The Raynaud syndrome MARTIN BIRNSTINGL Raynaud's disease, since the digital vessels retain their...

Postgraduate Medical Journal (May 1971) 47, 297-310.

The Raynaud syndrome

MARTIN BIRNSTINGLM.S., F.R.C.S.

St Bartholomew's Hospital, London, E.C.1

'Arteritis. Thank heaven I have not to expressany opinion either upon its frequency, or upon theshare which belongs to it in the different arterialchanges, or to the part which it plays in general.'Maurice Raynaud, 1862.

Maurice Raynaud described in his thesis 'Del'Aphyxie Locale et de la Gangrene Symetrique desExtremites' (1862) examples of both episodic digitalasphyxia and frank local gangrene, which justifiesthe broad pathological field covered by the presentarticle.

DefinitionsRaynaud's syndrome. The general syndrome of

arterial insufficiency of the fingers, regardless ofcause, and whether presenting as episodic or con-tinuous ischaemia, digital necrosis or gangrene.

Raynaud's phenomenon. Episodic digital asphyxia,due to arterial insufficiency.

Raynaud's disease. A disorder, seen principally inyoung, healthy women, who show episodic digitalasphyxia due to an exaggerated reaction to cold inotherwise normal digital vessels.

IntroductionRaynaud provides us with an accurate clinical

description of the disease which now bears his name.'Madame X, aged 26 years, has never been ill; butshe has been the subject since childhood of aninfirmity which makes her an object of curiosity toher acquaintances. Under the influence of verymoderate cold, and even at the height of summer,she sees her fingers become exsanguine, completelyinsensible, and of a whiteish yellow colour. Thisphenomenon happens often without reason, lasts avariable time and terminates by a period of verypainful reaction, during which the circulation isre-established little by little and returns to the normalstate. Madame X has no better remedy than shakingher hands hard, or soaking them in lukewarmwater.... This state, which I dare hardly call adisease, is local syncope in its simplest form' (1862).Raynaud clearly recognized the vasospastic nature

of this phenomenon in young, healthy women and

in a later paper (1874) he put forward 'the hypothesisof a contraction of the terminal vascular ramifica-tions, varying from a simple diminution of calibreup to complete narrowing of the lumen of the vessel.To the total closure of the arterial and venousvessels would correspond an exsanguine andcadaveric state of the extremities ... whilst thearterioles only being closed and the venules open,one would see a venous stasis produced by failureof vis a tergo, whence the cyanosis and livid ap.pearance'.

Unfortunately he failed to understand the widelyvarying pathology of the examples he described, orthat necrosis or frank gangrene can only result fromactual structural obliteration of the vessels and itwas left to Jonathan Hutchison (1901) to point outthe many different diseases which are liable to pre-sent with digital ischaemia. Hutchison also advo-cated the term 'Raynaud's phenomenon' to describethe intermittent episodes and showed that thesecould be due either to vasospasm or organic obstruc-tion, although even today this distinction remainsdifficult on clinical grounds alone.

Physiology of digital circulationThe rate of flow through any vascular bed depends

upon the pressure gradient across the bed and theresistance to flow through it. The gradient, in turn,depends upon vessel length, radius and the viscosityof the blood. Variation in any of these five para-meters may change the rate of blood flow; however,the local circulatory effects of digital vascularpathology are largely due to variations in digitalarterial and arteriolar radius. Digital blood flow isnormally concerned with temperature regulationrather than with local metabolic needs, and is remark-able both in the degree to which it is responsive tothe local temperature and in the great variation offlow rates attained, which may change by as muchas two hundred times (Burton, 1939). The mechanismby which local blood flow is varied is mainly in thearterioles and arteriovenous anastomoses, the latterbeing especially numerous in those parts of thefingers and toes-the nail beds and distal phalangealpulps-in which flow rates alter most.Normal control of digital blood flow is complex,

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but appears to be governed by (1) central nervousinfluence acting mainly through sympathetic vaso-constrictor fibres and (2) local responses in thesmooth muscle in the wall of the blood vesselsthemselves.

In true Raynaud's disease, or functional vaso-spasm, there is constriction of both arterioles andvenules, producing the characteristic waxy appear-ance. Occasionally the venules and capillaries maydilate, probably through local anoxic paralysis,producing a bluish tinge. When the spasm passesoff, a stage of reflex vasodilatation is produced dueto local accumulation of dilator substances in thetissues.

In organic obstruction, the block is usually at thelevel of the digital arteries or arterioles. Quite apartfrom the overt reduction in digital blood flow,important passive factors contribute to the resultingischaemia. The fall in transmural pressure in theartery beyond the block allows passive contractionof the elastic vessel wall, further decreasing flow.Moreover, this reduction in vessel radius producesa four-fold decrease in flow, according to Poiseuille'sLaw. Another passive factor is the apparent viscosityof the blood, which increases at low rates of bloodflow. The net result of these various influences is thatflow becomes dependent upon a state of unstableequilibrium, in which the intra-arterial pressuredistal to the obstruction may fall beyond the 'criticalclosing pressure' of the vessel at this level, causingsudden standstill (Roddie and Shepherd, 1957). Thisis particularly likely when vasomotor tone is high,for instance during exposure to cold or when vesselsare compressed by gripping with the hand, andexplains the intermittency of the ischaemic episodes(Raynaud's phenomenon) in the presence of per-manent organic blockage. But since the structuralchanges usually involve the arteries of differentfingers to varying extents, it is uncommon for theischaemia to occur symmetrically.

