Download Erythromelalgia: studies on pathogenesis and therapy

Erythromelalgia: studies on pathogenesis
and therapy.
ABSTRACT
Erythromelalgia (EM) is a rare condition characterized by red, hot and painful
extremities. Local skin cooling provides relief. Warmth, exercise and dependency of the
extremity intensify the discomfort.
Shunt hypothesis: Clinical observations and pathophysiological findings are compatible
with microvascular arteriovenous shunting of blood as a final common pathway of
pathogenesis of erythromelalgia in affected skin. The hypothesis postulates that available
blood is maldistributed. An insufficient proportion of blood is directed through nutritional
capillaries, leading to skin hypoxia. while a large proportion of blood is shunted through
microvascular anatomical or functional arteriovenous anastomoses. The skin hypoxia
induces arteriolar dilatation and hyperemia, resulting in elevated skin temperature and
accelerated metabolism. Because the hyperemic perfusion is still maldistributed, the
hypoxia is not revealed. This vicious cycle may be triggered by different mechanisms
related to hemorrheological problems, defects in prostaglandin metabolism, dysfunction
of endothelial cells or the autonomic nervous system.
Aim of the studies: The aim of this thesis was: to challenge the shunt hypothesis, to
characterize the mechanisms underlying the vascular dysfunction in erythromelalgia, and
to test if therapy, based on this understanding of the pathogenesis, would improve clinical
and objective outcome measures in patients with erythromelalgia.
Materials, methods and study design: Patients were selected from a database of EM
patients built up over nearly 20 years (n=160). The patients were characterized by
demographic and clinical parameters (cooling and pain scores, global assessment). Skin
perfusion was assessed using laser Doppler flowmetry (LDF), laser Doppler perfusion
imaging (LDPI) and computer assisted video microscopy (CAVM. LDPI assesses global
(thermoregulatory and nutritive) skin perfusion; CAVM evaluates skin capillary
morphology. Perfusion was assessed following vasoconstrictory and vasodilatory stimuli
to characterize central and local neurogenic reflexes as well as vascular smooth muscle
and vascular endothelial cell function and following central body heating to provoke EM
symptoms in patients and healthy controls. In a double blind, crossover, placebo
controlled clinical trial, EM patients were treated with misoprostol, a prostaglandin E 1
analogue with vasodilatory and thrombocyte inhibitory effects.
Results: In EM patients, LDF assessed skin microvascular perfusion was significantly
reduced during basal conditions. Vasoconstrictor responses involving central sympathetic
reflexes were attenuated in affected skin. Central body heating induced a significant
increase in LDPI-assessed perfusion and reduction in capillary density in affected EM
skin containing many anatomical arteriovenous shunts, as compared to asymptomatic
patients and controls. In areas with no or few shunts, the groups did not differ. We
demonstrated beneficial clinical effects of misoprostol and redistribution in skin
microcirculation in favor of nutritive perfusion.
Conclusion: Increased thermoregulatory flow and decreased capillary density during EM
attacks, as well as clinical improvement and redistribution of the skin microcirculation in
favor of the nutritive perfusion after misoprostol treatment give support to the shunt
hypothesis. Erythromelalgia was associated with neuropathy, which may be one
underlying mechanism for the disturbance in the vascular dynamics. On the other hand
vasculopathy with hypoxia may cause neuropathy.
LIST OF PAPERS ASSOCIATED WITH THIS THESIS
This thesis is based on the following papers, referred to in the text by their Roman
numerals:
I. Mørk C, Asker CL, Salerud EG, Kvernebo K: Microvascular shunting is a probable
pathogenetic mechanism in erythromelalgia. Jlnvest Dermatol 114:643-646, 2000
II. Mørk C, Kvernebo K, Asker CL, Salerud EG: Reduced skin capillary density during
attacks of erythromelalgia implies arteriovenous shunting as pathogenetic mechanism.
Jlnvest Dermatol 119:949-953, 2002
III. Mørk C, Kalgaard OM, Kvernebo K: Impaired neurogenic control of skin perfusion
in erythromelalgia. Jlnvest Dermatol 118:699-703, 2002
IV. Mørk C, Salerud EG, Asker CL, Kvernebo K: The prostaglandin E 1 analogue
misoprostol reduces symptoms and microvascular arteriovenous shunting in patients with
erythromelalgia. A double-blind, crossover, placebo-compared study. Jlnvest Dermatol
122, 587-593, 2004
PART ONE: INTRODUCTION
Erythromelalgia (EM) is a clinical syndrome characterized by heat, redness and pain.
EM symptoms are commonly intermittent, though constant in some patients. The
duration of episodes or "flare-ups" varies from minutes to hours. The attacks occur more
frequently during evenings and nights. Doctors therefore rarely observe the episodes
unless the patients are hospitalized. As many doctors are not familiar with the disease,
most patients have symptoms for many years before they get a diagnosis.
A short introduction to the present understanding of erythromelalgia is given in Appendix
I (Mørk & Kvernebo, 2000a).
1.1 History and nomenclature
Graves reported in 1834 a young lady who suffered from a "hot and painful" leg, and
the associated increase in temperature was found to be "so disagreeable" (Graves, 1834).
In 1878, Silas Weir Mitchell reported 16 cases with painful affections of the feet of
various types and severity and introduced the term "erythromelalgia" by combining the
three Greek words erythros (red), melos (extremities) and algos (pain) to illustrate the
triad of presenting symptoms and signs of the condition (Mitchell, 1872; Mitchell, 1878).
He also described erythromelalgia as a `vascular storm." Erythromelalgia has also been
named Mitchell's or Weir Mitchell's disease. Little notice was taken of the condition for
many years (Collier, 1898; Cassirer 1912; May & Hillemand, 1924).
In the literature, there has been confusion and inconsistency regarding the
nomenclature, classification, prevalence, and pathophysiology. In 1932, Brown proposed
five criteria for the diagnosis of erythromelalgia: (1) Attacks of bilateral or symmetrical
burning pain in the hands and/or feet, (2) During attacks, the affected parts are flushed
and congested and exhibit increased local temperature, (3) The attacks are initiated or
aggravated by standing, exercise or exposure to warmth (limb temperature >34 °C), (4)
Relief is obtained by elevation or exposure to cold, and (5) The condition is refractory to
treatment (Brown & Giffin, 1930; Brown, 1932). The term "erythermalgia" was
introduced by Smith and Allen to emphasize the rubor, calor, and dolor, and they
proposed a subdivision into a primary group, with no associated disease, and a secondary
group, particularly hyperviscosity syndromes (Smith & Allen, 1938). The term
"erythralgia" has also been used (Lewis, 1933; Lewis & Hess, 1933). In German
literature "erythroprosopalgia" (prosopon-face) describes the condition in the face (Regli,
1969). The term "erythermomelalgi" is a more complete description of the clinical
features, but this unwieldy label is not in general use (Zoppi et al, 1985). Other less
common terms are acromelalgia, erythrothermia, red neuralgia, vasomotor paralysis of
the extremities and Gerhardt's syndrome (Gerhardt, 1892). Lazareth et al proposed three
major criteria (paroxysmal pain, burning pain, redness of affected skin) and four minor
criteria (typical precipitating factors (heat exposure, effort), typical relieving factors
(cold, rest), elevated skin temperature in affected skin, response of symptoms to
acetylsalicylic acid) and demanded three major and two minor criteria for the diagnosis
(Lazareth et al, 1988). Erythromelalgia and erythermalgia have been used
interchangeable for many years, but Michiels et al proposed to restrict the term
erythromelalgia to aspirin-responsive disease associated with thrombocytosis related to
myeloproliferative disorder, and used erythermalgia for aspirin-resistant idiopathic cases
or conditions secondary to other diseases (Michiels et al, 1995).
Some authors subgroup their patients into "early-onset" and "late-onset" cases
irrespective of etiology (Kurzrock & Cohen, 1991; Kurzrock & Cohen, 1995). "Pediatric
erythromelalgia" has also been subdivided into a primary form with early debut, often
severe, resistance to treatment and sometimes with a family history, and a secondary
form associated with hypertension (Finley et al, 1992; Drenth et al, 1995). The term
"epidemic erythromelalgia" has been used for outbreaks in China (Zheng et al, 1988).
Some authors use a combination of the above terms to sub-classify cases based on the
underlying pathophysiology. A modified classification of erythromelalgia, type I
erythromelalgia ("classical") and type Il erythromelalgia, lacking the burning nature of
the pain, and lacking relief by cooling or limb elevation, has also been used (Littleford,
1997; Littleford et al, 1999a,b).
Like most authors, we use the term erythromelalgia, and in our work we have used the
following inclusion criteria for this clinical syndrome (Thompson et al, 1979; Mørk &
Kvernebo, 2000a):
• Burning extremity pain
• Pain aggravated by warming
• Pain relieved by cooling
• Erythema of affected skin
• Increased temperature of affected skin
Each criterion is dependent on individual clinical judgment.
