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ORIGINAL ARTICLE Juvenile
onset erythromelalgia with neuropathy.
Report of three patients and a review of the literature. Ruben
Cuttica R, Leonardo De Lillo, Alejandra
B Pringe, Julio E Puiggari. Hospital de Pediatría Dr. Pedro de
Elizalde Contact: Dr. Ruben J. Cuttica Pediatric Rheumatology Section Hospital de Pediatría Dr. Pedro de
Elizalde Av. Montes de Oca 40 1270 Tel./Fax
+54(11)4361-0900 e-mail cuttirub@rcc.com.ar
elizalde_reumato@buenosaires.gov.ar Key words: Erythromelalgia, children,
peripheral neuropathy, intrathecal anaesthetics Abstract Erythromelalgia
(EM) is a syndrome characterized by redness, increased temperature of the
skin, and severe extremity pain. EM is rare in children, in part due to
underdiagnosis. EM may be classified as primary or secondary to other
conditions. We report 3 patients with juvenile erythromelalgia associated
with peripheral neuropathy. The three adolescent patients developed an
illness characterized by edema, redness and severe extremity pain that
improved only with immersion of the affected extremities in freezing water.
Each teen varied in pain severity and in response to analgesics. The most
severe patient required intrathecal infusion of drug in the morphine class of
analgesic for pain control, and also developed gangrene requiring toe
amputations. All three patients had peripheral neuritis with demyelinization
on nerve biopsy. A review of the literature documented a small number of EM
patients in the juvenile age range. Most had neuropathy or other associated
conditions. We conclude that this syndrome should be considered in the
differential diagnosis of severe limb pain in children along with trauma, infection,
vasculitis, Raynaud’s phenomenon, reflex sympathetic dystrophy,
antiphospholipid syndrome, and other conditions. Clinicians must be vigilant
for the neuropathy and other associated pathology, especially the possible
complication of rapid, severe vascular compromise. In those cases resistant
to usual analgesics, the use of intrathecal infusion of anesthetics and
vasodilators should be considered. Diagnostic criteria, severity scores, and
more research in this area are needed. Introduction
Erythromelalgia
was first described by Mitchell in 1878. EM is a syndrome characterized by
redness, increased temperature of the skin, and very severe pain, mostly in
the extremities. EM is thought to be either primary or secondary. [1-2] The
idiopathic or primary EM is more frequent than the secondary and begins
spontaneously at any age, although it is more common in patients under
30. It is of unknown origin. The
secondary form has been reported associated with several conditions such as
diabetes, lupus or hypertension, but is most frequently secondary to
myeloproliferative diseases. [1-2, 3, 5-7] In juvenile patients the
prevalence is reported as low but the condition may be underdiagnosed. The
purpose of this paper is to report 3 adolescents with erythromelalgia and a
neuropathy that were seen at the Hospital de Pediatría “Pedro de Elizalde”
between October 2000 and November 2001 and to review the pertinent
literature.. Case
1 A thirteen year old boy was initially seen with
a 10 day history of very severe pain in his feet. His feet were warm. He
could not walk. He also had referred pain in his arms and fine tremors in his
hands as well as erythema and swelling.