Effect ofsympathetic denervationThe blood flow in the hand is first increased due to

removal of central vasoconstrictor activity. Peakflows are reached about 2 days after sympathectomy,with increases of the order of five to twelve timesresting flow. This is followed by gradual reductionin blood flow until, after a few weeks, the restingflow is close to the preoperative level (Barcroft,1952). The decline of flow occurs irrespective ofwhether preganglionic or postganglionic section hasbeen performed and is probably due to recovery ofintrinsic tone in the muscle of the vessel wall. Pro-vided sympathectomy is complete, reflex body heat-ing or body cooling has no effect upon flow rates inthe hand. However, after 1 or 2 years a vasoconstric-tor response usually returns to direct cooling of the

hand, which again appears to be a property of thedigital arterioles themselves.

Aetiology of Raynaud's diseaseMaurice Raynaud attributed the local syncope to

an exaggeration of the normal reflex response tocooling, but dominated by Claude Bernard's recentdescription of the sympathetic nervous system hethought that the abnormality was central or, in hisown words, due to 'increased irritability of thecentral parts of the cord presiding over vascularinnervation' (1874). However, the fact that localsyncope is usually unaccompanied by peripheralsweating and the frequency ofrelapse after apparentlycomplete sympathetic denervation are against thisexplanation.

Sir Thomas Lewis (1930) felt that the fault lay inabnormal susceptibility of the digital arteries them-selves to stimulation by local cooling. He showedthat when reflex vasodilation had been producedby warming the body, vasospasm could stillbe produced by putting the hands in coldwater. Conversely, vasospasm could not beproduced by body cooling if the hands werekept warm. Whatever the explanation of Lewis's'local fault', his theory accords with the clinicalpicture and explains the poor results of sympathec-tomy in Raynaud's disease, since the digital vesselsretain their hypersensitivity to local cooling andultimately regain their intrinsic tone. However,Raynaud was probably correct in maintaining thatemotional factors play an additional part in some ofthese patients, since peripheral vasoconstrictoractivity is undoubtedly influenced by the psyche(Fox, 1968).Raynaud postulated that veins as well as arteries

and arterioles share in the constriction, accountingfor the waxy pallor, but direct evidence is lackingon this point. The accompanying numbness of thefingers is presumably caused by temporary ischaemiaof sensory nerves.Peacock (1959) has shown by plethysmography

that blood flow in the hands of patients with Ray-naud's disease is reduced, compared with normalcontrols, even under warm resting conditions. It isdifficult to exclude the presence of secondary organicnarrowing in such subjects. Peacock also found thatthe concentration of catecholamines in venous bloodleaving the hands was higher in Raynaud's diseasethan in controls, particularly during reflex vaso-constriction. He suggested that this was due toincreased production of adrenaline and noradrena-line during vasoconstriction, but unfortunatelyfailed to exclude a more obvious cause for theobserved rise in concentration, namely the reducedblood flow which he recorded. Furthermore, he didnot measure the levels in the arterial inflow to the

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hand. These and other criticisms throw serious doubtupon the validity of Peacock's conclusions andKontos & Wasserman (1969) are categoric that thereis 'no evidence supporting a defect in catecholaminemetabolism in Raynaud's phenomenon'.

Pringle, Walder & Weaver (1965) reported thefinding of increased blood viscosity in twenty-twopatients with Raynaud's disease, compared withhealthy controls. They correlated this with a rise inboth plasma fibrinogen and red cell aggregation, buttheir diagnostic criteria were somewhat loose, makingit impossible to exclude the effect of an underlyingcollagen disorder.The precise cause of the local hypersensitivity of

the minute vessels in functional vasospasm (Ray-naud's disease) remains unknown.

PathologyThe term Raynaud's disease should be reserved

for the type of digital asphyxia seen usually in other-wise healthy young women, and shown by Lewis tobe an exaggerated reaction to cold in structurallynormal vessels. But intermittent asphyxia (Raynaud'sphenomenon) frequently complicates organic vascu-lar obstruction, due to atheroma, thrombosis orembolism, in which the episodes may be identical tothe vasospastic type. However, severe nutritionallesions, such as skin necrosis, atrophy or calcinosisinvariably indicate the presence of organic occlusion,usually in the fingers themselves; such changes arenot seen where vasospasm alone is responsible.Nevertheless difficulty arises in certain collagendisorders, notably systemic scleroderma, which maypresent with cold hypersensitivity several yearsbefore the other manifestations of organic disease.The symmetrical vasospasm of early scleroderma isoften indistinguishable from Raynaud's disease.

Table 1 includes most of the conditions which maypresent with digital ischaemia.

Vasospastic ischaemiaAbnormal reactivity of digital vessels ('localfault').

The hypersensitivity may be hereditary or acquired.In Raynaud's disease the reactivity is hereditary oridiopathic, and in early Raynaud's disease the digitalvessels are structurally normal; although patholo-gical examination is rarely possible, except by skinbiopsy, arteriography is normal (Lynn, Steiner &Van Wyk, 1955). In severe Raynaud's disease, con-centric intimal thickening of digital arteries andarterioles is present to a greater degree than innormal warm-handed subjects of the same age, anddigital artery thrombosis sometimes occurs (Figs. 1and 2). Biopsy of digital skin is normal in earlyRaynaud's disease (Lewis, 1938).Acquired reactivity probably occurs early in

collagen disorders such as systemic scleroderma and

TABLE 1. Classification of digital ischaemia

Vasospastic ischaemia1. Abnormal reactivity ('local fault'):(a) Hereditary or idiopathic (Raynaud's disease)(b) Acquired:

1. Collagen disorder2. Cold injury3. Vibrating tools

2. Endocrine disorders:1. Hypertension2. Phaeochromocytoma

Organic ischaemia1. Arterial disease:

1. Atherosclerosis2. Aortic arch syndrome3. Thrombo-angeitis obliterans4. Embolism

2. Arterial compression:Thoracic outlet compression

3. Collagen disorders:1. Systemic scleroderma. (a) Acrosclerosis;

(b) diffuse scleroderma2. Rheumatoid arthritis3. Disseminated lupus erythematosus4. Dermatomyositis5. Acute nodose polyarteritis

4. Blood disorders:1. Cold agglutinins2. Thrombogenic diathesis

FIG. 1. Raynaud's disease. Arteriogram of woman aged58. Digital arteries are fully patent throughout.

