Raynaud's Disease in ChildrenBy WARREN G. GUNTHEROTH, M.D., BEVERLY C. MORGAN, M.D.,

JOHN A. HARBINSON, M.D., AND GAY L. MULLINS, B.S.

SUMMARYSix children with primary Raynaud's disease have been studied with plethysmography

and multiple-site skin-temperature readings. All six were free of systemic disease. Eachdemonstrated the characteristic sequence of pallor, cyanosis, and rubor when subjectedto generalized cold, but application of local cold produced only modest reduction inskin temperature and digital pulse. Only one child had a history of vasospastic symptomsassociated with emotional stimuli, and she was the only one in whom an emotionalchallenge was able to produce Raynaud's phenomenon during the physiological studies.Tolazoline, in doses small enough to avoid generalized vasodilatation, was effectivein substantially increasing flow to the affected digits.The involvement of only one or two digits, next to completely uninvolved digits, is a

conclusive argument for a primarily local sensitivity. However, the ability to precipitatevasospasm with generalized cold, versus local cold applications, and emotional stimuliindicates the importance of the nervous system in the manifestation of Raynaud's disease.

Additional IndexingCold sensitivityReserpineVasospastic disorders

Words:Emotional stimuli and vasospasm

Skin temperaturePlethysmography

Tolazoline

RAYNAUD described a vasopastic disor-der in 1862 characterized by the sequence

of pallor, cyanosis, and rubor.1 Allen andBrown2',3 proposed more rigid requirementsfor the diagnosis of Raynaud's disease, whichhave been widely accepted since 1932: "(1)episodes of change in color, of the vasospastictype, excited by cold or emotion; (2) bilater-ality; (3) presence of normal pulsations in thepalpable arteries; (4) absence of gangrene, orits limitation to the minimal grades of cutane-ous gangrene; (5) absence of any primary dis-ease which might be causal, such as cervicalrib or organic disease of the nervous system,and (6) symptoms of two years or of longerduration."3 Allen and Brown attributed thefirst four criteria to Raynaud, but added the

From the Department of Pediatrics, University ofWashington School of Medicine, Seattle, Washington.

Investigation was supported in part by Grant HE-03998 from the U. S. Public Health Service. Studieswere carried out in the Clinical Research Center(Grant FR-37). Dr. Morgan holds Public Health Ser-vice Career Development Award HE 7945.

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last two criteria in order to separate the pri-mary disease from secondary vasomotor symp-toms. Gifford and Hines4 in a very completereview of 756 female patients at the MayoClinic found these criteria very effective. (Theyactually used only five criteria; the third cri-terion is inherent in the fifth.) Additionalcharacteristics of Raynaud's disease are predi-lection for young females and absence ofsevere pain. The sequence characteristic ofRaynaud's disease but associated with otherpathological states is usually called "secon-dary Raynaud's phenomenon."The underlying mechanism of Raynaud's

disease was thought to be hyperactive vaso-motor nerves by Raynaud, but Lewis5 favoredlocal hypersensitivity of the digital arteries.More recently, increased viscosity of the bloodhas been described in most patients as a majormechanism.6There have been no reports of Raynaud's

disease in the pediatric literature, althoughoccasionally a child has been discussed as partof a larger group of patients with the disorder.4

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RAYNAUD'S DISEASE IN CHILDREN

Yet, children with the disorder present anunusual opportunity to study Raynaud's dis-ease in a pure form, since obstructive arterialdisease is rare in children. We have studied sixchildren with Raynaud's disease with plethys-mography and multiple-site skin-temperaturerecordings.

Group StudiedThe six children ranged from 5 to 14 years

of age. There were two males and four fe-males. They all had had symptoms from sev-eral months up to 9 years. Underlying system-ic disease was ruled out as far as possible. Inparticular, cardiopulmonary disease, fever,anemia, arthritis, and elevated sedimentationrate were excluded.7 None of the subjects hadever had frost bite or prolonged exposure toextreme cold.

MethodsThe studies were performed with the subject

in a supine position at an initial ambient tem-perature of 23 C (74 F); in two children, Ray-naud's phenomenon was present at a roomtemperature of 23 C, and for these, the room tem-perature was raised to 27 C initially. After a pe-riod of rest, control records were obtained. Then,an emotionally charged incident was staged inan attempt to provoke Raynaud's phenomenon.The incident varied from patient to patient,such as confrontation with a 50-ml syringe at-tached to a spinal needle or searching questionsabout school performance. After a recovery pe-riod, the room temperature was gradually low-ered to 0 to 5 C (32 to 41 F). If Raynaud'sphenomena were observed at more moderatetemperatures, the room temperature was notlowered further, and the effect of a placebo andtolazoline (Priscoline) were investigated. A smallgauge needle was inserted into an antecubitalvein, and a slow drip of saline was begun. Rec-ords were taken during the insertion of the need-le, and after a rest period, and during the ad-ministration of an amount of saline similar to theamount of tolazoline.