The recent history was not helpful with absence of recent infections,
fevers, rashes, or other problems. The family history was non-contributory as
well. The pain, swelling, and redness of his hands did not improve with
NSAID’s but did show an immediate improvement with his immersion of hands and
feet in cold water. Physical examination revealed edema and erythema in his
hands and feet with severe pain on movement and tenderness on palpation. He
had a distal, fine tremor and enhanced reflexes without focal neurological
signs. His ophthalmologic examination was normal. He had no arthritis, rash,
other skin changes, or other significant physical findings. During
followup the patient worsened progressively, developing paraesthesias in his
hands and feet with an increase of extremity pain. He also demonstrated
hypereflexia in his lower limbs, dysphonia secondary to paralysis of the left
recurrent nerve, and the appearance of ulcerated lesions on his legs (Figure
1). No evidence of vasculitis was noted. Figure 1. Erythromelegia affecting
the feet of a thirteen year old boy including skin ulcerations
A brain and
spinal cord MRI was normal while an electromyelogram showed a mononeuritic
lesion of the radial nerve, fasciculations,
and axonal damage with loss of 30% of the neural parenchyma. The
patient became severely depressed, refused to eat, and required parenteral
nutrition. The pain was managed with several combinations of drugs including
calcitonin, dipirone, paracetamol, ibuprofen, diazepam, dextropropoxifen,
carbamazepine, tricyclic antidepressants and prednisone. Psychotherapy and
intense physical therapy were also utilized. The patient improved gradually
with complete recovery after a period of
52 days. Case
2 A twelve
year old boy developed very severe pain in his hands and feet that only
improved with the immersion of the extremities in cold water. He also had
hand and foot edema, redness (Figure 2), increased temperature of the
extremity skin, and progressive ulcerative skin lesions on the distal
extremities. No contributory recent or
family history was noted. The patient was admitted to the hospital 21 days
after the onset of his extremity pain with transient vision loss, difficulty
walking and a recent tonic/clonic seizure. Edema and skin lesions of the feet
worsened and the pain was very
difficult to control with analgesics such as NSAID´s. Routine laboratory tests, clotting assays,
and hypercoagulibity tests were normal. The following tests were normal or
negative: ESR, CRP, ANA, antiDNA, rheumatoid factor, C3, C4, serology for
bacteria and viruses including HIV 1-2, toxic (thallium, mercury, lead). Brain and spinal cord CT scan and magnetic
resonance were normal as were venous and arterial doppler studies. A bone
marrow biopsy showed only a mild megakaryocytic hyperplasia. Porphyria and
malignancy were thought to be very unlikely. Upper and
lower limb EMG showed moderate to severe polyneuropathy. An external
saphenous nerve biopsy including electronic microscopy demonstrated only a
mild involvement of myelin fibers and vasculitis was not seen. Muscle biopsy
also did not reveal vasculitis and only showed a selective atrophy of fibers
type 2 likely secondary to decreased physical activity. Several
analgesics such as aspirin, dextropropoxifen plus dipirone, carbamazepine
800mg/ per day, enalapril 5 mg/ per day, amitriptiline 40mg / per day were
tried but failed. Vitamins B1,B6, and B12 were added without response. By the
8th day of admission, the patient was put on gabapentín with a rapidly
increasing dose up to 1500 mg/day without change in the pain. Ketanserine,
tramadol, and mexilitine were also used without relief of pain. Finally,
after failure of all therapies used, it was decided to place an epidural
catheter in the lumbar spine with continuous infusion of 0.5% bupivacaine and
morphine with good control of pain. Unfortunately, cyanosis of the third
right toe and the forefoot (Figure 2) was observed and quickly progressed to
severe ischemia with necrosis. Figure 2. Erythromelegia in a 12 year
old boy with necrosis of several toes
Iloprost and hyperbaric chamber improved
the lesions but surgery with amputation of 2nd to 5th right toes was required
(Figure 3). Figure 3. Erythromelegia in a 12 year
old boy: Sequelae after amputation
During
followup, physical therapy and psychotherapy were needed. The total disease
duration was 130 days. The patient was discharged able to walk and with
almost full functional ability. Case
3 A seventeen
year old female developed EM two months after a miscarriage. She had been
diagnosed with primary Sjögren Syndrome associated with autoimmune
thyroiditis at the age of 12 years. Her symptoms
started with burning pain, heat, and erythema in both feet that improved only
with immersion in cold water. The physical examination was normal except for
redness and swelling of her feet with considerable pain and tenderness. The
neurological examination was normal but an electromyogram showed signs of
peripheral neuritis. Some psychological issues in the family were apparent.