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300 Martin Birnstingl

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FIG. 2. Raynaud's disease. Section of digital artery.Woman aged 40. There is minimal concentric intimalthickening.

rheumatoid arthritis, in the former sometimes yearsbefore the other manifestations. But it now seemslikely that the finding of Raynaud's phenomenon incollagen disorders indicates actual organic narrowingor obstruction of the digital arteries. Abnormalreactivity also develops during the post-hyperaemicstage of cold injury (e.g. frost-bite) and may persistas a late sequel, although it is again difficult todiscount organic intimal thickening in such cases.

Vibrating tool disease is an environmental dis-order seen in workers using pneumatic stone-cutters,metal chisels, hand grinding tools and chain saws(Jepson, 1951; Grounds, 1964). Symptoms usuallyappear within 1 year of starting the work and seemto be due to sensitization of the digital vessels bythe vibration. Unlike idiopathic Raynaud's disease,however, the vasospastic attacks are restricted totwo or three fingers of one hand, being those towhich the trauma is directed. The disorder is notseen in riveters and road-drillers, since high vibra-tion rates appear to be necessary (40-125 cycles/sec).Apart from cold hypersensitivity, which tends toremain after a change of occupation, the digitalvessels show no propensity to permanent narrowingor thrombosis and nutritional lesions do not occur.

Endocrine disorders. Rare causes of digital vaso-spasm are essential hypertension (Pickering, 1968)and phaeochromocytoma.

Organic ischaemiaAtherosclerosis is uncommon in the proximal

limb arteries, but thrombosis in the digital arteries isa frequent cause of ischaemia in middle-aged men.This condition, which Jepson (1951) called 'digitalartery disease', causes segmental occlusion in thearteries, usually in the proximal part of the fingersand also in the palmar and metacarpal arteries(Figs. 3 and 4). The onset may be simultaneous inseveral fingers of one or both hands, especially thering, middle or index, but the thumb is rarelyaffected. When the resulting ischaemia remains mild,the patient begins to complain of Raynaud's pheno-menon in the affected fingers; but the suddenness ofthe occlusion frequently results in severe ischaemia,and painful dry necrosis of part of the digital pulp,close to the nail (Fig. 5). Histological section of theoccluded segments show thrombosis, generally with-out obvious mural disease, and the unaffectedarteries are usually wide in calibre. A collateralcirculation develops in the soft tissues around theblocks, together with narrow recanalized channels

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FIG. 3. Digital artery thrombosis (atherosclerosis).Man aged 54. Segmental blocks in palmar arch andmany digital arteries.

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FIG. 4. Digital artery thrombosis (atherosclerosis). Managed 42. The artery is blocked by organized thrombus,with scanty recanalized channels.

through the thrombosed segments (Birnstingl, 1967).The cause of the disorder probably lies in a transientthrombotic tendency in the constituents of the blood,rather than any local abnormality in the vesselsthemselves. Co-existing coronary artery disease iscommon.

Aortic arch syndrome is a rare condition in whichthe origins of the innominate, subclavian or carotidarteries become obstructed, producing Raynaud'sphenomenon with forearm 'claudication' and some-times blindness. This 'pulseless disease' (Takayasu'ssyndrome) is commoner in middle-aged women andcan result from a variety of pathological processes,including giant-cell arteritis, rheumatoid arthritisand occasionally atherosclerosis.

Thrombo-angeitis obliterans involves the lowerlimbs to a greater extent than the upper, but theradial, ulnar and occasionally the digital arteriesmay be affected. The patient is almost invariably aheavy-smoking male and migratory thrombo-phlebitis is common. Histology shows thrombosis atvarious stages of development, usually with markedfibroblastic and endothelial cell proliferation. Someinfiltration of the wall of the vessel with lymphocytes

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FIG. 5. Digital artery thrombosis. Man aged 56. Thefingers healed after upper thoracic sympathectomy andhave been symptom-free during 13 years.

and polymorphs is usual and recanalization is aprominent feature, but it is doubtful if any histologicfeatures differentiate the disorder from athero-sclerosis. Nevertheless, Buerger's disease presents aclear-cut clinico-pathological syndrome. Since histo-logical material is seldom available, apart fromamputations for gangrene, little is known of theearly structural changes in this disease.

Arterial embolism in the upper limb may occurwith mitral stenosis, toxic goitre, myocardial infarc-tion or bacterial endocarditis. The embolus usuallyimpacts in the axillary artery or brachial bifurca-tion. Gradual recovery over 1-3 days is the usualsequel as the collateral circulation opens up, but thedegree of ischaemia is influenced by previous sub-clinical embolism and by the cardiac status at thetime of the incident.

Ischaemia of the hand due to embolism oftenarises in relation to fusiform aneurysm of the sub-clavian artery, associated with a cervical rib. Theaneurysm is a post-stenotic dilatation immediatelylateral to the constriction produced by the rib, andplatelet thrombi on the interior of the sac providethe source of the emboli (Figs. 6 and 7). Thrombosisof such an aneurysm occasionally causes seriousischaemia, because of previous embolic obstructionin the distal vessels (Wickham & Martin, 1962;Eastcott, 1962).

