]OURNAL o f t h e

AmeRICaN ACaDemY OF
fAAD
~r v~
DerMaTOLOGY
V O L U M E 18 NUMBER 5 PART 1 MAY 1988
I I |

Continuing medical e d u c a t i o n
Temperature-dependent skin disorders
Elizabeth Heller Page, M.D., F.R.C.P.(C.), and Neil H. Shear, M.D., F.R.C.P.(C)
Toronto, Ontario, Canada

The skin is important in preserving homeostasis between man and his

environment. One main role of the skin is in thermoregulation, where cutaneous
blood flow, and hence skin temperature, vary widely in order to help preserve
core body temperature. Under extreme conditions, frostbite or burns may
occur. Prolonged exposure to moderate degrees of heat or cold can result in
erythema ab igne and chilblains. Temperature plays a direct role in some
of the physical urticarias and is one of several important pathogenic factors in
conditions such as Raynaud's syndrome, cold panniculitis, and
cryoglobulinemia. These and other temperature-dependent skin disorders are
reviewed. (J AM ACAD DERMATOL1988;18: 1003-19.)

The skin is the interface between man and his
environment and is important in preserving ho-
meostasis in the face of environmental changes.
One main role is in thermoregulation, where the
skin functions to help maintain core temperature.
Preservation of core temperature involves regu-
lation of cutaneous blood flow, as well as other
factors such as basal metabolic rate, sweating, and
shivering. Hence, skin temperatures vary widely
in order to maintain a normal core temperature.
Although skin temperature can range between
20 ~ C and 40 ~ C without damage,, greater extremes
cause injury, such as frostbite.
In addition to physiologic responses to extreme
temperatures, abnormal reactions to heat and cold
may occur. Erythema ab igne and chilblains result
from chronic exposure to moderate levels of heat
and cold, respectively. Several of the physical ur-
ticarias are induced by heat and cold. Cold plays
an important role in disorders such as Raynaud's
phenomenon and cryoglobulinemia. In this article
these and other temperature-dependent skin dis-
orders are reviewed (Table I).
THE SKIN IN THERMOREGULATION
Core body temperature is maintained within a

~ The CME articles are made possible through an educational

grant from Syntex Laboratories, Inc.
From the Division of Deralatology, Departments of Medicine and
Pediatrics, University of Toronto.
Supported by a Career Scientist Award of the Ontario Ministry of
Health and the Canadian Dermatology Foundation.
Reprint requests to: Dr. Neil H. Shear, The Hospital for Sick Chil-
dren, Division of Clinical Pharmacology/Toxicology, 555 Uni-
versity Ave., Toronto, Ontario, Canada M5G IXS.
narrow range by thermoregulatory mechanisms
that rely largely on variations in cutaneous blood
flow. Normal blood flow to the skin is about 200
ml/min, or 4% of the cardiac output, 2 which
greatly exceeds baseline oxygen and nutrient re-
quirements. Several features make the cutaneous
circulatory system well suited for its role in
thermoregulation. Arteriovenous anastomoses are
abundant in acral areas and allow a large volume
1003

1004 P a g e and Shear
Table I. Temperature-dependent disorders
Reactions to extremes o f temperature
Burns
Cold injury
Frostbite
Nonfreezing cold injury
Abnormal reactions to cold
Chilblains
Pulling boat hands
Acrocyanosis
Erythrocyanosis
Livedo reticularis
Cold urticaria
Cold erythema
Cold panniculitis
Sclerema neonatorum
Subcutaneous fat necrosis of the newborn
Raynaud's phenomenon
Cryoglobulinemia
Disorders due to heat
Erythema ab igne
Infrared elastosis
Heat cancers
Urticaria--cholinergic localized
Erythermalgia
of blood to pass through the skin. This results in
a rise in skin temperature, with resultant heat loss.
In addition, the parallel arrangement of large ar-
teries and veins in the limbs allows countercurrent
exchange of heat. Vasoconstriction results in
shunting of blood from the superficial to the deep
venous system, and heat is transferred from
arteries to veins. Thus the blood going to the
limbs is precooled and less heat is lost to the en-
vironment.
Changes in temperature of perfusing blood are
detected by neurons in the preoptic area of the
hypothalamus.~ Receptors for cold and warmth in
the skin play a secondary role.~ These signals are
integrated in the posterior hypothalamus where ap-
propriate heat-generating or dissipating mecha-
nisms are put into effect. When core temperature
rises in a hot environment, inhibition of sympa-
thetic output occurs, resulting in cutaneous vaso-
dilation.~ Cutaneous blood flow may reach 3000
ml/min. 2 Skin temperature rises and heat is lost.
In addition, sweating is initiated to aid in heat
loss. t
Journal of the
American Academyof
Dermatology
Conversely, on cold exposure an increase in
sympathetic output from the posterior hypothala-
mus results in cutaneous vasoconstriction and heat
conservation.~ As mentioned above, shunting of
blood into the deep venous system allows an in-
sulating layer of subcutaneous fat to lie between
the blood and cold environment, and as well results
in countercurrent exchange of heat. The insulating
effect of subcutaneous fat is important, and obese
subjects can maintain a higher internal temperature
on cold exposure than thin people, but they may
have chronically cooler skin. 3"4 Finally, piloerec-
tion and shivering may occur.
Thus, by using several mechanisms, including
variations in cutaneous blood, the body can main-
tain a constant core temperature of approximately
37" C over a range of external temperatures be-
tween 15" C (60" F) and 54" C (130 ~ F). 5
The hunting phenomenon of Lewis
Cold exposure produces massive cutaneous va-
soconstriction, resulting in a fall in skin temper-
ature. This serves to maintain core temperature
but occurs at the expense of the skin. In 1930 Sir
Thomas Lewis described cold-induced vasodi-
lation6 that seems to exist as a protective mecha-
nism against skin necrosis. Lewis found that when
a finger is immersed in water at 0 ~ C, an initial
drop in skin temperature to 2 to 4 ~ C is followed
by a rise of 7 to 13 ~ C. With continued cold ex-
posure the temperature drops again and the cycle
is repeated over and over. This slow "hunt-
ing" of temperature is irregular, and the amplitude
of the temperature changes appears to decrease
with time. Termed the "hunting phenomenon of
Lewis," this paradoxical cyclic vasodilation is
highly developed in people acclimatized to cold,
who have rapid cycling times and higher final skin
temperature. 7,8 The reaction appears to be local,
as it is asynchronous in adjacent fingers immersed
in cold water? The mechanism is unknown, but it
is likely that both local vasodilatory metabolites
and neurogenic reflexes play a role. ~~ It has re-
cently been suggested that cold paralysis of blood
vessels occurs and that cold-induced vasodilation
is due to slow vasomotor muscle relaxation.11 The
phenomenon is much decreased in the presence of
high vasoconstrictor tone.
Volume 18
Number 5, Part 1
May 1988
REACTIONS TO EXTREMES
OF TEMPERATURE
Burns
Burns result from exposure to extremes of heat.
Factors influencing the degree of cutaneous injury
include duration of exposure, type of heat source,
temperature, and skin thickness. ~2The lowest tem-
perature at which a burn can occur is 44 ~ C, and
temperature-time curves have been plotted.t3 For
example, transepidermal necrosis occurs in 1 sec-
ond at 70 ~ C but takes almost 45 minutes at
47 ~ C. 13
The pathogenesis of heat injury involves dena-
turation and coagulation of cellular proteins and
enzyme inactivation. ~2 Edema results from in-
creased capillary permeability in burned tissue and
an increase in interstitial osmotic pressure, likely
caused by release of osmotically active particles
from damaged ceils.14 In addition, vasoactive me-
diators, including prostaglandins, kinins, seroto-
nin, histamine, oxygen radicals, and various lipid
peroxides, are released from burn tissue. Extensive
burns cause major alterations in the patient's im-
munologic, hemodynamic, and metabolic state.~4
In particular, impaired phagocyte and neutrophil
function occur ~5and T-suppressor ceils increase in
number, 16thus predisposing to infection. The basal
metabolic rate increases dramatically, accompa-
nied by a 1-2~ C increase in core temperature. TM
Burn patients should be kept in rooms with an
ambient temperature of 30 ~ C or more to prevent
excessive heat loss, which would exaggerate the
stress response. 17 Experimentally, it is known that
heat stress induces the synthesis of cellular pro-
teins known as heat shock proteins, but the ex-
act role of these proteins in thermotolerance is
unknown. ~s
Cold injury
Kulka's 19experimental studies on freezing cold
injury show that there are three stages of cooling.
The first is massive vasoconstriction, which causes
a rapid fall in skin temperature. The hunting phe-
nomenon then begins with a cyclic rise and fall in
skin temperature. If cold exposure continues,
freezing occurs as the skin temperature falls to
approach ambient temperature. The sequence of
events in freezing and nonfreezing cold injury is
Temperature-dependent skin disorders 1005
similar ~9and consists of: (1) arterial and arteriolar
vasoconstriction, (2) excessive venular and cap-
illary vasodilation, (3) increased endothelial leak-
age, (4) erythestasis, (5) arteriovenous shunting,
(6) segmental vascular necrosis, and (7) massive
thrombosis.
Arterial and arteriolar constriction, mediated by
sympathetic outflow, initiate and likely maintain
circulatory impairment. However, Kulka 19 found
that segmental vascular necrosis occurred in areas
of erythrostasis, suggesting that ultimate damage
may depend more on insufficient clearance of toxic
substances than on initial vasoconstriction.
At a cellular level, slow freezing produces ex-
tracellular ice crystal formation, resulting in cel-
lular dehydration with an increase in osmotic pres-
sure. Rapid freezing, for example with cryother-
apy, causes the formation of tiny intracellular ice
crystals, ~2,19,2~which are highly destructive. Ef-
fects on the cell may include mechanical damage
to the cell membrane, disruption of cellular me-
tabolism, denaturation of lipid-protein complexes,
and vascular damage. The degree of cellular injury
depends on the minimum temperature reached and
the duration of time at that temperature. The cool-
ing rate is important, with rapid cooling causing
more intracellular ice crystal formation and hence
more destruction. The rewarming rate is also im-
portant. In slow rewarming, intracellular ice crys-
tals become larger and more lethal and the cell is
exposed to a high concentration of electrolytes for
a longer period than with rapid rewarming. Fi-
nally, repeated freeze-thaw cycles lead to greater
injury.
Different cell types vary in their susceptibility
to cold injury. Melanocytes are very sensitive to
cold, and damage may occur at - 4 to - 7 ~ C. 21
This explains the hypopigmentation that follows
cryotherapy. In addition, it appears that black pa-
tients are more susceptible to frostbite, 22 and ex-
periments with cold injury in guinea pigs have
shown that a greater degree of damage occurs in
pigmented versus nonpigmented skin. 22 Nerve ax-
ons are also easily damaged by cold, and nerve
injury may occur with axonal degeneration of large
myelinated fibers. Autonomic fibers are also af-
fected and may account for the abnormal sweating
and cold sensitivity that follow cold injury, es-

