sarcoidosis - pmj.bmj.com · sarcoidosis lesions, ocular manifestations and alterations in the...

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SARCOIDOSISBy IAN MILLS HALL, M.D., M.R.C.P.

Assistant Physician,. German Hospital; Temporary Assistant Physician, London Chest Hospital.

In 1875 Jonathan Hutchinson made thefollowing description of a case of cutaneoussarcoid:-

' On the front of his legs, some of his fingersand on one forearm, were a number of patchesconsisting in the first instance of distincttubercles, which afterwards became confluentand then lost their tuberculous character.The patches were peculiar chiefly on accountof their dark purple colour; this tint seemedto depend partly upon venous congestion andpartly upon deposit of colouring matter in thetissues, for although their margins could bemade pale by pressure, no amount of squeezingaltered the colour of the central parts. Thepatches were irregular in size and shape, dis-tinctly raised above the general surface, theirmargin for the most part irregular and abuptlydefined, and their surface smooth and almostglossy, or sometimes covered with thin dryepidermic scales. Their elevation above thesurrounding skin was due in great part tooedema, for they could be made to pit bycontinued pressure and, in fact, could besqueezed until all thickening disappeared.They were neither tender nor painful. Theskin around them was slightly oedematous.'

This is probably one of the earliest recordsof the disease and Besnier (I889) referred tothis description of Hutchinson's and identifiedthe lesion as those of lupus pernio, whenwriting his own original article describing thiscondition.

In 1899 Boeck described the cutaneouslesions and microscopical structure of a dis-tinctive skin affection to which he applied theterm ' Sarcoids of the skin' thinking them tobe due to an infiltration of the skin by aleukaemoid tissue.

For many years Boeck's 'benign sarcoids''were regarded as purely a dermatologicalcondition. In 1914, J. Schaumann demon-strated that Boeck's sarcoid and lupus perniowere histologically the same disease. Later hedemonstrated that there were associated vis-ceral lesions showing the same histologicalpicture and developed the theory that thecutaneous lesions were but one manifestationof a generalized systemic affection.

Since this time, this disease entity hasreceived a much wider recognition and muchhas been added to our knowledge of the subjectby the many case reports which have beenpublished. Many and varied are the dis-tributions of the lesions, and it is now realizedthat there is no organ of the body which maynot become involved, and that it no longer canbe regarded as a comparative rarity only to beencountered at dermatological clinics.

PathologyThe histology of the sarcoid lesion forms a

well-recognized microscopical picture. Itconsists of a collection of pale stainingepithelioid cells among which giant cells of theIangham's type are frequently to be seen.Lymphocytes in small number are present atthe periphery. The diagnostic features whichdifferentiate this from other similar tissue re-actions are as follows :-(I) The absence ofany tendency to caseation, this feature beingresponsible for the term 'hard tubercle.' (2)The absence of tissue reaction around thetubercle. (3) A tendency to hyalinization inthe older nodules. (4) The absence of acid-fast bacilli in the lesion. This distinguishesthe microscopical picture from the hyper-plastic form of tuberculosis. The typical

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POST-GRADUATE MEDICAL JOURNAL

appearances of the histology of sarcoidosis iswell illustrated in Figures i and 2.The post-mortem appearances will depend

largely.upon the clinical form which the diseasehas taken. The cutaneous lesions are notobvious on superficial examination althoughsome pigmentation of the skin may remainafter death. Enlargement of the parotid, sub-maxillary, sublingual and lachrymal glands isa prominent feature in some cases. Superficiallymph nodes are frequently affected althoughthe enlargement may be insignificant. Nodulesof sarcoid tissue are occasionally to be foundin the mucous membrane of the mouth, throatand nose. The tonsils are very frequently in-volved and tonsillar biopsy forms a usefulmeans of diagnosis where there is no obviouslymph node enlargement. This has theadvantage of being safer than the practice ofliver puncture which has been advocated.