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FIG. 6(a). Cervical rib with post-stenotic dilatation ofsubclavian artery containing mural thrombus.

FIG. 6(b). More distal view of same arteriogram show-ing site of impaction of embolus in brachial artery.

Arterial compression. Thoracic outlet compressionof the subclavian artery may be due to the following:cervical rib; rudimentary first thoracic rib; costo-clavicular compression; scalenus anterior muscle;and pectoralis minor during hyperabduction of thearm. Pressure by a cervical rib or its bony anteriorend is the commonest of these; the rest are certainlyrare, although all can produce a post-stenoticdilatation of the artery, with liability to thrombo-

embolic complications particularly during a throm-botic phase due to changes in the constituents of theblood. In milder cases, the compression can produceRaynaud's phenomenon or forearm 'claudication'.These vascular symptoms rarely arise on both sidesand it is unusual for neurological and vascular com-pression to co-exist in the same patient, sincewhenever a rib is long enough to displace the artery,the brachial plexus is usually prefixed and out of theway (Ross, 1959).

It is important to remember that only about 10%of patients with a cervical rib develop vascularsymptoms and that Raynaud's dis-ase, its.lf com-mon, may occur in a patient who happens to possessa symptomless rib abnormality (Rob & Standeven,1958).

Carpal tunnel syndrome. Compression of themedian nerve under the flexor retinaculum is acommon cause of pain in the lateral part of the handand forearm. Paraesthesiae in the thumb and indexfinger and exacerbation of the pain in the early hoursof the morning are characteristic features. A few ofthese patients develop Raynaud's phenomenon inthe affected hand, usually because of a collagendisorder underlying both conditions (Linscheid,Peterson & Juergens, 1967).

Collagen disordersBoth Sokoloff, Willens & Bunim (1951) and

Bywaters (1949) have clearly described the changeswhich occur in blood vessels in rheumatoid arthritis.Involvement of small arteries, particularly the digitalarteries, is now known to be frequent in this diseaseand closely associated with nodules and serologicalchanges. Widespread vascular changes also accom-pany systemic scleroderma, in addition to the betterknown hyperplasia of collagen fibres in skin andviscera and the inflammatory changes. The Ray-naud's phenomenon seen in the collagen disordersis the result of these lesions, rather than the moretheoretical arteriospastic hypersensitivity which hasbeen invoked in the past.The vascular lesions accompanying the collagen

disorders are significant both from their associatedsymptoms and because they provide clues to theimmunological pathogenesis of these diseases(Rodnan, 1963). There is evidence that duringanaphylaxis, antigen-antibody precipitation takesplace within the bood vessels. It seems likely that thelocalization of the consequent intimal thickening orthrombosis to the digital arteries is due to theirparticular contractility, rather than to other factorssuch as their liability to trauma, the proximity ofjoint lesions, or compression by surrounding con-nective tissue changes.

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The principal pathological features of some in-dividual collagen disorders are as follows:

Systemic scleroderma (progressive systemic sclerosis)A disorder of connective tissue with characteristic

changes in the skin (scleroderma), synovium andcertain viscera. Tuffanelli & Winkelmann (1961)have subdivided the disease into two types: (1)acrosclerosis and (2) diffuse scleroderma, but theboundary is indistinct. Visceral changes occur inboth types, which probably represent the extremesof a wide spectrum of clinical behaviour.The classical skin changes are inelasticity, oedema,

patchy pigmentation or depigmentation, accom-panied by dermal atrophy and marked collagenosis.The initially oedematous skin later becomes smooth,waxy and bound down to the underlying structuresand the face becomes drawn, pinched and expression-less, with narrowing of the mouth.An increase in collagen content is also seen in the

synovia and in the viscera, producing atony andlack of peristalsis in the oesophagus and ureter,whilst blood vessels in the heart, lung and kidneyshow intimal hyperplasia and focal infarcts. Theafferent arterioles and glomerular tufts of thekidney may show fibrinoid necrosis.

Acrosclerosis and the 'CRST syndrome'. Acro-sclerosis is the commonest form of systemicscleroderma. It is usually seen in women and ischaracterized by Raynaud's phenomenon andsclerosis of the fingers. Raynaud described a com-mon late appearance: 'On the pulp of all the digits agreat number of small, white, depressed, very hardcicatrices is seen, which are, so to speak, the stigmataleft after the malady'. He goes on to describe 'theformation of veritable sloughs, especially on thelittle finger. But that which strikes one most is theslender form which the ends of the digits take, thehardness of their tissue, and their shrivelled aspect'(1862). The changes may later involve the forearms,face, upper part of the trunk and the feet. Pigmenta-tion, telangiectases, ulceration, and subcutaneouscalcification (hyperdermolithiasis) may occur (Fig.7). Gastrointestinal and other visceral involvementis common and the course is very chronic. Theassociation of calcinosis and scleroderma wasrecognized by Thibierge & Weissenbach in 1911; itis a late sequel.

In a study of 727 patients with systemic sclero-derma, Tufanelli & Winkelmann (1961), found thatmore than 90Y. showed 'vasospastic changes' in theextremities; Raynaud's phenomenon heralded theonset of the disease in 48%, often preceding theonset of the other changes by many years.

Johnston, Summerly & Birnstingl (1965) investi-gated seventy-five patients after sympathectomy for

FIG. 7. Acrosclerosis. Subcutaneous digital calcificationin woman aged 52 with facial scleroderma and telan-giectases.

what was originally thought to be functional vaso-spasm (Raynaud's disease). Prolonged follow-uprevealed that 19% had developed clinical evidenceof systemic scleroderma.

