10.5826/dpc.1303a191
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 patients' 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.
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 suggestive 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.
text/xml
2160-9381
3049
en
Camilla Vassallo
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
treatments
Clinical Challenges in Primary Erythromelalgia: A Real-Life Experience from a Single Center and a Diagnostic-Therapeutic Flow-Chart Proposal
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-07-31
2022-12-05
2023-07-31
2023-08-24
e2023191
Dermatol Pract Concept
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 patients' 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.
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 suggestive 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.
Camilla Vassallo
2023/07/31
10.5826/dpc.1303a191
e2023191
Dermatology Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
2160-9381
treatments
en
e2023191
Yang Y, Dib-Hajj SD, Zhang J, et al. Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Na(V)1.7 mutant channel. Nat Commun. 2012;3:1186. doi: 10.1038/ncomms2184. PMID: 23149731. PMC3530897.
Clinical Challenges in Primary Erythromelalgia: A Real-Life Experience from a Single Center and a Diagnostic-Therapeutic Flow-Chart Proposal
https://dpcj.org/index.php/dpc/article/download/3049/2195
     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.




  ABSTRACT              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.




Original Article | Dermatol Pract Concept. 2023;13(3):e2023191                                                                         1
                      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.




Introduction                                                          As a consequence of the disease, patients’ quality of life is
                                                                   greatly compromised, with patients avoiding school, work-
Erythromelalgia (EM) is a rare clinical syndrome character-        ing and limiting social activities. Disability is not uncommon
ized by the triad of recurrent erythema, burning pain and          as a result of intolerable pain, secondary tissue damage, or
warmth of the extremities. The burning sensation is the most       self-mutilation, leading in some cases to suicide [2,4]. As
predominant symptom and is usually triggered and exacer-           symptoms and signs of EM are subtle, especially in early
bated by heat, ambulation, physical activity, emotional stress,    stage, and/or mimicking other diseases, diagnosis is often de-
fever, sitting, leg dependence, and covering of extremities [1].   layed [21]. Thus, early recognition of the affection is crucial
The symptoms may occur intermittently or, in rare cases, con-      in order to establish an effective treatment. Further, despite
tinuously [2]. Rest, cold temperatures and elevation of the af-    the significant clinical impact, no clinical guidelines are cur-
fected limbs alleviate symptoms. Indeed, pain is often relieved    rently available for EM management or treatment.
by putting affected parts in ice cold water, which results in
immersion injury of the affected parts, uncovering their feet
                                                                   Objectives
during sleep or walking barefoot in winter [1-3]. The lower
limbs are more commonly affected than the upper limbs, usu-        The aims of this study were i) to describe the demographic
ally with bilateral and symmetrical involvement [2,3]. Occa-       and clinical characteristics of a series of patients with primary
sionally, the face, nose, ears, neck, and the genital area may     EM in our Center, ii) to assess the presence and mutation
be affected [2,4-6]. Despite not being always considered of        types in the SCN9A gene, iii) to evaluate the effectiveness of
dermatologic competence, EM patients are often referred to         several therapeutic approaches, and iiii) to propose a diag-
a dermatologist due to these symptoms.                             nostic algorithm with therapeutic implications.
    EM may be primary or secondary. As a primary disease, EM
can be inherited (familial) or non-inherited (sporadic) [3,4].     Methods
As a secondary disease, EM is usually associated with my-
eloproliferative disorders such as polycythemia vera and           We designed a monocentric retrospective study using the da-
thrombocytopenia, however paraneoplastic, drug-induced,            tabase of patients with a discharge diagnosis of EM visited
connective-tissue diseases, hypertension, poxviruses and vac-      between January 2009 and August 2022 at the Dermatology
cinations associated cases have also been described [2,7-19].      Clinic in collaboration with the Center for Inherited Diseases
    The primary form has an estimated annual incidence of          of our third-level referral Center.
1.1 cases per 100,000, with a female predominance [2,5].              Clinical criteria for the diagnosis of EM included: oc-
The discovery of a gain-of-function missense mutations in          currence of erythema, heat (subjectively and/or objectively
SCN9A, a gene encoding the voltage-gated sodium chan-              observed), and associated discomfort (pain, burning, or tin-
nel alpha subunit Na(v)1.7, in primary familial EM has             gling) in the extremities [22]. When no plausible underlying
provided insights into this disorder [20]. Yet, the patho-         disease could be identified through anamnesis, examinations,
genesis remains complex, involving both neurological and           or follow-up, EM was considered primary.
vascular mechanisms, and resulting in a challenging patient           Demographic and clinical data of patients were re-
management.                                                        viewed. Data as to gender, age at onset of symptoms, age