In the last three patients studied, the effectsof local cold were measured by the repeatedapplication of Turkish towels soaked in ice waterto both hands, one at a time. To study the effectsof generalized cold exposure, these patients werewheeled into a cold room at 5 C, instead ofgradually lowering the room temperature. Thesesubjects also were given a placebo and tolazolinesubsequently.Cif-culation, Volume XXXVI, Novenber 1967

Plethysmography was carried out in a supineposition with the fingers and toes at approximateheart level. The instrumentation was a modifiedsonar system.8' 9 Two small (5 mm in diameter)barium titanate crystals were placed across theanteroposterior dimension of the terminal pha-lanx, at the level of the nail bed. The velocity oftransmission for 3 megacycle ultrasound throughblood and most soft tissues is 1.5 mm per micro-second. The amplification of the system10 per-mits the recording of a pulse amplitude of lessthan a micron. The pulse can be expressed as apercentage of the diameter of the digit. In eachpatient, plethysmography was performed on anaffected digit and a digit that was little affectedaccording to history and examination. The meth-od permits evaluation of rapid changes in pulseamplitude in a digit directly exposed to theambient atmosphere, a distinct advantage in thestudy of Raynaud's disease over the water-filledplethysmograph of the entire hand."

Slower changes of blood flow are reflected inskin temperature of digits,'2 which was record-ed by use of thermocouples constructed of 30-gauge copper-constantin wires held on the vo-lar pads of the distal phalanx by a single layer ofnarrow adhesive tape. Up to eight sites weresampled sequentially on a Brown recording po-tentiometer by use of a telephone-type relay withautomatic switching at 7-second intervals.

Results

Clinical

The six children were all native to Washing-ton, and all but one came from the PugetSound area where moderate, cool temperatures,associated with considerable dampness, pre-vail. In connection with the humidity as a con-tributing factor, one of the girls spent one win-ter in the eastern part of Washington, whichenjoys a much colder but drier winter, and hadno Raynaud's phenomenon that year. Althoughher emotional milieu also changed that year,this patient had no history of Raynaud's phe-nomenon precipitated or aggravated by emo-tional upsets.The ages of onset were less than 3 years in

two children (table 1). The boy, J.S., withonset at age 232' years, had the most severe dis-ease and demonstrated significant scars of pre-vious ulcerations (fig. 1) and roentgenograph-ic changes of the terminal phalanges of severalfingers (fig. 2). He was examined by us at age532 years, and a thorough investigation waS

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Table I

Age (yr) atStudy Onset

5.5 2.511 511 1012 313 1214 13

Involvemiient

Fingers > toes

Toes >> fingersFinger > toes

Toes onlyFingers > toes

Toes >> fingers

Family Precipitated by Structuralhistory Cold Emotionl chatiges

O + 0 ++ + 0 0+ + 0 0+ + 0 0O + + +o + 0 0

Figure 1

Fingers of J.S., a 5-year-old boy, with scars of previousischemic ulcers. Onset of his symptoms occurred 3years earlier. He has been followed for 4 years sincethis photograph was made and has been evaluatedtwice for evidence of scleroderma and other systemicdisorders, with negative results. The thumbs, not wellshown, were characteristically spared except for mini-mal scarring in one.

made to rule out other systemic diseases, par-

ticularly scleroderma, with negative results.Some 3 years later his case was worked up inCalifornia and skin biopsies were obtained;again no evidence of other disease was found.Only one other patient (P.J.), a 14-year-oldgirl, had had ischemic ulcers. She had mini-mal cutaneous scarring but no bone changes.

Although hypesthesia- was commonly asso-

ciated with the pallid and cyanotic phases,and paresthesias with the subsequent rubor,severe pain was not described by any of thepatients.Family history for Raynaud's disease was

positive in one half of the subjects, and in twoof the families, there were multiple occur-

rences.