Winterbauer (1964), whilst still a medical student,gave an excellent account of the telangiectasia whichmay accompany acrosclerosis, and which may be soobvious as to mimic the hereditary haemorrhagiccondition. Winterbauer proposed the term 'CRSTsyndrome', to include the calcification, Raynaud'sphenomenon, sclerodactyly and telangiectasia. Heemphasized the benign prognosis of this variant.

Diffuse scleroderma is characterized by generalizedcutaneous sclerosis, beginning on the face, neck andupper trunk and usually sparing the extremities.Visceral involvement is often severe, but the changesare similar to those found in acrosclerosis, and theprognosis is poor, some patients dying within 1 year.Nevertheless, the 10-year survival in the 727 patientsstudied by Tuffanelli & Winkelmann was 59%/,although they failed to separate the much commoner,benign acrosclerosis cases from those with the so-called diffuse disorder.

Disseminated lupus erythematosus is also com-monest in women and characterized by widespread

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necrosis of small arteries and arterioles. About 50%4of those affected die within 3 years of onset of thesymptoms. Of 520 patients reviewed by Tufanelli &Dubois (1964), 18%Y presented Raynaud's pheno-menon, but it rarely preceded the other manifesta-tions. Digital necrosis or gangrene may occur (Fig. 8)

FIG. 8. Disseminated lupuslesions in woman aged 33.

erythematosis. Digital

but involve the toes more often than the fingers.Polyarthritis, leucopenia, raised gamma globulinand a positive LE cell phenomenon are pathogno-monic. Renal biopsy, when obtainable, shows 'wireloop' lesions in the glomeruli. The fibrinoid changein the renal arterioles has been shown to have apreferential concentration ofgamma globulin, ratherthan the fibrinogen found in systemic sclerosis andhypertension (Vazquez & Dixon, 1958).

Dermatomyositis. A rare condition of childrenand young adults. Raynaud's phenomenon iscommon, accompanied by fever, dermatitis and amyopathy.

Acute nodose polyarteritis (periarteritis). Thispresents only rarely with digital ischaemia, but hasprotean manifestations. The lesion is a widespread,focal inflammatory infiltration involving all thecoats of small muscular arteries and arterioles, lead-ing to thrombosis or aneurysm formation (micro-aneurysms). It is a type of diffuse hypersensitivityangiitis.

Rheumatoid arthritis. The vascular lesions ofrheumatoid arthritis have been documented by

Bywaters & Scott (1963). They present clinically asskin nodules and Raynaud's phenomenon and canbe demonstrated by brachial arteriography (Laws,Lillie & Scott, 1963). There is a close correlationwith a positive differential agglutinating titre (DAT)and with the finding of skin nodules. The term'rheumatoid arteritis' has been applied, but thevascular changes are the result of the basic im-munological disturbance.The vasculitis seems to have no bearing upon

prognosis, apart from the rare occurrence of digitalgangrene (Bywaters, 1957).There is a slight but inconstant tendency for the

digital arterial lesions to occur in relation to pha-langeal joint lesions.

Blood disordersRaynaud's phenomenon or even gangrene may

accompany high titres of cold agglutinins in theserum and appears to be due to temporary pluggingof minute vessels by masses of agglutinated red cells(Nelson & Marshall, 1953; Olesen, 1967). At tem-peratures between 34 and 240C the cold agglutininsadsorb onto the red cells, producing a reversibleagglutination, but subsequent haemolysis of theagglutinated cells may lead to paroxysmal coldhaemoglobinuria and haemolytic anaemia.Another rare cause of digital ischaemia is the

presence ofcryoglobulins in the blood, which undergocold precipitation within the vessels. The abnormalglobulin is usually secondary to a malignant reticu-losis, but an idiopathic type has been described(Ritmann & Levin, 1961).The rarity of these conditions does not justify

routine screening for cold agglutinins and cryo-globulins in patients presenting with Raynaud'sphenomenon unless haemoglobinuria, purpura,anaemia, lymphadenopathy or other bizarre featuresare discovered.

Digital necrosis may occur in the presence ofpreviously unrecognized malignant disease, thediscovery of which it may precede by months or evenyears (Hawley, Johnston & Rankin, 1967). It is theresult of digital artery thrombosis, presumably dueto transient thrombogenic changes in blood plateletsor clotting factors. Similar digital thrombosis, with-out co-existent malignant disease, occur in middle-aged men, described above under the heading'organic ischaemia' But its precise causation is un-clear and if the evidence is accepted that the commonwhite plaque of atherosclerosis arises by organizationof a thrombus, changes in the constituents of theblood seem likely (Rokitansky, 1852; Duguid, 1949;Haust, More & Movat, 1959). I have recently seenfour young women with digital artery thrombosisand local gangrene as a complication of oral con-traceptives, and further reports can be anticipated.

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Clinical diagnosisPresenting symptoms. Raynaud's phenomenon,

whether due to vasospasm or organic change, isbrought on by cooling of the hands or occasionallyby emotion. There is numbness and tingling of thefingers, which become waxy white or slightlycyanosed. As the episode passes off, often acceleratedby rubbing or shaking the fingers, they become morecyanosed and later suffused and this stage may bepainful. Raynaud's disease is about ten timescommoner in women and strikingly symmetrical,the thumbs being spared. Where the phenomenon issecondary to organic disease, the distribution variesamongst the fingers, although in digital thrombosisit is not uncommon for the same one or two fingerson both hands to be involved. When there is blockageof a proximal artery, as in subclavian compression,all the fingers of one hand may develop intermittentischaemia.The diagnosis of Raynaud's disease usually

presents no difficulty, but systemic scleroderma maystart with the same symmetrical distribution. Ray-naud's phenomenon in childhood is occasionallya manifestation of acute rheumatism due to hyper-sensitivity to the j-haemolytic Streptococcus.