1006 Page and Shear
pecially nonfreezing injury, tt Nerve sheaths are
quite resistant to cold injury, as are bone and car-
tilage.
Frostbite
Frostbite occurs when tissue freezes. The af-
fected part, usually a finger, toe, ear, nose, or
cheek, becomes white or bluish white. If the injury
is superficial, the part will be frozen on the surface,
but deeper tissues will be soft and resilient. In a
deeper injury the frozen part is hard and feels solid.
Large blisters form 1 to 2 days after rewarming,
and the blister fluid begins to be reabsorbed within
5 to 10 days, leading to formation of a hard black
eschar. Weeks later a line of demarcation occurs,
and the tissues distal to the line will undergo au-
toamputation.
Factors predisposing to frostbite include periph-
eral vascular disease, tight constrictive clothing,
immobility, previous frostbite, and nicotine.
Touching cold metal can cause immediate frost-
bite. A combination of high wind and cold is more
dangerous than cold alone. Historically, epidemics
of frostbite occurred during military campaigns.
Today, many cases are associated with alcohol
consumption and car breakdown. 23Frostbite is also
seen in connection with winter s p o r t s 24 such as in
cross-country skiers or backpackers who get lost
or trapped in a snowstrom.
The first consideration in treatment is to be cer-
tain the victim is not suffering from hypothermia.
Barring that, th.e main principles are to avoid me-
chanical trauma such as massaging with snow, to
avoid refreezing and to delay surgery. The prin-
ciples of cold injury can be applied to the treatment
of frostbite. As discussed, slow rewarming in-
creases tissue damage, and therefore rapid re-
warming should be performed. Rapid rewarming
should be performed in a warm water bath at 40
to 42 ~ C until the most distal part is flushed. 2~Large
amounts of analgesics may be required. The dam-
aged part should be elevated and blisters left intact.
Further opportunity for trauma, such as weight
beating, must be avoided. It is important to min-
imize friction and sterile cotton balls may be
placed between fingers and toes. Twice-daily soak-
ing for 20 minutes in a warm whirlpool bath with
Journal of the
American Academyof
Dermatology
a mild antiseptic added will serve to gently de-
bride, prevent infection, and encourage joint mo-
bility and circulation. With the exception of split-
ting eschars, which limit movement, debridement
should be delayed until spontaneous sloughing is
complete. This may take several months but will
minimize tissue loss. 26Other forms of therapy have
been tried based on presumed mechanisms of in-
jury in frostbite. Intra-arterial reserpine 27 and
sympathectomy2g have been used to reverse vaso-
spasm, which may be contributing to tissue loss.
Their role is controversialfl5 although some pa-
tients have benefited from therapy.27.2s Tetanus tox-
oid should be given.24 Sequelae of frostbite include
hypersensitivity to cold, hyperhidrosis, and epiph-
yseal plate damage in children.29 In addition, frost-
bite arthritis may occur weeks to years later and
resembles osteoarthritis. 3~
Nonfreezing cold injury
Nonfreezing cold injury occurs when tissues are
cooled to temperatures between about 15 ~ C and
their freezing point for prolonged periods of time.
This type of injury has claimed numerous casual-
ties in warfare, and the history of nonfreezing cold
injury in a military context makes fascinating read-
ing. 3t In the Crimean war, temperatures rarely fell
below freezing and battles were fought by trench
warfare. Cold injury, still termed "frostbite," was
common but followed a somewhat different clin-
ical course. 31 By 1916 trench foot had been rec-
ognized as a separate entity. Three stages were
described: initial erythema, edema, and tendemess
(stage I), followed within 24 hours by paresthesia,
marked edema, numbness, and sometimes bullae
(stage II), and progressing to gangrene (stage III),
if untreated. Cold, wet conditions and venous stag-
nation due to immobility and constrictive footwear
are important pathogenic factors. 32These were rec-
ognized and preventive measures were instituted,
resulting in a much lower incidence of trench foot
in 1918. 3t
Immersion foot, seen in shipwreck survivors,
was described in 1942. 33 This form of nonfreezing
cold injury occurs in four phases (exposure, pre-
hyperemic, hyperemic, and posthyperemic) and is
clinically similar to trench foot. 34 Both forms of
Volume 18
Number 5, Part i
May 1988
nonfreezing cold injury may be followed by cold
sensitivity and hyperhidrosis that may persist for
years.
Tropical immersion foot was described during
the Pacific campaign in World War II. 3~ Occurring
after exposure to the warm, wet conditions of jun-
gle warfare, this condition differs from classical
trench foot and immersion foot by showing less
tissue destruction, numbness, and anesthesia and
quicker complete recovery. 31,35The role of cold in
tropical immersion foot is unclear and may not be
important. Taplin et al3~ produced a similar syn-
drome by using an insulated rubber boot under
continuously wet conditions during which the foot
was kept warm. As with trench foot and immersion
foot, prevention is most important.
ABNORMAL REACTIONS TO COLD
Whereas frostbite will occur in any individual
exposed to extreme cold, the disorders described
below occur in some individuals with more mod-
erate cold exposure. They can thus be considered
to be abnormal reactions to cold.
Chilblains
Chilblains (or perniosis) are localized inflam-
matory lesions that are caused by continued ex-
posure to cold above the freezing point. Dampness
also seems to play a role, and the condition has
been most often described in Great Britain and
northwestern Europe where there is a lack of cen-
tral heating. 37Chilblains are less often seen in very
cold climates, where well-heated houses and warm
clothing are essential.
Chilblains develop acutely as single or multiple
burning, erythematous, or purplish swellings. Pa-
tients may complain of itching, burning, or pain.
In severe cases, blistering and ulceration may oc-
cur. Characteristic locations include the proximal
phalanges of the fingers and toes, plantar surfaces
of the toes, heels, nose, and ears. Chilblains may
also occur on the outer calves and thighs, espe-
cially in association with erythrocyanosis (see be-
low). They usually resolve in 1 to 3 weeks but
may become chronic in elderly people with venous
stasis.
Coskey and Mehregan 38 described children who
Temperature-dependent skin disorders 1007
got wet, cold feet while wearing shoe boots and
developed chilblains 24 hours later on the plantar
surface of one foot. Pemiotic lesions may also be
seen in lupus erythematosus 39 and have been de-
scribed in association with chronic myelomono-
cytic leukemia. 4~
Dana et al s described a syndrome of erythem-
atous, swollen, tender toes, which occurred in
middle-aged patients. Symptoms were markedly
increased by cold and regressed in the summer.
They believed this represented an exaggerated
hunting reaction.
The pathology of idiopathic perniosis shows
edema of the papillary dermis and a superficial or
superficial and deep perivascular lymphocytic in-
filtrate. 4t Cases with necrotic keratinocytes41,4~and
lymphocytic vasculitis 42 have also been reported.
Other authors have described thickening of blood
vessel walls, with intimal proliferation leading to
obliteration of the vascular l u m e n ) 8
The most important point in management is pro-
phylaxis with adequate clothing and appropriate
home heating. A short course of ultraviolet light
at the beginning of winter may help to prevent
chilblains. 43 It has been suggested that injury by
intense ultraviolet light is followed by diminished
ability of arterioles to contract, an effect that per-
sists for several months.43." Hence this may relieve
the chronic vasospasm believed to occur in per-
niosis. Once chilblains occur treatment is symp-
tomatic, with rest, warmth, and topical antiprur-
itics. In a recent double-blind study, nifedipine
was shown to be effective in the treatment of severe
recurrent pemiosis: S The dose used was 20 mg
three times daily. Established lesions resolved in
seven of ten patients on nifedipine, and no patient
developed new lesions while on the drug. 45
Pulling boat hands
This condition was recently described by To-
back et al. 46 Erythematous macules and plaques
developed on the dorsa of the hands and fingers
of students and instructors after 3 days to 2 weeks
aboard a pulling boat off the Atlantic coast of
Maine. Later, small vesicles appeared, accompa-
nied by itching, burning, and tenderness. Biopsy
examination showed hyperkeratosis with hydropic