1.2 Erythromelalgia in Norway
Einar Hval (1901-1958) at the Department of Dermatology, Rikshospitalet, reported
the first case of erythromelalgia in Norway (Hval, 1928). A renewed interest for
erythromelalgia in Norway started in 1983 when a patient with a medical history typical
for erythromelalgia was referred to Knut Kvernebo. Kvernebo was then working at the
Department of Surgery, Aker University Hospital in Oslo with a vascular laboratory for
examination of arterial and venous extremity blood flow as well as skin microvascular
perfusion. The patient had cooled her feet in a bucket of iced water for up to 20 hours a
day over 16 years. Together with Egil Seem, Kvernebo investigated the microvascular
hemodynamics in the affected EM skin. Her situation was mentioned in a national radio
program (Asa Rytter Evensen, "Saran er livet", NRK, Oslo), resulting in contact with a
large number of frustrated patients with similar symptoms. 39 patients (50% of the
respondents) suffered from erythromelalgia. Hemodynamic studies were performed in
1984-89, and a more thorough understanding of the pathophysiological and thereby
pathogenetic mechanisms was obtained, resulting in the hypothesis that erythromelalgia
is a condition caused by microvascular arteriovenous (AV) shunting. This work was
rewarded with the King Olav V's Gold Medal in 1990. Kvernebo's work is presented in a
monography (Kvernebo, 1998).
Kvernebo contacted the Department of Dermatology, Rikshospitalet University
Hospital, and presented his work, resulting in initiation of the scientific work presented in
this thesis. An Erythromelalgia Study Group (ESG) was established with focus on
epidemiology, pathogenesis and therapy. ESG is organized as a research network, so far
involving the following seven units: Department of Biomedical Engineering, University
Hospital, Linkopings Universitet, Sweden; Department of Cardiothoracic Surgery,
Ullevaal University Hospital; Rikshospitalet University Hospital with the following
departments: Institute of Laboratorium of Clinical Neurophysiology, Department of
Neurology, Department of Psychosomatic Medicine, Department of Pathology, and
Department of Dermatology; and The Erythromelalgia Association (TEA;
www.erythromelaliga.org). Patients have continuously been referred to Department of
Dermatology, Rikshospitalet University Hospital, and we have over a period of almost 20
years established a database of 160 patients, probably the largest EM cohort in the
western world. All patients have been examined by one of three physicians in the group
(Kvernebo, Kalgaard, Mork). Patients from Norway, Sweden, Denmark, UK, and USA
were included.
1.3 Clinical features
The EM diagnosis is based on the medical history and findings, and no objective
laboratory criteria are available. Erythromelalgia is heterogeneous with regard to severity,
localization, age at onset, etiology and prognosis.
1.3.1 Symptoms
Before erythromelalgia is diagnosed, heat intolerance and symptomatic relief from
cooling should be demonstrated. These features are hallmarks of erythromelalgia. The
patients report major adjustments to their lifestyle to avoid precipitation of an EM attack.
A prickling or itching sensation may herald the pain. All patients find self-induced
measures to control their burning pain or deep aching. Patients typically seek relief by
cooling of affected skin on cold floors, wet sand, wet towels, immersion in cold water, or
by applying cold objects. The patients frequently sleep with the affected extremities
outside the bed cover. Partial relief can be obtained by elevation of the affected
extremity. Some patients show peculiar behavior, like walking barefoot in the snow,
sleeping with the feet out of a window, putting the feet into a refrigerator or continuously
living with a bucket with iced water at their side day and night.
Cold and immersion may induce tissue damage, like immersion feet, infections,
reactive flaring, and severe ulcers that can take many months to heal. Beneficial effects of
aspirin is rarely seen, except for cases secondary to myeloproliferative conditions.
Analgesics have limited effect. Warm environments make the EM symptoms more
severe. Aggravating or inducing factors often reported are warm rooms, floors, water,
heating appliances, bed covers, shoes, and gloves. Walking, physical activity, placing the
limb in a dependent position (hanging down), and application of skin pressure may also
intensify or precipitate the symptoms. Many patients report an increase in severity and
frequency of erythromelalgia in the summer period. In addition, some patients have found
that foods, beverages (particularly alcohol), spices (monosodium glutamate), and some
drugs aggravate EM symptoms.
Some doctors may find the patients' stories bizarre and may not believe that the patient
is suffering from a genuine somatic condition. Some of the patients have significant
complaints without objective signs when seeing the doctors.
1.3.2 Signs
Affected skin in erythromelalgia is red to purple in color and may be warm or hot on
touching compared to the adjoining asymptomatic skin. After anemisation of affected
skin by diascopy, there is a short refilling time. Initially, the patients do not always notice
this redness and local heat. Skin temperature and color are often normal at the time of
physical examination, as the patients frequently are asymptomatic at the time of
examination. The skin may even be white/pale or blue/cyanotic, which is suggestive of
low basal skin blood flow in the asymptomatic skin.
The patients should be instructed to look for changes in skin temperature and color
during EM symptoms. Photography and measurements of skin temperature with and
without EM symptoms may be of help in assessing changes in skin color and
temperature. The affected limb can occasionally be oedematous.
Trophic skin changes of affected skin areas have been described (Belch, 1996). Nail
dystrophy and slow-healing skin ulcers of the feet without obvious signs of trauma or
infection has been observed in severely affected patients (Kvernebo, 1998). Biopsies
from affected skin may also heal slowly. Gangrene of the affected extremity, in spite of
open limb arteries, has also been observed.
1.3.3 Impact on quality of life
Erythromelalgia may have a severe impact on normal life. Diminished scores in quality
of life questionnaires have been reported, primarily due to the pain associated with
erythromelalgia (Davis et al, 2000a). Disabilities described in this study from USA
include inability to walk long distances (50%), stand for long periods (49%), having to
give up a job (12.5%), inability to drive (12.5%), use of wheel chair (3%), and being bed
bound (2%). Patients avoid warm weather and limit their activities to cool or air
conditioned locations. Some have to move to cooler climates. They cannot wear socks or
closed shoes even in winter. Work and social functioning may be disrupted. Sometimes
the patients avoid leaving their homes, leading to disablement and isolation. Restless
sleeping patterns affects family functioning. Over a third of a large cohort have reported
clinical depression or "depressed" states (Littleford, 1997).
Like most chronic pain conditions, psychological mechanisms probably play an
important part in the experience and coping of pain in many EM cases. Compared with an
age- and sex-matched population, an increased mortality rate, including suicide, has been
found (Davis et al, 2000a). No specific psychological profile has been found in the EM
patients compared to patients with other chronic disorders (Kalgaard et al, in manuscript).
Contact with The Erythromelalgia Association (TEA; www.erythromelalgia.org) may be
helpful for frustrated EM patients "shopping" from treatment to treatment and from
doctor to doctor in an effort to get answers and help for their problems.
1.3.4 Clinical classification
The severity of the symptoms varies widely, from mild discomfort to erythromelalgia
with gangrene that require amputation of the affected limb. In daily clinical work the
terms mild, moderate and severe may be used. Erythromelalgia can be regarded as the
antithesis to Raynaud's phenomenon representing an extreme condition on a continuous
spectrum from cold to warm hands and feet (Fig 1). A severity score scale has been
introduced based on the needs to cool the affected skin.
1. Feeling uncomfortably warm in periods. No active cooling.
2. Feeling uncomfortably warm in periods. Walking barefoot on cold floors etc.
3. Feeling burning pain in periods. Immersion in cold water <1 hour/d
4. Feeling burning pain in periods. Immersion in cold water 1-3 hours/d,
5. Feeling burning pain in periods. Immersion in cold water 3-6 hours/d,
6. Feeling strong burning pain. Immersion in cold water 6-12 hours/d
7. Feeling very strong burning pain. Immersion in cold water >12 hours/d
8. Feeling very strong burning pain continually. Continuous need for cooling or
plexus/epidural anesthesia
Based on clinical findings and etiology a classification has been proposed to
characterize the wide spectrum of erythromelalgia (Fig 2). The term "erythromelalgia
syndrome" is used when there is a family history of erythromelalgia, and when the
symptoms start during childhood or adolescence and gradually increase in intensity. The
disturbances are associated with structural changes in the microvascular architecture of
the skin. The term "erythromelalgia (Kvernebo, 1998) phenomenon" is used for all other
cases. Erythromelalgia may be primary (idiopathic) or secondary when considered to be
caused by a primary disease or condition. The term "acute" is used when the symptoms
increase and reach maximum severity within one month. Cases with persistent symptoms
over long periods are termed "chronic." Prognosis depends on the clinical subgroup:
erythromelalgia syndrome gradually gets worse, acute erythromelalgia gets better, while
chronic erythromelalgia seems to remain stable (Kalgaard et a1, 1997).
In all new cases, underlying causes should be looked
for, and a variety of etiological factors may be involved
in secondary erythromelalgia. Cases initially classified
as primary should be reclassified when an underlying
condition has been diagnosed. Several hematological,
metabolic, neurologic, connective tissue,
musculoskeletal, cardiovascular, and infectious
disorders as well as pharmacological substances have
Fig. 2: Clinical classification of
been described associated with erythromelalgia (Table
erythromelalgia (Kvernebo,
1).