Trophic lesions. The presence of terminal ulcera-tion or patches of dry pulp necrosis on the fingersindicates severe local ischaemia and is evidence thatthere is structural obliteration of the feeding arteries.In Raynaud's disease, where the condition is one ofuncomplicated vasospasm, ischaemic digital necrosisdoes not occur, although these patients are oftensusceptible to pyogenic or monilial paronychialinfections. The commonest cause of local digitalnecrosis in men is digital artery thrombosis, whilst inwomen it suggests a collagen disorder. More severenecrosis amounting to gangrene is also seen inthrombo-angeitis obliterans, ergot poisoning, dis-seminated lupus erythematosis and thrombo-embolic complications of cervical rib. Gangrene inchildhood raises a wide differential diagnosis(Lowenthal, 1967).Atrophy of the terminal digital pulp, producing a

'sharpened' effect, and trophic changes in the nailsindicate long-standing ischaemia, often seen insystemic scleroderma. In this disease, absorption ofalmost the entire distal phalanges may occur, sothat the deformed, claw-like nails come to overhangthe stunted pulps of the fingers. Other featuressuggesting scleroderma are subcutaneous calcifica-tion in the pulp and telangiectases on the face andlips. Loss of pulp may also accompany athero-sclerotic digital thrombosis, following separation ofthe necrotic eschars.

HistoryIn Raynaud's disease the patient is usually a

young woman complaining of coldness of the fingersfor as long as she can remember, with a worseningbetween 18 and 25. Later onset suggests the presenceof collagen disease, and although some menopausalwomen develop a functional vasospastic disorder,symptoms arising for the first time at this age aremore in favour of organic disease. A few patientspresenting Raynaud's phenomenon in the earlytwenties, develop stigmata of collagen disorder afew years later. There seems no infallible way ofpredicting this outcome.Sudden onset of severe ischaemia in a few fingers

of a middle-aged manual worker is a common pre-sentation of atherosclerotic digital thrombosis. Theusual combination is asymmetrical Raynaud'sphenomenon with painful necrosis of the terminalpulps. A similar event in a young woman suggestslupus erythematosis, idiosyncracy to contraceptivepills or very occasionally ergotism. A history ofmigratory thrombo-phlebitis suggests thrombo-angeitis obliterans, particularly if the patient is aheavy-smoking male. Careful questioning is necessaryfor any associated symptoms, since a history ofjointswelling may indicate rheumatoid disease or dis-seminated lupus, whilst dysphagia and other intes-tinal symptoms are typical of systemic scleroderma.The patient's occupation will be important invibrating tool disease.

ExaminationA careful look at the patient's face may help to

exclude established systemic scleroderma, in whichthe appearance is unmistakable, with a small, tightmouth and inelastic, slightly oedematous skin on theface and neck. Polygonal telangiectases on the lipsand buccal mucosa may also be present. The handsmust be examined for similar telangiectases and forthe presence of trophic lesions. Skin colour is noted,and the hands are elevated above the patient's headto observe whether postural colour change occurs:in the ischaemic hand associated with subclavianarterial obstruction, marked pallor is produced.The arterial pulses are next compared. Congenital

absence of the ulnar pulse is relatively common, sothat tests to demonstrate the patency of this vesselare of doubtful significance. In the aortic archsyndrome and after embolism, the axillary, brachialor radial pulses are often lost. The supraclavicularregion should be examined for aneurysm or a palp-able cervical rib; the effect of bracing back theshoulders and of hyperabduction of the arms shouldalso be noted. These manoeuvres sometimes obliter-ate the pulses of normal subjects and do not neces-sarily indicate the source of the symptoms. Thediagnosis of embolism requires the identification of

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a source, such as atrial fibrillation, myocardialinfarction or cervical rib; proximal atheroscleroticplaques or aneurysms are occasionally responsible.

Finally, auscultation with a stethoscope over thesubclavian artery above or below the clavicle mayreveal a murmur, indicating turbulent flow producedby stenosis or compression. When thoracic outletcompression is suspected, this test should be triedwith the shoulders in various positions. Differencesin blood pressure in the two arms are an occasionalindication of main vessel obstruction.

Reactive hyperaemia, after occlusion ofthe circula-tion for 3-5 min with a cuff, gives useful clinicalevidence of maximal blood flow in the variousfingers. This reflex is independent of nervous con-nexions with the central and sympathetic systems,being due to local chemical and physical changes.

RadiologyCervical rib is easily recognized in the chest X-ray,

but subclavian compression occasionally occurswithout bony abnormality (costo-clavicular com-pression and scalenus anterior syndrome).

Plain X-rays of the hands may help to excluderheumatoid arthritis. Calcification in the pulp com-partments of the fingers (hypodermolithiasis) ispathognomonic of systemic scleroderma, most oftenseen in acrosclerosis and the CRST syndrome, inwhich radiological changes in the viscera may beminimal.Barium studies reveal characteristic changes in

established diffuse scleroderma, due to interferencewith smooth muscle contractility. During examina-tion of the oesophagus in the supine position, thereis absence of peristalsis and pouch-like dilatation isseen. Radiological changes may precede the develop-ment of dysphagia and the barium swallow is prob-ably the most convenient way to demonstratechanges, but there are similar abnormalities in thesmall intestine, colon and upper urinary tract.Tuffanelli & Winkelmann (1961) found oesophagealchanges in 67%Y of481 patients studied radiologically.