In the thorax the most striking changes willusually be found in the hilar glands whichbecome considerably enlarged and which bybronchial compression may cause atelectasis ofone or more segments of the lung. If thelungs are involved they usually present a finelystriated appearance due to the involvement ofthe perilobular lymphatics and the presence ofa fine reticular fibrosis. Nodules are oc-casionally found involving the myocardiumand pericardium.

Splenic enlargement commonly occurs andsome degree of hepatomegaly is usuallypresent. Enlargement of the mesentericlymph nodes can be seen and cases have beendescribed where involvement of the intestineitself has occurred. Gore and McCarthy(x944) report a case in which the stomachshowed typical changes and it has been knownto produce an appearance closely resemblingCrohn's disease in the terminal ileum, Watson,Wagenstein et al. (I945), A. Morland (I946).

In the central nervous system the mostfrequent regions to be involved are thepituitary gland and the interpeduncular fossa.

Evidence of inflammation of the uveal tractmay be seen in the presence of keratic pre-cipitates in the anterior chamber of the eyeand thickening of the ciliary body.The bone marrow is infrequently involved

but where this does occur there may be somemalformation of the phalanges of the fingers

and toes. In such cases section of the boneswill show cyst-like areas which on microscopyprove to be filled with typical granulomatoustissue. Because of this involvement of themarrow, sternal puncture may establish thediagnosis during life. As will be seen fromthe foregoing, sarcoidosis is a generalizedsystemic condition in which the lymphoidtissue is predominantly involved and it istrue to say that there is no organ of the bodywhich may not show macroscopical or micro-scopical evidence of the disease.

Clinical FeaturesClinically sarcoidosis pursues a prolonged

and benign course. The disease commencesas a rule in young adult life, most casesdeveloping symptoms before the age of 35. Ina series of 200 cases collected by Kissmeyer(I93 ) half the cases developed under 30 yearsof age.The disease is usually monosymptomatic at

its commencement, but with the passage oftime manifestations of its more widespreadnature tend to develop. Some cases, however,remain monosymptomatic throughout theircourse. Fever and general constitutional dis-turbances are not common features of Boeck'ssarcoid, most patients being afebrile and onlyoccasionally a temperature recording as highas oo00 F. is encountered.Although carrying a low mortality rate,

death may ensue. This most frequentlyresults from cardiac failure secondary to thewidespread fibrosis which may occur in thelungs. Direct involvement of the heart itselfmay give rise to a similar termination.

Involvement of the central nervous systemmay also give rise to a fatal termination. Acase reported by Reis and Rothfeld (i93i)showed involvement of the brain and deathresulted from a series of epileptiform attacks.Death can occur from the development of

active tuberculosis, an interesting feature inview of the similarity of the histology and thetheories connecting the aetiology of Boeck'ssarcoid with the tubercle bacillus. Schaumannholds the view that this is often a cause ofdeath.The most frequent clinical findings are en-

countered within the thorax, next peripherallymph node involvement, followed by skin

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May 1947 SARCOIDOSIS 235

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High power of previous section showing epithelioid cells and giant cell.c)

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236 POST-GRADUATE MEDICAL JOURNAL May i947

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May 1947 SARCOIDOSIS 237

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SARCOIDOSIS

lesions, ocular manifestations and alterationsin the bones. Other organs are less frequentlyinvolved.

