, and iiii) to propose a diag-
nostic algorithm with therapeutic implications.
Methods
We designed a monocentric retrospective study using the da-
tabase of patients with a discharge diagnosis of EM visited
between January 2009 and August 2022 at the Dermatology
Clinic in collaboration with the Center for Inherited Diseases
of our third-level referral Center.
Clinical criteria for the diagnosis of EM included: oc-
currence of erythema, heat (subjectively and/or objectively
observed), and associated discomfort (pain, burning, or tin-
gling) in the extremities [22]. When no plausible underlying
disease could be identified through anamnesis, examinations,
or follow-up, EM was considered primary.
Demographic and clinical data of patients were re-
viewed. Data as to gender, age at onset of symptoms, age
Methods: A monocentric retrospective study using the database of patients with a discharge diagnosis
of primary EM of our Center. Demographic, clinical, instrumental and laboratory data of patients
were reviewed.
Results: Eleven female patients (age range 16 to 57) were selected. All patients were affected in both
the lower and upper extremities. Follow-up ranged from 2 to 9 years. Four patients had four different
heterozygous variants of the SCN9A gene. Two patients, although genetically negative, had a sugges-
tive family history. A variety of medications were tried in all our patients to alleviate symptoms, but
their efficacy was variable, partial and/or transitory. The most effective therapies were antihistamines,
venlafaxine, and mexiletine.
Conclusions: The diagnosis and treatment of EM remain challenging. Patients with this condition
display a wide spectrum of clinical manifestations and severity, as well as a paucity of resources and
structures to support them. Mutations in the SCN9A gene are not always detected.
Original Article | Dermatol Pract Concept. 2023;13(3):e2023191 3
at diagnosis, family history, comorbidities, symptom descrip-
tion, triggers and relieving factors, complications, treatment
and outcome were obtained for all cases. Laboratory investi-
gations, including complete blood count, coagulation panel,
autoimmunity panel, basic metabolic panel, hormone panel,
and urinalysis, were reviewed as well. In all cases, labora-
tory studies such as neurophysiological, neuroimaging, and
vascular studies were available. In 3 cases, skin biopsy spec-
imens were available and reviewed by one of us (CT). In all
patients, genetic consultation with SCN9A gene sequencing
and post-test genetic counseling have been provided. Se-
quence variants were classified according to the American
College of Medical Genetics and Genomics (ACMG) stan-
dards [23].
Results
A total of 17 patients met the clinical criteria for EM (14
females, 3 males). Fourteen (13 females, 1 male) were clas-
sified as primary EM. Three patients were excluded because
they had less than 2 accesses in our hospital, resulting in 11
enrolled patients. All the included patients were females, and
their average age at the time of the first visit was 36 years
(range: 16 to 57). The clinical data are summarized in Table 1.
Acral erythrosis, edema, and dysesthesias were experienced
by all patients (Figure 1). In 5 cases, the condition developed
during infancy, in 2 cases during adolescence and in 4 during
adulthood. All patients were affected in both the lower and
upper extremities. Five patients developed EM symptoms
first in the lower distal limbs (#2, #3, #4, #10, #11), whereas
5 patients developed symptoms in both the upper and lower
distal limbs simultaneously (#1, #5, #6, #7, #8). Only patient
9 presented with hand involvement before feet involvement.
The EM episodes affected the face in 2 patients (#5, #8), the
ears in 2 patients (#6, #8), the knees in 3 patients (#5, #6,
#8). Patient 9 complained of a heat sensation throughout her
body during EM attacks.
Symptoms were persistent in 3 cases (#1, #4, and #11)
and intermittent in 8 cases. The frequency of EM attacks
in these patients varied from one episode a day to 1 or 2
Figure 1. Erythromelalgia. Red, hot, and painful right (A) and left (B) leg in patient 1. The left leg presents ulceration due to repeated
cold-water immersions. (C) Characteristic redness and edema in patient 8 with small bilateral ulcerations. (D) Extreme measures to improve
their symptoms, such as going barefoot or cooling affected areas with cold water, are common in patients with erythromelalgia. (E) Persistent
erythrosis and pain of the hands in patient 11.
4 Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
Ta
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Original Article | Dermatol Pract Concept. 2023;13(3):e2023191 5
paternal aunt. It is likely that both these patients had familial
EM harboring an unknown gene mutation.
The histopathology examination from skin biopsies
performed in 3 patients (#1, #2, #6) showed substantially
similar changes consisting of increased numbers of small
vessels throughout the dermis, arranged in clusters in the
superficial dermis (Figure 2A-B-C) and around the peri-
adnexal and neurovascular plexuses in the mid and deep
reticular dermis (Figure 2D). The vessel lumen appeared
narrowed with wall thickening by PAS positive, hyaline ma-
terial (Figure 2E). In one case, endothelial cell hyperplasia
was prominent with nuclear atypia and mitoses suggesting
a malignant vascular process (Figure 2F). No intraluminal
thrombi or inflammatory infiltrate were found. The adnexal
structures were preserved, and no quantitative or qualitative
changes were observed in the small dermal nerves (Figure
2D). Extravasated erythrocytes were a common finding in
all cases (Figure 2F).