1998)
When erythromelalgia coexist with another disease or
condition, the question arises whether the relationship is a coincidental or causal. A high
incidence of co-occurrence, parallel and synchronous course of both conditions,
remission of erythromelalgia after treatment of the underlying condition, and
pathogenetic or etiological evidence of causality are all indications of a causal
relationship. Due to the low prevalence of erythromelalgia, statistical or epidemiological
evidence for a causal relationship is difficult to prove.
A beneficial effect on the EM symptoms after successful treatment of the primary
condition indicates a causal relationship. An understanding of the pathogenetic
mechanisms in the primary condition as in myeloproliferative diseases may indicate a
cause-and-effect linkage between the conditions. Many of the accompanying conditions
reported in erythromelalgia may produce physiological disturbances in the vessel wall
(blood/tissue diffusion barrier), in the composition of the blood (hemorrheological
properties), or in blood flow (microvascular maldistribution), which seems to be
important pathogenetic or etiological evidence for a linkage.
The temporal relationship between erythromelalgia and an underlying disease varies.
Since secondary erythromelalgia is caused by an underlying disease, the primary
condition by definition must precede the development of erythromelalgia, but the primary
disease may be undiagnosed for many years. The symptoms and signs of erythromelalgia
usually affect the extremities, most frequently the lower extremities, and usually
bilaterally and symmetrically. Most frequently the acral parts of hands and/or feet are
involved but more proximal parts of the extremities may also be affected Rarely,
erythromelalgia may appear in the face and ears. Primary erythromelalgia is localized to
skin areas distal to the ankle or wrist areas, where anatomical AV anastomoses have been
described. In secondary erythromelalgia and in erythromelalgia syndrome, symptoms
may occur in other skin areas.
Based on the follow-up of 112 patients from our EM cohort, the clinical and
demographic characteristics are presented in figure 3 and tables I-III. Twelve patients had
a family history of erythromelalgia. Four legs in three patients are amputated, in spite of
open limb arteries.
Table 1. Accompanying diseases, conditions and pharmacological substances described
to be associated with erythromelalgia. The number in brackets are the relevant number in
our cohort of 112 patients.
Metabolic conditions (n=12)



Diabetes mellitus (Babb et al. 1964: Vendrell et al. 1988; Belch, 1996; Kalgaard
et a1, 1997; Littleford 1997; Davis et al, 2000a)
Hyperlipidaemi (Kalgaard et al, 1997; Davis et al, 2000a)
Gout (Markel, 1938; Babb et al, 1964; Belch. 1996)
Blood dyscrasia (n=8)




Polycytemia, thrombocythemia (Babb et a1. 1964; Edwards & Cooley. 1979;
Redding, 1977; Kurzrock & Cohen, 1989; Mehle et al, 1990: Michiels et al, 1994:
Belch, 1996; Ongenae et al. 1996: Kalgaard et al, 1997. van Genderen et al, 1997:
Kvernebo. 1998. Davis et al, 2000a: Tarach et al, 2000: McCarthy et al, 2002:
Coppa et al, 2003: Michiels et al, 2003: Rey et al, 2003a)
Chronic myeloid leukemia (Kurzrock & Cohen, 1993: Belch, 1996: Kalgaard et
al, 1997; Davis et al, 2000a)
Hereditary spherocytosis (Kalgaard et al, 1997: Kvernebo, 1998)
Pernicious anemia (Mehle et al, 1990: Rauck et al, 1996)
Autoimmune diseases (n=6)





Systemic lupus erythematosus (Alarcon-Segovia et al, 1963: Babb et al, 1964:
Alaragon-Segovia & Diaz-Jouanen, 1973: Kraus, 1990: Michiels, 1991: Drenth et
al, 1993a: Levesque, 1996: Belch, 1996: Cailleux et al, 1996: Kalgaard et al,
1997)
Rheumatoid arthritis (Babb et al. 1964: Belch 1996: Kalgaard et al, 1997:
Littleford 1997)
Vasculitis (Ratz et al, 1979; Drenth et al, 1993b: Drenth et al, 1995: Kasapcopur
et al. 1998)
Lichen sclerosus et atrophicus (Hammar, 1978)
Sclerodenna (Daroczy. 1973)
Neurological diseases (n=3)









Neuropathy (Uno & Parker, 1983:Vendrelll et al, 1988: Nagamatsu et al, 1989:
Staub et al, 1992: Herskovitz et al, 1993; Kitajima et al, 1985: Belch, 1996;
Littleford et al, 1997; Sandroni et al. 1999: Davis et al, 2000a,b: Mork et al, 2002:
Kazemi et al, 2003: Ørstavik et al, 2003; Ørstavik et al, in press )
Cerebral vascular accident (Thomas. 1985; Littleford 1997)
Neurofibromatosis (Kikuchi et al, 1985)
Migraine (Michiels et al, 1996: Koudstaal & Koudstaal, 1997)
Astrocyroma (Levine & Gustafson, 1987)
Spinal cord disease (Collier. 1898. Takahashi et al, 1990: Kalgaard et al, 1997)
Multiple sclerosis (Cendrowski, 1988: Rauck et al, 1996; Littleford, 1997)P
Parkinson's disease (Littleford, 1997)
Carpal tunnel syndrome (Kalgaard et al, 1997)
Pharmacological substances (n=3)










Calcium antagonists (Fisher et al, 1983: Brodrnerkel, 1983: Alcalay et al.1987:
Levesque et al. 1989: Levesque & Moore. 1989: Drenth, 1989: Drenth et al, 1992:
Sunahara et al, 1996)
Bromocriptine (Calne et al, 1978: Eisler et a1, 1981: Dupont et al, 1983)
Norepinephrine (Wagner et al, 1993)
Pergolide (Monk et al, 1984)
Ticlopidine (Yasipovitch et al, 1999)
Cyclosporine (Thami & Bhalla, 2003)
Iodide contrast injection (Kalgaard et al, 1997)
Vaccines (hepatitis and influenza) (Confino et al, 1997: Rabaud et al, 1999)
Mushroom (Saviuc et al, 2001; Saviuc et al, 2002)
Mercury (Martin et al, 1994)
Musculoskeletal disorders (n=3)



Peritendinitis (Kalgaard et al, 1997)
Surgery/trauma (Collier, 1898; Strukelj & Antonutti, 1964; Belch, 1996: Kalgaard
et al, 1997: Littleford, 1997. Kvemebo, 1998)
Osteoarthrosis (Kvemebo,1998)
Infections (n=2)






Bacterial infections (Kalgaard et al, 1997)
HIV (Itin et al, 1996: Mørk et al, 2000a; Dolan et al, 2003)
Poxvirus (Zheng et al, 1988: Wang, 1988: Zheng et al, 1991: Zheng et al, 1992)
Herpes zoster (Jabs & Druke, 1994)
Mononucleosis (Clayton & Faden, 1993)
Syphilis (Collier, 1898; Hval, 1928)
Cancer (n=l)

Internal malignancy (Lantrade et al, 1980; Levine et al, 1987: Mørk et al, 1999:
Davis et al, 2000a)
Cardiovascular diseases (n=1)





Hypertension (Martorell & Martorell, 1953, Creyx et al, 1953, Babb et al, 1964;
Ratz et al, 1979; Özsoylu et al, 1979: Blanchard et al, 1987, Alcalay et al, 1987:
Belch, 1996: Drenth et al, 1995: Kasapcopur et al, 1998: Zenz et al, 1999: Davis
et al, 2000)
Atherosclerosis (Kalgaard et al, 1997)
Raynaud's disease (Garrett & Robinson, 1990: Lazareth & Priollet, 1990:
Slutsker, 1990; Littleford, 1997: Maldonado et al, 1999)
Venous insufficiency (Babb et al, 1964; Pistorius et al, 1995: Rauk et al, 1996)
Cholesterol emboli syndrome (Kalgaard et al, 1997)
Miscellaneous (n=5)




Frostbite (Kalgaard et al, 1997)
Nephritis (Cross, 1962)
Small bowel disease (Littleford, 1997)
Psychiatric disorders (Munford. 1929; Kalgaard et al, 1997; Kvernebo, 1998)
1.4 Epidemiology of
erythromelalgia
Based on the different
nomenclature and
definitions of
erythromelalgia, it is
difficult to estimate the
prevalence and incidence
of erythromelalgia
(Belch & Mackay,
1992). Literature reports
are biased by different
referral patterns and
severity. As
erythromelalgia can
predate the development
of an associated disease
by many years, the
prevalence of secondary erythromelalgia is even more difficult to estimate (Babb et al,
1964; Michiels et al, 1995). Many doctors are not aware of cases, and persons with mild
erythromelalgia may never consult a doctor.
The EM entity was controversial some years ago (Snapper & Kahn, 1967; Housley,
1986), but is not questioned in newer leading textbooks in dermatology. In
Medline/PubMed, using the mesh-term erythromelalgia, 348 publications are listed from
1952 to January 2004. A review of the literature published in 1972 concluded that only
half of the published reports deal with true erythromelalgia (Fairbairn et al, 1972).