1008 Page and Shear
change of the basal cell layer, dermal papillary
edema, and a subepidermal vesicle. There were
also a superficial and deep perivascular lympho-
histiocytic infiltrate and red blood cell extravasa-
tion. Subjects were exposed to long periods of high
humidity, cool air, and wind, an ideal setting for
the development of nonfreezing cold injury. In ad-
dition, hours of vigorous rowing daily provided
repetitive hand trauma. Many patients had a his-
tory of Raynaud's phenomenon or frostbite.
The authors concluded that this entity was a
unique syndrome caused by a combination of
nonfreezing cold and the mechanical effects of
rowing.
Acrocyanosis
Acrocyanosis is a bilateral dusky, mottled dis-
coloring of the hands, feet, and sometimes the
face, which is persistent and accentuated by cold
exposure. 37.47 Trophic changes and pain do not oc-
cur, and pulses are present. There is often a family
history of the disorder. 37 Clinically, the condition
must be distinguished from Raynaud's phenome-
non, which is clearly episodic, and from obstruc-
tive arterial disease.
The etiology is unknown, but chronic vaso-
spasm of small cutaneous arterioles with a sec-
ondary dilation of the capillaries and subpapillary
venous plexus has been postulated. 48 Capillary mi-
croscopy studies of patients with acrocyanosis
have shown stasis in the papillary loops with an-
eurysmal dilatation at the tips. 49 Flow was redis-
tributed to the subpapillary venous plexus. In-
creased platelet adhesiveness was noted in several
patients. 49
Remittent necrotizing acrocyanosis is a more
severe form of acrocyanosis that is associated with
pain, as well as ulceration and gangrene of the
fingers. Biopsy examination has shown arteriolar
occlusion by thrombi or internal proliferation. 5~
Erythrocyanosis
Erythrocyanosis is a cyanotic discoloration,
worse in winter, which occurs over areas with a
thick: layer of subcutaneous fat, such as the
legs and thighs of adolescent and middle-aged
women. 37.51 Nodular lesions identical to chilblains
may occur and have been described in women with
Journal of the
American Academy of
Dermatology
severe erythrocyanosis, paraplegia, and "broadly-
based young women who ride and look after
horses. ''37 Treatment involves wearing warm
clothes and reducing the insulating layer of sub-
cutaneous fat, which is responsible for a chroni-
cally lower skin temperature. This entity is mainly
described in the older British literature and is rarely
diagnosed now. However, a recent report described
four young women who rode horses for several
hours daily throughout the winter in Virginia. 52
They developed indurated red-to-violet, tender
plaques on the lateral thighs. Although the authors
believed this was a form of cold panniculitis, the
condition is quite similar to the nodular pemiotic
lesions described in erythrocyanosis. In fact, bi-
opsy specimens of perniotic lesions of the thighs
in similar cases show lymphocytes at the dermal-
subcutaneous junction and extending into the fat. 4J
Livedo reticularis
Livedo reticularis is a mottled bluish (livid) dis-
coloration of the skin that occurs in a netlike pat-
tern. The discoloration is persistent and may
change from reddish blue in a warm environment
to a deep blue color in a cold environment. Livedo
reticularis must be distinguished from cutis mar-
morata, a physiologic transient reaction to cold
exposure that is seen in 50% of normal children
and in many adults) 7 It has been suggested that
the netlike pattern is due to venous drainage at the
margins of areas of skin richly supplied by arterial
cones. When factors such as cold cause increased
viscosity and low flow rates in the superficial ve-
nous plexus, further deoxygenation occurs and the
cyanotic reticular pattern becomes more pro-
nounced. 53 Therefore, this pattern may result from
arteriolar disease, causing obstruction to inflow
and blood hyperviscosity, or it may result from
obstruction to outflow of blood in the venules, s3
Livedo reticularis is not a diagnosis in itself but
is a nonspecific reaction pattern. It may be clas-
sified as idiopathic livedo reticularis and secondary
livedo reticularis.
Idiopathic livedo reticularis may overlap with
curls marmorata and is most often seen in women
as symmetric diffuse mottling on cold exposure,
which may become permanent, s4 Numbness and
tingling on cold exposure are common. Two vari-
Volume 18
Number 5, Part 1
May 1988 Temperature-dependent skin disorders 1009

ants with ulceration have been described, one with Table II. Causes of livedo reticularis
ulceration in the winters5 and one with edema of
Physiologic
the ankles and ulceration in the spring and sum- Curls marmorata
merY These small painful ulcers heal with atro-
Intravascular obstruction
phic pigmented scars ~4,56 and skin biopsy exami- Viscosity changes
nation has shown fibrinoid necrosis of small blood Stasis
vessels, hyaline thrombi, and mild perivascular Paralysis
lymphocytic infiltrates? 6 Cardiac failure
A rare group of patients with diffuse, wide- Organic
spread livedo reticularis and cerebrovascular le- Emboli
Thrombocythemia
sions has been described. ~7,58 Livedo reticularis is Cryoglobulinemia
progressive and usually precedes the neurologic
Vessel wall disease
symptoms by several years. Evidence of peripheral Arteriosclerosis
ischemia may also occur. Digital artery biopsy Hyperparathyroidism
specimens have shown intimal hyperplasia but no Arteritis
vasculitis.58 Polyarteritis nodosa
Secondary livedo reticularis is more likely to be Cutaneous polyarteritis nodosa
Rheumatoid arteritis
asymmetric and patchy. Possible causes are listed Lupus erythematosus
in Table II. It is important to stress that underlying Dermatomyositis
conditions, such as systemic lupus erythematosus, Lymphomas
periarteritis nodosa, and cryoglobulinemia, must Syphilis
be excluded in patients with livedo reticularis. Tuberculosis
Other conditions to consider in the differential di- Pancreatitis
agnosis of a livedo pattern include congenital Idiopathic
Uncomplicated
anomalies such as cutis marmorata telangiectasia With winter ulceration
congenita, vascular anomalies such as angioma With summer ulceration
serpiginosum, and other dermatoses occurring in With systemic involvement
a livedo pattern. Treatment of livedo reticularis Drugs--amantidine, quinine, quinidine
involves avoiding cold and dealing with the pri-
mary cause. Idiopathic livedo reticularis with ul-
ceration has been treated with low molecular generalized cooling, rather than local cold appli-
weight dextran with good results? ~ cation, and may be associated with headache, fe-
ver, and arthralgias. 63 A delayed type of familial
Cold urticaria cold urticaria with localized angioedema devel-
Cold urticaria occurs at sites of localized cool- oping 9 to 18 hours after cold exposure has been
ing, usually when the area is rewarmed. It may be described. 64
classified as (1) cold urticaria associated with a Idiopathic cold urticaria is most common in
serologic abnormality, (2) familial, or (3) idio- young adults and accounts for over 90% of cases
pathic. Cold urticaria has been said to occur in 3% of cold urticaria. 65 Cold food and drink can cause
to 4% of patients with cryoglobulinemia59 and has edema of the tongue and lips. 65 Systemic reactions
also been reported in association with cold agglu- characterized by generalized urticaria or angio-
tinins, ~ cryofibrinogens, 6~ and cold hemolysins. 62 edema with or without hypotension occur in over
Cold urticaria has been reported in cases of infec- 50% o f patients. ~6 Most of these reactions are as-
tious mononucleosis in association with either cry- sociated with swimming in cold water. ~ Syncope
oglobulins or cold agglutinins, but the reports are may occur in a significant percentage. 65 Cold ur-
rare. Familial cold urticaria is a rare autosomal ticaria may coexist with other physical urticarias. 6s
dominant condition with onset at an early age. One study showed mean duration of symptoms to
Urticaria develops when the patient is exposed to be over 6 years. 6s Variants include persistent re-

1010 Page and Shear
actions lasting up to 1 week, 67 delayed reactions
that begin 1 to 3 days after cold challenge, as and
generalized cold urticaria in which patients de-
velop cholinergic-type wheals on generalized cold
exposure. 69
The diagnostic test for cold urticaria is the ap-
plication of an ice cube to the forearm or thigh.
In 86 patients with a positive test, 72% had wheal
formation after 10 minutes challenge time, while
100% reacted with 20 minutes challenge time. 65 If
cold urticaria is strongly suspected and the ice cube
test is negative, the forearm may be immersed in
10~ C water for 5 minutes. 67 Patients with familial
cold urticaria or the generalized variant will have
a negative ice cube test but will develop symptoms
when placed in a cold room at 4 ~ C. 67 Other cases
of atypical acquired cold urticaria with negative
ice cube tests have been reported. ~6
The pathogenesis of cold urticaria is poorly un-
derstood. Passive transfer of cold urticaria by a
serum factor (IgE7~ or IgM 71) has been demon-
strated in some cases. Degranulation of mast cells
with histamine release has been shown to occur, 72
but histamine may not be the principal mediator. 73
Increased levels of chemotactic factors, 74'7s ki-
nins, 76 platelet-activating factor, 77 platelet fac-
tor 4, 78 and prostaglandin D279 have been found in
venous blood or exudate from cold-challenged
skin. Treatment includes avoiding precipitating
factors. In particular, patients should be warned
of the danger of swimming in cold water. Cypro-
heptadine has been found to be effective in treating
cold urticaria67.8~ and may be used as a single
evening dose of 4 to 8 mg to avoid daytime drows-
iness. More recently doxepin has been reported to
be effective, with fewer subjective side effects
than cyproheptadine. 8: It blocks H~ and H2 recep-
tors and has little anticholinergic effect in low
doses such as 10 to 25 mg three times daily. 82 A
recent study showed that suppression of experi-
mentally induced cold urticaria with doxepin cor-
related with inhibition of platelet-activating factor
release. 77Induction of tolerance may be tried a3 but
is time-consuming and unpleasant. 67
Cold erythema
In 1962 Shelley and Caro s4 described a 5-year-
old boy who since birth had reacted to cold stimuli,
Journal of the
American Academyof
Dermatology
with local pain and erythema but not urticaria. He
also occasionally developed muscle spasm and col-
lapse. Ice cube testing produced pain and erythema
only; no serologic abnormality was found. The
authors termed this entity "cold erythema."
Cold panniculitis and related entities
In 1902 Hochsingers5 reported the development
of tender erythematous induration in the submental
areas of children when exposed to cold. Since then
many cases have been reported in infants and
children859~ and a few cases have been seen in
adults who had a very severe cold exposure. 86'9~
The lesions appear 1 to 3 days after cold exposure
and subside spontaneously within 2 weeks. Ap-
plication of an ice cube to the child's skin for 10
minutes will result in the development of an ery-
thematous plaque 12 to 18 hours later. Serial biop-
sies following ice cube challenge have revealed a
perivascular lymphohistiocytic infiltrate at the der-
mal subcutaneous junction after 24 hours, with a
well-developed panniculitis at 48 to 72 hours) 8
Some fat cells rupture to form cystic spaces and
the reaction completely subsides by 2 weeks. In-
fants have a higher content of saturated fatty acids
in adipose tissue than adults do, and this may result
in solidification at a higher temperature, s9
Selerema neonatorum and subcutaneous fat
necrosis of the newborn
Sclerema neonatorum is a rare disorder char-
acterized by diffuse, rapidly spreading hardening
of the skin and subcutaneous tissue of infants. 92'9~
It starts on the buttocks and trunk and is usually
seen in the setting of a major illness, for example,
sepsis or a congenita! anomaty. Affected infants
are cyanotic at birth, have difficulty in maintaining
body temperature, and have a poor prognosis. Pa-
thology shows a subcutaneous layer greatly thick-
ened by enlarged fat cells and wide fibrous bands.
No fat necrosis is present and many of the fat cells
contain fine needlelike clefts. 93
Some authors believe sclerema neonatorum is a
nonspecific finding in severe illness, 94 whereas
others think it is a distinct disorder caused by an
exaggeration of the normal saturated to unsaturated
fatty acid ratio seen in infants. 93 Cold exposure
does not seem to be important in the etiology of
Volume 18
Number 5, Part 1
May 1988 Temperature-dependent skin disorders 1011