Thoracic ManifestationsPulmonary lesions are among the most

common to be encountered in this disease, andLongcope records 29 out of his 31 cases havingshown radiological evidence of pulmonary sar-coidosis. Symptoms only occur in a relativelysmall proportion of cases, and the diagnosiswill depend upon routine radiological examina-tion whenever there are other signs suggestinga diagnosis of Boeck's sarcoid.The radiological appearances fall into five

groups :

I. Bilateral hilar glandular enlargement,without parenchymal opacities.

2. Hilar gland enlargement with strand-likeprocesses radiating from the increased rootshadows.

3. Miliary type.4. Nodular infiltration.5. Diffuse and confluent infiltration.Figures 3-6 illustrate some characteristic

examples.The radiological appearances are in no way

pathognomonic of the disease and have to bedifferentiated on clinical grounds from suchconditions as erythema nodosum, rheumaticpneumonitis, eosinophilic infiltrations, otherforms of lymphadenopathy and the pneumo-conioses (Berstein and Sussman (1945)). Themiliary type closely resembles tuberculosis andit is possible that some reported instances of'healed miliary tuberculosis' of the lungswere, in fact, cases of pulmonary sarcoidosis.Dyspnoea is the commonest symptom en-

countered in the pulmonary form of thedisease. This is often slight, but Isbister(945) .records a case in which bilateralspontaneous pneumothorax occurred, andSnapper (1938) states that in one of his casesenlargement of hilar glands gave rise to ex-tensive atelectasis. One case observed by thewriter presented itself as a case of left sidedchest pain.

Despite the very evident radiological ap-pearances physical signs are negligible exceptin such uncommon cases as mentioned above.

The prognosis in these cases is good. King(1945) reports a clearing of the lesions in 60per cent. of cases within a period of threeyears. Death, when it does occur, may resultfrom right heart failure due to extensive pul-monary fibrosis, or as the result of the develop-ment of active pulmonary tuberculosis.

Invasion of the myocardium and peri-cardium is reported in a series of 28 autopsies(Berstein (idem)). There is usually littleclinical evidence of such involvement althougharrhythmias, conduction defects and myo-cardial failure have been mentioned.

Glandular FormReference has already been made to the

frequent involvement of the hilar glands insarcoidosis.The more peripherally situated lymphatic

glands are also found to be enlarged in aconsiderable number of cases, such enlarge-ment may be slight or gross, and glandularbiopsy is the usual method of establishing thediagnosis.The glands are discrete and firm, and it is

the cervical group which is most often to befound the site of election, especially when theglandular lesions are of the localized form.

Occasionally a generalized lymphadenopathyis encountered, when the axillary, inguinal andepitrochlear glands become implicated. Ref-erence here must once more be made to thefact that the tonsils commonly show evidenceof the disease although no gross clinical signsmay be detected, and section will often giveconclusive proof of the nature of the disease.Not only are the lymphatic glands of the neckenlarged, but the salivary and lachrymal glandsmay also take part in the clinical picture. Withsuch enlargement of the lachrymal, parotidand submaxillary glands one form of Miku-licz's syndrome may be seen. Disease of theparotids alone may give rise to a mistakendiagnosis of mumps.

Ocular symptoms and signs accompany orprecede salivary disturbances in a number ofcases and this will be referred to in the section.dealing with such lesions.

In the abdomen, splenomegaly and mesen-teric lymph node enlargement are encounteredand the diagnosis may be confused withHodgkin's disease or tuberculosis.

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Ocular ManifestationsCorneal lesions, when present, take the

form of an intestitial keratitis. Iritis andiridocyclitis are also to be encountered as asign of sarcoidosis of the uveal tract, and inconjunction .with other lesions are a usefuldiagnostic pointer.The writer was able to establish a diagnosis

of sarcoidosis over the telephone when apatient stated that she was suffering from hersecond attack of 'mumps' in two years andthat she had not enjoyed good health since asimilar attack three years previously.The combination of swelling of the parotid

glands together with ocular symptoms in-dicating an inflammatory lesion of the uvealtract, is a well recognized syndrome to whichthe name of uveoparotid fever has been given.It is a condition with which the name ofHeerfordt is justly linked since it was he whodrew attention to the combination of theselesions.

