Erythromelalgia

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Eryth romelalgia

Frederick Mandell, M.D., Judah Folkman, M.D., and Shuzo Matsumoto, M.D.

From tile Departments of .fedicine (ln(l Surgery, Children s Hospital Medical Center, and tue Department of Pediatrics, Harvard Medical School, Boston, Massaci,usetts, and tue Department of Pediatrics, liokkaido Unicersity School of Medicine, Sapporro, Hokkaido, Japan

ABSTRACT. Erythromelalgia is an extraordinary disease which remams elusive in its pathophysiology and

manage-nient. Victims stiffer intense burning and redness of the

hands and feet. In what appears to be the antithesis of

Raynaud’s disease, the pain is relieved by emersion in cold. A

child with erythronielalgia is described whose symptoms began at age 3 years. Pharmacological management trials and thermography are incorporated in the report. Pediatrics, 59:45-48, 1977, ERYTHROMELALGLA, PERIPHERAL VASCULAR I)ISEA5E.

Uncomnion in adults and unlikely in children, erthron3elalgia is an unusual disease. From the first description nearly 100 years ago,’ the im-probability of this disease precluded

determina-tions of cause and treatment. Intense, burning extremity pain, redness, and increased skin temperature characterize

the

affliction.

Warmth

intensifies discomfort and cold provides relief. Therapy, except for a few cases, has been ineffec-tual, and attempts to find prolonged easement have been disappointing. The following report traces the natural course of erythromelalgia in a child.

CASE REPORT

An 1 1-year-old Japanese girl arrived in Boston from Hokkaido, Japan. She complained of burning distress of her

hands and feet attended by local redness and heat.

At 3 years 5 months of age, the girl had begun to complain

of pain. It gradually became clear that the pain was in the tips of her fingers and toes. In the beginning, there were no

color changes. Attacks of pain tended to occur in warm

environments, following exercise, especially walking, and

accompanied febrile episodes. At age 5, attacks of pain,

redness, and local skin temperature elevation in the hands

and feet were followed by superficial desquamation of the toes. It was hard for her to walk to and from school, She had

learned earlier that rest and local application of cold brought

relief, and at school during the warm weather she would sit in her classroom with her feet immersed in a bucket of ice

water to reduce her discomfort.

As the severity and frequency of the attacks gradually increased, the family moved to Hokkaido, the coldest part of

Japan

to remove the child from the warm environmental

temperatures which increased her discomfort. At times the

family could not use the heating system in the house, even in the winter.

At the present time, at age 1 1, she experiences episodes of

pain, heat, and redness 20 to 30 times a day. The areas of

(Received April 30, 1975; revision accepted for publication

May 1, 1976.)

ADDRESS FOR REPRINTS: (F.M.) Children’s Hospital Medical Center, 300 Longwood Avenue, Boston,

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F,;. 1. The reddened, desquamated hot feet of erythromelal- FIG. 2. The ice bucket relief of pain.

46 ERYTHROMELALGIA

gia.

redness have extended to the elbows and knees but only the

more distal elements are painful. The feet are more involved than the tipper limbs (Fig. 1). In school, she continues to use

her ice 1)ucket daily, and in Boston her father carried an

insulated picnic bag filled with ice water which she required

for about ten minutes after 30 or 40 minutes of walking (Fig. 2). She often has attacks during the night and has a bucket 1w

her bed. As she sits in the bath, her hands and feet are held out of the hot water.

On present examination her blood pressures are: right arm,

118/72; leftarm, 122/70; right leg, 124/68; and left leg, 126/

70. She has normal pedal and radial pulses and her feet are

red to the ankles with several small areas of superficial desquamation on the toes. The hands are pink and warni, and red at the finger tips. Fundascopic exam is normal, the chest clear, no murmur heard, and the heart sounds are normal.

The al)donlen is soft and no organomegal or masses are

present. The core temperature is 37.0 C (oral), the skin

temperature on the abdomen is 33.2 C, on the palm 35.2 C,

and on the sole 35.8 C. During an attack the core

tempera-tore was 37.0 C and the skin temperatures were :3:3.3 C n

the abdomen, 36.2 C on the palm and 36.8 C on the sole. The

hands and feet were moist with perspiration.