sclerema neonatorum; however, similar clinical Table HI. Treatment of Raynaud's

findings have been seen in cases of primary cold phenomenon
injury, as described by Bower et al. 9~ This study
General measures
reviewed the findings in 70 infants admitted to Remove cause (drugs, occupation)
hospital in Britain with primary cold injury, usu- Treat underlying disease
ally due to poorly heated houses. The infants had Avoid precipitating factors
difficulty feeding and lethargy, and 39% showed Stop smoking
nonpitting induration of the cheeks, buttocks, and Biofeedback
limbs, with resulting immobility. Treatment was Wear gloves
that of gentle rewarming. There was a 25% mor- First-line drug therapy (efficacious in randomized,
tality. blinded, controlled studies)
NifedipinelSO.~l
In contrast, subcutaneous fat necrosis of the Di.ltiazem 1~2
newborn is characterized by discrete plaques and Prazosin'53.~
nodules that usually appear within a few days after Ketanserin 109
birth. In most cases the condition is benign and Prostaglandin El ~5 and prostaglandin 12TM
infusions
self-limited, although it has been associated with
Transderrnal prostaglandin E21~7
hypercalcemia and death. 9~
Second-line drug therapy
As in sclerema neonatroum, there is no clear Methyldopa
etiologic relationship to cold, and the etiology may Reserpine
be multifactorial. It has been postulated that an Phenoxybenzamine
underlying defect in fat composition, poor nutri- Guanethidine
tion, and various physical stresses, such as hy- Stanozolol
pothermia, may be important. 97 Griseofulvin
Topical nitroglycerin (adjuvant)
Raynaud's phenomenon Others
Intra-arterial reserpine
Raynaud's phenomenon is an episodic reversi- Low molecular weight dextran
ble vascular spasm of the extremities. Patients ex- Sympathectomy
perience a biphasic or triphasic color change, pre- Captopril
cipitated by cold or emotional stress. The classic Plasmapheresis 11~
succession of pallor, cyanosis, and erythema pre-
sumably represents vasospasm, venostasis, and re-
active hyperemia in the digital blood vessels. Ray- defect resulted from cold sensitization of the
naud's phenomenon may be idiopathic (and then a-adrenergic system, to3
termed Raynaud's disease) or it may be secondary Other reported abnormalities that may be im-
to an underlying disease. Causes of secondary portant in the pathophysiology of Raynaud's phe-
Raynaud's phenomenon include connective tis- nomenon were recently reviewed by Dowd. 104Re-
sue disorders, arterial diseases, neurovascular ported pharmacologic abnormalities of the digital
compression, hematologic abnormalities, as well vessels include hypersensitivity to the vasocon-
as certain occupational and drug exposures. These strictor serotonin, ~osa defect of histamine-induced
are discussed in more detail in one of the excellent vasodilation,l~ and an imbalance in the vasoactive
recent reviews of Raynaud's phenomenon. 98-1~ prostaglandins. 1~ Increased platelet aggregation
The pathophysiology of Raynaud's phenome- and activation/~ with increased release of sero-
non remains poorly understood. Lewis showed that tonin, 1~ have been shown to occur in some pa-
direct local cooling could induce attacks, while tients. Reduced deformability of red blood cells
indirect cooling had no effect if the hand was kept in primary and secondary Raynaud's phenomenon
locally warm. 1o2 He hypothesized that a local de- has been reported 1~ in patients with Raynaud's
fect in the digital arteries made them hypersensi- phenomenon and scleroderma; this may be due to
tive to cold. Later studies suggested that the local a serum factor. 1~ Some patients have increased

1012 Page and Shear
levels of cryoglublins and circulating immune
complexes, and others have increased plasma vis-
cosity due to increased fibrinogens. ~~ It is likely
that Raynaud's phenomenon is a heterogeneous
condition with several possible underlying mech-
anisms. The exact role of cold is poorly under-
stood, but it seems clear that the situation is more
complex than Lewis first proposed.
All patients with Raynaud's phenomenon
should be advised to stop smoking, avoid cold,
and wear warm gloves and socks. If severe symp-
toms persist despite these conservative measures
or if digital infarcts are present, drug therapy is
indicated, lo4 In an excellent review of the treatment
of Raynaud's phenomenon,'~ Dowd listed nifed-
ipine as the drug of choice. Other new treatments
have been directed against the various abnormal-
ities detected in patients with Raynaud's. Ketan-
serin is a selective blocker of serotonin receptors
and was shown to give clinical improvement in 8
of 10 patients with Raynaud's phenomenon and
connective tissue disease. ~~ Plasmapheresis has
been used in controlled studies tt~ and has been
shown to result in a reduction of blood viscosity
and platelet aggregation, as well as an increase in
deformability of red blood cells, t~ Other treat-
ments are listed in Table III and are well reviewed
elsewhere, t04.Ht
Cryoglobulinemia
Cryoglobulins are serum irnmunoglobulins that
undergo reversible precipitation at low tempera-
tures. A full discussion o f cryoglobulins is beyond
the scope of this article, and the reader is referred
to several comprehensive reviews. ~a-~4 Cryoglob-
ulins can be broadly classified into three types. ~t2
Type I are monoclonal immunoglobulins of a sin-
gle class, usually IgM or IgG with IgA or light
chains occurring rarely. This type accounts for
25% of cryoglobulins and occurs in patients with
multiple myeloma, Waldenstrtm's macroglobuli-
nemia, and other lymphoproliferative diseases.
Type II cryoglobulins account for approximately
another 25% of cases and are composed of one
monoclonal and one polyclonal immunoglobulin.
These mixed cryoglobulins are most often made
up of a monoclonal IgM and a polyclonal IgG and
Journal of the
American Academy of
Dermatology
occur in lymphoproliferative and autoimmune dis-
eases and infections. Type III cryoglobulins are
also mixed, and both components are polyclonal.
They account for 50% of cases and occur in as-
sociation with chronic autoimmune or connective
tissue disease, chronic infections, or inflammatory
conditions such as chronic hepatitis. They may
also occur transiently in acute infections such as
infectious mononucleosis or hepatitis. Essential
mixed cryoglobulinemia, in which no cause can
be found, is usually associated with a type Ill
cryoglobulin.
For reliable detection, blood for cryoglobulin
determination must be maintained at 37 ~ C during
transport and clotting. Serum must then be stored
at 4 ~ C for at least 7 days to exclude the presence
of cryoglobulins. ~s In both types I and II, cry-
oglobulins are usually present in high concentra-
tion (75 m g / m l ) , whereas in type III the concen-
tration is low (<1 mg/ml), t~s
The most common manifestations of cryoglob-
ulinemia are cutaneous symptoms, such as pur-
pura, distal necrosis, livedo, urticaria, leg ulcers,
and Raynaud's phenomenon.~2.1~4 Acrocyanosis
may also occur. The frequency of these and other
symptoms is listed in Table IV. Cold sensitivity is
not a consistent feature and may be noted in less
than 50% of cases. H2 It is most often seen in
type I and least often in type HI disease. 1~.~Purpura
is common and begins in the lower extremities,
with extension to the thighs and abdomen. Crops
of purpuric lesions may be precipitated by stand-
ing, with only 30% of patients noting aggravation
by cold. Skin necrosis and ulceration are seen less
often and may occur on the tip of the nose, ears,
fingers, toes, or legs after exposure to severe cold.
Urticaria and livedo reticularis are induced by cold
and are usually associated with purpura. Consti-
tutional symptoms, including chills, fever, dys-
pnea, and diarrhea, may occur with cold ex-
posure. ~t4
In general, type I cryoglobulins are present in
large amounts and precipitate to cause vessel oc-
clusion. Hyperviscosity may also play an impor-
tant role. This results in a higher incidence of
severe Raynaud's phenomenon and distal skin ne-
crosis. In contrast, type III cryoglobulins cause an
Volume 18
Number 5, Part 1
May 1988 Temperature-dependent skin disorders 1013