Cutaneous LesionsThe dermatological manifestations of

Boeck's sarcoid have attracted the greatestattention, and the greater part of the literatureupon the subject deals with the skin lesions.The commonest type of lesion is the chil-

blain type, lupus pernio. The nose, cheeks,ears and forehead become involved in a pro-cess which produces violaceous induratedpatches, which can be made to blanche onpressure and then reveal the small yellowishnodules which suggested their lupoidcharacter. The areas involved usually showwell-defined margins which, when central in-volvution occurs, gives the lesions a ring-likeappearance. Other forms include a miliarytype which consists of multiple small nodulessituated about the nose, cheeks and lips; andcoalescence of these nodules may give rise toactual tumour formation of the type describedby Boeck.

This nodular form may closely resembleleprosy and will then produce great dis-figurement of the features. The commonestsituation of the lesions has already beenmentioned, but in addition to these regions,the outer surface of the arms and shouldersmay be involved and more rarely the trunk.

When the trunk is implicated the lesions fre-quently take the form of deeply induratedplaques with well-defined raised margins.

Healing eventually occurs, and usuallyleaves no trace, or there may be some slightresidual scarring or atrophy of the skin.

Osseous LesionsThe bone marrow may become infiltrated

by epithelioid cells and giant cell systems. Asa rule there is no clinical evidence of thisoccurrence, radiological changes alone beingdemonstrable. The commonest site of theselesions is in the phalanges of the fingers ortoes. The radiological appearance is charac-teristic and may be of great value in estab-lishing the diagnosis in cases of doubt. Small,well-defined punched-out areas may be seenin one or more of the phalanges, metacarpalsor metatarsals. These are frequently single,but more than one such lesion may be seen.There is also described a more generalizedlattice-like alteration in the pattern of thecancellous bone.At times the infiltrated area may be

sufficiently large as actually to expand thecortex of the bone, and it is important to notethat there is no evidence of periosteal reaction.

In this latter type of case deformities of thedigits tends to occur. The skin is often dis-coloured being purplish in hue, and there isthickening of the skin, producing a swollenappearance of the fingers or toes similar tothat seen with true chilblains. The finger-tipsare often square-ended and some dorsiflexionof the terminal phalanx may be seen, and theremay be later even some loss of substance.The fully developed lesions were admirablydescribed by Jungling (I92I) to which he gavethe descriptive term 'Osteitis tuberculosamultiplex cystica.'Where skin changes accompany the

phalangeal swelling there is a very closeresemblance to tuberculous dactylitis.Gastro-Intestinal LesionsInvolvement of the intestinal tract by sar-

coid tissue is extremely uncommon but thereis at least one confirmed case of sarcoidosis ofthe stomach which has been reported, Goreand McCarthy (I944). Lesions within the

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SARCOIDOSIS

small intestine have given rise to some specu-lation. The question as to whether ' regionalileitis' is a manifestation of ' Boeck's sarcoid'is not as yet settled. Snapper and Pompen(1938) in their monograph upon regionalileitis maintain that there is no link betweenthe two conditions, since they had never seena case of sarcoidosis with intestinal involvementnor had they seen a case of ileitis showingother features of sarcoid. Against this objec-tion is Morland's case (1947) in which regionalileitis occurred in a patient showing thetypical radiological changes of sarcoidosis ofthe lungs. In addition to this Watson, Rigler,Wagenstein and McCartney (1945) report acase of sarcoidosis of the small intestinesimulating ileojejunitis. Undoubtedly there isextreme similarity in the histological picture ofthe two conditions and it is of interest to notethat Williams and Nickerson (I935) report apositive skin reaction to an emulsion of sarcoidtissue in one case of' regional ileitis.'

Central Nervous SystemInvasion of the central nervous system by

sarcoidosis is extremely uncommon, but severalexamples have been recorded. The pituitarybody and interpeduncular fossa seem to bethe region of choice, and in the pituitary itselfit would appear that the pars posterior is themore usually damaged, diabetes insipidus re-sulting from such a lesion.The case of Reis and Rothfeld has already

been referred to in which death resulted fromepileptiform attacks; here a tumour-like masswas found upon the optic nerve.An unusual case was reported by Lewis

(I941) in which Adie's Syndrome occurred ina case which later showed generalized mani-festations of sarcoidosis.