Erythromelalgia was documented in three of 5000 patients referred to a pain clinic (Zoppi
et al, 1985). Estimates of the prevalence of erythromelalgia in patients with
myeloproliferative diseases vary from 3 to 65% (Brown & Giffin, 1930; Michiels et al,
1985; McIntyre et al, 1991). Epidemics have occurred in China since 1954, at intervals of
three to five years, mainly among teenage female students, during winter and spring
(Wei, 1984, Zheng et al, 1988; Zhu, 1989; Mo, 1989; Zheng et al, 1991)
The prevalence of moderate to severe erythromelalgia has been estimated to 2.09 per
100,000 in the Norwegian population, and the incidence 0.33 per 100 000, assuming that
we see 50% of EM patients with severity group plus or equal to 3(Mork & Kvernebo,
1997).
1.5 Skin vasculature
and blood flow
regulation
1.5.1 Morphology and
function of skin
microcirculation
The main functions of
the skin circulation are
tissue nutrition,
thermoregulation and being a reserve for repair following injury. The skin vessels are
arranged in a delicate network for ready transfer of heat from the blood to the external
environment. The cutaneous microcirculation is organized as two horizontal plexa
(Braverman et al, 1992; Braverman, 2000). The superficial plexus is situated in papillary
dermis 1.0-1.5 mm below skin surface. The deep plexus is at the dermal-subcutaneous
junction 3.0-5.0 mm below skin surface, depending on the skin region. Most vessels are
found in the upper plexus, which is composed of terminal arterioles, capillary loops, and
postcapillary venules, the latter being the most numerous. Thus plexus may be called the
"radiator of the skin." The lower plexus is formed by perforating vessels (with diameter
50-100 gym) from the underlying muscle and subcutaneous tissue. Ascending arterioles
and descending venules are paired as they connect the two plexa. The deep plexus is the
source of perpendicular ascending arterioles (diameter 25-30 gym), which divide into
four to five arterioles. The ascending arterioles are 2-7 mm apart in almost all areas of the
skin surface, closer at the toe and fingertips, and supply a specific number of capillaries.
The sympathetic fibers to the arterioles run along the adventitialmedia border, ending in
small swellings or simply fades out as free endings
Fig 3. Epidemiology and clinical characteristics of 112 EM patients.
*Clinical subgroup (number of patients).
**Females (%) in the clinical category.
***Age (years, mean with total range) at the time of onset of EM symptoms.
****Time from initial symptoms to diagnosis (mean with total range).
EPPA = erythromelalgia-phenomenon-primary- acute
EPPC = erythromelalgia-phenomenon-primary-chronic
EPSA = erythromelalgia-phenomenon-secondary-acute
EPSC = erythromelalgia-phenomenon-secondary-chronic
(Levick, 1995). The arterioles may be heat sensitive or non-heat sensitive. The terminal
arterioles, with their strong muscular coating, are important resistance vessels in the
microvasculature and play a key role in the regulation of blood flow to the capillaries.
A smooth muscle encircles the entrance of the capillary, the capillary sphincter. The
capillaries are organized in loops, which are composed of an ascending limb, an
intrapapillary loop with a hairpin turn, and a descending venous limb to the postcapillary
venule. Each dermal papilla is supplied by a single capillary loop. The loops are
perpendicular to the skin surface, except those in the nail beds, which run parallel to the
surface of the skin. The capillary density is about 50 per mm2, but varies at different
locations (Rothman. 1954; Pasyk et al, 1989). Exchange of respiratory gases, fluids and
metabolites takes place mainly during the passage of the capillaries by filtration,
diffusion, osmosis and pinocytosis. The nutrients migrate out into the interstitial space
towards the cells in the tissue and waste products in the opposite direction.
The capillary is 0.5 ¦Ìm thick, consisting of only a single layer of endothelial cells, and is
surrounded by a basement membrane. The diameter is 49 gym, and the length 1-2 mm.
As there is no nerve endings and nor smooth muscles in the vessel wall, the size of the
capillaries are dependent on the arterial pressure and the tonus of the precapillary
sphincter (Nelms, 1963). The disc shaped erythrocytes, with an average diameter of 8
¦Ìm, have to fold in order to pass through the capillary. The erythrocytes move with a
velocity of 0.4-0.8 mm/s. The endothelial cells are active multifunctional cells and are
important in the evolution of inflammatory disorders.
Eight to ten postcapillary venules converge to the descending venule, running
alongside the ascending arteriole, which connect the venous side of the upper plexus to
the lower horizontal plexus. At the lower plexus, collecting veins with two-cusped valves
prevent retrograde flow of blood. An umbrella-like vascular unit could be defined, where
the ascending arteriole and the descending venule represent the handle, and the umbrella
proper is formed by branching arterioles in the center, and venules in the periphery.
The skin vasculature largely exceeds what is necessary
to meet the metabolic demands of the skin. To regulate the
heat loss, the blood can be passed through microvascular
AV anastomoses, shunt vessels that connect arterioles with
venules (Fig 4). AV anastomoses are, as the arterioles,
important resistance vessels, but with a more specialized
function. The diameter of the AV anastomoses in the skin
range from 35 to 165 ¦Ìm. Their locations are somewhere
above the level of the sweat glands, deep in dermis. The
anastomotic channel may be single or multiple, straight or
curved. The intermediate segment, called Suquet-Hoyer
canal, between the arterial and the venous part of the AV
anastomoses, has a lumen diameter that varies between 20
and 70 ¦Ìm, three to ten times the size of an erythrocyte
Fig 4. Simplified model of
(Johnson et al, 1986). The vessel wall of this canal consists
skin microvascular
of a thick layer of smooth muscle cells with a "muff' of
anatomy (modified after
nerve fibers (Nelms, 1963; Ijima & Tagawa, 1976;
Conrad, 1971)
Molyneux, 1977; Morishima & Hanawa, 1978). They can
rapidly redistribute blood in the skin to the deep layer and thereby depriving the capillary
loops of blood flow and simultaneously directing the flow into the venular bed giving
increased skin temperature. Heat from the core of the body is conducted to the skin
surface where it is lost to the surroundings by radiation, conduction, convection or
evaporation.
AV anastomoses are confined to apical or acral skin, i.e. distal part of the limbs, the
nose and the external ear. The highest concentration of shunts is found in the nail beds,
about 500/cm2. The fingertips and toe tips have about 50% of the number of shunts found
in the nail bed; the palmar and plantar surfaces about 20-25%. None or few AV
anastomoses are found on the dorsal surfaces of hands and feet, and it is generally
assumed that they are not found in the skin of the thorax and abdomen (Suquet 1862;
Hoyer 1877; Grosser, 1902; Grant & Bland, 1931; Popoff, 1934; Mescon et al, 1956;
Sherman, 1963).
1.5.2 Morphology in erythromelalgia
No diagnostic structural diagnostic criteria for erythromelalgia have been described. In
many cases, no pathological findings are described, while other authors report nonspecific histological changes of skin vessels (Cross, 1962; Eisler et al, 1981; Vendrell et
al, 1988; Kvemebo, 1998). Perivascular inflammation, fibromuscular intima
proliferation, thickened blood vessel basement membranes, perivascular edema,
endothelial swelling, as well as thrombotic occlusion have been reported in
erythromelalgia secondary to trombocythemia (Michiels et al, 1984; Michiels et al, 1985;
Crone et al, 1993; Drenth et al, 1996).
1.5.3 Regulation of skin blood flow
Regulation of skin blood flow is complex and is dependent on perfusion pressure,
blood viscosity, and diameter of the blood vessels. The skin blood flow range from 0.3 to
150 ml/100 g tissue/min (Sejrsen, 1971). In steady state conditions, about 250 ml/min
goes to healthy skin and up to 6-81/min during hyperthermia. Diseases in the arteries
(atherosclerosis) and arterioles (B¨¹rger's disease) may reduce the perfusion pressure.
Viscosity of the blood and thereby changes in the hemoreological properties of the blood
may be influenced by the concentration, aggregation and flexibility of blood cells
(thrombocytes, erythrocytes, leukocytes), plasma proteins, clotting factors, and
environmental temperature.
The vessel diameter is controlled by the muscle tone in the arterial tree, the contractile
activity of the pericytes and endothelial cells. Nervous stimuli, local pH, oxygen tension,
and vasoactive mediators control the vascular tone of the arterioles, AV anastomoses and
precapillary sphincters (Table IV; Strand, 1983).
Vasomotor neurons
are mainly activated by
thermoregulatory,
arousal and emotional
reactions. Acral, nonglabrous skin
vasculature is under
strong central nervous
control and is innervated
Table IV. Vasoactive substances controlling cutaneous
by sympathetic
vasculature
vasoconstrictor nerves,
whereas non-acral skin is regulated by both vasoconstrictory and vasodilatory nerves
governed by local and central factors (Burton, 1939; Thoresen & Walloe, 1980; Levick,
1995; Johnson & Poppe, 1996; Morris & Gibbins, 1997). Axon reflexes in afferent Cfibers mediate vasodilatation.
1.5.4 Regulation of skin blood flow in erythromelalgia
Few reports have been published on regulation on skin vasculature in erythromelalgia.