When she was 8 years old, the following studies were normal: ECG, chest X-ray film, urinalysis, total protein, liver

hmnction tests, protein-bound iodine, basal metabolic rate,

nlercury excretion, and EEC. Normal responses for

adren-aIm, pilocarpin, atropine, mecholyl, and cold pressor were

recorded. Plethsmograph was normal and the

determina-tions of skin temperatures by Thermister were recorded as

follows: room temperature, 26.5 C: core (oral) temperature,

36.4 C; and skin temperature of patient’s sole, .35.4 to :35.9 C. Iii a control group of 20 patients of the same age, their sole telnperatlire range was .32.4 to .33.4 C.

The patient was examined thermographicallv (Fig. :3).

Normally the heat distribution to the limbs is constant and

homogeneous, and the legs in the normal person are warmer

than the insteps and toes. In this patient, however, the heat

distribution is mottled and the tips of the toes and ankles are

warmer than other parts of the lower legs.

B using an isotherm display of the thermograph- which

produces a selected temperature range shown as an area of

saturated white superimposed upon the regular display, it is

possil)le to determine the amount of temperature variation

1)etween adjacent parts tinder examination. By this means

the temperature difference between the tips of the toes and the legs in the patient was + 3.0 C, the difference in the healthy control was -6.0 C.

Laboratory Studies

Laboratory examination showed a WBC of 7,400/cu mm with 51% neutrophils, 1% bands, 44% lymphocytes, and 4% nionocvtes. The corrected sedimentation rate was 1 1 mm; the RBC was 4,830,000/cu mm; hemoglobin, 13.3 gm/100 1111; hematocrit, 40.9%; antinuclear factor and cryoglobulins,

negative; BUN 16 mg/ 1(X) ml; blood sugar, 103 mg/ 1(5) ml;

calcium, 10 ing/ 100 ml; and phosphorus 5 mgI 1(X) nil.

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FIG. 3. Ordinary gray-tone thermograms of a healthy boy (N) and the patient (P). The whiter tones represent the highest

temperatures.

A protein electrophoresis revealed a total protein of 8.1

gm/100 ml; albumin, 4.89 gm/100 ml; alpha-,, 0.18 gm/100

ml; alpha-2,

0.83 gm/100 ml; beta, 11.3 gm/100 ml; and gamma, 1.07 gm I 100 ml. Mercury was not present in the

blood and a blood lead level was 8sg/ 100 mg of whole

blood. Spine and chest X-ray films were normal and no

calcifications were noted in the aorta. X-ray films of the extremities revealed linear and rounded densities in the

subcutaneous fat and the normally sharp plane between subcutaneous fat and muscle was obscured.

The course of clinical trials is shown in Table I.

DISCUSSION

Erythromelalgia is an extraordinary symptom

complex.

In

what

superficially

appears

to be

the

antithesis of Raynaud’s disease, victims of erythromelalgia seek relief in buckets of ice

water.

A cursory

look

at the

hands,

which

are

red

and

hot,

would

presume

that

blood

flow

to these

areas

is increased.

But

must

this

be

the

case?

It is

also possible that, due to increased tone in the

precapillary

arterioles,

blood

is diverted

to

the

deep,

sub-dermal

A-V

shunts.

Therefore,

although

the

foot

may

appear

red,

blood

flow

through

the

skin

is actually

deficient.

The

skin

then,

is

chron-ically ischemic, and the products of ischemic metabolism appear to stimulate increased flow to

the

extremity,

just

as they

do in dependent

rubor

observed

in

patients

with

peripheral

vascular

occlusive

disease.

Elucidation

of

peripheral

vascular

disease

is

difficult, and made more problematic by limited

knowledge

of

the

factors

controlling

vasomotor

effects.

The

actual

mechanisms

of pathogenesis

of

erythromelalgia are certainly beyond the scope of this report. However, the hypothesis that

vasodi-latation

is a direct

cause

of spontaneous

attacks2

appears oversimplified. Our patient and others

with

erythromelalgia

remain

symptomatic

even

when blood flow is internipted by proximal cuff

pressure.

In adults, erythromelalgia has been separated

into

a

primary

(nonassociated

disease)

and

secondary

phenomenon.

In

the

secondary

state,

erythromelalgia

has

been

associated

with

lupus

erythematosus,

myeloproliferative

disease,

dia-betes

mellitus,

and

hypertension.

Fifty-one

adult

patients

were

studied

by Babb

and

his associates.3

Thirty

were

of

the

primary

type

and

21 had

associated diseases. The older patients, over 40 years of age, were more likely to have the type of

erythromelalgia

associated

with

other

disease

states.

Typically,

adults

complained

of bilateral

burning

pain

and

redness

of the

extremities.

Attacks

last

from

several

minutes

to

two

or

three

hours

and

occasionally

longer.