Table IV. Incidence of symptoms observed in 86 patients with cryoglobulinemia N2

Incidence (%) according to cryoglobulin
General type
incidence
Symptoms (%) Ill
' I " 1
Cutaneous symptoms
Vascular purpura 55 15 60 70
Distal necrosis 14 40 20 0
Urticaria 10 15 0 10
Livedo 8 1 0 14
Leg ulcers 5 8 0 4
Raynaud's phenomenon 50 40 40 60
Acrocyanosis 9 15 15 2
Articular manifestations 35 5 20 58
Renal symptoms 21 25 35 12
Neurologic symptoms 17 15 5 25
Hemorrhages 7 20 5 0
Abdominal pains 2 0 0 5
Arterial thrombosis ! 5 0 0

acute leukocytoclastic vasculitis with mild Ray-
naud's phenomenon, purpura, arthralgias, and glo-
merulonephritis being more common. However
pathophysiologic and clinical overlap occurs, and
patients with type II disease may show both types
of symptoms.lt2'~15
Cryofibrinogenemia may produce similar clini-
cal manifestations, including cold urticaria, livedo
reticularis, acral necrosis, gangrene, and Ray-
naud's phenomenon. ~t4 Patients may also have
thrombotic or hemorrhagic manifestations. The di-
agnosis is made by demonstrating the presence of
cold-precipitable protein in plasma but not in se-
rum."4 Small amounts of cryofibrinogens may oc-
cur in healthy people. Other causes are listed by
Moroz and Rose.114 The most important cause of
secondary cryofibrinogenemia is underlying ma-
lignancy, particularly prostatic carcinoma. TM
Finally, some antibodies bind to red blood cell
antigens in cold temperatures and may cause
red blood cell agglutination (cold agglutinins)
or complement-mediated intravascular hemolysis
(cold hemolysins). 1~4Chronic cold agglutinin dis-
ease occurs in the elderly and may be associated
with acrocyanosis, distal gangrene, and Raynaud' s
phenomenon. Hemolytic anemia and cold hemo-
globinuria may occur. In contrast to the cold
urticaria seen in patients with transient acute ele-
vation of cold agglutinins in infectious mononu-
cleosis, 6~ cold urticaria is absent in chronic cold
agglutinin disease. TM The cold hemolysin syn-
drome, mainly seen with tertiary or congenital
syphilis, is now very rare. ~t* Patients experience
attacks of paroxysmal hemogloblinuria in associ-
ation with chills, fever, weakness, abdominal pain,
vomiting and diarrhea, wheezing and hypotension
when exposed to cold. Acrocyanosis and Ray-
naud's phenomenon may also occur.
DISORDERS DUE TO HEAT
Infrared radiation, composed of wavelengths of
800 to 170,000 nm, results in thermal burns at
temperatures over 44 ~ C. tz Chronic exposure to
more moderate heat can cause erythema ab igne
and skin cancer.
Erythema ab igne, infrared elastosis, and
heat cancers
Prolonged and recurrent exposure to moderate
heat results in reticulate erythema and hyperpig-
mentation, epidermal atrophy, scaling, and telan-
giectasis. In the past, erythema ab igne was seen
on the inner thighs and legs of women who sat in
front of open fires or coal stoves. It is much less
common now because of the more general avail-
ability of central heating, but it is still seen with

1014 Page and Shear
local application of heating pads or hot water
bottles for ailments such as chronic backache.
Similar changes can be seen on the faces of
bakers, silversmiths, and others working over a
heat source.~16
Histopathologic changes include epidermal thin-
ning and flattening of the dermoepidermal j unction
with vacuolar change in the basal cell layer. The
dermis shows thinning with fragmented collagen
bundles and deposition of melanin and hemosi-
derin. There is an accumulation of elastic tissue,
but, unlike the changes seen in solar elastosis,
there is no basophilia, ltv,lls Some cases show hy-
perkeratosis and epidermal dysplasia, similar to
changes seen in actinic keratoses. "7
Infrared radiation may contribute to premature
aging, as was vividly demonstrated by Kligman
and Kligman, "6 who described a woman who sat
under a hood-type hairdryer for 1.5 hours a day
for 7 years and developed pouches of lax inelastic
skin on both cheeks. Kligman and Kligman con-
cluded that infrared radiation may significantly en-
hance the aging and carcinogenic effects of ultra-
violet radiation.
Skin cancer is well known to occur in burn scars
but can also result from chronic heat. This has
been described in erythema ab igne. ~t9 Cross t2~
reported over 160 cases of cancer of the lower legs
in rural Irish women who spent hours in front of
open hearths containing burning peat. 12~ Kangri
cancers of Kashmir arise from holding earthenware
pots containing burning coal against the skill, tzt
and kang cancers are seen in northwest China and
arise over the greater trochanter of the hip from
sleeping on heated bricks. ~1~ Thermally induced
cancers are usually squamous cell carcinomas and
occur after a long latent period of over 30
years. ~2z,123 Squamous cell carcinomas arising in
bum scars most often are first seen as an indolent
chronic ulcer that slowly enlarges. Although of
low to intermediate grade histologically, these can-
cers are aggressive, with metastases occurring in
over 30%; they have a poor prognosis. ~3
Urticaria induced by heat
Cholinergie urticaria, Cholinergic urticaria is
common, especially in young adults. 67,124 Trig-
gered by exercise, heat, and emotion, a sensation
Journal of the
American Academyof
Dermatology
of warmth is followed by the development of pru-
ritic I- to 3-ram wheals with a surrounding ery-
thematous flare. This most often involves the chest
and back, and in several cases can be generalized.
Uncommonly, wheezing and other systemic symp-
toms, such as nausea, abdominal pain, and head-
aches, may occur. 125 Angioedema may also oc-
cur, ~26 and cholinergic urticaria may coexist with
other physical urticarias.
The most effective techniques for producing
cholinergic symptoms are having the patient take
a hot bath or exercise until sweating. 1~7Intradermal
testing with mecholyl is positive only in patients
with severe cholinergic urticaria and is not a re-
liable means of diagnosis. 127
Treatment includes avoiding triggers and use of
an H~ antihistamine such as hydroxyzine. Wong
et al t28 recently concluded that danazol is a useful
treatment. The clinical improvement seen is as-
sociated with a rise in serum protease inhibitors. ,28
Regular exercise may induce tolerance but may be
dangerous in patients with a history of systemic
symptoms. Aspirin should be avoided because it
will aggravate the urticaria in about 50% of
cases. ~29 Individuals prone to systemic reactions
should carry an ANA-Kit (injectable epinephrine)
and never exercise alone.
Localized heat urticaria. Localized heat urti-
caria is a very rare entity in which urticaria occurs
at the site of direct contact with heat. ~30.131Women
are more often affected and systemic symptoms
may occur if large areas of skin are exposed to
heat. m A rare delayed type of localized heat ur-
ticaria was described in one family, in whom
wheals developed 1.5 to 2 hours after heat expo-
sure. 133The pathogenesis is unknown, and passive
transfer test results have been negative.~31 Hista-
mine and nonhistamine substance with ability to
cause smooth muscle contraction have been re-
covered from heat-urticated skin, TM and histamine
release into venous blood of the heat-challenged
arm has been documented. 134 Recently, increased
plasma levels of prostaglandin D2 have been iden-
tiffed. 13s Biopsies after local heat challenge have
revealed mononuclear perivascular inflammation
by 6 hours, with degranulated mast cells on elec-
tron microscopy.134 As in the other physical urti-
carias, treatment includes avoidance of precipitat-
Volume 18
Number 5, Part 1
May 1988
ing factors and administration of antihistamines.
Leigh and Ramsay ~32 induced tolerance in a 36-
year-old patient by immersing one arm in hot water
for 1 minute every hour until the skin no longer
reacted, and then increasing length of immersion
and time between immersions. ,32 The other limbs
and trunk were then treated in a similar way. Tol-
erance could be maintained by taking a hot bath
for 5 minutes every 12 hours. In a recent report,
treatment with hydroxyzine plus cimetidine com-
pletely abolished symptoms in two patients) 34 Fi-
nally, indomethacin was added to desensitization
treatment in one patient and seemed to give ad-
ditional benefit. Treatment resulted in suppression
of prostaglandin D~ release. ,3~
Erythermalgia
Erythermalgia was first described by Mitchell
in 1878 under the name "erthromelalgia. '''3s This
was renamed erythermalgia in 1938 by Smith and
Allen, '37 who described the typical symptoms of
erythema and burning distress in the lower and/
or upper extremities resulting from an increase in
local skin temperature. They also divided the dis-
order into primary (idiopathic) and secondary
forms.
In 1964 Babb et al '3s reviewed 51 cases from
the Mayo clinic. Patients with primary eryther-
malgia had intermittent attacks of severe burning
pain and erythema, precipitated by increased heat
or dependency. Symptoms most often involved the
lower extremities and were bilateral in 28 of 30
cases. Patients sought relief by various means,
including walking on snow or cold floors, by sleep-
ing with their feet outside the covers, or by using
fans or ice packs to cool the affected parts. Men
were affected twice as often as women.
In contrast, the 21 patients with secondary er-
ythermalgia were older (all over 40 years of age),
with an equal sex distribution. Their symptoms
were less intense and more often asymmetric. The
most common associated condition was polycy-
themia rubra vera, which occurred in nine patients.
Other associations included myeloid metaplasia,
hypertension, venous insufficiency, diabetes mel-
litus, rheumatoid arthritis, and systemic lupus er-
ythematosus. Erythermalgia often preceded the di-
agnosis of myeloproliferative disease by several
Temperature-dependent skin disorders 1015
years. Temperature studies were performed to de-
termine the relationship between symptoms and
skin temperature. Positive results were said to oc-
cur when an increase in skin temperature induced
the burning distress and the retum to colder tem-
peratures made it disappear. Twenty-six of 31 pa-
tients showed a positive result, and the critical
temperature needed to cause symptoms was 32 to
36 ~ C.
The association of erythermalgia with myelo-
proliferative disease has been substantiated by
other reports. ~39:4~Michiels et al '4~ found that er-
ythermalgia was the presenting symptom in 26 of
40 patients with primary thrombocythemia or
thrombocythemia associated with polycythemia
rubra vera. Symptoms were relieved when the
platelet count fell or with cyclooxygenase inhibitor
treatment such as aspirin. Other diseases associ-
ated with 2 ~ erythermalgia that have been reported
since Babb's article include systemic lupus ery-
thematosus in patients under 40 years of age, TM
hypertension with vasculitis, '4~ and lichen scle-
rosis et atrophicus.'43
The pathogenesis is unknown but it has been
proposed that a primary or secondary vascular ab-
normality manifested by endothelial swelling is
present in all patients. ~42 This swelling is then en-
hanced by increases in temperature or limb de-
pendence, resulting in a narrow lumen with sludg-
ing of blood and platelet aggregation. Mediator
release, likely including prostaglandins from ac-
tivated platelets, '4~ then results in pain and ery-
thema. Pathologically, arterioles show endothelial
cell swelling and proliferation of smooth muscle
cells in the vessel wall, resulting in narrowing of
the lumen. ~4~In a case study, Uno and Parker '~
showed a reduction of nerve terminals in the per-
iarterial and sweat gland plexuses.
Numerous treatment modalities have been tried,
with aspirin giving the most consistently good re-
suits. 137'138'x4~ In one study 70% of patients re-
sponded well to 650 m g daily, t38 and the authors
considered response to aspirin to be a valuable
diagnostic clue. Methysergide maleate has occa-
sionally been of benefit. ,45 Other methods that have
given relief in some cases include epinephrine, '46
nitroglycerin ointment, '47 sublingua] isoprotere-
no1,'47 propranolol,'4a and, in severe cases, lumbar