Affected EM skin is hyperemic (Kvernebo, 1998), while reduced perfusion have reported
between EM attacks compared to controls (Littleford et al, 1999a). The normal ability to
post-ischemic hyperemia is impaired in affected skin, but intact in the underlying muscle
(Kvernebo, 1998). Reduced vasoconstriction in response to inspiratory gasp and
contralateral cold challenge has been described (Littleford et al, 1999b).
1.5.5 Temperature regulation
Skin microcirculation regulates the temperature of the body, and the skin vessels are
under central control. The central control of thermoregulation is located in the
preoptic/anterior hypothalamus, which co-ordinates the different efferent nerves in
response to changes in core temperature. In the thermoneutral zone, the core temperature
is controlled solely by increased or reduced vasoconstrictor nerve impulses. During cold
exposure, vasoconstriction, and heat production (shivering) protect against hypothermia.
The arterioles and AV anastomoses constrict, and the blood is shifted from the superficial
to the deep circulation, bringing the venous blood closer to the arteries, and the
countercurrent flow of heat from the warm arterial blood to the returning venous blood is
facilitated.
The first response to heat stress is cessation of vasoconstrictory nerve impulses to the
arterioles and AV anastomoses. Through the AV anastomoses the blood can pass directly
to the superficial veins without being precooled when passing through the capillaries. If
the core temperature continues to rise, the arterioles of non-acral skin dilate further by
activation of the active cutaneous vasodilatation system. Active cutaneous vasodilatation
and sweating occur simultaneously. Local warming induces vasodilatation via antidromic
peptidergic afferent C-fibres and nitric oxide (Charkoudian, 2003; Fig 5).
1.6 Pathogenesis of erythromelalgia
1.6.1 Clinical findings indicating
coexistence of skin hypoxia and
hyperemia
In a few patients, the following
clinical findings indicate skin hypoxia:
nail growth disturbances following
periods with severe EM distress,
spontaneous and/or slow healing skin
ulcers, gangrene and amputation of the Fig 5. Thermoregulatory control of cutaneous
lower extremities in spite of open limb blood flow. (+) refer to positive relationship:
increases in temp cause increases in activity and
arteries (four extremities in three
patients; Kvernebo, 1998) and trophic vice versa. (-) negative relationship: increases in
temp cause decreases in activity.
skin changes (Belch, 1996). The pain
in erythromelalgia is relieved by
cooling, but difficult to treat by opiates, which is typical of pain induced by hypoxia. On
the other hand, red and warm skin, as well as reduced capillary refilling time after
anemisation, indicate hyperemia.
1.6.2 Pathophysiological findings indicating coexistence of hypoxia and hyperemia
Few physiological studies of the circulation have been performed in EM patients.
Increased content of oxygen of venous blood from the affected extremity has been
demonstrated (Brown et al, 1932). A correlation has been found between skin
temperature and EM distress, and a critical temperature of 32-36 °C for eliciting EM
symptoms has been claimed (Lewis, 1930; Lewis, 1933; Lewis & Hess, 1933; Babb et al,
1964). Elevated skin temperature increases skin metabolism and oxygen consumption.
Severely disturbed hemodynamics has been demonstrated in severely affected EM
patients (Kvernebo, 1998). Using laser Doppler flowmetry (LDF), affected EM skin is
found to be hyperemic compared to unaffected skin. The normal ability to post-ischemic
hyperemia is impaired in affected skin, but intact in the underlying resting muscle. These
findings are interpreted as nearly maximal dilatation of the skin vessels in patients with
EM symptoms before arterial cuff occlusion. Furthermore, the microvascular
abnormalities are confined to the skin. Ultrasound flow velocity measurements
demonstrate that skin hyperemia coincide with hyperemic flow velocity profiles in the
arteries (posterior tibial artery) supplying the affected skin area. This pattern is typical of
low peripheral resistance. Using strain gauge pletysmography, increase in calf blood flow
has also been recorded. Transcutaneous oxygen tensiometry measurements demonstrate
critical hypoxia in affected skin in some patients, and normal values in unaffected skin. In
severe erythromelalgia, measurement of high cardiac output and reduced core
temperature secondary to continuous limb cooling has been reported.
1.6.3 Histological findings indicating hypoxia
Increased number of clustered, small and dilated vessels have been demonstrated in
erythromelalgia syndrome (Kvernebo, 1998). Capillary proliferation has been shown in
12 out of 36 patients with primary erythromelalgia (Kalgaard, personal communication).
1.6.4 The
shunt
hypothesis
Clinical
observation
s and
pathophysi
ological
findings
indicate a
coexistence
of
hyperemia
and
hypoxia in
affected
EM skin
areas.
Based on
these
observation
s.
Kvernebo
proposed
the shunt
hypothesis
for the
pathogenes
is of
erythromel
algia (Kvernebo, 1998):
Skin hypoxia is postulated to be a key to the initiation of EM symptoms. Oxygen
tension in affected skin varies considerably, and with normal levels next to perfused
vessels, if the blood-tissue barrier is not disturbed, and with lower levels between the
vessels. As the oxygen diffusion capacity is poor, areas relatively far from the nearest
perfused vessels may be hypoxic. If there is a distribution mismatch, there will be a
considerable variation in the oxygen tension offered to different skin cells. Some cells
may have adequate supply, while others may be severely hypoxic (Fig 5). Hypoxia is
caused by maldistribution of skin perfusion, with high levels of microvascular
arteriovenous shunting of blood resulting in increased thermoregulatory and insufficient
nutritive perfusion. The maldistribution of blood flow may be caused by an opening of
acral microvascular AV anastomoses and, at the same time, increased tone in the
precapillary sphincter. In primary erythromelalgia, the symptoms are located only in
areas with anatomical microvascular AV anastomoses, i.e. hands and/or feet. In
erythromelalgia syndrome, the shunting may occur through proliferated microvessels.
With plugging of capillaries, the density of perfused capillaries may be reduced, and the
tissue hypoxic in certain areas due to increased diffusion distances and increased blood
flow velocities in the perfused micro-vessels (as in myeloproliferative disorders). The
passage time of the erythrocytes may be too short for equilibration of oxygen with the
surrounding tissue. The oxygen diffusion may also be disturbed in case of pathologically
increased blood-tissue diffusion barrier (as in vasculitis and diabetes mellitus). Shunting
through capillaries serving physiologically as "through-fare channels" may occur in
secondary erythromelalgia.
The consequence of tissue
hypoxia is arteriolar
dilatation and hyperemia
(Fig 6). As the increased
perfusion is once more
maldistributed, the skin
temperature increase and
accelerate the skin
metabolism, causing an
increased oxygen
consumption, and a further
deterioration of the skin
nutrition. A vicious circle is
maintained by
maldistribution of the
perfusion. This shunt
hypothesis for the
pathogenesis of
erythromelalgia can explain
the effect of cooling, the
effect of treatment of the
primary disease in secondary erythromelalgia, as well as the beneficial effect of
vasodilatory treatment (Özsoylu et a1, 1979; Özsoylu & Coskun, 1984; Belch, 1992;
Kvernebo, 1998), and deterioration caused by vasoconstrictor treatment (Kvernebo,
1998).
1.7 Therapy of erythromelalgia
Erythromelalgia has for many years been described as difficult to treat (Brown, 1930;
Smith & Allen, 1938), and a long list of different types of medications and treatments
have been used, most of which give no or partial symptomatic relief (Cohen, 2000; Davis
& Rooke, 2002). The wide spectrum of approaches (oral and parenteral medications,
topical treatment, and parenteral, invasive, nonmedicational approaches) in the
management of erythromelalgia reflects that the treatments are based on anecdotal
evidence and heterogeneity in etiology of erythromelalgia.
A recent review of the literature on the treatment of erythromelalgia is given in
Appendix II (Mørk & Kvernebo, 2002).
PART TWO: AIM OF THESIS
The objectives of these studies on EM patients were:
1. To challenge the shunt hypothesis of the pathogenesis of erythromelalgia
2. To characterize the mechanisms underlying the vascular dysfunction
3. To treat patients based on the present understanding of the pathogenesis
PART THREE: METHODS USED IN THE STUDIES
3.1 Laser Doppler flowmetry
Laser Doppler flowmetry (LDF) is based on a bio-optical technique studying the
interaction mechanism between monochromatic laser light and living tissue. When laser
light penetrates a tissue, some photons are absorbed, while others are scattered by moving
particles (erythrocytes) in the skin tissue or in the microvascular network, so that the light
changes wavelength (frequency and amplitude) according to the Doppler principle
(Doppler-broadened or shifted light). The back-scattered Doppler-broadened light is
detected by recording optical fibers. A signal-processing unit converts the light intensity
into an electrical output signal. The signal equals the product of average velocity () and
the concentration of the moving blood cells (CMBC) within the sample volume
(perfusion = x CMBC). In in vitro models this signal is proportional to perfusion. The
perfusion is expressed in arbitrary units (AU). A probe must be attached to the tissue
during recording. LDF exhibit spatial variation in its measurements, explained by the
random distribution of the ascending arterioles at 1.5-7.0 mm intervals. The method is
more suited for stimuli-response experiments, than for mapping of the blood flow
distribution over a specific tissue area. The laser beam illuminates the tissue volume to a
depth of a few hundred gm, but the exact measuring volume cannot be predicted
precisely. The measuring depth and volume are influenced by the wavelength of the laser
light, the size of the probes, the number, diameter and separation of the optical fibers, and
optical properties (coefficients for light absorption) of the illuminated tissue (Wardell et
al, 1993).