In

the

usual

case,

peripheral

pulses

and

blood

pressures

are

normal

and

most

patients

seek

relief

by

cooling

the

extremity.

The

course

in children

has

not

been

well

documented.

A 13-year-old

girl

described

by

Catchpole responded to methysergide after two

years of characteristic symptoms.4 Spontaneous remissions have been described in older patients’

and descriptions of patient relief with small doses

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TABLE I

48 ERYTHROMELALGIA

COURSE OF THERAPEUTIC TRIALS

Drug Dosage Result

Prednisolone 10 to 15 mng/da’v Initially effective; then sInptoms returned

Hydantoin 1(10 mg/day Slight initial effect; then smnptonis

returned

-______________________________

-Aspirin 6(X) ing every 4 hr Inconsistent relief

!he11olabital 50 mg 3 tilnes/day Not effective

Reserpiiie hy-drochloride

0.5 rng/da Not effective

Diazepani 20 mg/day Not effective

Chlorproniazine hydrochloride

30 ing 3 times/day Not effective

Methsergide 2 ing 2 times/day Not effective

Carbamazepine 200 mg/day Partially effective but not consistent

Allan

observed

that

a single

dose

of

650 mg

of

aspirin dramatically relieved symptoms in some erythromelalgia patients for as long as four days.5

The role of proliferative disease in the

patho-genesis of erythromelalgia is unclear. The degen-erative process of systemic lupus erythematosus

predominately

involves

the

small

arteries

and

arterioles

and

the

symptoms

of

erythromelalgia

may

precede

systemic

disease

diagnoses

by

as

long as 12 years.71

Aside

from

aspirin,

other

forms

of therapy

have

been

varied

and

the

interpretation

of therapeutic

trials

on

so few

patients

has

been

difficult.

Scat-tered

case

studies

have

reported

relief

with

typhoid vaccine,7 isoproterenol, epinephrine,”

m’#{176} nitroglycerine and

phenoxybenzamine

7

In the brief time since thermography has been

introduced,

it has been adopted for infrared studies in a variety of medical applications. This equipment may

be

useful

in

performing

earlier

vascular

studies

in the

examination

of peripheral

vascular diseases. By means of thermography, it is

often possible to assess and follow the day-to-day

effect

of

treatment.”

Measurements

of the

ther-mographic

skin

patterns

would

then

be

effica-cious

in

following

peripheral

vascular

disorders

such as erythromelalgia.

In the present case, unclear pathophysiology

complicated therapy. The patient had poor responses to most compound.s previously used successfully in the literature in small numbers of patients, and at present continues to have an

unrelenting symptom pattern. She shows no

evidence

of

systemic

disease

and,

after

eight

years, no sign of prolonged relief. She has

demon-strated

in this

period

involvement

which

began

in

the

fingers

and

toes,

and

extended

to

the

elbows

and

knees,

and

an

increase

in

attack

frequency

with greater dependence on the local application

of

cold

for

relief.

The

disease

course

for

this

patient

has

been

one

of

heightened

incapacita-tion.

REFERENCES

1. Mitchell SW: On a rare vaso-,notor neurosis of the extremities and on the maladies with which it may be confounded. Am

J

Med Sci 76:2, 1878.

2. Allan EV, Barker HW, Hines EA Jr (eds): Peripheral

Vascular Diseases. Philadelphia, WB Saunders,

1962, p 1005.

3. Babb RR, Alacron-Sergovia D, Fairbairn JF: Erythro-melalgia: Review of 51 cases. Circulation 24:136, 1964.

4. Catchpole BN: Erythromelalgia. Lancet 2:909, 1964. 5. Smith LA, Allan EV: Erythermalgia (erythromelalgia) of

the extremities: A syndrome characterized by redness, heat and pain. Am Heart

J

16:175, 1938. 6. Bloom 5: Erthromelalgia. NY State Med

J

64:2470,

1964.

7. Markel

J:

Erthroinelalgia: Report of a case. Arch

Dermatol S 38:73, 1938.

8. Cross EG: The familial occurrence of erythromelalgia and nephritis. Can Med Assoc

J

87:1, 1962. 9. Mufson I: Clinical observations in erythromelalgia and a

method for symptolnatic relief. Am Heart

J

13:483, 1937.

10. Telford ED, Simlnons HT: Erythromelalgia. Br Med

J

2:782, 1940.

11. Ryan

J:

Thermography. Aust Radiol 13:23, 1969.

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1977;59;45

Pediatrics

Frederick Mandell, Judah Folkman and Shuzo Matsumoto

Erythromelalgia

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