2                                                                      Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
at diagnosis, family history, comorbidities, symptom descrip-           they had less than 2 accesses in our hospital, resulting in 11
tion, triggers and relieving factors, complications, treatment          enrolled patients. All the included patients were females, and
and outcome were obtained for all cases. Laboratory investi-            their average age at the time of the first visit was 36 years
gations, including complete blood count, coagulation panel,             (range: 16 to 57). The clinical data are summarized in Table 1.
autoimmunity panel, basic metabolic panel, hormone panel,               Acral erythrosis, edema, and dysesthesias were experienced
and urinalysis, were reviewed as well. In all cases, labora-            by all patients (Figure 1). In 5 cases, the condition developed
tory studies such as neurophysiological, neuroimaging, and              during infancy, in 2 cases during adolescence and in 4 during
vascular studies were available. In 3 cases, skin biopsy spec-          adulthood. All patients were affected in both the lower and
imens were available and reviewed by one of us (CT). In all             upper extremities. Five patients developed EM symptoms
patients, genetic consultation with SCN9A gene sequencing               first in the lower distal limbs (#2, #3, #4, #10, #11), whereas
and post-test genetic counseling have been provided. Se-                5 patients developed symptoms in both the upper and lower
quence variants were classified according to the American               distal limbs simultaneously (#1, #5, #6, #7, #8). Only patient
College of Medical Genetics and Genomics (ACMG) stan-                   9 presented with hand involvement before feet involvement.
dards [23].                                                             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,

Results                                                                 #8). Patient 9 complained of a heat sensation throughout her
                                                                        body during EM attacks.
A total of 17 patients met the clinical criteria for EM (14                 Symptoms were persistent in 3 cases (#1, #4, and #11)
females, 3 males). Fourteen (13 females, 1 male) were clas-             and intermittent in 8 cases. The frequency of EM attacks
sified as primary EM. Three patients were excluded because              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.




Original Article | Dermatol Pract Concept. 2023;13(3):e2023191                                                                             3
4
                                                                                                                                     Table 1. Clinical data of the patients.
                                                                             Age at lower      Age at upper
                                                                              extremities       extremities   Age at
                                                                             involvement       involvement     visit    Other involved         Persistent                   Triggering                             Erythromelalgia       Disease
                                                                  Patient         (y)               (y)         (y)         sites                pain       Seasonality       factors        SCNA9 mutation        crisis frequency      control
                                                                      1             7                 7        18                            yes                          heat, humidity, c.2572C>T(e)            every day              not
                                                                                                                                                                          emotional stress (p.Leu858Phe)                                 sufficient
                                                                                                                                                                                           (pathogenetic);
                                                                                                                                                                                           c.58C>T(e)
                                                                                                                                                                                           (p.Leu20Phe) (VUS)
                                                                      2             8                12        43                                           yes, summer   sun exposure      c.3734A>G             once or twice weekly good
                                                                                                                                                                                            (p.Asn1245Ser)        during summer
                                                                                                                                                                                            (benign)              months
                                                                      3            10                43        43                                                         heat, evening,    c.1999G<A             every day in the       good
                                                                                                                                                                          alcohol           (p.Asp678Asn) (VUS)   evening
                                                                      4            15                21        21                            yes                          heat, humidity, none                    every day              good
                                                                                                                                                                          physical activity
                                                                      5            4                 4         42      knees, face                          yes, summer   sun exposure      none                  once or twice weekly discrete
                                                                                                                                                                                                                  in summer months
                                                                      6            42                42        44      knees, ears, diffuse no, but                       heat, humidity, none                    once or twice weekly discrete
                                                                                                                       heat over the        persistent                    emotional stress
                                                                                                                       entire body          erythrosis
                                                                      7            24                24        37                            no, but        yes, winter   heat              none                  every day in winter    poor
                                                                                                                                             persistent                                                           months
                                                                                                                                             erythrosis
                                                                      8            12                12        16      face, ears, knees                                  emotional         none                  every day              poor
                                                                                                                                                                          stress, evening
                                                                      9            39                37        39      occasionally                         yes, summer   heat, evening     none                  once or twice weekly discrete
                                                                                                                       burning sensation                                                                          in summer months
                                                                                                                       in other body sites
                                                                     10            7                 14        57                                           yes, summer   heat, sun         none                  once or twice          discrete
                                                                                                                                                                          exposure                                weekly, every day in
                                                                                                                                                                                                                  summer months
                                                                     11            37                39        39                            yes, with                    heat              c.4067G>A             every day              poor
                                                                                                                                             persistent                                     (p.Arg1356His)
                                                                                                                                             edema                                          (benign)




Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
                                                                 VUS = variant of uncertain significance.
episodes per week. In patients 6 and 7, erythrosis persisted       paternal aunt. It is likely that both these patients had familial
between attacks.                                                   EM harboring an unknown gene mutation.
    A history of sweating disorders was present in 3 patients         The histopathology examination from skin biopsies
before the onset of EM: 2 patients had respectively palmo-         performed in 3 patients (#1, #2, #6) showed substantially
plantar and axillary hyperhidrosis (#1, #6), and 1 had hypo-       similar changes consisting of increased numbers of small
hidrosis (#7). In one case (#1) the sweeting disorder presented    vessels throughout the dermis, arranged in clusters in the
in infancy, whilst in 2 cases (#6, #7) in early adulthood.         superficial dermis (Figure 2A-B-C) and around the peri-
    The triggering factors included heat exposure (8 pa-           adnexal and neurovascular plexuses in the mid and deep
tients), sun exposure (3 patients), humidity (three patients),     reticular dermis (Figure 2D). The vessel lumen appeared
emotional stress (3 patients), evening time (3 patients), phys-    narrowed with wall thickening by PAS positive, hyaline ma-
ical activity (1 patient), and alcohol intake (1 patient). In      terial (Figure 2E). In one case, endothelial cell hyperplasia
4 patients (#2, #5, #9, #10), EM crises were more frequent         was prominent with nuclear atypia and mitoses suggesting
in summer, while 1 patient (#7) reported a winter seasonal-        a malignant vascular process (Figure 2F). No intraluminal
ity. Seven patients reported that cold was a reliving factor       thrombi or inflammatory infiltrate were found. The adnexal
(#1, #2, #3, #4, #5, #6, #8), with one of them (#1) walking        structures were preserved, and no quantitative or qualitative
barefoot in winter in the attempt to alleviate symptoms.           changes were observed in the small dermal nerves (Figure
    Three patients (#2, #8, #10) were misdiagnosed with            2D). Extravasated erythrocytes were a common finding in
solar urticaria, rosacea, venous insufficiency, and connec-        all cases (Figure 2F).
tive tissue disorders. One patient (#1) was diagnosed with            A variety of medications were tried in all our patients
restless legs syndrome and dermatitis factitia secondary to        in order to alleviate symptoms, but their efficacy was vari-
obsessive-compulsive disorder.                                     able, partial and/or transitory (Table 2). Three patients
    In 2 cases (#1, #8), foot ulcers, intertrigo, and maceration   (#2, #3, #4) reported a good reduction in pain intensity
were present as a result of prolonged immersion in cold wa-        and episodes, while four patients (#5, #6, #9, #10) reported
ter or ice (Figure 1 ABC). In all cases there was no evidence      a sufficient improvement with the therapy. Four patients