We used a Helium-Neon laser operating at 632.8 run (Periflux, Perimed, Sweden). In
all measurements (paper III) an output circuit time constant of 0.2 s was chosen. The cutoff filter was set to 12 kHz. The optical zero of the instrument was obtained by holding
the probe against a white reflecting surface. The biological zero value was recorded
following tourniquet pressure above systolic blood pressure. The difference between the
optical and the biological zero value can be explained by Brownian movements of blood
cells, vaso-motion activity and "rolling" of cellular aggregates which are formed as the
blood velocity approximates zero. The biological zero value was lows (< 5% of the
measured LDF value) in our experiments and was therefore not extracted from measured
values.
3.2 Laser Doppler perfusion imaging
Laser Doppler perfusion imaging (LDPI) is based on the LDF-principle. LDPI is a noninvasive, non-touch technique recording perfusion by two-dimensional beam scans of a
tissue area (Wardell et al, 1993). In the LDPI system (PIM, Lisca AB, Sweden) a
computer-controlled optical scanner was used. The laser light (Helium-Neon 632.5 nm)
was directed sequentially in a rectangular pattern over the skin surface giving twodimensional mapping of tissue blood flow. The backscattered Doppler broadened light
was detected by a photo-detector positioned in the scanner head and processed to form a
measure of the blood perfusion within the illuminated volume of the complex network of
vessels in the microcirculation of the skin. To eliminate interference from ambient light,
measurements were performed in a dark room. A full format image includes 64 x 64
pixels corresponding to a 12 x 12 cm area and is captured in 4.5 minutes. When all
measurement values had been recorded, processed, and stored, a color coded perfusion
image, showing the spatial heterogeneity of the tissue perfusion, was displayed on a
monitor. The average perfusion and spatial heterogeneity expressed as coefficient of
variation of the recordings were determined
In our experiments the resulting estimates, comprising 20 x 20 pixels, represented the
blood perfusion within a skin area of approximately 3.75 x 3.75 cm. Resolution was set to
high. The test subjects were positioned such that gross movement artifacts were avoided.
The measurement area was marked on the skin surface, and these marks, which were
depicted gray on the color coded image (zero perfusion), were used as fixed points. The
scanner head was adjusted parallel to the measurement area.
3.3 Capillary assisted video microscopy
Capillary assisted video microscopy (CAVM) makes possible in vivo analysis of
capillary density in a tissue surface (Zhong et al, 2000). CAVM combines modem
microscopic techniques and information technology. The hardware comprises a PC and a
portable video capillary microscope consisting of a video signal control unit and a
handheld mini-video camera. A computerized imaging system was used to extract the
individual capillaries for objective and accurate analysis of the capillary ensemble
(topology heterogeneity). Approximately 100 capillaries can be investigated in a field of
view of 1. 7 mm' if the magnification is set to 200. The captured color images show dark
red spots with comma-like shapes, which correspond to the apex of the capillary loops
perpendicular to the skin surface. The following parameters were extracted: capillary
density, capillary size, distance to the neighboring capillaries and heterogeneity in the
distribution of capillaries (mutual distance).
PART FOUR: SUMMARY OF PAPERS
4.1 Paper I
Aim of the study: Anatomical AV anastomoses are located in acral areas, mainly on the
plantar and palmar aspects of feet and hands. By relating the perfusion increase in plantar
and dorsal aspects of the feet in EM patients and controls during central body heating
with the occurrence of EM symptoms, we wanted to test the hypothesis of AV shunting.
Materials, methods, and experimental design: LDPI-assessed skin perfusion and skin
temperature were recorded in plantar and dorsal aspects of the feet in primary EM
patients with moderate severity (n=14) and healthy controls (n=11) following central
body heating. LDPI record global skin perfusion, i.e. nutritive and thermoregulatory
perfusion, and the main part of the output signal originate from the thermoregulatory part
of the perfusion. Two measurement sites were chosen at the left foot: (1) the anterior
section of the foot arch, where the epidermis is thin compared to the weight bearing parts
of the foot (many AV anastomoses), and (2) at the dorsal region of the foot just proximal
to the first and second toe (no or few AV anastomoses). To provoke EM symptoms,
central body heating, which increase skin perfusion through reduced sympathetic action
on the AV anastomoses, was used The patients were covered with twelve duvets, except
for the head and left foot, in order not to disturb the LDPI recordings. The heat
provocation was terminated when skin temperature of the plantar surface of the first toe
reached 32 °C ("critical" temperature), patients reported pain (cut-off value for VAS score
>50) and 100 min heating time (logistical reasons).
Results: EM symptoms were induced in eight patients. Following the same heat
provocation, the increase in perfusion was significantly higher in symptomatic EM
patients in areas with many AV anastomoses (plantar area) compared to asymptomatic
patients and controls. In areas with no or few AV anastomoses, no such difference was
demonstrated between the same groups. The skin temperature recordings were in
accordance with the results of the perfusion studies.
Interpretation: The increased LDPI-assessed perfusion in symptomatic EM patients
compared to asymptomatic EM patients and controls can be interpreted as increased
thermoregulatory AV shunt flow in symptomatic erythromelalgia support the shunt
hypothesis.
4.2 Paper II
Aim of the study: The shunt hypothesis implies inadequate nutritional skin perfusion as
compared to needs in affected skin of patients with erythromelalgia during attacks. To
challenge this hypothesis we analysed the capillary bed before and after heat provocation
in EM patients and healthy controls in areas with different density of AV anastomoses.
Materials, methods, and experimental design: We analyzed the capillary bed
morphology using CAVM in primary EM (n--14) and controls (n=10). CAVM recordings
were performed at two sites with thin epidermis on the left
foot: (1) just proximal to the nail bed of the first toe where the capillary loops were
perpendicular to the skin surface and with a high density of AV anastomoses, and (2) in
the foot arch with fewer AV anastomoses. The same heating protocol as in paper I was
chosen, except for a prolonged maximum heating time (120 min).
Results: In EM patients, capillary density was significantly reduced after central body
heating in areas with many AV anastomoses (nail bed area), in contrast to skin areas with
fewer AV anastomoses (foot arch). This fording was most pronounced in symptomatic
patients. In healthy controls and in EM patients who did not develop symptoms after heat
provocation, no changes were demonstrated. In symptomatic EM patients the change in
capillary density was significantly larger in the capillary bed compared to asymptomatic
patients and controls, in contrast to the foot arch. Symptomatic patients showed a
significantly higher increase in skin temperature following central body heating, as
compared to asymptomatic patients and controls.
Interpretation: AV anastomoses stay permanently open in symptomatic EM patients
after central warming, causing a steal phenomenon of blood from the capillaries, resulting
in a relative lack of capillary perfusion. The consequence of a larger increase in
temperature in affected skin is higher metabolism of the skin and thereby higher
nutritional needs. Tissue hypoxia is therefore likely in affected skin during EM attacks,
and is maintained by a maldistribution of skin perfusion.
4.3 Paper III
Aim of the study: The smooth muscle activity of the arterioles and the precapillary
sphincters regulate the distribution of blood flow. This muscle tone is under control of the
local metabolism, neurogenic and endothelial activity, and transmural hydrostatic
pressure. To characterize the mechanisms underlying the vascular dysfunction in EM, the
response in skin microcirculation to local and central vasoconstrictory stimuli was
studied In addition, endothelial function was tested indirectly by studying the postischemic hyperemic response.
Material, methods, and experimental procedure: Microvascular skin perfusion at rest
and during well-known physiologic provocation tests were assessed by LDF at the pulp
of the first toe in primary EM patients (n=14) with moderate severity and compared to
healthy controls. The patients were asymptomatic during the measurements.
Vasoconstriction in response to forced expiration against closed glottis (Valsalva's
maneuver), contralateral cooling (water temperature 15 °C), venous cuff occlusion and
change in position from supine to standing were recorded. Vasodilator response to local
heating (probe temperature 28, 32, 36, 40, and 44°C) and hyperemic response to 3 min
arterial occlusion were recorded
Results: EM patients had a significantly reduced skin microvascular perfusion during
basal conditions compared to healthy control subjects. Attenuated vasoconstrictor
responses involving central sympathetic reflexes (Valsalva's maneuver and cold
challenge) were found in patients with erythromelalgia compared to control subjects.
Local neurogenic vasoconstrictor regulation (venoarteriolar reflex and venous cuff
occlusion test), vasodilator response to local heating and hyperemic response to ischemia
were maintained in the EM patients.
Interpretation: The finding of impaired Valsalva's maneuver and cold challenge reflexes
with different afferent and common efferent pathways imply a postganglionic
sympathetic dysfunction. This neuropathy may be primary or secondary to tissue
hypoxia. The vasoconstrictor tendency seems to be a paradoxical finding, but may
indicate denervation supersensitivity. Local neurogenic and endothelial function is
unaffected, which is in favor of a primary sympathetic dysfunction.