The pain was controlled with NSAID´s, physical therapy, and psychotherapy
with complete recovery after 60 days. Discussion
History The word
erythromelalgia comes from 3 Greek words: erythros (red), melos (extremity)
and algos (pain). [2-4,6]. It was described for the first time by Weir
Mitchell in 1878. Mitchell intended to restrict the term erythromelalgia to
the secondary forms associated with myeloproliferative illnesses that respond
to aspirin, and suggested the word erythermelalgia
for the idiopathic forms without aspirin response. The symptoms of the
illness are distinguished by the coexistence of increased temperature of the
skin, marked redness, swelling and severe burning pain of the involved
extremity. [1-2] These signs and symptoms typically improve when exposing the
affected area to the cold and usually there is no response to analgesics. Epidemiology Kvernebo
estimated an incidence in The illness
appears to be more frequent in females. Davis et al reported that 72.6% out
of 168 cases were female (mean age was 55.8 years, range 5-91 years). [3] Kalgaard noted a
male:female ratio of 1:2 (mean age 43.4 years, range 7.8-76.6 years). [8] The
patients in both studies were mostly adults as only 7 cases began in
childhood. However, in the reported series of juvenile patients, 66% were
boys which is in agreement with our observation (Table 1). Table 1 – Reported series of patients
with juvenile onset erythromelalgia
Kurzrock and
Cohen differentiate two categories: a) an adult form, which can be idiopathic
or secondary; b) an early idiopathic childhood form. [4, 6-7] EM is considered acute when the symptoms
last less than 1 month and chronic if greater than 1 month. [4-8] All 3
patients in our series had the chronic form with a mean duration of 80 days
(range 52 -130 days). Table 2 illustrates differences between the adult and
child forms of EM. Table 2 – Erythromelagia: Differences
clinical features between adults and children
Classification A
classification of EM has been proposed and three forms were described: a) a thrombocytosis/hyperviscosity
form, b) vasoconstrictor form and c) vasodilator form. The different forms of
EM suggested in this classification may explain the considerable variability
of treatment responses. Most of the patients show the
vasoconstrictor/reactive hyperemia form. The less common form is the
vasodilator form that can respond to vasoconstriction with beta selective
blockers such as propanolol, while it may worsen with other treatments. To
distinguish these forms of EM, vascular studies are recommended. These
studies are carried out in cold and hot environments using doppler, doppler
fluxometry, thermography, and tissue oxygen pressure control. Pathology/pathophysiology As EM can be
primary or secondary, the search of underlying pathology is important. In our
patients, a wide range of conditions were considered and eliminated. A
notable point was that all of them had both peripheral neuritis and
psychological stress. Whether the psychological problems were just secondary
to this painful condition or were an important part of the etiology, as may
be seen in reflex sympathetic dystrophy in adolescents, remains unclear. Recent
studies attempting to explain the physiopathology of EM suggest that
pre-capillary sphincters may close, leading to the opening of arterial-venous
shunting. This inbalance may increase perfusion but decrease tissue oxygen,
leading to both hyperemia and hypoxia in the affected skin. Tissue hypoxia
leads to a reactive increase in blood flow
thus worsening the erythema, heat and pain. [1-4,6,16] Acrocyanosis
and ischemic ulcers can develop with risk of secondary infection, sometimes
progressing to distal necrosis. [6] This vascular dysfunction could be
potentially reversible in some cases but in others could lead to chronic
ischemia in spite of the high perfusion of the limb. There could be due to a
chronic dysregulation of the
sympathetic nervous system, showing increased sympathetic tone in some
patients with primary EM. The denervation of the sympathetic
system through epidural anaesthesia can explain the benefit obtained in some
patients with this treatment, as in our second case. Genetic predisposition
was also studied. A common haplotype located on the chromosome 2q31-32 has
been described. [14] Course of EM Relief
of the symptoms is obtained by decreasing the temperature of the skin with
immersion in freezing water, ice or snow, and this is so common that it is
now considered characteristic of EM.
All our patients described improvement of pain only with immersion of
the limbs in a pail of cold water. In the severe forms, the patients carry
out cold water immersion almost constantly. There are patients who
permanently have a pail of cold water by their side and they immerse their
feet for 15-30 minutes every hour and sleep with their feet in the cold
water. [1,4,5-6] The pain relief with cold could be explained by the decrease
of the metabolic index and therefore the oxygen requirement. EM can
significantly alter daily life activities. Primary and secondary forms As noted
above, when evaluating a patient with EM, it is essential to distinguish
between the primary and secondary forms. Therefore, in all the new cases of
EM, an underlying cause should be sought. The most frequent associations are
myeloproliferative illnesses [1-3,6-7] such as polycythemia vera and
idiopathic thrombocytopenia. Sometimes EM precedes the diagnosis of these
illnesses by an average of 2.5 years. Other associated diseases are diabetes