Facial palsy resulting from interruption ofimpulses along the seventh cranial nerve isoccasionally seen when the parotid gland be-comes enlarged. Bilateral facial paralysis ofthe lower motor neurone type occurred in thecase already mentioned who suffered fromrecurrent ' mumps.'Blood Changes

Blood changes are often absent, although amonocytosis is stated to be the change which is

most often seen if the blood picture is abnor-mal. Longcope and Pearson (i937) in theirseries of cases, record an eosinophilia rising to35 per cent. in one instance and in yet anothercase record 7 per cent. of eosinophils.

Perhaps one of the most striking alterationswhich has been noted by several observers isthe presence of a hyperprotinaemia. Figuresin the region of 8-9 gms. per cent. are quoted,and it is the globulin fraction which shows thegreater relative increase, although a rise in thelevel of albumin resulting in a similar elevationof the total proteins has also been recorded.The sedimentation rate is variable, abnormal

figures being encountered chiefly in those casesin which the albumin-globulin ratio is altered.

DiagnosisThe diagnosis of Boeck's sarcoid is not

usually difficult, provided that the condition isborn in mind as a possible cause of lymphaticenlargement, or in cases where the radiologicalappearances suggest pulmonary tuberculosis inthe absence of the usual symptoms..The most useful diagnostic pointer is the

demonstration of a negative tuberculin re-action to all dilutions, and this should suggestthe need for microscopical examination of anyavailable tissue; be it the result of glandular,tonsillar or liver biopsy, or the examination ofmarrow smears.The hyperproteinaemia when present, par-

ticularly with an absolute increase of theglobulin fraction is valuable additionalevidence.The Scandinavian observer, Kweim (I94I),

used an emulsion of sarcoid tissue as anantigen for an intracutaneous test. Theresults obtained appeared to show a highdegree of accuracy in confirming the diagnosis.A positive reaction to the intracutaneous test,consisting of an indolent erytheniatous areaoccasionally ulcerating, was obtained in 12 outof 13 established cases. The reaction wasnegative in all controls. The slight dis-advantages to the use of this test lie in thepersistence of the positive reaction and in thedelay occurring before a positive result mayappear.A series of cases investigated by Danbolt

and Nilssen (I945) showed a definite positiveresult within two weeks in 30 of their 34

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positive reactions, and out of 36 establishedcases of sarcoidosis they showed an incidenceof 94.5 per cent. positive reactions.

AetiologyThe discussions centering around the under-

lying cause of the lesions now recognized asforming the essential pathological picture ofsarcoidosis have been varied, but so far in-conclusive. The difficulty which has presenteditself is the similarity of the cellular reactionin this specific disease to many other granu-lomata, and the inability to either demonstratea specific causative organism or to transmit thedisease to the experimental animal.

Tissue reactions such as have been describedin the pathological section, may be producedby a variety of foreign agents including in-animate substances of a fatty nature. Incertain respects the tubercle bacillus evokessuch a response, in leprosy a very similarhistological picture may be seen and there aresome adherents to the view that these last twoconditions are closely related, Kissmeyer(1932), Kissmeyer and Nielsen (I933).

Attention has been drawn to the closesimilarity to Hodgkin's disease, hence theterm ' lymphogranuloma Benigna' of Schau-mann. Indeed Hadfield and Garrod (1942)consider this condition in close relationship tothe endothelioses.

However, the relationship of this disease toinfections with the tubercle bacillus has ex-cited the greatest controversy. The results ofclinical and pathological investigations havecertainly shown a very strong link between thetwo.The similarity of the histology is but one

feature which stresses this, and the high in-cidence of negative reactions to one or othertest for tuberculin sensitivity it seems cannotbe due to chance alone. This has been held tobe due to a state of 'allergy' by severalobservers. (Boeck, Schaumann, Jungling andothers.) In further support of the allergictheory are the results observed by Lemming(1940) when he failed to convert his cases ofsarcoid to a positive tuberculin reaction withB.C.G.