4.4 Paper IV
Aim of the study: According
to the shunt hypothesis,
substances that improve
capillary perfusion and/or
improve hemoreological
properties of the blood, may
enhance nutrition and thereby
improve skin oxygenation and
induce relief of EM symptoms.
Prostanoids have dilatory
effects on cutaneous
circulation as well as
thrombocyte inhibitory effects.
Beneficial clinical effect has
been reported using parenteral
treatment. The present study
was designed to determine
whether treatment with
misoprostol, an oral
prostaglandin E 1 analogue,
leads to improvement in EM
symptoms and redistribution of
skin microcirculation in favor
of nutritive perfusion,
compared to placebo
treatment.
Material, methods and
experimental procedure:
Inclusion/exclusion criteria
and study design (doubleblind, crossover, placebo
compared) were chosen based
on number of available
patients and a pre-study
definition of clinical
significant improvement of the
primary efficacy variable (pain
VAS). 21 EM patients were recruited (Table V). Secondary efficacy variables included
change in cooling score and patient's global assessment (PGA). Six weeks treatment with
placebo was followed by six weeks treatment with misoprostol, as randomization could
result in a hangover effect of misoprostol. The patients were also evaluated at three
months follow-up. Skin microcirculation was assessed using LDPI and CAVM following
central body heating at baseline, and after placebo and misoprostol treatment, and
compared to healthy controls (n=11). The heating protocol was the same as in paper I, but
with a fixed 30 min heating time. Pain VAS was recorded following heat provocation.
Results: Change in pain and cooling scores were significantly better following
misoprostol treatment compared to placebo treatment and after three months follow-up
without treatment. The number of responders were significantly higher during treatment
with misoprostol (n=14), compared to placebo (n=4) and at follow-up (n=0). Based on
PGA, treatment with misoprostol was superior to placebo, but this difference did not
persist at follow-up. The number of symptomatic patients and the increase in pain score
after central body heating were significantly lower after misoprostol treatment compared
to baseline and after placebo treatment. After misoprostol treatment, the increase in LDPI
assessed skin perfusion following heating did not differ from the response in the control
group. This was in contrast to assessments at baseline and after placebo treatment, where
the increase in skin perfusion was significantly larger as compared to assessments after
misoprostol treatment and in controls. After central body warming, CAVM-assessed
capillary density was reduced in EM patients at baseline, after placebo and after
misoprostol treatment, in spite of the significant increase in temperature and perfusion.
This was in contrast to findings in the controls where capillary density was unchanged in
response to heat provocation. The average distance between neighboring skin capillaries,
an estimate of diffusion distances for oxygen and nutrients, increased in patients after
warming, but not in controls.
Interpretation: our knowledge, this is the first report of a properly designed, placebocontrolled clinical trial for treatment of erythromelalgia. A statistical significant and
clinically relevant reduction in EM symptoms was demonstrated after misoprostol
treatment compared to placebo. The mechanism of action may be reduced microvascular
AV shunting in affected skin based on quantitative measurements of skin
microcirculation.
PART FIVE: DISCUSSION
5.1 Is skin with erythromelalgia hypoxic during attacks?
The coexistence of hypoxia and hyperemia was first proposed in 1987 based on
transcutaneous oxygen tension measurements and quantification of skin microvascular
perfusion with LDF in a severely affected patient (Kvernebo & Seem, 1987). The
transcutaneous measurements showed an average value for a measurement area of around
one cm2. In EM affected skin, there is, however, probably a varying oxygen tension
throughout the tissue with excellent oxygenation close to perfused vessels, while tissue
cells further away from perfused capillaries may live in a hypoxic environment. Current
transcutaneous oxygen tension measurement techniques average oxygen tension values of
an area that may be too large to detect any heterogeneity in oxygen levels. Implanted
probes that measure oxygen levels in smaller areas induce trauma and bleeding that may
disturb recordings.
The following evidence indicate hypoxia in erythromelalgia:
In patients with primary erythromelalgia, we have demonstrated during EM attacks
following central body warming (paper II):
1. Significant reduction in CAVM-assessed capillary density in areas with many AV
anastomoses
2. Temperature in plantar toe, an area with many AV anastomoses, increased
significantly more as compared to asymptomatic EM patients and control subjects
Since the temperature increased by the warming provocation, the local skin metabolism
will accelerate. To account for the increased need for oxygen a maintained or increased
capillary density could be expected. This was the case in asymptomatic EM patients and
controls, although an actual reduction was observed in symptomatic EM.
Further evidence for hypoxia in erythromelalgia is:
Clinical symptoms (pain relieved by cooling and relatively resistant to opiates) and signs
(trophic skin changes, nail growth disturbances, spontaneous and/or slow healing ulcers
and gangrene) indicative of skin hypoxia has been described (Belch, 1992; Kvernebo,
1998). Increased content of oxygen in venous blood from the affected extremity has been
demonstrated (Brown, 1932). Oxygenation of the affected areas during symptomatic
periods using transcutaneous oximetry pressure has been found to be decreased or
unchanged, despite a marked increase in blood flow and temperature (Kvernebo, 1998;
Sandroni et al, 1999; Davis et al, 2003). Histological examinations have demonstrated
capillary proliferation in affected skin, which may be interpreted as a response to hypoxia
(Kalgaard, personal communication).
5.2 Is arteriovenous shunting a common final pathway of the pathogenesis of
erythromelalgia?
In favor of microvascular AV shunting in the pathogenesis of erythromelalgia, we have
the following observations:
• In primary EM patients with central warming induced EM attacks (paper I), we
demonstrated: Significantly higher increase in overall or global skin perfusion (LDPI)
from baseline perfusion in areas with many AV anastomoses compared to EM patients
without symptoms and healthy control subjects. No such difference between the groups
was demonstrated for global skin perfusion in areas with no or few AV anastomoses.
Plantar toe temperature increased significantly more as compared to asymptomatic EM
patients and control subjects.
• We found reduced increase in LDPI-assessed skin perfusion after central body warming
following treatment with misoprostol, a prostaglandin El analogue as compared to values
with after placebo treatment (paper IV). This effect coincides with a significant treatment
effect of misoprostol as also assessed by clinical outcome variables.
LDPI was used to indirectly demonstrate the occurrence of increased shunt flow during
EM symptoms. Despite an increase in global perfusion of affected skin, the EM
symptoms are accompanied by a decreased number of perfused superficial capillaries in
areas with the highest density of AV anastemoses. The observations support the
occurrence of a steal phenomenon away from the superficial nutritive vascular plexus to
the deeper thermoregulatory shunt perfusion.
Other observations in favor of AV shunting are:
• The clinical findings of hyperemia (red and warm skin with rapid refilling time after
anemisation).
• Hyperemia is demonstrated in affected EM skin by LDF measurements, in calf blood
flow by strain gauge pletysmography, and in the arteries supplying the affected skin by
ultrasound Doppler (Kvernebo, 1998). The post-ischemic hyperemia response is impaired
in symptomatic skin, but intact in the underlying muscle (Kvernebo, 1998). Increased
cardiac output and decreased core temperature has also been demonstrated in severe cases
(Kvernebo, 1998). The demonstrated increase in blood flow indicates low vascular
resistance in the skin. The low resistance is most probably caused by opening of the AV
shunts in acral skin.
• Histological examination has demonstrated proliferating vessels in erythromelalgic
syndrome that may serve as shunts (Kvernebo, 1998).
5.3 Is erythromelalgia associated with neuropathy?
In patients with primary erythromelalgia we induced EM attacks during central
warming (paper III). Under basal conditions asymptomatic EM patients had reduced skin
blood flow and reduced perfusion in response to local heating. We also demonstrate
diminished vasoconstrictor responses to central sympathetic reflexes (Valsalva's
maneuver and contralateral cooling). Local neurogenic and endothelial function were
unaffected. Valsalva's maneuver and contralateral cooling have different afferent
pathways and common efferent pathways, implying an impaired efferent limb and
consequently a postganglionic sympathetic dysfunction. Denervation supersensitivity
may explain the vasoconstriction demonstrated between attacks.
In the literature there are further support for neuropathy in patients with erythromelalgia:
· There have only been a few reports on beneficial effect of sympathectomy (Bonica,
1953; Telford & Simmons, 1940; Zoppi et al, 1985; Shiga et al, 1999; Seishima et al,
2000), while others have found aggravation of EM symptoms following sympathetic
blocks (Rosati & Verga, 1955; Cross, 1962; Smith & Allen, 1938; Kvernebo, 1998).

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Pharmacological substances used for the treatment of neuropathy (gabapentin.
antidepressants and serotonin reuptake inhibitors) have been reported to have
beneficial clinical effects in erythromelalgia (Herskovitz et al, 1993; McGraw &
Kosek, 1997, Rudikoff & Jaffe, 1997; Maldonova et al, 1999; Moiin et al, 2002;
Pandey et al, 2002; Rey et al, 2003b). Improved sympathetic dysfunction and
clinical outcomes following intravenous treatment with iloprost in a double-blind
pilot study in 12 patients with erythromelalgia is recently pubhshed(Kalgaard et
al, 2003).