A variety of medications were tried in all our patients
in order to alleviate symptoms, but their efficacy was vari-
able, partial and/or transitory (Table 2). Three patients
(#2, #3, #4) reported a good reduction in pain intensity
and episodes, while four patients (#5, #6, #9, #10) reported
a sufficient improvement with the therapy. Four patients
(#1, #7, #8, #11) had a poor response to the multiple treat-
ments and one of them committed suicide as a result of
the disability and depression caused by the disease (#1).
As a result of the persistent edema and pain, patient 11
was unable to maintain an upright position and had severe
limitations in her walking ability, even for short distances,
needing a walker.
The association of 2 second-generation non-sedating
antihistamines, desloratadine 4 mg/day and rupatadine 10
mg/day, was the most frequently prescribed treatment (10
patients) and was associated with magnesium pidolate sup-
plementation in 5 cases. Serotonin-norepinephrine reuptake
inhibitors (SNRIs) such as venlafaxine 75 mg to 150 mg/
day or duloxetine were prescribed in 6 cases. Five cases
were treated with mexiletine a sodium channel blocker, at
the dosage of 600-1200 mg/day, with good results in 3 of
them. Other treatments included caardioaspirin, amlodipine,
escitalopram, beta-blockers and pregabalin. An attempt was
made to treat patient 1 with a spinal cord stimulator, but it
was unsuccessful.
Conclusions
The dermatologist faces two challenges with EM patients:
determining the correct path for a definite diagnosis and
engaging other specialists in a multidisciplinary inte-
grated approach. To assist clinicians, we propose here a
diagnostic-therapeutic flowchart for EM (Figure 3).
episodes per week. In patients 6 and 7, erythrosis persisted
between attacks.
A history of sweating disorders was present in 3 patients
before the onset of EM: 2 patients had respectively palmo-
plantar and axillary hyperhidrosis (#1, #6), and 1 had hypo-
hidrosis (#7). In one case (#1) the sweeting disorder presented
in infancy, whilst in 2 cases (#6, #7) in early adulthood.
The triggering factors included heat exposure (8 pa-
tients), sun exposure (3 patients), humidity (three patients),
emotional stress (3 patients), evening time (3 patients), phys-
ical activity (1 patient), and alcohol intake (1 patient). In
4 patients (#2, #5, #9, #10), EM crises were more frequent
in summer, while 1 patient (#7) reported a winter seasonal-
ity. Seven patients reported that cold was a reliving factor
(#1, #2, #3, #4, #5, #6, #8), with one of them (#1) walking
barefoot in winter in the attempt to alleviate symptoms.
Three patients (#2, #8, #10) were misdiagnosed with
solar urticaria, rosacea, venous insufficiency, and connec-
tive tissue disorders. One patient (#1) was diagnosed with
restless legs syndrome and dermatitis factitia secondary to
obsessive-compulsive disorder.
In 2 cases (#1, #8), foot ulcers, intertrigo, and maceration
were present as a result of prolonged immersion in cold wa-
ter or ice (Figure 1 ABC). In all cases there was no evidence
of rheumatological disease. In two patients anti-nuclear anti-
bodies (ANA) were positive (1:160). In all cases, extractable
nuclear antigen (ENA) panel and other autoimmune serol-
ogy tests were negative. Follow-up ranged from 2 to 9 years
(median 5 years). In all patients, the coagulation parameters
were within the normal range.
Neuroimaging and vascular studies were normal in all
patients. Despite needle electromyography being normal in
all patients, nerve conduction studies and quantitative su-
domotor axon reflex revealed small fiber neuropathy in pa-
tients 1, 6 and 7.
Four patients with primary EM had 4 different heterozy-
gous variants of the SCN9A gene (Nav1.7 channel). Accord-
ing the American College of Medical Genetics and Genomics
(ACMG) criteria [23], Patient 1 was found to have a patho-
genic variant, c.2572C>T(e) (p.Leu858Phe), and a variant
of uncertain significance (VUS), c.58C>T(e) (p.Leu20Phe).
Patient 2 had a benign variant, c.3734A>G (p.Asn1245Ser),
patient 3 presented a VUS, c.1999GA
(p.Arg1356His).