of rheumatological disease. In two patients anti-nuclear anti-     (#1, #7, #8, #11) had a poor response to the multiple treat-
bodies (ANA) were positive (1:160). In all cases, extractable      ments and one of them committed suicide as a result of
nuclear antigen (ENA) panel and other autoimmune serol-            the disability and depression caused by the disease (#1).
ogy tests were negative. Follow-up ranged from 2 to 9 years        As a result of the persistent edema and pain, patient 11
(median 5 years). In all patients, the coagulation parameters      was unable to maintain an upright position and had severe
were within the normal range.                                      limitations in her walking ability, even for short distances,
    Neuroimaging and vascular studies were normal in all           needing a walker.
patients. Despite needle electromyography being normal in             The association of 2 second-generation non-sedating
all patients, nerve conduction studies and quantitative su-        antihistamines, desloratadine 4 mg/day and rupatadine 10
domotor axon reflex revealed small fiber neuropathy in pa-         mg/day, was the most frequently prescribed treatment (10
tients 1, 6 and 7.                                                 patients) and was associated with magnesium pidolate sup-
    Four patients with primary EM had 4 different heterozy-        plementation in 5 cases. Serotonin-norepinephrine reuptake
gous variants of the SCN9A gene (Nav1.7 channel). Accord-          inhibitors (SNRIs) such as venlafaxine 75 mg to 150 mg/
ing the American College of Medical Genetics and Genomics          day or duloxetine were prescribed in 6 cases. Five cases
(ACMG) criteria [23], Patient 1 was found to have a patho-         were treated with mexiletine a sodium channel blocker, at
genic variant, c.2572C>T(e) (p.Leu858Phe), and a variant           the dosage of 600-1200 mg/day, with good results in 3 of
of uncertain significance (VUS), c.58C>T(e) (p.Leu20Phe).          them. Other treatments included caardioaspirin, amlodipine,
Patient 2 had a benign variant, c.3734A>G (p.Asn1245Ser),          escitalopram, beta-blockers and pregabalin. An attempt was
patient 3 presented a VUS, c.1999G<A (p.Asp678Asn),                made to treat patient 1 with a spinal cord stimulator, but it
and patient 11 presented a benign variant, c.4067G>A               was unsuccessful.
(p.Arg1356His).
    Two patients (#4, #10), although genetically negative,         Conclusions
had a family history of EM-like disorder, but their relatives
were not examined. The father of patient 4 suffered from           The dermatologist faces two challenges with EM patients:
of paroxystic pain in the hands and feet and the patient’s         determining the correct path for a definite diagnosis and
grandmother was diagnosed with palmar-plantar erythro-             engaging other specialists in a multidisciplinary inte-
dysesthesia. Patient 10 described EM-like symptoms in her          grated approach. To assist clinicians, we propose here a
                                                                   diagnostic-therapeutic flowchart for EM (Figure 3).