Case reports have demonstrated neuropathy (Uno & Parker, 1983; Kitajima et al,
1985; Vendrell et al, 1988; Nagamatsu et al, 1989, Liu, 1990; Sugiyama, 1991;
Staub et al, 1992; Herskovitz et al, 1993; Sakamoto, 2003).
Attenuated vasoconstriction in response to inspiratory gasp and contralateral cold
challenge and reduced basal skin perfusion has been reported in EM patients
(Littleford et al, 1999b).
Axonal neuropathy and abnormal sudomotor function have been demonstrated in
EM patients (Sandroni et al, 1999). The authors suggest the presence of efferent
small fiber neuropathy.
Abnormal sympathetic skin responses have been described in patients with
erythromelalgia in a controlled study. The authors conclude that C fibers may be
involved in the pathogenesis of EM (Kazemi et al, 2003)
Pathological C-fibers have been described by Ørstavik in our group (Orstavik et al,
2003). Recently, further neurophysiological laboratory tests of our patients have
demonstrated tactile hyperalgesia and involvement of afferent small fibers (Ørstavik et al,
in press). No changes were demonstrated in the efferent fibers in this study.
5.4 Is vasculopathy or neuropathy the primary event?
Reduced perfusion between EM attacks (paper III) is in accordance with previous
findings (Littleford, 1997; Littleford et al, 1999a) and clinical observations that many EM
patients may have pale/white or blue/cyanotic skin color, reduced toe temperature and
concomitant Raynaud's phenomenon between attacks. The EM patients seem to be cold
between attacks and warm during attacks. The reduced perfusion may be explained by
structural microvascular changes, increased adrenergic vasomotor activity or increased
adrenergic receptor sensitivity, as well as dysfunction of endothelial cells with imbalance
in secretion of vasoactive mediators (endothelin, nitric oxide). Structural changes can be
caused by reduced vascular density, endothelial swelling, thickened vessel basement
membrane, intimal proliferation, perivascular edema or microthrombi with occlusion of
microvessels as a result of changes in blood viscosity, platelet aggregation, fibrinolytic
activity and erythrocyte deformability.
Capillary density is not reduced in asymptomatic erythromelalgia (paper II) and
endothelial function, as assessed by postocclusive hyperemia response, is maintained
(paper III). An elevated sympathetic vasomotor activity in erythromelalgia seems
unlikely, based on our findings in paper In. Structural changes in the vessel walls,
perivascular inflammation and edema, as well as thrombi, have been described (Michiels
et al, 1985; Drenth et al, 1996; Kvernebo, 1998). We postulate, like other authors, that
increased adrenergic receptor sensitivity may be involved in erythromelalgia (Uno &
Parker, 1983; Littleford et al, 1999b; Mørk et al, 2002b).
We have demonstrated that erythromelalgia is associated with both vasculopathy and
neuropathy (Fig 12). Dysfunctional AV anastomoses and precapillary sphincters are
probably essential elements of the vascular dysfunction in erythromelalgia. The shunting
of blood in the skin is probably triggered by a number of mechanisms related to
hemorrheological problems, defects in prostaglandin metabolism, or defects in
sympathetic or endothelial function (Littleford et al, 1999a,b; Sandroni et al, 1999;
Ørstavik et al, 2003; Drenth et al, 1996; van Genderen et al, 1996; Jørgensen &
Søndergaard, 1978; Michiels et al, 1997; Chan et al, 2002). Vasculopathy and neuropathy
may therefore coexist, like microangiopathy and neuropathy in diabetes mellitus (Tesfaye
et al, 1993).
We believe that both phenomena are important in the pathogenesis of erythromelalgia.
Vasculopathy may cause skin and neural hypoxia resulting in neural dysfunction. On the
other hand, neuropathy may underlie the microvascular dysfunction. A vascular and a
neurological pathophysiology do not exclude each other. Our group has demonstrated
improvement in neuropathy and clinical outcome measures following treatment of the
vasculopathy with iloprost (Kalgaard et al, 2003). On the other hand, medications used
for the treatment of neuropathy have been reported to have a beneficial clinical effect
(McGraw & Kosek, 1997; Rudikoff & Jaffe, 1997; Maldonova et al, 1999; Moiin et al,
2002; Rey et al, 2003). Neuropathy has been demonstrated only in some patients with
erythromelalgia (Ørstavik et al, submitted; Davis et al, 2003), but EM has been reported
following neuropathy (Herskovitz et al, 1993).
Further studies are needed to determine if erythromelalgia is primarily a vasculopathy
leading to neuropathy, or vice versa (Sandroni et al, 1999; Davis et al, 2000b; Mark &
Kvernebo, 2000b; Davis et al, 2003).
5.5 Is erythromelalgia a separate disease entity?
From a clinical point of view it is appropriate to regard EM as a disease or syndrome
(Kvernebo M, 2003). A pathologist will hesitate to regard erythromelalgia as a specific
disease, as there is no common etiological factor, and as pathognomonic structural
changes are difficult to find. The shunt hypothesis implies that erythromelalgia is not a
separate disease entity, but rather a condition with a specific pathophysiological response
pattern of skin circulation with a common final pathway of increased thermoregulatory
shunt flow and insufficient nutritive perfusion. No single treatment is effective in
erythromelalgia. Therapy must be tailored for each patient based on the underlying
conditions. This view is analogous to the concept that inflammation is not a specific
disease, but a condition (rubor, tumor, calor, dolor, functio laesa) with a specific
physiological response to stimuli such as infection, trauma, or tumor.
5.6 Therapy with misoprostol
Improvement in clinical outcome measures and redistribution of skin microcirculation
in favor of nutritive perfusion following treatment with misoprostol was demonstrated
(paper IV).
The study was based on the shunt hypothesis and experiences from vasodilator
treatment of EM patients. According to the shunt hypothesis, the aim of therapy is to
increase skin oxygen supply and/or reduce oxygen consumption. This can be achieved by
cooling, by treatment of underlying conditions or by redistribution of skin
microcirculation in affected skin. The rationale of misoprostol treatment is vasodilatation
and reduction in the formation of microthrombi. Enhancement in nutritional blood flow
and improvement in tissue oxygenation will break the vicious cycle that maintains
erythromelalgia (Fig 8). Theoretically, dilatation in the precapillary sphincter with
concurrent constriction of the AV shunts would be the optimal intervention in primary
erythromelalgia, but currently no single pharmacological substance or combination of
drugs, according to our knowledge, have this targeted effects on skin vasculature. The
success of a treatment is dependent on redistribution of skin perfusion in favor of the
capillaries, improving the relative hypoperfusion in the nutritive vessels. A vasodilator
that predominantly increases the shunt flow, may deteriorate erythromelalgia, as the steal
phenomenon may increase.
The study design was determined by the number of available patients (Table V). A
parallel group study would require more patients, but the crossover design used in our
study had sufficient power to detect a statistically significant change in key parameters.
An additional effect after placebo treatment support the efficacy of misoprostol. Blinding
was necessary to reduce bias, but blinding may have been disturbed by adverse events
associated with misoprostol. A very long washout period (months to years) would be
required in a randomized trial based on long-term effects after PGE1 infusions
(Kvernebo, 1998). Pain VAS was defined as the primary endpoint as thus parameter has
been widely used in other studies (including paper 1 and II) and validated in pain
assessments. The effect of misoprostol could be called statistical and clinical significant
in terms of difference in change from placebo and number of responders (success rate).
Cooling score and PGA was chosen as secondary efficacy variables. Cooling score has
previously been used in the characterization and monitoring of EM severity (Kalgaard et
al, 1997; Kalgaard et al, 2003), and global response to treatment is well known in clinical
trials. A statistical correlation between the clinical outcome measures supports our
interpretation.
We focused on pathogenetic mechanisms, using hard endpoints. The effect of
misoprostol on skin microcirculation was studied using LDPI and CAVM and heat
provocation. The selection of measurement sites and heat provocation test was based on
experience from the studies reported in paper I and II. The reduction in heat-induced pain
corresponds with the physiological assessments of skin microcirculation following
treatment. Bonferroni adjustments of data were made to avoid misleading false positive
results. The recorded changes in the clinical outcome measures were larger than the prestudy definition for treatment success. Evidence for the clinical effectiveness of
prostanoids is presented in paper IV from a physiological point of view. The results give
further support for the shunt hypothesis.
PART SIX: CONCLUSIONS



In this thesis, increased AV shunting and reduced nutritive capillary density in
affected skin of patients with primary EM were demonstrated. These findings are
compatible with skin hypoxia during EM attacks. These studies support the shunt
hypothesis in the pathogenesis of erythromelalgia, i.e. skin microvascular
arteriovenous shunting as a final common pathway leading to tissue hypoxia, a
uniform vascular response to different etiological factors.
In primary EM patients, we demonstrated attenuated central sympathetic
vasomotor reflexes, which indicate autonomic dysfunction. Local reflexes and
endothelial function were intact. This neuropathy may be an underlying
mechanism for the dysfunctional vascular dynamics. Vasculopathy with hypoxia
may also cause neuropathy.
Furthermore, we found improvement in clinical outcome measures and changes in
the skin vasculature in favor of reduced microvascular AV shunting following
misoprostol, an oral prostaglandin E1 analogue.
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