Strengthening these conclusions are theobservations that the skin lesions of sarcoidtend to resolve where active tuberculosis has

developed, and in the development of tubercu-losis as a terminal event in many cases. Thislatter claim of Schaumann has not beenconfirmed by other authorities.

Against the tuberculous hypothesis is theinability to demonstrate the bacilli in thelesions or to transmit tuberculosis from thelesions by animal inoculation. On the otherhand Schaumann (I934) holds the view thatsingle inoculation is insufficient to demon-strate the bacillus and maintains that severalre-inoculations through a series of animals arenecessary, owing to the tubercle bacillus havingbecome converted to a filterable form.

It is indeed difficult to correlate these twoconflicting views upon the aetiology of thiscondition. There are, however, the results oftwo separate experimental studies which maybe considered to supply an answer to some tothe discrepancies in the foregoing hypothesis.

Firstly there are the interesting resultsobtained by Sabin, Doan and Forkner (1930)when observing the tissue reactions of animalsto the lipoids of the tubercle bacillus. Aphosphatide fraction was demonstrated to bevery active in producing an exudation ofepithelioid cells and giant cell formation.Reference has already been made to similarreactions produced by other fats and oils.

Secondly, must be mentioned, the workcarried out by Rothchild, Friedenwald andBerstein (I934) upon desensitization of animalsto tuberculin after infection with tuberclebacilli.The object of this work was to observe

whether the exclusion of the allergic factor inany way influenced the course of the disease.In connection with the present study, theirobservation is of the greatest interest that underthese circumstances the lesions were harderand showed much.less tendency to caseation.Can it be that the characteristic lesions of

sarcoidosis result from bacterial moietiesrather than from the bacteria themselves ?Many of the observed features of this disease

can be explained upon such an hypothesis.The high incidence of tuberculin negativitywould point to a process of natural de-sensitization, similar to that carried out byRothchild and would also conform to theobservation that in the!e cases a history ofcontact with active tuberculosis is extremely

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May I947 SARCOIDOSIS 243rare. Under the latter conditions, massiveinfection with tubercle bacilli would occurearly and there would be no opportunity for aprocess of desensitization to take .place.Sabin's work shows that such a lesion may beproduced by fractions of the tubercle bacillusand if the lesions of sarcoid were due to such'fractions' it would naturally follow that noorganisms could be demonstrated.The one great objection to the view held by

Schaumann, who maintains that these lesionsare the result of invasion of the body bytubercle bacili, are the completely negativebacteriological investigations.. The inability of Lemming to produce astate of sensitivity with B.C.G., also tends to

support the view that there is a pre-existingstate of desensitization in these cases.

It has been suggested that there may be adifferent aetiological factor in some cases ofBoeck's sarcoid, since a positive Mantoux re-action is occasionally found, but it must beborn in mind that later infection with tubercu-losis may occur and under such circumstancesa positive reaction would not be surprising.Many have been the theories put forward to

account for the causation of this interestingclinical condition, but at the present momentone may say that a satisfactory explanation isnot forthcoming and one can only concludethat here is yet another medical mystery whoseperpetration must be laid at the door of an' unknown virus.'

BIBLIOGRAPHY

BERSTEIN, S. S., SUSSMAN, L. M. (945), Radiology, 44, 37-43.BESNIER (x889), Am. de Dermat. et Syphil., xo, 333.DANBOLT, N., and NILSSEN, R. (I945), Acta. Dermat. Veneroel,

52, 489-502.GORE and McCARTHY (x944), Surgery, x6, 865.GOUGEROT, H. (1934), Bull. Soc. France de Dermat. et Syph.,

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