Original Article | Dermatol Pract Concept. 2023;13(3):e2023191                                                                    5
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).


    Anamnesis. The diagnosis of EM depends on clinical                  include a complete blood count, peripheral blood smear, and
history and physical examination. When EM is suspected,                 serum tumor markers. Cancer screening exams, based on
a detailed review of patients’ medical history should be col-           gender and age, should be performed. Inflammatory markers,
lected to provide information about possible factors that               serum protein electrophoresis, cryoglobulins, anti-nuclear
might lead to secondary EM. A positive or negative family               antibody (ANA), extractable nuclear antigen (ENA) panel,
history can further help to confirm familial/sporadic form.             autoantibody panel, complement levels should be assessed
Due to the intermittent nature of this disorder, many Authors           to rule out connective tissue diseases, including systemic lu-
consider an EM diagnosis even if the typical findings are ab-           pus erythematosus, rheumatoid arthritis, and systemic scle-
sent at the time of examination but the history of recurrent            rosis [2,4,12,31]. If a coexisting connective tissue disease or
episodes of redness, heat and discomfort of the extremities             Reynaud’s phenomenon is suspected, nailfold capillaroscopy
is suggestive for the disease [2–4,24,25]. According to the             should also be performed. Other neuropathies, such as those
patients, symptoms have been variably described as “hot”,               caused by diabetes or other neurological diseases, should be
“burning” or “numbness” feeling, or “tingling”, “prickling”,            excluded [32].
“throbbing” [2,24,26].                                                      EM can be confused with complex regional pain syn-
    The onset age and the family history can assist in the              drome (CRPS), which also has similar symptoms but is often
determination of a primary or secondary form of EM, but                 unilateral, proximal and less commonly triggered by warm-
this is not always conclusive [3,4,24]. Most cases of primary           ing [33]. EM should also be distinguished from Fabry dis-
EM are not inherited [4]. Episode frequency, characteristics,           ease, a rare genetic disorder that presents with burning pain,
and seasonality, as well as presence of triggering and reliev-          acroparesthesias, angiokeratomas, proteinuria, hypohidrosis/
ing factors, should be investigated. Asymmetric or unilat-              anhidrosis, and cardiac symptoms. Fabry disease can be di-
eral involvement should raise the suspicion of a secondary              agnosed by testing for a deficiency of alpha-galactosidase
form [27,28]. An accurate drug anamnesis is essential, since            activity [34].
erythromelalgia-like symptoms have been reported in associ-                 Instrumental investigations may provide diagnostic com-
ation with a variety of drugs (iodine contrast, calcium chan-           plementary information. Infrared thermography, laser Dop-
nel blockers, bromocriptine, ticlopidine, vaccines) and even            pler flow and transcutaneous oxygenation measurements
intoxicants [2,9,11,28–30].                                             usually document an increase in skin temperature and blood
    Diagnostics. To rule out myeloproliferative disorders               flow and a paradoxical decrease in oxygenation in affected
and paraneoplastic cases, the laboratory examination should             areas during EM attacks [35].



6                                                                            Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
                                                                                               Table 2. Medications used for erythromelalgia symptoms by the study patients and their reported efficacy.
                                                                                                        Magnesium

                                                                 Patient   Desloratadine   Rupatadine   supplement   Cardioaspirin   Amlodipine   Pregabalin   Venlafaxine   Duloxetin   Escitalopram   Propranolol   Metoprolol   Mexiletine   Clonazepam   Brotizolam   Opioids

                                                                   1
                                                                   2
                                                                   3
                                                                   4
                                                                   5                                                                                                                                                                                         At need
                                                                   6




Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
                                                                   7
                                                                   8
                                                                   9
                                                                  10                                                                                                                                                                                                       At
                                                                                                                                                                                                                                                                          need
                                                                  11                                                                                                                                                                                                       At
                                                                                                                                                                                                                                                                          need


                                                                                     Not helpful
                                                                                     Somewhat helpful
                                                                                     Helpful




7
Figure 3. Diagnostic-therapeutic flow-chart proposal or erythromelalgia patients.

    Nerve conduction studies, needle electromyography,                 whilst neither luminal thrombi or reduction of small nerve

and quantitative sudomotor axon reflex test (QSART, or                 fibers were observed. Intermittent skin hypoxia may well be

sweat test) are useful and sensitive tools to demonstrate a            considered a stimulus for capillary proliferation in the af-

small-fiber distal neuropathy, which is most prevalent in              fected skin, as also previously suggested [37].