1016 Page and Shear
g a n g l i o n e c t o m y '49 and peripheral n e r v e divi-
sion. '37 In s e c o n d a r y e r y t h e r m a l g i a the underlying
disease should be treated. For example, in ery-
therraalgia s e c o n d a r y to p o l y c y t h e m i a , patients
e x p e r i e n c e d relief of their erythermalgia after ap-
propriate t r e a t m e n t of their p o l y c y t h e m i a , a3a
CONCLUSION
T h e t e m p e r a t u r e - d e p e n d e n t skin disorders c o m -
prise a heterogenous g r o u p o f conditions. Burns
and frostbite are the direct result of d a m a g e f r o m
e x t r e m e t e m p e r a t u r e s , but m o r e moderate degrees
o f heat and cold can also c a u s e disorders such as
e r y t h e m a ab igne and chilblains. In disease such
as cryoglobulinemia, cold panniculitis, and ery-
thermalgia, cold or heat can precipitate s y m p t o m s
but t e m p e r a t u r e is only one o f several pathogenic
factors. S o m e o f the physical urticarias are
temperature-dependent, and the pathophysiology
o f these conditions is not well understood. Finally,
heat has b e e n implicated in infrared elastosis and
heat cancers. While a v o i d a n c e of heat or cold is
important in the prevention a n d treatment o f these
d i s o r d e r s , m o r e specific therapy is often needed.
Although available for s o m e disorders, for ex-
ample, R a y n a u d ' s p h e n o m e n o n and cold urticaria,
definitive therapy is often lacking and treatment
can be a difficult challenge. M u c h remains to be
learned a b o u t the pathogenesis and m a n a g e m e n t
o f these conditions.
REFERENCES
1. Scheuplein RJ. Mechanism of temperature regulation
in the skin. In: Fitzpatrick TB, Eisen AZ, Wolff K,
Freedberg IM, Austen KF, eds. Dermatology in general
medicine. 3rd ed. New York: McGraw-Hill, 1987:
347-57.
2. Ross G. The cardiovascular system. In: Ross G, ed.
Essentials of human physiology. Chicago: Year Book,
1978:192.
3. Daniels F Jr, Baker PT. Relationship between body fat
and shivering in air at 15~ C. J Appl Physiol 1961;
16:421-5.
4. Daniels F Jr. Physiologic factors in the skin's reactions
to heat and cold. In: Fitzpatrick TB, Eisen AZ,
Wolff K, Freedberg IM, Austen KF, eds. Dermatology
in general medicine. 3rd ed. New York: McGraw-Hill,
1987:1412-24.
5. Hammel HT. Regulation of internal body temperature.
Ann Rev Physiol 1968;30:641-710.
6. Lewis T. Observations upon the reactions of the vessels
of the human skin to cold. Heart 1930;15:I77-208.
7. Adams T, Smith RE. Effect of chronic local cold ex-
Journal of the
American Academy of
Dermatology
posure on finger temperature responses. J Appl Physiol
1962;17:317-22.
8. Dana AS Jr, Rex IH Jr, Samitz MH. The hunting re-
action. Arch Dermatol 1969;99:441-50.
9. Edholm OG. In discussion, Shumacker HB Jr. Animal
studies. In: FetTer MI, ed. Cold injury: transaction of
the first conference. New York: Josiah Macy Jr Foun-
dation, 1951:17-57.
10. Folkow B, Fox RH, Krog J, Odelram H, Thoren O.
Studies on the reactions of the cutaneous vessels to cold
exposure. Acta Physiol Stand 1963;58:342-54.
11. Francis TJR, Golden F St C. Non-freezing cold injury:
the pathogenesis. J R Nav Med Serv 1985;71:3-8.
12. Zalar GL, Harber LC. Reactions to physical agents. In:
Moschella SL, Hurley HJ, eds. Dermatology. 2rid ed.
Philadelphia: WB Saunders, 1985:1672-90.
13. Moritz AR, Henriques FC Jr. Studies in thermal inju-
ries. II. The relative importance of time and surface
temperature in the causation of cutaneous bums. Am J
Pathol 1947;23:695-720.
14. Demling RH. Bums. N Engl J Med 1985;313:1389-98.
15. Alexander JW, Ogle CK, Stinnett JD, MacMillan BG.
A sequential, prospective analysis of immunologic ab-
normalities and infection following severe thermal in-
jury. Ann Surg 1978;188:809-16.
16. McIrvine AJ, O'Mahony JB, Saporoschetz F, Mannick
JA. Depressed immune response in burn patients: use
of monoclonal antibodies and functional assays to define
the role of suppressor cells. Ann Surg 1982;196:297-
304.
17. Wilmore DW, Mason AD Jr, Johnson DW, Pruitt BA
Jr. Effect of ambient temperature on heat production
and heat loss in bum patients. J Appl Physiol 1975;
38:593-7.
18. Subjeck JR, Shyy T. Stress protein systems of mam-
malian cells. Am J Physiol 1986;250:C1-C17.
19. Kulka JP. Cold injury of the skin. Arch Environ Health
1965;11:484-97.
20. Meryman HT. Review of biologic freezing. In: Cry-
obiology. New York: Academic Press, 1966:2-106.
21. Gage AA. What temperature is lethal for cells? J Der-
matol Surg Oncol 1979;5:459-60, 64.
22. Post PW, Daniels F Jr, Binford RT Jr. Cold injury and
the evolution of "white" skin. Hum Biol 1975;47:
65-80.
23. Miller BJ, Chasmar LR. Frostbite in Saskatoon: a re-
view of 10 winters. Can J Surg 1980;23:423-6.
24. D'Ambrosia RD. Cold injuries encountered in a winter
resort. Cutis 1977;20:365-8.
25. Anonymous. Treatment of frostbite. Med Lett Drugs
Ther 1980;22: l 12-4.
26. Mills WJ. Frostbite. A discussion of the problem and
a review of an Alaska experience. Alaska Med 1973;
15:28-30.
27. Porter JM, Wesche DH, Rosch J, Baur GM. Intra-
arterial sympathetic blockade in the treatment of frost-
bite. Am J Surg 1976;132:625-30.
28. Shumacker HB Jr, Kilman JW. Sympathectomy in the
treatment of frostbite. Arch Surg 1964;89:575-84.
29. Carrera GF, Kozin F, McCarty DJ. Arthritis after frost-
bite injury in children. Arthritis Rheum 1979;22:
1082-7.
Volume 18
Number 5, Part 1
May 1988
30. McKendry RJR. Frostbite arthritis. Can Med Assoc J
1981;125:1128-30.