Emotional factors played a significant rolein only one girl (S.L.), a 13-year-old. Her firstepisode of Raynaud's phenomenon occurredthe same week she learned that her father hadincurable carcinoma, and most of her subse-quent attacks correlated with various crises inher school work and family relationships.Although toes are reportedly less frequently

involved than fingers,'3 they were involvedin all of our patients and more severely in-volved than the fingers in half of them. Indeed,in one patient, the fingers were completelyfree of symptoms. Two of these patients withmore severe involvement of the toes had no

palpable dorsalis pedis pulses, although theyhad excellent posterior tibial pulses. (Approxi-mately 3% of normal subjects have no dorsalispedis anatomically, and 12% of normal sub-jects have no palpable pulse in that artery).t4

Experimental Results

In four of the six patients, there were no

Raynaud's phenomena at the start of our ob-servations, and in three of them, the fingertemperatures were quite normal, above 28 C."'The toes were invariably I to 3 C cooler, a

normal finding. Two patients upon arriving forthe study demonstrated pale or blue fingerswhich persisted after an hour of supine rest atcomfortable room temperatures (23 C). Forthese two patients, the room temperature was

increased to 27 C, and they were allowed to

warm their hands; in this manner, all subjectswere free of vasospastic phenomenon at thebeginning of the studies of local and generalcold stress and emotional stress.

Crculation, Volume XXXVI, November 1967

Pat icits

J.S.S.C.S.S.T.B.S.L.P.J.

Sex

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RAYNAUD'S DISEASE IN CHIILDREN

Figure 2The hands of J.S., a 5-year-old boy. The changes, although bilateral, are not symmetrical.The index and middle fingers are most severely affected, with greater bone destruction on theleft. The severity of these changes are unique to this child, although the disease appears to beprimary Raynaud's disease after thorough evaluation over several years.

Contralateralficod Ipsiloteral

" cold

Figure 3

Plot of skini temperatures in S.S., an 11-year-old boy.There was mild pallor when the patient was initiallyexamined, necessitating a higher room temperature27 C (80 F). The patient was exposed to cold room

temperatures twice, and after the second exposuirc,

received 10 mg of tolazoline intravenously. At thebottom of the chart are six representative plethysmo-graphic recordings from an affected finger. The timingof these recordings is indicated by the large numbersclose to the finger temperature plot. The pulse di-

Circulation, Voluine XXXVI, November 1967

When the subjects were challenged with anunexpected emotional stimulus, there was in-variably a transient diminution in pulse am-plitude and the volume of the digit, ofbrief duration, unaccompanied by significantchanges in skin temperature, a nornal reac-tion. In only patient S.L. was there a markedand sustained reaction to emotional stimula-tion which produced definite Raynaud's phe-nomenon.

Local cold applications were surprisinglyineffective in producing vasospastic reactions.Although towels soaked in ice water produceda transient decrease in the skin temperatureof the contralateral digits and a more sustaineddecrease with ipsilateral application, thechanges were of much smaller magnitude thanwhen the room temperature was low (fig. 3).

mension is expressed as a percentage of the fingerdiameter. Note the relatively slight changes in skintemperature and pulse magnitude when a Turkishtowel soaked in ice water was applied to the otherhand, or even the hand being studied, as comparedto the exposure of the entire patient to roughly thesame temperature in a cold room.

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In every one of the six subjects, room tem-peratures below 10 C invoked white digits,succeeded by blueness. In all six subjects, atleast one or more digits still demonstratedan abnormally small pulse on plethysmographyand subnormal temperature after return tocomfortable room temperatures. Injection of asmall volume of normal saline intravenouslyproduced no change in the vasospasm, butsmall amounts (10 mg or less) of tolazoline(Priscoline) produced a prompt improvementin skin temperature and digital pulses, evenwhen amounts were used that produced nogeneralized vasodilatation. Of particular in-terest were the effects of tolazoline on the ab-normal digit in contrast to the effects on a nor-mal digit in the same individual. For example,in patient S.C., who had minimal involvementof her fingers and marked vasospastic involve-ment of her toes, 10 mg of tolazoline produceda 300% increase in pulse amplitude in thetoes, only 50% increase in the fingers, and nochange in blood pressure as determined byauscultation. These results were achieved witha dosage only one tenth of the dosage recom-mended for adrenergic blockade.

Tolazoline was given too rapidly intravenous-lv to S.L., and the patient experienced gener-alized vasodilatation. She became very upsetand cried; the digits involved in the Raynaudphenomenon showed a brief increase in pulseamplitude and then showed the most intensevasoconstriction that we had observed, whichpersisted for almost an hour. This patientwas the only one in the series with a convinc-ing history of precipitation of vasospasm byemotional stimuli.