EM patients [2,22,35]. Quantitative sudomotor axon re-                     Once a primary EM diagnosis is established, the patient

flex test (QSART, or sweat test) may provide evidence of               should be referred to the center where a SCN9A gene se-

a sudomotor abnormality, which was clinically evident in               quencing can be performed. Unfortunately, even in the pres-

three of our patients even before the onset of EM symp-                ence of a family history, only approximately 10% of families

toms [35].                                                             have mutations in SCN9A [38]. In our case series, among the

    Skin biopsy is considered of little help in EM due to the          11 patients, seven presented with a classic early onset pri-

lack of specific pathologic changes [24]. Davis et al suggested        mary EM, but only four had SCN9A mutations and only in

that the presence of thrombi within vessels would distinguish          one of them the mutation was pathogenetic. In Patients 4 and

primary from secondary EM [24,36]. In our study, capillary             10 the genetic SCN9A gene mutation analysis was negative,

proliferation, narrowing of the lumina, endothelial swelling           although the family history was highly suggestive for heredi-

and hyperplasia were common histopathologic findings,                  tary EM. This underlies the limitation of SCN9A sequencing,




8                                                                           Original Article | Dermatol Pract Concept. 2023;13(3):e2023191
as the same mutation can result in phenotypic variability [39]    in EM patients harboring V400M and S241T mutations in
and patients may also display protein-modifying mutations         the Nav1.7 sequence but ineffective in patients with F1449V
in other genes [39,40]. Consequently, if the sequencing result    mutations [53,54].
is negative for mutations, the primary EM diagnosis should           Finally, a correct and early diagnosis of EM is crucial as
not be questioned. On the other side, if any mutation is          it may provide psychological and emotional relief, relieving
found, the Literature should be reviewed to determine if the      the burden of a possible malingering or other psychiatric dis-
genotype is associated with sensitivity to specific treatments.   ease diagnosis. Chronic pain may lead to sleeping disorders,
    Treatment. As a matter of fact, EM is resistant to many       school difficulties and poor participation in physical activ-
treatments and our findings confirm its refractory nature         ity in children. Unusual or peculiar behaviors that patients
[1,2,4,15]. Various pharmacologic trials have been con-           adopt to relieve their pain, such as repeated immersions in
ducted with varied results, and no single medication or drug      water or walking barefoot in the snow can be misinterpreted
combination has been found to be universally helpful in re-       by the clinician as obsessive-compulsive behaviors or signs
lieving patients symptoms.                                        of another mental illness. In our case series, Patient 1 had an
    In our study, the most effective therapies were antihis-      EM patient typical history: symptoms misinterpretation and
tamines, venlafaxine, and mexiletine. With regard to anti-        misdiagnoses over a period of many years, poor response
histamines, therapeutic efficacy in our EM patients might         to many therapies, progressive worsening, social isolation
be attributed to their action against neurogenic inflamma-        and severe psychiatric complications culminating in suicide.
tion [41]. Although these drugs are safe, their use in EM is      Extreme self-harm and even suicide as in our patient are a
off-label. Five patients were given magnesium pidolate in         rare but well-recognized consequence of EM, with high so-
combination with antihistamines, which would act as a cal-        cial costs and great impact on the patients and their fam-
cium antagonist, a sympatholytic and a muscle-relaxant [42].      ilies [2,4]. Information about online patient communities,
    In 3 patients, venlafaxine has provided some relief from      which may offer users a valuable educational resource and a
symptoms of by acting both on sympathetic fibers by inhib-        source of psychological and social support, should be offered
iting the reuptake of noradrenaline, as well as on hormonal       (https://erythromelalgia.org/).
vascular control by inhibiting the reuptake of serotonin             To conclude, EM involves several medical fields, and the
[43-45]. As this medication is approved to treat major de-        path from diagnosis to treatment, involving all the necessary
pression, which is a common comorbidity among these pa-           specialists, may be frustrating, both for patients and clini-
tients, it is likely to prove useful for both diseases.           cians. In our experience, patients with this condition display
    Mexiletine is a class IB orally active sodium channel         a wide spectrum of clinical manifestations and severity, as
blocker structurally similar to lidocaine, which appears to be    well as a paucity of resources and structures to support them.
particularly effective in neuropathic pain by shortening the
action potential duration [46]. This drug was very effective      References
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Original Article | Dermatol Pract Concept. 2023;13(3):e2023191                                                                              11