Two patients (#4, #10), although genetically negative,
had a family history of EM-like disorder, but their relatives
were not examined. The father of patient 4 suffered from
of paroxystic pain in the hands and feet and the patient’s
grandmother was diagnosed with palmar-plantar erythro-
dysesthesia. Patient 10 described EM-like symptoms in her
6 Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
include a complete blood count, peripheral blood smear, and
serum tumor markers. Cancer screening exams, based on
gender and age, should be performed. Inflammatory markers,
serum protein electrophoresis, cryoglobulins, anti-nuclear
antibody (ANA), extractable nuclear antigen (ENA) panel,
autoantibody panel, complement levels should be assessed
to rule out connective tissue diseases, including systemic lu-
pus erythematosus, rheumatoid arthritis, and systemic scle-
rosis [2,4,12,31]. If a coexisting connective tissue disease or
Reynaud’s phenomenon is suspected, nailfold capillaroscopy
should also be performed. Other neuropathies, such as those
caused by diabetes or other neurological diseases, should be
excluded [32].
EM can be confused with complex regional pain syn-
drome (CRPS), which also has similar symptoms but is often
unilateral, proximal and less commonly triggered by warm-
ing [33]. EM should also be distinguished from Fabry dis-
ease, a rare genetic disorder that presents with burning pain,
acroparesthesias, angiokeratomas, proteinuria, hypohidrosis/
anhidrosis, and cardiac symptoms. Fabry disease can be di-
agnosed by testing for a deficiency of alpha-galactosidase
activity [34].
Instrumental investigations may provide diagnostic com-
plementary information. Infrared thermography, laser Dop-
pler flow and transcutaneous oxygenation measurements
usually document an increase in skin temperature and blood
flow and a paradoxical decrease in oxygenation in affected
areas during EM attacks [35].
Anamnesis. The diagnosis of EM depends on clinical
history and physical examination. When EM is suspected,
a detailed review of patients’ medical history should be col-
lected to provide information about possible factors that
might lead to secondary EM. A positive or negative family
history can further help to confirm familial/sporadic form.
Due to the intermittent nature of this disorder, many Authors
consider an EM diagnosis even if the typical findings are ab-
sent at the time of examination but the history of recurrent
episodes of redness, heat and discomfort of the extremities
is suggestive for the disease [2–4,24,25]. According to the
patients, symptoms have been variably described as “hot”,
“burning” or “numbness” feeling, or “tingling”, “prickling”,
“throbbing” [2,24,26].
The onset age and the family history can assist in the
determination of a primary or secondary form of EM, but
this is not always conclusive [3,4,24]. Most cases of primary
EM are not inherited [4]. Episode frequency, characteristics,
and seasonality, as well as presence of triggering and reliev-
ing factors, should be investigated. Asymmetric or unilat-
eral involvement should raise the suspicion of a secondary
form [27,28]. An accurate drug anamnesis is essential, since
erythromelalgia-like symptoms have been reported in associ-
ation with a variety of drugs (iodine contrast, calcium chan-
nel blockers, bromocriptine, ticlopidine, vaccines) and even
intoxicants [2,9,11,28–30].
Diagnostics. To rule out myeloproliferative disorders
and paraneoplastic cases, the laboratory examination should
Figure 2. (A,B) The biopsy specimen of patient 1 shows an increased number of small vessels in the papillary and mid dermis, mainly clus-
tered in small groups. The epidermis with a cornified layer is typical for the region (H&E ×20, H&E ×100). (C) CD34 positivity in endothelial
cells (CD34, x100). (D) Neurovascular plexus with increased numbers of capillaries with narrowed lumen and wall thickening. Note the close
relation of small vessels with small nerve endings ((H&E ×40). (E) Groups of capillaries with narrowed lumen, endothelial swelling and wall
thickening by hyaline material (H&E ×400). (F) Endothelial cell hyperplasia was prominent with nuclear atypia, mitoses and extravasated
erythrocytes (H&E ×100).
Original Article | Dermatol Pract Concept. 2023;13(3):e2023191 7
Ta
b
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2
. M
ed
ic
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ns
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8 Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
whilst neither luminal thrombi or reduction of small nerve
fibers were observed. Intermittent skin hypoxia may well be
considered a stimulus for capillary proliferation in the af-
fected skin, as also previously suggested [37].
Once a primary EM diagnosis is established, the patient
should be referred to the center where a SCN9A gene se-
quencing can be performed. Unfortunately, even in the pres-
ence of a family history, only approximately 10% of families
have mutations in SCN9A [38]. In our case series, among the
11 patients, seven presented with a classic early onset pri-
mary EM, but only four had SCN9A mutations and only in
one of them the mutation was pathogenetic. In Patients 4 and
10 the genetic SCN9A gene mutation analysis was negative,
although the family history was highly suggestive for heredi-
tary EM. This underlies the limitation of SCN9A sequencing,
Nerve conduction studies, needle electromyography,
and quantitative sudomotor axon reflex test (QSART, or
sweat test) are useful and sensitive tools to demonstrate a
small-fiber distal neuropathy, which is most prevalent in
EM patients [2,22,35]. Quantitative sudomotor axon re-
flex test (QSART, or sweat test) may provide evidence of
a sudomotor abnormality, which was clinically evident in
three of our patients even before the onset of EM symp-
toms [35].