DiscussionAlthough only one of the patients showed a

close relationship between emotional stimuliand Raynaud's phenomenon, the more potenteffect of generalized cold versus local appli-cation of cold in the other subjects suggeststhat the mechanism operating in Raynaud'sdisease is a combination of unique local hyper-sensitivity of the arterioles superimposed on acardiovascular system with normal-and in

some cases increased-reactivity. The occur-rence of the vasospastic disorder in one digitof a limb and not in the next digit obviouslymilitates against the hypothesis that Raynaud'sdisease is due simply to alterations in vis-cosity,6 although blood will, of course, be moreviscous at lower temperatures. If a primarydisease state produces increased viscosity ofthe blood, and the patient has a tendency to-ward vasospasm, Raynaud's phenomenon willlikely occur. Similarly, anatomic variationswhich might be unimportant in a normal in-dividual may contribute significantly to theseverity of a vasospastic diathesis, a distinctpossibility in two of our patients with absenceof dorsalis pedis pulses.The efficacy of tolazoline selectively to

increase flow in the spastic arteries makes itan ideal agent for use in the milder cases. Theboy with structural changes moved to a warm-er, dry climate and enjoyed considerable im-provement except for one unusually cold win-ter which produced a recurrence. Reserpinewas prescribed in addition to tolazoline forS.L., whose attacks were precipitated by emo-tional stimuli; she did well thereafter, but it isnot possible to state whether the addition ofreserpine was beneficial.

All of the children have been followed forover 2 years, and none has developed evi-dence of systemic disease such as sclero-derma. It is still possible that underlying dis-ease may eventually appear, but all six chil-dren continue to fulfill the criteria for primaryRaynaud's disease.

References1. RAYNAUD, A. G. M.: De l'asphyxie locale et de la

gangrene symetrique des extremites. Paris: Rig-noux, 1862. (For extensive verbatim transla-tion, see ref. 2 below.)

2. ALLEN, E. V., ANTD BROWN, G. E.: Raynaud'sdisease: A critical review of minimal requisitesfor diagnosis. Amer J Med Sci 183: 187, 1932.

3. ALIMN, E. V., AND BROWN, G. E.: Raynaud's dis-ease affecting men. Ann Intern Med 5: 1384,1932.

4. GIFFORD, R. W., JR., AND HiNEs, E. A., JR.:Raynaud's disease among women anid girls.Circulation 16: 1012, 1957.

5. LEWIS, T.: Experiments relating to the peripheral

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mechanism involved in spasmodic arrest of thecirculation in the fingers: A variety of Ray-naud's disease. Heart 15: 7, 1929.

6. PRINGLE, R., WALDER, D. N., AND WEAVER,J. P. A.: Blood viscosity and Raynaud's dis-ease. Lancet 1: 1086, 1965.

7. GIFFORD, R. W., JR.: Arteriospastic disorders ofthe extremities. Circulation 27: 970, 1963.

8. RUSHMER, R. F., FRANKLIN, D. L., AND ELLIS,R. M.: Left ventricular dimensions recordedby sonocardiometry. Circulation Research 4:684, 1956.

9. GUNTHROTH, W. G., AND MU-LLINS, G. L.: Liverand spleen as venous reservoirs. Amer J Physi-ol 204: 35, 1963.

10. MULLINS, G. L., AND GUNTHEROTH, W. G.: A

Pulsed Ultrasonic Transit Time Instrument.Proc Sixteenth Ann Conf Eng Med Biol,1963, p. 146.

11. PEACOCK, J. H.: A comparative study of thedigital cutaneous temperatures and hand bloodflows in the normal hand, primary Raynaud'sdisease and primary acrocyanosis. Clin Sci18: 25, 1959.

12. HONDA, N., CARLSON, L. D., AND JUDY, W. V.:Skin temperature and blood flow in the rabbitear. Amer J Physiol 204: 615, 1963.

13. SHEPHERD, J. T.: Physiology of the Circulationin Human Limbs in Health and Disease. Phila-delphia, W. B. Saunders Co., 1963, p. 277.

14. GRoss, C. M.: Gray's Anatomy, ed. 27. Philadel-phia, Lea and Febiger, 1959, p. 709.

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and GAY L. MULLINSWARREN G. GUNTHEROTH, BEVERLY C. MORGAN, JOHN A. HARBINSON

Raynaud's Disease in Children

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1967 American Heart Association, Inc. All rights reserved.

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