Arteriography can give valuable information, buthas the obvious limitation that the demonstration ofa blocked artery does not indicate what caused it.The most useful techniques are brachial arterio-graphy, for the demonstration of the digital andhand vessels and retrograde arch aortography, toshow the origin of the trunks to the head and neckand demonstrate the subclavian arteries. Directpuncture of the subclavian or axillary are occasion-ally useful.

Raynaud's disease. The digital arteries are patentand appear normal on arteriography. Anatomicalabnormalities are common in the hand and may lead

to misinterpretation. Examples include absence ofthe ulnar artery, the palmar arches and the lateraldigital artery of the index.

Thoracic outlet compression. In patients withthrombo-embolism associated with cervical rib, thesite of impaction of emboli is readily demonstrated(Fig. 6). These are usually multiple. A subclaviananeurysm can sometimes be shown.

Arterial thrombosis. Arteriography reveals theextent and distribution of the blockage accurately,but it does not indicate its aetiology. Identicalarteriographic pictures may be obtained in athero-sclerosis, thrombo-angeitis obliterans and the colla-gen disorders, and rarely as a complication of long-standing Raynaud's disease. In digital arterythrombosis, whatever the cause, segmental blocks areusually multiple, lying opposite the proximalphalanges. A tuft of minute collateral vessels isvisible in good quality films, but occlusion shouldnot be diagnosed unless opaque medium is szen inthe arteries distal to the block and in the digital pulp.The arteriogram may give an indication of the extentof the digital collateral circulation.

Collagen disorders. Arteriography is of little usein the early diagnosis of collagen disorders, althoughpatients with systemic scleroderma may show apeculiar susceptibility to vasospasm, the vesselscontracting down to fine threads during the investiga-tion. The digital thrombosis, seen in both systemicscleroderma and rheumatoid arthritis, has nospecific arteriographic features, although the blocksare often sited in relation to the peri-articularswellings. Occlusions also occur in patients withnodose polyarteritis, said to be accompanied by anirregular network of abnormal collaterals in thehand (Laws et al., 1963).

Laboratory testsHaemoglobin, white cell and platelet counts,

blood smear examination and erythrocyte sedimenta-tion rate should always be obtained. A moderateelevation of ESR is common in collagen disorders,whilst very rapid sedimentation may indicate thepresence of haemagglutination. Screening tests forcold agglutination and the presence of cryoglobulinsare occasionally needed. When digital arterythrombosis or digital gangrene is present, smearsshould be examined for the LE cell phenomenon,bearing in mind that a negative result does notexclude disseminated LE and that the test may needto be repeated. Examination for differential sheepcell agglutinins (DAT) and a latex test should bedone where collagen disorder is suspected. Anti-

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streptolysin-0 titre should be estimated when acuterheumatism is a possibility and when Raynaud'sphenomenon is encountered in infancy. Serologicaltests for syphilis are occasionally needed.

TreatmentRaynaud's disease

Results ofsympathectomy in functional vasospasmof the upper limbs are disappointing, mainly due tothe high local reactivity of the hand blood vesselsand the eally return of autonomous vascular tone.Relapse after sympathectomy is liable at any timeduring the first 5 years after operation (Felder et al.,1949; Jepson, 1951; Johnston et al., 1965). By theend of 5 years only about two-thirds of patientsoperated for Raynaud's disease are left with im-provement in their symptoms. The remaining one-third are found to have reverted to their originalstate, with the added disadvantage that their handsare uncomfortably dry as the result of sudomotordenervation. The main causes of relapse are asfollows:

Persistence ofthe 'localfault'. Although sympathec-tomy causes an initial twelve-fold increase in handblood flows in patients with Raynaud's disease, thevasodilation almost disappears in the weeks follow-ing operation. Cold hypersensitivity can be demon-strated within a few days of operation (Lewis, 1938;Hyndman & Wolkin, 1942). As Lewis maintained,the response to local cooling predominates in Ray-naud's disease over the neurogenic vasoconstrictorpathway. This hypersensitivity persists after sym-pathectomy, although partly offset by abolition ofreflex vasoconstriction, which keeps the fingerswarmer and consequently helps to prevent the coldstimulus.

Re-innervation of sympathetic effectors. Thisaccounts for a few relapses which may be (1) early,due to incomplete sympathetic denervation, or (2)late, due to the development of alternative anatomicalpathways-particularly along the vertebral bodies(Boyd, 1957)-or to collateral axonal sprouting(Murray & Thompson, 1957). Re-innervation isdiagnosed when reflex heating can be shown toproduce an increase in finger blood flow or evidenceof sweating in the hand.

Incorrect initial diagnosis. A few patients sym-pathectomized for what appears to be Raynaud'sdisease later develop florid systemic scleroderma,and the 'relapse' is then due to progression of thecollagen disorder. This occurred in 19%. of a groupof seventy-five patients with Raynaud's disease(Johnston et al., 1965). There appears to be no

certain way of diagnosing systemic scleroderma inits early stages.

Medical treatment of functional vasospasm isequally unsatisfactory because cold vasoconstrictionoverrides the vasodilator influence of the drugs.The best cure is to avoid local cooling or seek awarmer climate. However, several lines of empiricaltreatment may be tried.

Reassurance is important. As Raynaud remarked'this strange disease, so striking in appearance, is farfrom having the seriousness to which one is at firstglance led'. Nevertheless, the clinician may have toeat his words several years later, since about 20%4of these patients develop overt evidence of collagendisorder.

General metabolic stimulation. Thyroxine must begiven when there is evidence of hypothyroidism, butsometimes benefits euthyroid patients. There seemsno sound reason for giving tri-iodothyronine insteadof thyroxine.