Skin biopsy is considered of little help in EM due to the
lack of specific pathologic changes [24]. Davis et al suggested
that the presence of thrombi within vessels would distinguish
primary from secondary EM [24,36]. In our study, capillary
proliferation, narrowing of the lumina, endothelial swelling
and hyperplasia were common histopathologic findings,
Figure 3. Diagnostic-therapeutic flow-chart proposal or erythromelalgia patients.
Original Article | Dermatol Pract Concept. 2023;13(3):e2023191 9
in EM patients harboring V400M and S241T mutations in
the Nav1.7 sequence but ineffective in patients with F1449V
mutations [53,54].
Finally, a correct and early diagnosis of EM is crucial as
it may provide psychological and emotional relief, relieving
the burden of a possible malingering or other psychiatric dis-
ease diagnosis. Chronic pain may lead to sleeping disorders,
school difficulties and poor participation in physical activ-
ity in children. Unusual or peculiar behaviors that patients
adopt to relieve their pain, such as repeated immersions in
water or walking barefoot in the snow can be misinterpreted
by the clinician as obsessive-compulsive behaviors or signs
of another mental illness. In our case series, Patient 1 had an
EM patient typical history: symptoms misinterpretation and
misdiagnoses over a period of many years, poor response
to many therapies, progressive worsening, social isolation
and severe psychiatric complications culminating in suicide.
Extreme self-harm and even suicide as in our patient are a
rare but well-recognized consequence of EM, with high so-
cial costs and great impact on the patients and their fam-
ilies [2,4]. Information about online patient communities,
which may offer users a valuable educational resource and a
source of psychological and social support, should be offered
(https://erythromelalgia.org/).
To conclude, EM involves several medical fields, and the
path from diagnosis to treatment, involving all the necessary
specialists, may be frustrating, both for patients and clini-
cians. In our experience, patients with this condition display
a wide spectrum of clinical manifestations and severity, as
well as a paucity of resources and structures to support them.
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as the same mutation can result in phenotypic variability [39]
and patients may also display protein-modifying mutations
in other genes [39,40]. Consequently, if the sequencing result
is negative for mutations, the primary EM diagnosis should
not be questioned. On the other side, if any mutation is
found, the Literature should be reviewed to determine if the
genotype is associated with sensitivity to specific treatments.
Treatment. As a matter of fact, EM is resistant to many
treatments and our findings confirm its refractory nature
[1,2,4,15]. Various pharmacologic trials have been con-
ducted with varied results, and no single medication or drug
combination has been found to be universally helpful in re-
lieving patients symptoms.
In our study, the most effective therapies were antihis-
tamines, venlafaxine, and mexiletine. With regard to anti-
histamines, therapeutic efficacy in our EM patients might
be attributed to their action against neurogenic inflamma-
tion [41]. Although these drugs are safe, their use in EM is
off-label. Five patients were given magnesium pidolate in
combination with antihistamines, which would act as a cal-
cium antagonist, a sympatholytic and a muscle-relaxant [42].
In 3 patients, venlafaxine has provided some relief from
symptoms of by acting both on sympathetic fibers by inhib-
iting the reuptake of noradrenaline, as well as on hormonal
vascular control by inhibiting the reuptake of serotonin
[43-45]. As this medication is approved to treat major de-
pression, which is a common comorbidity among these pa-
tients, it is likely to prove useful for both diseases.
Mexiletine is a class IB orally active sodium channel
blocker structurally similar to lidocaine, which appears to be
particularly effective in neuropathic pain by shortening the
action potential duration [46]. This drug was very effective
in 3 patients and moderately effective in one, whilst in an-
other was totally ineffective. Pharmacodynamic factors and
genetic polymorphisms of the SCN9A gene, encoding the so-
dium channel Nav1.7, may for the variable efficacy of mex-
iletine in EM. Based on the available literature, a therapeutic
attempt with mexiletine may be recommended for patients
with V872G, L858F, and I848T mutant Nav1.7 channels,
while the same treatment may not be appropriate for patients
with I136V and V1316A mutations [47-49]. Furthermore,
a clinically favorable response to intravenous lidocaine may
predict a favorable response to oral mexiletine [50]. Patients
should undergo periodic cardiological examinations, espe-
cially during drug titration, and be informed about common
side effects involving the gastrointestinal and central nervous
systems [51,52]. The use of mexiletine for EM is off-label.
A literature review may assist in providing other treat-
ment options for EM. These include use of tricyclic an-
tidepressants, gabapentin, anticonvulsants, and others.
Carbamazepine, for instance, has been shown to be effective
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