31. Francis TJR. Nonfreezing cold injury: a historical re-
view. J R Nay Med Serv 1984;70:134-9.
32. Smith JL, Ritchie J, Dawson J. On the pathology of
trench frostbite. Lancet 1915;2:595-8.
33. Webster DR, Woodhouse FM, Johnson JC. Immersion
foot. J Bone J'oint Surg 1942;24:785-9.
34. Ungley CC, Channell GD, Richards RL. The immersion
foot syndrome. Br J Surg 1945;33:17-31.
35. Whayne TF, DeBakey ME. Cold injury: ground type.
Office of the Surgeon General, Department of the Army,
Washington, DC, 1958.
36. Taplin D, Zaias N, Blank H. The role of temperature
in tropical immersion foot syndrome. JAMA 1967;
202:210-3.
37. Champion RH. Cutaneous reactions to cold. In:
Rook A, Wilkinson DS, Ebling FJG, eds. Textbook of
dermatology. 3rd ed. Oxford: Blackwell, 1979:509-21.
38. Coskey RJ, Mehregan All. Shoe boot perniosis. Arch
Dermatol 1974;109:56-7.
39. Millard LG, Rowell NR. Chilblain lupus erythematosus
(Hutchinson). Clinical and laboratory study of 17 pa-
tients. Br J Dermatol 1978;98:497-506.
40. Kelly JW, Dowling JP. Pemio. A possible association
with chronic myelomonocytic leukemia. Arch Dermatol
1985;121:1048-52.
41. Wall LM, Smith NP. Pemiosis: a histopathological re-
view. Clin Exp Dermatol 1981;6:263-71.
42. Herman EW, Kezis JS, Silvers DN. A distinctive variant
of pernio. Arch Dermatol 1981;117:26-8.
43. Holti G, Ingrain JT. Physiotherapy in dermatology. Lan-
cet 1963;1:141-2.
44. Holti G. Measurements of the vascular responses in skin
at various time intervals after damage with histamine
and ultraviolet radiation. Clin Sci 1955;14:143-55.
45. Dowd PM, Rustin MHA, Lanigan S. Nifedipine in the
treatment of chilblains. Br Med J 1986;293:923-4.
46. Toback AC, Korson R, Krusinski PA. Pulling boat
hands: a unique dermatosis from coastal New England.
J AM AC.AODERMATOL1985;12:649-55.
47. Edwards EA, Coffman JD. Cutaneous changes in pe-
ripheral vascular diseases. In: Fitzpatrick TB, Eisen AZ,
Wolff K, Freedberg IM, Austen KF, eds. Dermatology
in general medicine. 3rd ed. New York: McGraw-Hill,
1997-2022.
48. Lewis T, Landis EM. Observations upon vascular mech-
anisms in acrocyanosis. Heart 1930;15:229-46.
49. Ryan TJ, Copeman PWM. Microvascular pattern and
blood stasis in skin disease. Br J Dermatol 1969;81:
563-73.
50. Edwards EA. Remittent necrotizing acrocyanosis.
JAMA 1956;161:1530-4.
51. Garretts M, Jarrett A, Osbom SB. Radio-active sodium
absorption studies in erythrocyanosis crurum puellarum
frigida. Br J Dermatol 1958;70:22-6.
52. Beacham BE, Cooper PH, Buchanan CS, Weary PE.
Equestrian cold panniculitis in women. Arch Dermatol
1980;116:1025-7.
53. Copeman PWM. Livedo reticularis. Br J Dermatol
1975;93:519-29.
54. Feldaker M, Hines EA Jr, Kierland RR. Livedo reti-
Temperature-dependent skin disorders 1017
cularis with summer ulcerations. Arch Dermatol 1955;
72:31-42.
55. Barker NW, HinesEA Jr, Craig WM. Livedo reticularis:
a peripheral arteriolar disease. Am Heart J 1941;21:592-
604.
56. Issroff SW, Whiting DA. Low molecular weight dextran
in the treatment of livedo reticularis with ulceration. Br
J Dermatol 1971 ;85:26-31.
57. Sneddon IB. Cerebro-vascular lesions and livedo reti-
cularis. Br J Dermatol 1965;77:180-5.
58. Rebollo M, Val JF, Garijo F, Quintana F, Berciano J.
Livedo reticularis and cerebrovascular lesions (Sned-
don's syndrome). Brain 1983;106:965-79.
59. Costanzi JJ, Coltman CA Jr. Kappa chain cold precip-
itable immunoglobulin G (IgG) associated with cold
urticaria. Clin Exp Immunol 1967;2:167-78.
60. Wu LYF, Mesko JW, Petersen BH. Cold urticaria as-
sociated with infectious mononucleosis. Ann Allergy
1983;50:271-4.
61. Miller DA, Freeman GL, Akers WA. Chronic urticaria,
a clinical study of fifty patients. Am J Med 1968;44:
68-86.
62. Becker RM. Paroxysmal cold hemoglobinurias. Arch
Intern Med 1948;81:630-48.
63. Doeglas HMG, Bleumink E. Familial cold urticaria:
clinical findings. Arch Dermatol 1974;110:382-8.
64. Sorer NA, Joshi NP, Twarog FJ, Zeiger RS, Rothman
PM, Colten HR. Delayed cold-induced urticaria. A
dominantly inherited disorder. J Allergy Clin Immunol
1977;59:294-7.
65. Neittaanm~d H. Cold urticaria. J AM AC.ADDE~MKrOL
1985;13:636-44.
66. Wanderer AA, Grandel KE, Wasserman SI, Farr RS.
Clinical characteristics of cold-induced systemic reac-
tions in acquired cold urticaria syndromes: recommen-
dations for prevention of this complication and a pro-
posal for a diagnostic classification of cold urticaria.
J Allergy Clin Immunol 1986;78:417-23.
67. Sibbald RG. Physical urticaria. Dermatol Clin 1984;
3:57-69.
68. B~ck O, Larsen A. Delayed cold urticaria. Acta Derm
Venereol (Stockh) 1982;58:369-71.
69. Aoki T, Horiko T, Akimoto T. Generalized cold urti-
caria: detection of heat-sensitive passive transfer sub-
stance active at moderate temperature. Clin Exp Der-
matol 1982;7:377-86.
70. Houser DD, Arbesman CE, Ito K, Wicber K. Cold
urticaria. Immunologic studies. Am J Med 1970;49:
23-33.
71. Wanderer AA, Maselli R, Ellis EF, Ishizaka K. Im-
munologic characterization of serum factors responsible
for cold urticaria. 3 Allergy Clin lmmunol 1971;48:
13-22.
72. Kaplan AP, Gray L, Shaft RE, et al. In vivo studies of
mediator release in cold urticaria and cholinergic urti-
carias. J Allergy Clin Immunol 1975;55:394-402.
73. Keahey TM, Greaves MW. Dissociation of cold-evoked
histamine release and urticaria following cold challenge.
Arch Dermatol 1980;116:174-7.
74. Wasserman SI, Soter NA, Center DM, Austen KF. Cold
urticaria--recognition and characterization of neutro-
phil chemotactic factor which appears in serum during