Adrenergic blockage. Reserpine 0-25 mg twicedaily acts partly by depressing the vasoconstrictoroutflow centrally and partly by generalized depletionof catecholamine, both in the wall of blood vesselsand elsewhere in the body (Kontos & Wasserman,1969). It may be combined with thyroxine. Guane-thidine 10-50 mg each morning has a postganglionicblocking effect as well as depleting catechol amines.

Other vasodilator drugs. In general these are oflittle value in Raynaud's disease but phenoxybenz-amine (alpha-adrenergic blocker) 10-20 mg threetimes daily, nicotinyl alcohol (smooth musclerelaxant) 25-50 mg three times daily or thymoxaminehydrochloride (alpha-adrenergic blocker) 40 mgthree times daily and tolazoline hydrochloride(alpha-adrenergic blocker and vascular smoothmuscle relaxant) 25-50 mg three times daily havetheir advocates.

Organic ischaemiaPreliminary sympathetic nerve block is valueless

in predicting the outcome ofsurgical sympathectomy,because results depend as much upon growth ofcollateral vessels as on any immediate vasodilatationin the skin. Furthermore, the test cannot indicatethe likelihood of later relapse, dependent on recoveryof intrinsic vascular tone and progression of theoriginal disease. Selection for sympathectomy musttherefore be made on clinical grounds alone.Table 2 shows the final diagnosis and result of

sympathectomy in a series of forty-three patientswith organic digital artery disease. The criteria forinclusion in this series were severe ischaemia (necrosis

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TABLE 2. Results of sympathectomy in organic digital ischaemia(forty-three patients; follow-up 2-25 years)

Males Females

No. of No. improved No. of No. improvedFinal diagnosis cases after sympathectomy cases after sympathectomy

Atherosclerosis 19 16 (84%) 4 1Systemic scleroderma 3 1 3 1Acrosclerosis - - 12 5Other - - 2 -

Total 22 17 (77%) 21 7 (33%)

or gangrene) or arteriographic evidence of digitalartery occlusion (Birnstingl, 1967).

It can be seen that the late results are largelydependent upon the underlying pathology. Thus innineteen men with atherosclerosis (thrombosis ofdigital arteries) sixteen improved although most hadnecrosis prior to the operation. Digital arterythrombosis seldom progresses, once the patient hasrecovered from the initial episode. On the other handfifteen of twenty-one women had a collagen dis-order, reflected in an overall improvement rate of33%4. Nevertheless the operation seemed justifiablein women when they had active pulp ulceration,since five out of nine showed no further nutritionallesions, although ischaemic symptoms continued.Methods of treatment which have been insuffic-

iently tried are the use oflow-molecular weight dextran(10%Y Rheomacrodex) by Holti (1965) and ofhyperbaric oxygen (Copeman, Ashfield & Dowling,1967). In patients with systemic scleroderma, im-provement has been claimed for several weeks aftertreatment by either method.

Technique of upper thoracic sympathectomy. Theoperation can be performed by any one of threealternative routes: (1) anterior supraclavicular, (2)posterior and (3) axillary transthoracic (Atkins,1954). Resection of the second and third thoracicganglia provides a sympathectomized hand withouta Homer's syndrome. There is no clinical differencebetween preganglionic sympathectomy and (post-ganglionic) ganglionectomy and Baddeley (1965)found no improvement in results after an extendedintrathoracic procedure.

Operation for thoracic outlet compression. Wherethere is evidence of compression of the subclavianartery, and particularly when this is complicated byaneurysm or embolism, operation should be under-taken. Through a supraclavicular approach, thescalenus anterior is divided, and this step may allowthe artery to bulge forward sufficiently to relievethe symptoms. Where a cervical rib is found. it isusually preferable to remove most of this togetherwith its periosteum using rongeurs. The rib must

be resected back as far as the costo-transverse joint,taking great care to avoid injury to the first thoracicroot of the brachial plexus. The rib having beenremoved, a sympathectomy can be done if ischaemicsymptoms are severe enough. Where a substantialaneurysm is present, it should be replaced orrepaired with Dacron fabric or cephalic vein. Distalembolism requires the use of a Fogarty embolectomycatheter.A few authors have advised resection of the first

rib for the relief of thoracic outlet compression,amongst them Roos (1966) who advocates a trans-axillary approach. However, in the absence of clearevidence of aneurysm or thrombo-embolism, it isdoubtful if these patients need operation.

Conclusions1. In Raynaud's syndrome, whether presenting as

episodic ischaemia or frank finger-pulp necrosis, it isessential to separate patients with organic digitalartery disease from those with vasospasm. This hasbeen greatly helped by brachial arteriography.

2. Severe nutritional lesions invariably indicateorganic occlusion, which is also likely when ischaemicsymptoms show an asymmetrical distribution andwhen there is evidence of arterial disease in otherparts of the body.

3. The prevalence of organic vascular lesions inall forms of collagen disorder and their demonstra-tion, in particular, in systemic scleroderma andrheumatoid arthritis is closely related to their im-munological character. It is necessary constantly tobe aware of these disorders masquerading in variousguises, from mild Raynaud's phenomenon to actualdigital gangrene.

4. The natural reactivity and autonomous tone ofthe digital vessels makes it difficult to secure per-manent vasodilatation and largely explains the poorresults of both sympathectomy and vasodilatortherapy in Raynaud's phenomenon, whatever itscause. But the initial effect of sympathetic denerva-tion may be sufficient to secure healing of nutritionallesions. The operation should therefore only beadvised when these are present.

5. The results of treatment in digital ischaemia

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depend largely upon the underlying pathology andemphasize the importance of accurate diagnosis.

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