mellitus type 1 and 2, hypercholesterolemia, amaurosis, connective tissue
diseases, several infections including Epstein-Barr viral infections [9] and
also post-vaccination reactions to influenza and hepatitis B. [1,13-14] Other associated entities include trauma,
drug reactions, neuropathies [10] and genetic diseases. [3,6,8] In our
patients, peripheral neuropathy was the only condition that we could
associate with the EM. Another interesting finding was that all of the
children had had recent psychological stress. Though there are no
evidence-based studies for confirmation, it is our belief that stress may be
a trigger of EM as noted in cases of reflex sympathetic dystrophy. Differential diagnosis of
erythromelalgia Table 3
summarizes the differential diagnosis of EM . Table 3 – Erythromelalgia
differential diagnosis
Complications There are
several complications associated with EM that seem to be present more
frequently in patients with platelet-mediated illnesses. [6] These can
include maceration of the skin and skin ulceration. These chronic ulcers may
develop secondary infection leading to digital necrosis or gangrene that may
result in the amputation of the affected extremity [1-2,6-7]. Our second
patient presented with gangrene leading to amputation of 4 toes. This can be
explained on the basis of the existence of inflammatory and proliferative
changes that can increase the ischemic dysfunctions, acrocyanosis and
outlying gangrene. This is directly related to artery damage and an increase
of platelet aggregation. [7] In the report of Kalgaad, several patients
presented with severe complications leading in two of them to amputation of
lower limbs. [8] Diagnostic criteria Several
authors have proposed diagnostic criteria for this disease. Mitchell
initially proposed three criteria: red, hot and burning extremities. [2] In
1932, Brown added other signs for a total of 6 criteria. [4] In 1979 Thompson
proposed a new group of criteria and in 1988. [11] Lazareth defined the
current criteria (Table 4). A patient must have 3 major and at least 2 minor
criteria for a diagnosis of erythromelalgia. [13] Table 4 – Erythromelalgia diagnostic
criteria
Treatment The
treatment of EM is difficult and can often be discouraging. The use of a
medication or group of drugs is sometimes insufficient and other therapeutic methods
may be needed. In one survey by Davis et al, the patients received a total of
84 different drugs to treat their symptoms. [3] The first step in the
treatment is to educate the patient so that he/she learns how to avoid
excessive heat, limit vigorous exercises and overuse of the affected
extremity, and also keep the affected extremity elevated as much as possible. [6] The patient should
not use cold or icy water and should maintain excellent skin hygiene of the
affected area to avoid infection. Also, in the secondary forms of EM,
treatment of the underlying illness should improve the EM. Different
medications can be used for the control of the symptoms (Table 5). Several
reports have advocated the effectiveness of aspirin for EM, likely due to the
antiplatelet aggregation effect of this drug. Aspirin may only be effective
in the cases associated with thrombocytosis, polycythemia or other blood
dyscrasias. [1-2,6] Table 5 – Drugs and other therapies
used in the management of erythromelalgia
The response
to medical treatment is unpredictable and remissions are uncommon. However, through careful trial and error,
benefits can be obtained in many patients. Oral medications should initially
be used especially in milder cases of EM, but infusions or invasive treatments
may be necessary for the severe ones. The ideal therapy has not yet been
defined. Conclusions
EM is a
condition that requires a multidisciplinary team for its management.
Diagnosis is often not easy. A patient
may initially be classified as having primary EM, and may declare later that
the EM is a secondary condition. It is important to be vigilant and watch for
an associated condition. Diagnostic tests should be repeated if symptoms
worsen in spite of therapy. In some patients, a hematologic evaluation
including bone marrow biopsy is necessary in order to diagnose associated
myeloproliferative conditions that may precede or follow the diagnosis of
EM. Treatment is
often unsuccessful but any treatment used must be closely monitored as
progression of the disease can lead to several complications such as
infections, tissue hypoxia and gangrene. In resistant cases, the possibility
of intrathecal infusion of opioids should be considered since it appears to
shorten disease evolution. Multiple
disease associations, varying degrees of disease severity, potential of
severe complications, and inadequate treatment suggest a need for an
international consensus to clarify nomenclature, develop severity and damage
scores, and to encourage better research into the etiopathogenesis of this
unusual but very painful disorder. References 1. Cohen JS. Erythromelalgia: New theories
and new therapies. J Am Acad Dermatol. 2000;43:
841- 7. 2. Rauck RL, Naveira F, Speight KL, Smith
BP. Refractory Idiopathic Erythromelalgia. Anesth
Analg. 1996; 82:1097-101. 3.
Presentation and outcome in 168 patients. Arch Dermatol. 2000;
136:330-36. 4. Mork C, Kvernebo K: Erythromelalgia. A
mysterious condition? Arch Dermatol. 2000;
136(3):406-9. 5. Cassidy
JT, Petty R. Erythromelalgia. Text Book of Pediatric Rheumatology.
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