1018 Page and Shear
experimental cold challenge. J Clin Invest 1977;60:
189-96.
75. Soter NA, Wasserman SI, Austen KF. Cold urticaria
release into the circulation of histamine and eosinophil
chemotactic factor of anaphylaxis during cold chal-
lenge. N Engl J Med 1976;294:687-90.
76. DeLaus FV, Winkelmann RK. Kinins in cold urticaria.
Arch Dermatol 1968;98:67-74.
77. Grandel KE, Farr RS, Wanderer AA, Eisenstadt TC,
Wassermann SI. Association of platelet-activating factor
with primary acquired cold urticaria. N Engl J Med
1985;313:405-9.
78. Wasserman SI, Ginsberg MH. Release of platelet fac-
tor 4 into the blood after cold challenge of patients with
cold urticaria. J Allergy Clin Irnmunol 1984;74:275-9.
79. Heave), D J, Kobza-Black A, Barrow SE, Chappell CG,
Greaves MW, Dollery CT. Prostaglandin D2 and his-
tamine release in cold urticaria. J Allergy Clin Immunol
1986;458-61.
80. Wanderer AA, St. Pierre JP, Ellis EF. Primary acquired
cold urticaria: double-blind comparative study of treat-
ment with cyproheptadine, ehlorpheniramine, and pla-
cebo. Arch Dermatol 1977; 113:1357-77.
81. Sigler RW, Evans R, Horakova Z, Ottesen E, Kaplan
AP. The role of cyproheptadine in the treatment of cold
urticaria. J Allergy Clin Immunol 1980;65:309-12.
82. NeittaanmLki H, My~ShfinenT, Fraki JE. Comparison
of cinnarizine, cyproheptadine, doxepin and hydroxy-
zinc in treatment of idiopathic cold urticaria: usefulness
of doxepin. J AM AC_ADDERMATOL1984;11:483-9.
83. Bentley-Phillips CB, Kobza-Black A, Greaves MW.
Induced tolerance in cold urticaria caused by cold-
evoked histamine release. Lancet 1976;2:63-6.
84. Shelley WB, Caro WA. Cold erytfiema: a new hyper-
sensitivity syndrome. JAMA 1962;180:639-42.
85. Hochsinger C. Uber eine akute kongelative zellgew-
ebsverh~'tung in der Submentalregion bei kindern.
Monatsschr Kinderheilk 1902;1:323-7.
86. Haxthausen H. Adiponecrosis e frigore. Br J Dermatol
1941 ;53:83-9.
87. Rotman H. Cold panniculitis in children. Arch Dermatol
1966;94: 720-1.
88. Duncan WG, Freeman RG, Heaton CL. Cold panni-
culitis. Arch Dermatol 1966;94:722-4.
89. Lowe LB Jr. Cold panniculitis in children. Am J Dis
Child 1968;115:709-13.
90. Epstein EH Jr, Oren ME. Popsicle panniculitis. N Engl
J Med 1970;282:966-7.
91. Cohen I. Traumatic fat necrosis of the breast. JAMA
1923;80:770-1.
92. Hughes WE, Hammond ML. Sclerema neonatorum.
J Pediatr 1948;32:676-92.
93. Kellum RE, Ray TL, Brown GB. Sclerema neonato-
rum. Arch Dermatol 1968;97:372-80.
94. Warwick W J, Ruttenberg HD, Quie PG. Selerema neon-
atorum--a sign, not a disease. JAMA 1963;184:
680-3.
95. Bower BD, Jones LF, Weeks MM. Cold injury in the
newborn. Br Med J 1960;1:303-9.
96. Thomsen RJ. Subcutaneous fat necrosis of the newborn
and idiopathic hypercalcemia. Arch Dermatol 1980;
116:1155-8.
Journal of the
American Academy of
Dermatology
97. Silverman AK, Michels EH, Rasmussen JE. Subcuta-
neous fat necrosis in an infant, occurring after hypo-
thermic cardiac surgery. J AM AC.ADDERMATOL1986;
15:331-6.
98. Blunt RJ, Porter JM. Raynaud syndrome. Semin Ar-
thritis Rheum 1981; 10:282-308.
99. Belch JJF, Sturrock RD. Raynaud's syndrome: current
trends. Br J Rheumatol 1983;22:50-5.
100. Spencer-Green G. Raynaud phenomenon. Bull Rheum
Dis 1983;33:1-8.
101. Day TW, Mendoza F. Pharmacologic management of
Raynaud's phenomenon. South Med J 1984;77: I 160-4.
102. Lewis T. Experiments relating to the peripheral mech-
anism involved in spasmodic arrest of the circulation in
the fingers, a variety of Raynaud's disease. Heart
t929;15:7-101.
103. Jamieson GG, Lundbrook J, Wilson A. Cold hyper-
sensitivity in Raynaud's phenomenon. Circulation 1971;
44:254-64,
104. Dowd PM, Cold-related disorders. Prog Dermatol
1986;20:1-8.
105. Halpern JL, Coffman JD. Pathophysiology of Ray-
naud's disease. Arch Intern Med 1979;139:89-92.
106. Lafferty K, Roberts VC, DeTrafford JC, Cotton LT. On
the nature of Raynaud's phenomenon. Lancet 1983;
2:313-5.
107. Majerus PW. Arachidonate metabolism in vascular dis-
orders. J Clin Invest 1983;72:1521-5.
108. Kovacs IB, Sowemino-Coker SO, Kirby JDT, Tur-
ner P. Altered behaviour of erythrocytes in scleroderma.
Clin Sci 1983;65:515-9.
109. Roald OK, Seem E. Treatment of Raynaud's phenom-
enon with Ketanserin in patients with connective tissue
disorders. Br Med J 1984;289:577-9.
110. O'Reilly MJG, Talpos G, Roberts VC, White JM, Cot-
ton LT. Controlled trial of plasma exchange in treatment
of Raynaud's syndrome. Br Med J 1979;1:1113-5.
111. Dowd PM. The treatment of Raynaud's phenomenon.
Br J Dermatol 1986;114:527-33.
112. Brouet J-C, Clauvel J-P, Danon F, Klein M, Selig-
mann N. Biologic and clinical significance of cryoglob-
ulins. A report of 86 cases. Am J Med 1974;57:
775-88.
113. Winfield JB. Cryoblobulinemia. Hum Pathol 1983;
14:350-4.
114. Moroz LA, Rose B. The cryopathies. In: Samter M,
ed. Immunological disease. 3rd ed. Boston: Little
Brown, 1978;570-91.
115. Jones RR. The cutaneous manifestations of paraprotein-
aemia. I. Br J Dermatol 1980;103:336-45.
116. Kligman LH, Kligman AM. Reflections on heat. Br J
Dermatol 1984;110:369-75.
117. Shahrad P, Marks R. The wages of warmth: changes in
erythema ab igne. Br J Dermatol 1977;97:179-86.
118. Finlayson GR, Sams WM Jr, Smith JG Jr. Erythema
ab igne: a histopathological study. J Invest Dermatol
1966;46:104-8.
119. Peterkins GA. Malignant changes in erythema ab igne.
Br Med J 1955;2:1599-602.
120. Cross F. On a turf (peat) fire cancer: malignant change
superimposed in erythema ab igne. Proc R Soc Med
1967;60:1307-8.
Volume 18
Number 5, Part 1
May 1988
121. Neve EF. Kangri-bum cancer. Br Med J 1923;2:
1255-6.
122. Treves N, Pack GT. The development of cancer in burn
scars. Surg Gynecol Obstet 1930;60:749-82.
123. Kaplan RP. Cancer complicating chronic ulcerative and
scarifying mucocutaneous disorders. Adv Dermatol
1987;2:19-46.
124. Moore-Robinson M, Warin RP. Some clinical aspects
of cholinergic urticaria. Br J Dermatol 1968;80:794-9.
125. Kounis NG, MacMahon RG. Cholinergic urticaria with
systemic manifestations. Ann Allergy 1975;35:243-5.
126. Lawrence CM, Jorizzo JL, Kobza-Black A, Coutts A,
Greaves MW. Cholinergic urticaria with associated
angio-edema. Br J Dermatol 1981;105:543-50.
127. Commens CA, Greaves MW. Tests to establish the di-
agnosis in cholinergic urticaria. Br J Dermatol 1978;
98:47-51.
128. Wong E, Eftekhari N, Greaves MW, Ward AM. Ben-
eficial effects of danazol on symptoms and laboratory
changes in cholinergic urticaria. Br J Dermatol 1987;
116:553-6.
129. Doeglas HMG. Reactions to aspirin and food additives
in patients with chronic urticaria, including the physical
urticarias. Br J Dermatol 1975;93:135-44.
130. Delorme P. Localized heat urticaria. J Allergy 1969;
43:284-91.
131. Greaves MW, Sneddon IB, Smith AK, et al. Heat ur-
ticaria. Br J Dermatol 1974;90:289-92.
132. Leigh IM, Ramsay CA. Localized heat urticaria treated
by inducing tolerance to heat. Br J Dermatol 1975;
92:191-4.
133. Micha~lsson G, Ros A. Familial localized heat urticaria
of delayed type. Acta Derm Venereol (Stockh) 1971;
51:279-83.
134. Irwin RB, Lieberman P, Friedman MM, et al. Mediator
release in local heat urticaria: protection with combined
Ht and H2 antagonists. J Allergy Clin Immunol
1985;76:35-9.
135. Koro O, Dover JS, Francis DM, et al. Release of pros-
taglandin D2 and histamine in a case of localized heat
urticaria and effects of treatment. Br J Dermatol
1986;115:721-8.
136. Mitchell SW. On a rare vaso-motor neurosis of the
extremities, and on the maladies with which it may be
confounded. Am J Med Sci 1878;76:17-36.
137. Smith LA, Allen EV. Erythernaalgia (erythromelalgia)
of the extremities: a syndrome characterized by redness,
heat, and pain. Am Heart J 1938;16:175-88.
138. Babb RR, Alarcon-Segovia D, Fairbaim JF II. Ery-
thermalgia, review of 51 cases. Circulation 1964;
29:136-41.
139. Redding KG. Thrombocythemia as a cause of eryther-
malgia. Arch Dermatol 1977; 113:468-71.
140. Michiels J J, Abels J, Steketee J, Van Vliet H, Vuzevski
VD. Erythromelalgia caused by platelet-mediated ar-
Temperature-dependent skin disorders 1019
teriolar inflammation and thrombosis in thrombocy-
thernia. Ann Intern Med 1985;102;466-71.
141. Alarcon-Segovia D, Diaz-Jouanen E. Erythermalgia in
systemic lupus erythematosus. Am J Med Sci 1973;
266:149-51.
142. Ratz JL, Bergfeld WF, Steck WD. Erythermalgia with
vasculitis: a review. J AM ACAO DERMATOL1979;1:
443-50.
143. Hammar H. Plantar lesions of lichen sclerosis et atro-
phicus accompanied by erythermalgia. Acta Derma Ve-
nereol (Stockh) 1978;58:91-2.
144. Uno H, Parker F. Autonomic innervation of the skin in
primary erythermalgia. Arch Dermatol 1983; 119:65-7I.
145. Pepper H. Primary erythermalgia: report of a patient
treated with methysergide maleate, lAMA 1968;203:
]066-7.
146. Mufson I. Clinical observations in erythromelalgia: a
method for its symptomatic relief. Am Heart J
1937;13:483-91.
147. Cross EG. The familial occurrence of erythromelalgia
and nephritis. Can Med Assoc J 1962;87:1-4.
148. Bada JL. Treatment of erythromelalgia with propran-
olol. Lancet 1977;2:412.
149. Telford ED, Simmons HT. Erythromelalgia. Br Med J
1940;2:782-3.
150. Smith CD, McKendry RJR. Controlled trial of nifedi-
pine in the treatment of Raynaud's phenomenon. Lancet
1982;2:1299-301.
151. Rodeheffer RJ, Rommer JA, Wigley F, Smith CR. Con-
trolled double-blind trial of nifedipine in the treatment
of Raynaud's phenomenon. N Engl J Med 1983;
308:880-3.
152. Vayssairat M, Capron L, Fiessinger J-N, Mathieu J-F,
Housset E. Calcium channel blockers and Raynaud's
disease. Ann Intern Med 1981;95:243.
153. Surwit RS, Gilgor RS, Allen LM, Duvic M. A double-
blind study of prazosin in the treatment of Raynaud's
phenomenon in scleroderma. Arch Dermatol 1984;
120:329-31.
154. Wollersheim H, Thien T, Fennis J, van Elteren P, van't
Laar A. Double-blind, placebo-controlled study of pra-
zosin in Raynaud's phenomenon. Clin Pharmacol Ther
1986;40:219-25.
155. Martin MFR, Dowd PM, Ring EFJ, Cooke ED, Dieppe
PA, Kirby JDT. Prostaglandin E~ infusions for vascular
insufficiency in progressive systemic sclerosis. Ann
Rheum Dis 1981;40:350-4.
156. Belch JJF, Newman P, Drury JK, et al. Intermittent
epoprostenol (prostacyclin) infusion in patients with
Raynaud's syndrome. Lancet 1983;1:313-5.
157. Belch JJF, Madhok R, Shaw B, Leiberman P, Sturrock
RD, Forbes CD. Double-blind trial of CLl15,347, a
transdermally absorbed prostaglandin ~ analogue, in
treatment of Raynaud's phenomenon. Lancet 1985;
1:1180-3.